[ CAS No. 764659-72-5 ] {[proInfo.proName]}

Name: 764659-72-5|(2R,5S)-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolane-2-carboxylate|95%
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SKU: A143613
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Quality Control of [ 764659-72-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 764659-72-5 ]

Product Details of [ 764659-72-5 ]

CAS No. :	764659-72-5	MDL No. :	MFCD09753268
Formula :	C₁₈H₂₆FN₃O₄S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AUTCQXVTOIJYOT-KKVJTYSWSA-N
M.W :	399.48	Pubchem ID :	42629214
Synonyms :

Calculated chemistry of [ 764659-72-5 ]

Physicochemical Properties

Num. heavy atoms :	27
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.72
Num. rotatable bonds :	5
Num. H-bond acceptors :	6.0
Num. H-bond donors :	1.0
Molar Refractivity :	102.35
TPSA :	121.74 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.49 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.25
Log Po/w (XLOGP3) :	3.16
Log Po/w (WLOGP) :	2.66
Log Po/w (MLOGP) :	2.41
Log Po/w (SILICOS-IT) :	1.82
Consensus Log Po/w :	2.66

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.14
Solubility :	0.0288 mg/ml ; 0.0000721 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.39
Solubility :	0.00164 mg/ml ; 0.0000041 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-2.67
Solubility :	0.85 mg/ml ; 0.00213 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	5.09

Safety of [ 764659-72-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 764659-72-5 ]

* 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 [ 764659-72-5 ]
Downstream synthetic route of [ 764659-72-5 ]

[ 764659-72-5 ] Synthesis Path-Upstream 1~13

1
[ 764659-72-5 ]
[ 143491-57-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium tetrahydroborate; dipotassium hydrogenphosphate; water; sodium hydroxide In ethanol at 20℃;	Potassium hydrogen phosphate (26.91 g, 117.9 mmol) was added to water (43 ml), stirred and dissolved,(2R, 5S) - (5-fluorocytosidin-1-yl) -1,3-oxathiolane-2-carboxylic acid L-menthyl ester (15 g, 37.5 mmol)Ethanol (106 ml) was added.Sodium borohydride (3 g, 79 mmol) was added dropwise at room temperature,Of 0.12 mol / L aqueous sodium hydroxide solution (14.4 ml).After completion of the dropwise addition, the mixture was stirred at room temperature until the reaction was complete. Static stratification.The organic layer was separated, adjusted to pH = 4 with 6 mol / L hydrochloric acid, and adjusted to pH 7 with 2 mol / L aqueous sodium hydroxide solution.Concentrated under reduced pressure. To the resulting residue was added water (200 ml) and washed with toluene (3 x 110 ml). Salicylic acid (5.19 g, 37.5 mmol) was added and the mixture was heated to 70-80 ° C.Inoculated, cooled to room temperature and filtered, dried in vacuo (80 ° C, 4 h)Deltamethasone salicylate (10.1 g, yield 70percent): Moisture (Karl Fischer Titration) 0.35percent
65%	Stage #1: With sodium tetrahydroborate In methanol at -5℃; for 5 h; Inert atmosphere Stage #2: With isopropyl alcohol In water at 60℃; for 1 h; Stage #3: With methanol In water	Example 1; Preparation of emtricitabine via B(0'Pr)₃ A suspension of (2R,5S)-((1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 5-(4-amino-5- fluoro-2-oxopyrimidin-1 (2H)-yl)-1 ,3-oxathiolane-2-carboxylate (30.0 g) in MeOH (300 mL) was cooled to -7 °C under a nitrogen atmosphere. Then, NaBH₄ (6.8 g) was added in portions for 1 h and the reaction mixture was stirred at -5 °C for 5 h. The resulting solution was heated to 5°C, water (105 mL) was added and was slowly titrated to pH 5.5 with 35percent aqueous H CI solution at 1 0 °C . The solution was concentrated under reduced pressure to 140 mL total internal volume. Toluene (90 mL) was added and the layers were separated after 10 min stirring. The aqueous phase was washed again with toluene (2 x 90 mL) and, after phase separation, neutralized (pH 7.5) with 25percent aqueous NaOH solution. Part of the solvent was evaporated under reduced pressure until reaching a internal volume of 60 mL. Celite (6 g) was charged to the aqueous solution and the mixture stirred for 5 min. Isopropanol (300 mL) was added and the solvent was evaporated under reduced pressure until the residual volume reached 75 mL. This last operation was repeated twice. Isopropanol (470 mL) was added and the suspension was heated to 60 °C, stirred for 1 h, filtered while hot and washed with hot isopropanol (2 x 30 mL). The filtrate and washing were combined and partially concentrated under reduced pressure to 75 mL total internal volume. MeOH (1 50 m L) was charged and the mixture was concentrated under reduced pressure to 75 mL, thus removing the boron species. Isopropanol (300 mL) was added and the solvent was evaporated under reduced pressure to 160 total internal volume. The suspension was heated to 80 °C and water (6 mL) was added . The resulting solution was cooled to 60 °C, seeded, stirred for 1 h at 60 °C, cooled to 0 °C and held at this temperature for 1 h. The solid was collected by filtration, washed with chilled isopropanol (2 x 15 mL) and dried in vacuo (40 °C) to give 12.1 g of emtricitabine (65percent yield; purity by H PLC 99.77 area percent; assay by H PLC 99.8percent w/w; boric acid and chloride not detected by capillary electrophoresis).
65%	at -7 - -5℃; for 6 h; Inert atmosphere	A suspension of (2R,5S)-((1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolane-2-carboxylate (30.0 g) in MeOH (300 mL) was cooled to -7 °C under a nitrogen atmosphere. Then, NaBH₄ (6.8 g) was added in portions for 1 h and the reaction mixture was stirred at -5 °C for 5 h. The resulting solution was heated to 5°C, water (105 mL) was added and was slowly titrated to pH 5.5 with 35percent aqueous HCl solution at 10 °C. The solution was concentrated under reduced pressure to 140 mL total internal volume. Toluene (90 mL) was added and the layers were separated after 10 min stirring. The aqueous phase was washed again with toluene (2 x 90 mL) and, after phase separation, neutralized (pH 7.5) with 25percent aqueous NaOH solution. Part of the solvent was evaporated under reduced pressure until reaching a internal volume of 60 mL. Celite (6 g) was charged to the aqueous solution and the mixture stirred for 5 min. Isopropanol (300 mL) was added and the solvent was evaporated under reduced pressure until the residual volume reached 75 mL. This last operation was repeated twice. Isopropanol (470 mL) was added and the suspension was heated to 60 °C, stirred for 1 h, filtered while hot and washed with hot isopropanol (2 x 30 mL). The filtrate and washing were combined and partially concentrated under reduced pressure to 75 mL total internal volume. MeOH (150 mL) was charged and the mixture was concentrated under reduced pressure to 75 mL, thus removing the boron species. Isopropanol (300 mL) was added and the solvent was evaporated under reduced pressure to 160 total internal volume. The suspension was heated to 80 °C and water (6 mL) was added. The resulting solution was cooled to 60 °C, seeded, stirred for 1 h at 60 °C, cooled to 0 °C and held at this temperature for 1 h. The solid was collected by filtration, washed with chilled isopropanol (2 x 15 mL) and dried in vacuo (40 °C) to give 12.1 g of emtricitabine (65percent yield; purity by HPLC 99.77 area percent; assay by HPLC 99.8percent w/w; boric acid and chloride not detected by capillary electrophoresis).

62%	With sodium tetrahydroborate; dipotassium hydrogenphosphate; water In isopropyl alcohol at 15 - 20℃;	To a 2.0 L capacity jacketed flask equipped with a mechanical stirrer, thermometer pocket, dipotassium hydrogen phosphate (147. lg) and water (330ml) was charged and stirred the reaction mixture for 15 minutes. To the reaction mixture then charged isopropyl alcohol (800ml) and further stirred for 15 minutes and cooled the reaction mixture to a temperature of 15°C to 20°C. Then charged FCME (lOOg) dissolved in isopropyl alcohol (100ml) to the reaction mixture and stirred at a temperature of 15°C to 20°C for 1 hour. A separately prepared solution of sodium borohydride (26g) dissolved in aqueous sodium hydroxide was added dropwise to the reaction mixture over the period of 1-1.5 hours. The reaction mixture further stirred for 4 - 5 hours and the two layers formed were separated. To the separated organic layer 20percent (v/v) dilute hydrochloric acid (4.6ml) was added dropwise to adjust the pH to 8.0-8.5 and the reaction mixture was further stirred for 15 minutes. The reaction mixture was then distilled out and the aqueous solution obtained was extracted with toluene (200ml). The reaction mixture then treated with charcoal (5g) and filtered. The filtrate obtained was distilled out to obtain a liquid and diluted with isopropyl alcohol (200ml), distilled out the isopropyl alcohol. Diluted the reaction mixture again with isopropyl alcohol (200ml) and distilled out. The reaction mixture further diluted with isopropyl alcohol (400ml) and refluxed the reaction mixture to a temperature of 85°C to 90°C for 30 minutes to obtain the residue. Cooled the reaction mixture and filtered, the filtrate obtained was then distilled out to obtain the residue. Diluted the residue obtained with ethanol (100ml) and distilled out. The reaction mixture again diluted with ethanol (200ml) and heated at a temperature of 85°C to 90°C for 30 minutes and then cooled at a temperature of 10°C to 15°C to precipitate the product, emtricitabine. The resulting product was filtered and washed with ethanol. Dry the product under vacuum.Yield = 62percentAssay = 98.7percentPurity = 99.86percent
57.4%	Stage #1: With dipotassium hydrogenphosphate In denaturated spirit; water at 15 - 30℃; for 0.5 h; Stage #2: With sodium tetrahydroborate; water In denaturated spirit; water at 15 - 30℃; for 2 h; Stage #3: With hydrogenchloride In water	Example 4: Preparation of EmtricitabineDenatured spirit (210 mL) and menthyl emtricitabine (24.5 g) were charged at 25- 30 ⁰C. The mixture was cooled to 15-20 ⁰C and charged with a solution of dipotassium hydrogen phosphate (30 g) and water (30 mL) at 25-30⁰C and stirred for 0.5 hour at 25-30 ⁰C. The stirred mixture was cooled to 15 ⁰C and charged with sodium borohydride (4.66 g) and deionized water (30 mL) over 1.5 hour maintaining the temperature of the reaction mixture below 25 ⁰C. The reaction mixture was stirred at the same temperature till the level of menthyl emtricitabine was less than 0.5 percent as measured by High Performance Liquid Chromatography. The reaction mixture was allowed to stand for 0.5 hour at 25-30 ⁰C. The organic layer was separated and the pH adjusted to 7.2 with concentrated hydrochloric acid (0.5 mL) at 25-30 ⁰C. To the resultant mixture activated carbon (3 g) was added at 25-30 ⁰C. The mixture was stirred for 0.5 hour, filtered through hyflo bed and washed with denatured spirit (30 mL) at 25-30 ⁰C. The stirred mixture was concentrated under vacuum (720 mmHg) at 45 ⁰C to an oily residue. The residue was charged with absolute ethanol (75 mL) and the resultant mass was concentrated under vacuum (720 mm Hg) at 45 ⁰C to a foamy residue. The foam was charged with absolute ethanol (75 mL) and the resultant mass was concentrated under vacuum (720 mmHg) at 45 ⁰C to a foamy residue. The residue was charged with absolute ethanol (60 mL) at 25-30 ⁰C and the temperature of the resultant mixture raised to 78 ⁰C and the mixture was refluxed for 0.5 hour. The mixture was cooled slowly to 60 ⁰C in 1 hour and stirred for 1 hour at 60 ⁰C and further cooled to 25-30 ⁰C in 1 hour and stirred at the same temperature for 4 hours. The solid so obtained was filtered, washed with ethyl acetate (30 mL) at 25- 30 ⁰C and dried under vacuum at 40-45 ⁰C for 12 hours to afford the title compound. Yield: 8.6 g (57.4percent) Purity: 99.65 percent (by HPLC)

Reference： [1] Patent: CN104487437, 2017, B, . Location in patent: Paragraph 0155-00157
[2] Patent: WO2011/120927, 2011, A1, . Location in patent: Page/Page column 12-13
[3] Patent: EP2377862, 2011, A1, . Location in patent: Page/Page column 7
[4] Patent: WO2012/131541, 2012, A1, . Location in patent: Page/Page column 25-26
[5] Patent: WO2007/77505, 2007, A2, . Location in patent: Page/Page column 9
[6] Patent: WO2004/85432, 2004, A1, . Location in patent: Page 14
[7] Patent: WO2013/21290, 2013, A1, . Location in patent: Page/Page column 27; 28
[8] Patent: WO2014/174532, 2014, A2, . Location in patent: Page/Page column 9; 15; 16
[9] Patent: CN106478618, 2017, A, . Location in patent: Paragraph 0051; 0053

2
[ 2022-85-7 ]
[ 147027-09-6 ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: at 25 - 130℃; Inert atmosphere Stage #2: With zirconium(IV) chloride In dichloromethane at 25 - 30℃; for 6 h; Inert atmosphere	Fluorocytosine (22.4 g, 0.173 mol, 1.1 molar equivalents), Hexamethyl disilazane (HMDS) (100 ml, 0.477 mol, 3.1 molar equivalents) and trimethylsilyl chloride (TMSCL), ( 1 1.2 ml) were mixed at 25-30°C under Nitrogen atmosphere. The reaction mixture was heated up to 120- 130°C to get clear solution and excess solvent was distilled out under vacuum at 90- 100°C to get the residue of silylated fluorocytosine. The residue of silylated fluorocytosine was cooled to room temperature and fresh dichlorome thane (100 ml) was added (solution A). In a separate flask L-menthyl-5R-acetoxy- l ,3-oxathiolane-2R-carboxylate (50 g, 0.151 mol, 1.0 molar equivalents), dichloromethane (250 ml) and zirconium tetrachloride (ZrCU) (17.6 g, 0.075 mole, 0.5 molar equivalents) were mixed under nitrogen atmosphere (solution B). Presilylated fluorocytosine solution A was added into solution B at 25-30°C and reaction mixture was stirred at the same temperature for 6 hrs. The reaction was monitored by HPLC or thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 10-20°C and precooled ( 10-20°C) water (250 ml) was added under stirring. pH was adjusted at 8 to 8.5 using triethylamine under stirring. The layers were separated and the organic layer was washed with 250 ml of water. The organic layer was concentrated under vacuum to get the residue. The residue was dissolved in methanol (200 ml) and n- heptane (100 ml) under stirring. The said solution was added into water (200 ml). The isolated solid was filtered and washed with water followed by n-heptane. The solid was dried under vacuum at 40-45°C. Yield: 48.5 g (80 percent). Chiral Purity: 99.94 percent; 0.06 percent undesired isomer. Ή NMR (DMSO-d6) δ (ppm): 0.70-0.99 (m, 10H), 1.02- 1.10 (m, 2H), 1.39- 1.49 8 (m, 2H), 1.63- 1.66 8 (d, 2H), 1.88- 1.95 8 (m, 2H), 3.20-3.24 8 (m, 1H), 3.53-3.57 8 (m, 1H), 4.66-4.72 (m, 1H), 5.71 8 (s, 1H), 6.29- 6.30 8 (d, 1H), 7.69 (s, 1H), 7.94 8 (s, 1H), 8.16-8. 18 8 (d, 1H); i3C NMR (DMSO- d6): 16.5, 20.9, 22.2.3.2, 26.1 , 31.8, 34, 35.8, 46.8, 76, 78.3, 89.5, 125.4, 135.2, 137.6, 153.4, 158, 169.8; IR (KBr) (cm-i): 3323, 3083, 2956, 2869, 1754, 1687, 1640, 1513, 1348, 1287, 1 178, 1090, 940, 774, 678, 498; MS (EI) m/z = 400 (M+ l); [a]_D²⁵ = -45.23° (c = 0.2percent, MeOH).

Reference： [1] Organic Letters, 2015, vol. 17, # 11, p. 2626 - 2629
[2] Patent: WO2013/21290, 2013, A1, . Location in patent: Page/Page column 24; 25

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[ 111878-21-8 ]
[ 288325-76-8 ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: With triethylamine In dichloromethane at 42 - 45℃; for 19 h; Heating / reflux Stage #2: at 25℃; for 0.5 h;	Example 1: Preparation of (5-Fluoro-2-trimethylsilanyloxy-pyrimidin-4-yl)- trimethylsilanyl-amine5-fluorocytosine (100 g), hexamethyldisilazane (400 mL) and ammonium sulphate (5 g) were charged at 25 ⁰C. The mixture was refluxed at 135 ⁰C for 4 hours where a clear solution was obtained. The solution was cooled to 80 ⁰C and excess hexamethyldisilazne was recovered under vacuum at a pressure of 700 mm Hg to form a residue. The residue <n="9"/>was cooled to 30 ⁰C and methylene chloride (1000 mL) was added. To this mixture triethylamine (140 mL) was added over 0.5 hours at 25 ⁰C and the resultant mixture stirred for 0.5 hours at 25 ⁰C and used as such in the next step.; Example 2: Preparation of 5S-Chloro-[l,3]oxathiolane-2R-carboxylic acid 2-(l'R, 2'S, S'RHsopropyl-S-methyl-cyclohexyl esterMethylene chloride (3000 mL), 5R-Hydroxy-[l,3]oxathiolane-2S-carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (300 g), methanesulphonic acid (1 mL) and dimethylformamide (85 mL) were charged at 25 ⁰C and the mixture stirred for 0.5 hours at 25 ⁰C. The mixture was cooled to 5 ⁰C to 10 ⁰C and thionyl chloride (80 mL) was added at 5 ⁰C to 10 ⁰C over 0.5 hours. The reaction mixture was stirred 10 ⁰C to 15 ⁰C for 2 hours. Excess methylene chloride was recovered under vacuum at a pressure of 650-700 mmHg and 40 ⁰C to 45 ⁰C to get a residue. To the residue methylene chloride (600 mL) was added and the excess methylene chloride was recovered under vacuum at a pressure of 650-700 mm Hg and 40 ⁰C to 45 ⁰C to get a residue. To the residue methylene chloride (600 mL) was added and the mixture used as such in the next step.; Example 3: Preparation of crystalline L-menthyl emtricitabineThe mixture obtained in Example 1 was refluxed at 42 ⁰C to 45 ⁰C. The mixture obtained in Example 2 was slowly charged over 1 hour at refluxing temperature. The combined reaction mixture was refluxed for 18 hours at 42 ⁰C to 45 ⁰C and the reaction was monitored by high performance liquid chromatography. The mixture was cooled to 25 ⁰C and deionized water (500 mL) was added at 25 ⁰C. The resultant mixture was stirred for 0.5 hours at 25 ⁰C. The organic layer was separated and washed twice with a concentrated hydrochloric acid solution (1 mL) and deionized water (500 mL) and then with aqueous sodium chloride solution (10percent, 500 mL) at 25 ⁰C. The organic layer was recovered under vacuum at a pressure of 650-700 mm at 40 ⁰C to 45 ⁰C to get a residue. To the residue ethyl acetate (1000 mL) was charged at 25 ⁰C and the mixture refluxed at 78 ⁰C. To the mixture methanol (200 mL) was charged slowly and the resultant mixture slowly cooled to 25 ⁰C over 2 hours. The product so obtained was filtered and dried under vacuum at 30 ⁰C to 35 ⁰C to obtain the title compound. Yield: 25O g (81percent) <n="10"/>XRD as per Figure 1 DSC as per Figure 2 Purity: 100percent (by HPLC)

Reference： [1] Patent: WO2007/77505, 2007, A2, . Location in patent: Page/Page column 8

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Yield	Reaction Conditions	Operation in experiment
50.5%	Stage #1: With thionyl chloride In dichloromethane at 0 - 15℃; for 2 h; Stage #2: With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane In tolueneReflux Stage #3: at 90℃; Reflux	720 g Emtricitabine Intermediate IV 7.2 L dichloromethane was added, 20 mL DMF, Cooled to 0 ~ 5 deg C, A solution of 192 mL of thionyl chloride in 1.2 L of dichloromethane was added dropwise. After stirring for 2 hours at 10-15 ° C, Concentrated under reduced pressure, Then add 2.2 L of toluene and cool for use. 324 g of 5-fluorocytosine, 12g ammonium sulfate, 600mL hexamethyldisilazane, 960 mL of toluene was added, Heated to reflux for 1 to 2 hours. Slightly cooled to below 90 deg C, Add dropwise 350 mL of triethylamine, It was heated to reflux, but not vigorous. The chlorinated solution prepared above was added dropwise, Wash with 240 mL of toluene. Reflux for 2 to 3 hours, Cooled to 30 ~ 35 deg C, Dropping a solution of 180 mL triethylamine in water 2.9 L, Cooled to 15 ~ 20 deg C, Stirred for 1 hour, 2.9 L of n-heptane was dropped, Stir for 16 hours, filter, Washed, Emtricitabine Intermediate III was obtained after drying, 504g, Yield 50.5percent HPLC purity 98.17percent.
50.5%	Stage #1: With thionyl chloride In dichloromethane; toluene; N,N-dimethyl-d₆-formamide at 10 - 15℃; for 2 h; Stage #2: With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane; N,N-dimethyl-formamide; tolueneReflux	720 g Emtricitabine Intermediate IV 7.2 L dichloromethane was added,20mLDMF, cooled to 0 ~ 5 ,A solution of 192 mL of thionyl chloride in 1.2 L of dichloromethane was added dropwise.After stirring at 10-15 ° C for 2 hours, concentrated under reduced pressure,Then add 2.2 L of toluene and cool for use.324 g of 5-fluorocytosine, 12 g of ammonium sulfate, 600 mL of hexamethyldisilazane, 960 mL of toluene was added and the mixture was heated to reflux1 ~ 2 hours. Slightly cooled to below 90 , 350mL triethylamine dropwise, heated to reflux but not severe.The chlorinated solution prepared above was added dropwise and washed with 240 mL of toluene. Refluxed for 2 to 3 hours, cooled to 30 to 35 ° C, and added dropwise 2.9 mL of a solution of 180 mL of triethylamine in water, cooled to 15 to 20 ° C and stirred for 1 hour,2.9 L of n-heptane was added dropwise and the mixture was stirred for 16 hours, filtered, washed with water and dried to yield Emtricitabine Intermediate III,504g, yield 50.5percentHPLC purity 98.17percent.

Reference： [1] Patent: CN106496208, 2017, A, . Location in patent: Paragraph 0047; 0048; 0049
[2] Patent: CN106478618, 2017, A, . Location in patent: Paragraph 0048; 0049; 0050

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[ 764659-72-5 ]

Reference： [1] Patent: WO2009/84033, 2009, A2, . Location in patent: Page/Page column 8-9

6
[ 147126-65-6 ]
[ 764659-72-5 ]

Reference： [1] Patent: WO2004/85432, 2004, A1, . Location in patent: Page 14

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[ 111969-64-3 ]
[ 764659-72-5 ]

Reference： [1] Patent: WO2013/21290, 2013, A1,
[2] Organic Letters, 2015, vol. 17, # 11, p. 2626 - 2629
[3] Organic Letters, 2015, vol. 17, # 11, p. 2626 - 2629

8
[ 200396-19-6 ]
[ 764659-72-5 ]

Reference： [1] Organic Letters, 2015, vol. 17, # 11, p. 2626 - 2629
[2] Organic Letters, 2015, vol. 17, # 11, p. 2626 - 2629

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[ 147126-62-3 ]
[ 764659-72-5 ]

Reference： [1] Patent: WO2011/83484, 2011, A2,

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[ 1144099-18-2 ]
[ 764659-72-5 ]

Reference： [1] Patent: WO2011/83484, 2011, A2,

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[ 1321928-75-9 ]
[ 764659-72-5 ]

Reference： [1] Patent: WO2011/95987, 2011, A1, . Location in patent: Page/Page column 33

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[ 1309459-32-2 ]
[ 764659-72-5 ]

Reference： [1] Patent: WO2011/95987, 2011, A1,

13
[ 1321928-66-8 ]
[ 764659-72-5 ]

Reference： [1] Patent: WO2011/95987, 2011, A1,

[ 764659-72-5 ] Synthesis Path-Downstream 1~26

1
[ 764659-72-5 ]
[ 143491-57-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium tetrahydroborate; dipotassium hydrogenphosphate; water; sodium hydroxide; In ethanol; at 20℃;	Potassium hydrogen phosphate (26.91 g, 117.9 mmol) was added to water (43 ml), stirred and dissolved,(2R, 5S) - (5-fluorocytosidin-1-yl) -1,3-oxathiolane-2-carboxylic acid L-menthyl ester (15 g, 37.5 mmol)Ethanol (106 ml) was added.Sodium borohydride (3 g, 79 mmol) was added dropwise at room temperature,Of 0.12 mol / L aqueous sodium hydroxide solution (14.4 ml).After completion of the dropwise addition, the mixture was stirred at room temperature until the reaction was complete. Static stratification.The organic layer was separated, adjusted to pH = 4 with 6 mol / L hydrochloric acid, and adjusted to pH 7 with 2 mol / L aqueous sodium hydroxide solution.Concentrated under reduced pressure. To the resulting residue was added water (200 ml) and washed with toluene (3 x 110 ml). Salicylic acid (5.19 g, 37.5 mmol) was added and the mixture was heated to 70-80 C.Inoculated, cooled to room temperature and filtered, dried in vacuo (80 C, 4 h)Deltamethasone salicylate (10.1 g, yield 70%): Moisture (Karl Fischer Titration) 0.35%
65%		Example 1; Preparation of emtricitabine via B(0'Pr)3 A suspension of (2R,5S)-((1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 5-(4-amino-5- fluoro-2-oxopyrimidin-1 (2H)-yl)-1 ,3-oxathiolane-2-carboxylate (30.0 g) in MeOH (300 mL) was cooled to -7 C under a nitrogen atmosphere. Then, NaBH4 (6.8 g) was added in portions for 1 h and the reaction mixture was stirred at -5 C for 5 h. The resulting solution was heated to 5C, water (105 mL) was added and was slowly titrated to pH 5.5 with 35% aqueous H CI solution at 1 0 C . The solution was concentrated under reduced pressure to 140 mL total internal volume. Toluene (90 mL) was added and the layers were separated after 10 min stirring. The aqueous phase was washed again with toluene (2 x 90 mL) and, after phase separation, neutralized (pH 7.5) with 25% aqueous NaOH solution. Part of the solvent was evaporated under reduced pressure until reaching a internal volume of 60 mL. Celite (6 g) was charged to the aqueous solution and the mixture stirred for 5 min. Isopropanol (300 mL) was added and the solvent was evaporated under reduced pressure until the residual volume reached 75 mL. This last operation was repeated twice. Isopropanol (470 mL) was added and the suspension was heated to 60 C, stirred for 1 h, filtered while hot and washed with hot isopropanol (2 x 30 mL). The filtrate and washing were combined and partially concentrated under reduced pressure to 75 mL total internal volume. MeOH (1 50 m L) was charged and the mixture was concentrated under reduced pressure to 75 mL, thus removing the boron species. Isopropanol (300 mL) was added and the solvent was evaporated under reduced pressure to 160 total internal volume. The suspension was heated to 80 C and water (6 mL) was added . The resulting solution was cooled to 60 C, seeded, stirred for 1 h at 60 C, cooled to 0 C and held at this temperature for 1 h. The solid was collected by filtration, washed with chilled isopropanol (2 x 15 mL) and dried in vacuo (40 C) to give 12.1 g of emtricitabine (65% yield; purity by H PLC 99.77 area %; assay by H PLC 99.8% w/w; boric acid and chloride not detected by capillary electrophoresis).
65%	With methanol; sodium tetrahydroborate; at -7 - -5℃; for 6h;Inert atmosphere;Product distribution / selectivity;	A suspension of (2R,5S)-((1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolane-2-carboxylate (30.0 g) in MeOH (300 mL) was cooled to -7 C under a nitrogen atmosphere. Then, NaBH4 (6.8 g) was added in portions for 1 h and the reaction mixture was stirred at -5 C for 5 h. The resulting solution was heated to 5C, water (105 mL) was added and was slowly titrated to pH 5.5 with 35% aqueous HCl solution at 10 C. The solution was concentrated under reduced pressure to 140 mL total internal volume. Toluene (90 mL) was added and the layers were separated after 10 min stirring. The aqueous phase was washed again with toluene (2 x 90 mL) and, after phase separation, neutralized (pH 7.5) with 25% aqueous NaOH solution. Part of the solvent was evaporated under reduced pressure until reaching a internal volume of 60 mL. Celite (6 g) was charged to the aqueous solution and the mixture stirred for 5 min. Isopropanol (300 mL) was added and the solvent was evaporated under reduced pressure until the residual volume reached 75 mL. This last operation was repeated twice. Isopropanol (470 mL) was added and the suspension was heated to 60 C, stirred for 1 h, filtered while hot and washed with hot isopropanol (2 x 30 mL). The filtrate and washing were combined and partially concentrated under reduced pressure to 75 mL total internal volume. MeOH (150 mL) was charged and the mixture was concentrated under reduced pressure to 75 mL, thus removing the boron species. Isopropanol (300 mL) was added and the solvent was evaporated under reduced pressure to 160 total internal volume. The suspension was heated to 80 C and water (6 mL) was added. The resulting solution was cooled to 60 C, seeded, stirred for 1 h at 60 C, cooled to 0 C and held at this temperature for 1 h. The solid was collected by filtration, washed with chilled isopropanol (2 x 15 mL) and dried in vacuo (40 C) to give 12.1 g of emtricitabine (65% yield; purity by HPLC 99.77 area %; assay by HPLC 99.8% w/w; boric acid and chloride not detected by capillary electrophoresis).

62%	With sodium tetrahydroborate; dipotassium hydrogenphosphate; water; In isopropyl alcohol; at 15 - 20℃;Product distribution / selectivity;	To a 2.0 L capacity jacketed flask equipped with a mechanical stirrer, thermometer pocket, dipotassium hydrogen phosphate (147. lg) and water (330ml) was charged and stirred the reaction mixture for 15 minutes. To the reaction mixture then charged isopropyl alcohol (800ml) and further stirred for 15 minutes and cooled the reaction mixture to a temperature of 15C to 20C. Then charged FCME (lOOg) dissolved in isopropyl alcohol (100ml) to the reaction mixture and stirred at a temperature of 15C to 20C for 1 hour. A separately prepared solution of sodium borohydride (26g) dissolved in aqueous sodium hydroxide was added dropwise to the reaction mixture over the period of 1-1.5 hours. The reaction mixture further stirred for 4 - 5 hours and the two layers formed were separated. To the separated organic layer 20% (v/v) dilute hydrochloric acid (4.6ml) was added dropwise to adjust the pH to 8.0-8.5 and the reaction mixture was further stirred for 15 minutes. The reaction mixture was then distilled out and the aqueous solution obtained was extracted with toluene (200ml). The reaction mixture then treated with charcoal (5g) and filtered. The filtrate obtained was distilled out to obtain a liquid and diluted with isopropyl alcohol (200ml), distilled out the isopropyl alcohol. Diluted the reaction mixture again with isopropyl alcohol (200ml) and distilled out. The reaction mixture further diluted with isopropyl alcohol (400ml) and refluxed the reaction mixture to a temperature of 85C to 90C for 30 minutes to obtain the residue. Cooled the reaction mixture and filtered, the filtrate obtained was then distilled out to obtain the residue. Diluted the residue obtained with ethanol (100ml) and distilled out. The reaction mixture again diluted with ethanol (200ml) and heated at a temperature of 85C to 90C for 30 minutes and then cooled at a temperature of 10C to 15C to precipitate the product, emtricitabine. The resulting product was filtered and washed with ethanol. Dry the product under vacuum.Yield = 62%Assay = 98.7%Purity = 99.86%
57.4%		Example 4: Preparation of EmtricitabineDenatured spirit (210 mL) and menthyl emtricitabine (24.5 g) were charged at 25- 30 0C. The mixture was cooled to 15-20 0C and charged with a solution of dipotassium hydrogen phosphate (30 g) and water (30 mL) at 25-300C and stirred for 0.5 hour at 25-30 0C. The stirred mixture was cooled to 15 0C and charged with sodium borohydride (4.66 g) and deionized water (30 mL) over 1.5 hour maintaining the temperature of the reaction mixture below 25 0C. The reaction mixture was stirred at the same temperature till the level of menthyl emtricitabine was less than 0.5 % as measured by High Performance Liquid Chromatography. The reaction mixture was allowed to stand for 0.5 hour at 25-30 0C. The organic layer was separated and the pH adjusted to 7.2 with concentrated hydrochloric acid (0.5 mL) at 25-30 0C. To the resultant mixture activated carbon (3 g) was added at 25-30 0C. The mixture was stirred for 0.5 hour, filtered through hyflo bed and washed with denatured spirit (30 mL) at 25-30 0C. The stirred mixture was concentrated under vacuum (720 mmHg) at 45 0C to an oily residue. The residue was charged with absolute ethanol (75 mL) and the resultant mass was concentrated under vacuum (720 mm Hg) at 45 0C to a foamy residue. The foam was charged with absolute ethanol (75 mL) and the resultant mass was concentrated under vacuum (720 mmHg) at 45 0C to a foamy residue. The residue was charged with absolute ethanol (60 mL) at 25-30 0C and the temperature of the resultant mixture raised to 78 0C and the mixture was refluxed for 0.5 hour. The mixture was cooled slowly to 60 0C in 1 hour and stirred for 1 hour at 60 0C and further cooled to 25-30 0C in 1 hour and stirred at the same temperature for 4 hours. The solid so obtained was filtered, washed with ethyl acetate (30 mL) at 25- 30 0C and dried under vacuum at 40-45 0C for 12 hours to afford the title compound. Yield: 8.6 g (57.4%) Purity: 99.65 % (by HPLC)
	With sodium hydroxide; sodium tetrahydroborate; dipotassium hydrogenphosphate; water; potassium hydrogencarbonate; In tetrahydrofuran; methanol; at 0 - 25℃; for 3 - 4h;	2 S-ISOPROPYL-5 R-METHYL-9 R-CYCLOHEXYL (2R, 5S)-5- (4-AMINO-5-FLUORO-2-OXO-2H- pyrimidin-1-yl) [1,3] oxathiolane-2-carboxylate (31.5 g) was suspended in a mixture of tetrahydrofuran (140 ml), methanol (28 ML) and water (46.6 g). Potassium bicarbonate (6.5 g) and potassium hydrogen phosphate (14 g) were added. The suspension was cooled to 0-5C and a solution of sodium borohydride (11.2 g) and 30% sodium hydroxide (1.1 ml) in water (112 mi) was added slowly over about 2-3 hours. The reaction mixture was then stirred at 20-25C for 1 hour. The pH was then brought to 4.0 with 37% hydrochloric acid and the organic solvents were then evaporated off under vacuum. The remaining aqueous phase was extracted three times with toluene (3 x 70 ML) and the pH of the aqueous solution was then brought to 7.3-7. 4 with 30% sodium hydroxide and the water was evaporated off under vacuum. The residue was taken up in isopropanol (100 mi) and evaporated under vacuum, and then taken up again in isopropanol (200 ML). The mineral salts were filtered off and the filtrate was evaporated under vacuum. The crude product was dissolved in methanol (15 ml) and crystallized by adding isopropyl acetate (35 ML). The suspension was stirred overnight at 20C and the solid was filtered off and dried to give 5 g of emtricitabine.
		Di-potassium hydrogen phosphate ( 65.5 g, 0.376 mol, 3.0 molar equivalents) and DM water (75 ml) as mixed at RT and L-menthyl-5S-(4-amino-5-fluro-2- oxopyrimidin- l-(2H)-yl)- l,3-oxathiolane-2R-carboxylate (50 g, 0.125 mol, 1.0 molar equivalents) in ethanol (350 ml) was added to it. The reaction mixture was cooled to 15-20C (solution A). In another flask sodium borohydride (NaBH4) (13.5 g, 0.330 mol, 2.85 molar equivalents) in DM water (135 ml) containing 25% w/w NaOH was dissolved at 10- 15C (solution B). Solution B was added into solution A at 15-20C. The reaction was maintained at 15-20C and monitored by TLC or HPLC. After completion of reaction the layers were separated and adjusted the pH of upper layer to 4-4.5 using the concentrated HC1 (20 ml) and then to pH 6.8-7.2 using 2M NaOH solution. The mixture was stirred and concentrated under vacuum. Water (150 ml) was added to the mixture followed by activated Carbon (5 gm). The mixture was heated up to 70-75C and maintained for 30 min. The mixture was filtered through Celite bed. The filtrate was cooled to RT and washed with toluene. Aqueous layer was concentrated under vacuum and co-distill the traces of water with methanol (50 ml x 2). The residue was dissolved in methanol (300 ml) and heated to 60-65C for 30 min under stirring. The inorganic solid mixture was filtered and the filtrate was distilled under vacuum up to 1 volume remains in the flask. The mixture was stirred and isolated solid was filtered. The wet cake of solid product was washed with methanol (10 ml) and suck dried. The solid product was further dried under vacuum to afford crude Emtricitabine. Yield: 25 g. Chiral Purity: cis-(-) Emtricitabine = 98% and cis-(+) Emtricitabine = 2 %. ? NMR (DMSO-d6) 8 (ppm): 3.10-3.14 (m, 1H), 3.40-3.44 (m, 1H), 3.70-3.81 (m, 2H), 5. 17- 5.19 (t, 1H), 5.43-5.45 (t, 1H), 6.13-6.15 (t, 1H), 7.59 8 (s, 1H), 7.84 8 (s, 1H), 8.20- 8.22 (d, 1H); i3C NMR (DMSO-d6) 8 (ppm): 37.2, 62.5, 87, 126.2, 135, 137.4, 153.4, 158; IR (KBr) (cm-'): 3420, 3248, 3104, 3083, 29.02, 1695, 1625, 1520, 1407, 1343, 1298, 1251 , 1 169, 1092, 776, 619, 465; MS (EI) m/z = 246 (M- l); [a]D20 = - 106.47 (c = 0.25%, water), [a]D25 = - 141.37 (c = 1%, MeOH).
	With sodium tetrahydroborate; dipotassium hydrogenphosphate; In water; isopropyl alcohol; at 8 - 12℃; for 9.25h;	To a 2.0 L round bottom flask equipped with a mechanical stirrer, thermometer pocket, water (330 ml) and dipotassium hydrogen orthophosphate (137 g) was charged. The reaction mixture was allowed to cool to 25-35C and stirred for 10 min. To the reaction mixture, isopropanol (800 ml) was charged at 25-35C, cooled to 8-12C and then charged with L-menthyl emtricitabine (100 g). To the reaction mixture, sodium borohydride (20 g) was added lot wise over 5 hr 15 min in 8 equal lots and in equal time intervals at 8-12C and stirred the reaction mass for 4 hrs at same temperature. After completion of the reaction by HPLC, the two layers were separated. To the organic layer diluted sulphuric acid (3.5 g of H2S04 dilute with 35 ml of D.M water) was added to adjust the pH to 5-6 at 8-12C, and the reaction mass temperature was raised to 25-35C, stirred for 30 min and filtered the undissolved salts. To the filtrate, aqueous ammonia (4 ml) was added to adjust the pH to 8-8.5 at 25-35C and the reaction mass was distilled out and the aqueous solution was extracted with toluene (200+100 ml). The two layers formed were separated and the aqueous layer was filtered and the organic layer was washed with water (50 ml). The total aqueous layer was treated with charcoal (lOg) and filtered. The filtrate obtained was distilled out completely under vacuum at below 60C to get residue. The residue was diluted with isopropanol (200 ml) and distilled out isopropanol completely at below 60C to obtain semisolid material. The semisolid material was allowed to cool to 25-35C and further diluted with isopropanol (600 ml) and heated to about 75-82C and stirred for 30 minutes. The reaction mixture was allowed to cool to 70-75 C and filtered. The filtrate obtained was distilled out completely at below 60C to obtain semisolid material. The semisolid material was diluted with acetone (100 ml) at 55C and distilled out acetone completely to obtain residue. The obtained residue was again diluted with acetone (300 ml) at about 55C and then cooled to 5-10C. The reaction mass was stirred for 2 hrs at the same temperature and filtered to obtain wet cake. The obtained wet cake was dried at 50- 55C to obtain crude Emtricitabine. The crude Emtricitabine was diluted with isopropanol (660 ml) at 25-35C and the reaction mass was heated to reflux temperature (78-82C), stirred for 30 min at same temperature followed by allowed to cool to 68-72C and treated with charcoal (4.4 g) and filtered. The filtrate obtained was partially concentrated at 65-70C and then cooled to 5-10C. The reaction mass was maintained 4 hrs at the same temperature and the product was filtered, washed with isopropanol. The wet product was dried at 60-65C for 12 hrs to provide the title compound. Yield: 44 gms Purity: 99.86% Acid impurity: 0.10%.
	With sodium tetrahydroborate; potassium dihydrogenphosphate; sodium hydroxide; In ethanol; water; at 10 - 30℃;	420 g Emtricitabine Intermediate III (HPLC purity: 98.17%) was added to 540 g of potassium dihydrogen phosphate, 600 ml of water,Ethanol 300mL, at 10 ~ 15 C was added dropwise 160g of sodium borohydride in 800mL of water and 8mL mass percentage of 25% aqueous sodium hydroxide solution (the mass percentage refers to the mass percentage of sodium hydroxide aqueous sodium hydroxide solution as a percentage of the total mass ),Stirring at 20 ~ 30 for 2 ~ 3 hours,The mixture was adjusted to pH 4~5 with 1 mol / L hydrochloric acid, stirred for 0.5 hour, adjusted to pH 7 with 2 mol / L aqueous sodium hydroxide and extracted three times with toluene and water. The organic phase is discarded as menthol. The aqueous phase was separated and concentrated to dryness Emtricitabine I crude (HPLC purity 95.73%).
22.69 g		Add 21.5 g (0.05 mol) of 5S-(5'-fluorocytosinyl)-1,3-oxathiolan-2R-carboxylic acid menthyl ester and 150 ml of tetrahydrofuran to the reactor at room temperature of 25 C. Slowly add a solution of 10% NaOH (1.2 ml) and 5.45 g (0.11 mol) of KBH4 in 60 ml of water. After the dropwise addition, the reaction is held for 2 hours.After 5S- (5'-fluorocytosinyl) -1,3-oxetane-2R-menthyl carboxylate was sufficiently reduced by KBH4, it was allowed to stand and separate.The organic phase was adjusted to pH 4.0-4.5 with 10% dilute hydrochloric acid, and then adjusted to pH 6.8-7.2 with 2mol / L NaOH solution.The solvent was distilled off under reduced pressure, 7.6 g (0.055 mol) of salicylic acid was added, the temperature was raised to 60 C, and the reaction was stirred for 2 h. After the salt-forming reaction has fully proceeded, it is cooled to 0 C., kept under stirring for 1 h, filtered, and dried to obtain 20.41 solid form of emtricitabine salicylate. The calculated yield is 89.72%. 7) Preparation of emtricitabine:Add 40.3 g (0.1 mol) emtricitabine salicylate, 320 ml of absolute ethanol and 15.15 g (0.15 mol) of ethylamine to the reactor, warm to 50 C, and hold the reaction for 1 h. After emtricitabine salicylate was sufficiently recrystallized, the solvent was distilled off under reduced pressure, 300 ml of ethyl acetate was added, and the mixture was cooled to 10 C. and kept under stirring for 1 h.Filtration, washing twice with 100 ml of ethyl acetate, and drying to obtain 22.69 g of emtricitabine in the form of a white powder. The calculated yield is 91.88%

Reference： [1]Patent: CN104487437,2017,B .Location in patent: Paragraph 0155-00157
[2]Patent: WO2011/120927,2011,A1 .Location in patent: Page/Page column 12-13
[3]Patent: EP2377862,2011,A1 .Location in patent: Page/Page column 7
[4]Patent: WO2012/131541,2012,A1 .Location in patent: Page/Page column 25-26
[5]Patent: WO2007/77505,2007,A2 .Location in patent: Page/Page column 9
[6]Patent: WO2004/85432,2004,A1 .Location in patent: Page 14
[7]Patent: WO2013/21290,2013,A1 .Location in patent: Page/Page column 27; 28
[8]Patent: WO2014/174532,2014,A2 .Location in patent: Page/Page column 9; 15; 16
[9]Patent: CN106478618,2017,A .Location in patent: Paragraph 0051; 0053
[10]Patent: CN110467608,2019,A .Location in patent: Paragraph 0028; 0035; 0036; 0038

2
5-chloro-[1,3]oxathiolane-2-carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester [ No CAS ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
		In another flask, a mixture of 5-FLUOROCYTOSINE (20 g), HEXAMETHYLDISILAZANE (43 ML) and methanesulphonic acid (0.2 ml) in toluene (75 ML) was refluxed for about 3 hours. The reaction mixture was then distilled under vacuum down to a residue, methylene chloride (about 100 ml) was then added and the mixture was re- evaporated under vacuum. The residue was then redissolved in methylene chloride (250 ml) and triethylamine (28 mi) was added dropwise at 20-25C. This 5-fluorocytosine silylate mixture was heated to reflux and the solution prepared in point A was slowly added dropwise over 2-3 hours while maintaining the reflux. The reaction mixture thus obtained was refluxed for about 18 hours and then cooled to 20-25C and water (150 ml) was added.

Reference： [1]Patent: WO2004/85432,2004,A1 .Location in patent: Page 12-13
[2]Patent: WO2011/95987,2011,A1

3
[ 147126-65-6 ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of 5-fluorocytosine (3.8 g), HEXAMETHYLDISILAZANE (8.1 mi) and methanesul- phonic acid (0.02 ml) in toluene (27 ml) was refluxed for about 3 hours. The reaction mixture was then distilled to dryness under vacuum and methylene chloride (about 15 ML) was then added and re-evaporated under vacuum. The residue was then redis- solved in methylene chloride (30 mi) and a solution of 2S-ISOPROPYL-5R-METHYL-1R- cyclohexyl (2R, 5S)-5-acetoxy [1, 3] oxathiolane-2-carboxylate (12.1 g) in methylene chloride (30 mi) was added. TRIMETHYLIODOSILANE (5.3 ml) was added slowly and the reaction mixture was stirred at room temperature for about 2 hours. The mixture was diluted with methylene chloride (400 ml) and the aqueous phase was washed with saturated sodium metabisulphite solution (100 ml) and then with water (100 ml) and with saturated sodium chloride solution (100 ML).

Reference： [1]Patent: WO2004/85432,2004,A1 .Location in patent: Page 14

4
[ 111878-21-8 ]
[ 288325-76-8 ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
81%		Example 1: Preparation of (5-Fluoro-2-trimethylsilanyloxy-pyrimidin-4-yl)- trimethylsilanyl-amine5-fluorocytosine (100 g), hexamethyldisilazane (400 mL) and ammonium sulphate (5 g) were charged at 25 0C. The mixture was refluxed at 135 0C for 4 hours where a clear solution was obtained. The solution was cooled to 80 0C and excess hexamethyldisilazne was recovered under vacuum at a pressure of 700 mm Hg to form a residue. The residue <n="9"/>was cooled to 30 0C and methylene chloride (1000 mL) was added. To this mixture triethylamine (140 mL) was added over 0.5 hours at 25 0C and the resultant mixture stirred for 0.5 hours at 25 0C and used as such in the next step.; Example 2: Preparation of 5S-Chloro-[l,3]oxathiolane-2R-carboxylic acid 2-(l'R, 2'S, S'RHsopropyl-S-methyl-cyclohexyl esterMethylene chloride (3000 mL), 5R-Hydroxy-[l,3]oxathiolane-2S-carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (300 g), methanesulphonic acid (1 mL) and dimethylformamide (85 mL) were charged at 25 0C and the mixture stirred for 0.5 hours at 25 0C. The mixture was cooled to 5 0C to 10 0C and thionyl chloride (80 mL) was added at 5 0C to 10 0C over 0.5 hours. The reaction mixture was stirred 10 0C to 15 0C for 2 hours. Excess methylene chloride was recovered under vacuum at a pressure of 650-700 mmHg and 40 0C to 45 0C to get a residue. To the residue methylene chloride (600 mL) was added and the excess methylene chloride was recovered under vacuum at a pressure of 650-700 mm Hg and 40 0C to 45 0C to get a residue. To the residue methylene chloride (600 mL) was added and the mixture used as such in the next step.; Example 3: Preparation of crystalline L-menthyl emtricitabineThe mixture obtained in Example 1 was refluxed at 42 0C to 45 0C. The mixture obtained in Example 2 was slowly charged over 1 hour at refluxing temperature. The combined reaction mixture was refluxed for 18 hours at 42 0C to 45 0C and the reaction was monitored by high performance liquid chromatography. The mixture was cooled to 25 0C and deionized water (500 mL) was added at 25 0C. The resultant mixture was stirred for 0.5 hours at 25 0C. The organic layer was separated and washed twice with a concentrated hydrochloric acid solution (1 mL) and deionized water (500 mL) and then with aqueous sodium chloride solution (10%, 500 mL) at 25 0C. The organic layer was recovered under vacuum at a pressure of 650-700 mm at 40 0C to 45 0C to get a residue. To the residue ethyl acetate (1000 mL) was charged at 25 0C and the mixture refluxed at 78 0C. To the mixture methanol (200 mL) was charged slowly and the resultant mixture slowly cooled to 25 0C over 2 hours. The product so obtained was filtered and dried under vacuum at 30 0C to 35 0C to obtain the title compound. Yield: 25O g (81%) <n="10"/>XRD as per Figure 1 DSC as per Figure 2 Purity: 100% (by HPLC)

Reference： [1]Patent: WO2007/77505,2007,A2 .Location in patent: Page/Page column 8

5
[ 764659-72-5 ]
[ 258832-61-0 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of dipotassium hydrogen phosphate (137 g) in water (330 ml) was stirred for 10 mins. Ethanol (900 ml) was added and the mass was cooled to 18C. (2R, 5S)-5-(4-Amino-5-fluoro-2-oxo-2H-pyrimidin-l-yl)-[l,3]-oxathiolane-2- carboxylic acid, 2S-isopropyl-5R-methyl-lR-cyclohexyl ester (100 gm} was added at 15-200C. The suspension was stirred for 1 hr at 18-2O0C. A solution of sodium borohydride [(20 gm) in 0.12 N Sodium hydroxide solution (95 ml)] was added dropwise maintaining the temperature at 18-200C. The mixture was stirred at 18- 220C for 4 hrs. On completion of the reaction as confirmed by TLC, the reaction mass was transferred into a separating funnel and the layers were separated. pH of organic layer was adjusted to 6.0-6.5 with 6 N HCl (-13 ml) and again adjusted to pH 8.0 to 8.5 with 2N Sodium hydroxide. Reaction mass was transferred and distilled at atmospheric pressure to ~ 250 ml residual volume. Residue was cooled to 25-350C. Menthol was extracted with toluene. Aqueous solution is decolourised with activated carbon (5 gm) and filter bed is washed with water (100 ml). Water is distilled under vacuum at 45-55C to thick mass. Residual moisture was recovered by co-distillation with isopropanol. Finally thick mass was dissolved in isopropanol (500 ml) by heating to reflux and maintaining for 30 mins. The isopropanol solution was cooled to 25-35C. A solution of IPA. HCl (75 gms -15% w/w) was added during at 25- 35C. The suspension of hydrochloride salt was maintained for 1 hr at 25- 50C. The <n="11"/>mass was cooled to 00C and stirred for 2 hrs at 0- 5C. The off white to light brown solid is collected by filtration and solid was washed with chilled isopropanol (50 ml)The product is dried at 5O-55C to give 59 gm off white-light brown coloured HCl salt

Reference： [1]Patent: WO2009/84033,2009,A2 .Location in patent: Page/Page column 9-10

6
[ 2022-85-7 ]
(2R,5R)-5-hydroxy-[1,3]-oxathiolane-2-carboxylic acid, 2S-isopropyl-5R-methyl-1R-cyclohexyl ester [ No CAS ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
		Methylene chloride (450 ml) and methane sulfonic acid (0.80 g) was charged and the solution was cooled to 2O0C. (2R, 5R)-5-Hydroxy-[l,3]-oxathiolane-2- carboxylic acid, 2S-isopropyl-5R-methyl-lR-cyclohexyl ester (100 g,) was charged at 200C. To this solution dimethyl formamide (28 g) was added. The solution was further cooled to 8C. Thionyl chloride (44 g) was added drop wise at 8-1O0C. The temperature of the reaction mass was maintained at 10-150C for 4 hrs. The reaction mass was heated to reflux and maintained at reflux temperature for 4 hrs. Methylene chloride was distilled at atmospheric pressure up to residual volume of 300 ml-350 ml5-Fluorocytosine (45 g) was dissolved in toluene (120 ml) and subsequently hexamethyldisilazane (65.4 g) and methane sulfonic acid (0.4 g) were added. The entire reaction mass was heated to reflux and maintained for 5 hrs. 40 ml toluene was> distilled at atmospheric pressure. The reaction mass was cooled to 650C and triethylamine (35.5 g) was added at 65C. The reaction mass was cooled to 600C and the above residue was added drop wise at 55 - 65C. Temperature was maintained at mild reflux (53-560C) for 5 hrs. The reaction was monitored by HPLC and then reaction mass was cooled to 350C. The above reaction mass was added to a mixture of water (600 ml) and triethylamine (24.5 g) during at 25- 350C. The reaction mass was stirred for 1 hr at 25-35C. pH of the mass was adjusted to 7.8 with triethylamine. The organic layer was separated and solvent was distilled under vacuum completely <n="10"/>to give thick residue and a mixture of n-hexane (450 ml) and ethylacetate (50 ml) were added. The suspension was heated to reflux and maintained at reflux temperature for 2 hrs. The mass was slowly cooled to 25-35C. Stirring wais maintained for 10 hrs at 25-35C. Off white to light brown solid is filtered and washed with water.Wet cake was suspended in a mixture of water (200 ml), hexane (100 ml) and ethylacetate (100 ml). The suspension was stirred for 1 hr at 25-350C and filtered, washed with water (200 ml). Solid was dried at 60-650C to give 78 gm

Reference： [1]Patent: WO2009/84033,2009,A2 .Location in patent: Page/Page column 8-9

7
[ 764659-72-5 ]
[ 110-15-6 ]
[ 1235712-39-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 8:Preparation of 4-amino-5-fluoro- l-[(2R,5S)-2-(hydroxymethyl)-[l,31-oxathiolan-5- ylj-(l H)-pyrimidin-2-one monosuccinate monohydrate (emtricitabine succinate monohydrate); Ethanol (350 ml) was added to a solution of dipotassium hydrogen phosphate (52 gm) in water (70 ml) at room temperature. The reaction mass was cooled to 12C and (2R,5S)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin- l -yl)-[ l ,3]-oxathiolane-2-carboxylic acid, 2S-isopropyl-5R-methyl- l R-cyclohexyl ester (59 gm ) in methanol (30 ml) was added to the reaction mass. A solution of sodium hydroxide (10 mg) in water (70 ml) and then added sodium borohydride (12 gm) under stirring at 12C. The solution was added to the above reaction mass and maintained for 2 hour at 12C. The reaction mass was stirred for 1 hour at room temperature and separated aqueous layer was extracted with ethanol. Combined the organic layers and filtered through hiflo, washed with ethanol. The pH of the filtrate was adjusted to 5.9 to 6.2 with diluted aqueous hydrochloric acid ( 1 : 1 , 10 ml) and raised the pH immediately to 7.6 to 7.8 with aqueous sodium hydroxide ( 10% w/v, 1 5 ml) at 1 7C. The reaction mass was distilled under atmospheric pressure at below 84C. To the residue was added water (200 ml) at 60C and cooled to room temperature, the solution was extracted with toluene. To the solution was added carbon enoantiocromos (2 gm) and stirred for 15 minutes, filtered the solution through hyflo and washed with water. To the filtrate was added succinic acid (20 gm) and the contents were stirred for 10 hours at room temperature. The contents were cooled to 0C and stirred for 1 hour at same temperature. The separated solid was filtered and washed with chilled acetone. The solid was dried at 35C under reduced pressure for 4 hours to obtain 40 gm of 4-amino-5- fluoro- l -[(2R,5S)-2-(hydroxymethyl)-[ l ,3]-oxatKiolan-5-yl]-( l H)-pyrimidin-2-one monosuccinate monohydrate.

Reference： [1]Patent: WO2011/83484,2011,A2 .Location in patent: Page/Page column 16-17

8
[ 147126-62-3 ]
[ 764659-72-5 ]

Reference： [1]Patent: WO2011/83484,2011,A2

9
[ 1144099-18-2 ]
[ 764659-72-5 ]

Reference： [1]Patent: WO2011/83484,2011,A2

10
C₂₁H₃₀FN₃O₅S [ No CAS ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 7:Preparation of (2R,5S)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-l-yI)-l l ,3]- oxathiolane-2-carboxylic acid, 2S-isopropyl-5R-methyl-lR-cyc.ohexyl ester.; N-propionyl-5-fluorocytosine (60 gm) was suspended in toluene (200 ml) and then added hexamethyl disilazane (70 gm) and methane sulfonic acid ( 1 gm) at room temperature. The contents were heated to reflux and maintained for 6 hours at reflux. The reaction was distilled at atmospheric pressure at 1 10C and then added toluene (120 ml). The reaction mass was cooled to 30C and then added methylene chloride (300 ml). The solution was cooled to 10C and then added (rR,2'S,5'R)-menthyl-5(R,S)-acetoxy-[ l ,3]- oxathiolane-2R-carboxylate (130 gm). Trityl perchlorate (140 gm) was added at room temperature. The contents were heated to 50 to 55C and cooled to room temperature, and then added methylene chloride (300 ml). Aqueous sodium bicarbonate solution (1500 ml) was added and separated aqueous layer was extracted with methylene chloride at room temperature. Combined the organic layers was washed with aqueous sodium bicarbonate solution and the resulting organic layers were concentrated by distillation under atmospheric pressure at below 57C. To the residue was added ethanol (50 ml) and stirred for 15 minutes at below 57C to obtain slurry. The resulting slurry was concentrated by distillation under reduced pressure at below 57C and then maintained for 30 minutes at below 57C to obtai n a solid residue.Methanol (400 ml) was added to the above obtained solid residue at 57C. The reaction mass was cooled to room temperature and then added methane sulfonic acid (70 gm). Diisopropyl ether (600 ml) was added and stirred for 50 minutes at room temperature. The reaction mass was cooled to 15C and stirred for 1 hour at same temperature. The separated solid was filtered and washed with a mixture of ethanol and diisopropyl ether to obtain solid. To a solution of ethyl acetate (200 ml) in hexane (100 ml) was added above solid at room temperature. A mixture of triethylamine (20 gm) and cyclohexane (40 ml) was added slowly to the reaction mass. Water (300 ml) was added and stirred for 1 hour at room temperature, filtered. The solid obtained was washed with a mixture of ethyl acetate and hexane and dried at 45 to 50C under reduced pressure to obtain 60 gm of (2R,5S)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin- l -yl)-[l ,3]- oxathiolane-2-carboxylic acid, 2S-isopropyl-5R-methyl-l R-cyclohexyl ester.

Reference： [1]Patent: WO2011/83484,2011,A2 .Location in patent: Page/Page column 15-16

11
[ 764659-72-5 ]
[ 445-29-4 ]
[ 1321928-76-0 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE-13: Synthesis of 4-amino-5-fluoro-1-(2 ?-hydroxymethyl-[1,3]-oxothiolane- 5S-yl)1tf-pyrimidin-3-one. 2-fluorobenzoic acid salt (formula-8b1); Dipotassium hydrogen orthophosphate (83.3 g) was dissolved in a mixture of industrially methylated spirit (IMS, 600 mL) & purified water (200 mL) and the obtained solution was cooled to 18C. The compound of formula-7b (100 g, 0.26 mol) was added at 15-22C and the suspension was stirred at 18-22C for 1 h. A solution of sodium borohydride (20. 4 g (0.54 mol) in water (110 mL) containing sodium hydroxide (40 mg)) was added drop wise by keeping temperature at 18-22C and maintained for 4 h. The completion of the reaction was confirmed by TLC. The reaction mass was transferred into a separating funnel and the layers were separated. The organic layer pH was adjusted to 5.9-6.3 with aq. HCI (~25 mL) and readjusted to pH 7.5-7.8 with sodium hydroxide (15 mL, 15% w/w) and filtered. IMS (~790 mL) was distilled out initially atmospherically followed by reduced pressure to reduce the traces of IMS. The resultant residue was diluted with water (200 mL) and then cooled to 22-30C. Toluene (150 mL) was added to the reaction mass under stirring, allowed the layers to settle and separate the layers. Toluene layer was washed with water (100 mL) and combined aqueous layer was charcoalized. The filtrate was warmed to 38-42C, 2- fluorobenzoic acid (37 g, 0.26 mol) was added and stirred for 2h at the same temperature. The reaction mass was cooled to 22-30C and maintained for 3-4h. The separated solid was filtered and washed with pre-cooled water and dried to get compound of formula-8b. in 80 g. 1H NMR (300 MHz, DMSO-d6): delta 13.40 (brs, 1H), 8.20 (d, 1 H, J=7.2 Hz), 7.84-8.00 (m, 2H), 7.58-7.68 (m, 2H), 7.28-7.34 (m, 2H), 6.12-6.16 (m, 1H), 5.41 (t, 1 H, J=5.4 Hz), 5.18-5.20 (t, 1 H, J=3.9 Hz), 3.70 -3.82 (m, 2H), 3.39-3.45 (m, 1H), 3.09-3.15 (dd, 1 H, J=11.85 & 4.35 Hz).

Reference： [1]Patent: WO2011/95987,2011,A1 .Location in patent: Page/Page column 39

12
C₂₁H₃₂NO₄S⁽¹⁺⁾*I^(1-) [ No CAS ]
[ 764659-72-5 ]

Reference： [1]Patent: WO2011/95987,2011,A1

13
[ 1321928-75-9 ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE-11: Synthesis of 5-(4-amino-5-fluoro-2-oxo-2W-pyrimidin-1-yl)- [1,3]oxathiolane-2-carboxylic acid 2-isopropyl-5-methylcyclohexyl ester (7b); The compound of formula-6b was suspended in methanol (20 mL) and methanesulphonic acid (2 g) was added. The resultant solution was stirred for 4h. The reaction mixture was slowly added to a solution of DCM and aq NaHC03 solution carefully and stirred for 10min. The solvent was evaporated. The product was dissolved in ethyl acetate and precipitated by adding hexanes. The pure product was filtered and dried to get the compound of formula-7b.

Reference： [1]Patent: WO2011/95987,2011,A1 .Location in patent: Page/Page column 33

14
[ 1321928-66-8 ]
[ 764659-72-5 ]

Reference： [1]Patent: WO2011/95987,2011,A1

15
[ 1309459-32-2 ]
[ 764659-72-5 ]

Reference： [1]Patent: WO2011/95987,2011,A1

16
[ 2022-85-7 ]
[ 147027-09-6 ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
80%		Fluorocytosine (22.4 g, 0.173 mol, 1.1 molar equivalents), Hexamethyl disilazane (HMDS) (100 ml, 0.477 mol, 3.1 molar equivalents) and trimethylsilyl chloride (TMSCL), ( 1 1.2 ml) were mixed at 25-30C under Nitrogen atmosphere. The reaction mixture was heated up to 120- 130C to get clear solution and excess solvent was distilled out under vacuum at 90- 100C to get the residue of silylated fluorocytosine. The residue of silylated fluorocytosine was cooled to room temperature and fresh dichlorome thane (100 ml) was added (solution A). In a separate flask L-menthyl-5R-acetoxy- l ,3-oxathiolane-2R-carboxylate (50 g, 0.151 mol, 1.0 molar equivalents), dichloromethane (250 ml) and zirconium tetrachloride (ZrCU) (17.6 g, 0.075 mole, 0.5 molar equivalents) were mixed under nitrogen atmosphere (solution B). Presilylated fluorocytosine solution A was added into solution B at 25-30C and reaction mixture was stirred at the same temperature for 6 hrs. The reaction was monitored by HPLC or thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 10-20C and precooled ( 10-20C) water (250 ml) was added under stirring. pH was adjusted at 8 to 8.5 using triethylamine under stirring. The layers were separated and the organic layer was washed with 250 ml of water. The organic layer was concentrated under vacuum to get the residue. The residue was dissolved in methanol (200 ml) and n- heptane (100 ml) under stirring. The said solution was added into water (200 ml). The isolated solid was filtered and washed with water followed by n-heptane. The solid was dried under vacuum at 40-45C. Yield: 48.5 g (80 %). Chiral Purity: 99.94 %; 0.06 % undesired isomer. ? NMR (DMSO-d6) delta (ppm): 0.70-0.99 (m, 10H), 1.02- 1.10 (m, 2H), 1.39- 1.49 8 (m, 2H), 1.63- 1.66 8 (d, 2H), 1.88- 1.95 8 (m, 2H), 3.20-3.24 8 (m, 1H), 3.53-3.57 8 (m, 1H), 4.66-4.72 (m, 1H), 5.71 8 (s, 1H), 6.29- 6.30 8 (d, 1H), 7.69 (s, 1H), 7.94 8 (s, 1H), 8.16-8. 18 8 (d, 1H); i3C NMR (DMSO- d6): 16.5, 20.9, 22.2.3.2, 26.1 , 31.8, 34, 35.8, 46.8, 76, 78.3, 89.5, 125.4, 135.2, 137.6, 153.4, 158, 169.8; IR (KBr) (cm-i): 3323, 3083, 2956, 2869, 1754, 1687, 1640, 1513, 1348, 1287, 1 178, 1090, 940, 774, 678, 498; MS (EI) m/z = 400 (M+ l); [a]D25 = -45.23 (c = 0.2%, MeOH).

Reference： [1]Organic Letters,2015,vol. 17,p. 2626 - 2629
[2]Patent: WO2013/21290,2013,A1 .Location in patent: Page/Page column 24; 25

17
[ 111969-64-3 ]
[ 764659-72-5 ]

Reference： [1]Patent: WO2013/21290,2013,A1
[2]Organic Letters,2015,vol. 17,p. 2626 - 2629
[3]Organic Letters,2015,vol. 17,p. 2626 - 2629

18
[ 200396-19-6 ]
[ 764659-72-5 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 2626 - 2629
[2]Organic Letters,2015,vol. 17,p. 2626 - 2629

Yield	Reaction Conditions	Operation in experiment
87%	With methanesulfonic acid; triethylamine; 1,1,1,3,3,3-hexamethyl-disilazane; In dichloromethane; toluene; at 25 - 60℃; for 4h;Reflux;	General procedure: nto the other reaction flask115. 5 g cytosine, 0.7 mL methanesulfonic acid, 242 OmL hexamethyldisilazane and290 mL of toluene,Heated to reflux; to be all the dissolved solids, the cooling to 25 C, then add 145mL of triethylamine, and then warmingTo 60 C, dropping the dichloromethane solution of the chlorinated product, dropping, heating to reflux, the reaction after 4 hours by the highThe relative amount of the diastereomer was determined to be 3.5% (relative to CME) by the performance liquid chromatography analysis. After cooling to 30-35 C,Ethylamine (73 mL) and water (1200 mL) was added, followed by addition of 1,200 mL of n-hexane, cooling to 25 C,To obtain 337. 0 g of white solid CME, the molar yield of 85%, HPLC purity of 99.6%.
		General procedure: A solution of (2R, 5R)-(( I R, 2 S, 5R)-2-isop ropyl-5-methylcyclohexyl) 5-acetoxy- I ,3-oxathiolane-2-carboxylate (1.0 eq) in acetonitrile (10 mL) was added to the above mixture, and stirred for 10 minutes. lodotrimethylsilane (1.0 eq) was introduced drop wise via a cannula at room temperature. The reaction mixture was heated to 80C for 2 hours with the progress of the reaction monitored by TLC and GC. After completion of the reaction the reaction mixture was quenched with the addition of an aqueous solution of Na2S2O3 (15 mL). The solvent was removed by rotary evaporation and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) solution, and a saturated solution of NaHCO3 (25 mL). The organic layer was dried under the anhydrous Na2SO4 and concentrated by using rotary pressure to get the crude residue. The crude compound was purified by column chromatography using 100-200 silica mesh and MeCH:DCM (6:94) as a diluent. The 1H-NMR spectrum of this material indicated that it was a mixture of the cis- and trans- diastereomers. The solid product was recrystallised using a mixture of ethyl acetate, hexane, and methanol to produce the required isomer. Spectral analysis:Analytical data for (1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl(2R,5S)-5-(4-am in o-2-oxo-1 ,2-dihydro-1 -pyri midinyl )-1 , 3-oxat Lila lane-2-carbaxylate

20
[ 2022-85-7 ]
5R-hydroxy-[1,3]oxathiolane-2R-carboxylic acid 2-(1'R,2'S,5'R)-isopropyl-5-methyl-cyclohexyl ester [ No CAS ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
50.5%		720 g Emtricitabine Intermediate IV 7.2 L dichloromethane was added, 20 mL DMF, Cooled to 0 ~ 5 deg C, A solution of 192 mL of thionyl chloride in 1.2 L of dichloromethane was added dropwise. After stirring for 2 hours at 10-15 C, Concentrated under reduced pressure, Then add 2.2 L of toluene and cool for use. 324 g of 5-fluorocytosine, 12g ammonium sulfate, 600mL hexamethyldisilazane, 960 mL of toluene was added, Heated to reflux for 1 to 2 hours. Slightly cooled to below 90 deg C, Add dropwise 350 mL of triethylamine, It was heated to reflux, but not vigorous. The chlorinated solution prepared above was added dropwise, Wash with 240 mL of toluene. Reflux for 2 to 3 hours, Cooled to 30 ~ 35 deg C, Dropping a solution of 180 mL triethylamine in water 2.9 L, Cooled to 15 ~ 20 deg C, Stirred for 1 hour, 2.9 L of n-heptane was dropped, Stir for 16 hours, filter, Washed, Emtricitabine Intermediate III was obtained after drying, 504g, Yield 50.5% HPLC purity 98.17%.
50.5%		720 g Emtricitabine Intermediate IV 7.2 L dichloromethane was added,20mLDMF, cooled to 0 ~ 5 ,A solution of 192 mL of thionyl chloride in 1.2 L of dichloromethane was added dropwise.After stirring at 10-15 C for 2 hours, concentrated under reduced pressure,Then add 2.2 L of toluene and cool for use.324 g of 5-fluorocytosine, 12 g of ammonium sulfate, 600 mL of hexamethyldisilazane, 960 mL of toluene was added and the mixture was heated to reflux1 ~ 2 hours. Slightly cooled to below 90 , 350mL triethylamine dropwise, heated to reflux but not severe.The chlorinated solution prepared above was added dropwise and washed with 240 mL of toluene. Refluxed for 2 to 3 hours, cooled to 30 to 35 C, and added dropwise 2.9 mL of a solution of 180 mL of triethylamine in water, cooled to 15 to 20 C and stirred for 1 hour,2.9 L of n-heptane was added dropwise and the mixture was stirred for 16 hours, filtered, washed with water and dried to yield Emtricitabine Intermediate III,504g, yield 50.5%HPLC purity 98.17%.

Reference： [1]Patent: CN106496208,2017,A .Location in patent: Paragraph 0047; 0048; 0049
[2]Patent: CN106478618,2017,A .Location in patent: Paragraph 0048; 0049; 0050

21
[ 764659-72-5 ]
C₁₈H₂₆FN₃O₄S*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		420g emtricitabine Intermediate III (HPLC purity 98.17%) was added potassium dihydrogen phosphate 540g, Water 600mL, Ethanol 300mL, 160g of sodium borohydride in 800mL of water and 8mL of 25wt% aqueous sodium hydroxide solution (the mass percentage is the percentage of the mass of sodium hydroxide in the total mass of sodium hydroxide aqueous solution) is added dropwise at 10-15 DEG C, Stirring at 20 ~ 30 deg C for 2 ~ 3 hours, With 1mol / L hydrochloric acid adjusted to pH 4 ~ 5, Stirred for 0.5 hours, Then 2mol / L aqueous sodium hydroxide solution was adjusted to pH 7, Extract three times with toluene and water. The organic phase is discarded as menthol. The aqueous phase was separated and concentrated to dryness Emtricitabine I crude (HPLC purity 95.73%).

Reference： [1]Patent: CN106496208,2017,A .Location in patent: Paragraph 0050; 0051; 0052

22
C₂₁H₃₁FN₄O₄S [ No CAS ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
96.7%	With hydrogenchloride; In dichloromethane; water; at 20 - 25℃;	A, hydrolysis: 250mL three-necked flask,100 mL of dichloromethane was added,50 grams of 5% diluted hydrochloric acid,22.7 g (50 mmol) of Compound 22 are stirred at 20-25 C for 7-8 hours,HPLC tracked compound 22 less than 0.5%.B, after treatment: After the reaction,Solid sodium bicarbonate to pH 7, evaporated to dryness dichloromethane,Add cyclohexane 100 grams, beating dispersion, filtration, F-CME 19.3 grams.HPLC Purity: 99.8%, Chiral Purity: 99.8%Yield: 96.7%.

Reference： [1]Patent: CN106831740,2017,A .Location in patent: Paragraph 0074-0076; 0081; 0085; 0086; 0091; 0095

23
trans 5-chloro-1,3-oxathiolane-2-carboxylic acid menthyl ester [ No CAS ]
[ 111878-21-8 ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
15.42 g	With triethylamine; at 75℃; for 7h;	Add 6.45g (0.05mol) 5-fluorocytosine, 0.025ml methanesulfonic acid,8.09 g (0.05 mol) of hexamethyldisilazane and 75 ml of dichloromethane,Heat to reflux until the solution becomes transparent to obtain a methyl silylated cytosine solution, that is, a silylated 5-fluorocytosine;7.3 ml of triethylamine was added to the methyl silylated cytosine solution, heated under reflux, and then,Slowly add the reaction solution obtained in one step (trans 5-chloro-1,3-oxetane-2-carboxylic acid menthol), raise the temperature to 75 C, and react for 7 hours.After sufficiently coupling trans 5-chloro-1,3-oxetane-2-carboxylic acid menthyl ester with silylated 5-fluorocytosine (methyl silylated cytosine solution),The reaction solution was poured into water, and the organic layer was washed with a saturated sodium bicarbonate solution, saturated brine, and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and the obtained oil was obtained with n-hexane, ethyl acetate,A mixed solution of methanol (volume ratio 1: 1: 1) was used as a solvent to recrystallize to obtain 15.42 g of 5S-(5'-fluorocytosinyl)-1,3-oxathiolan-2R-carboxylic acid menthyl ester,The calculated yield is 71.7%

Reference： [1]Patent: CN110467608,2019,A .Location in patent: Paragraph 0028; 0034; 0038

24
[ 2216-51-5 ]
[ 764659-72-5 ]

Reference： [1]Patent: CN110467608,2019,A

25
[ 21758-30-5 ]
[ 764659-72-5 ]

Reference： [1]Patent: CN110467608,2019,A

26
[ 26315-61-7 ]
[ 764659-72-5 ]

Reference： [1]Patent: CN110467608,2019,A

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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. 764659-72-5 ] {[proInfo.proName]}

Quality Control of [ 764659-72-5 ]

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[ 764659-72-5 ] Synthesis Path-Upstream 1~13

[ 764659-72-5 ] Synthesis Path-Downstream 1~26

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Amides

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Pyrimidines

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[ 764659-72-5 ]

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[ 764659-72-5 ]