Industrial preparation method for lamivudine

Abstract

The invention discloses an industrial preparation method for lamivudine (3TC). The method is characterized in that: 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1<,>R, 2<,>S, 5<,>R)-5<,>-methyl-2<,>-(1-methylethyl) cyclohexyl] ester reacts with a acylating agent to obtain a acylate; the acylate and monosilylated acyl cytosine or monosilylated cytosine schiff's base are subjected to a glycosylation through a catalysis of lewis acid to obtain a 3TC intermediate, followed by reducing and deacylating or hydrolyzing and reducing to obtain the 3TC. The method provided by the present invention has advantages of simple, available and cheap raw materials, simple operation, safe production, high yield, less waste pollution, and is applicable for industrial production.

Description

technical field

[0001] The invention belongs to the field of chemistry or pharmaceutical chemistry, and in particular relates to an industrialized preparation method of anti-hepatitis B virus drug lamivudine. Background technique

[0002] Lamivudine (Lamivudine, 3TC) is shown in formula (I), and its chemical name is (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolane -5-yl)-1H-pyrimidin-2-one is a nucleoside analog antiviral drug. Nucleotides are the raw materials for the synthesis of human genetic material DNA and RNA. Lamivudine mimics the structure of nucleotides in structure, but it does not have the function of nucleotides. Its mechanism of action is to inhibit viral DNA polymerase and reverse transcriptase activity, and has a competitive inhibitory effect on the synthesis and elongation of viral DNA chains. Therefore, in the process of DNA synthesis, nucleoside analogs can be incorporated, but they cannot synthesize nucleic acid chains with normal functions, so that ...

Examples

Embodiment 1

[0066] (5R)-Acetoxy-1,3-oxathiolane-(2R)-carboxylic acid-[(1′R, 2′S, 5′R)-5′-methyl-2′- Preparation of (1-methylethyl)cyclohexyl] ester (IIIA)

[0067] Compound (II) 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1'R, 2'S, 5'R)-5'-methyl-2'-(1 -Methylethyl)cyclohexyl]ester (200g) was put into a 2L three-necked flask, DMAP (10.16g) and tetrahydrofuran 600ml were added, stirred and dissolved, cooled to -25~-20°C, and diethyl ether was added dropwise within 2~3 hours. Acid anhydride 99ml, continue to react for 45-60min after the dropwise addition, then slowly add 10% sodium carbonate aqueous solution dropwise to adjust the pH to 7, transfer it to a separatory funnel, let stand to separate layers, extract the water layer twice with 100ml tetrahydrofuran, collect organic layer, dried over anhydrous magnesium sulfate overnight, filtered, the filter cake was washed with a small amount of tetrahydrofuran, the filtrate was concentrated under reduced pressure at 60°C, recrystallized wi...

Embodiment 2

[0069] (5R)-propionyloxy-1,3-oxathiolane-(2R)-carboxylic acid-[(1′R, 2′S, 5′R)-5′-methyl-2′ Preparation of -(1-methylethyl)cyclohexyl]ester (IIIB)

[0070] Compound (II) 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1'R, 2'S, 5'R)-5'-methyl-2'-(1 -Methylethyl)cyclohexyl]ester (200g) was put into a 2L three-necked flask, DMAP (10.16g) and tetrahydrofuran 600ml were added, stirred and dissolved, cooled to -25~-20°C, and propane was added dropwise within 2~3 hours. Acid anhydride 134ml, continue to react for 45-60min after the dropwise addition, then slowly add 10% sodium carbonate aqueous solution dropwise to adjust the pH to 7, transfer it to a separatory funnel, let stand to separate layers, extract the water layer twice with 110ml tetrahydrofuran, collect organic layer, dried over anhydrous magnesium sulfate overnight, filtered, the filter cake was washed with a small amount of tetrahydrofuran, the filtrate was concentrated under reduced pressure at 60°C, recrystallized wit...

Embodiment 3

[0075] 5S-[5-(4-acetylamino-2-oxo-1(2H)-pyrimidine base)]-1,3-oxathiolane-2R-carboxylic acid-[(1′R,2 Preparation of 'S, 5'R)-5'-methyl-2'-(1-methylethyl)cyclohexyl]ester (VA)

[0076] Put 25.5g of N-acetylcytosine, 0.77g of ammonium sulfate, 22.0ml of hexamethyldisilazane and 500ml of chloroform into a 1L three-necked flask, stir and raise the temperature and reflux for 2 hours until the reaction solution is dissolved and clear, and cool to the internal temperature 0°C to obtain a chloroform solution of compound (IVA); under nitrogen protection, add 44.0ml of iodotrimethylsilane dropwise to the chloroform solution of compound (IVA) while stirring while maintaining the internal temperature at 0°C, dropwise within 1.5 to 2 hours After the addition, 100ml of compound (IIIA) (48.0g) in chloroform was added dropwise within 2 hours, and the temperature was raised to 30-35°C to react for 15h. The reaction solution was concentrated to dryness under reduced pressure, and 100ml of methy...

technical field

[0001] The invention belongs to the field of chemistry or pharmaceutical chemistry, and in particular relates to an industrialized preparation method of anti-hepatitis B virus drug lamivudine. Background technique

[0002] Lamivudine (Lamivudine, 3TC) is shown in formula (I), and its chemical name is (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolane -5-yl)-1H-pyrimidin-2-one is a nucleoside analog antiviral drug. Nucleotides are the raw materials for the synthesis of human genetic material DNA and RNA. Lamivudine mimics the structure of nucleotides in structure, but it does not have the function of nucleotides. Its mechanism of action is to inhibit viral DNA polymerase and reverse transcriptase activity, and has a competitive inhibitory effect on the synthesis and elongation of viral DNA chains. Therefore, in the process of DNA synthesis, nucleoside analogs can be incorporated, but they cannot synthesize nucleic acid chains with normal functions, so that ...

Examples

Embodiment 1

[0066] (5R)-Acetoxy-1,3-oxathiolane-(2R)-carboxylic acid-[(1′R, 2′S, 5′R)-5′-methyl-2′- Preparation of (1-methylethyl)cyclohexyl] ester (IIIA)

[0067] Compound (II) 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1'R, 2'S, 5'R)-5'-methyl-2'-(1 -Methylethyl)cyclohexyl]ester (200g) was put into a 2L three-necked flask, DMAP (10.16g) and tetrahydrofuran 600ml were added, stirred and dissolved, cooled to -25~-20°C, and diethyl ether was added dropwise within 2~3 hours. Acid anhydride 99ml, continue to react for 45-60min after the dropwise addition, then slowly add 10% sodium carbonate aqueous solution dropwise to adjust the pH to 7, transfer it to a separatory funnel, let stand to separate layers, extract the water layer twice with 100ml tetrahydrofuran, collect organic layer, dried over anhydrous magnesium sulfate overnight, filtered, the filter cake was washed with a small amount of tetrahydrofuran, the filtrate was concentrated under reduced pressure at 60°C, recrystallized wi...

Embodiment 2

[0069] (5R)-propionyloxy-1,3-oxathiolane-(2R)-carboxylic acid-[(1′R, 2′S, 5′R)-5′-methyl-2′ Preparation of -(1-methylethyl)cyclohexyl]ester (IIIB)

[0070] Compound (II) 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1'R, 2'S, 5'R)-5'-methyl-2'-(1 -Methylethyl)cyclohexyl]ester (200g) was put into a 2L three-necked flask, DMAP (10.16g) and tetrahydrofuran 600ml were added, stirred and dissolved, cooled to -25~-20°C, and propane was added dropwise within 2~3 hours. Acid anhydride 134ml, continue to react for 45-60min after the dropwise addition, then slowly add 10% sodium carbonate aqueous solution dropwise to adjust the pH to 7, transfer it to a separatory funnel, let stand to separate layers, extract the water layer twice with 110ml tetrahydrofuran, collect organic layer, dried over anhydrous magnesium sulfate overnight, filtered, the filter cake was washed with a small amount of tetrahydrofuran, the filtrate was concentrated under reduced pressure at 60°C, recrystallized wit...

Embodiment 3

[0075] 5S-[5-(4-acetylamino-2-oxo-1(2H)-pyrimidine base)]-1,3-oxathiolane-2R-carboxylic acid-[(1′R,2 Preparation of 'S, 5'R)-5'-methyl-2'-(1-methylethyl)cyclohexyl]ester (VA)

[0076] Put 25.5g of N-acetylcytosine, 0.77g of ammonium sulfate, 22.0ml of hexamethyldisilazane and 500ml of chloroform into a 1L three-necked flask, stir and raise the temperature and reflux for 2 hours until the reaction solution is dissolved and clear, and cool to the internal temperature 0°C to obtain a chloroform solution of compound (IVA); under nitrogen protection, add 44.0ml of iodotrimethylsilane dropwise to the chloroform solution of compound (IVA) while stirring while maintaining the internal temperature at 0°C, dropwise within 1.5 to 2 hours After the addition, 100ml of compound (IIIA) (48.0g) in chloroform was added dropwise within 2 hours, and the temperature was raised to 30-35°C to react for 15h. The reaction solution was concentrated to dryness under reduced pressure, and 100ml of methy...

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