[ CAS No. 80715-22-6 ] {[proInfo.proName]}

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Quality Control of [ 80715-22-6 ]

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Product Details of [ 80715-22-6 ]

CAS No. :	80715-22-6	MDL No. :	MFCD07787463
Formula :	C₅H₅BrO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GWFALVUXAGYMHR-UHFFFAOYSA-N
M.W :	193.00	Pubchem ID :	10774141
Synonyms :

Safety of [ 80715-22-6 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P210-P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P330-P332+P313-P362-P370+P378-P403+P233-P403+P235-P405-P501	UN#:	3265
Hazard Statements:	H302-H315-H318-H335-H227	Packing Group:	Ⅲ
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Application In Synthesis of [ 80715-22-6 ]

* 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 [ 80715-22-6 ]
Downstream synthetic route of [ 80715-22-6 ]

[ 80715-22-6 ] Synthesis Path-Upstream 1~7

1
[ 80715-22-6 ]
[ 91526-18-0 ]

Reference： [1] Patent: US5416208, 1995, A,

2
[ 80715-22-6 ]
[ 91526-18-0 ]

Reference： [1] Synthetic Communications, 1995, vol. 25, # 23, p. 3875 - 3881
[2] Synthetic Communications, 1992, vol. 22, # 9, p. 1277 - 1282

3
[ 80715-22-6 ]
[ 112984-60-8 ]
[ 123447-62-1 ]

Yield	Reaction Conditions	Operation in experiment
95.4%	With potassium hydrogencarbonate In N,N-dimethyl-formamide at 0℃; for 5 h; Large scale	the reaction vessel in step (3) obtained in prulifloxacin crude acetonitrile and 358L stirred heated to reflux to dissolve transparent, coolish, adding 0. 05kg charcoal, keep stirring under reflux for 30 minutes, filtered hot and the filtrate was natural cooled to room temperature and crystallization, through chilled water cooling crystallization overnight, centrifugation, washing the filter cake with a small amount of acetonitrile frozen crystal, drying, 80 ° C and dried under vacuum to dryness to give prulifloxacin finished 8. 73kg, yield (mole ) 92.4percent, purity 99.5percent 7. 0kg adding the compound of formula (III) in a reaction vessel, 2. 31kg potassium bicarbonate and 42L N, N- dimethylformamide, cooling down to 4 ° C, was added dropwise at a concentration of 0. 6kg / L of formula ( V) DMF solution of compound 12. 3L, controlling the internal temperature 4 ° C, dropwise Bi, 4 ° C with stirring, and the reaction time was 5.5 hours, the reaction solution was poured into ice water with stirring, and stirred for 0.5 hours, the crystals were collected by filtration, the filter cake washed with water until neutral, drained, 60~70 ° C hot air circulation drying, a compound of formula (I) prulifloxacin crude 9. 34kg, yield (moles) 96.8 percent, purity 92.6percent; (4) was added to the reaction vessel in step (3) obtained in prulifloxacin crude acetonitrile and 358L stirred heated to reflux to dissolve transparent, coolish, adding 0. 05kg activated carbon, insulation was stirred at reflux for 30 minutes, filtered hot and the filtrate cooled to room temperature crystallization, crystallization through the chilled water cooling overnight, centrifugation, washing the filter cake with a small amount of acetonitrile frozen crystal, drying, 80 ° C under vacuum to dryness to give Cape Lu Lisha star finished 8. 94kg, yield (mol) of 95.4percent, a purity of 99.7percent

Reference： [1] Patent: CN103113392, 2016, B, . Location in patent: Paragraph 0044; 0058; 0059; 0060
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738
[3] Patent: WO2008/59512, 2008, A1, . Location in patent: Page/Page column 8
[4] Patent: WO2008/111016, 2008, A1, . Location in patent: Page/Page column 5
[5] Patent: WO2012/1357, 2012, A1, . Location in patent: Page/Page column 22-23

4
[ 80715-22-6 ]
[ 112984-60-8 ]
[ 123447-62-1 ]
[ 156834-57-0 ]

Reference： [1] Bulletin of the Chemical Society of Japan, 1994, vol. 67, # 5, p. 1419 - 1426

5
[ 80715-22-6 ]
[ 112984-60-8 ]
[ 123447-62-1 ]

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

6
[ 80715-22-6 ]
[ 144689-93-0 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	Stage #1: With tert-butylamine hydrobromide; potassium carbonate In acetone at 0 - 55℃; for 32 h; Stage #2: With potassium carbonate; potassium iodide In acetone at 20 - 55℃; for 3 h;	Ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate (100 gm) was dissolved in acetone (2500 ml) and then added potassium carbonate (100 gm), 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-(triphenylmethyl)-1H-tetrazole (250 gm) and tert-butyl ammonium bromide (15 gm) under stirring at room temperature. The temperature of the reaction mass was raised to 50 to 55° C. and maintained for 15 hours at 50 to 55° C. The reaction mass was cooled to 45° C. and passed over celite bed. The collected filtrate was cooled to 0 to 5° C. and then added a solution of potassium carbonate (36 gm) in water (36 ml) for 1 hour. The temperature of the reaction mass was raised to room temperature and maintained for 16 hours at room temperature. The acetone was distilled off completely under vacuum at below 40° C. to obtain residue. To the residue was added sodium chloride solution (10percent, 900 ml) and then added ethyl acetate (1500 ml). The layers were separated and the aqueous layer was extracted. Combined the both organic layers and dried over sodium sulfate. The solvent was distilled off completely to obtain a residual mass. A mixture of acetone (1200 ml), potassium carbonate (100 gm), (4-bromoethyl)-5-methyl-oxo-1,3-dioxane (105 gm) and potassium iodide (17 gm) were added under stirring at room temperature and then the contents were heated to 50 to 55° C. The solution was added to the above residual mass for 1 hour 30 minutes and maintained for 1 hour 30 minutes at 50 to 55° C. The reaction mass was cooled to 45° C. and filtered. The solvent was distilled off completely to obtain residue. Toluene (1500 ml) was added to the residue and the layers were separated. The toluene layer was dried over sodium sulfate and distilled off the layer under vacuum up to obtain clear residual mass. To the residual mass was added methanol (1500 ml) and stirred for 30 minutes at room temperature. The reaction mass was cooled to 10 to 15° C. and maintained for 1 hour 30 minutes. The separated solid was filtered and dried at 40 to 45° C. for 7 hours to obtain 270 gm of trityl olmesartan medoxomil. Trityl olmesartan medoxomil: 98.5percent; Trityl olmesartan ethyl ester impurity: 0.35percent; Bromo trityl olmesartan medoxomil impurity: 0.35percent; Methyl trityl olmesartan medoxomil impurity: 0.34percent.

Reference： [1] Patent: US2013/190506, 2013, A1, . Location in patent: Paragraph 0050

7
[ 936114-12-4 ]
[ 80715-22-6 ]
[ 144690-92-6 ]

Reference： [1] Patent: WO2012/1694, 2012, A1, . Location in patent: Page/Page column 9-10

[ 80715-22-6 ] Synthesis Path-Downstream 1~26

1
[ 37830-90-3 ]
[ 80715-22-6 ]

Yield	Reaction Conditions	Operation in experiment
93.8%	With N-Bromosuccinimide; In chloroform;Reflux; Large scale;	5. 0kg adding the compound of formula (IV) in a reaction vessel, 8. 0kg N- bromosuccinimide (NBS), 0. 30kg of azobisisobutyronitrile was added as the reaction solvent chloroform 100L, stirring was warmed to 38 ° C, the reaction system to be stable, then slowly heated to reflux for 2-3 hours, the reaction was completed, cooled to room temperature, insolubles were removed by filtration, the filtrate was atmospheric recovery chloroform, 4 ° C refrigerated overnight and filtered again after crystallization the insoluble matter was removed, and then distilled under reduced pressure collecting ll ° C~120 ° C / 5mmHg fractions, the compound of formula (V) 8. 66kg, yield (mole) 938percent, purity 95.1percent.;
92%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 77℃; for 6h;	Step III: 4-Bromomethyl-5-methyl~l,3-dioxol~2-one; A mixture of 4,5-dimethyl-l,3-dioxol-2-one (1.5 g, 0.013158 mol), NBS (2.34 g, 0.013158 mol) and benzoyl peroxide (0.089 g, 0.0003684 mol) in CCl4 (20 mL) was stirred at 77°C for 6 hrs (TLC monitoring: cyclohexane/AcOEt 6:4). The solution was treated with an aqueous solution OfNaHCO3 and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give 4-bromomethyl-5 -methyl- 1,3- dioxol-2-one (2.34 g). Yield: 92percent.1H-NMR (400 MHz, CDCl3, delta): 2.13 (s, 3H, CH3), 4.18 (s, 2H, CH2Br).
73%	With N-Bromosuccinimide;azobisisobutyronitrile; In tetrachloromethane;	(1) Synthesis of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one[the compound of formula (III) in which X is a bromine atom]: 3.42 g of 4,5-dimethyl-1,3-dioxolen-2-one (synthesised in accordance with Tetrahedron Letters, (1972), pages 1701-1704) was dissolved in 150 ml of carbon tetrachloride, and 5.34 g of N-bromosuccinimide and a catalytic amount of alpha,alpha'-azobisisobutyronitrile were added. The mixture was heated under reflux for 15 minutes. The reaction mixture was concentrated to half of its volume and the resulting insoluble matter was removed by filtration. Concentrating the filtrate gave a syrupy residue. The residue was distilled under reduced pressure to give a fraction boiling at 115° to 120° C./5 mm Hg which was 4.2 g (yield 73percent) of the captioned compound.

58%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 78℃; for 0.333333h;Darkness;	Example 12: (5-Methyl-2-oxo-l,3-dioxol-4-yl)methyl 4-[(4-methoxyphenyl)amino]-6- (methylcarbamoy^quinoline-S-carboxylate. a) Preparation of the intermed 4-bromomethyl-5-methyl-2-oxo-l,3-dioxolene; To a solution of 4,5-dimethyl-l,3-dioxol-2-one (342 mg, 3.0 mmol) in carbon tetrachloride (10 mL) was added azobisisobutyronitrile (AIBN, 9.8 mg, 0.06 mmol) and iV-bromosuccinimide NBS (580 mg, 3.3 mmol). The reaction mixture was heated in the dark in a stem block at 78 C for 20 minutes. The mixture was cooled and evaporated almost into dryness. The mixture was filtered and the residue was evaporated to give a light yellow solid, which contained 20 percent starting material Yield: 450 mg (58percent). The mixture was used in the next step without further purifi- cation.
49%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2.5h;Heating / reflux;	To a solution of 4,5-dimethyl-1,3-dioxolene-2-one (TCI, 10 g, 88 mmol) and N- bromosuccinimide (Fluka, 15.69 g, 88 mmol) in carbon tetrachloride (250 mL) was added benzoyl peroxide (Acros, 500 mg, 2.1 mmol). The reaction mixture was then refluxed for 2.5 h after which time the volatiles were evaporated under vacuum. The resulting residue was triturated with some carbon tetrachloride, filtered and the solid cake was washed with carbon tetrachloride. The filtrate volatiles were removed under vacuum and the yellow oily residue was distilled under vacuum (2-5 torr) to give 4-bromomethyl-5-methyl-1,3-dioxolene-2-one 903 (8.35 g, b.p. 94-98 °C, 49percent) as a pale yellow oil. 1H NMR (CDCI3) 8 4.21 (s, 2H), 2.17 (s, 3H).
	With N-Bromosuccinimide; azobisisobutyronitrile; In tetrachloromethane;	PREPARATION 18 4-Carbo-(5-methyl-2-oxo-1,3-dioxol-4-ylmethoxy)methylpiperazine hydrochloric acid salt Combine <strong>[37830-90-3]4,5-dimethyl-1,3-dioxol-2-one</strong> (3.42 g, 30 mmol), N-bromosuccinimide (5.34 g, 30 mmol) and AIBN (500 mg, 3 mmol) in anhydrous carbon tetrachloride (100 mL). Heat at reflux. After 2 hours, cool and filter. Concentrate the filtrate to give 4-bromomethyl-5-methyl-1,3-dioxol-2-one (6.5 g, crude) as an oil, which can be used for the next step without further purification.
	With N-Bromosuccinimide;azobisisobutyronitrile; In tetrachloromethane;	PREPARATION 2 Preparation of 4-bromomethyl-5-methyl-1,3-dioxole-2-one According to the method described in Liebigs. Ann. Chem., 1977, 27-32 4,5-dimethyl-1,3-dioxole-2-one (500 mg, 4.38 mmol) and N-bromosuccinimide (0.78 g, 4.38 mmol) were heated under reflux in dry carbon tetrachloride in the presence of alpha-alpha'-azobisisobutyronitrile (7.5 mg) for 20 minutes. The reaction mixture was concentrated under reduced pressure to half the volume, and the precipitated solid was filtered by suction. After removing the solvent from the filtrate, the residue was analyzed by gas chromatography. The obtained mixture (792 mg), contained 70percent of the desired title compound and used for the subsequent reactions.
	With N-Bromosuccinimide; In tetrachloromethane;	PREPARATION 1 4-Bromomethyl-5-methyl-2-oxo-1,3-dioxole To a stirred solution of 3.0 g of <strong>[37830-90-3]4,5-dimethyl-2-oxo-1,3-dioxole</strong> in 100 ml of carbon tetrachloride was added 4.63 g of N-bromosuccinimide. The resulting solution was heated under reflux and irradiated for 15 minutes. The reaction mixture was cooled to 0°-5° C., filtered and evaporated to give the title product. The NMR spectrum (CDCl3) showed absorptions at 2.05 (5percent of starting material), 2.18 (3H, s), 4.30 (2H, s) and 4.35 (5percent of dibromo compound) ppm downfield from tetramethylsilane. The IR spectrum showed an absorption at 5.49 microns.
	With N-Bromosuccinimide;azobisisobutyronitrile; In tetrachloromethane;	(1) 4-Bromomethyl-5-methyl-1,3-dioxolen-2-one [compound of formula (III) in which R is methyl and X is bromine] 3.42 g of 4,5-dimethyl-1,3-dioxolen-2-one [compound of formula (III') in which R is methyl, prepared in accordance with the procedure described in Tetrahedron Letters, pages 1701-1704, (1972)] was dissolved in 150 ml of carbon tetrachloride. To the solution were added 5.34 g of N-bromosuccinimide and a catalytic amount of alpha,alpha'-azobisisobutyronitrile. The mixture was heated under reflux for 15 minutes. The reaction mixture was cooled with ice, and the insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to give a syrupy residue. The residue was distilled under reduced pressure, and a fraction having a boiling point of 115° to 120° C./5 mmHg was recovered. Thus, 4.2 g (yield 73percent) of the captioned compound having the following properties was obtained as a colorless liquid. Elemental analysis for C5 H5 BrO3: IR (neat) nu(cm-1): near 18 25 (carbonyl). NMR (CCl4) delta(ppm): 2.10 (3H, --CH3, s), 4.10 (2H, --CH2 Br, s).
	With N-Bromosuccinimide; In tetrachloromethane;	PREPARATION 1 4-Bromomethyl-5-methyl-2-oxo-1,3-dioxole To a stirred solution of 3.0 g of <strong>[37830-90-3]4,5-dimethyl-2-oxo-1,3-dioxole</strong> in 100 ml of carbon tetrachloride was added 4.63 g of N-bromosuccinimide. The resulting solution was heated under reflux and irradiated for 15 minutes. The reaction mixture was cooled to 0°-5° C., filtered and evaporated to give the title product. The NMR spectrum (CDCl3) showed absorptions at 2.05 (5percent of starting material), 2.18 (3H, s), 4.30 (2H, s) and 4.35 (5percent of dibromo compound) ppm downfield from tetramethylsilane. The infrared spectrum showed an absorption at 5.49 microns.
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2h;Reflux;	A mixture of <strong>[37830-90-3]4,5-dimethyl-1,3-dioxol-2-one</strong> (1.0 g, 8.8 mmol), benzoylperoxide (60 mg, 0.25 mmol) and N-bromosuccinimide (1.6 g, 9.0 mmol) in carbon tetrachloride (10 mL) was heated at reflux for 2 h. The solid was removed from the reaction mixture by filtration. The mother liquid was washed with sat. NaHCO3 and brine, dried over MgSO4 and concentrated. The crude product, 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one, was obtained as a yellow oil (1.7 g) and was used without further purification in the next step.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 2h;	To a solution of 16 grams 4,5-dimethyl-1, 3-dioxol-2-one in CC14 (250 mE) was added N135 (23.4 g,131.5 mmol) and AII3N (1.3 g, 7.88 mmol), then the reaction mixture was heated to 80° C. and stirred for 2 hrs. Monitored the starting material gone by TLC. The mixture was filtered and the filtrate was washed with water and brine, the organic phase was dried over Na2504 and concentrated to give crude product as a yellow oil which was used directly next step (25.3 g, yield 93percent).
	With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane;	Compound 20 was prepared following the steps disclosed in the literature (Sakamoto er a/., Chem. Pharm. Bull, 1984, 32, 2241).

Reference： [1]Patent: CN103113392,2016,B .Location in patent: Paragraph 0056; 0057; 0058
[2]Patent: WO2008/12852,2008,A1 .Location in patent: Page/Page column 23; 36
[3]Chemical and Pharmaceutical Bulletin,1984,vol. 32,p. 2241 - 2248
[4]Patent: US4455310,1984,A
[5]Patent: WO2010/133669,2010,A1 .Location in patent: Page/Page column 42
[6]Patent: WO2005/97760,2005,A1 .Location in patent: Page/Page column 56-57; 5/24
[7]Journal of Medicinal Chemistry,1986,vol. 29,p. 448 - 453
[8]Patent: US5977139,1999,A
[9]Patent: US5006548,1991,A
[10]Patent: US4434173,1984,A
[11]Patent: US4448769,1984,A
[12]Patent: US4448732,1984,A
[13]Patent: US2015/25068,2015,A1 .Location in patent: Paragraph 0725
[14]Patent: US2017/298090,2017,A1 .Location in patent: Paragraph 0138; 0139
[15]Patent: WO2009/118580,2009,A2 .Location in patent: Page/Page column 25-26

2
[ 555-30-6 ]
[ 80715-22-6 ]
[ 86005-09-6 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 713 - 717

3
[ 80715-22-6 ]
[ 112984-60-8 ]
[ 123447-62-1 ]

Yield	Reaction Conditions	Operation in experiment
95.4%	With potassium hydrogencarbonate; In N,N-dimethyl-formamide; at 0℃; for 5h;Large scale;	the reaction vessel in step (3) obtained in prulifloxacin crude acetonitrile and 358L stirred heated to reflux to dissolve transparent, coolish, adding 0. 05kg charcoal, keep stirring under reflux for 30 minutes, filtered hot and the filtrate was natural cooled to room temperature and crystallization, through chilled water cooling crystallization overnight, centrifugation, washing the filter cake with a small amount of acetonitrile frozen crystal, drying, 80 C and dried under vacuum to dryness to give prulifloxacin finished 8. 73kg, yield (mole ) 92.4%, purity 99.5% 7. 0kg adding the compound of formula (III) in a reaction vessel, 2. 31kg potassium bicarbonate and 42L N, N- dimethylformamide, cooling down to 4 C, was added dropwise at a concentration of 0. 6kg / L of formula ( V) DMF solution of compound 12. 3L, controlling the internal temperature 4 C, dropwise Bi, 4 C with stirring, and the reaction time was 5.5 hours, the reaction solution was poured into ice water with stirring, and stirred for 0.5 hours, the crystals were collected by filtration, the filter cake washed with water until neutral, drained, 60~70 C hot air circulation drying, a compound of formula (I) prulifloxacin crude 9. 34kg, yield (moles) 96.8 percent, purity 92.6%; (4) was added to the reaction vessel in step (3) obtained in prulifloxacin crude acetonitrile and 358L stirred heated to reflux to dissolve transparent, coolish, adding 0. 05kg activated carbon, insulation was stirred at reflux for 30 minutes, filtered hot and the filtrate cooled to room temperature crystallization, crystallization through the chilled water cooling overnight, centrifugation, washing the filter cake with a small amount of acetonitrile frozen crystal, drying, 80 C under vacuum to dryness to give Cape Lu Lisha star finished 8. 94kg, yield (mol) of 95.4%, a purity of 99.7%
		Acetonitrile (560 ml) and potassium bicarbonate (8 gm) are added to 6- fluoro-i-methyM-oxo-y-CI-piperazinyO^H-CI .SKhiazetofS^-alquinoline-S- carboxylic acid (14 gm, obtained as per the processes described in examples 1 and 2) under stirring at 25 - 300C, the contents are cooled to 150C and then the solution of 4-bromomethyl-5-methyl-1 ,3-dioxolen-2-one (10 gm) in acetonitrile (140 ml) is added at 15 - 200C for 30 to 45 minutes. The contents are stirred for 25 hours at 25 to 300C, filtered and the resulting filtrate is distilled under vacuum. To the residue added acetonitrile (70 ml), cooled the mass to 200C and then stirred for 1 hour to 1 hour 30 minutes at 20 - 250C. Filtered the solid, washed the solid with 15 ml of chilled acetonitrile and then dried to give 16 gm of prulifloxacin crude (HPLC Purity: 98.8%).To the prulifloxacin crude (obtained above) added acetonitrile (200 ml) at 25 - 300C, the contents are heated to reflux and then refluxed for 30 minutes. To the reaction mass added activated carbon (5 gm) and refluxed for 15 minutes. The reaction mass is filtered on hi-flo bed, the resulting filtrate is cooled to 200C and then stirred for 3 - 4 hours at 20 - 250C. Filtered the solid, washed with 20 ml of acetonitrile and then dried to give 14 gm of prulifloxacin (HPLC Purity: 99.9%).
		Example 1: Process for the Preparation of Prulifloxacin:Step A): A solution of 4-(bromomethyl)-5-methyl-l,3-dioxol-2-one (35.5 g, 0.184 mole) in N,N-dimethylformamide (200 ml) was added dropwise at 0 to 5 C to a stirred solution of 6-fluoro-l-methyl-4-oxo-7-piperazin-l-yl-4H-[l,3]thiazeto[3,2-alpha]quinoline-3- carboxylic acid (50 g, 0.143 mole and potassium bicarbonate (15.8 g, 0.1578 mole) in N,N-dimethylformamide (200 ml). The resulting mixture was stirred at 25 to 28C for 3 to 4 hours. After the completion of the reaction, the reaction mixture was poured into water (1250 ml). The solid obtained was filtered, washed with water (100 ml), and subsequently dissolved in a mixture of chloroform: methanol (7:3; 1250 ml). The lower organic layer was separated and water (500 ml) was added to the organic layer. A dilute aqueous solution of hydrochloric acid was added to the biphasic reaction mixture to adjust peta to 0.8 to 1.0. The reaction mixture was stirred for 15 minutes, allowed to settle and the upper aqueous layer was separated. The process was repeated twice and the aqueous layers were combined. Activated charcoal (10%) was added to the combined aqueous layer and stirred for 30 minutes, filtered and cooled to 20 to 25 C. The peta of the reaction mixture was adjusted to 6.5 to 7.0 by adding an aqueous solution of sodium bicarbonate. The solid obtained was extracted with chloroform (375 ml), stirred for 15 minutes and the organic layer was separated. The aqueous layer was further extracted with a mixture of chloroform: methanol (7:3 ratio; 50 ml). The combined organic layer was distilled under vacuum at 35 to 40 C to recover the solvent up to 125 ml. The reaction mass so obtained was stirred for 3 to 4 hours at 28 to 30 C, filtered and washed with chilled chloroform (50 ml). The wet cake obtained was dried at 45 C for 12 hours to obtain the title compound.

To a solution of 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1 ,3]-thiazeto-[3,2-a]- quinoline-3-carboxylic acid of formula IV (100 gms, 0.286 moles) in 4.0 It of acetonitrile, DIPEA (70 ml , 0.402 moles)) was added at room temperature, stirred for 10 minutes. The reaction mass was cooled to 10-15C and a solution of 4-(bromomethyl)-5-methyl- 1 ,3-dioxol-2-one (formula V) in 500 ml of acetonitrile was slowly added at 10-15C over a period of 1 hour. The contents were stirred at 25-30C for 20 hour, filtered over hyflo, and the bed washed with 200 ml of acetonitrile. The solvent was distilled off completely under vacuum below 50C. Acetonitrile (100 ml) was added at 50C and the contents were stirred for 30-60 minutes. The reaction mass was slowly chilled to 0-5C and the precipitated solid was filtered, washed with acetonitrile (25 ml) and dried to yield 65 gms of prulifloxacin.

Reference： [1]Patent: CN103113392,2016,B .Location in patent: Paragraph 0044; 0058; 0059; 0060
[2]Journal of Medicinal Chemistry,1992,vol. 35,p. 4727 - 4738
[3]Patent: WO2008/59512,2008,A1 .Location in patent: Page/Page column 8
[4]Patent: WO2008/111016,2008,A1 .Location in patent: Page/Page column 5
[5]Patent: WO2012/1357,2012,A1 .Location in patent: Page/Page column 22-23

4
[ 80715-22-6 ]
[ 112984-60-8 ]
[ 123447-62-1 ]
[ 156834-57-0 ]
7-<4-<1-<4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinolin-7-yl)>-1-piperazinylmethyl>-2-oxopropoxycarbonyl>-1-piperazinyl>-6-fluoro-1-methyl-4-oxo-4H-<1,3>thazeto<3,2-a>quinoline-3-carboxylic acid [ No CAS ]
1,1-bis<(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl>-4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline-7-yl)-1-piperazinium bromide [ No CAS ]

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

5
[ 80715-22-6 ]
[ 112984-60-8 ]
[ 156834-57-0 ]
7-<4-<1-<4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinolin-7-yl)>-1-piperazinylmethyl>-2-oxopropoxycarbonyl>-1-piperazinyl>-6-fluoro-1-methyl-4-oxo-4H-<1,3>thazeto<3,2-a>quinoline-3-carboxylic acid [ No CAS ]
1,1-bis<(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl>-4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline-7-yl)-1-piperazinium bromide [ No CAS ]

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

6
[ 80715-22-6 ]
[ 113028-17-4 ]
ethyl 6-fluoro-1-methyl-7-<4-<(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl>-1-piperazyl>-4-oxo-4H-<1,3>thiazeto<3,2-a>-quinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydrogencarbonate; In N,N-dimethyl-formamide;	EXAMPLE 1 Ethyl 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4yl)methyl-1-piperazinyl]-4oxo-4H-[1,3-]thiazeto[3,2-a]quinoline-3-carboxylate. Ethyl 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate (3.88 g) and 1.23 g of potassium bicarbonate were suspended in 20 ml of N,N-dimethylformamide, 2.38 g of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one was dropped thereinto with ice cooling, and the mixture was stirred for 3 hours. After the reaction, the solvent was evaporated in vacuo therefrom at 50 C. and the residue was extracted with chloroform containing a few amount of methanol. The extract was washed with water, dried, the solvent was evaporated therefrom and the residue was purified by a column chromatography (chloroform-methanol/silica gel) to give 3.32 g of desired product. M.p. 241-243 C. (decompn.) Elem. Anal. for C23 H24 FN3 O6 S; Calcd. (%) C: 56.43 H: 4.94 N: 8.58; Found (%) C: 56.13 H: 4.99 N: 8.26. IR (KBr) nu (cm-1): 1820, 1720 (carbon-yl). NMR (CF3 CO2 D)(ppm) 1.51(3H, COOCH2 CH3, t), 2.31(3H, STR10 s), 2.35(3H, STR11 d), 3.40~4.30(8H, proton in piperazine ring, m), 4.55(2H, STR12 s), 4.65(2H, COOCH2 CH3, q), 6.51(1H, STR13 q), 7.05(1H, 8-proton, d), 8.11(1H, 5-proton, d).

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4727 - 4738
[2]Patent: US5086049,1992,A

7
[ 80715-22-6 ]
[ 123447-62-1 ]
1,1-bis<(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl>-4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline-7-yl)-1-piperazinium bromide [ No CAS ]

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

8
[ 80715-22-6 ]
[ 112984-60-8 ]
[ 123447-62-1 ]
6-Fluoro-1-methyl-7-[4-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-piperazin-1-yl]-4-oxo-4H-2-thia-8b-aza-cyclobuta[a]naphthalene-3-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester [ No CAS ]

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

9
[ 80715-22-6 ]
[ 123447-62-1 ]
6-Fluoro-1-methyl-7-[4-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-piperazin-1-yl]-4-oxo-4H-2-thia-8b-aza-cyclobuta[a]naphthalene-3-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester [ No CAS ]

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

10
[ 80715-22-6 ]
[ 91526-18-0 ]

Reference： [1]Synthetic Communications,1995,vol. 25,p. 3875 - 3881
[2]Synthetic Communications,1992,vol. 22,p. 1277 - 1282

11
[ 128-08-5 ]
[ 37830-90-3 ]
[ 80715-22-6 ]

Yield	Reaction Conditions	Operation in experiment
	2,2'-azobis(isobutyronitrile); In benzene; at 20℃; for 0.5h;Heating / reflux;	(1) 2.08 g of <strong>[37830-90-3]4,5-dimethyl-1,3-dioxol-2-one</strong> was dissolved in 24 mL of benzene, to which 3.25 g of N-bromosuccinimide and 86 mg of 2,2'-azobis(isobutyronitrile) were added at room temperature, and this mixture was stirred for 30 minutes while heating it under reflux. The reaction mixture was cooled to room temperature, and consequently, a solution of 4-bromomethyl-5-methyl-1,3-dioxol-2-one in benzene was obtained.(2) 3.00 g of methyl 3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[3-(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoate was dissolved in 15 mL of methanol and 15 mL of tetrahydrofuran, to which a solution of 1.08 g of potassium hydroxide in 4.5 mL of water was added, and this mixture was stirred for one hour at room temperature, and then the solvent was distilled out under reduced pressure. The resultant residue was dissolved in 40 mL of N,N-dimethylformamide, to which 3.60 g of potassium carbonate was added. Then, the benzene solution prepared in (1) was added thereto, and was stirred for one hour at room temperature. The reaction mixture was poured into a mixture of ethyl acetate and water, and adjusted to pH 7 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; toluene:ethyl acetate=5:1] to yield 1.58 g of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[3-(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoate as yellow oil. NMR(400MHz,CDCl3) delta value: 1.5-2.0(8H,m), 2.16(3H,s), 2.75(2H,t,J=7.6Hz), 3.10(2H,t,J=7.6Hz), 3.65(3H,s), 4.5-5.0(3H,m), 5.33(2H,s), 5.57(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.47(1H,d,J=2.4Hz), 6.95(1H,d,J=8.4Hz), 7.35(1H,dd,J=8.4,1.2Hz), 7.4-7.6(4H,m), 7.72(1H,d,J=8.0Hz), 12.67(1H,s).

Reference： [1]Patent: EP1445249,2004,A1 .Location in patent: Page 116

12
[ 37830-90-3 ]
a,a-azobisisobutyronitrile (AIBN) [ No CAS ]
[ 80715-22-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-Bromosuccinimide; In tetrachloromethane;	Example 9 Synthesis of 4-bromomethyl-5-methyl-1,3-dioxol-2-one A mixture of <strong>[37830-90-3]4,5-dimethyl-1,3-dioxol-2-one</strong> (15.0 g, 0.132 mol), a,a-azobisisobutyronitrile (AIBN) (1.08 g, 0.0066 mol) and N-bromosuccinimide (23.4 g, 0.132 mol) in freshly distilled carbon tetrachloride (350 mL) was refluxed under nitrogen for 16 h. The mixture was concentrated to one-half the initial volume, cooled in an ice bath and the white solid was filtered off. Concentration of the filtrate (CCl4 solution) in a rotavap under reduced pressure gave 4-bromomethyl-5-methyl-1,3-dioxol-2-one as a pale brown liquid in 90percent yield (25 g).

Reference： [1]Patent: US2002/19437,2002,A1

13
[ 37830-90-3 ]
[ 34241-39-9 ]
[ 80715-22-6 ]

Yield	Reaction Conditions	Operation in experiment
48%	With N-Bromosuccinimide; In tetrachloromethane;	1-bromomethyl-2-methylvinylene carbonate A mixture of <strong>[37830-90-3]dimethylvinylene carbonate</strong> (11.4 g, 100 mmol), N-bromosuccinimide (17.8 g, 100 mmol) and 2,2'-azobisisobutyronitrile (250 mg) in carbon tetrachloride (400 mL) was stirred at reflux for 4 hours. Aqueous workup followed by vacuum distillation (110-112° C., 3.5 mm Hg) gave the desired compound (9.26 g, 48percent).
	With N-Bromosuccinimide; In tetrachloromethane;	EXAMPLE 2 Preparation of 4-bromomethyl-5-methyl-1,3-dioxolene-2-one STR13 4,5-Dimethyl-1,3-dioxolene-2-one (11.4 g) was mixed with N-bromosuccinimide (19.6 g) and 2,2-azobis(2-methylpropionitrile) (0.5 g) in freshly distilled carbon tetrachloride (350 mL) and refluxed for 6 hours under an argon atmosphere. The reaction mixture was cooled in an ice bath after reflux and the precipitate formed was filtered off. The tiltrate was washed with water and brine, and dried over sodium sulfate. The solvent was evaporated to yield a yellow oil (20.54 g) which was distilled to obtain the pure monobromomethyl compound as a light yellow oil (11.86 g, 54percent), bp 93° C. at 0.45 mm; 1 H NMR (CDCl3) delta2.15 (s, 3H), 4.21 (S, 2H); IR (film) 1820, 1728, 1392, 1201, 1236, 768 cm-1.

Reference： [1]Patent: US2002/193596,2002,A1
[2]Patent: US5466811,1995,A

14
ethyl acetate-cyclohexane [ No CAS ]
[ 80715-22-6 ]
[ 91526-18-0 ]

Yield	Reaction Conditions	Operation in experiment
	With silver nitrate; acetic acid; In acetonitrile;	EXAMPLE 3 4-hydroxymethyl-5-methyl-1,3-dioxolen-2-one A solution of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one (960 mg) in dry CH3 CN (15 ml) was treated with silver nitrate (830 mg). The mixture was stirred 15 minutes at r.t. diluted with benzene (20 ml) and filtered. The filtrate was heated at reflux for 2.5 h, then cooled to 20 C. and treated with acetic acid (10 ml) and excess zinc powder. Stirring was continued for few hours at r.t. (until completion of the reaction: TLC monitoring: ethyl acetate-cyclohexane 1:1, detection with aqueous KMnO4). Removal of the solvent in vacuo and flash chromatography of the residue afforded a light yellow oil (470 mg). Alternatively the mixture was filtered, concentrated, and the residue purified by distillation under reduced pressure (108 C./0.5 mmHg) IR (CHCl3)numax 3300-3600, 1810 (strong), 1740 cm-1 NMR (CDCl3, 90 MHZ)delta: 2.13 (3H, s) 2.6 (1H, br.s, exch.D2 O) 4.30 (2H, S)

Reference： [1]Patent: US5416208,1995,A

15
[ 4263-93-8 ]
[ 80715-22-6 ]
5-Methyl-1,3-dioxolen-2-on-4-ylmethyl 2R-hydroxy-4-phenylbutyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydrogencarbonate In <i>N</i>-methyl-acetamide; ethanol; water	2.a 5-Methyl-1,3-dioxolen-2-on-4-ylmethyl 2R-hydroxy-4-phenylbutyrate 2a 5-Methyl-1,3-dioxolen-2-on-4-ylmethyl 2R-hydroxy-4-phenylbutyrate 9.0 g (0.05 mol) of 2R-hydroxy-4-phenylbutyric acid are dissolved in 200 ml of absolute dimethylformamide, 10.0 g (0.10 mol) of potassium bicarbonate are added, the mixture is stirred at 50° C. for 90 minutes and then, while cooling in ice at 0° C., a solution of 11.6 g (0.06 mol) of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one in 50 ml of absolute dimethylformamide is added dropwise. The mixture is stirred at 0° C. for one hour and then at room temperature for 30 minutes, and is poured into 1 l of water, and the mixture is extracted twice with ethyl acetate. The combined extracts are washed twice with saturated sodium bicarbonate solution and twice with water, dried over sodium sulfate and concentrated, and impurities are removed form the crude product by column chromatography on 600 g of silica gel (mobile phase toluene/ethanol 199:1). 12.6 g (60%) of colorless oil are obtained. [α]D25 =-8.2° (C=1, methanol).

Reference： [1]Current Patent Assignee: SANOFI - US5114962, 1992, A

16
potassium bicarbonate [ No CAS ]
[ 80715-22-6 ]
[ 68373-14-8 ]
[ 85871-31-4 ]

Yield	Reaction Conditions	Operation in experiment
47%	With sodium chloride; In N-methyl-acetamide; water; ethyl acetate;	(2) 1,1-Dioxopenicillanic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester (compound I-A) 200 mg of 1,1-dioxopenicillanic acid (II) was dissolved in 2 ml of dimethylformamide, and with ice cooling, 90 mg of potassium hydrogen carbonate and 170 mg of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one were added. The mixture was stirred for 5 hours with ice cooling. To the reaction mixture were added 15 ml of ethyl acetate and 8 ml of water, and the mixture was well stirred. The ethyl acetate layer was separated, and washed successively with water and a saturated aqueous solution of sodium chloride. The ethyl acetate layer was then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting syrup was treated with a mixture of ethyl acetate and ether to give 140 mg (yield 47%) of the captioned compound having the following properties as a colorless amorphous solid. Melting point: 122-125 C. (decomp.) Elemental analysis for C13 H15 O8 NS: IR (KBr) nu(cm-1): 1835, 1815, 1795, 1765 (carbonyl). NMR (CDCl3) delta(ppm): 1.40, 1.62 (6H, CH3 at the 2-position, s), 2.22 STR14

Reference： [1]Patent: US4448769,1984,A

17
[ 80715-22-6 ]
[ 36322-90-4 ]
4-[(4-Methyl-2-oxo-1,3-dioxol-5-yl)methyloxy]-2-methyl-N-(pyridin-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-Dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dichloromethane; water; ethyl acetate; acetone	3 4-[(4-Methyl-2-oxo-1,3-dioxol-5-yl)methyloxy]-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-Dioxide EXAMPLE 3 4-[(4-Methyl-2-oxo-1,3-dioxol-5-yl)methyloxy]-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-Dioxide To a round bottomed flask equipped with a reflux condenser and stirring bar was added piroxicam (5.00 g, 15.1 mmol), potassium carbonate (4.20 g, 30.2 mmol), 5-bromomethyl-4-methyl-2-oxo-1,3-dioxole (prepared according to European patent application No. 39,477; 4.37 g, 22.6 mmol) and acetone (60 ml). The heterogenous reaction mixture was heated to reflux under a nitrogen atmosphere for 20 minutes, at which time no piroxicam was visible by TLC (1:4 ethyl acetate:methylene chloride, visualization by UV light). The acetone was removed in vacuo leaving a brown residue which was treated with water (200 mL) and methylene chloride (200 mL). The organic layer was separated and the aqueous layer extracted with additional methylene chloride (200 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried (Na2 SO4) and concentrated in vacuo to a brown oil. Column chromatography on silica gel, eluding with 1:4 ethyl acetate:methylene chloride and collecting all fractions containing the Rf 0.30 spot, afforded a yellow solid. The latter was recrystallized from hot toluene to yield 3.08 g white crystals (6.95 mmol, 46.0%): mp 157°-158° C.; IR (KBr) 1836, 1824, 1671 cm-1; 1 H NMR (CDCl3) delta 1.95 (s, 3H), 3.13 (s, 3H), 4.79 (s, 2H), 7.10-7.21 (m, 1H), 7.70-7.99, (m, 5H), 8.27-8.42, (m, 2H), 9.45 (br s, 1H); Precise mass calcd for C15 H12 N3 O4 S m/e 330.0553, found 330.0567, for C5 H5 O3 m/e 113.0243, found 113.0244. Anal. Calcd. for C20 H17 N3 O7 S: C, 54.17; H, 3.86; N, 9.48. Found C, 54.52; H, 3.93; N, 9.41.

Reference： [1]Current Patent Assignee: PFIZER INC - US4551452, 1985, A

18
[ 80715-22-6 ]
[ 649748-09-4 ]
[ 1026789-40-1 ]

Yield	Reaction Conditions	Operation in experiment
72%		EXAMPLE 8 Synthesis of PGB-07 (3-Aminomethyl-5-methyl-hexanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester) Procedure: Compound 20 was prepared following the steps disclosed in the literature (Sakamoto et al., Chem. Pharm. Bull, 1984, 32, 2241). Cesium carbonate (0.20 g, 0.61 mmol) was dissolved in methanol and S-form of compound 3 (0.32 g) was added. After stirring for 2 hours at room temperature, the solvent was removed under reduced pressure. The residue was diluted with N,N-dimethylacetamide ("DMA", 3.8 mL), where a solution of compound 20 (0.2 g, 0.032 mmol) in DMA (1 mL) was added. After stirring overnight, the reaction solution was diluted with water (50 mL), extracted with EtOAc, washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The oil crude product (0.63 g) was purified by chromatography on a column of silica gel (70-230 mesh, elution: EA/Hexane=1/3) to give 0.33 g of 3-(tert-butoxycarbonylamino-methyl)-5-methyl-hexanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester 21 (Yield: 72%). 1H-NMR (CDCl3, 500 MHz) delta 0.87-0.91 (m, 6H), 1.07-1.15 (m, 1H), 1.16-1.21 (m, 1H), 1.43 (s, 9H), 1.59-1.67 (m, 1H), 2.09-2.12 (m, 1H), 2.18 (s, 3H), 2.23-2.36 (m, 2H), 2.96-3.03 (m, 1H), 3.17-3.23 (m, 1H), 4.68 (br s, 1H), 4.85 (s, 2H). 13C-NMR (CDCl3, 125 MHz) delta 9.25, 22.57, 22.60, 25.13, 28.29, 29.59, 33.62 6.2, 4.38 43.79, 53.56, 79.7, 13.51, 13.9, 152.00, 5.02, 172.38.
72%		Cesium carbonate (0.20 g, 0.61 mmol) was dissolved in methanol and S-form of compound 3 (0.32 g) was added. After stirring for 2 hours at room temperature, the solvent was removed under reduced pressure. The residue was diluted with N,N-dimethylacetamide ("DMA", 3.8 ml_), where a solution of compound 20 (0.2g, 0.032 mmol) in DMA (1 mL) was added. After stirring overnight, the reaction solution was diluted with water (50 mL), extracted with EtOAc, washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The oil crude product (0.63 g) was purified by chromatography on a column of silica gel (70-230 mesh, elution: EA/Hexane = 1/3) to give 0.33 g of 3-(tert-butoxycarborTylamino-methyl)-5-methyl-hexanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester 21 (Yield: 72%). 1HNMR(CDCI3, 500 MHz) delta 0.87-0.91 (m,6H), 1.07-1.15(m, 1 H), 1.16-1.21(m, 1 H), 1.43(s, 9H), 1.59-1.67(m, 1 H), 2.09-2.12(m, 1H), 2.18(s, 3H), 2.23-2.36(m, 2H), 2.96-3.03(m, 1H), 3.17-3.23(m, 1 H), 4.68(br s, 1H), 4.85(s, 2H). 13CNMR (CDCI3, 125 MHz) delta 9.25, 22.57, 22.60, 25.13, 28.29, 29.59, 33.62 6.2, 4.3843.79, 53.56, 79.7,13.51 , 13.9, 152.00, 5.02, 172.38.

Reference： [1]Patent: US2008/125483,2008,A1 .Location in patent: Page/Page column 10
[2]Patent: WO2009/118580,2009,A2 .Location in patent: Page/Page column 26

19
[ 80715-22-6 ]
[ 113028-17-4 ]
6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 10: Preparation of prulifloxacin hydrochloride; Method A: To the mixture of dimethylformamide (1.5 It) and 6-fluoro-l-methyl-4-oxo-7-(l- piperazinyl)-lH,4H-[l,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (0.3kg), 4-bromomethyl-5- methyl- 1, 3 -dioxolen-2-one, obtained above was added and cooled to 0-50C. Triethylamine (0.87kg) in dimethylformamide (0.3 It) was added slowly in 1-2 hours. After completion of the reaction (monitored by TLC), dichloromethane (3.0 It) and water (1.5 It) were added to the reaction mixture. The layers were separated and aqueous layer was extracted twice with dichloromethane (1.5 It). All organic layers were combined, dried over sodium sulfate followed by distillation. Methanolic hydrochloride (20-25 % w/w, 0.24 It) was added to organic layer at 0- 5C and stirred. The solid, thus precipitated out was filtered, washed with dichloromethane and dried to obtain 0.36kg of the title compound having purity 92.73 % by HPLC. Example 11: Purification of prulifloxacin hydrochlorideDimethylformamide (1.34 It) was added to prulifloxacin hydrochloride (67g) and reaction mass was heated to 110-112C for 1 hour. The reaction mixture was cooled to 25-300C and stirred for 2 hours, filtered, washed with N,iV-dimethylforamide. The product was slurry washed with isopropanol (0.670 It) and dried to obtain 48.8g of title compound having purity 99.30 % by HPLC.

Reference： [1]Patent: WO2009/93268,2009,A1 .Location in patent: Page/Page column 16

20
[ 1004758-90-0 ]
[ 1004758-92-2 ]
[ 80715-22-6 ]
[ 144689-93-0 ]
[ 144689-63-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 6:; (5-MethyI-2-oxo-l,3-dioxol-4-yI)methyl 5-(2-hydroxypropan-2-yl)-2-propyl-3-[[4-[2- (2H-tetrazoI-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylate (olmesartan medoxomil) (Ie); Step I: 5-(2-Hydroxypropan-2-yl)-2-propyl-3-[[4-[2-(N-(2-trimethylsilylethoxymethyl) tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-ethylcarboxylate (Vd); 2-Propyl-5-[(l-hydroxy-l-methyl)ethyl]-3H-imidazole-4-ethylcarboxylate (0.808 g, 0.0033675 mol) was added to the two isomers (IVb) (1.5 g, 0.0033675 mol) and K2CO3 (0.558 g, 0.0040382 mol) in anhydrous DMF (10 mL) under N2 atmosphere. The mixture was stirred at room temperature for 17 hrs (TLC monitoring: cyclohexane/AcOEt 6:4). The mixture was partitioned between water and AcOEt. The organic layer was washed with water (3 times), dried over Na2SO4 and concentrated under reduced pressure to give a residue (1.8 g) that was purified by flash chromatography on silica (cyclohexane/AcOEt 6:4) to give the isomer (Vd1) (0.499 g) and the isomer (Vd2) (0.206 g) as oils. Yield: 35%. <n="36"/>(Vd1) (isomer with lower elution time):1H-NMR (400 MHz, CDCl3, delta): -0.03 (s, 9H, Me3Si), 0.92 (t, J=8.2Hz, 2H, SiCH2CH2O), 0.96 (t, J=7.2Hz, 3H, CH2CH2CH3), 1.18 (t, J=7.2etaz, 3H, OCH2CHi), 1.64 (s, 6eta, CMe2), 1.67-1.76 (m, 2H5 CH2CH2CH3), 2.66 (t, J=7.6Hz, 2H, CH2CH2CH3), 3.66 (t, J=8.2Hz, 2H, SiCH2CH2O), 4.22 (q, J=7.2etaz, 2H, OCH2CH3), 5.44 (s, 2H, ArCH2N), 5.78 (s, 2H, OCH2N), 6.84-6.86 (m, 2H) 7.14-7.16 (m, 2H) 7.41-7.43 (m, IH) 7.46-7.56 (m, 2H) 7.84- 7.86 (m, IH) (aromatic protons).(Vd2) (isomer with higher elution time): 1H-NMR (400 MHz, CDCl3, delta): -0.10 (s, 9H, Me3Si), 0.70 (t, J=8.4Hz, 2H, SiCH2CH2O), 0.92 (t, J=7.4Hz, 3H, CH2CH2CH5), 1.13 (t, J=7.0etaz, .3eta, OCH2CH3), 1.60 (s, 6eta, CMe2), 1.62-1.71 (m, 2H, CH2CH2CH3), 2.58 (t, J=7.8Hz, 2H, CH2CH2CH3), 3.39 (t, J=8.4Hz, 2H, SiCH2CH2O), 4.17 (q, J=7.2etaz, 2H, OCH2CH3), 5.05 (s, 2H, ArCH2N), 5.38 (s, 2H, OCH2N), 6.81-6.83 (m, 2H) 7.05-7.07 (m, 2H) 7.49-7.52 (m, 2H) 7.55-7.57 (m, IH) 7.61- 7.65 (m, IH) (aromatic protons). Step II: 5-(2-Hydroxypropan-2-yl)-2-propyl-3-[[4-[2-(N-(2-trimethylsilylethoxymethyl) tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylic acid (Ve i); A solution of NaOH (0.052 g, 0.001311 mol> in water (1 mL) was added to compound (VdO (0.262 g, 0.0004337 mol) in THF (1 mL). The mixture was stirred at room temperature for 23 hrs (TLC monitoring: CH2Cl2/MeOH/AcOH 85:10:5). HCl IN was added until pH 4 was reached. The mixture was extracted with AcOEt. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give the compound (Vei) (0.261 g) as a white solid, m.p. 68-69C. Yield: 99%. <n="37"/>1H-NMR (400 MHz, CDCl3, delta): -0.05 (s, 9H, Me3Si), 0.86 (t, J-7.2Hz, 3H, CH2CH2CH3), 0.89 (t, J=8.1etaz, 2H, SiCH2CH2O), 1.54-1.60 (m, 2H, CH2CH2CH3) 1.67 (s, 6H, CMe2), 2.94 (t, J-7.2Hz, 2H, CH2CH2CH3), 3.65 (t, J=8.1Hz, 2H, SiCH2CH2O), 5.75 (s, 2eta, ArCH2N), 5.79 (s, 2H, OCH2N), 6.97-6.99 (m, 2H) 7.12-7.14 (m, 2H) 7.35-7.38 (m, IH) 7.44-7.53 (m, 2H) 7.83-7.85 (m, IH) (aromatic protons). Step III: 4-Bromomethyl-5-methyl~l,3-dioxol~2-one; A mixture of 4,5-dimethyl-l,3-dioxol-2-one (1.5 g, 0.013158 mol), NBS (2.34 g, 0.013158 mol) and benzoyl peroxide (0.089 g, 0.0003684 mol) in CCl4 (20 mL) was stirred at 77C for 6 hrs (TLC monitoring: cyclohexane/AcOEt 6:4). The solution was treated with an aqueous solution OfNaHCO3 and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give 4-bromomethyl-5 -methyl- 1,3- dioxol-2-one (2.34 g). Yield: 92%.1H-NMR (400 MHz, CDCl3, delta): 2.13 (s, 3H, CH3), 4.18 (s, 2H, CH2Br). Stp IV: (5-Methyl-2-oxo-l,3-dioxol-4-yl)methyl 5-(2~hydroxypropan-2-yl)-2-propyl-3-[[4- [2-(N-(2-trimethylsilylethoxymethyl)tetrazol-5-yl)pherpsil]phenyl]methyl]imidazole-4- carboxylate (Vf1); A mixture of the compound (Ve1) (0.260 g, 0.0004516 mol), 4-bromomethyl-5-methyl-l,3- dioxol-2-one (0.1 g, 0.000518 mol) and K2CO3 (0.033 g, 0.000239 mol) in anhydrous DMF (1.5 mL) was stirred for 1.5 hrs at room temperature under N2 atmosphere (TLC monitoring: CH2Cl2/Me0H/Ac0H 85:10:5). The mixture was partitioned between a saturated solution of NaHCO3 and AcOEt. The organic phase was washed with water (3 <n="38"/>times), dried over Na2SO4 and concentrated under reduced pressure to give the compound (Vf1) (0.3042g) as a yellow oil. Yield: 98%.1H-NMR (400 MHz, CDCl3, delta): -0.02 (s, 9H, Me3Si), 0.92 (t, J=8.1Hz, 2H, SiCH2CH2O), 0.98 (t, J=7.2Hz, 3H, CH2CH2CH3), 1.64 (s, 6eta, CMe2), 1.70-1.80 (m, 2H, CH2CH2CH3), 2.07 (s, 3H, CH3C=C), 2.76 (m, 2H, CH2CH2CH3), 3.67 (t, J=8.1Hz, 2H, SiCH2CH2O), 4.89 (s, 2eta, COOCH2), 5.41 (s, 2H, ArCH2N), 5.79 (s, 2H, OCH2N), 6.80-6.82 (m, 2H) 7.14-7.16 (m, 2H) 7.44-7.52 (m, 2H) 7.54-7.58 (m, IH) 7.85-7.87 (m, IH) (aromatic protons). Step V: (5-Methyl-2-oxo-l,3-dioxol-4-yl)methyl 5-(2-hydroxypropan-2-yl)~2~propyl~3-[[4- [2~(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylate (olmesartan medo...

Reference： [1]Patent: WO2008/12852,2008,A1 .Location in patent: Page/Page column 23; 35-36

21
[ 80715-22-6 ]
[ 54857-86-2 ]
[ 1261491-55-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 14h;	7 To a stirred, room temperature solution of 5-(tetradecyloxy)furan-2-carboxylic acid (0.228 g, 0.70 mmol) in DMF (4 ml.) was added potassium carbonate (0.146 g, 1.05 mmol) and 4-(bromomethyl)-5-methyl-1 ,3-dioxol-2-one (0.160 g, 0.84 mmol). The reaction vessel was capped and stirring was continued for 14 hrs at which time TLC ((20% EtOAc in Hexanes Rf = 0.10 (SM) and 0.40 (Prod)) indicated complete consumption of the starting material. The reaction was quenched by the addition of water (5 mL), brine (5 mL) and EtOAc (30 mL). The biphasic mixture was transferred to a seperatory funnel and the organic phase was extracted 3 times with brine (3 x 10 mL). The organic phase was dried and concentrated to give a colourless oil. The resulting crude material was purified by flash chromatography eluting with 5-20% EtOAc in hexanes to yield a colourless syrup that solidified on standing. 1H NMR (400 MHz, DMSO-de) δ: 7.2 (d, 1 H), 5.6 (d, 1 H), 5.1 (s, 2H), 4.1 (t, 2H), 2.18 (s, 3H), 1.6-1.8 (m, 2H), 1.3-1.4 (m, 2H), 1.23 (d, 6H), 1.2 (s, 20H), 0.85 (t, 3H).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2011/5660, 2011, A1 Location in patent: Page/Page column 33

22
[ 106941-25-7 ]
[ 80715-22-6 ]
[ 1313815-83-6 ]

Yield	Reaction Conditions	Operation in experiment
16%		A suspension of 1 (450 mg, 1.65 mmol) in methanol (5 ml) was neutralized with a 1 M solution of methanolic tetrabutylammonium bromide (1.65 ml, 1.65 mmol). <strong>[106941-25-7]PMEA</strong> (1) was dissolved, the solution was evaporated and co-distilled with ethanol and toluene. The residue was dissolved in anhydrous DMF (10 ml) and (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylbromide5 (350 mg, 1.81 mmol) was added. The mixture was stirred for four days at room temperature. The resulting precipitate (400 mg) was purified on a Dowex 1 column ([AcO-], 50 ml, gradient water?1% aqueous acetic acid). Unreacted 1 was eluted at first, then 15. The fractions containing the product were lyophilized. Yield: 100 mg (16%).; mp 196 C. 1H NMR (DMSO-d6, ppm) delta: 1.99 (s, 3H, H-4''), 3.67 (d, 2H, J3'-P = 9.2, H-3'), 3.88 (m, 2H, H-2'), 4.29 (bd, 2H, J1''-P = 7.0, H-1''), 4.41 (m, 2H, H-1'), 8.13 (s, H-2), 8.14 (s, H-8). 13C NMR (DMSO-d6, ppm) delta: 8.74 (C-4''), 44.29 (C-1'), 55.26 (d, J1''-P = 4.4, C-1''), 66.94 (d, J3'-P = 157.5, C-3'), 71.18 (d, J2'-P = 14.3, C-2'), 118.53 (C-5), 135.25 (d, J2''-P = 6.8, C-2''), 140.35 (C-3''), 143.52 (C-8), 149.23 (C-4), 152.79 (C-2), 154.63 (CO), 155.75 (C-6). 31P NMR (D2O, ppm) delta: 18.20 (m). ESI-MS, m/z: 384.1 (100) [M-H]-, 385.1 (13) [M-H]-. ESI-HRMS: calcd for C13H15N5O7P 384.0715, found: 384.0717 [M-H]-.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3527 - 3539

23
[ 936114-12-4 ]
[ 80715-22-6 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide; In acetone; at 50 - 55℃; for 3h;	Example 1 :Preparation of trityl olmesartan medoxomilEthyl-4-( 1 -hydroxy- 1 -methylethyl)-2-propyl-imidazole-5-carboxylate ( 100 gm) was dissolved in acetone (2500 ml) and then added potassium carbonate (100 gm), 5-[4'- (bromomethyl)[ 1,1 '-biphenyl] -2-yl]-2-(triphenylmethyl)-lH-tetrazole (250 gm) and tert- butyl ammonium bromide (15 gm) under stirring at room temperature. The temperature of the reaction mass was raised to 50 to 55C and maintained for 15 hours at 50 to 55C. The reaction mass was cooled to 45C and passed over celite bed. The collected filtrate was cooled to 0 to 5C and then added a solution of potassium carbonate (36 gm) in water (36 ml) for 1 hour. The temperature of the reaction mass was raised to room temperature and maintained for 16 hours at room temperature. The acetone was distilled off completely under vacuum at below 40C to obtain residue. To the residue was added sodium chloride solution (10%, 900 ml) and then added ethyl acetate (1500 ml). The layers were separated and the aqueous layer was extracted. Combined the both organic layers and dried over sodium sulfate. The solvent was distilled off completely to obtain a residual mass. A mixture of acetone (1200 ml), potassium carbonate (100 gm), (4- bromoethyl)-5-methyl-oxo-l,3-dioxane (105 gm) and potassium iodide (17 gm) were added under stirring at room temperature and then the contents were heated to 50 to 55C. The solution was added to the above residual mass for 1 hour 30 minutes and maintained for 1 hour 30 minutes at 50 to 55C. The reaction mass was cooled to 45C and filtered. The solvent was distilled off completely to obtain residue. Toluene (1500 ml) was added to the residue and the layers were separated. The toluene layer was dried over sodium sulfate and distilled off the layer under vacuum up to obtain clear residual mass. To the residual mass was added methanol (1500 ml) and stirred for 30 minutes at room temperature. The reaction mass was cooled to 10 to 15C and maintained for 1 hour 30 minutes. The separated solid was filtered and dried at 40 to 45C for 7 hours to obtain 270 gm of trityl olmesartan medoxomil.Trityl olmesartan medoxomil: 98.5%;Trityl olmesartan ethyl ester impurity: 0.35%;Bromo trityl olmesartan medoxomil impurity: 0.35%;Methyl trityl olmesartan medoxomil impurity: 0.34%.

Reference： [1]Patent: WO2012/1694,2012,A1 .Location in patent: Page/Page column 9-10

24
5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-(triphenylmethyl)-1H-tetrazole [ No CAS ]
[ 80715-22-6 ]
[ 144689-93-0 ]
[ 144690-92-6 ]

Yield	Reaction Conditions	Operation in experiment
98.5%		Ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate (100 gm) was dissolved in acetone (2500 ml) and then added potassium carbonate (100 gm), 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-(triphenylmethyl)-1H-tetrazole (250 gm) and tert-butyl ammonium bromide (15 gm) under stirring at room temperature. The temperature of the reaction mass was raised to 50 to 55 C. and maintained for 15 hours at 50 to 55 C. The reaction mass was cooled to 45 C. and passed over celite bed. The collected filtrate was cooled to 0 to 5 C. and then added a solution of potassium carbonate (36 gm) in water (36 ml) for 1 hour. The temperature of the reaction mass was raised to room temperature and maintained for 16 hours at room temperature. The acetone was distilled off completely under vacuum at below 40 C. to obtain residue. To the residue was added sodium chloride solution (10%, 900 ml) and then added ethyl acetate (1500 ml). The layers were separated and the aqueous layer was extracted. Combined the both organic layers and dried over sodium sulfate. The solvent was distilled off completely to obtain a residual mass. A mixture of acetone (1200 ml), potassium carbonate (100 gm), (4-bromoethyl)-5-methyl-oxo-1,3-dioxane (105 gm) and potassium iodide (17 gm) were added under stirring at room temperature and then the contents were heated to 50 to 55 C. The solution was added to the above residual mass for 1 hour 30 minutes and maintained for 1 hour 30 minutes at 50 to 55 C. The reaction mass was cooled to 45 C. and filtered. The solvent was distilled off completely to obtain residue. Toluene (1500 ml) was added to the residue and the layers were separated. The toluene layer was dried over sodium sulfate and distilled off the layer under vacuum up to obtain clear residual mass. To the residual mass was added methanol (1500 ml) and stirred for 30 minutes at room temperature. The reaction mass was cooled to 10 to 15 C. and maintained for 1 hour 30 minutes. The separated solid was filtered and dried at 40 to 45 C. for 7 hours to obtain 270 gm of trityl olmesartan medoxomil. Trityl olmesartan medoxomil: 98.5%; Trityl olmesartan ethyl ester impurity: 0.35%; Bromo trityl olmesartan medoxomil impurity: 0.35%; Methyl trityl olmesartan medoxomil impurity: 0.34%.

Reference： [1]Patent: US2013/190506,2013,A1 .Location in patent: Paragraph 0050

25
[ 80715-22-6 ]
[ 147403-52-9 ]
C₃₁H₂₆N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.5%		Into 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, and DMF 70 mL were placed, and the mixture was cooled to -10 to 0 ° C and stirred for 0.5 hour. 2.1 g of 4-bromomethyl-5-methyl-1,3-dioxol-2-one in 30 mL of DMF 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 97.1percent.

Reference： [1]Patent: CN108822097,2018,A .Location in patent: Page/Page column 0121; 0122

26
[ 80715-22-6 ]
[ 147403-03-0 ]
C₃₅H₂₈N₄O₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 6h;	Add 5g of <strong>[147403-03-0]azilsartan</strong> to a 250ml round bottom flask Potassium carbonate 5.8 g and DMF 70 mL were stirred for 1 hour.5.2 g of 4-bromomethyl-5-methyl-1,3-dioxol-2-one in 30 mL of DMF was added dropwise to the above reaction system.After the addition was completed, the temperature was raised to 60 C for 6 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 = 100:1).The product was obtained in an amount of 6.2 g, a yield of 83.0%, and a purity of 98.6%.

Reference： [1]Patent: CN108822097,2018,A .Location in patent: Paragraph 0127; 0128

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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. 80715-22-6 ] {[proInfo.proName]}

Quality Control of [ 80715-22-6 ]

Related Doc. of [ 80715-22-6 ]

Product Details of [ 80715-22-6 ]

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Application In Synthesis of [ 80715-22-6 ]

[ 80715-22-6 ] Synthesis Path-Upstream 1~7

[ 80715-22-6 ] Synthesis Path-Downstream 1~26

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