CN1120840C - Preparation method of lamifudin - Google Patents

Abstract

The present invention belongs to a preparation method of lamivudine, which selects cis-BCH-189 as a raw material, uses chiral carboxylic acid or chiral acyl chloride compound as chiral resolution reagents, and utilizes chemical esterification and resolution to obtain optically rotation pure lamivudine.

Description

The preparation method of lamifudin

The invention belongs to the preparation method of lamifudin.

Lamifudin belongs to the deoxycytidine analogue, it is 2-methylol-5-(cytosine(Cyt)-1 '-yl)-1, the cis left-handed rotation enantiomorph of one of four optically active isomers of 3-oxathiolane (BCH-189), compare with other isomer, its drug effect is identical, but the toxicity minimum be the ucleosides antiviral of new generation that is better than inverase AZT, and lamifudin has good function of resisting hepatitis B virus.

About the acquisition of activity of optically active compounds lamifudin, Chinese patent 92103921.2 discloses and has been entitled as " method of cis-selectivity synthetic nucleosides ", has introduced the fractionation to oxygen thia ring intermediate.Splitting principle is (-)-menthol and 2-carboxyl-5-acetoxyl group-1, and the 3-oxathiolane becomes ester, is separated into single diastereomer through cryogenic freezing.Then with Iodotrimethylsilane as Lewis acid, connect cytosine(Cyt) through the carbon-nitrogen bond coupling, and utilize the reductive agent lithium aluminium hydride reduction to get the end product lamifudin to obtain the lamifudin specific rotation and be [α] _D ²²-135 ° (c1.01, MeOH).This method overall yield is not high, and used industrial chemicals is more expensive.

Chinese patent 91102778.5 discloses and has been entitled as " 1, the preparation method of 3-oxathiolane nucleoside analogues ", has related to the fractionation by chirality HPLC and biological enzyme to BCH-189.The lamifudin specific rotation [α] that obtains _D ²¹-132 ° (c1.08, MeOH).Wherein the HPLC method can only split the trace sample, and the biological enzymolysis rule have the experiment loaded down with trivial details, consuming time many,

Shortcomings such as price is more expensive, and is not easy to be recycled.

The preparation method who the purpose of this invention is to provide a kind of lamifudin, it is initial feed that this method is selected cis-BCH-189, is chiral selectors with chiral carboxylic acids or chirality acyl chlorideization and thing, becomes ester to split by chemistry, thereby obtains optically pure lamifudin.

It is initial feed that the present invention selects cis-BCH-189, at first with it and equimolar anhydride reaction, aminoly protected by ethanoyl, and hydroxyl has neither part nor lot in reaction; Because cis-BCH-189 aerobic thia ring structure must have similar ring texture can take the principle of raw material apart in line with resolution reagent, select the chirality acids or chirality acyl chloride compound and the cis-2-methylol-5-(N that contain ring texture for use ₄'-ethanoyl-cytosine(Cyt)-1 '-yl)-1, the hydroxyl reaction of 3-oxathiolane generates the ester of diastereomer; Because low temperature helps the formation of chipal compounds,, and separate out the principle of ester during low temperature so when obtaining the ester of opticity by racemic ester, selected temperature is between-78 ℃～0 ℃, and choice of Solvent dissolving ester during with room temperature or heating; Because raw material contains aerobic thia ring structure, this structure is unsettled under acidic conditions, so select room temperature and in the alcoholic solvent of alkaline matter, make optically pure ester generation esterlysis, amido linkage fracture simultaneously, generate lamifudin, purify, can get the pure product of lamifudin through recrystallization or silica gel chromatographic column.

It is initial feed that the present invention selects cis-BCH-189, divides four-step reaction to finish, and its reactions steps is as follows:

Wherein, R ' is the basic group of chiral carboxylic acids or chirality acyl chloride, and R ' CO group comprises camphoroyl, prolyl,  oxygen base formyl radical;

A) the mole proportioning of raw material and diacetyl oxide is 1: 1, and selected solvent is an anhydrous dimethyl formamide, with the molar feed ratio of raw material be 500～2000 milliliters/1: 1, temperature of reaction is a room temperature, the reaction times is 8～20 hours;

When B) being become ester by the cis-BCH-189 of amido protecting with chirality acids or chirality acyl chloride, the molar feed ratio of raw material and chirality acids or chirality acyl chloride all is 1: 1～2; The chirality acids is: (-)-dextrocamphoric acid, (-)-proline(Pro), (-) or (+)  oxygen base formic acid; The chirality acyl chloride is: (-)-camphor acyl chlorides, (-)-prolyl chlorine, (-) or (+)- oxygen base formyl chloride when the chirality acids becomes ester with hydroxyl, selects for use dicyclohexylcarbodiimide to make dewatering agent, with material molar ratio be 1～2: 1; With the 4-Dimethylamino pyridine is catalyzer, with material molar ratio be 0.1: 1; When chirality acyl chloride compound becomes ester with hydroxyl, selecting triethylamine or pyridine for use is alkali, with material molar ratio be 1～2: 1, the reaction all in polar solvent acetonitrile or halohydrocarbon, finish as methylene dichloride and trichloromethane, the molar feed ratio of solvent and raw material is 100～1000 milliliters/1: 1; Temperature of reaction is between 0 ℃ and 80 ℃, and the reaction times is 4～20 hours;

C) the diastereoisomeric racemic ester of gained in alcoholic solvent, esters solvent, ketones solvent or their mixed solvent under low temperature fractional crystallization and separating, alcoholic solvent is: methyl alcohol; Esters solvent is: ethyl formate; Ketones solvent is: butanone; Mixed solvent is: ethanol: ethyl acetate=5: 1; Solvent and material molar ratio are 1000～5000 milliliters/1: 1, separate the ester of diastereomer, and selected temperature is during recrystallization :-78 ℃～0 ℃;

D) after recrystallization separates, the ester that the gained left-handed rotation is pure passes through the alkaline system hydrolysis, and alkaline system is salt of wormwood/methanol system, ammonia/methanol system, yellow soda ash/methanol system or sodium bicarbonate/methanol system; The molar feed ratio of alkali and starting ester is 1～2: 1, and the feed ratio of solvent methanol and starting ester is 1000～10000 milliliters/1: 1; Temperature of reaction is a room temperature, and the reaction times is 2～10 hours; Gained lamifudin specific rotation reaches [α] _D ²⁰-137 ° (c0.21, MeOH), polarimetry purity is 100%.

The inventive method begins to count from initial feed cis-BCH-189, obtains the lamifudin overall yield and is about 50%.Raw materials used cheap, synthesis step is few, simple possible, and the productive rate height, and chiral selectors can reclaim.

Lamifudin can be the 5-triphosphate that acts on the viral DNA chain end at endocellular metabolism, suppresses duplicating of viral reverse transcriptase, thereby is applied to treat AIDS and hepatitis B virus, and hepatitis C virus is also had effect definitely.

Embodiment provided by the invention is as follows:

Embodiment 1

Cis-2-methylol-5-(N4 '-ethanoyl-cytosine(Cyt)-1 '-yl)-1,3-oxathiolane I

Under room temperature and nitrogen protection; the diacetyl oxide 0.1ml of 1mmol is slowly splashed into; suitable-2-methylol-5-of 1mmol (cytosine(Cyt)-1 '-yl)-1; in the solution of 3-oxathiolane 0.229g and dry DMF 10ml, stirring reaction 10 hours, decompression goes down to desolventize; add dry toluene 5ml again; solvent is removed in decompression, resistates with the silica gel chromatographic column technical point from, eluent is that ratio is 5: 1 ethyl acetate and methyl alcohol.Product is the white powder 0.26g of 0.95mmol, productive rate 95%, fusing point: 164 ℃.

Embodiment 2

The preparation of racemization diastereomer  oxygen base oxygen thia ring carboxylicesters II

I3.70g and anhydrous acetonitrile 100ml and the pyridine 3.5ml of 13.6mmol are housed in the round-bottomed flask, stir, nitrogen protection, and be cooled to 0 ℃ with ice cube.Use the flexible needle technology, dropwise add (+)- oxygen base formyl chloride 3ml of 13.6mmol, and continue 0 ℃ of stirring reaction 48 hours.Solvent is removed in decompression, surplus faint yellow viscous material, with the silica gel chromatographic column technical point from, eluent is an ethyl acetate, the target product II of 9.88mmol is white solid 4.50g, productive rate is 73%.

Embodiment 3

The preparation of left-handed diastereomer  oxygen base oxathiolane carboxylic acid esters III

The II4.50g of 9.88mmol is dissolved among the anhydrous methanol 100ml, under the nitrogen protection, reflux half an hour, in refrigerator, placed about 40 hours then.The white solid of separating out is filtered, drying under reduced pressure, and under similarity condition, use methyl alcohol 50ml * 2 recrystallizations twice, get the white needles N-type waferN.After the filtration, can get the product III1.56g of 3.4mmol, productive rate 50.6%, fusing point: 186-188 ℃.Optical value [α] _D ²⁰-12.5 ° of (c0.01, CHCl ₃).

Embodiment 4

The preparation of racemization diastereomer camphor acyloxy oxathiolane carboxylicesters IV

To exsiccant circularly flask add the I1.26g of 4.6mmol, anhydrous acetonitrile 50ml, pyridine 1.0ml under the nitrogen protection, adds (-)-camphor acyl chlorides 1.0g of 7.8mmol, stirs and backflow 8h.Solvent is removed in decompression, surplus faint yellow viscous material, with the silica gel chromatographic column technical point from, eluent is an ethyl acetate, the target product of 3.3mmol is white solid 1.48g, productive rate 71%.

Embodiment 5

The preparation of left-handed diastereomer camphor acyloxy oxathiolane carboxylicesters V

In ethyl formate 20ml, in the dry ice bath of-78 ℃ freezing 2 ~ 5 minutes rapidly, the adularescent solid was separated out with the IV1.48g thermosol of 3.3mmol.Inclining solution, and vacuum pump is drained the solid residual solvent, is weighed as 0.56g, is total to 1.2mmol, productive rate 75%, fusing point: 190-192 ℃.Optical value [α] _D ²⁰-90 ° of (c0.41, CHCl ₃).

Embodiment 6

The preparation of racemization diastereomer prolyl oxygen base oxathiolane carboxylicesters VI

I3.2g with 11.8mmol, 11.8mmol (+)-proline(Pro) 1.4g, 1.2mmol catalytic amount 4-Dimethylamino pyridine 0.1g and anhydrous acetonitrile 100ml, place single necked round bottom flask, with dropping funnel the solution that the dicyclohexylcarbodiimide 2.43g of 12mmol is dissolved in anhydrous acetonitrile 20ml is slowly splashed in this round-bottomed flask under the room temperature, continue to stir 5h.Cross filter to remove white solid after, with the solution evaporate to dryness, resistates with the silica gel chromatographic column technical point from, eluent is 4: 1 ethyl acetate of ratio and methyl alcohol, the product VI of 7mmol is white solid 2.61g, productive rate 60%.

Embodiment 7

The preparation of left-handed diastereomer prolyl oxygen base oxathiolane carboxylicesters VII

The VI2.61g thermosol of 7mmol in butanone 30ml, was placed two days in-25 ℃ cryosels are bathed, and the adularescent solid is separated out.Inclining solution, and vacuum pump is drained the solid residual solvent, is weighed as 0.91g, is total to 2.5mmol, productive rate 70%, fusing point: 173-194 ℃.Optical value [α] _D ²⁰-65 ° of (c0.41, CHCl ₃).

Embodiment 8

The preparation of lamifudin VIII

The ester V0.56g of 1.2mmol opticity is placed single necked round bottom flask, add methyl alcohol 20ml, under the room temperature, feed ammonia, stir 12h with airway.After removing solvent, residuum is with 1: 2 ethanol of ratio and re-crystallizing in ethyl acetate, the lamifudin 0.26g of 1.14mmol, productive rate 95%, fusing point: 156 ℃, optical value [α] _D ²⁰-98 ° (c0.45, MeOH).

Embodiment 9

The preparation of lamifudin VIII

K with laevorotatory ester III0.6g of 1.3mmol and 2.6mmol ₂CO ₃0.54g and the mixture of methyl alcohol 20ml about 10 hours in stirring at room.After the filtration, remove solvent with Rotary Evaporators.Residuum silica gel chromatographic column technology separation and purification, eluent is 6: 1 ethyl acetate of ratio and methyl alcohol.The lamifudin VIII that gets 1.2mmol is white solid sprills 0.29g.Productive rate 95%, fusing point: 156 ℃, optical value [α] _D ²⁰-137 ° (c0.21, MeOH).

Claims (1)

1. the preparation method of a lamifudin, it is characterized in that selecting cis-BCH-189 is initial feed, divides four-step reaction to finish, its reactions steps is as follows:

Wherein, R ' is the basic group of chiral carboxylic acids or chirality acyl chloride, and R ' CO group comprises camphoroyl, prolyl,  oxygen base formyl radical;

A) the mole proportioning of raw material and diacetyl oxide is 1: 1, and selected solvent is an anhydrous dimethyl formamide, with the molar feed ratio of raw material be 500～2000 milliliters/1: 1, temperature of reaction is a room temperature, the reaction times is 8～20 hours;

When B) being become ester by the cis-BCH-189 of amido protecting with chirality acids or chirality acyl chloride, the molar feed ratio of raw material and chirality acids or chirality acyl chloride all is 1: 1～2; The chirality acids is: (-)-dextrocamphoric acid, (-)-proline(Pro), (-) or (+)  oxygen base formic acid; The chirality acyl chloride is: (-)-camphor acyl chlorides, (-)-prolyl chlorine, (-) or (+)- oxygen base formyl chloride when the chirality acids becomes ester with hydroxyl, selects for use dicyclohexylcarbodiimide to make dewatering agent, with material molar ratio be 1～2: 1; With the 4-Dimethylamino pyridine is catalyzer, with material molar ratio be 0.1: 1; When chirality acyl chloride compound becomes ester with hydroxyl, selecting triethylamine or pyridine for use is alkali, with material molar ratio be 1～2: 1, the reaction all in polar solvent acetonitrile or halohydrocarbon, finish as methylene dichloride and trichloromethane, the molar feed ratio of solvent and raw material is 100～1000 milliliters/1: 1; Temperature of reaction is between 0 ℃ and 80 ℃, and the reaction times is 4～20 hours;

C) the diastereoisomeric racemic ester of gained in alcoholic solvent, esters solvent, ketones solvent or their mixed solvent under low temperature fractional crystallization and separating, alcoholic solvent is: methyl alcohol; Esters solvent is: ethyl formate; Ketones solvent is: butanone; Mixed solvent is: ethanol: ethyl acetate=5: 1; Solvent and material molar ratio are 1000～5000 milliliters/1: 1, separate the ester of diastereomer, and selected temperature is during recrystallization :-78 ℃～0 ℃;

D) after recrystallization separates, the ester that the gained left-handed rotation is pure passes through the alkaline system hydrolysis, and alkaline system is salt of wormwood/methanol system, ammonia/methanol system, yellow soda ash/methanol system or sodium bicarbonate/methanol system; The molar feed ratio of alkali and starting ester is 1～2: 1, and the feed ratio of solvent methanol and starting ester is 1000～10000 milliliters/1: 1; Temperature of reaction is a room temperature, and the reaction times is 2～10 hours; Gained lamifudin specific rotation reaches [α] _D ²⁰-137 ° (c0.21, MeOH), polarimetry purity is 100%.