[ CAS No. 80841-78-7 ] {[proInfo.proName]}

Name: 80841-78-7|4-(Chloromethyl)-5-methyl-1,3-dioxol-2-one|97%
Brand: Ambeed
SKU: A146976
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Quality Control of [ 80841-78-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 80841-78-7 ]

CAS No. :	80841-78-7	MDL No. :	MFCD07787494
Formula :	C₅H₅ClO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QCLFSYYUWPUWQR-UHFFFAOYSA-N
M.W :	148.54	Pubchem ID :	9855518
Synonyms :

Calculated chemistry of [ 80841-78-7 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.4
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	31.97
TPSA :	43.35 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.45 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.65
Log Po/w (XLOGP3) :	1.07
Log Po/w (WLOGP) :	1.13
Log Po/w (MLOGP) :	0.16
Log Po/w (SILICOS-IT) :	2.24
Consensus Log Po/w :	1.25

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.78
Solubility :	2.46 mg/ml ; 0.0166 mol/l
Class :	Very soluble
Log S (Ali) :	-1.57
Solubility :	3.98 mg/ml ; 0.0268 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.54
Solubility :	0.431 mg/ml ; 0.0029 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.67

Safety of [ 80841-78-7 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501	UN#:	3265
Hazard Statements:	H302-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 80841-78-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 80841-78-7 ]
Downstream synthetic route of [ 80841-78-7 ]

[ 80841-78-7 ] Synthesis Path-Upstream 1~11

1
[ 80841-78-7 ]
[ 91526-18-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: With formic acid; triethylamine In acetonitrile at 10 - 65℃; Stage #2: With hydrogenchloride In isopropyl alcoholReflux	Example 4APreparation of 4-hydroxymethyl-5-methyl-l, 3-dioxol-2-oneTo a solution of 4-chloromethyl-5methyl-l ,3-dioxol-2-one (50 g) in acetonitrile (500 ml), formic acid (45 g) was added at 20-25°C and the reaction mass cool to 10-15°C followed by addition of triethylamine (95 g). Reaction mass was heated to 60-65 °C and stirred at the same temperature for about 5-6 hrs. Reaction mass was cooled to 15-20°C, filtered and washed by acetonitrile. Filtrate was taken and acetonitrile was distilled out under vacuum to concentrate the solution. Reaction mass was cooled to 25-30°C and ethyl acetate and water was added, followed by stirring for about 15-20 minutes at 25- 30°C. Aqueous layer extracted with ethyl acetate and combined organic layer were washed with brine solution. Organic layer was separated and evaporated completely under vacuum below 35-40°C. To the oily mass, methanol was added and heated to reflux temperature. A solution of HC1 in isopropyl alcohol was added and the resulting solution was refluxed for about 60-75 mins. Reaction mass was cooled to 30-35°C. Distilled out the solvent completely to obtain title compound as oily mass. (Yield: 34.6 g; 79percent)
43%	Stage #1: With formic acid In acetonitrile at 20℃; for 0.0833333 h; Stage #2: With triethylamine In acetonitrile at 0 - 60℃; for 8 h; Stage #3: With hydrogenchloride In methanol at 20℃; for 2 h;	4- (chloromethyl)-5-methyl-1,3-dioxol-2-one (400mg, 2.7mmol) was dissolved in acetonitrile 10ml) was added dropwise formic acid (496mg, 10.8mmol ), then the mixture was stirred at room temperature for 5 minutes. The reaction mixture was cooled to 0 deg.] C, thereto was added triethylamine (0.8ml, 5.4mmol), and the mixture was stirred at 60 8 hours, and then water is introduced, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in methanol (10ml), and thereto was added concentrated hydrochloric acid (1ml), then, the mixture was stirred at room temperature for 2 hours. To the reaction mixture, saturated aqueous sodium bicarbonate is introduced, the mixture was extracted with ethyl acetate, then washed with saturated brine and the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 (v / v)) for purification to prepare the title compound 150mg (43percent yield).

Reference： [1] Patent: WO2012/107814, 2012, A1, . Location in patent: Page/Page column 14-15
[2] Patent: CN105492423, 2016, A, . Location in patent: Paragraph 0741; 0742; 0743; 0744
[3] Patent: TW2016/2093, 2016, A, . Location in patent: Paragraph 0323
[4] Patent: US2016/194302, 2016, A1, . Location in patent: Paragraph 0413; 0414

2
[ 37830-90-3 ]
[ 80841-78-7 ]

Yield	Reaction Conditions	Operation in experiment
326 g	at 90℃; for 5.5 h; Large scale	4725 g of dichloroethane was added to the DMDO that was stirred up.1012.5g N-chlorosuccinimideAnd 45g benzoyl peroxide,Reaction temperature 90°C, reaction time 5.5h,The crude product obtained DMDO-Cl 382.5g, a yield of 85.00percent; Step 3: Distillation: The DMDO-Cl crude product at -0.1MPa vacuum,Distilled at 110°C to produce 326g of DMDO-ClThe purity by gas chromatography was 99.06percent.

Reference： [1] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 6, p. 2241 - 2248
[2] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, # 1, p. 394 - 397
[3] Patent: US4554358, 1985, A,
[4] Patent: CN107892681, 2018, A, . Location in patent: Paragraph 0015-0022

3
[ 95579-71-8 ]
[ 80841-78-7 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, # 1, p. 394 - 397
[2] Patent: US4554358, 1985, A,

4
[ 37830-90-3 ]
[ 80841-78-7 ]
[ 95579-71-8 ]
[ 129482-56-0 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, # 1, p. 394 - 397

5
[ 80841-78-7 ]
[ 112984-60-8 ]
[ 123447-62-1 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 11, p. 1872 - 1877

6
[ 936114-12-4 ]
[ 80841-78-7 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; potassium iodide In N,N-dimethyl acetamide at 0 - 45℃; for 3 h;	In 130 ml of N,N-dimethyl acetamide, 14.5 g (20 mmol) of potassium 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate, 3.0 g (2.2 mmol) of potassium carbonate powder and 1.4 g (8.4 mmol) of potassium iodide were added. The mixture was cooled to 0 °C and 5.0 g (33 mmol) of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one was added at 0 to 5°C. After the addition, the reaction mixture was warmed to 40-45 °C within one hour, then the mixture was stirred at this temperature for 2h. The sample of reaction mixture was analysed (HPLC; tritylolmesartan medoxomil, 97.44percent, 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate 0.06 percent). The mixture was cooled to 10 to 20°C and then 250 ml of ethyl acetate was added. The mixture was cooled again to 5-10 °C and then 200 ml of 10percent NaCl was added slowly. The temperature should not be higher than 25 °C during the addition. The phases were mixed separated and organic phase was washed with 100 ml of 10percent NaCl (2*) and dried over anhydrous sodium sulphate. After the filtration filtrate was evaporated under reduced pressure at temperature under 45°C to oily residue. To the residue 30 ml of acetonitrile was added at temperature not more than 45°C. The mixture was stirred at this temperature for 10 minutes then was cooled to 20 to 25°C and stirred at this temperature for 0.5 h and after that 3h at 0 to 5°C. The suspension was filtered, washed with cold acetonitrile and dried at 40 to 50°C. Yield: 17.0 g (91percent) HPLC: 99.64 percent of the product, all other impurities under 0.1percent. IR: 3408, 1818, 1805, 1741, 1681, 1529, 1148, 1002, 699
86%	With potassium iodide In butanone at 50℃; for 7.5 h;	Example 3; Trityl olmesartan medoxomil (III); A solution of potassium salt 4 in methyl ethyl ketone from the preceding experiment (ca. 20 g of the salt) was diluted with methyl ethyl ketone (290 ml), and, after adding potassium iodide (2 g) and 4-chloromethyl-5-methyl-l,3-dioxol-2-one (7 g), the mixture was stirred at 50 ⁰C for 7.5 h. After the reaction was completed, the mixture was filtered, and the filtrate was washed with methyl ethyl ketone (3 x 50 ml). After concentrating to ca. 160 ml in vacuo, ethanol (250 ml) was added, and the reaction mixture was again concentrated to ca. 300 ml in vacuo.The concentrated product in ethanol was inoculated and stirred at 50 ⁰C for 0.5 h, and after getting thicker, diluted with ethanol (50 ml) and cooled to 20 °C. The precipitated product was sucked off, washed with ethanol (2 x 20 ml) and dried in a vacuum drier at 50 °C. 14.4 g (86 percent) of the product was obtained.
84.4%	With potassium iodide In butanone at 50℃; for 20 h;	Example 1-5 (0330) (0331) A mixture of BIC (0.6 g, 0.83 mmol), potassium iodide (0.069 g, 0.41 mmol), OXC (0.245 g, 1.65 mmol) and methyl ethyl ketone (9.0 mL, 15 vol) was stirred at 50° C. for 20 hr. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the obtained concentrated residue was purified by silica gel column chromatography (20-22percent ethyl acetate/hexane) to give TOLM (650 mg, yield 84.4percent). (0332) Mass: 801 [M+H]⁺, 824 [M+Na]⁺.

76 g

Stage #1: With sodium carbonate; potassium iodide In acetone at 25 - 30℃; for 0.166667 h;
Stage #2: at 45 - 50℃; for 12 h;

To BIC (110 g, 1 eq) was added acetone (385 mL, 3.5 vol) at 25°C - 30°C, and the mixture was dissolved by stirring for 5 min. Sodium carbonate (20.85 g, 1.3 eq) and potassium iodide (0.25 g, 0.01) were added, and the mixture was stirred for 10 min. A solution of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (31.456 g, 1.4 eq) in acetone (165 mL, 1.5 vol) was added thereto. The reaction mixture was heated to 45°C - 50°C, and stirred at the same temperature for 12 hr. Using TLC (thin layer chromatography) (TLC eluent: 10percent methanol/methylene chloride, detection method: UV), complete disappearance of BIC was confirmed. The reaction mixture was cooled to 25°C - 30°C. Then, the solvent contained in the reaction mixture was evaporated under reduced pressure at 40°C - 45°C. To the obtained residue were added 10percent brine (550 mL, 5 vol) and toluene (550 mL, 5 vol). Furthermore, the mixture was adjusted to pH 7 - 8 by adding 5percent hydrochloric acid (33 mL), stirred for 10 min, left standing for 5 min and partitioned. The aqueous layer was extracted with toluene (2x330 mL, 2x3 vol). The extracts were combined with the organic layer, 10percent brine (550 mL, 5 vol) was added, and the mixture was stirred for 5 min, left standing for 45 min, partitioned, and concentrated under reduced pressure at 40°C - 45°C to give TOLM (110 g, 90percent). [0306] To the obtained TOLM was added acetone (110 mL, 1 vol), and the mixture was stirred at 25°C - 30°C for 30 min. n-Heptane (440 mL, 4 vol) was added, and the mixture was cooled to 5°C - 10°C and stirred at 5°C - 10°C for 30 min, whereby precipitation of a solid was confirmed. The solid (80 g, 66percent) was collected by filtration, and blast dried. To the obtained solid was added isopropyl alcohol (400 mL, 5 vol), and the mixture was heated to 50°C - 55°C and stirred at 50°C - 55°C for 1 hr. Then, the mixture was cooled to 25°C - 30°C, and stirred at 25°C - 30°C for 1 hr. The resulting solid was filtered and suction-filtered for 10 min to give TOLM (76 g, 62percent).

Reference： [1] Patent: EP2334668, 2011, A1, . Location in patent: Paragraph 0079-0080
[2] Patent: WO2007/48361, 2007, A1, . Location in patent: Page/Page column 9; 10
[3] Patent: US2015/239854, 2015, A1, . Location in patent: Page/Page column 40
[4] Patent: EP2891650, 2015, A1, . Location in patent: Paragraph 0304-0306

7
[ 879097-59-3 ]
[ 80841-78-7 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate In N,N-dimethyl acetamide at 5 - 10℃; for 4 h;	Example 4; The reaction was carried out in the same manner as in Example 1 except that 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] -carboxylic acid sodium salt (Chemical Formula 5) and 50 mL of N, N-dimethylacetamide were added, the temperature was adjusted to 5 to 10 DEG C and 4 g of potassium carbonate was added. A solution of 6.2 g of 4- (chloromethyl) -5-methyl-1,3-dioxol-2-one (Formula 6) in 6 mL of N, N-dimethylacetamide was added dropwise to the reaction portion, For 4 hours. After the reaction was completed, the reaction solution was cooled to 20 to 25 ° C, and then 220 mL of ethyl acetate, 30 g of salt, and 170 mL of purified water were sequentially added to the reaction mixture, followed by separation of the organic layer, followed by the addition of 30 g of salt and 170 mL of purified water . & Lt; / RTI & gt; 1 g of activated carbon and 20 g of anhydrous sodium sulfate were added to the organic layer, followed by stirring for 30 minutes to 1 hour, followed by filtration. The filtrate was concentrated under reduced pressure, and 100 mL of acetonitrile was added to the residue, followed by stirring at 50 to 55 DEG C for 1 hour. The crystals were cooled to 0 to 5 ° C., stirred for 2 hours, filtered, washed with 50 mL of isopropyl alcohol and dried to obtain 21.7 g (yield: 93percent, purity: 99.96percent) of tritylolemethanemethoxysilane
45g	With sodium iodide In N,N-dimethyl-formamide at 55℃; for 7.5 h;	A solution containing about 46 g of compound 4 was taken, 3.5g sodium iodide was added, 280 mL N, N-dimethylformamide, 11.2g DMDO-Cl was slowly added dropwise, 30 Minute addition is completed. After dropping, Heated to 55 , Reaction for 7 hours, The reaction is completely over. filter, Remove insolubles, The filtrate was poured into 700mL of water, Extraction with ethyl acetate, The ethyl acetate layer was collected, dry, filter, The filtrate is concentrated. To the oily substance obtained after the concentration was added 200 mL of ethanol, Stirring, A white solid precipitation, Collect the solid, Washed with 50mL cyclohexane beating, 45.0 g of product was obtained, Two-step total yield of 80.6percent The purity of the product was 98percent by HPLC.

Reference： [1] Patent: KR101526249, 2015, B1, . Location in patent: Paragraph 0068; 0069
[2] Synthetic Communications, 2009, vol. 39, # 2, p. 291 - 298
[3] Patent: CN107311989, 2017, A, . Location in patent: Paragraph 0028; 0036; 0037
[4] Patent: CN103012382, 2016, B, . Location in patent: Paragraph 0021; 0030-0031

8
[ 144690-33-5 ]
[ 80841-78-7 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: With sodium hydroxide In ethanol at 20 - 25℃; Stage #2: With potassium carbonate In N,N-dimethyl acetamide at 45 - 50℃; for 4 h;	Example 5: The reaction part was charged with ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] 22 g of 5-carboxylate (Formula 4), 3.1 g of sodium hydroxide and 90 mL of ethanol were added and the mixture was stirred at 20 to 25 ° C for 4 to 5 hours. When the reaction was completed, the reaction solution was concentrated. To the residue were added 50 mL of ethyl acetate and 50 mL of purified water. The mixture was stirred for 1 hour and then layered. The separated organic layer was washed twice with an aqueous solution containing 30 g of salt and 170 mL of purified water. 1 g of activated carbon and 20 g of anhydrous sodium sulfate were added to the organic layer, followed by stirring for 30 minutes to 1 hour, followed by filtration Respectively. After the filtrate was concentrated under reduced pressure, 50 mL of N, N-dimethylacetamide was added to the residue, the temperature was adjusted to 5 to 10 DEG C 4 g of potassium carbonate was added and 6.2 g of 4- (chloromethyl) -5-methyl-1,3-dioxol-2-one (Formula 6) was dissolved in N, N-dimethylacetamide 6 ML was added dropwise, and the mixture was reacted at 45 to 50 ° C for 4 hours with stirring. When the reaction is completed, the reaction solution is cooled to 20 to 25 After cooling, 220 mL of ethyl acetate, 30 g of salt and 170 mL of purified water were added successively. The organic layer was separated And then washed once more with an aqueous solution containing 30 g of salt and 170 mL of purified water. The organic layer was washed with 1 g of activated carbon, 20 g of sodium was added and stirred for 30 minutes to 1 hour, followed by filtration. The filtrate was concentrated under reduced pressure, and then acetone 100 mL of i-tril was added, and the mixture was stirred at 50 to 55 ° C for 1 hour. The crystals were cooled to 0 to 5 [deg.] C and stirred for 2 hours. Followed by washing with 50 mL of isopropyl alcohol, followed by drying to obtain 21.6 g (yield: 88percent) of tritylolemecanemethoxysilane (formula 1a) Purity 99.97percent) was obtained
85.8%	Stage #1: With sodium hydroxide In acetone at 50 - 60℃; for 5 h; Green chemistry Stage #2: With potassium iodide In acetone at 20 - 60℃; for 1 h; Green chemistry	1L glass reaction flask was added with 600ml of acetone, 114.8g of intermediate 1 was added with stirring, then 12.8g of sodium hydroxide was added, the temperature was raised to 50-60 °C, and the reaction was incubated for 5 hours, and the reaction was monitored by HPLC. To 20-30 °C, add 2.8g potassium iodide, 36.0g 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and increase the temperature to 50-60 °C after the addition After 1 hour of heat preservation reaction, the temperature was lowered to 20-30 ° C, filtered, and the filter cake was rinsed with 115 ml of acetone, and the filtrate was combined. The filtrate was concentrated under reduced pressure at 40-50 °C until no obvious solvent flowed out, and 320 ml of acetonitrile was added to cool down. The mixture was decanted to 20-30 °C for 1 hour, filtered, and the filter cake was rinsed with 320 ml of acetonitrile. The filter cake was blast dried at 40-50 °C for 12 hours to obtain a white solid 110.0 g (intermediate 2). The rate was 85.8percent, HPLC: 99.2percent.
309 g	Stage #1: Reflux Stage #2: Reflux	To the flask was added 2000 g of acetone, 160 g of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (II), 150 g of K2CO3, 460 g of 4- [2- (Trityltetrazol-5-yl) phenyl] benzyl bromide (III), 20g KI, the temperature was raised to reflux, the reaction was incubated for 34-38 hours under stirring.Then add 102g KOH, reflux reaction 6 ~ 8h. Cool to 10 ~ 20 , add 170g DMDO-Cl, incubated for 30 ~ 60min.Heating to reflux, the reaction 22 to 26 hours.After the reaction was added 40g of diatomaceous earth, stirring for 30 to 60 minutes, suction filtration, 200g acetone rinse cake. To the filtrate was added 800g of drinking water and 200g of refined hydrochloric acid, the reaction at room temperature for 2 to 4 hours, filtered to remove by-product triphenylcarbinol. Dropping 10percent K2CO3 aqueous solution, adjusting feedstock pH to 4, cooling to 10 ~ 20 , stirring crystallization 2h, filtration, the filter cake with a mixture of pre-cooled 45g acetone and 230g of drinking water washing and drying, to obtain Olmesartan Medoxomil 309 g, total yield 83.1percent (relative to ethyl-4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5- carboxylate (II)), purity: 99.27percent of the main peak, 0.08percent of the olmesartan acid, 0.14percent of the triphenylmethanol, and 0.13percent of the largest unidentified one.

Reference： [1] Patent: KR101526249, 2015, B1, . Location in patent: Paragraph 0071; 0072
[2] Patent: CN108341804, 2018, A, . Location in patent: Paragraph 0015; 0033; 0034
[3] Patent: WO2008/43996, 2008, A2, . Location in patent: Page/Page column 16-17; 18
[4] Patent: WO2008/43996, 2008, A2, . Location in patent: Page/Page column 17-18
[5] Patent: WO2008/43996, 2008, A2, . Location in patent: Page/Page column 18-19
[6] Patent: US2009/131680, 2009, A1, . Location in patent: Page/Page column 8
[7] Patent: WO2007/17135, 2007, A2, . Location in patent: Page/Page column 5; 21-22
[8] Patent: EP1816131, 2007, A1, . Location in patent: Page/Page column 12
[9] Patent: WO2011/14611, 2011, A2, . Location in patent: Page/Page column 11
[10] Patent: WO2012/55994, 2012, A1, . Location in patent: Page/Page column 19
[11] Patent: CN107311990, 2017, A, . Location in patent: Paragraph 0043; 0044; 0045; 0046

9
[ 761404-85-7 ]
[ 80841-78-7 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; potassium iodide In N,N-dimethyl acetamide at 0 - 45℃; for 3 h; Inert atmosphere	130 ml of N,N-dimethylacetamide, 14.0 g (20 mmol) of ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate and 2.2 g (16 mmol) of KOH were charged into reaction vessel at room temperature under inert atmosphere. The mixture was stirred at room temperature for 2 h, and then the sample of reaction mixture was analysed (HPLC; starting material 0.2 percent, hydrolysed starting material 98.11 percent). Then 3.0 g (2.2 mmol) of potassium carbonate powder and 1.4 g (8.4 mmol) of potassium iodide were added. The reaction mixture was cooled to 0 °C and 5.0 g (33 mmol) of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one was added at 0 to 5°C. After the addition, the reaction mixture was warmed to 40-45 °C within one hour, then the mixture was stirred at this temperature for 2h. The sample of reaction mixture was analysed (HPLC; tritylolmesartan medoxomil 97.22 percent, 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate 0.09 percent). The mixture was cooled to 10 to 20 °C and then 250 ml of ethyl acetate was added. The mixture was cooled again to 5-10 °C and then 200 ml of 10 percent NaCl was added slowly. The temperature should not be higher than 25 °C during the addition. The phases were mixed separated and organic phase was washed with 100 ml of 10 percent NaCl (2*) and dried over anhydrous sodium sulphate. After the filtration filtrate was evaporated under reduced pressure at temperature under 45°C to oily residue. To the residue 30 ml of acetonitrile was added at temperature not more than 45°C. The mixture was stirred at this temperature for 10 minutes then was cooled to 20 to 25°C and stirred at this temperature for 0.5 h and after that 3h at 0 to 5°C. The suspension was filtered, the cake washed with cold acetonitrile and dried at 40 to 50°C. Yield: 17.0 g (94percent) HPLC: 99.72 percent of the product, all impurities are under 0.1percent. IR: 3408, 1818, 1805, 1741, 1681, 1529, 1147, 1003, 699 XRD:
91.6%	Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; Autoclave Stage #2: With potassium iodide In N,N-dimethyl-formamide at 20℃;	10L autoclave, 520g (0.75mol) Compound 5, DMF3kg, potassium carbonate and 215.3g (1.6mol), stirred at room temperature 1.5-2.5h added to the system after 63.0g (0.38mol) of potassium iodide was added dropwise while - Chloromethyl -5-methyl-1,3-dioxol-2-one 40.0g (0.94mol). Dropping was completed, the reaction at room temperature after 3-4h TLC or HPLC in control, raw reaction was complete. To the system was added ethyl acetate and 3L 3L water and 200g of sodium chloride, stirring separated and the aqueous layer was washed with 3X1L ethyl acetate, the combined organic layers, the organic layer was dried, filtered and the solvent was evaporated cooling is added 0-10 , methanol was added 1600g beating 30min, filtered, then the filter cake was slurried at room temperature in acetonitrile 1600g 30min, filtered to afford intermediate 6 about 553.8g,
23.2 g	With potassium bromide In N,N-dimethyl acetamide at 15 - 50℃; for 8.6 h; Green chemistry	123.2g of compound and 2.5g of potassium hydroxide solid were added to a 500ml four-necked flask.DMAC76g, heated to 50 ° C, stirred for about 6h,The TLC dot plate showed that the compound 1 point disappeared, that is, the end of the hydrolysis reaction was judged.Cool to 15 ± 5 ° C, add KBr 0.64g, add DMDO-C16.5g, DMAC 10g,After about 40 minutes, the temperature was raised to 25±5°C for 2h, then the temperature was raised to 50°C, the reaction was about 6h, and the temperature was lowered again to 20±5°C for 5h. The reaction solution was added with 324g water and 208g of dichloromethane.Shake well and let the layers separate. The aqueous layer was extracted with 70 g of dichloromethane and combined with several layers.It was washed twice with 206 g of water, and the last aqueous layer was extracted with 100 g of dichloromethane.The organic layers were combined and dried under reduced pressure at 45 ° C.After adding 100g of the upper batch of crystallization, the mother liquid is heated and refluxed for 25±5 minutes, and then naturally cooled.Then crystallization at 0 ° C for 6 h,Drying by suction filtration to obtain 23.2 g of trityl olmesartan medoxomil white solid powder.The yield was 93.4percent. HPLC analysis, purity 99.7percent, acid miscellaneous <0.05percent,The olefinic impurity is <0.1percent, and the other unknown single impurities are <0.1percent.

Reference： [1] Patent: EP2334668, 2011, A1, . Location in patent: Paragraph 0077-0078
[2] Patent: CN105481842, 2016, A, . Location in patent: Paragraph 0050; 0053; 0054
[3] Patent: US2009/281327, 2009, A1, . Location in patent: Page/Page column 5-6
[4] Patent: US2012/59172, 2012, A1, . Location in patent: Page/Page column 5
[5] Patent: CN103880825, 2019, B, . Location in patent: Paragraph 0020; 0039-0044

10
[ 1114761-92-0 ]
[ 80841-78-7 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
683.2 g	With potassium carbonate In acetonitrile for 2 h; Reflux	The reaction flask was charged with 697.5 g of compound V obtained in the previous step,414 g of anhydrous potassium carbonate (3.00 mol)163.4 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one (Compound VI) (1.10 mol)And 2500 ml of acetonitrile were refluxed for 2 hours,After the reaction,filter,The filtrate was concentrated to dryness,The residue was stirred in 1500 ml of ethyl acetate and 500 ml of water for 15 minutes,Layered, organic layer and then washed with water,Dried over anhydrous sodium sulfate,filter,The filtrate was concentrated to dryness,To give the crude product of compound VII,Recrystallization from toluene and petroleum ether,To obtain pure product 683.2 grams; two-step yield:85.40percent (calculated as compound II).

Reference： [1] Patent: CN103304550, 2016, B, . Location in patent: Paragraph 0051-0052

11
[ 80841-78-7 ]
[ 124750-51-2 ]
[ 144689-93-0 ]
[ 144690-92-6 ]

Reference： [1] Patent: WO2011/14611, 2011, A2, . Location in patent: Page/Page column 12; 13

[ 80841-78-7 ] Synthesis Path-Downstream 1~80

1
[ 37830-90-3 ]
[ 80841-78-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuryl dichloride; In dichloromethane;	REFERENCE EXAMPLE 2 Preparation of 4-chloromethyl-5-methyl-1,3-dioxolene-2-one (II) To a solution of 75 g of 4,5-dimethyl-1,3-dioxolene-2-one (IV) in 750 ml of methylene chloride was added 97.6 g of sulfuryl chloride dropwise at 40°-42° C. over 2 hours. The mixture was stirred for 40 minutes at the same temperature and evaporated in vacuo to remove the solvent. NMR spectrometry of the resulting oil revealed that the product was 4-chloro-4-methyl-5-methylene-1,3-dioxolane-2-one (III) containing a trace amount of unreacted 4,5-dimethyl-1,3-dioxolene-2-one (IV). This oil was heated at 90° C. with stirring for 2 hours without isolating 4-chloro-4-methyl-5-methylene-1,3-dioxolane-2-one (III) and then distilled in vacuo. 75.4 g (corresponding to an overall yield from 4,5-dimethyl-1,3-dioxolene-2-one (IV) of 77percent) of 4-chloromethyl-5-methyl-1,3-dioxolene-2-one (II) having the physicochemical properties described in Reference Example 1 was obtained.
326 g	With N-chloro-succinimide; dibenzoyl peroxide; at 90℃; for 5.5h;Large scale;	4725 g of dichloroethane was added to the DMDO that was stirred up.1012.5g N-chlorosuccinimideAnd 45g benzoyl peroxide,Reaction temperature 90°C, reaction time 5.5h,The crude product obtained DMDO-Cl 382.5g, a yield of 85.00percent; Step 3: Distillation: The DMDO-Cl crude product at -0.1MPa vacuum,Distilled at 110°C to produce 326g of DMDO-ClThe purity by gas chromatography was 99.06percent.

Reference： [1]Chemical and Pharmaceutical Bulletin,1984,vol. 32,p. 2241 - 2248
[2]Chemical and pharmaceutical bulletin,1988,vol. 36,p. 394 - 397
[3]Patent: US4554358,1985,A
[4]Patent: CN107892681,2018,A .Location in patent: Paragraph 0015-0022

2
[ 37830-90-3 ]
[ 80841-78-7 ]
[ 95579-71-8 ]
[ 129482-56-0 ]

Reference： [1]Chemical and pharmaceutical bulletin,1988,vol. 36,p. 394 - 397

3
[ 7134-41-0 ]
[ 80841-78-7 ]
[ 111738-22-8 ]

Yield	Reaction Conditions	Operation in experiment
58%	With triethylamine In dichloromethane for 3h; Ambient temperature;

Reference： [1]Kawai; Sakamoto; Taguchi; Kitamura; Sotomura; Tsukamoto [Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 6, p. 1422 - 1425]

4
[ 80841-78-7 ]
[ 112984-60-8 ]
[ 156834-57-0 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1994,vol. 67,p. 1419 - 1426

5
[ 80841-78-7 ]
[ 112984-60-8 ]
[ 123447-62-1 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1995,vol. 43,p. 1872 - 1877

6
[ 80841-78-7 ]
4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylic acid lithium salt [ No CAS ]
[ 1020157-01-0 ]

Yield	Reaction Conditions	Operation in experiment
75 - 80%		Example-4 Preparation of trityl protected olmesartan medoxomil To the solution of lithium salt of 4-(1-hydroxy-1-methylethyl) 2-propyl- 1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl] biphenyl-4-yl] methyl] imidazole -5-carboxylic acid , (97 g, 0.13 mol) in N, N-dimethyl acetamide(200 ml) was added triethylamine(12.7 g, 0.12 mol), stirred at room temperature for 0.5 hours. 5-methyl-2-oxo-(1,3-dioxolene-4-yl)methyl chloride (85% purity, 37.3 g, 0.25 mol) was added below 10C. The mixture was stirred at 50-55C for 4 hours, checked TLC. Dichloromethane (400 ml) and chilled water (500 ml) were added under stirring. The organic phase was separated, given brine wash (50 ml), dried over sodium sulphate and concentrated under vacuum to get a residue. To the residue methanol was added, stirred for 1hr, cooled to 5-10, filtered and washed with chilled methanol and dried. Yield: 75-80%, Purity by HPLC: 96-98%. 1H-NMR (CDCl3) delta: 7.87(d, 1H), 6.90-7.52(m, 20H), 6.68(d, 2H), 5.61(s, 1H), 5.3(s, 2H), 4.7(s, 2H), 2.54(t, 2H), 1.97(s, 3H), 1.6-1.75(m, 2H), 1.62(s, 6H), 0.87(t, 3H).

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 323 - 338
[2]Patent: EP1916246,2008,A2 .Location in patent: Page/Page column 6

7
[ 161715-21-5 ]
[ 80841-78-7 ]
[ 909779-82-4 ]

Yield	Reaction Conditions	Operation in experiment
54%	With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;

Reference： [1]Isoda, Takeshi; Ushirogochi, Hideki; Satoh, Koichi; Takasaki, Tsuyoshi; Yamamura, Itsuki; Sato, Chisato; Mihira, Ado; Abe, Takao; Tamai, Satoshi; Yamamoto, Shigeki; Kumagai, Toshio; Nagao, Yoshimitsu [Journal of Antibiotics, 2006, vol. 59, # 4, p. 241 - 247]

8
[ 122547-49-3 ]
[ 80841-78-7 ]
faropenem medoxomil [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.11%	With sodium hydrogencarbonate; potassium iodide;benzyltri(n-butyl)ammonium chloride; In tetrahydrofuran; at 30 - 55℃; for 5.0h;	Example 1 Production of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-2-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate A weight (17.9 g) of sodium salt 2.5 hydrate of (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-2-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (purity: 98.05%), potassium iodide (2.08 g), sodium hydrogencarbonate (0.84 g) and BTBAC (1.56 g) were mixed in THF (150 ml); to the mixture, 17.02 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (purity: 93.3%) was added and agitation was effected at 30C for 2 hours, then at 55C for 3 hours.. After the end of the reaction, the reaction mixture was washed once with 50 ml of water and twice with 50 ml of 20% aqueous sodium chloride adjusted to PH = 8 with sodium hydrogencarbonate; thereafter, the organic layer was concentrated under reduced pressure to give a mixture of the desired product and impurities.. The obtained mixture was subjected to quantitative analysis by liquid chromatography using acetophenone as an internal standard material; the end product was obtained in a yield of 99.11%.
94.2%	With sodium hydrogencarbonate; potassium iodide;tetrabutyl-ammonium chloride; In acetone; at 50℃; for 4.0h;Conversion of starting material;	Example 2 Production of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-2-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate A weight (8.95 g) of sodium salt 2.5 hydrate of (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-2-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (purity: 98.4%), potassium iodide (0.51 g), sodium hydrogencarbonate (0.21 g) and TBAC (0.40 g) were mixed in acetone (25 ml); to the mixture, 4.13 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (purity: 97.2%) was added and agitation was effected at 50C for 4 hours to perform the reaction.. After filtering the reaction mixture to separate the inorganic salts insoluble in acetone, the solvent was distilled off under reduced pressure to obtain a mixture of the desired product and impurities.. The obtained mixture was subjected to quantitative analysis by liquid chromatography using acetophenone as an internal standard material; the desired product was obtained in a yield of 94.2%.
70 - 97.4%	With benzyltri(n-butyl)ammonium chloride; sodium hydrogencarbonate; potassium iodide; In tetrahydrofuran; at 30 - 55℃; for 6.0h;Product distribution / selectivity;	(Example 1) (5R,6S)-6-(1-(R)-Hydroxyethyl)-7-oxo-3-(2-(R)-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt 2.5-hydrate (111.0 g, purity: 98.4%), potassium iodide (5.15 g), sodium bicarbonate (2.60 g) and BTBAC (3.87 g) were mixed in THF (465 ml). To this mixture, 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (50.48 g, purity: 97.2%) was added and stirred at 30C for 2 hours and then at 55C for 4 hours. After completion of the reaction, the reaction solution was washed once with water (155 ml) and twice with 20% aqueous sodium chloride (155 ml) which had been adjusted to pH 8 with potassium bicarbonate, followed by isolating the organic layer. In this way, a beta-lactam compound solution (534.7 g, hereinafter referred to as 'Solution A') was obtained, which contained a beta-lactam compound of Formula (5) (hereinafter referred to as 'Compound (5)'), iodine compounds, water and THF. By quantitative analysis using high performance liquid column chromatography, Solution A was found to contain the target Compound (5) in an amount of 22.44% by weight (yield: 97.4%). The water content in Solution A was about 4% by weight. Solution A thus obtained was placed in a vacuum of 17.3 to 19.3 kPa and at a temperature of 20C to 32C (bath temperature: 40C) to distill off THF. Whenever about 90 ml of THF was distilled off, Solution A was supplemented with 90 ml fresh THF. This procedure was repeated three times. In this way, a THF solution of Compound (5) was obtained. The resulting solution was a 0.9 L/mol solution of Compound (5). When the water content in Solution A was measured, it was 0.47% by weight. Solution A was then warmed to 75C and THF was distilled off to give a concentrated THF solution of Compound (5) (about 0.25 L/mol in THF), followed by addition of ethanol (95 ml). The resulting solution was stirred to give a homogenous solution and placed in a vacuum of 16 to 20 kPa at 23C to 40C (bath temperature: 23C to 40C) to distill off THF and ethanol. At this time, ethanol was added dropwise at a constant speed to keep the solution volume unchanged, thus obtaining Solution B. The total amount of ethanol added dropwise was 105 ml. Solution B was a 1.2 L/mol solution of Compound (5). Solution B was then cooled to 15C for 30 minutes to crystallize Compound (5). The precipitated crystals were collected by filtration and washed twice with cold ethanol (12 ml). The resulting crystals were dried to give crude crystals of Compound (5) (35.65 g) in 98.9% purity and 88.7% yield. The crude crystals of Compound (5) were suspended in ethanol (180 ml) and heated at 60C for 10 minutes to completely dissolve the crystals. After this solution was filtered under pressure, the resulting filtrate was held at around 30C for 30 minutes and then placed in a vacuum of 10.6 to 13.3 kPa at 30C to 35C to distill off 80 ml ethanol. The resulting solution was then cooled at 15C for 30 minutes to crystallize Compound (5). The crystallized crystals were collected by filtration and washed twice with cold ethanol (13 ml) to give crystals of Compound (5) in 99.5% purity and 85.1% yield.

36.7%

With sodium hydrogencarbonate;benzyltri(n-butyl)ammonium chloride; In tetrahydrofuran; at 50℃; for 4.0h;Conversion of starting material;

Comparative Example 1 Production of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-2-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate A weight (17.9 g) of sodium salt 2.5 hydrate of (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-2-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (purity: 98.4%), sodium hydrogencarbonate (0.42 g) and BTBAC (0.78 g) were mixed in THF (75 ml); to the mixture, 8.25 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (purity: 97.2%) was added and agitation was effected at 50C for 4 hours to perform the reaction.. After the end of the reaction, the reaction mixture was filtered to separate the inorganic salts insoluble in THF and the filtrate was concentrated under reduced pressure to obtain a mixture of the desired product and impurities.. The obtained mixture was subjected to quantitative analysis by liquid chromatography using acetophenone as an internal standard material; the desired product was obtained in a yield of 36.7%.

Reference： [1]Patent: EP1375492,2004,A1 .Location in patent: Page 13
[2]Patent: EP1375492,2004,A1 .Location in patent: Page 13-14
[3]Patent: EP1548017,2005,A1 .Location in patent: Page/Page column 14-15
[4]Patent: EP1375492,2004,A1 .Location in patent: Page 14

9
[ 80841-78-7 ]
[ 218600-44-3 ]
C₃₆H₄₅NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In toluene;Heating / reflux;	Dinitrile 1 was synthesized from CDDO by the method as shown in Scheme 1. Oxalyl chloride gave acyl chloride 19 in quantitative yield. Amide 3 was prepared in 91% yield from 19 with ammonia gas in benzene. Dehydration of 3 with thionyl chloride gave 1 in 89% yield (Drefahl and Huneck, 1958). Ester 5 was synthesized in 83% yield from CDDO by a nucleophilic substitution method using an alkyl halide and DBU in toluene (reflux) (Ono et al., 1978) (Method A) Amides including imidazolides were synthesized in good yield by condensation reactions (Method B, scheme 1) between acyl chloride 19 and the corresponding amines and imidazoles. Tetra-O-acetyl-beta-D-glucopyranoside 2 was prepared in 75% yield from tetra-O-acetyl-alpha-D-glucopyranoside bromide (Lemieux, 1963) and CDDO using a phase-transfer catalyst (Bliard et al., 1994) (Scheme 2) (Method C). Because in the 1H-NMR spectrum (300 MHz, CDCl3) of 2 the anomeric proton was observed at delta5.70 ppm (1H, d, J=7.8 Hz) the proton was assigned the beta-configuration.

Reference： [1]Patent: US2004/2463,2004,A1 .Location in patent: Page/Page column 9

10
[ 851577-43-0 ]
[ 80841-78-7 ]
[ 851581-35-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 1h;	1) To a solution (20 mL) of 5-[(tert- butoxycarbonyl) aminolmethyl}-6-isobutyl-2-methyl-4- (4- methylphenyl) nicotinic acid (1.50 g, 3.37 mmol) in N, N- dimethylformamide were'added 4- (chloromethyl)-5-methyl-1, 3- dioxol-2-one (0.60 g, 4.04 mmol) and potassium carbonate (0.93 g, 6.72 mmol) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (100 mL) and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to give (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl 5- { [ (tert- butoxycarbonyl) amino] methyl}-6-isobutyl-2-methyl-4- (4- methylphenyl) nicotinate (1.50 g, yield 85%) as a colorless oil. H-NMR (CDC13) : 0.97 (6H, d, J = 6.8 Hz), 1. 38 (9H, s), 1.97 (3H, s), 2.16-2. 26 (1H, m), 2.40 (3H, s), 2.54 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 4.09 (2H, s), 4.74 (2H, s), 7.10 (2H, d, J = 7.9 Hz), 7.17 (2H, d, J = 7.9 Hz).

Reference： [1]Patent: WO2005/42488,2005,A1 .Location in patent: Page/Page column 200-201

11
disodium 2-ethoxy-1-[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate [ No CAS ]
[ 80841-78-7 ]
[ 863031-21-4 ]

Yield	Reaction Conditions	Operation in experiment
14%		To a solution of disodium 2-ethoxy-1-[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (2.0 g) in DMF (20 mL) was added 4-chloromethyl-5-methyl-1,3-dioxol-2-one (0.99 g) and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated and the residue was dissolved in chloroform and 1N hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.26 g, 14%) as a colorless solid. 1H NMR (300 MHz, CDCl3) delta: 1.43 (3H, t, J=7.1 Hz), 2.14 (3H, s), 4.46 (2H, q, J=7.1 Hz), 4.87 (2H, s), 5.63 (2H, s), 6.93 (2H, d, J=8.3 Hz), 7.07 (1H, t, J=7.9 Hz), 7.16 (2H, d, J=8.1 Hz), 7.32-7.37 (2H, m), 7.53-7.64 (3H, m), 7.83 (1H, dd, J=1.4 Hz, 7.6 Hz)

Reference： [1]Patent: US2005/187269,2005,A1 .Location in patent: Page/Page column 12-13

12
[ 907611-17-0 ]
[ 80841-78-7 ]
[ 907611-15-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;	A mixture of [5-{ [ (tert-butoxycarbonyl) amino]methyl}-2- ethyl-4- (4-methylphenyl) -beta-neopentylpyridin-3-yl] acetic acid (0.77 g, 1.7 mmol), 4- (chloromethyl) -5-methyl-l, 3-dioxol-2-one (0.38 g, 2.5 mmol), potassium carbonate (0.35 g, 2.5 mmol) and N,N-dimethylformamide (10 mL) was stirred at 600C for 2 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diisopropyl ether to give the title compound (0.67 g, yield 71%) as a white powder.MS 567 (M+l) .

Reference： [1]Patent: WO2006/90915,2006,A1 .Location in patent: Page/Page column 80

13
[ 858114-25-7 ]
[ 80841-78-7 ]
3-[4-[[4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]benzyl]oxy]phenyl]propanoic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With potassium carbonate; In N,N-dimethyl-formamide; at 10 - 35℃; for 5h;	Example 34 3-[4-[[4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]benzyl]oxy]phenyl]propanoic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester A solution of 3-[4-[[4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]benzyl]oxy]phenyl]propanoic acid (450 mg, 0.82 mmol), 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (146 mg, 0.99 mmol) and potassium carbonate (170 mg, 1.23 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (175 mg, yield 32%) as a colorless oil. 1H NMR (CDCl3) delta 2.12(3H,s), 2.63(2H,t,J=7.5Hz), 2.89(2H,t,J=7.5Hz), 2.94-3.03(2H,m), 3.62-3.72(2H,m), 4.66(2H,s), 4.80(2H,s), 5.01(2H,s), 6.74(1H,s), 6.84-6.91(2H,m), 7.08(2H,d,J=8.7Hz), 7.19-7.41(12H,m), 7.84-7.91(2H,m).

Reference： [1]Patent: EP1698624,2006,A1 .Location in patent: Page/Page column 67

14
[ 936114-12-4 ]
[ 80841-78-7 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; potassium iodide; In N,N-dimethyl acetamide; at 0 - 45℃; for 3h;	In 130 ml of N,N-dimethyl acetamide, 14.5 g (20 mmol) of potassium 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate, 3.0 g (2.2 mmol) of potassium carbonate powder and 1.4 g (8.4 mmol) of potassium iodide were added. The mixture was cooled to 0 C and 5.0 g (33 mmol) of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one was added at 0 to 5C. After the addition, the reaction mixture was warmed to 40-45 C within one hour, then the mixture was stirred at this temperature for 2h. The sample of reaction mixture was analysed (HPLC; tritylolmesartan medoxomil, 97.44%, 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate 0.06 %). The mixture was cooled to 10 to 20C and then 250 ml of ethyl acetate was added. The mixture was cooled again to 5-10 C and then 200 ml of 10% NaCl was added slowly. The temperature should not be higher than 25 C during the addition. The phases were mixed separated and organic phase was washed with 100 ml of 10% NaCl (2*) and dried over anhydrous sodium sulphate. After the filtration filtrate was evaporated under reduced pressure at temperature under 45C to oily residue. To the residue 30 ml of acetonitrile was added at temperature not more than 45C. The mixture was stirred at this temperature for 10 minutes then was cooled to 20 to 25C and stirred at this temperature for 0.5 h and after that 3h at 0 to 5C. The suspension was filtered, washed with cold acetonitrile and dried at 40 to 50C. Yield: 17.0 g (91%) HPLC: 99.64 % of the product, all other impurities under 0.1%. IR: 3408, 1818, 1805, 1741, 1681, 1529, 1148, 1002, 699
86%	With potassium iodide; In butanone; at 50℃; for 7.5h;	Example 3; Trityl olmesartan medoxomil (III); A solution of potassium salt 4 in methyl ethyl ketone from the preceding experiment (ca. 20 g of the salt) was diluted with methyl ethyl ketone (290 ml), and, after adding potassium iodide (2 g) and 4-chloromethyl-5-methyl-l,3-dioxol-2-one (7 g), the mixture was stirred at 50 0C for 7.5 h. After the reaction was completed, the mixture was filtered, and the filtrate was washed with methyl ethyl ketone (3 x 50 ml). After concentrating to ca. 160 ml in vacuo, ethanol (250 ml) was added, and the reaction mixture was again concentrated to ca. 300 ml in vacuo.The concentrated product in ethanol was inoculated and stirred at 50 0C for 0.5 h, and after getting thicker, diluted with ethanol (50 ml) and cooled to 20 C. The precipitated product was sucked off, washed with ethanol (2 x 20 ml) and dried in a vacuum drier at 50 C. 14.4 g (86 %) of the product was obtained.
84.4%	With potassium iodide; In butanone; at 50℃; for 20h;	Example 1-5 (0330) (0331) A mixture of BIC (0.6 g, 0.83 mmol), potassium iodide (0.069 g, 0.41 mmol), OXC (0.245 g, 1.65 mmol) and methyl ethyl ketone (9.0 mL, 15 vol) was stirred at 50 C. for 20 hr. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the obtained concentrated residue was purified by silica gel column chromatography (20-22% ethyl acetate/hexane) to give TOLM (650 mg, yield 84.4%). (0332) Mass: 801 [M+H]+, 824 [M+Na]+.

76 g		To BIC (110 g, 1 eq) was added acetone (385 mL, 3.5 vol) at 25C - 30C, and the mixture was dissolved by stirring for 5 min. Sodium carbonate (20.85 g, 1.3 eq) and potassium iodide (0.25 g, 0.01) were added, and the mixture was stirred for 10 min. A solution of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (31.456 g, 1.4 eq) in acetone (165 mL, 1.5 vol) was added thereto. The reaction mixture was heated to 45C - 50C, and stirred at the same temperature for 12 hr. Using TLC (thin layer chromatography) (TLC eluent: 10% methanol/methylene chloride, detection method: UV), complete disappearance of BIC was confirmed. The reaction mixture was cooled to 25C - 30C. Then, the solvent contained in the reaction mixture was evaporated under reduced pressure at 40C - 45C. To the obtained residue were added 10% brine (550 mL, 5 vol) and toluene (550 mL, 5 vol). Furthermore, the mixture was adjusted to pH 7 - 8 by adding 5% hydrochloric acid (33 mL), stirred for 10 min, left standing for 5 min and partitioned. The aqueous layer was extracted with toluene (2x330 mL, 2x3 vol). The extracts were combined with the organic layer, 10% brine (550 mL, 5 vol) was added, and the mixture was stirred for 5 min, left standing for 45 min, partitioned, and concentrated under reduced pressure at 40C - 45C to give TOLM (110 g, 90%). [0306] To the obtained TOLM was added acetone (110 mL, 1 vol), and the mixture was stirred at 25C - 30C for 30 min. n-Heptane (440 mL, 4 vol) was added, and the mixture was cooled to 5C - 10C and stirred at 5C - 10C for 30 min, whereby precipitation of a solid was confirmed. The solid (80 g, 66%) was collected by filtration, and blast dried. To the obtained solid was added isopropyl alcohol (400 mL, 5 vol), and the mixture was heated to 50C - 55C and stirred at 50C - 55C for 1 hr. Then, the mixture was cooled to 25C - 30C, and stirred at 25C - 30C for 1 hr. The resulting solid was filtered and suction-filtered for 10 min to give TOLM (76 g, 62%).
54.06 kg	With iodine; potassium carbonate; at 50℃; under 75.0075 Torr;Inert atmosphere; Large scale;	Step B, go to the reaction solution of compound (II) obtained in Step A with stirring,Add 6.27kg of anhydrous potassium carbonate powder and2.01kg iodine, replace the air with nitrogen, the nitrogen pressure in the kettle is ?0.01Mpa,The temperature was controlled at 50 ± 2 , and 13.80 kg of compound (IV) was added dropwise at a constant pressure.Add within 40 to 60 minutes. After the incubation reaction for 1.25 hours,Reduce the reaction mixture to below 10 C, extract with conventional solvents in an extraction kettle, wash with water, and separate the layers.The organic phase was distilled under reduced pressure to recover the solvent, crystallized, centrifuged,Drying gave 55.03 kg of crude compound (I).Step C: Add 192.61 kg of ethyl acetate to the 500L refining kettle, start stirring,55.03 kg of the crude compound (I) obtained in step B is added, and the feeding port is closed,Keep the pressure ?0.01MPa after replacing air with nitrogen,The temperature was raised to 75 C and dissolved for 25 minutes until it was clear. The filtrate was filtered and the temperature was reduced to 2.5 C.Centrifuge, put the filter cake into the double cone dryer,Under reduced pressure, a small flow of nitrogen was passed in for replacement three times, and the drying temperature was controlled to 40-50 C.Vacuum degree ?-0.09MPa, after drying for 1 hour,Increase the drying temperature to 50 60 and continue drying for 3 hours.54.06kg compound (1) finished product,The HPLC content was 99.93%, and the residual content of the compound (III) was 0.05%.

Reference： [1]Patent: EP2334668,2011,A1 .Location in patent: Paragraph 0079-0080
[2]Patent: WO2007/48361,2007,A1 .Location in patent: Page/Page column 9; 10
[3]Patent: US2015/239854,2015,A1 .Location in patent: Page/Page column 40
[4]Patent: EP2891650,2015,A1 .Location in patent: Paragraph 0304-0306
[5]Patent: CN110590758,2019,A .Location in patent: Paragraph 0016; 0018; 0019; 0024; 0026; 0027

15
[ 144690-33-5 ]
[ 80841-78-7 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
96.5%		188.0kg of tetrahydrofuran was added to a glass-lined reactor, 54.0kg 4- (1- hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityl-tetrazol -5 - yl) phenyl] phenyl} methylimidazole-5-carboxylate, 92.0.0kg 4.0kg purified water and lithium hydroxide monohydrate.After complete addition, 20 stirred for 18 hours, once every 2 hours the reaction temperature recording, tracking and detection TLC starting material to substantially complete the reaction.After completion of the reaction, 240.0kg Ethyl acetate and sodium chloride solution (20.0 kg of sodium chloride was added to 180.0kg purified water, and dissolved with stirring), stirred for 10 minutes, allowed to stand for 20 minutes stratification.The organic phase was washed with sodium chloride solution (32.0 kg of sodium chloride was added to 288.0kg purified water, stirred and dissolved) Average washed twice, each wash was stirred for 10 minutes and allowed to stand for 20 minutes.The organic phase was collected, dried over anhydrous sodium sulfate and stirred for 4 hours.Filtered, and the filtrate was concentrated under reduced pressure to remove ethyl acetate (water bath temperature controlled at 45 ± 5 , the degree of vacuum at -0.1 ~ -0.06MPa), a solution 188.0kg N, N- dimethylformamide, is added 15.3kg anhydrous potassium carbonate, 2.7kg of potassium iodide was stirred at 20 ± 10 was slowly added 14.5kg 4- chloro-5-methyl-1,3-dioxol-2-one, addition was completed, heating, feed temperature control reaction was stirred for 2 hours at 40 ± 2 .After completion of the reaction, the material was cooled to 15 ± 5 rejection filter, and the filtrate was added to a solution of sodium chloride (338.0kg sodium chloride to 940.0kg purified water, and dissolved with stirring), the following -5 ~ 0 stirred for 4h, rejection was filtered, the filter cake was charged to an oven baking pan blast drying oven at a temperature of 40 ± 5 8 hours.To give 58.2kg of trityl olmesartan medoxomil, a yield of 96.5%.
88%		Example 5: The reaction part was charged with ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] 22 g of 5-carboxylate (Formula 4), 3.1 g of sodium hydroxide and 90 mL of ethanol were added and the mixture was stirred at 20 to 25 C for 4 to 5 hours. When the reaction was completed, the reaction solution was concentrated. To the residue were added 50 mL of ethyl acetate and 50 mL of purified water. The mixture was stirred for 1 hour and then layered. The separated organic layer was washed twice with an aqueous solution containing 30 g of salt and 170 mL of purified water. 1 g of activated carbon and 20 g of anhydrous sodium sulfate were added to the organic layer, followed by stirring for 30 minutes to 1 hour, followed by filtration Respectively. After the filtrate was concentrated under reduced pressure, 50 mL of N, N-dimethylacetamide was added to the residue, the temperature was adjusted to 5 to 10 DEG C 4 g of potassium carbonate was added and 6.2 g of 4- (chloromethyl) -5-methyl-1,3-dioxol-2-one (Formula 6) was dissolved in N, N-dimethylacetamide 6 ML was added dropwise, and the mixture was reacted at 45 to 50 C for 4 hours with stirring. When the reaction is completed, the reaction solution is cooled to 20 to 25 After cooling, 220 mL of ethyl acetate, 30 g of salt and 170 mL of purified water were added successively. The organic layer was separated And then washed once more with an aqueous solution containing 30 g of salt and 170 mL of purified water. The organic layer was washed with 1 g of activated carbon, 20 g of sodium was added and stirred for 30 minutes to 1 hour, followed by filtration. The filtrate was concentrated under reduced pressure, and then acetone 100 mL of i-tril was added, and the mixture was stirred at 50 to 55 C for 1 hour. The crystals were cooled to 0 to 5 [deg.] C and stirred for 2 hours. Followed by washing with 50 mL of isopropyl alcohol, followed by drying to obtain 21.6 g (yield: 88%) of tritylolemecanemethoxysilane (formula 1a) Purity 99.97%) was obtained
85.8%		1L glass reaction flask was added with 600ml of acetone, 114.8g of intermediate 1 was added with stirring, then 12.8g of sodium hydroxide was added, the temperature was raised to 50-60 C, and the reaction was incubated for 5 hours, and the reaction was monitored by HPLC. To 20-30 C, add 2.8g potassium iodide, 36.0g 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and increase the temperature to 50-60 C after the addition After 1 hour of heat preservation reaction, the temperature was lowered to 20-30 C, filtered, and the filter cake was rinsed with 115 ml of acetone, and the filtrate was combined. The filtrate was concentrated under reduced pressure at 40-50 C until no obvious solvent flowed out, and 320 ml of acetonitrile was added to cool down. The mixture was decanted to 20-30 C for 1 hour, filtered, and the filter cake was rinsed with 320 ml of acetonitrile. The filter cake was blast dried at 40-50 C for 12 hours to obtain a white solid 110.0 g (intermediate 2). The rate was 85.8%, HPLC: 99.2%.

	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 40 - 65℃; for 5h;Product distribution / selectivity;	Example 1; Preparation of olmesartan medoxomilTo dimethyl acetamide (300 ml) was added 4-(1-hydroxy-1-methylethyl)-2-propyl imidazol- 5-carboxylic acid ethyl ester (50 gms) and powdered sodium hydroxide (26 gms). To this, 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (135 gms) was charged at 45-500C. The contents were stirred for 5 hours at 45-500C. Diisopropylethyl amine (100 ml) was charged to the reaction mass at 40-450C. A solution of 5-methyl-2-oxo-1 , 3-dioxane-4-yl)methyl chloride (80 gms) diluted with dimethyl acetamide (160 ml) was slowly added to the reaction mass at 40-450C over a period of 1 hour. The contents were heated to 60-650C and maintained for 4 hours. The reaction mass was then cooled to 30-350C and neutralized with concentrated hydrochloride acid. The reaction mass was filtered to remove inorganic impurities, charcoalized using charcoal (10 gms) andstirred for 30 minutes at 40-450C. The reaction mass was filtered over hyflo. The clear filtrate was acidified with hydrochloric acid (100 ml) slowly at 25-30C. The contents were stirred at 60C for 1 hour. The reaction mass was chilled to 0-5C and filtered to remove tritanol. The reaction mass was concentrated under reduced pressure. The residue was quenched with water (500ml), neutralized with base and extracted in dichloromethane (500 ml). The clear dichloromethane extract was then concentrated under reduced pressure and stripped off with acetone. The residue thus obtained was isolated from acetone (250 ml) to give 55 gms of the title compound. Chromatographic purity- > 99%; Example 2Preparation of olmesartan medoxomilTo dimethyl acetamide (600 ml) was added 4-(1-hydroxy-1-methylethyl)-2-propyl imidazol- 5-carboxylic acid ethyl ester (100 gms) and powdered potassium hydroxide (50 gms). To this was charged 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (270 gms) at 45-50C. The contents were stirred for 5 hours at 45-50C. Diisopropylethyl amine (200 ml) was charged to the reaction mass at 40-450C. To this was slowly added a solution of 5-methyl-2-oxo- 1 ,3-dioxane-4-yl)methyl chloride (160 gms) diluted with dimethyl acetamide (320 ml) at 40- <n="18"/>45C over a period of 1 hour. The contents were heated to 60-650C and maintained for 4 hours. The reaction mass was then cooled to 30-350C and was neutralized with concentrated hydrochloride acid. The reaction mass was filtered to remove inorganic impurities. The reaction mass was charcoalized using charcoal (20 gms) and was stirred for 30 minutes at 40-450C. The reaction mass was filtered over hyflo. The clear filtrate was acidified with hydrochloric acid (200 ml) slowly at 25-300C. The contents were stirred at 60C for 1 hour. The reaction mass was chilled to 0-50C and was filtered to remove tritanol. The reaction mass was concentrated under reduced pressure. The residue was quenched with water (1000 ml), neutralized with base and extracted in dichloromethane (1000 ml). The clear dichloromethane extract was then concentrated under reduced pressure, stripped off with acetone. The residue thus obtained was isolated from the acetone (500 ml) to give 110 gms of the title compound. Chromatogrphic purity- > 99%; Example 4Preparation of trityl olmesartan medoxomilTo dimethyl acetamide (300 ml) was added 4-(1-hydroxy-1-methylethyl)-2-propyl imidazol- 5-carboxylic acid ethyl ester (50 gms) and powdered potassium hydroxide (25 gms). To this was charged 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (135 gms) at 45-500C. The contents were stirred for 5 hours at 45-500C. Diisopropylethyl amine (100 ml) was charged to the reaction mass at 40-45C. To this was slowly added a solution of 5-methyl-2-oxo- 1 ,3-dioxane-4-yl) methyl chloride (80 gms) diluted with dimethyl acetamide (160 ml) at 40- 45C over a period of 1 hour. The contents were heated to 60-650C and maintained for 4 hours. The reaction mass was then cooled to 30-350C. and was neutralized with concentrated hydrochloride acid. The reaction mass was filtered to remove inorganics. The reaction mass was charcoalized using charcoal (10 gms) and was stirred for 30 minutes at 40-450C. The reaction mass was filtered over hyflo. The clear filtrate was quenched with purified water(200 ml)at 25-30C over a period of 3-4 hours. The contents were stirred at 25-300C for 30 minutes. Crude trityl olmesartan medoxomil was isolated by filtration, slurried in water (500 ml), centrifuged and dried under reduced pressure at 45-50C.
		Example 3; Preparation of olmesartan medoxomilTo dimethyl acetamide (800 ml) was added 4-(1-hydroxy-1-methylethyl)-2-propyl imidazol- 5-carboxylic acid ethyl ester (100 gms) and powdered potassium carbonate (200 gms). To this was charged 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (300 gms) at 45-50C. The contents were stirred for 8-10 hours at 45-50C. The insolubles were filtered. The contents were cooled to 5-100C. Potassium tertiary butoxide (100 gms) was charged at a temperature below 45C. The reaction was maintained at 40-450C for 3 hrs. To this was slowly added 5-methyl-2-oxo-1 ,3-dioxane-4-yl) methyl chloride at 40-450C over a period of 1 hour. The contents were heated to 60-650C and maintained for 4 hours. The reaction mass was then cooled to 30-350C and was neutralized with concentrated hydrochloride acid. The reaction mass was filtered to remove inorganics. The reaction mass was charcoalized using charcoal (10 gms) and was stirred for 30 minutes at 40-450C. The reaction mass was filtered over hyflo. The clear filtrate was acidified with hydrochloric acid (100 ml) slowly at 25-30C. The contents were stirred at 60C for 1 hour. The reaction mass was chilled to 0-5C and was filtered to remove tritanol. The reaction mass was <n="19"/>concentrated under reduced pressure. The residue was quenched with water (500 ml), neutralized with base and extracted in dichloromethane (500 ml).The clear dichloromethane extract was then concentrated under reduced pressure, stripped off with acetone. The residue thus obtained was isolated from the acetone (250 ml) to give 55 gms of the title compound. Chromatogrphic purity- > 99%
		Example 5; <n="20"/>Preparation of trityl olmesartan medoxomilTo dimethyl sulphoxide (800 ml), sodium hydroxide powder (50 gms) was added under nitrogen atmosphere and stirred at 20-250C for 10 minutes. To this, 4-( 1 -hydroxy- 1- methylethyl)-2-propyl-imidazole-5-ethyl carboxylate (100 gms) was added at 20-250C. 5- (4'-bromomethyl-biphenyl)-2-yl-1 -trityl tetrazole (270 gms) was added slowly at 20-250C, and the reaction mass was stirred at 20-250C for 12 hours. Further 10% sodium hydroxide solution (100 ml) was added to the reaction mass at 20-250C. The temperature of the reaction mass was raised to 40-450C, the contents stirred at 40-450C for 2 hours and 5- methyl-2-oxo-1 ,3-dioxane-4-yl)methyl chloride (160 gms) was added slowly at 45-5O0C over a period of 45 minutes. The contents were stirred at 45-5O0C for 2 hours. The reaction mass was then cooled to 0-50C, stirred for 1 hour at 0-50C, filtered and slurried in water (1.0 It) at 40-450C for 1 hour, filtered at 4O0C and dried at 4O0C. To the dried material, ethyl acetate (2.5 It) was added, heated to 50-550C for complete dissolution, ethyl acetate was distilled off to 1.0 It stage under vacuum at 45-5O0C. The contents were cooled to 0-50C, stirred at 0-50C for 3 hours, filtered, washed with chilled methanol (100 ml) and dried under vacuum at 40-450C to give 250 gms of the title compound. Purity by HPLC : > 99%
		Example 236.0 g (50.3 mmol) ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)-phenyl]phenyl}-methyl imidazole-5-carboxylate (Va) and 3.0 g (75.4 mmol) of NaOH were suspended in 413 ml dimethylacetamide. The suspension was then stirred at room temperature for 20 h and after that 6.9 g (50.3 mmol) of K2CO3, were added. The mixture was cooled to 0 C. and solution of 15.4 g (70.4 mmol) 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene in 39 ml of dimethylacetamide were slowly added. The mixture was slowly heated to 50 C. and stirred at this temperature for 2 h. After esterification was completed, the mixture was cooled to 10 C. and poured into a mixture of 625 ml of ethyl acetate and 625 ml of 10% NaCl, and stirred at 25 C. for 15 min. The phases were separated and organic phase was washed 2× with 500 ml of 10% NaCl, dried over Na2SO4 and filtered. The filtrate was concentrated up to ½ (approximately 270 g) at reduced pressure.To the resulting solution, 80 ml of ethanol and 8.3 ml (100 mmol) of conc. HCl were added and stirred at 24-26 C. for 3 h. To the cooled mixture 600 ml of water was added and pH of the suspension was estimated to 5 by addition of 5 M NaOH. The phases were stirred for 15 min and separated. Water phase was reextracted with 150 ml of ethyl acetate. Collected organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. 560 ml of ethyl acetate were added and the mixture was evaporated again. After that, 300 ml of ethyl acetate were added and the mixture was cooled to 20 C. and stirred for 1 h, filtered off and washed with 20 ml of fresh ethyl acetate. The yield of the product (I) was 21 g (75%).
		Example 2; 36.0 g (50.3 mmol) ethyl 4-(l -hydroxy- 1-methy lethyl)-2-propy 1-1- {4-[2-(trityltetrazol-5-y I)- phenyl]phenyl} -methyl imidazole-5-carboxylate (Va) and 3.0 g (75.4 mmol) of NaOH were suspended in 413 ml dimethylacetamide. The suspension was then stirred at room temperature for 20 h and after that 6.9 g (50.3 mmol) of K2CO3, were added. The mixture was cooled to 00C and solution of 15.4 g (70.4 mmol) 4-chloromethyl-5-methyl-2-oxo-l,3- dioxolene in 39 ml of dimethylacetamide were slowly added. The mixture was slowly heated to 500C and stirred at this temperature for 2 h. After esterification was completed, the mixture was cooled to 10 0C and poured into a mixture of 625 ml of ethyl acetate and 625 ml of 10 % NaCl, and stirred at 25 0C for 15 min. The phases were separated and organic phase was washed 2chi with 500 ml of 10 % NaCl, dried over Na2SO4 and filtered. The filtrate was concentrated up to 14 (approximately 270 g) at reduced pressure.To the resulting solution, 80 ml of ethanol and 8.3 ml (100 mmol) of cone. HCl were added EPO <DP n="23"/>and stirred at 24-26C for 3h. To the cooled mixture 600 ml of water was added and pH of the suspension was estimated to 5 by addition of 5 M NaOH. The phases were stirred for 15 min and separated. Water phase was reextracted with 150 ml of ethyl acetate. Collected organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. 560 ml of ethyl acetate were added and the mixture was evaporated again. After that, 300 ml of ethyl acetate were added and the mixture was cooled to 20 0C and stirred for Ih, filtered off and washed with 20 ml of fresh ethyl acetate. The yield of the product (I) was 21 g (75 %).
		Example 2; 36.0 g (50.3 mmol) ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-(4-[2-(trityltetrazol-5-yl)-phenyl]phenyl}-methyl imidazole-5-carboxylate (Va) and 3.0 g (75.4 mmol) of NaOH were suspended in 413 ml dimethylacetamide. The suspension was then stirred at room temperature for 20 h and after that 6.9 g (50.3 mmol) of K2CO3 were added. The mixture was cooled to 0C and solution of 15.4 g (70.4 mmol) 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene in 39 ml of dimethylacetamide were slowly added. The mixture was slowly heated to 50C and stirred at this temperature for 2 h. After esterification was completed, the mixture was cooled to 10 C and poured into a mixture of 625 ml of ethyl acetate and 625 ml of 10 % NaCl, and stirred at 25 C for 15 min. The phases were separated and organic phase was washed 2x with 500 ml of 10 % NaCl, dried over Na2SO4 and filtered. The filtrate was concentrated up to ½ (approximately 270 g) at reduced pressure. To the resulting solution, 80 ml of ethanol and 8.3 ml (100 mmol) of conc. HCl were added and stirred at 24-26C for 3h. To the cooled mixture 600 ml of water was added and pH of the suspension was estimated to 5 by addition of 5 M NaOH. The phases were stirred for 15 min and separated. Water phase was reextracted with 150 ml of ethyl acetate. Collected organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. 560 ml of ethyl acetate were added and the mixture was evaporated again. After that, 300 ml of ethyl acetate were added and the mixture was cooled to 20 C and stirred for 1h, filtered off and washed with 20 ml of fresh ethyl acetate. The yield of the product (I) was 21 g (75 %).
		To a solution of the compound of Formula IV (5.0 g) in toluene (40 mL), dimethylacetamide (10 mL) is added, followed by addition of sodium hydroxide (1.2 g) and N,N-diisopropylamine (3.7 g) at 25-35C. The mixture is stirred at 40- 45C for 4 hours. 5-Methyl-2-oxo-(1 ,3-dioxolene-4-yl)methyl chloride (1.5 g) and tetrabutylammonium bromide (0.5 g) are added at 40-450C. The mixture is stirred at 60-70C for 8 hours. The mass is cooled to 25-35C, water (50 mL) is added, and the pH is adjusted to about 6-7 by adding 10% aqueous HCI. The layers are separated. The aqueous layer is extracted with toluene (25 mL). The organic layers are combined and washed with water (25 mL). The solvent is distilled under reduced pressure. Methanol (25 mL) is added to the residue. The mixture is cooled to 0-50C and stirred at that temperature for 45 minutes. The formed solid is filtered, washed with methanol (10 mL) and dried for 45 minutes under vacuum (yield 3.0 g).
		Example 96.20 g of (III) were suspended in a mixture of 15.5 ml of tetrahydrofuran:dimethyl sulfoxide (2:3, v/v). The mixture was cooled to 17C in order to add 0.45 g (1.3 equivalents) of sodium hydroxide. The mixture was then heated to 60C. After two hours 1 .55 g (1 .1 equivalents) of potassium carbonate were added to the mixture. The mixture was heated to 70C and 1 .41 g of (IV) dissolved in 16.2 ml of tetrahydrofuran were added to the mixture over 1 .5 hours. The reaction was completed in one hour. The mixture was cooled to room temperature. The mixture was then washed three times with a 29% solution of sodium chloride in water. Finally, the organic solvent was distilled and 18.6 ml of ethyl acetate were added. Finally (V) was crystallised from ethyl acetate by cooling. The mixture was cooled to 0-5C, it was filtered, washed with ethyl acetate and heptane and the resulting solid was dried in a heat cabinet. 5.54 g of (V) were obtained (80% yield). The resulting solid was analysed by HPLC, showing a purity of more than 97%.
309 g		To the flask was added 2000 g of acetone, 160 g of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (II), 150 g of K2CO3, 460 g of 4- [2- (Trityltetrazol-5-yl) phenyl] benzyl bromide (III), 20g KI, the temperature was raised to reflux, the reaction was incubated for 34-38 hours under stirring.Then add 102g KOH, reflux reaction 6 ~ 8h. Cool to 10 ~ 20 , add 170g DMDO-Cl, incubated for 30 ~ 60min.Heating to reflux, the reaction 22 to 26 hours.After the reaction was added 40g of diatomaceous earth, stirring for 30 to 60 minutes, suction filtration, 200g acetone rinse cake. To the filtrate was added 800g of drinking water and 200g of refined hydrochloric acid, the reaction at room temperature for 2 to 4 hours, filtered to remove by-product triphenylcarbinol. Dropping 10% K2CO3 aqueous solution, adjusting feedstock pH to 4, cooling to 10 ~ 20 , stirring crystallization 2h, filtration, the filter cake with a mixture of pre-cooled 45g acetone and 230g of drinking water washing and drying, to obtain Olmesartan Medoxomil 309 g, total yield 83.1% (relative to ethyl-4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5- carboxylate (II)), purity: 99.27% of the main peak, 0.08% of the olmesartan acid, 0.14% of the triphenylmethanol, and 0.13% of the largest unidentified one.

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16
[ 879097-59-3 ]
[ 80841-78-7 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In N,N-dimethyl acetamide; at 5 - 10℃; for 4h;	Example 4; The reaction was carried out in the same manner as in Example 1 except that 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] -carboxylic acid sodium salt (Chemical Formula 5) and 50 mL of N, N-dimethylacetamide were added, the temperature was adjusted to 5 to 10 DEG C and 4 g of potassium carbonate was added. A solution of 6.2 g of 4- (chloromethyl) -5-methyl-1,3-dioxol-2-one (Formula 6) in 6 mL of N, N-dimethylacetamide was added dropwise to the reaction portion, For 4 hours. After the reaction was completed, the reaction solution was cooled to 20 to 25 C, and then 220 mL of ethyl acetate, 30 g of salt, and 170 mL of purified water were sequentially added to the reaction mixture, followed by separation of the organic layer, followed by the addition of 30 g of salt and 170 mL of purified water . & Lt; / RTI & gt; 1 g of activated carbon and 20 g of anhydrous sodium sulfate were added to the organic layer, followed by stirring for 30 minutes to 1 hour, followed by filtration. The filtrate was concentrated under reduced pressure, and 100 mL of acetonitrile was added to the residue, followed by stirring at 50 to 55 DEG C for 1 hour. The crystals were cooled to 0 to 5 C., stirred for 2 hours, filtered, washed with 50 mL of isopropyl alcohol and dried to obtain 21.7 g (yield: 93%, purity: 99.96%) of tritylolemethanemethoxysilane
	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 85℃; for 4h;	(3) the C43 H39 N6 NaO3 AMST - 4 and DMF added in a reaction kettle, lowering the temperature to 0 C, adding potassium carbonate, maintain 0 C dropwise C5 H5 ClO3 AMST - 5 dissolved in DMF solution, after the completion of the dropping 85 C reaction 4 hours, monitoring the reaction is finished adding water, sodium chloride and ethyl acetate stirring extraction, liquid, separating the upper organic phase, a mixed solution of water and sodium chloride washing, separating the organic phase at upper layer for sodium sulfate drying, filtering, 60 C concentrated to the reagent, in acetonitrile for 30 C beating 1 hour, cooling to 25 C, filtering, cake isopropyl alcohol leaching, 75 C drying to constant weight to obtain the product C48 H44 N6 O6 AMST - 6; the C43 H39 N6 NaO3 AMST - 4, DMF, potassium carbonate, C5 H5 ClO3 AMST - 5, ethyl acetate, acetonitrile, water, sodium chloride and sodium sulfate the mass ratio of the 192:560: 62:1500: 1000:1500: 300:50;
45g	With sodium iodide; In N,N-dimethyl-formamide; at 55℃; for 7.5h;	A solution containing about 46 g of compound 4 was taken, 3.5g sodium iodide was added, 280 mL N, N-dimethylformamide, 11.2g DMDO-Cl was slowly added dropwise, 30 Minute addition is completed. After dropping, Heated to 55 , Reaction for 7 hours, The reaction is completely over. filter, Remove insolubles, The filtrate was poured into 700mL of water, Extraction with ethyl acetate, The ethyl acetate layer was collected, dry, filter, The filtrate is concentrated. To the oily substance obtained after the concentration was added 200 mL of ethanol, Stirring, A white solid precipitation, Collect the solid, Washed with 50mL cyclohexane beating, 45.0 g of product was obtained, Two-step total yield of 80.6% The purity of the product was 98% by HPLC.

53.6 kg

With iodine; sodium carbonate; at 50℃; under 75.0075 Torr;Inert atmosphere; Large scale;

Step B, go to the reaction solution of compound (II) obtained in Step A with stirring,Add 6.27kg of anhydrous sodium carbonate powder and 2.01kg of iodine, replace the air with nitrogen,The nitrogen pressure in the kettle is ?0.01Mpa, the control temperature is 50 ± 2 ,15.05 kg of compound (IV) was added dropwise at a constant pressure, and the addition was completed within 40 to 60 minutes.After the reaction was held for 1 hour, the reaction mixture was reduced to below 10 C.Extract with conventional solvents in an extraction kettle, wash with water, and separate the layers.The organic phase was distilled under reduced pressure to recover the solvent, crystallized, centrifuged,After drying, 54.88 kg of the crude compound (I) was obtained.Step C: Add 192.08 kg of ethyl acetate to the 500L refining kettle, start stirring,Add 54.88 kg of crude compound (I) obtained in step B, close the feed port,Keep the pressure ?0.01MPa after replacing air with nitrogen,The temperature was raised to 75 C and dissolved for 25 minutes until it was clear. The filtrate was filtered and the temperature was reduced to 2.5 C.Centrifuge, put the filter cake into the double cone dryer,Under reduced pressure, a small flow of nitrogen was passed in for replacement three times, and the drying temperature was controlled to 40-50 C.Vacuum degree ?-0.09MPa, after drying for 1 hour,Increase the drying temperature to 50 60 and continue drying for 3 hours.After cooling down, 53.60 kg of compound (1) was obtained, and the HPLC content was 99.87%.Compound (III) had a residual content of 0.06%.

Reference： [1]Patent: KR101526249,2015,B1 .Location in patent: Paragraph 0068; 0069
[2]Synthetic Communications,2009,vol. 39,p. 291 - 298
[3]Patent: CN107311989,2017,A .Location in patent: Paragraph 0028; 0036; 0037
[4]Patent: CN103012382,2016,B .Location in patent: Paragraph 0021; 0030-0031
[5]Patent: CN110590758,2019,A .Location in patent: Paragraph 0020; 0022; 0023; 0028; 0030; 0031

17
[ 761404-85-7 ]
[ 80841-78-7 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; potassium iodide; In N,N-dimethyl acetamide; at 0 - 45℃; for 3h;Inert atmosphere;	130 ml of N,N-dimethylacetamide, 14.0 g (20 mmol) of ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate and 2.2 g (16 mmol) of KOH were charged into reaction vessel at room temperature under inert atmosphere. The mixture was stirred at room temperature for 2 h, and then the sample of reaction mixture was analysed (HPLC; starting material 0.2 %, hydrolysed starting material 98.11 %). Then 3.0 g (2.2 mmol) of potassium carbonate powder and 1.4 g (8.4 mmol) of potassium iodide were added. The reaction mixture was cooled to 0 C and 5.0 g (33 mmol) of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one was added at 0 to 5C. After the addition, the reaction mixture was warmed to 40-45 C within one hour, then the mixture was stirred at this temperature for 2h. The sample of reaction mixture was analysed (HPLC; tritylolmesartan medoxomil 97.22 %, 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate 0.09 %). The mixture was cooled to 10 to 20 C and then 250 ml of ethyl acetate was added. The mixture was cooled again to 5-10 C and then 200 ml of 10 % NaCl was added slowly. The temperature should not be higher than 25 C during the addition. The phases were mixed separated and organic phase was washed with 100 ml of 10 % NaCl (2*) and dried over anhydrous sodium sulphate. After the filtration filtrate was evaporated under reduced pressure at temperature under 45C to oily residue. To the residue 30 ml of acetonitrile was added at temperature not more than 45C. The mixture was stirred at this temperature for 10 minutes then was cooled to 20 to 25C and stirred at this temperature for 0.5 h and after that 3h at 0 to 5C. The suspension was filtered, the cake washed with cold acetonitrile and dried at 40 to 50C. Yield: 17.0 g (94%) HPLC: 99.72 % of the product, all impurities are under 0.1%. IR: 3408, 1818, 1805, 1741, 1681, 1529, 1147, 1003, 699 XRD:
91.6%		10L autoclave, 520g (0.75mol) Compound 5, DMF3kg, potassium carbonate and 215.3g (1.6mol), stirred at room temperature 1.5-2.5h added to the system after 63.0g (0.38mol) of potassium iodide was added dropwise while - Chloromethyl -5-methyl-1,3-dioxol-2-one 40.0g (0.94mol). Dropping was completed, the reaction at room temperature after 3-4h TLC or HPLC in control, raw reaction was complete. To the system was added ethyl acetate and 3L 3L water and 200g of sodium chloride, stirring separated and the aqueous layer was washed with 3X1L ethyl acetate, the combined organic layers, the organic layer was dried, filtered and the solvent was evaporated cooling is added 0-10 , methanol was added 1600g beating 30min, filtered, then the filter cake was slurried at room temperature in acetonitrile 1600g 30min, filtered to afford intermediate 6 about 553.8g,
	With potassium carbonate;potassium iodide; In acetone;Reflux;Product distribution / selectivity;	Example 7; Preparation of Trityl Olmesartan Medoxomil4-(1-Hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid dehydrate (100 g) was suspended in acetone (1 L) & heated to reflux; the solution obtained was added to suspension of potassium carbonate (15 g), potassium iodide (6 g) & 4-chloromethyl-5-methyl-1,3-dioxol-2-one (35 g) in acetone (500 mL) at reflux temperature. Reaction mass was refluxed for 2-6 hrs. After competition of reaction, the reaction mass was filtered & the acetone was distilled from combined mother liquor. The residue obtained was dissolved in toluene (1 L) toluene layer was washed with brine (3×250 mL). Toluene was removed under reduced pressure & residue thus obtained was recrystallized from methanol to give trityl OlmesartanMedoxomil (100 g).HPLC purity=99.5%

	In water; acetone; at 48 - 52℃; for 5h;Product distribution / selectivity;	Example 1(1) Tritylation and DMDO Esterification ReactionsAfter mixing 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[1H-tetrazol-5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylic acid (30 g), acetone (210 mL), 1,8-diazabicyclo[5,4,0]-7-undecene [DBU] (25.5 g) and triphenylmethyl chloride [TPC] (23.79 g), water (0.6 mL) was added and acetone (30 mL) was poured into the mixture, and the reaction mixture was stirred at 48 to 52 C. for 2 hours. Then, water (0.9 mL) was added and 4-chloromethyl-5-methyl-1,3-dioxol-2-one [DMDO-Cl] (18.5 g) was poured in, and the reaction mixture was stirred at 48 to 52 C. for 5 hours.(2) Obtaining Crude Crystals of Trityl Olmesartan Medoxomil (Acetone Solvate Crystals)After the reaction mixture was cooled to 20 C. to precipitate crystals, it was stirred at 15 to 25 C. for 40 minutes, and water (96 mL) was added dropwise over a period of 25 minutes, and then the reaction mixture was cooled to 0 to 5 C. and stirred for 30 minutes. The precipitated crystals were filtered out and washed with acetone-water (150 mL), and wet crude crystals of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate (57.83 g) were obtained. These were then dried in vacuo at 60 C. for approximately 15 hours, and the dry acetone solvate crystals (57.50 g) were obtained.
23.2 g	With potassium bromide; In N,N-dimethyl acetamide; at 15 - 50℃; for 8.6h;Green chemistry;	123.2g of compound and 2.5g of potassium hydroxide solid were added to a 500ml four-necked flask.DMAC76g, heated to 50 C, stirred for about 6h,The TLC dot plate showed that the compound 1 point disappeared, that is, the end of the hydrolysis reaction was judged.Cool to 15 ± 5 C, add KBr 0.64g, add DMDO-C16.5g, DMAC 10g,After about 40 minutes, the temperature was raised to 25±5C for 2h, then the temperature was raised to 50C, the reaction was about 6h, and the temperature was lowered again to 20±5C for 5h. The reaction solution was added with 324g water and 208g of dichloromethane.Shake well and let the layers separate. The aqueous layer was extracted with 70 g of dichloromethane and combined with several layers.It was washed twice with 206 g of water, and the last aqueous layer was extracted with 100 g of dichloromethane.The organic layers were combined and dried under reduced pressure at 45 C.After adding 100g of the upper batch of crystallization, the mother liquid is heated and refluxed for 25±5 minutes, and then naturally cooled.Then crystallization at 0 C for 6 h,Drying by suction filtration to obtain 23.2 g of trityl olmesartan medoxomil white solid powder.The yield was 93.4%. HPLC analysis, purity 99.7%, acid miscellaneous <0.05%,The olefinic impurity is <0.1%, and the other unknown single impurities are <0.1%.

Reference： [1]Patent: EP2334668,2011,A1 .Location in patent: Paragraph 0077-0078
[2]Patent: CN105481842,2016,A .Location in patent: Paragraph 0050; 0053; 0054
[3]Patent: US2009/281327,2009,A1 .Location in patent: Page/Page column 5-6
[4]Patent: US2012/59172,2012,A1 .Location in patent: Page/Page column 5
[5]Patent: CN103880825,2019,B .Location in patent: Paragraph 0020; 0039-0044

18
[ 1088409-50-0 ]
[ 80841-78-7 ]
[ 1088410-47-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1.5h;	Step (iv) of Example 18: Methyl 6-N-((2S,4R)-4-cyclopropylmethyl-1-((5-methyl-2-oxo-1,3-diox ol-4-yl)methyl)pipecoloyl-7-deoxy-7-epi-7-(4-(pyrimidin-5-ylph enylthio)-1-thio-alpha-lincosamide (compound 129) Sodium carbonate (5.9 mg, 56 mumol) and 13 mg (56 mumol) of <strong>[80841-78-7]4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene</strong> produced as described in Chem. Pharm. Bull., 32, 2241 (1984) were added to a solution of 30 mg (51 mumol) of the compound (72) in N,N-dimethylformamide (0.5 ml), and the mixture was stirred at room temperature for 1.5 hr. The reaction solution was diluted with ethyl acetate. The diluted solution was washed with a 10% aqueous sodium chloride solution followed by drying over anhydrous sodium sulfate. After filtration, the filtrate concentrated, and the residue was purified by column chromatography on silica gel (ethyl acetate : acetone = 100 : 0 ? 80 : 20) to give 37 mg (yield 100%) of the title compound. For the title compound (129) produced in step (iv) of Example 18, 1H-NMR data and MS data are shown in Table 7.

Reference： [1]Patent: EP2166015,2010,A1 .Location in patent: Page/Page column 41

19
[ 1152636-93-5 ]
[ 80841-78-7 ]
[ 1152636-96-8 ]

Yield	Reaction Conditions	Operation in experiment
86%		11-(a) (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetate To 1.0 mL of a dimethylformamide solution containing 113 mg (0.200 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) was added 21 mg (0.25 mmol) of sodium hydrogen carbonate, and the mixture was stirred under argon gas atmosphere and ice-cooling. Then, 29.7 mg (0.200 mmol) of <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong> was added to the mixture, and the resulting mixture was stirred at the same temperature for 2.5 hours. After elevating to room temperature, 55.3 mg (0.400 mmol) of potassium carbonate was added to the mixture, and the resulting mixture was stirred at room temperature for 6 hours. 7.4 mg (0.050 mmol) of <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong> was further added to the mixture, and the resulting mixture was stirred at room temperature for 15.5 hours. After completion of the reaction, the reaction mixture was poured into 10 mL of water, and extracted with 30 mL of ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then, it was concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (eluent; chloroform: methanol=39:1? 25:1(V/V)), and the separated fractions containing the desired product were concentrated under reduced pressure to obtain 116 mg of the title compound as brown oil. (Yield 86%) Mass spectrum (FAB, m/z): 679 (M++1). 1H-NMR spectrum (CDCl3, delta ppm): 1.54 (s, 9H), 2.05-2.13 (m, 2H), 2.16 (s, 3H), 2.49 (dd, J1=17.0Hz, J2=4.8Hz, 1H), 2.84-3.06 (m, 5H), 3.78-4.00 (m, 7H), 4.15-4.29 (m, 3H), 4.81 (d, J=13.8Hz, 1H), 4.91 (d, J=13.8Hz, 1H), 5.31 (d, J=16.4Hz, 1H), 6.50 (s, 1H), 6.64 (d, J=2.7Hz, 1H), 6.81 (dd, J1=8.4Hz, J2=2.7Hz, 1H), 7.00 (d, J=8.bHz, 1H).
86%		11-(a) (5-Methyl-2-oxo-[1,3]dioxolen-4-yl)methyl (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetate To 1.0 mL of a dimethylformamide solution containing 113 mg (0.200 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) was added 21 mg (0.25 mmol) of sodium hydrogen carbonate, and the mixture was stirred under argon gas atmosphere and under ice-cooling. Then, to the mixture was added 29.7 mg (0.200 mmol) of <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong>, and the resulting mixture was stirred at the same temperature for 2.5 hours. After raising the temperature to room temperature, 55.3 mg (0.400 mmol) of potassium carbonate was added to the mixture, and the resulting mixture was stirred at room temperature for 6 hours. Further, 7.4 mg (0.050 mmol) of <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong> was added to the mixture, the mixture was stirred at room temperature for 15.5 hours. After completion of the reaction, the reaction mixture was poured into 10 ml of water, and extracted with 30 mL of ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (eluent; chloroform:methanol=39:1? 25:1 (V/V)), and the separated fractions containing the objective material were concentrated under reduced pressure to obtain 116 mg of the title compound as brown oily product. (Yield: 86%) Mass Spectrum (FAB, m/z): 679 (M++1). 1H-NMR Spectrum (CDCl3, delta ppm): 1.54 (s, 9H), 2.05-2.13 (m, 2H), 2.16 (s, 3H), 2.49 (dd, J1=17.0Hz, J2=4.8Hz, 1H), 2.84-3.06 (m, 5H), 3.78-4.00 (m, 7H), 4.15-4.29 (m, 3H), 4.81. (d, J=13.8Hz, 1H), 4.91 (d, J=13.8Hz, 1H), 5.31 (d, J=16.4Hz, 1H), 6.50 (s, 1H), 6.64 (d, J=2.7Hz, 1H), 6.81 (dd, J1=8.4Hz, J2=2.7Hz, 1H), 7.00 (d, J=8.6Hz, 1H).

Reference： [1]Patent: EP2221308,2010,A1 .Location in patent: Page/Page column 28
[2]Patent: EP2415474,2012,A1 .Location in patent: Page/Page column 32

20
[ 144690-92-6 ]
[ 80841-78-7 ]
[ 144689-63-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 2; 36.0 g (50.3 mmol) ethyl 4-(l -hydroxy- 1-methy lethyl)-2-propy 1-1- {4-[2-(trityltetrazol-5-y I)- phenyl]phenyl} -methyl imidazole-5-carboxylate (Va) and 3.0 g (75.4 mmol) of NaOH were suspended in 413 ml dimethylacetamide. The suspension was then stirred at room temperature for 20 h and after that 6.9 g (50.3 mmol) of K2CO3, were added. The mixture was cooled to 00C and solution of 15.4 g (70.4 mmol) 4-chloromethyl-5-methyl-2-oxo-l,3- dioxolene in 39 ml of dimethylacetamide were slowly added. The mixture was slowly heated to 500C and stirred at this temperature for 2 h. After esterification was completed, the mixture was cooled to 10 0C and poured into a mixture of 625 ml of ethyl acetate and 625 ml of 10 % NaCl, and stirred at 25 0C for 15 min. The phases were separated and organic phase was washed 2chi with 500 ml of 10 % NaCl, dried over Na2SO4 and filtered. The filtrate was concentrated up to 14 (approximately 270 g) at reduced pressure.To the resulting solution, 80 ml of ethanol and 8.3 ml (100 mmol) of cone. HCl were added EPO <DP n="23"/>and stirred at 24-26C for 3h. To the cooled mixture 600 ml of water was added and pH of the suspension was estimated to 5 by addition of 5 M NaOH. The phases were stirred for 15 min and separated. Water phase was reextracted with 150 ml of ethyl acetate. Collected organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. 560 ml of ethyl acetate were added and the mixture was evaporated again. After that, 300 ml of ethyl acetate were added and the mixture was cooled to 20 0C and stirred for Ih, filtered off and washed with 20 ml of fresh ethyl acetate. The yield of the product (I) was 21 g (75 %).

Reference： [1]Patent: WO2007/17135,2007,A2 .Location in patent: Page/Page column 5; 21-22

21
[ 1190221-98-7 ]
[ 80841-78-7 ]
[ 1190220-96-2 ]

Yield	Reaction Conditions	Operation in experiment
19%	With sodium iodide; In N,N-dimethyl-formamide; at 30℃; for 3h;	0.69 g (1.5 mmol) of 5-chloro-2-([(2-oxo-2-([3-(pyridin-4-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid · sodium salt, 0.35 g (1.8 mmol) of 4-(chloromethyl)-5-methyl-1,3-dioxole-2-one, and 0.25 g (1.65 mmol) of sodium iodide were stirred in DMF (7 mL) at 30C for 3 hours. After completion of the reaction, ethyl acetate was added to the mixture, and the mixture was washed with a sodium chloride solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography to give the target 5-chloro-2-([(2-oxo-2-([3-(pyridin-4-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid · (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (yield: 19%). 1H-NMR (CDCl3) delta: 1. 96 (3H, s), 4.32 (2H, s), 4.33 (2H, s), 4.82 (2H, s), 7.41-7.72 (6H, m), 8.01 (1H, d, J = 2.6 Hz), 8.06-8.07 (1H, m), 8.66-8.67 (2H, m), 8.80 (1H, d, J= 9.0 Hz), 8.82 (1H, s), 11.6 (1H, br).

Reference： [1]Patent: EP2272822,2011,A1 .Location in patent: Page/Page column 51

22
[ 80841-78-7 ]
[ 124750-51-2 ]
[ 144689-93-0 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
		Toluene (180 L) is placed into a reactor and water (3.17 L) is added, followed by addition of ethyl-4-(1 -hydroxy-1 -methylethyl)-2-propylimidazole-5- carboxylate (18.0 Kg). The mass is stirred for about 10 minutes, heated to about 45C, and potassium carbonate (25.85 Kg) is added. The temperature of the mass is raised to about 65C and maintained for about 45 minutes. N-(triphenylmethyl)- 5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (48.9 Kg) and tetrabutylammonium bromide (4.82 Kg) are added at the same temperature and the mixture is stirred at 60-700C for 10 hours. Reaction completion is verified using thin layerchromatography (TLC). After the reaction is complete, the mass is washed with water (3*120 L) at about 500C. The mass is cooled to about 25C and toluene (468 L) and potassium tertiary-butoxide (12.6 Kg) is added, then the mass is maintained at the same temperature for about 1 hour. Water (0.85 L) is added and the mass is maintained at the same temperature for about 2 hours. Reaction completion is verified using TLC, then 5-methyl-2-oxo-(1 ,3-dioxolene-4-yl)methyl chloride (20 Kg), tetrabutylammonium bromide (4.82 Kg), and sodium carbonate (3.96 Kg) are added at 40-450C. The mass is stirred at about 55C for about 11 hours. After the reaction is complete, the mass is cooled to about 20C, water (540 L) is added and the pH is adjusted to about 6-7 by adding 10% aqueous HCI. The layers are separated. The aqueous layer is extracted with toluene (240 L). The organic layers are combined and washed with water (270 L). The solvent is distilled under reduced pressure. Acetone (189 L) is added to the residue and the mixture is heated to about 45C to produce a solution, then the solution is cooled to about 300C and maintained for about 20 minutes, followed by cooling to about 2C and maintaining for about 3 hours. The formed solid is filtered, washed with acetone (54 L), and dried for about 4 hours. The material obtained is re- crystallized from acetonitrile to yield 34.0 Kg of the title compound.

Reference： [1]Patent: WO2011/14611,2011,A2 .Location in patent: Page/Page column 12; 13

23
[ 1331782-42-3 ]
[ 80841-78-7 ]
[ 1331782-60-5 ]

Yield	Reaction Conditions	Operation in experiment
60%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	Example 27Synthesis of 5-methyl-2-oxo-l , 3-dioxol-4-yl { 2- ( 1- (5-methyl-ll- (nitrooxy) -3, 7-dioxo-4, 6, 9-trioxa-2-azaundecyl) cyclohexyl } acetate (compound 27) (27)To a stirred solution of 2- (1- (5-methyl-ll- (nitrooxy) -3, 7- dioxo-4, 6, 9-trioxa-2-azaundecyl) cyclohexyl) acetic acid (Example 23) (600 mg, 1.47 mmol) in dry DMF (20 mL) was added 4-chloromethyl-5-methyl-l , 3-dioxol-2-one (241 mg, 1.62 mmol) and CS2CO3 carbonate (327 mg, 1.62 mmol) . The mixture was stirred at room temperature for 2 hours. The reaction was diluted with Na¾P04 5% and extracted with EtOAc. The organic phase was washed with brine and dried over a2S04. The crude material was purified by silica gel chromatography (eluting with EtOAC/Hexane 20 to 80 %) affording the product (450 mg, 60 %) as a clear oil.1H-NMR (CDCI3) : 6.86 (1H, m) ; 5.23 (1H, bt) ; 4.85 (2H, s); 4.65 (2H, t) ; 4.14 (2h, m) ; 3.86 (2H, m) ; 3.19 (2H, m) ; 2.36 (2H, s); 2.20 (3H, s) ; 1.6-1.3 (13H, m) .

Reference： [1]Patent: WO2011/101245,2011,A1 .Location in patent: Page/Page column 50-51

24
[ 42017-89-0 ]
[ 80841-78-7 ]
[ 1319719-25-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In N,N-dimethyl acetamide; at 65℃;	A solution of 4-chloromethyl-5-1,3-dioxolen-2-one(2.94 g, 20 mmol) was added to <strong>[42017-89-0]fenofibric acid</strong>(3.18 g, 10 mmol) and K2CO3 (2.76 g, 20 mmol) inN,N-dimethylacetamide (64 mL) at room temperatureat such a rate that the reaction maintained an internaltemperature of 60-65 C overnight. The reaction mixturewas cooled to 0 C and water (100 mL) was added slowly.The resulting mixture was stirred at room temperature for1.5 h, extracted with ethyl acetate (100 mL), and washedwith brine (150 mL × 3). The solvent was distilled offunder reduced pressure to obtain a residue. The residue waspurified further by column chromatography to give the titlecompounds. The following compounds were synthesizedaccording to this procedure.

Reference： [1]Journal of the Brazilian Chemical Society,2020,vol. 31,p. 280 - 287
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 5915 - 5926

25
[ 1187450-51-6 ]
[ 80841-78-7 ]
[(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl] (6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-ylamino)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 15h;	[Example 7] [(5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl](6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-ylamino)acetate To 1.2 ml of an N,N-dimethylformamide solution containing 198 mg (0.400 mmol) of (6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-ylamino)acetic acid obtained by the same manner as in Reference example 3-(b) was added 0.2 ml of an N,N-dimethylformamide solution containing 71 mg (0.51 mmol) of potassium carbonate and 89 mg (0.60 mmol) of 4-chloromethyl-5-methyl-1,3-dioxolen-2-one, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:2 (V/V)), and the fractions containing the objective material were concentrated under reduced pressure to obtain 203 mg of the title compound as pale yellowish-brown foam. (Yield: 84%) Mass spectrum (FAB, m/z): 608 (M++1). 1H-NMR spectrum (DMSO-d6, delta ppm): 8.66 (ddd, J=4.7, 1.8, 0.8 Hz, 1H), 7.98 (ddd, J=7.7, 7.7, 1.8 Hz, 1H), 7.91 (d, J=3.3 Hz, 1H), 7.87-7.81 (m, 3H), 7.78 (d, J=3.3 Hz, 1H), 7.60 (ddd, J=7.7, 4.7, 1.1 Hz, 1H), 7.36-7.29 (m, 2H), 7.21 (dd, J=8.3, 7.2 Hz, 1H), 6.95 (t, J=6.2 Hz, 0.8H), 6.36 (d, J=8.3 Hz, 1H), 6.31 (d, J=7.2 Hz, 1H), 4.95 (s, 2H), 4.69 (s, 2H), 4.24 (s, 2H), 3.95 (d, J=6.2 Hz, 2H), 2.07 (s, 3H). Rf value: 0.67 (ethyl acetate:methanol=50:1).

Reference： [1]Patent: EP2476678,2012,A1 .Location in patent: Page/Page column 20

26
[ 80841-78-7 ]
[ 91526-18-0 ]

Yield	Reaction Conditions	Operation in experiment
79%		Example 4APreparation of 4-hydroxymethyl-5-methyl-l, 3-dioxol-2-oneTo a solution of 4-chloromethyl-5methyl-l ,3-dioxol-2-one (50 g) in acetonitrile (500 ml), formic acid (45 g) was added at 20-25C and the reaction mass cool to 10-15C followed by addition of triethylamine (95 g). Reaction mass was heated to 60-65 C and stirred at the same temperature for about 5-6 hrs. Reaction mass was cooled to 15-20C, filtered and washed by acetonitrile. Filtrate was taken and acetonitrile was distilled out under vacuum to concentrate the solution. Reaction mass was cooled to 25-30C and ethyl acetate and water was added, followed by stirring for about 15-20 minutes at 25- 30C. Aqueous layer extracted with ethyl acetate and combined organic layer were washed with brine solution. Organic layer was separated and evaporated completely under vacuum below 35-40C. To the oily mass, methanol was added and heated to reflux temperature. A solution of HC1 in isopropyl alcohol was added and the resulting solution was refluxed for about 60-75 mins. Reaction mass was cooled to 30-35C. Distilled out the solvent completely to obtain title compound as oily mass. (Yield: 34.6 g; 79%)
43%		4- (chloromethyl)-5-methyl-1,3-dioxol-2-one (400mg, 2.7mmol) was dissolved in acetonitrile 10ml) was added dropwise formic acid (496mg, 10.8mmol ), then the mixture was stirred at room temperature for 5 minutes. The reaction mixture was cooled to 0 deg.] C, thereto was added triethylamine (0.8ml, 5.4mmol), and the mixture was stirred at 60 8 hours, and then water is introduced, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in methanol (10ml), and thereto was added concentrated hydrochloric acid (1ml), then, the mixture was stirred at room temperature for 2 hours. To the reaction mixture, saturated aqueous sodium bicarbonate is introduced, the mixture was extracted with ethyl acetate, then washed with saturated brine and the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 (v / v)) for purification to prepare the title compound 150mg (43% yield).
	With formic acid; triethylamine; In acetonitrile; at 0 - 65℃; for 3h;	Formic acid (0.750 mL, 19.6 mmol) and triethylamine (2.62 mL, 18.8 mmol) were added to a solution of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (1.00 g, 6.73 mmol) in acetonitrile (10.0 mL) at 0 C., the temperature of the reaction liquid was raised to 65 C., and the reaction liquid was stirred for 3 hours. The precipitate was filtered through Celite, and the filtrate was concentrated under reduced pressure. Distilled water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Methanol (10.0 mL) was added to the obtained residue at room temperature and the obtained residue was dissolved. Distilled water (3.0 mL) and concentrated hydrochloric acid (0.120 mL, 3.95 mmol) were added to the reaction liquid at room temperature, and the resulting mixture was stirred at the same temperature for 3 hours. Distilled water was added to the reaction liquid, and the reaction liquid was concentrated under reduced pressure. Distilled water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one.

Reference Example 25 Synthesis of crude 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (0413) (0414) Formic acid (0.750 mL, 19.6 mmol) and triethylamine (2.62 mL, 18.8 mmol) were added to a solution of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (1.00 g, 6.73 mmol) in acetonitrile (10.0 mL) at 0 C., the temperature of the reaction liquid was raised to 65 C., and the reaction liquid was stirred for 3 hours. The precipitate was filtered through Celite, and the filtrate was concentrated under reduced pressure. Distilled water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Methanol (10.0 mL) was added to the obtained residue at room temperature and the obtained residue was dissolved. Distilled water (3.0 mL) and concentrated hydrochloric acid (0.120 mL, 3.95 mmol) were added to the reaction liquid at room temperature, and the resulting mixture was stirred at the same temperature for 3 hours. Distilled water was added to the reaction liquid, and the reaction liquid was concentrated under reduced pressure. Distilled water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one.

Reference： [1]Patent: WO2012/107814,2012,A1 .Location in patent: Page/Page column 14-15
[2]Patent: CN105492423,2016,A .Location in patent: Paragraph 0741; 0742; 0743; 0744
[3]Patent: TW2016/2093,2016,A .Location in patent: Paragraph 0323
[4]Patent: US2016/194302,2016,A1 .Location in patent: Paragraph 0413; 0414

27
[ 80841-78-7 ]
[ 863031-21-4 ]

Reference： [1]Patent: WO2012/107814,2012,A1

28
[ 1394050-30-6 ]
[ 80841-78-7 ]
[ 1394050-47-5 ]

Yield	Reaction Conditions	Operation in experiment
		Crude Compound 6 (79.4 g) was dissolved in DMF (640 mL). K2CO3 (23.8 g, 172 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. The mixture was cooled at 0 C. followed by addition of <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong> (20.6 mL, 188 mmol). The mixture was maintained at 0 C. and stirred over 3 hours (55% starting material and 38% product). The mixture was then stirred at room temperature (20.2 C.) overnight (16 hours; starting material was non-detectable). EtOAc (1.5 L) was added. The organic layer was washed with 3 M aqueous NH4Cl (2×1.5 L) and saturated aqueous NaCl (1.5 L), dried with Na2SO4 (40 g), followed by solvent removal to yield crude Compound 7 as a thick oil. The crude Compound 7 was dissolved in DCM (500 ml) followed by the addition of 3.0 M aqueous HCl in CPME (798 mL, 2.4 mol). Seed crystals were added and the resulting mixture was stirred overnight to yield a free flowing slurry. The volume was reduced by half and the resulting slurry was filtered, flasked, and the filter cake was washed with diisopropyl ether to yield the title compound as a off-white solid HCl salt (69.1 g; 96.2% purity).
		Example 4 (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(1H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic Acid 5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl Ester [0187] [0188] (2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-methyl-2-(tetrahydro-pyran-2-yloxymethyl)-pentanoic acid (79.4 g; crude) was dissolved in DMF (640 mL). K2CO3 (23.8 g, 172 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. The mixture was cooled at 0 C. followed by addition of <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong> (20.6 mL, 188 mmol). The mixture was maintained at 0 C. and stirred over 3 hours (55% starting material and 38% product). The mixture was then stirred at room temperature (20.2 C.) overnight (16 hours; starting material was non-detectable). EtOAc (1.5 L) was added. The organic layer was washed with 3 M aqueous NH4Cl (2×1.5 L) and saturated aqueous NaCl (1.5 L), dried with Na2SO4 (40 g), followed by solvent removal to yield crude Compound 1 as a thick oil.
		Crude Compound 3 (79.4 g) was dissolved in DMF (640 mL). K2CO3 (23.8 g, 172 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. The mixture was cooled at 0 C. followed by addition of <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong> (20.6 mL, 188 mmol). The mixture was maintained at 0 C. and stirred over 3 hours (55% starting material and 38% product). The mixture was then stirred at room temperature (20.2 C.) overnight (16 hours; starting material was non-detectable). EtOAc (1.5 L) was added. The organic layer was washed with 3 M aqueous NH4Cl (2×1.5 L) and saturated aqueous NaCl (1.5 L), dried with Na2SO4 (40 g), followed by solvent removal to yield crude Compound 4 as a thick oil. The crude Compound 4 was dissolved in DCM (500 ml) followed by the addition of 3.0 M aqueous HCl in CPME (798 mL, 2.4 mol). Seed crystals were added and the resulting mixture was stirred overnight to yield a free flowing slurry. The volume was reduced by half and the resulting slurry was filtered, flasked, and the filter cake was washed with diisopropyl ether to yield the title compound as a off-white solid HCl salt (69.1 g; 96.2% purity).

Reference： [1]Patent: US2012/213806,2012,A1 .Location in patent: Page/Page column 59
[2]Patent: US2013/211098,2013,A1 .Location in patent: Paragraph 0187; 0188
[3]Patent: US2013/209505,2013,A1 .Location in patent: Paragraph 0171

29
[ 1415043-08-1 ]
[ 80841-78-7 ]
[ 1415043-85-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	The title compound of Example 4 (150 mg, 0.33 mmol) and potassium carbonate (114 mg, 0.82 mmol) were suspended in 2 ml dimethylformamide. 4-(Chloromethyl)-5-methyl-1,3-dioxol-2-one (117 mg, 0.79 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. The organics were washed sequentially three times with water and once with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse-phase chromatography using the SP1 Purification system to give a solid. The solid was triturated with ether to give 140 mg (0.24 mmol, 75%) of the title compound. Purity 98%. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.22 (1 H, d, J=7.0 Hz), 7.94 (2 H, dd, J=8.8, 4.9 Hz), 7.41 (1 H, t, J=6.8 Hz), 7.33 (1 H, t, J=7.2 Hz), 7.18 (2 H, t, J=8.6 Hz), 7.08 (1 H, d, J=7.4 Hz), 5.03 (1 H, br. s.), 4.94 (2 H, s), 4.56 (2 H, s), 4.37 (2 H, s), 3.55 (2 H, td, J=6.7, 2.5 Hz), 2.75 (2 H, t, J=6.8 Hz), 2.18 (3 H, s), 1.89 (3 H, s). HPLC/MS (30 min) retention time 14.55 min. LRMS: m/z 569 (M+1).

Reference： [1]Patent: EP2526945,2012,A1 .Location in patent: Page/Page column 108

30
[ 41859-67-0 ]
[ 80841-78-7 ]
[ 1415335-13-5 ]

Yield	Reaction Conditions	Operation in experiment
73%	With sodium carbonate; In N,N-dimethyl acetamide; at 32℃; for 70h;Inert atmosphere;	A solution of 1a (2.0 g, 5.52 mmol) in DMAc (10 mL) was treated with micronized sodium carbonate (0.44 g, 4.1 mmol) and 5-methyl-2-oxo-1, 3-dioxolene-4-yl-4-methylene chloride (0.9 g, 6.06 mmol) for 70 h at 32 C under N2 atmosphere. Reaction progress was monitored by HPLC. The reaction mixture was transferred to a mixture of ethyl acetate (50 mL) and water (100 mL) under vigorous stirring. The pH of reaction mixture was adjusted to 11.0 with sodium carbonate, and stirred for 10 min at 25 C. The organic phase was separated, washed with brine solution (2 × 100 mL), filtered, and solvent was evaporated completely under vacuum at 35-40 C to give solid residue. Then, water (50 mL) was added, stirred for 10 min, filtered, washed with water (50 mL), and dried in vacuo at 45 C to afford the title compound 7 as white solid (1.9 g, 73%). Chromatographic purity (HPLC) 98.87%; mp 129.8 C; MS (ESI+) m/z = 474.1 [M + H].+; IR (KBr) cm-1: 3282, 1823, 1743, 1634; 1H NMR (DMSO, 400 MHz) delta 1.55 (s, 6H, -OC(CH3)2), 2.13 (s, 3H, -C=CCH3), 2.77 (t, 2H, J = 7.7 Hz, -NHCH2CH2Ar), 3.45 (t, 2H, J = 7.7 Hz, -NHCH2CH2Ar), 5.07 (s, 2H, -OCH2), 6.69-7.84 (m, 8H, Ar-H), 8.65 (bs, 1H, -NH); 13C NMR (DMSO, 100 MHz) delta 8.80 (-CCH3), 24.96 (2C, -OCH(CH3)2), 34.21 (-HNCH2CH2Ar), 40.96 (-HNCH2CH2Ar), 54.47 (-OCH2C), 78.67 (-OCHCOO), 118.73-153.19 (12C, Ar + 2C, ethylene), 151.71 (-OCOO), 165.04 (ArCONH), 172.89 (-OCHCOO). Anal. Calcd. for C24H24ClNO7: C, 60.83; H, 5.10; N, 2.96. Found: C, 60.77; H, 5.07; N, 2.94.

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 57,p. 217 - 224

31
[ 80841-78-7 ]
[ 77171-41-6 ]
(2R,3R)-3-amino-2-hydroxy-4-phenyl-butyric acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-chloromethyl-5-methyl-1,3-dioxol-2-one With caesium carbonate In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: (2R,3R)-N-(tert-butoxycarbonyl)-3-amino-2-hydroxy-4-phenylbutanoic acid In N,N-dimethyl-formamide at 0℃; for 1h; Stage #3: With hydrogenchloride In 1,4-dioxane	9 4-Chloromethyl-5-methyl-1,3-dioxol-2-one (212 mg, 1.4 mmol, 1.0 eq.) was dissolved in dry DMF (2 mL) and cooled to 0° C. Dicesium carbonate (465 mg, 1.4 mmol, 1.0 eq.) was added and the mixture was stirred for 30 minutes at 0° C. (2R,3R)-3-(BOC-amino)-2-hydroxy-4-phenylbutyric acid (421 mg, 1.4 mmol, 1.0 eq.) was added and the mixture was stirred for 1 hour at 0° C. and then warmed to room temperature, while stirring. EtOAc (20 mL) was added and the mixture was saturated aqueous NaCl (100 mL) then vacuumed to dryness. The product was purified using reverse phase chromatography (10-70% MeCN gradient). Acid deprotection was accomplished by dissolving the product in 4N HCl in dioxane (10 mL). The product was then vacuumed to dryness, taken up in toluene and vacuumed to dryness again to yield the title compound as an HCl salt (0.3 g).

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2012/308587, 2012, A1 Location in patent: Page/Page column 45

32
[ 80841-78-7 ]
[ 77171-41-6 ]
5-[(1R,2R)-1-benzyl-2-hydroxy-2-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl)-ethylcarbamoyl]-2-(4-methoxybenzyl)-2H-pyrazole-3-carboxylic acid trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 1 h / 0 °C 2.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 1 h / 20 °C

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2012/308587, 2012, A1

33
[ 1247008-23-6 ]
[ 80841-78-7 ]
[ 1247008-25-8 ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium carbonate; In N,N-dimethyl acetamide; at 20℃; for 12h;	6.1.8 Preparation of [1-[[4-[1,1-dimethyl-2-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy]-2-oxo-ethyl]phenyl]methyl]-4-piperidinyl]methyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate hydrochloride (10) 4-Chloromethyl-5-methyl-1,3-dioxol-2-one (78 mg, 0.53 mmol) was added to a suspension of carboxylic acid 9 (0.20 g, 0.40 mmol) and K2CO3 (0.16 g, 1.2 mmol) in dimethylacetamide (1.0 ml). The mixture was stirred at room temperature for 12 h, evaporated in vacuo and the residue separated by flash chromatography (CH2Cl2:MeOH 9:1) to leave the title compound 10 as a white solid (0.12 g, 50%).

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 64,p. 629 - 637

34
[ 80841-78-7 ]
[ 95233-18-4 ]
[ 1445850-06-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In acetonitrile; at 60 - 65℃;	Charged Atovaquone (1 equivalent, obtained by the process described in example 1 of the U.S. Patent No. 4,981,874), Acetonitrile (20V), K2C03 (2.5 equivalent) to the reactor fitted with a guard tube. Added 5-methyl- 4-chloromethyldioxalone(2.5eq) drop wise to the mass at room temperature. The mass was further heated to 60-65C for 16-18 hrs. Reaction was monitored by TLC. After the completion of the reaction, distilled of the solvent completely under vacuum. To the mass added water (10V) and Ethyl acetate (5V) and stirred the mass at room temperature for hr. Filtered the heterogeneous mass under suction. Bed washed with IV of Ethyl acetate. Suction dried the mass for 2 hrs. Dried the mass in Vacuum tray dryer (VTD) at 65-70C for 4hrs. Yield: 90 % Purity: 98.7%

Reference： [1]Patent: WO2013/93937,2013,A2 .Location in patent: Page/Page column 12

35
[ 1397836-49-5 ]
[ 80841-78-7 ]
[ 1449029-77-9 ]

Yield	Reaction Conditions	Operation in experiment
22.5 g		The 2-ethoxy-1-[2-(N-hydroxycarbamimidoyl)biphenyl-4-yl]methyl} -1H-benzimidazole-7-carboxylic acid (25 g) prepared in Example 2B, acetone (250 mL), and potassium carbonate (8.1 g) were heated to 45 C to 50 C for 2 hours. The reaction mixture was cooled to 25 C to 30 C. Tetrabutyl ammonium bromide (0.94 g), sodium iodide (0.44 g), and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (9.5 g) were added to the reaction mixture and stirred for 4 hours at 25 C to 30 C The reaction mixture was cooled to 5 C to 10 C. 2N Hydrochloric acid (50 mL) was added to the reaction mixture to adjust the pH to 1.5 to 2.0. De-ionized water (250 mL) was added to the reaction mixture and washed with toluene (50 mL). Sodium bicarbonate solution (12.5 g sodium bicarbonate in 150 mL de-ionized water) was added to the reaction mixture to adjust the pH to 7.0 to 7.5. The solid obtained was filtered, washed with de-ionized water (50 mL) and dried. The reaction mixture was purified with ethyl acetate (150 mL) to obtain the title compound. Yield: 22.5 g HPLC purity: 96.78%
90 g		The 2-ethoxy-1-[2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (100 g) prepared in Example 2A, dimethyl acetamide (450 mL), and potassium carbonate (20.9 g) were heated to 80 C. to 85 C. for 2 hours. The reaction mixture was cooled to 45 C. to 50 C. A solution of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (41.44 g) in N,N-dimethylformamide (50 mL) was added to the reaction mixture at 40 C. to 45 C. The reaction mixture was stirred at 45 C. to 55 C. for 6 to 8 hours. The reaction mixture was cooled to 15 C. to 20 C. A solution of sodium bicarbonate (100 g) in water (2000 mL) was added to the reaction mixture. The solid obtained was filtered and washed with water (500 mL) and dried below 50 C. to obtain the title compound. Yield: 90 g

Reference： [1]Patent: WO2013/114305,2013,A1 .Location in patent: Page/Page column 18; 19
[2]Patent: US2015/11774,2015,A1 .Location in patent: Paragraph 0070; 0071

36
4'-((4-(((3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carbonyl)oxy)methyl)piperidin-1-yl)methyl)[1,1'-biphenyl]-2-carboxylic acid [ No CAS ]
[ 80841-78-7 ]
(1-((2'-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)[1,1'-biphenyl]-4-yl)methyl)piperidin-4-yl)methyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 12h;	6.1.8.6 (1-((2'-(((5-Methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)[1,1'-biphenyl]-4-yl)methyl)piperidin-4-yl)methyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate methanesulfonate (23e) Following the general procedure, carboxylic acid 21 (0.15 g, 0.29 mmol) was alkylated with <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong> (54 mg, 0.36 mmol) to leave the free base 23e as a yellow solid (50 mg, 27%). 1H NMR (CDCl3): delta 7.95 (d, J = 7.1 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.53-7.11 (m, 10H), 4.78 (s, 2H), 4.52 (t, J = 5.1 Hz, 2H), 4.18 (d, J = 6.1 Hz, 2H), 4.08 (t, J = 6.3 Hz, 2H), 3.57 (s, 2H), 2.94-2.90 (m, 2H), 2.35-2.29 (m, 2H), 2.07-2.04 (m, 5H), 1.86-1.81 (m, 2H), 1.53-1.39 (m, 3H). 13C NMR (CDCl3): delta 168.3, 161.2, 154.1, 152.1, 143.2, 141.6, 138.9, 134.6, 131.5, 131.3, 131.0, 130.7, 130.3, 130.0, 129.2, 127.6, 124.9, 122.5, 120.9, 120.2, 107.9, 86.2, 67.9, 66.5, 65.9, 53.7, 39.1, 34.2, 33.4, 26.1, 20.9, 9.7. HRMS (TOF MS ES+) for C37H36N2O8 [M+H]+: calcd 637.2549 found 637.2468.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7134 - 7145

37
[ 936114-12-4 ]
[ 80841-78-7 ]
[ 144689-63-4 ]

Reference： [1]Patent: EP2334668,2011,A1

38
[ 80841-78-7 ]
trans-atovaquone [ No CAS ]
3-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyloxy-2-trans-[(4-chlorophenyl)cyclohexyl][1,4]naphthaquinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In acetonitrile; at 60 - 65℃;	10049] Charged Atovaquone (1 equivalent, obtained by the process described in example 1 of the U.S. Pat. No. 4,981, 874), Acetonitrile (20V), K2C03 (2.5 equivalent) to the reactor fitted with a guard tube. Added 5-methyl-4-chlorometh- yldioxalone (2.Seq) drop wise to the mass at room temperature. The mass was further heated to 60-65 C. for 16-18 irs. Reaction was monitored by TLC. After the completion of the reaction, distilled of the solvent completely under vacuum. To the mass added water (1OV) and Ethyl acetate (5V) and stirred the mass at room temperature for hr. Filtered the heterogeneous mass under suction. Bed washed with lv of Ethyl acetate. Suction dried the mass for 2 hrs. Dried the mass in Vacuum tray dryer (VTD) at 65-70 C. for4hrs.10050] Yield: 90%10051] Purity: 98.7%

Reference： [1]Patent: US2014/343297,2014,A1 .Location in patent: Paragraph 0049; 0050; 0051

39
5-({(3R)-1-[(trans-4-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-fluoroethyl}cyclohexyl)carbonyl]-3-phenyl-L-prolyl}amino)-1H-indole-2-carboxylic acid [ No CAS ]
[ 80841-78-7 ]
(5-methyl-2-oxo-1,3-disoxol-4-yl)methyl 5-({(3R)-1-(trans-4-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-fluoroethyl}cyclohexyl)carbonyl-3-phenyl-L-prolyl}amino)-1H-indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	To a solution of the compound of Reference Example 140 (60.0 mg, 0.0967 mmol) in DMF (1 mL), potassium carbonate (26.7 mg, 0.193 mmol) and <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong> (14.6muL, 0.126 mmol) were added, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride twice and with a saturated saline solution, then dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (59.4 mg, 84%). MS (ESI+) 733 (M+1, 49%)

Reference： [1]Patent: EP2876105,2015,A1 .Location in patent: Paragraph 1259; 1260

40
5-[(3S)-1-[(trans-4-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-fluoroethyl}cyclohexyl)carbonyl]-3-(cis-4-methoxycyclohexyl)-L-prolyl]amino}-1-benzofuran-2-carboxylic acid [ No CAS ]
[ 80841-78-7 ]
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl5-[(3S)-1-[(trans-4-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-fluoroethyl}cyclohexyl)carbonyl]-3-(trans-4-methoxycyclohexyl)-L-prolyl]amino}-1-benzofuran-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃;	To a solution of the compound of Reference Example 174-1 (20.2 mg, 0.031 mmol) in DMF (2 mL), potassium carbonate (12.8 mg, 0.093 mmol), potassium iodide (1.0 mg, 0.003 mmol), and <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong> (6.8 mg, 0.046 mmol) were added, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride twice and with a saturated saline solution, then dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (19.0 mg, 82%). MS (ESI+) 771 (M+1, 75%)

Reference： [1]Patent: EP2876105,2015,A1 .Location in patent: Paragraph 1484; 1485

41
1-tert-butyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxyphenyl)-1-methoxycarbonylethylcarbamoyl]-10-oxoheptadec-2-enyl}-2-hydroxysuccinate [ No CAS ]
[ 80841-78-7 ]
4-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl) 1-tert-butyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With N-ethyl-N,N-diisopropylamine; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 39h;Inert atmosphere;	(S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate No. 5317776 (Compound E; 53.3 mg, 0.0747 mmol) was dissolved in N,N-dimethylformamide (0.64 mL), and then N,N-diisopropylethylamine (14 muL, 0.0804 mmol), 4-chloromethyl-5-methyl 1,3-dioxole (14 mg, 0.0943 mmol), and sodium iodide (10 mg, 0.0667 mmol) were added at room temperature. After the mixture was stirred for 39 hours, the reaction solution was concentrated under reduced pressure, and then purified by preparative HPLC to obtain 37.8 mg (0.0458 mmol, yield 61%, ESI (LC/MS positive mode) m/z 826 (M+H); Rt 3.49 min.) of 4-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl) 1-tert-butyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate.

Reference： [1]Patent: EP2886530,2015,A1 .Location in patent: Paragraph 0223; 0224

42
(E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxyphenyl)-1-methoxycarbonylethylcarbamoyl]-2-hydroxy-2-(2-hydroxyethyl)-12-oxononadec-4-enoic acid potassium salt [ No CAS ]
[ 80841-78-7 ]
C₄₁H₅₇NO₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium iodide; In N,N-dimethyl-formamide; at 40℃; for 1h;Inert atmosphere;	Synthetic method 2 of Compound 2 (No. 5169356) To a mixture of No. 5214357: Compound T (5.0 g, 7.33 mmol), NaI (1.65 g, 10.99 mmol), and DMF was added 4-chloromethyl-5-methyl-[1,3]dioxol-2-one (1.59 mL, 14.66 mmol) and the mixture was stirred at 40 C for 1 hour. After confirming the consumption of the starting materials, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by diol column chromatography to obtain No. 5725513: Compound H (5.36 g, yield 97%, colorless oil, ESI (LC/MS positive mode) m/z 756 (M+H); Rt 1.09 min). To a mixture of the obtained No. 5725513, Compound H (5.31 g, 7.02 mmol), acetonitrile (106 mL), and distilled water (5.3 mL) were added 4-acetamide-TEMPO (TEMPO-AA; 449 mg, 2.10 mmol) and iodobenzene diacetate (9.05 g, 28.1 mmol) and the mixture was stirred at room temperature. After confirming the consumption of the starting materials by LCMS, an aqueous solution of 0.5 M citric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of 5% sodium thiosulfate and a saturated brine and dried over anhydrous sodium sulfate, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by diol column chromatography to obtain Compound 2 (4.40 g, 82% yield, yellow oil

Reference： [1]Patent: EP2886530,2015,A1 .Location in patent: Paragraph 0302; 0303; 0304; 0305; 0306

43
4-methyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate [ No CAS ]
[ 80841-78-7 ]
1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl) 4-methyl(S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With tetra-(n-butyl)ammonium iodide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;Inert atmosphere;	(S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate To a mixture of No. 5045280: Compound 36 (22 mg, 0.0327 mmol) and THF (1 mL) were added <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong> (7.1 mg, 0.0655 mmol), tetrabutyl ammonium iodide (1.2 mg, 0.0033 mmol), and N,N-diisopropylethylamine (11.4 muL, 0.0655 mmol) and the mixture was stirred at room temperature. After confirming the consumption of the starting materials by LCMS, the product was purified by preparative HPLC. Water was added to the purified fraction, which was followed by extraction with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain Compound 70 (13 mg, 51 % yield). 1H-NMR (CD3OD) delta: 0.89 (3H, t, J = 7.1 Hz), 1.27-1.30 (16H, m), 1.50-1.57 (4H, m), 1.82 (3H, t, J = 2.2 Hz), 1.95-1.97 (2H, m), 2.17 (3H, s), 2.44 (4H, t, J = 7.5 Hz), 2.60 (1H, d, J = 15.9 Hz), 2.86-2.95 (2H, m), 3.12 (1 H, dd, J = 13.9, 5.1 Hz), 3.20 (1H, d, J = 8.4 Hz), 3.62 (3H, s), 3.72 (3H, s), 4.62-4.64 (3H, m), 4.96 (2H, s), 5.47-5.53 (2H, m), 6.84 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.4 Hz), 8.25 (1H, d, J = 7.9 Hz).

Reference： [1]Patent: EP2886530,2015,A1 .Location in patent: Paragraph 0391; 0392; 0393; 0394

44
1-tert-butyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonylmethoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate [ No CAS ]
[ 80841-78-7 ]
C₄₇H₆₅NO₁₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine; sodium iodide; In dichloromethane; at 45℃;Inert atmosphere;	To a mixture of the obtained No. 5725529: Compound L (1.87 g, 2.42 mmol), dichloromethane (37.4 mL), sodium iodide (1.09 g, 7.27 mmol), and 4-chloromethyl-5-methyl-[1,3]dioxol-2-one (788 muL, 7.27 mmol) was added N,N-diisopropylethylamine (1.26 mL, 7.27 mmol) and the mixture was stirred at 45 C. After confirming the consumption of the starting materials by LCMS, dichloromethane was added. The mixture was washed with a saturated aqueous solution of ammonium chloride. The resulting organic layer was dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain No. 5724907: Compound M (1.61 g, 75% yield, (ESI (LC/MS positive mode) m/z 885 (M+H); Rt 3.28 min.).

Reference： [1]Patent: EP2886530,2015,A1 .Location in patent: Paragraph 0612; 0618

45
(E)-(2S,3S)-3-[(S)-2-(4-butoxyphenyl)-1-methoxycarbonylethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxyethyl)-nonadec-4-enoic acid [ No CAS ]
[ 80841-78-7 ]
(5-methyl-2-oxo-[1,3]dioxol-4-yl)methyl(E)-(2S,3S)-3-[(S)-2-(4-butoxyphenyl)-1-methoxycarbonylethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxyethyl)-nonadec-4-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium hydrogencarbonate; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 22h;Inert atmosphere;	(E)-(2S,3 S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 6808755) To the mixture of (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoic acid (No. 5514403, 50 mg, 0.0731 mmol), sodium iodide (16.4 mg, 0.110 mmol), sodium bicarbonate (7.4 mg, 0.877 mmol) and the DMF (1 mL) was added commercially available <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong> (15.9 muL, 0.145 mmol) at room temperature, and the mixture was stirred as it was for 22 hours. After confirming the consumption of the starting materials by LCMS, the reaction solution was filtered through a syringe filter, and purified as it was by preparative HPLC. The purified fraction was freeze-dried to obtain the title compound (48 mg, 83% yield) as yellow oil. Physicochemical properties of Compound No. 6808755 [0132] 1H-NMR (CD3OD) delta: 0.90 (3H, t, J = 6.8 Hz), 0.98 (3H, t, J = 9.5 Hz), 1.25-1.36 (14H, m), 1.39-1.55 (6H, m), 1.63 (1H, td, J = 9.3, 4.7 Hz), 1.70-1.85 (6H, m), 1.90-1.97 (2H, m), 2.05-2.13 (1H, m), 2.16 (3H, s), 2.86 (1H, dd, J = 13.9, 9.5 Hz), 3.11 (1H, dd, J = 13.9, 5.1 Hz), 3.18 (3H, s), 3.22 (1H, d, J = 8.8 Hz), 3.32-3.37 (1H, m), 3.45 (1H, td, J = 9.7, 4.4 Hz), 3.70 (3H, s), 3.92 (2H, t, J = 6.4 Hz), 4.60-4.66 (1H, m), 4.83 (1H, d, J = 13.7 Hz), 4.95 (1H, d, J = 13.7 Hz), 5.42-5.57 (2H, m), 6.79 (2H, d, J = 8.4 Hz), 7.06 (2H, d, J = 8.4 Hz), 8.24 (1H, d, J = 7.9 Hz). [0133] ESI (LC/MS positive mode) m/z 796 (M+H); Rt 1.22 min.

Reference： [1]Patent: EP2886530,2015,A1 .Location in patent: Paragraph 0103; 0131; 0132; 0133

46
(E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-methoxy-ethyl)-12-oxo-nonadec-4-enoic acid [ No CAS ]
[ 80841-78-7 ]
5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-methoxy-ethyl)-12-oxo-nonadec-4-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium hydrogencarbonate; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 5h;Inert atmosphere;	No. 6808754 Synthesis of 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl RRN 1873(E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy -2-(2-methoxy-ethyl)-12-oxo-nonadec-4-enoate To a mixture of No. 5444958 (50 mg, 0.0733 mmol), sodium iodide (16.5 mg, 0.110 mmol), sodium bicarbonate (7.4 mg, 0.0880 mmol), and DMF (1.0 mL) was added a commercially available reagent of <strong>[80841-78-7]4-chloromethyl-5-methyl-1,3-dioxol-2-one</strong> (15.9 muL, 0.146 mmol) at room temperature, and the mixture was stirred as it was for 5 hours. After confirming the consumption of the starting materials by LCMS, the reaction solution was filtered through a syringe filter, and purified as it was by preparative HPLC. The purified fraction was freeze-dried to obtain the title compound (47 mg, 83% yield, colorless oil). [1722] 1H-NMR (CD3OD) delta: 0.89 (3H, t, J = 6.8 Hz), 0.98 (3H, t, J = 7.5 Hz), 1.20-1.40 (14H, m), 1.43-1.57 (6H, m), 1.62 (1H, td, J = 9.4, 4.6 Hz), 1.70-1.77 (2H, m), 1.86-2.01 (2H, m), 2.05-2.12 (1H, m), 2.43 (3H, t, J = 7.3 Hz), 2.86 (1H, dd, J = 14.1, 9.3 Hz), 3.10 (1H, dd, J = 14.3, 5.1 Hz), 3.18 (3H, s), 3.22 (1H, d, J = 8.4 Hz), 3.32-3.37 (1H, m), 3.44 (1H, td, J = 9.7, 4.4 Hz), 3.70 (3H, s), 3.92 (2H, t, J = 6.4 Hz), 4.63 (1H, td, J = 8.6, 4.9 Hz), 4.83 (1H, d, J = 14.1 Hz), 4.95 (1H, d, J = 14.1 Hz), 5.42-5.57 (2H, m), 6.79 (2H, d, J = 8.8 Hz), 7.06 (2H, d, J = 8.8 Hz), 8.23 (1H, d, J = 7.9 Hz). [1723] ESI (LC/MS positive mode) m/z 774 (M+H); Rt 1.14 min.

Reference： [1]Patent: EP2886530,2015,A1 .Location in patent: Paragraph 1720; 1721; 1722; 1723

47
[ 915-79-7 ]
[ 80841-78-7 ]
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3β-acetoxyurs-12-en-28-oate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.7 g	With potassium carbonate; potassium iodide; In acetone; at 20℃; for 24h;	1.0 g of the compound obtained from Reference Example 1 was dissolved in 20 ml of acetone. 0.9 g of potassium carbonate and 0.4 g of potassium iodide (KI) were added thereto, and 0.6 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolane was added thereto. The mixture was reacted at room temperature for 24 hours and concentrated. 10 ml of ethyl acetate was added to the concentrate, the concentrate was washed with 10 ml of water and brine, respectively, and dried over anhydrous sodium sulfate. After filtration under reduced pressure and concentration to obtain residue, the residue was separated and purified by column chromatography to thereby obtain 0.7 g of a target compound. 1H-NMR(DMSO-d6, 500 MHz) 4.764.99(2H, dd) 5.17(1H, t), 2.152.17(1H, d, J=11.0 Hz), 2.11(3H,s), 2.00(3H, s), 1.06(3H, s), 0.900.92(6H, d), 0.810.86(9H, m), 0.76(3H,s); IR(cm-1) 2924, 1819, 1732, 1447, 1371, 1244, 1129, 1010.

Reference： [1]Patent: US2015/218206,2015,A1 .Location in patent: Paragraph 0056-0059
[2]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5524 - 5527

48
1-({2'-[1-(2,4-dimethoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)-4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid [ No CAS ]
[ 80841-78-7 ]
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-({2'-[1-(2,4-dimethoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)-4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%		An oven-dried flask was sequentially charged with carboxylic acid 9 (5.8 g, 7.98 mmol), Na2CO3 (1.1 g, 10.4 mmol), KI (0.0133 g, 0.08mmol), and acetone (20.0 mL), and the mixture was stirred for 10 min. A solution of medoxomil chloride (10; 1.66 g, 11.2 mmol) in acetone (9.0 mL) was added over 10 min at 25 C, and the mixture was heated at 45-50 C until the reaction was complete (11 h). The mixture was then cooled to 25 C and the acetone was removed under reduced pressure. To the resulting mixture were added 10% aq NaCl(29.0 mL) and toluene (29.0 mL). The pH of the solution was adjusted to 7-8 by using 5% aq HCl (6.3 mL), and the mixture was stirred for 10min. The two layers were separated and the aqueous layer was extracted with toluene (2 × 15.0 mL). The organic layers were combinedand washed with 10% aq NaCl (29.0 mL). The toluene was distilled off under reduced pressure to give a crude product that was purified by column chromatography (silica gel, 0.4-0.5% MeOH-CH2Cl2) to give acolorless solid; yield: 4.19 g (74%); mp 139.8 C.

Reference： [1]Synthesis,2015,vol. 47,p. 2985 - 2990

49
[ 76-83-5 ]
[ 80841-78-7 ]
[ 147403-65-4 ]
C₆₇H₅₄N₄O₇ [ No CAS ]
(5-methyl-2-oxo-2H-1,3-dioxol-4yl)methyl 2-ethoxy-1-[(4-(2-[N′-(triphenylmehoxy)carbamimidoyl]phenyl)-phenyl)methyl]-1H-1,3-benzodiazole-7-carboxylate [ No CAS ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 514 - 519

50
[ 76-83-5 ]
[ 80841-78-7 ]
[ 147403-65-4 ]
[ 1449029-77-9 ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 514 - 519

51
4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylic acid dipotassium salt [ No CAS ]
[ 80841-78-7 ]
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{2'-[2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-2H-tetrazol-5-yl]biphenyl-4-yl}methyl-1H-imidazole-5-carboxylate [ No CAS ]
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{2'-[1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1H-tetrazol-5-yl]biphenyl-4-yl}methyl-1H-imidazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.82 g; 1.36 g	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 22h;	K2CO3 (1.95 g, 14.11 mmol, 2.1 eq), KI (0.67 g, 4.03 mmol, 0.6 eq) and medoxomil chloride(5) (2.20 g, 14.78 mmol, 2.2 eq) were added to a suspension of olmesartan (8, 3.00 g, 6.72 mmol,1.0 eq) in DMF (60 mL). After being stirred at room temperature for 22 h, TLC analysis (30%MeOH/AcOEt) indicated the disappearance of the starting material 8 and formation of two reactionproducts characterized by similar, but different from OM (7), polarity. The reaction mixture wasdiluted with H2O (50 mL) and the products were extracted with AcOEt (2 50 mL). The combinedorganic phases were dried over anhydrous MgSO4, filtered and concentrated under reduced pressureto give an oily residue. The crude mixture of products (6.36 g, according to the HPLC analysis9:10-42.56%:57.44%) was purified by column chromatography over silica gel with 50%-100%AcOEt/hexanes gradient elution to afford N-2-medoxomil derivative 9 (glassy oil containing ethylacetate, 0.82 g, Rf = 0.76 for 10% MeOH/AcOEt), a mixture of N-2- 9 and N-1-medoxomil 10 derivatives(2.09 g) and N-1-medoxomil derivative 10 (1.36 g, Rf = 0.70 for 10% MeOH/AcOEt). Total reactionyield was 95%.9: FT-IR (KBr) : 3438, 2968, 2933, 2874, 1828, 1738, 1708, 1675, 1529, 1463, 1433, 1392, 1308, 1227, 1131,1033, 1066, 765 cm1.1H-NMR (CDCl3, 600 MHz) : 7.84 (1H, dd, J = 7.7 and 1.0 Hz, biphenyl H-31), 7.56 (1H, td, J = 7.5 Hzand 1.4 Hz, biphenyl H-51), 7.49 (1H, td, J = 7.6 and 1.3 Hz, biphenyl H-41), 7.44 (1H, dd, J = 7.7and 0.9 Hz, biphenyl H-61), 7.11 (2H, BB1 of AA1BB1 system, biphenyl H-2 and H-6), 6.82 (2H, AA1of AA1BB1 system, biphenyl H-3 and H-5), 5.46 (2H, s, tetrazole -CH2-NN-CH2-), 4.90 (2H, s, -CH2O-), 2.72 (2H, t, J = 7.2 Hz, -CH2CH2CH3), 2.19 (3H, s, medoxomil CH3-5at N-2 of tetrazole), 2.08 (3H, s, medoxomil CH3-5 of ester group), 1.74 (2H, m, -CH2CH2CH3), 1.62(6H, s, -C(OH)(CH3)2), 0.98 (3H, t, J = 7.2 Hz, -CH2CH2CH3).13C-NMR (CDCl3, 150 MHz) : 165.9 (tetrazole C-5), 160.8 (>C=O), 160.0 (imidazole C-4), 152.3(imidazole C-2), 151.8 (medoxomil >C=O of ester group), 151.3 (medoxomil >C=O at N-2 of tetrazole),141.3 (biphenyl C-11), 140.6 (medoxomil C-4 or C-5 of ester group), 140.5 (medoxomil C-4 or C-5 atN-2 of tetrazole), 140.0 (biphenyl C-1), 135.7 (biphenyl C-4), 132.8 (medoxomil C-4 or C-5 of estergroup), 130.8 (biphenyl C-61), 130.7 (medoxomil C-4 or C-5 at N-2), 130.4 (biphenyl C-51), 129.6 (2C,biphenyl C-2 and C-6), 127.8 (biphenyl C-41), 125.5 (biphenyl C-21), 125.0 (2C, biphenyl C-3 and C-5),116.0 (imidazole C-5), 70.4 (-C(OH)(CH3)2), 54.0 (-CH2O-), 49.2 (imidazole >N-CH2-), 45.1 (tetrazole-CH2-NN-CH2-), 5.21(1H, s, -OH), 5.07 (2H, s, -CH2O-), 2.65 (2H, t, J = 7.2 Hz, -CH2CH2CH3), 2.17 (3H, s, medoxomil CH3-5at N-2 of tetrazole), 2.08 (3H, s, medoxomil CH3-5 of ester group), 1.63 (2H, m, -CH2CH2CH3), 1.48(6H, s, -C(OH)(CH3)2), 0.90 (3H, t, J = 7.2 Hz, -CH2CH2CH3).13C-NMR (DMSO-d6, 150 MHz) : 164.7 (tetrazole C-5), 160.7 (>C=O), 157.6 (imidazole C-4), 151.7(medoxomil >C=O of ester group), 151.5 (medoxomil >C=O at N-2 of tetrazole), 151.0 (imidazoleC-2), 140.9 (biphenyl C-11), 140.4 (medoxomil C-4 or C-5 of ester group), 140.4 (medoxomil C-4 or C-5 at N-2 of tetrazole), 139.0 (biphenyl C-1), 136.2 (biphenyl C-4), 132.8 (medoxomil C-4 or C-5 ofester group), 131.2 (medoxomil C-4 or C-5 at N-2 of tetrazole), 130.8 (biphenyl C-61), 130.5 (biphenylC-51), 130.3 (biphenyl C-31), 129.1 (2C, biphenyl C-2 and C-6), 127.8 (biphenyl C-41), 125.4 (biphenylC-21), 125.2 (2C, biphenyl C-3 and C-5), 116.1 (imidazole C-5), 69.6 (-C(OH)(CH3)2), 54.1 (-CH2O-), 48.0(imidazole >N-CH2-), 44.9 (tetrazole -CH2-NN-CH2-), 4.91 (2H, s, -CH2O-),4.67 (2H, s, tetrazole -CH2-NC=O), 160.6 (imidazole C-4), 154.6 (tetrazole C-5), 152.4(imidazole C-2), 151.7 (medoxomil >C=O of ester group), 151.0 (medoxomil >C=O at N-1 of tetrazole),141.0 (biphenyl C-11), 140.6 (medoxomil C-4 or C-5 of ester group), 140.0 (medoxomil C-4 or C-5 atN-1 of tetrazole), 137.7 (biphenyl C-1), 137.1 (biphenyl C-4), 132.8 (medoxomil C-4 or C-5 of estergroup), 132.2 (biphenyl C-51), 131.1 (biphenyl C-31), 130.6 (biphenyl C-61), 130.3 (medoxomil C-4 orC-5 at N-1 of tetrazole), 129.0 (2C, biphenyl C-2 and C-6), 128.4 (biphenyl C-41), 126.2 (2C, biphenylC-3 and C-5), 121.6 (biphenyl C-21), 115.9 (imidazole C-5), 70.4 (-C(OH)(CH3)2), 53.9 (-CH2O-), 48.9(imidazole >N-CH2-), 39.8 (tetrazole -CH2-NN-CH2-), 5.21 (1H, s, -OH), 5.19 (2H, s, tetrazole-CH2-NC=O), 157.6 (imidazole C-4), 154.0 (tetrazole C-5), 151.6(medoxomil >C=O of medoxomil ester), 151.2 (medoxomil >C=O at N-1 of tetrazole), 151.0 (imidazoleC-2), 141.1 (biphenyl C-11), 140.4 (medoxomil C-4 or C-5 of ester group), 139.7 (medoxomil C-4 or C-5 at N-1 of tetrazole), 137.2 (biphenyl C-1), 137.1 (biphenyl C-4), 132.8 (medoxomil C-4 or C-5of ester group), 131.8 (biphenyl C-51), 131.0 (2C, biphenyl C-31 and C-61), 130.7 (medoxomil C-4 orC-5 at N-1 of tetrazole), 128.5 (2C, biphenyl C-2 and C-6), 128.0 (biphenyl C-41), 125.6 (2C, biphenylC-3 and C-5), 121.6 (biphenyl C-21), 116.2 (...

Reference： [1]Molecules,2015,vol. 20,p. 21346 - 21363

52
2-(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-tetrahydro-1,6-naphthyridin-6 (5H)-yl)carbonyl)cyclobutyl)acetic acid [ No CAS ]
[ 80841-78-7 ]
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.5%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;	Example 38 (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl (cis-3-(( (5R)-5-((7- fluoro-l, l-dimethyl-2, 3-dihydro-1H-inden-5-yl) carbamoyl) -2- methoxy-7, 8-dihydro-l, 6-naphthyridin--6 (5H) - yl) carbonyl)cyclobutyl) acetate4-(Chloromethyl)-5-methyl-1,3-dioxol-2-one (77 pL, 0.71mmol) was added toa mixture of 2-(cis-3-(((5R)-5-((7-fluoro- 1, 1-dimethyl-2, 3-dihydro-1H-inden-5-yl) carbamoyl) -2-methoxy-7, 8-tetrahydro-1, 6-naphthyridin-6 (5H) -yl)carbonyl)cyclobutyl)acetic acid (300 mg, 0.59 mmol) andpotassium carbonate (98 nig, 0.71 nimol) in DMF (5 mL) at room temperature, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added water (60 rnL), and the mixturewas extracted with ethyl acetate (x 3) . The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50-*71% ethyl acetate/hexane) to give the title compound (258.0 mg, 0.415 mmol, 70.5%) as a colorless amorphous solid.?HNMR(300MHz,CDC13) :l.32(6H,s),l.89(2H,t,J=7.4Hz),2.11(2H,d,J=lO6Hz) , 2. 17 (3H, 5) ,2. 42-2 . 53 (4H,m) ,2. 62-2.77 (1H,m) ,2. 85 (2H,t, J=7. 4Hz) ,2. 91-3.03(2H,m),3.31(1H,quin,J=8.9Hz),3.61-3.72(1H,m) ,3.84(1H,dt) ,3.91(3H,s),4.82(2H,s) ,5.96(1H,s) ,6.64(1H,d,J=8.7Hz),7.05(1H,s),7l0(1H,d,J=11.7Hz),7.43(lH,d,J=8.7Hz),9.09 (1H, s)

Reference： [1]Patent: WO2016/2968,2016,A1 .Location in patent: Paragraph 0481

53
[ 331763-75-8 ]
[ 80841-78-7 ]
[ 1257446-42-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	Following intermediates are prepared using similar procedure as described for intermediate 4:

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - EP2640375, 2016, B1 Location in patent: Paragraph 0477

54
1-(2,4-difluorophenyl)-2-((3-fluorophenyl)sulfonyl)-N-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-amine [ No CAS ]
[ 80841-78-7 ]
4-(((1-(2,4-difluorophenyl)-2-((3-fluorophenyl)sulfonyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-4-yl)(methyl)amino)methyl)-5-methyl-1,3-dioxol-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%		The example 113 of 1-(2,4-difluorophenyl)-2-((3-fluorophenyl)sulfonyl)-N-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-amine (30mg, 0.07mmol) was dissolved in N,N-dimethylformamide solution (1ml) and added dropwise sodium carbonate (16mg, 0.15mmol). The reaction mixture was stirred at room temperature for 10 minutes, and then slowly added dropwise 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (16.5mg, 0.1mmol) . The reaction mixture was stirred at room temperature for 20 hours, then, water is introduced to the reaction mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 4: 1 (v/v)) to prepare a purified 8mg of the title compound (21% yield).

Reference： [1]Patent: CN105492423,2016,A .Location in patent: Paragraph 0736; 0737; 0738; 0739

55
2-((3-chlorophenyl)sulfonyl)-1-(2-fluorophenyl)-N-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-amine [ No CAS ]
[ 80841-78-7 ]
4-(((2-((3-chlorophenyl)sulfonyl)-1-(2-fluorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-4-yl)(methyl)amino)methyl)-5-methyl-1,3-dioxol-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33.6%		The examples 1 2-((3-chlorophenyl)sulfonyl)-1-(2-fluorophenyl)-N-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-amine (35mg, 0.09mmol) was dissolved in N,N-dimethylformamide solution (1ml) and added dropwise sodium carbonate (13.7mg, 0.13mmol). The reaction mixture was stirred for 10 minutes at room temperature and then slowly added dropwise 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (19mg, 0.13mmol). The reaction mixture was stirred at room temperature for 20 hours, then, water is introduced, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol: ethyl acetate = 1: 5 (v / v)) was purified to produce the title compound 15mg (yield 33.6%).

Reference： [1]Patent: CN105492423,2016,A .Location in patent: Paragraph 0753; 0754; 0755; 0756

56
[ 80841-78-7 ]
[ 144701-48-4 ]
4'-[[2-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)benzimidazole-1-yl]methyl]-2-biphenylcarboxylic acid(5-methyl-1,3-dioxol-2-one-4-yl)methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%		4'-[ [2-propyl-4-methyl -6 (1-methylbenzimidazole-2-yl)-benzimidazol-1-yl] methyl] - 2-biphenyl carboxylic acid-(5-methyl -1,3-dioxols-2-one-4-yl) methyl esterReagent and reaction conditions: Et3N, DMF, 60 CExperimental operation: in 50 ml by adding rotor single-port in the bottle, by adding 2.66g (0.026mol) triethylamine, 20mlN, N-dimethyl formamide, opening stirring, room temperature next adds by drops 3g (0.020mol) DMDOCl, add stirring after 20 min, solution turns into red-brown, DMDO quaternary ammonium salt solution obtained. The other 100 ml three-neck bottle, by adding rotor, a thermometer, constant pressure low fluid funnel, adding 7.8g (0.016mol) telmisartan, 30mlN, N-dimethyl formamide, opening stirring, add 2.1g (0.021mol) triethylamine, quaternary ammonium salt solution will be of constant pressure for gradually dropping funnel low fluid wherein after the add heat to the return line 60 C reaction 5h. Cooling to room temperature, add 150 ml methylene chloride, with 450 ml water extraction three times (150 ml × 3), takes organically, saturated salt water for extraction, anhydrous sodium sulfate for drying, reduced pressure distillation to remove the solvent. Residue post chromatographic separation, elution agent is ethyl acetate and petroleum ether, to obtain the target product white solid 7.7g, yield 81%.

Reference： [1]Patent: CN105384729,2016,A .Location in patent: Paragraph 0060; 0061; 0062; 0063; 0064; 0065

57
[ 879097-59-3 ]
[ 80841-78-7 ]
[ 144689-63-4 ]

Reference： [1]Patent: KR101526249,2015,B1

58
[ 80841-78-7 ]
[ 172875-59-1 ]
[ 144689-63-4 ]

Yield	Reaction Conditions	Operation in experiment
90%		45.3 g of compound VI and 5.0 g of sodium hydroxide powder were suspended in 500 ml of dimethylacetamide and stirred at a temperature of 10 C to 15 C for 8 hours to complete the reaction of compound VI.The reaction mixture was cooled to 0 C, 6.9 g of potassium carbonate was added and, with stirring, 9.4 g of 4-chloromethyl-5-methyl-2-oxo-1, 3-dimethylaminopyridine dissolved in 50 ml of dimethylacetamide (VII). After addition, the reaction mixture was slowly heated to 60 C to 65 C and incubated for 10 hours.After completion of the reaction, the reaction mixture was cooled to 5 C to 10 C, poured into 1000 ml of ice water, filtered and concentrated to give a pale yellow solid.The solid was treated with a 75% (v / v) aqueous acetic acid solution, the solution was cooled to remove the triphenylbenzyl alcohol, and the filtrate was concentrated. Toluene was added to remove excess water and acetic acid, and the residue was recrystallized from ethyl acetate to give pale yellow The crystal was further recrystallized from ethanol to obtain 25.4 g of olmesartan medoxomil (I) as a white crystal. The yield was 90% and the HPLC purity was 99.8%.

Reference： [1]Patent: CN105906614,2016,A .Location in patent: Paragraph 0045; 0046; 0047; 0048

59
[ 80841-78-7 ]
[ 80841-79-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium iodide; In acetonitrile; at 30℃; for 0.5h;	INTERMEDIATE 142: 4-(iodomethyl)-5- 3-dioxol-2-one A suspension containing 4-(chloromethyl)-5-methyl-1 ,3-dioxol-2-one (0.5 g, 3.37 mmol) and sodium iodide (0.908 g, 6.06 mmol) in MeCN (1.122 mL) was stirred at 30 C for ~ 30 min. MeOH (~1 mL) was added and the reaction was filtered and washed with DCM. Water was added and layers were separated. The organic layer was washed with a solution of Na2S203 (2%) and passed through a hydrophobic cartridge and concentrated to afford the title compound as a brown oil. (0.7 g, 87% yield). MS (m/z) 241 .0 (M+H)+
77%	With sodium iodide; In butanone; at 20 - 60℃; for 1.5h;	To a solution of 4-(chloromethyl)-5-methyl-1 ,3-dioxol-2-one (500 mg, 3.37 mmol) in butanone (10 mL) at RT was added sodium iodide (1 .51 g, 10.1 mmol) and the mixture was stirred at 60 C for 90 min. The reaction was filtered and concentrated. Silica gel column chromatography (EtOAc/heptane) provided 4-(iodomethyl)-5-methyl-1 ,3-dioxol-2-one (622 mg, 2.59 mmol) in 77% yield. MS m/z 241 .0 (MH+).

Reference： [1]Patent: WO2017/6296,2017,A1 .Location in patent: Page/Page column 209-210
[2]Patent: WO2019/166950,2019,A1 .Location in patent: Paragraph 00189

60
dibenzyl (3-ethoxy-5-(5-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)furan-2-yl)phenyl)phosphonate [ No CAS ]
[ 80841-78-7 ]
dibenzyl (3-ethoxy-5-(5-((((R)-2-((R)-1-(N-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)formamido)propyl)heptanamido)methyl)carbamoyl)furan-2-yl)phenyl)phosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium carbonate; sodium iodide; In tetrahydrofuran; at 20℃;	I NTERMEDIATE 20: dibenzyl (3-ethoxy-5-(5-((((R)-2-((R)-1 -(N-((5-methyl-2-oxo-1 ,3-dioxol- 4-yl)methoxy)formamido)propyl)heptanamido)methyl)carbamoyl)furan-2- yl)phenyl)phosphonate To a solution containing dibenzyl (3-ethoxy-5-(5-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)furan-2-yl)phenyl)phosphonate (1 17 mg, 0.159 mmol) in TH F (2 ml_) was added potassium carbonate (66.1 mg, 0.478 mmol) and 4-(chloromethyl)-5-methyl-1 ,3-dioxol-2-one (71.1 mg, 0.478 mmol), followed by addition of sodium iodide (1 1.95 mg, 0.080 mmol). The reaction was stirred at RT overnight. The reaction was concentrated. Purification on Si (0-100% EtOAc/Hexanes) afforded the title compound as an off white solid. (70 mg, 52 % yield). MS (m/z) 846.3 (M+H)+

Reference： [1]Patent: WO2017/6296,2017,A1 .Location in patent: Page/Page column 123

61
[ 1114761-92-0 ]
[ 80841-78-7 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
683.2 g	With potassium carbonate; In acetonitrile; for 2h;Reflux;	The reaction flask was charged with 697.5 g of compound V obtained in the previous step,414 g of anhydrous potassium carbonate (3.00 mol)163.4 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one (Compound VI) (1.10 mol)And 2500 ml of acetonitrile were refluxed for 2 hours,After the reaction,filter,The filtrate was concentrated to dryness,The residue was stirred in 1500 ml of ethyl acetate and 500 ml of water for 15 minutes,Layered, organic layer and then washed with water,Dried over anhydrous sodium sulfate,filter,The filtrate was concentrated to dryness,To give the crude product of compound VII,Recrystallization from toluene and petroleum ether,To obtain pure product 683.2 grams; two-step yield:85.40% (calculated as compound II).

Reference： [1]Patent: CN103304550,2016,B .Location in patent: Paragraph 0051-0052

62
2-(4-[(tert-butoxy)carbonyl](hydroxy)amino}-3-(4-methanesulfonylphenyl)-4-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)acetic acid [ No CAS ]
[ 80841-78-7 ]
(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl 2-(4-[(tert-butoxy)carbonyl][(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]amino}-3-(4-methanesulfonylphenyl)-4-methyl-5-oxo-4,5-dihydro-1Hpyrazol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 21.8333h;	To a solution of 2-(4- { [(tert-Butoxy)carbonylj (hydroxy)amino } -3 -(4-methanesulfonylphenyl)- 4-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)acetic acid (50 mg, 0.11 mmol) and potassium carbonate(17.22 mg, 0.12 mmol) in DMF (1 mL) was added 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (13.61 .il, 0.12 mmol) and the mixture was stirred at room temperature for 17 hours. <strong>[80841-78-7]4-(chloromethyl)-5- methyl-1,3-dioxol-2-one</strong> (13.61 .il, 0.12 mmol) was added and the reaction continued at room temperature for 170 minutes. Potassium carbonate (17.22 mg, 0.12 mmol) was added and the reaction stirred for an additional 2 hours. The reaction mixture was diluted with ethyl acetate (10 mL) andwashed with water (10 mL). The aqueous layer was re-extracted with ethyl acetate (3 x 10 mL), the organics were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (46 mg, 53 % yield). LC-MS tR = 1.17 mi [M+Naj = 688.

Reference： [1]Patent: WO2017/70081,2017,A1 .Location in patent: Page/Page column 210

63
[ 80841-78-7 ]
[ 148016-81-3 ]
(4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)amino]methyl]pyrrolidin-3-yl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41.3%	With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 45℃; for 4h;	monohydrationDonipenem 4.39 g (10 mmol)4-chloromethyl-5-ethyl-1,3-Dioxol-2-one2.97 g (20 mmol) and benzyltriethylammonium chloride (20 mmol) were added to 9 ml of DMF,4.4 ml (20 mmol) of diisopropylethylamine was added with stirring, reacted at 45 for 4 hours,TLC detection reaction is complete, cold to 5 degrees, add ethyl acetate 20ml, water 20ml,Stirring with 1M citric acid solution adjusted to pH4, liquid, the water phase with saturated potassium bicarbonate solution adjusted to pH 7.6, ethyl acetate extraction after washing, anhydrous magnesium sulfate drying, evaporated solvent,Residue Preparation Column Separation (Ethanol-Dichloromethane-Acetone, 1: 20: 40) evaporated to dryness to give a white amorphous foamy solid 2.20 g (41.3%)

Reference： [1]Patent: CN104496993,2017,B .Location in patent: Paragraph 0080; 0081; 0082

64
[ 524-38-9 ]
[ 80841-78-7 ]
2-[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]-2,3-dihydro-1H-isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%		To a suspension of NaH (287 mg, 7.18 mmol, 1.1 eq) inDMF (10 mL) was slowly added (over 5 min) a solution ofN-hydroxyphthalimide (1.21 g, 7.18 mmol, 1.1 eq) in DMF(10 mL) at 0 C under an argon atmosphere. After 5 minutes of stirring, a solution of 13 (1.00 g, 6.53 mmol) in DMF (5 mL) was added. The mixture was warmed up to rt and then heated at 70C for 1 h, during which time the dark red mixture turned middle beige and the starting material disappeared on TLC. Water (50 mL) was then added to the mixture and the resulting mixture was extracted with EtOAc (120 mLchi3). The combined organic extracts were washed with water (100 mLchi3) to remove DMF, dried over MgSCn, and concentrated. EtOAc (4 mL) was then added to the residual material and it was sonicated for 10 min. Hexanes (40 mL) was added and after a short sonication and filtration 1.64 g of 14 was obtained as an off-white solid (92 % yield, 5.98 mmol): iotaEta NMR (CDCl3) delta 2.14 (s, 3H), 4.95 (s, 2H), 7.76-7.81 (m, 2H), 7.83-7.88 (m, 2H). 13C NMR (CDCl3) delta 9.5, 66.7, 124.0, 128.7, 132.8, 135.0, 142.2, 151.9, 163.3. HRMS (ESI): [M+Na]+ m/z 298.03227 (calcd 298.03221 for C13H9O6NNa).

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 7799 - 7809
[2]Patent: WO2018/94334,2018,A1 .Location in patent: Page/Page column 49; 63; 65

65
4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid [ No CAS ]
[ 80841-78-7 ]
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;	General procedure: Standard procedure H for the alkylation of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid To a solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid in DMF was added K2CO3 and chloro-substituted derivative at room temperature. The reaction mixture was stirred for 18 h, and then DMF was removed under reduced pressure. The residue was purified by Isco Combi-Flash Companion column chromatography to give the desired products. In one of example, the desired compound was collected by vacuum filtered and washed with water and diethyl ether. Example 239 (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate Following standard procedure H, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (159 mg, 0.480 mmol), K2CO3 (133 mg, 0.960 mmol), 4-chloromethyl-5-methyl-1,3-dioxal-2-one (74.8 mg, 0.504 mmol), and DMF (1.0 mL) were used to carry out the reaction. The desird product was collected by filtered and washed with water and diethyl ether to give (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (145 mg, 68%) as a beige solid. 1H NMR (CDCl3, 400 MHz) delta 7.86 (br s, 1H), 7.75 (br s, 1H), 7.32-7.28 (m, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 5.03 (s, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.30-2.10 (br, 6H); LC-MS (ESI) m/z 466.2 [M+Na]+.

Reference： [1]Patent: US2017/253569,2017,A1 .Location in patent: Paragraph 0059; 0683-0684

66
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(4-chlorobenzamido)-2-methylpropanamido)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid [ No CAS ]
[ 80841-78-7 ]
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(4-chlorobenzamido)-2-methylpropanamido)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) 2,2-dimethylsuccinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.2%	With potassium carbonate; In N,N-dimethyl acetamide; at 50℃; for 2h;	To a stirred solution of 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(4-chlorobenzamido)-2-methylpropanamido)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (Example 3, 0.120 g, 0.151 mmol, 1.0 eq) in N,N-dimethyl acetamide (5 ml) was added potassium carbonate (0.083 g, 0.604 mmol, 4.0 eq) and 4- (chloromethyl)-5-methyl-l,3-dioxol-2-one (0.067 g, 0.453 mmol, 3.0 eq). The reaction mixture was heated to 50 C for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (15 mL) and stirred at room temperature for about 30 minutes. The precipitates formed were collected by filtration, washed with water (30 mL) and dried under vacuum. The obtained solid was purified by silicagel column chromatography by using 70-80% ethyl acetate in hexane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure. The obtained solid was further purified by recrystallization over ethyl acetate (1 mL) and hexane (10 mL) gave the title compound (0.04 g, yield: 29.2%) as an off-white solid. 1H NMR (300 MHz, CDC13): delta ppm 7.72 (d, = 8.4 Hz, 2H), 7.41 (d, = 8.4 Hz, 2H), 7.08 (s, 1H), 6.84 (s, 1H), 4.87, 4.82 (ABq, JAB = 14.1 Hz, 2H), 4.45 (dd, = 10.5, 6.3 Hz, 1H), 3.21-3.12 (m, 1H), 2.85-2.76 (m, 1H), 2.70-2.58 (m, 3H), 2.44 (s, 3H), 2.37-2.25 (m, 2H), 2.10-1.0 (m, 28H), 1.69 (s, 3H), 1.67 (s, 3H), 1.03 (s, 3H), 0.93 (s, 3H), 0.88-0.76 (m, 10H); ESI-MS: m/z 905.48 (M+H)+.

Reference： [1]Patent: WO2018/65930,2018,A1 .Location in patent: Page/Page column 33-34

67
[ 80841-78-7 ]
[ 80370-57-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium carbonate; sodium iodide / methanol; ethyl acetate / 1.5 h / 35 - 40 °C / Sonication 2.1: pyrographite / isopropyl alcohol / 0.5 h 2.2: 2 h

Reference： [1]Current Patent Assignee: JINING CHEMICAL INDUSTRY RES INSTITUTE; JINING HONGAN CHEMICAL - CN108440570, 2018, A

68
[ 80841-78-7 ]
[ 80370-57-6 ]
[ 2244865-85-6 ]

Yield	Reaction Conditions	Operation in experiment
18.2 g	With potassium carbonate; sodium iodide In methanol; ethyl acetate at 35 - 40℃; for 1.5h; Sonication;	5 Weigh 21 g (0.04 mom ceftiofur (made in 20170816), add to a 500 mL three-necked flask, add 40 mL of methanol,Then, 5.5 g (0.04 mol) of potassium carbonate was added and stirred to dissolve, 50 g of D201 resin was added, and the mixture was heated to 40 ° C.40 ml of ethyl acetate was added, and 10.5 g (0.06 mol) of DMDO-Cl and 2.0 g of sodium iodide were added, and ultrasonication was carried out at 35 ° C for 90 min.After filtration, the filter cake was washed with ethyl acetate, and the filtrate was rotary evaporated to 30 mL at 40 ° C, diluted with 50 ml of isopropanol, and 150 mL of isopropyl ether was added dropwise.The dropping time is not less than 30 min, the crystal is raised at room temperature for 1 h, filtered, and dried under vacuum at 40 ° C for 8 h to obtain 18.2 g of a white powder with a purity of 97%.

Reference： [1]Current Patent Assignee: JINING CHEMICAL INDUSTRY RES INSTITUTE; JINING HONGAN CHEMICAL - CN108440570, 2018, A Location in patent: Paragraph 0047; 0048

69
C₉H₁₄N₅O₃P [ No CAS ]
[ 80841-78-7 ]
C₁₉H₂₂N₅O₁₀P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.4%		5 (45.0 g, 0.16 mol) in Example 1 and triethylamine (63·8 g, 0.63mol) are added into DMF (200 ml), stir at room temperature for 0.5 h and then add 6 (98·0 g, 0.66 mol) and carry on reaction with KI (25·0g, 0.15mol) at 60 C for 12 h, cool at room temperature, add ethyl acetate (200ml), stir for 1h, suction filtered, the filtrate was washed with a saturated sodium chloride solution (100mlchi2), drying with anhydrous magnesium sulfate and then filtering. Filtrate concentrated under reduced pressure, into residue add petroleum ether (150 ml), and stir at 4 C for 12 h, suction filtration, dry and obtained a white solid 7 (48.4 g, 60.4%).

Reference： [1]Patent: CN108586534,2018,A .Location in patent: Paragraph 0012; 0014; 0018

70
[ 761404-85-7 ]
[ 80841-78-7 ]
[ 144689-63-4 ]

Reference： [1]Patent: EP2334668,2011,A1

71
[ 80841-78-7 ]
[ 147403-52-9 ]
C₃₁H₂₆N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.5%		In a 250 ml round bottom flask, 5 g of <strong>[147403-52-9]<strong>[147403-52-9]azilsartan</strong> methyl ester</strong> intermediate A4, potassium carbonate 2.2 g, potassium iodide 0.15 g, DMSO 70 mL, cooled to -10 to 0 ° C and stirred for 1 hour. A solution of 1.9 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one in 30 mL of DMSO was added dropwise to the above reaction system. After the addition is completed, the reaction is allowed to rise to room temperature for 2 to 4 hours. After the reaction was completed, 200 mL of water was added, and the pH was adjusted to 2 to 3 with dilute hydrochloric acid, and filtered, and the residue was washed three times with water and then dried. The crude product was purified by silica gel column chromatography. The eluent was dichloromethane-methanol (DCM: MeOH = 50:1). The product was obtained in an amount of 4.8 g, a yield of 77.5percent, and a purity of 96.2percent.

Reference： [1]Patent: CN108822097,2018,A .Location in patent: Paragraph 0102-0116; 0119; 0120

72
[ 80841-78-7 ]
[ 147403-03-0 ]
C₃₅H₂₈N₄O₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.9%	With sodium carbonate; sodium iodide; In N,N-dimethyl acetamide; at 35℃; for 3h;	10 g of <strong>[147403-03-0]azilsartan</strong>, 6.5 g of 4-chloromethyl-5-methyl-1,3-dioxole-2-one, 3.5 g of sodium carbonate, 0.5 g of sodium iodide and 45 g of N,N-dimethylacetamide were added to the reaction flask. Reacted at 35 C for 3 h.After completion of the reaction, the mixture was filtered, and 50 g of dichloromethane and 50 g of purified water were added to the filtrate. After separation, the aqueous layer was extracted with 20 g of dichloromethane, and the methylene chloride layer was combined, washed once with brine, and concentrated under reduced pressure. 30 g of methanol, stirred at 30 C for 5 h, filtered to give an impurity crude product.The crude product was added with 30 g of methanol, stirred and heated, filtered, cooled and crystallized, filtered, and dried to obtain 12.8 g of <strong>[147403-03-0]azilsartan</strong> ester impurity fine product, the total yield was 85.9%, and the liquid phase purity was 98.5%.

Reference： [1]Patent: CN108774222,2018,A .Location in patent: Paragraph 0021-0026; 0029-0053

73
[ 80841-78-7 ]
[ 19171-19-8 ]
C₁₈H₁₅N₃O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
290 mg		S.M.B (2.5 g, 9.15 mmol, 1.00 eq), DMF 65 mL, was added to a 250 ml three-necked reaction flask under nitrogen.The temperature of the reaction system was cooled to below -20 C, LiHMDS (9.15 ml, 9.15 mmol, 1.00 eq) was added dropwise, and stirring was continued for 10 minutes at low temperature.Subsequently, S.M.8 (2.72 g, 11.89 mmol, 2.00 eq) in DMF was added.The reaction was carried out in an ice bath.The reaction was stopped and the reaction system was poured into 1% NH4Cl (300 mL) ice water.The precipitated solid was stirred, filtered, and the filtered cake was evaporatedEtOAc.(PE: EtOAc = 2:1) gave 290 mg of product.

Reference： [1]Patent: TW2019/12636,2019,A .Location in patent: Paragraph 0090-0095

74
[ 80841-78-7 ]
[ 31431-39-7 ]
methyl (5-benzoyl-1H-benzo[d]imidazol-2-yl)((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%		A suspension of MBZ (590 mg, 2.0 mmol) and t-BuOK (247 mg, 2.2 mmol) in anhydrous DMSO (10 mL) was sonicated until complete dissolution and then the solution was stirred 15 min at RT. 4-(Chloromethyl)-5-methyl-l,3-dioxol-2-one (4.0 mmol, 594 mg) , the solution was stirred lh at RT and the solvent was then evaporated (60 C). The residue was chromatographed on a silica gel column in 40% acetone/hexanes. The predominant product was purified again in the same way giving 186 mg of solid (23% yield).3H NMR (500 MHz, DMSO-de): d 2.21 (s, 3H), 3.91 (s, 3H), 5.13 (bs, 2H), 7.54 -7.58 (m, 2H), 7.61 - 7.63 (m, 2H), 7.66 (m, 1H), 7.71 - 7.74 (m, 2H), 7.79 - 7.97 (bm, 1H), 12.33 and 12.43 (2 x bs, 1H).13C NMR (126 MHz, DMSO-de): d 9.27, 54.48, 111.62, 114.74, 117.13, 119.92, 124.00, 128.57, 129.55, 132.12, 133.95, 138.46, 139.14, 150.14, 152.27, 153.53, 195.73MS (ESI) m/z (%): 408 (29, [M+H]+), 430 (100, [M+Na]+), 837 (20, [2M+Na]+) HRMS (ESI): [M+H] (C2iHi806N3) calc. 408.11901, found 408.11922.

Reference： [1]Patent: WO2019/157338,2019,A1 .Location in patent: Page/Page column 62; 77

75
5-((4'-isopropyl-[1,1'-biphenyl]-4-yl)oxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid [ No CAS ]
[ 80841-78-7 ]
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 5-((4'-isopropyl-[1,1'-biphenyl]-4-yl)oxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.9%		To a stirred solution of 5-((4'-isopropyl-[l,r-biphenyl]-4-yl)oxy)-l-(4-methoxybenzyl)-lH-l,2,3-triazole-4- carboxylic acid 23 (100 mg, 0.225 mmol), prepared as described in Example 125, in acetone (5mL) in sealed tube was added potassium carbonate (93.5 mg, 676 pmol) and stirred for 30 min at rt. To the previous mixture was added 4-chloromethyl-5-methyl-l,3 dioxol-2- one (36.8 mg, 0.676 mmol). After a period of 16 hrs at 60 C, the reaction mixture was filtered, concentrated and purified on combiflash using 25 g silica gel column and eluting with 0-100% hexane/ethylacetate to afford the title compound 37 (50 mg). 47.9% yield. 'H NMR (400 MHz, Acetone-de) d 7.60 - 7.50 (m, 4H), 7.34 (m, 2H), 7.28 (m, 2H), 6.99-6.91 (m, 2H), 6.85 (m, 2h), 5.54 (s, 2H), 4.95 (s, 2H), 3.73 (s, 3H), 3.04-2.90 (m,lH), 2.01 (s, 3H), 1.26 (t, J = 6.1 Hz, 6H).

Reference： [1]Patent: WO2020/10309,2020,A1 .Location in patent: Paragraph 0265

76
[ 7338-27-4 ]
[ 80841-78-7 ]
4-methyl 1-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-methylenesuccinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 4-methoxy-2-methylene-4-oxobutanoic acid With potassium carbonate; sodium iodide In acetonitrile at 40℃; for 0.166667h; Inert atmosphere; Stage #2: 4-chloromethyl-5-methyl-1,3-dioxol-2-one In acetonitrile at 40℃; for 48h; Inert atmosphere;	5 4-Methyl l-((5-methy1-2-oxo- l,3-dioxo1-4-yl)methyl 2-methylenesuccinate (L TP 1025) β-Methyl itaconate (200 mg, 1.39 mmol) was dissolved in anhydrous MeCN (5 mL), K2CO3(384 mg, 2.78 mmol, 2 equiv.) and Nal (416 mg, 2.78 mmol, 2 equiv.) were added and the resulting mixture was heated to 40 °C for 10 minutes under inert. Finally (4-chloromethyl)-5-methy1-l,3-dioxo1-2-one (412 mg, 303 μL. 2.78 mmol, 2 equiv.) was added and the mixture was heated to 40 °C for 48h. MeCN was evaporated, EtOAc (50 mL) was added and the organic phase was washed with 10 % Na2S205 (50 mL), distilled H2O (50 mL) and sat. NaCl (2x50 mL). The organic phase was dried over MgSO4, volatiles were evaporated and the residue was subjected to flash column chromatography (Silicagel 60 mesh 70-230, solvent: cyclohexane/EtOAc, 2: 1) to afford 320 mg (90%) of compound LTP1025 as a light yellow oil. NMR (401 MHz, CDC13): 5H 2.15 (s, 3H), 3.31 (s, 2H), 3.65 (s, 3H), 4.89 (s, 2H), 5.75 (s, 1H), 6.33 (s, 1H).13C NMR (101 MHZ, CDC13): δc 9.36, 37.36, 52.12, 54.28, 129.98, 132.99, 133.36, 140.30, 152.11, 165.51, 170.91. ESI MS: 279.1 ([M + Na]+).HRMS (ESI): Calcd. for C11H12O7Na 279.04752. Found: 279.04757.

Reference： [1]Current Patent Assignee: THE JOHNS HOPKINS UNIVERSITY; CZECH ACADEMY OF SCIENCES - WO2021/87082, 2021, A1 Location in patent: Page/Page column 47; 52-53

77
[ 80841-78-7 ]
[ 594839-88-0 ]
[ 2564746-82-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.0833333h; Stage #2: 4-chloromethyl-5-methyl-1,3-dioxol-2-one In water; N,N-dimethyl-formamide	24 Compound 24: (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-(3,5- dichlorophenyl)benzo[d] oxazole-6-carboxylate A mixture of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (100 mg, 324 miho, 1 eq) and K2CO3 (112 mg, 811 miho, 2.5 eq) in DMF (4 mL) was stirred at 25 °C for 5 min, then 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one (62.67 mg, 421 mhio. 1.3 eq) was added. The mixture was added to H2O (20 mL), yellow solid was formed. The solid was collected and purified by column chromatography (S1O2, petroleum ether/EtOAc = 10/1 to 5/1) to give the title compound (32.78 mg, 73.8 pmol, 22.7% yield, 94.6% purity) as a white solid. LC-MS: m/z [M]+; calcd Mass for {Ci9HiiCl2N06}+ 420.01, observed 420.2 [M+H]+. NMR (400 MHz, CDCb) d = 8.30 (d, J = 1.0 Hz, 1H), 8.17 (d, J = 2.0 Hz, 2H), 8.13 (dd, J = 1.6, 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 2.0 Hz, 1H), 5.14 (s, 2H), 2.27 (s, 3H).

Reference： [1]Current Patent Assignee: PROTEGO BIOPHARMA INC - WO2021/154842, 2021, A1 Location in patent: Paragraph 0419-0422

78
[ 552292-08-7 ]
[ 80841-78-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
40.8%	Stage #1: Rolapitant With potassium carbonate In propan-2-one at 20℃; for 0.5h; Stage #2: 4-(chloromethyl)-5-methyl-2H-1,3-dioxol-2-one In propan-2-one at 20℃; for 18h;	3 Example 3: 2 ml of acetone and 100 mg compound 1 were added into a 25 ml flask and stirred. Potassium carbonate (42 mg, 0.3 mmol, 1.5 eq) was added in batches and the mixture was stirred at room temperature for half an hour. 36 mg compound 2 was added to the reaction flask. The reaction mixture was stirred at room temperature for about 18 hours until completion of the reaction, and purified by column chromatography to give 50 mg 3 (yield 40.8%). 1H-NMR (400 MHz, CDCl3): δ=7.79 (s, 1H), 7.72 (s, 2H), 7.42-7.40 (d, J=8Hz, 2H), 7.31-7.27 (m, 2H), 7.27-7.21 (m, 1H), 5.58 (s, 1H), 4.55-4.53 (m, 1H), 4.06-3.99 (m, 2H), 3.69-3.67 (d, J=8Hz, 1H), 3.53-3.49 (d, J=16Hz,1H), 3.25-3.21 (d, J=16Hz, 1H), 2.77-2.74(d, J=12Hz, 1H), 2.59-2.57(d, J=8Hz, 1H), 2.34-2.31 (m, 3H), 1.97-1.71 (m, 7H), 1.46-1.45 (d, J=4Hz, 3H).
40.8%	Stage #1: Rolapitant With potassium carbonate In propan-2-one at 20℃; for 0.5h; Stage #2: 4-(chloromethyl)-5-methyl-2H-1,3-dioxol-2-one In propan-2-one at 20℃; for 18h;	3 Example 3: 2 ml of acetone and 100 mg compound 1 were added into a 25 ml flask and stirred. Potassium carbonate (42 mg, 0.3 mmol, 1.5 eq) was added in batches and the mixture was stirred at room temperature for half an hour. 36 mg compound 2 was added to the reaction flask. The reaction mixture was stirred at room temperature for about 18 hours until completion of the reaction, and purified by column chromatography to give 50 mg 3 (yield 40.8%). 1H-NMR (400 MHz, CDCl3): δ=7.79 (s, 1H), 7.72 (s, 2H), 7.42-7.40 (d, J=8Hz, 2H), 7.31-7.27 (m, 2H), 7.27-7.21 (m, 1H), 5.58 (s, 1H), 4.55-4.53 (m, 1H), 4.06-3.99 (m, 2H), 3.69-3.67 (d, J=8Hz, 1H), 3.53-3.49 (d, J=16Hz,1H), 3.25-3.21 (d, J=16Hz, 1H), 2.77-2.74(d, J=12Hz, 1H), 2.59-2.57(d, J=8Hz, 1H), 2.34-2.31 (m, 3H), 1.97-1.71 (m, 7H), 1.46-1.45 (d, J=4Hz, 3H).

Reference： [1]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - EP3991730, 2022, A1 Location in patent: Paragraph 0101-0103
[2]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - EP3991730, 2022, A1 Location in patent: Paragraph 0101-0103

79
[ 74103-06-3 ]
[ 80841-78-7 ]
[ 2767571-63-9 ]

Yield	Reaction Conditions	Operation in experiment
90.4%	With anhydrous sodium carbonate In N,N-dimethyl-formamide at 20℃; Cooling with ice;	1; 3 The synthesis of embodiment 1 compound N23 At room temperature, weigh ketorolac (5.0 g, 19.6 mmol), add DMF (10 mL) and stir to dissolve, then add 4-chloromethyl-5-methyl-1,3-dioxol-2- ketone (2.91 g, 19.6 mmol), then the reaction flask was moved to an ice bath and stirred, and sodium carbonate (1.46 g, 15.7 mmol) was added to the reaction flask in 5 batches, and the addition was completed. The reaction was moved to room temperature and stirred overnight. After TLC detected the completion of the reaction, 100 mL of ethyl acetate and 70 mL of water were added to the reaction flask, shaken to separate the liquid, and the organic layer was washed with 5% sodium thiosulfate (30 mL), washed with water (30 mL), and dried over anhydrous sodium sulfate. , concentrated, sand making, white solid 6.5g was obtained by flash column chromatography, the yield was 90.4%.

Reference： [1]Current Patent Assignee: NANJING HAIHU MEDICINE SCIENCE AND TECH - CN114380834, 2022, A Location in patent: Paragraph 0038-0042; 0048-0049

80
[ 290297-26-6 ]
[ 80841-78-7 ]
[ 2579686-08-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	In dichloromethane	10 Example 10: Compound netupitant (0.4 mmol, 230 mg) was dissolved in dichloromethane (10 mL), compound 10-1 (1.2 mmol, 178 mg) was added, stirred overnight, filtered, and the filter cake was washed with dichloromethane. Vacuum drying gave 150 mg of compound 10 in 50% yield.

Reference： [1]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - CN112174881, 2022, B Location in patent: Paragraph 0256-0261

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P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 80841-78-7 ] {[proInfo.proName]}

Quality Control of [ 80841-78-7 ]

Related Doc. of [ 80841-78-7 ]

Product Details of [ 80841-78-7 ]

Calculated chemistry of [ 80841-78-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 80841-78-7 ]

Application In Synthesis of [ 80841-78-7 ]

[ 80841-78-7 ] Synthesis Path-Upstream 1~11

[ 80841-78-7 ] Synthesis Path-Downstream 1~80

Related Functional Groups of [ 80841-78-7 ]

Chlorides

Esters

Related Parent Nucleus of [ 80841-78-7 ]

Aliphatic Heterocycles

Dioxoles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 80841-78-7 ]

Related Parent Nucleus of
[ 80841-78-7 ]