[ CAS No. 134678-17-4 ] {[proInfo.proName]}

Name: 134678-17-4|4-Amino-1-((2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl)pyrimidin-2(1H)-one|98%
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Quality Control of [ 134678-17-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 134678-17-4 ]

CAS No. :	134678-17-4	MDL No. :	MFCD00869739
Formula :	C₈H₁₁N₃O₃S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JTEGQNOMFQHVDC-NKWVEPMBSA-N
M.W :	229.26	Pubchem ID :	60825
Synonyms :	BCH-189;3TC;Lamivudine, 3TC, Epivir, Zeffix, Heptovir, BCH-189;2’,3’-dideoxy-3’-Thiacytidine;(-)-BCH 189;GR109714X	Chemical Name :	4-Amino-1-((2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl)pyrimidin-2(1H)-one

Calculated chemistry of [ 134678-17-4 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.5
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	56.31
TPSA :	115.67 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-8.36 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.97
Log Po/w (XLOGP3) :	-0.93
Log Po/w (WLOGP) :	-0.91
Log Po/w (MLOGP) :	-1.02
Log Po/w (SILICOS-IT) :	-0.47
Consensus Log Po/w :	-0.47

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.84
Solubility :	33.2 mg/ml ; 0.145 mol/l
Class :	Very soluble
Log S (Ali) :	-1.02
Solubility :	22.1 mg/ml ; 0.0966 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.43
Solubility :	84.6 mg/ml ; 0.369 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.57

Safety of [ 134678-17-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 134678-17-4 ]

* 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 [ 134678-17-4 ]
Downstream synthetic route of [ 134678-17-4 ]

[ 134678-17-4 ] Synthesis Path-Upstream 1~1

1
[ 131086-21-0 ]
[ 131086-21-0 ]
[ 134678-17-4 ]

Yield	Reaction Conditions	Operation in experiment
40 % ee	Stage #1: With (S)-N-acetyl-2-phenylglycine In ethanol at -30 - -20℃; for 48 h; Stage #2: With sodium hydroxide In dichloromethane; water for 0.5 h;	Comparative Example 7 was performed in the same manner as Example 16, except for using ethanol, instead of the protic organic solvent, methanol, and except for not using the aprotic organic solvent
20 % ee	Stage #1: With O,O'-dibenzoyl-L-tartaric acid In methanol; acetone at -30 - 20℃; for 48 h; Stage #2: With sodium hydroxide In dichloromethane; water for 0.5 h;	Comparative Example 8 was performed in the same manner as Example 16, except for using (L)-O,O'-dibenzoyl tartaric acid, instead of (S)-N-acetyl-2-phenylglycine used in Example 16.
10 - 40 % ee	Stage #1: With (S)-N-acetyl-2-phenylglycine In methanol; acetone at -50 - 25℃; for 48 h; Stage #2: With sodium hydroxide In dichloromethane; water for 0.5 h;	Comparative Example 9 was carried out in the same manner as Example 16 except for the process of crystallization performed at 0 to 25° C., instead of -30 to -20° C. in Example 1.COMPARATIVE EXAMPLE 10Comparative Example 10 was carried out in the same manner as Example 16, except for the process of crystallization performed at -50 to -30° C., instead of to -20° C. in Example 1.

20 % ee	Stage #1: With O,O'-dibenzoyl-L-tartaric acid In methanol; acetone at -30 - -20℃; for 48 h; Resolution of racemate Stage #2: With sodium hydroxide In dichloromethane; water for 0.5 h;	[Comparative Example 8] [219] Comparative Example 8 was performed in the same manner as Example 16, except for using (L)-O5O' -dibenzoyl tartaric acid, instead of (S)-N-acetyl-2-phenylglycine used in Example 16.
40 % ee	Stage #1: With (S)-N-acetyl-2-phenylglycine In ethanol at -30 - -20℃; for 48 h; Resolution of racemate Stage #2: With sodium hydroxide In dichloromethane; water for 0.5 h;	Comparative Example 7] [216] Comparative Example 7 was performed in the same manner as Example 16, except for using ethanol, instead of the protic organic solvent, methanol, and except for not using the aprotic organic solvent.
10 - 40 % ee	Stage #1: With (S)-N-acetyl-2-phenylglycine In methanol; acetone at -50 - 25℃; for 48 h; Resolution of racemate Stage #2: With sodium hydroxide In dichloromethane; water for 0.5 h;	Comparative Example 9] [222] Comparative Example 9 was carried out in the same manner as Example 16 , except for the process of crystallization performed at 0 to 25 °C, instead of -30 to -20 °C in Example 1.[223] [224] [Comparative Example 10] [225] Comparative Example 10 was carried out in the same manner as Example 16, except for the process of crystallization performed at -50 to -30 °C, instead of -30 to - 20 °C in Example 1.

Reference： [1] Patent: US2009/36679, 2009, A1, . Location in patent: Page/Page column 6-7
[2] Patent: US2009/36679, 2009, A1, . Location in patent: Page/Page column 6; 9
[3] Patent: US2009/36679, 2009, A1, . Location in patent: Page/Page column 6-8
[4] Patent: WO2007/91753, 2007, A1, . Location in patent: Page/Page column 17; 21
[5] Patent: WO2007/91753, 2007, A1, . Location in patent: Page/Page column 17; 18-19
[6] Patent: WO2007/91753, 2007, A1, . Location in patent: Page/Page column 17; 20

[ 134678-17-4 ] Synthesis Path-Downstream 1~11

1
Benzoic acid (R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-[1,3]oxathiolan-2-ylmethyl ester [ No CAS ]
[ 131086-21-0 ]
[ 134678-17-4 ]
[ 139757-68-9 ]

Reference： [1]Tetrahedron Asymmetry,1995,vol. 6,p. 393 - 396
[2]Tetrahedron Asymmetry,1995,vol. 6,p. 393 - 396

2
((2R,5S)-5-(4-acetamido-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolan-2-yl)methyl benzoate [ No CAS ]
[ 131086-21-0 ]
[ 134678-17-4 ]

Reference： [1]Tetrahedron Letters,1995,vol. 36,p. 6961 - 6964

3
[ 131086-21-0 ]
[ 131086-21-0 ]
[ 134678-17-4 ]

Yield	Reaction Conditions	Operation in experiment
		Comparative Example 7 was performed in the same manner as Example 16, except for using ethanol, instead of the protic organic solvent, methanol, and except for not using the aprotic organic solvent
		Comparative Example 8 was performed in the same manner as Example 16, except for using (L)-O,O'-dibenzoyl tartaric acid, instead of (S)-N-acetyl-2-phenylglycine used in Example 16.
		Comparative Example 9 was carried out in the same manner as Example 16 except for the process of crystallization performed at 0 to 25 C., instead of -30 to -20 C. in Example 1.COMPARATIVE EXAMPLE 10Comparative Example 10 was carried out in the same manner as Example 16, except for the process of crystallization performed at -50 to -30 C., instead of to -20 C. in Example 1.

		[Comparative Example 8] [219] Comparative Example 8 was performed in the same manner as Example 16, except for using (L)-O5O' -dibenzoyl tartaric acid, instead of (S)-N-acetyl-2-phenylglycine used in Example 16.
		Comparative Example 7] [216] Comparative Example 7 was performed in the same manner as Example 16, except for using ethanol, instead of the protic organic solvent, methanol, and except for not using the aprotic organic solvent.
		Comparative Example 9] [222] Comparative Example 9 was carried out in the same manner as Example 16 , except for the process of crystallization performed at 0 to 25 C, instead of -30 to -20 C in Example 1.[223] [224] [Comparative Example 10] [225] Comparative Example 10 was carried out in the same manner as Example 16, except for the process of crystallization performed at -50 to -30 C, instead of -30 to - 20 C in Example 1.

Reference： [1]Patent: US2009/36679,2009,A1 .Location in patent: Page/Page column 6-7
[2]Patent: US2009/36679,2009,A1 .Location in patent: Page/Page column 6; 9
[3]Patent: US2009/36679,2009,A1 .Location in patent: Page/Page column 6-8
[4]Patent: WO2007/91753,2007,A1 .Location in patent: Page/Page column 17; 21
[5]Patent: WO2007/91753,2007,A1 .Location in patent: Page/Page column 17; 18-19
[6]Patent: WO2007/91753,2007,A1 .Location in patent: Page/Page column 17; 20

4
[ 173522-96-8 ]
[ 136891-12-8 ]

Yield	Reaction Conditions	Operation in experiment
92.63%	With triethylamine In ethanol at 50℃; for 1h;	1.7 7) Preparation of lamivudine: Add 38.5g (0.1mol) lamivudine salicylate,320ml of absolute ethanol and 15.15g (0.15mol) of triethylamine,The temperature was raised to 50 ° C, and the reaction was held for 1 h.After the lamivudine salicylate is 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 hour.Filtered, washed twice with 100 ml ethyl acetate,Dried to give 21.21g of lamivudine as a white powder,After calculation, the yield is 92.63%.
	With triethylamine In water; ethyl acetate at 25 - 50℃; for 5h;	4 Example 4: Preparation of LamivudineLamivudine salicylate (120 g) obtained from Example 3 was added to a mixture of ethyl acetate (720 mL) and water (6 mL) at 25° to 35°C. The reaction mixture was heated to 45° to 500C, followed by the addition of triethylamine (104.76 g) over 30 minutes at 45° to 500C. The reaction mixture was stirred for 4 hours at the same temperature and cooled to 25° to 300C. The reaction mixture was stirred for further 30 minutes at 25° to 300C, filtered and dried by suction. The solid obtained was washed with ethyl acetate. Ethyl acetate (600 mL) was added to the washed solid and heated to 50° to 55°C. The mixture was stirred at 50° to 55°C for 15 minutes, cooled to 25° to 3O0C and stirred for further 30 minutes. The solid was filtered at 25° to 3O0C, washed with ethyl acetate (60 mL) and dried under vacuum at 45° to 500C to obtain the title compound.Yield: 68.5 g
	With triethylamine In water; ethyl acetate at 45 - 50℃; for 4.5h;	5 Example 5: Preparation of Lamivudine. Lamivudine salicylate (120 g) was added to a mixture of ethyl acetate (720 mL) and water (6 mL) at 25° to 35°C. The reaction mixture was heated to 45° to 500C, followed by the addition of triethylamine (104.76 g) over 30 minutes at 45° to 500C. The reaction mixture was stirred for 4 h at the same temperature and cooled to 25° to 300C. The reaction mixture was stirred for further 30 minutes at 25° to 300C, filtered and dried by suction. The solid obtained was washed with ethyl acetate. Ethyl acetate (600 mL) was added to the washed solid and heated to 50° to 55°C. The mixture was stirred at 50° to 55°C for 15 minutes, cooled to 25° to 3O0C and stirred for further 30 minutes. The solid was filtered at 25° to 3O0C, washed with ethyl acetate (60 mL) and dried under vacuum at 45° to 500C to obtain the title compound.

	With triethylamine In ethyl acetate at 25 - 30℃; for 2h;	2 4-Amino-l-[(2R,5S)-2-(hydroxymethyl)-l,3-oxathiolan-5-yl]-(lH)-pyrimidin-2-one monosalicylate monohydrate (Lamivudine salicylate, 100 g) was added slowly over 30 min to a mixture of triethylamine (55 g) and ethyl acetate (650 ml), under stirring at 25-3O0C. The resulting product slurry was stirred for 2 h at 25-3O0C. The product was filtered and washed with ethyl acetate (100 ml) at 25-300C. The solid obtained was dried under reduced pressure at 5O0C to yield the polymorphic Form I of Lamivudine (58 g), mp 122-124°C. The above obtained Lamivudine Form I can be further recrystallized using the procedure described in example 1.
	With triethylamine In (methyl)isobutyl ketone at 25 - 30℃; for 2h;	5 4-Amino-l-[(2R,5S)-2-(hydroxymethyl)-l,3-oxathiolan-5-yl]-(lH)-pyi-imidin-2-one monosalicylate monohydrate (Lamivudine salicylate, 100 g) was added slowly over 30 min to a mixture of triethylamine (55 g) and Methylisobutyl ketone (700 ml), under stirring at 25-30°C. The resulting product slurry was stirred for 2 h at 25- 300C. The product was filtered and washed with Methylisobutyl ketone (100 ml) at 25-3O0C. The solid obtained was dried under reduced pressure at 500C to yield the polymorphic Form I of Lamivudine (59 g), mp 123-126.50C.The above obtained Lamivudine Form I can be further recrystallized using the procedure described in example 4.
	With triethylamine In water; ethyl acetate at 45 - 50℃; for 4.5h;	1.b Lamivudine salicylate (120 g) was added to a mixture of ethyl acetate (720 mL) and water (6 mL) at 25° to 35°C. The reaction mixture was heated to 45° to 500C, followed by the addition of triethylamine (104.76 g) over 30 minutes at 45° to 500C. The reaction mixture was stirred for 4 hours at the same temperature and cooled to 25° to 300C. The reaction mixture was stirred for further 30 minutes at 25° to 300C, filtered and dried by suction. The solid obtained was washed with ethyl acetate. Ethyl acetate (600 mL) was added to the washed solid and heated to 50° to 55°C. The mixture was stirred at 50° to 55°C for 15 minutes, cooled to 25° to 3O0C and stirred for further 30 minutes. The solid was filtered at 25° to 3O0C, washed with ethyl acetate (60 mL) and dried under vacuum at 45° to 500C to obtain lamivudine. Lamivudine (60 g) so obtained was added to absolute alcohol (1.2 L) at 25° to 35°C. The reaction mixture was heated to 75° to 78°C and stirred to obtain a solution. Activated carbon (6 g) was added to the solution so obtained at 75° to 78°C, stirred for 30 minutes at the same temperature and filtered through Celite bed at the same temperature. The carbon bed was washed with absolute alcohol (60 mL; preheated to 75° to 76°C) and the reaction mixture was concentrated under vacuum to obtain a volume of about 300 mL. The concentrated reaction mixture was heated to 74° to 76°C, stirred for 15 minutes and 0IO0C in 1 h time and stirred for 30 minutes. The solid was filtered, washed with absolute alcohol (30 mL, pre-cooled to 5° to 100C) and dried under vacuum at 50° to 55°C to obtain the title compound. Yield: 53 gHPLC Purity: 99.0%Chiral Purity: 99.8%
	With triethylamine In water; ethyl acetate at 25 - 50℃;	1.b Lamivudine salicylate (120 g) was added to a mixture of ethyl acetate (720 mL) and water (6 mL) at 25° to 35°C. The reaction mixture was heated to 45° to 500C, followed by the addition of triethylamine (104.76 g) over 30 minutes at 45° to 500C. The reaction mixture was stirred for 4 hours at the same temperature and cooled to 25° to 300C. The reaction mixture was stirred for further 30 minutes at 25° to 300C, filtered and dried by suction. The solid obtained was washed with ethyl acetate. Ethyl acetate (600 mL) was added to the washed solid and heated to 50° to 55°C. The mixture was stirred at 50° to 55°C for 15 minutes, cooled to 25° to 3O0C and stirred for further 30 minutes. The solid was filtered at 25° to 3O0C, washed with ethyl acetate (60 mL) and dried under vacuum at 45° to 500C to obtain lamivudine. Lamivudine (60 g) so obtained was added to absolute alcohol (1.2 L) at 25° to 35°C. The reaction mixture was heated to 75° to 78°C and stirred to obtain a solution. Activated carbon (6 g) was added to the solution so obtained at 75° to 78°C, stirred for 30 minutes at the same temperature and filtered through Celite bed at the same temperature. The carbon bed was washed with absolute alcohol (60 mL; preheated to 75° to 76°C) and the reaction mixture was concentrated under vacuum to obtain a volume of about 300 mL. The concentrated reaction mixture was heated to 74° to 76°C, stirred for 15 minutes and cooled to 20° to 25°C in 1 hour time. The reaction mixture was further cooled to 5° to 100C in 1 hour time and stirred for 30 minutes. The solid was filtered, washed with absolute alcohol (30 mL, pre-cooled to 5° to 100C) and dried under vacuum at 50° to 55°C to obtain the title compound.Yield: 53 g HPLC Purity: 99.0%Chiral Purity: 99.8%
	With triethylamine In 4-methyl-2-pentanone at 25 - 30℃; for 2.5h;	5 Example-54-Amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-(1H)-pyrimidin-2-one monosalicylate monohydrate (Lamivudine salicylate, 100 g) was added slowly over 30 min to a mixture of triethylamine (55 g) and Methylisobutyl ketone (700 ml), under stirring at 25-30° C. The resulting product slurry was stirred for 2 h at 25-30° C. The product was filtered and washed with Methylisobutyl ketone (100 ml) at 25-30° C. The solid obtained was dried under reduced pressure at 50° C. to yield the polymorphic Form I of Lamivudine (59 g), mp 123-126.5° C.The above obtained Lamivudine Form I can be further recrystallized using the procedure described in example 4.
	With triethylamine In water; ethyl acetate at 45 - 50℃; for 4.5h;	4; 5 Example 4; Preparation of Lamivudine; Lamivudine salicylate (120 g) obtained from Example 3 was added to a mixture of ethyl acetate (720 mL) and water (6 mL) at 25° to 35° C. The reaction mixture was heated to 45° to 50° C., followed by the addition of triethylamine (104.76 g) over 30 minutes at 45° to 50° C. The reaction mixture was stirred for 4 hours at the same temperature and cooled to 25° to 30° C. The reaction mixture was stirred for further 30 minutes at 25° to 30° C., filtered and dried by suction. The solid obtained was washed with ethyl acetate. Ethyl acetate (600 mL) was added to the washed solid and heated to 50° to 55° C. The mixture was stirred at 50° to 55° C. for 15 minutes, cooled to 25° to 30° C. and stirred for further 30 minutes. The solid was filtered at 25° to 30° C., washed with ethyl acetate (60 mL) and dried under vacuum at 45° to 50° C. to obtain the title compound.Yield: 68.5 g; Example 5; Purification of Lamivudine; Lamivudine (60 g) obtained from Example 4 was added to absolute alcohol (1.2 L) at 25° to 35° C. The reaction mixture was heated to 75° to 78° C. and stirred to obtain a solution. Activated carbon (6 g) was added to the solution so obtained at 75° to 78° C., stirred for 30 minutes at the same temperature and filtered through Celite bed at the same temperature. The carbon bed was washed with absolute alcohol (60 mL; preheated to 75° to 76° C.) and the reaction mixture was concentrated under vacuum to obtain a volume of about 300 mL. The concentrated reaction mixture was heated to 74° to 76° C., stirred for 15 minutes and cooled to 20° to 25° C. in 1 hour time. The reaction mixture was further cooled to 5° to 10° C. in 1 hour time and stirred for 30 minutes. The solid was filtered, washed with absolute alcohol (30 mL, pre-cooled to 5° to 10° C.) and dried under vacuum at 50° to 55° C. to obtain the title compound.Yield: 53 gHPLC Purity: 99.0%Chiral Purity: 99.8%Salicylic acid content (HPLC): Not detectable
	With water; triethylamine In ethyl acetate at 25 - 50℃; for 5h;	1.b b) Preparation of pure lamivudine: Lamivudine salicylate (120 g) was added to a mixture of ethyl acetate (720 mL) and water (6 mL) at 25° to 35° C. The reaction mixture was heated to 45° to 50° C., followed by the addition of triethylamine (104.76 g) over 30 minutes at 45° to 50° C. The reaction mixture was stirred for 4 hours at the same temperature and cooled to 25° to 30° C. The reaction mixture was stirred for further 30 minutes at 25° to 30° C., filtered and dried by suction. The solid obtained was washed with ethyl acetate. Ethyl acetate (600 mL) was added to the washed solid and heated to 50° to 55° C. The mixture was stirred at 50° to 55° C. for 15 minutes, cooled to 25° to 30° C. and stirred for further 30 minutes. The solid was filtered at 25° to 30° C., washed with ethyl acetate (60 mL) and dried under vacuum at 45° to 50° C. to obtain lamivudine. Lamivudine (60 g) so obtained was added to absolute alcohol (1.2 L) at 25° to 35° C. The reaction mixture was heated to 75° to 78° C. and stirred to obtain a solution. Activated carbon (6 g) was added to the solution so obtained at 75° to 78° C., stirred for 30 minutes at the same temperature and filtered through Celite bed at the same temperature. The carbon bed was washed with absolute alcohol (60 mL; preheated to 75° to 76° C.) and the reaction mixture was concentrated under vacuum to obtain a volume of about 300 mL. The concentrated reaction mixture was heated to 74° to 76° C., stirred for 15 minutes and ° 10° C. in 1 h time and stirred for 30 minutes. The solid was filtered, washed with absolute alcohol (30 mL, pre-cooled to 5° to 10° C.) and dried under vacuum at 50° to 55° C. to obtain the title compound. Yield: 53 gHPLC Purity: 99.0%Chiral Purity: 99.8%

Reference： [1]Current Patent Assignee: WUHAN INSTITUTE OF TECHNOLOGY - CN110437216, 2019, A Location in patent: Paragraph 0028; 0036; 0038
[2]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2009/69011, 2009, A1 Location in patent: Page/Page column 19
[3]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2009/69012, 2009, A1 Location in patent: Page/Page column 24
[4]Current Patent Assignee: AUROBINDO PHARMA LIMITED - WO2009/37538, 2009, A2 Location in patent: Page/Page column 7-8
[5]Current Patent Assignee: AUROBINDO PHARMA LIMITED - WO2009/37538, 2009, A2 Location in patent: Page/Page column 9
[6]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2009/69013, 2009, A1 Location in patent: Page/Page column 9-10
[7]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2009/69014, 2009, A1 Location in patent: Page/Page column 7
[8]Current Patent Assignee: AUROBINDO PHARMA LIMITED - US2010/190982, 2010, A1 Location in patent: Page/Page column 3
[9]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - US2010/311970, 2010, A1 Location in patent: Page/Page column 7-8
[10]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - US2010/324290, 2010, A1 Location in patent: Page/Page column 3-4

5
[ 1116489-35-0 ]
[ 136891-12-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 4-amino-1-[(2R,5S)-(2-hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one (S)-BINOL co-crystal With hydrogenchloride In water; ethyl acetate at 20℃; for 1h; Stage #2: With sodium hydroxide In water	6; 2 Charged (S) BINOL Cocrystal (20g) in ethyl acetate (100ml) and D.M. water (100ml) at RT. Cone. Hydrochloric acid (4 to 5 ml) was added to the mixture gradually and stirred (pH of the mixture was between about 3 to 4) for an hour and allowed the layers to settle, separated the layers. Aqueous layer was washed with fresh ethyl acetate to remove S(-) BINOL completely. pH of the solution was adjusted to about 7 using 10% sodium hydroxide solution. The solution was then passed though activated resin 225-H column. The column was then washed with purified water, thereafter with 15% aqueous ammonia solution. Combined solutions were subjected to evaporation till 20 to 50 ml. To the mass was then added .8 ml of DNS and stirred to homogenize. The solution was then passed through 0.5 micron filter and then the solution was seeded with Lamivudine form I. Further, the mixture was cooled to around 8 - 10°C and stirred for an hour maintaining the same temperature. The crystalline product was then filtered and washed with precooled water and DNS mixture. The product was then dried under vacuum to afford Lamivudine form I.Results:Out put Yield (w/w) % Yield in HPLC purity (RS) Chiral purity by (Range) (Range) Range HPLC6.5-8 gm 0.30-0.40 68-90% Cis (-): 99.94 % Cis (-): 99.95%Individual Impurity: Cis (+): 0.06 % 0.03 %
70.02%	With hydrogenchloride In water; ethyl acetate Large scale reaction; optical yield given as %ee;
	With hydrogenchloride In water; ethyl acetate	9 Preparation of Lamivudine: (-)-[2R,5S]-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidin-2-oneCompound I5 mL of conc. HCl was slowly added to a solution of 20 g of Lamivudine-BINOL complex in 100 ml of ethylacetate and 100 mL of DM water (pH 2-2.5). The layers were separated and a 100 mL aliquot of ethylacetate was added to the aqueous layer. The layers were separated again and the aqueous layer was neutralized using 10 mL of 10% aqueous NaOH solution. The solvent was recovered under vacuum at 40-45° C., the product obtained was dissolved in 160 mL of methanol, filtered, the filtrate was concentrated and 32 mL of water-ethanol mixture (3:1) was added to this product, heated to get a clear solution, cooled to 5-10° C. and then filtered. The residue was vacuum dried at 45-50° C. Yield: 4-5 g.Enantiomeric excess=99.74%m.p.=133-135° C.[α]D at 25° C.=98.32° (c=5 water)1H NMR (DMSO d6): 2.99-3.07 (dd, 1H), 3.35-3.38 (dd, 1H), 3.72-3.74 (m, 2H), 5.14-5.18 (t, 1H), 5.32-5.38 (t, 1H), 5.71-5.75 (d, 1H), 6.16-6.21 (t, 1H), 7.22-7.27 (d, 2H), 7.80-7.83 (d, 1H)Moisture content: 1.67%IR (in KBr, cm-1): 3551, 3236, 2927, 1614, 1492, 1404, 1336, 1253, 1146, 1052, 967, 786.MS: M+1=230XRD [2θ] (Cu-Kα1=1.54060 , Kα2=1.54443 Kβ=1.39225 ; 40 mA, 45 kV): 5.08, 9.89, 10.16, 11.40, 11.65, 12.96, 13.23, 15.26, 15.82, 17.74, 18.74, 18.88, 19.67, 20.69, 22.13, 22.88, 23.71, 25.47, 26.07.

7 g	Stage #1: 4-amino-1-[(2R,5S)-(2-hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one (S)-BINOL co-crystal With hydrogenchloride In water; ethyl acetate at 20℃; for 0.0833333h; Stage #2: With sodium hydroxide In water	14 Example 14: Preparation of 4-amino-l-[(2R,5S)-2-(hydroxy methyl)- 1,3- oxathiolan-5-yl]- 1 ,2-dihydropyrimidin-2-one (Lamivudine). (S) BINOL Co-crystal (20 g), ethyl acetate (100 ml) and D.M. water (100 ml) were mixed at RT. Concentrated HC1 (4 ml) was added to adjust the pH 3-4 and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was washed with fresh ethyl acetate (100 ml). The pH of aqueous layer was adjusted to 6.8-7.2 using 10 % NaOH ( 10 ml). The aqueous layer was passed through activated resin 225-H column and the column was washed with chloride free water. 10% aqueous ammonia solution was added to resin column to elute the product. After the completion of elution, distilled out the solvent till 10 ml remains in the flask. Fresh chloride free water (100 ml) and activated carbon (2.0 gm) was added and heated the mixture up to 45-50°C. The mixture was stirred and filtered through celite bed which was washed with 20 ml chloride free water. The solution was distilled under vacuum at 45-50°C till 1.2 volumes remains in the flask. DNS (8 ml) was added to the solution and stirred for 5 min. The solution was filtered through 0.5μ and cooled to 30-32°C. The solution was seeded with of 0.025 g Lamivudine Form-I at 30-32°C. The mixture was further cooled up to 8- 10°C and stirred the isolated solid for 1 hrs. The solid was filtered and washed the wet cake with 4 ml of pre-cooled (8- 10°C) DM Water and DNS mixture (3: 1). The solid product was suck dried and further dried under vacuum to afford Lamivudine. Yield: 7 g. Chiral Purity: cis-(-) Lamivudine = 99.8 %.
33.3 kg	In water; ethyl acetate at 2 - 45℃; Industrial scale;

Reference： [1]Current Patent Assignee: LUPIN LIMITED - WO2011/141805, 2011, A2 Location in patent: Page/Page column 14; 21
[2]Location in patent: experimental part Roy, Bhairab Nath; Singh, Girij Pal; Srivastava, Dhananjai; Jadhav, Harishchandra S.; Saini, Manmeet B.; Aher, Umesh P. [Organic Process Research and Development, 2009, vol. 13, # 3, p. 450 - 455]
[3]Current Patent Assignee: LUPIN LIMITED - US2011/257396, 2011, A1 Location in patent: Page/Page column 10
[4]Current Patent Assignee: LUPIN LIMITED - WO2013/21290, 2013, A1 Location in patent: Page/Page column 29
[5]Aher, Umesh P.; Jadhav, Harishchandra S.; Jayashree, B. S.; Shenoy, Gautham G.; Singh, Girij P.; Srivastava, Dhananjai [Organic process research and development, 2020, vol. 24, # 3, p. 387 - 397]

6
[ 1640108-34-4 ]
[ 136891-12-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine In ethanol at 70 - 75℃; Inert atmosphere; Industry scale;	27 The resulting salt and ethanol (11L) were added to a reaction flask. Under a nitrogen atmosphere, the mixture was elevated to a temperature of 70-75 °C, and then triethylamine (850ml) was added slowly. After the addition was complete, the reaction mixture was kept at that temperature under stirring for 0.5 hour. Two thirds of the solvent was evaporated under reduced pressure, and ethyl acetate (5.6L) was added slowly drop by drop at 50-55 °C. After the addition was complete, the mixture was cooled to room temperature, stirred for 5 hours, cooled to 10 °C and then further stirred for 1 hour, after which, the reaction mixture was filtered and the resulting solid was recrystallized by ethanol to give 1.0 Kg of Lamivudine, and the yield was 90%.

Reference： [1]Current Patent Assignee: JIANGSU PUXIN PHARMACEUTICALS - EP2161267, 2010, A1 Location in patent: Page/Page column 14

7
[ 18162-48-6 ]
[ 136891-12-8 ]
[ 956896-97-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 16h;	Preparation of Silylated Compound To a solution of lamivudine (500 mg, 1.0 mmol) in DMF (4 mL) at 0° C., were added sequentially imidazole (222 mg, 3.271 mmol) and tert-butyldimethylsilyl chloride (TBS-Cl) (406 mg, 2.617 mmol). The mixture was stirred and gradually warmed to room temperature over 16 hours. The mixture was then concentrated and the product was isolated by flash chromatography, eluting with 90% CH2C12/CH3OH to give the silyl ether as a colorless solid (741 mg, 99%).
95%	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 18h;
	With 1H-imidazole In N,N-dimethyl-formamide at 20℃;

Reference： [1]Current Patent Assignee: UNIVERSITY OF NEBRASKA SYSTEM - US11311545, 2022, B2 Location in patent: Page/Page column 19
[2]Location in patent: experimental part Agarwal, Hitesh K.; Chhikara, Bhupender S.; Hanley, Michael J.; Ye, Guofeng; Doncel, Gustavo F.; Parang, Keykavous [Journal of Medicinal Chemistry, 2012, vol. 55, # 10, p. 4861 - 4871]
[3]Location in patent: scheme or table Agarwal, Hitesh K.; Buckheit, Karen W.; Buckheit Jr., Robert W.; Parang, Keykavous [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 17, p. 5451 - 5454]

8
[ 136891-12-8 ]
[ 17341-93-4 ]
[ 1443545-12-7 ]

Yield	Reaction Conditions	Operation in experiment
49%	With pyridine; dmap In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;	36 Example 36Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-((2R,5S)-5-(4-amino-2-oxopyrimidin-l(2H)-yl)- -oxathiolan-2-yl)methyl docosa-4,7,10,13,16,19-hexaenoate To a solution of lamivudine (6.0 g, 26.17 mmol) in DMF (50 mL) under nitrogen at room temperature was added DMAP (3.19 g, 26.17 mmol), pyridine (3.10 g, 39.26 mmol) and 2,2,2-trichloroethyl carbonochloridate (5.50 g, 26.17 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (250 mL) and washed with saturated aq. NH4CI (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 5.2 g of 2,2,2-trichloroethyl (l-((2R,5S)-2-(hydroxymethyl)-l ,3-oxathiolan-5-yl)-2-oxo-l,2-dihydropyrimidin-4- yl)carbamate (49%).
49%	With pyridine; dmap In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;	36 Example 36 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-((2R,5S)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolan-2-yl)methyl docosa-4,7,10,13,16,19-hexaenoate (V-16) To a solution of lamivudine (6.0 g, 26.17 mmol) in DMF (50 mL) under nitrogen at room temperature was added DMAP (3.19 g, 26.17 mmol), pyridine (3.10 g, 39.26 mmol) and 2,2,2-trichloroethyl carbonochloridate (5.50 g, 26.17 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (250 mL) and washed with saturated aq. NH4Cl (350 mL) and brine (350 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 5.2 g of 2,2,2-trichloroethyl (1-((2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate (49%).
49%	With pyridine; dmap In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;	36 To a solution of lamivudine (6.0 g, 26.17 mmol) in DMF (50 mL) under nitrogen at room temperature was added DMAP (3.19 g, 26.17 mmol), pyridine (3.10 g, 39.26 mmol) and 2,2,2-trichloroethyl carbonochloridate (5.50 g, 26.17 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (250 mL) and washed with saturated aq. NH4Cl (3×50 mL) and brine (3×50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 5.2 g of 2,2,2-trichloroethyl (1-((2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate (49%).

Reference： [1]Current Patent Assignee: ASTRIA THERAPEUTICS INC - WO2013/90420, 2013, A2 Location in patent: Paragraph 00185
[2]Current Patent Assignee: ASTRIA THERAPEUTICS INC - US2014/288025, 2014, A1 Location in patent: Paragraph 0921; 0922
[3]Current Patent Assignee: ASTRIA THERAPEUTICS INC - US2016/129122, 2016, A1 Location in patent: Paragraph 0799; 0800

9
[ 134678-17-4 ]
[ 7481-89-2 ]
C₈H₁₁N₃O₃S*C₉H₁₃N₃O₃*2ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: lamivudine; 2`,3`-dideoxycytidine In isopropyl alcohol at 34.84℃; for 0.0833333h; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 24.84℃; for 0.0833333h;

Reference： [1]Martins, Felipe Terra; Correa, Rodrigo S.; Batista, Alzir Azevedo; Ellena, Javier [CrystEngComm, 2014, vol. 16, # 30, p. 7013 - 7022]

10
[ 14631-20-0 ]
[ 143919-90-8 ]
[ 131086-21-0 ]
[ 134678-17-4 ]

Reference： [1]Molecular catalysis,2019,vol. 468,p. 52 - 56

11
[ 1012053-56-3 ]
[ 136891-12-8 ]

Yield	Reaction Conditions	Operation in experiment
87.17%	With potassium carbonate In methanol at 0 - 25℃; for 3h;	1.6 6) Preparation of lamivudine: Add 20.55g to a round bottom three-necked flask equipped with a mechanical stirrer and thermometer(0.05mol)5S- (cytosinyl) -1,3-oxetane-2R-methyl optically active ester and 250 ml of methanol,Cool to 0 ° C, stir to dissolve, then add 12.36g (0.06mol) K2CO3,Continue to stir for 1 h, raise the temperature to 25 ° C, and stir the reaction for 2 h.The 5S- (cytosinyl) -1,3-oxetane-2R-methyl optically active ester is fully hydrolyzed to remove the chiral auxiliary, cooled, and the precipitate is separated by filtration.The mother liquor was evaporated under reduced pressure to remove the solvent, and then recrystallized from ethyl acetate, filtered, and dried.Get 10.77gLamivudine as a white solid has a calculated yield of 87.17%.
86%	With potassium carbonate In methanol at 0 - 25℃; for 2h;	7 Example 7 In a round bottom flask equipped with a mechanical stirring and a thermometer, 21.45 g (0.05 mol) of the obtained compound 8 and 250 ml of methanol were added, and the mixture was cooled to 0 ° C, and stirred to dissolve.Further, 12.36 g (0.06 mol) of K2CO3 was added, and stirring was continued for 1 hour, and the temperature was raised to 25 ° C.The reaction was stirred for 2 hours, cooled, and the precipitate was separated by filtration, and the solvent was evaporated to remove solvent.Reusing acetic acidEster recrystallization, filtration,dry, Obtained 13.31g of a white solid. The yield was 86%.

Reference： [1]Current Patent Assignee: WUHAN INSTITUTE OF TECHNOLOGY - CN110467607, 2019, A Location in patent: Paragraph 0027; 0028; 0034; 0035; 0036
[2]Current Patent Assignee: WUHAN INSTITUTE OF TECHNOLOGY - CN109438431, 2019, A Location in patent: Paragraph 0042; 0064; 0065

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A1269626[ 1217746-03-6 ]

rel-4-amino-1-((2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl)pyrimidin-2(1H)-one-2-13C-1,3-15N2

Reason: Stable Isotope

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