CN110467608B - Synthetic method of emtricitabine - Google Patents
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- CN110467608B CN110467608B CN201910773540.6A CN201910773540A CN110467608B CN 110467608 B CN110467608 B CN 110467608B CN 201910773540 A CN201910773540 A CN 201910773540A CN 110467608 B CN110467608 B CN 110467608B
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Abstract
The invention provides a synthetic method of emtricitabine, which takes dihaloacetic acid which is cheap and easy to obtain as a raw material, and the dihaloacetic acid is condensed with L-menthol, hydrolyzed to obtain glyoxylic acid menthyl ester, then condensed with 2, 5-dihydroxy-1, 4-dithiane, coupled with silanized 5-fluorocytosine after halogenation, reduced, salified with salicylic acid to obtain emtricitabine salicylate, and finally recrystallized to obtain the emtricitabine which is optically pure.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of emtricitabine.
Background
Emtricitabine (FTC) is a novel nucleoside reverse transcriptase inhibitor and is approved by the FDA in the united states on day 2, 7/2003. The clinical experiment result shows that the compound has obvious virus inhibiting effect on HIV infected person and hepatitis B HBV. The chemical name is: (2R, 5S) -4-amino-5-fluoro-1- (2-hydroxymethyl-1, 3-oxathiolan-5-yl) -2 (1F) -pyrimidinone. The chemical structural formula is as follows:
at present, more methods for synthesizing emtricitabine exist, but the following problems generally exist in the synthesis process: the synthesis process is complex, the selectivity of the reaction is poor, the product yield is low, and the purity of the product cannot reach the medicinal standard; the reaction conditions are harsh, the utilization rate of raw materials is low, the raw materials are expensive, and the synthesis cost is high; the used reagent is harmful to human body and can cause environmental pollution.
Disclosure of Invention
In view of the above, the invention aims to provide a method for synthesizing emtricitabine, which solves the problems of high synthesis cost, low yield, complex process and easy environmental pollution of the existing emtricitabine.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a synthetic method of emtricitabine comprises the following steps:
1) Under the condition of a catalyst and a solvent, L-menthol and dihaloacetic acid are subjected to esterification reaction to obtain dihaloacetic acid menthyl ester;
2) Hydrolyzing the dihalo-menthyl acetate under the condition of a catalyst to obtain glyoxylic acid menthyl ester;
3) Condensing the menthyl glyoxylate with 2, 5-dihydroxy-1, 4-dithiane under the condition of a solvent to obtain trans-menthyl 5-hydroxy-1, 3-oxathiolane-2-carboxylate;
4) Under the condition of an acid-binding agent and a solvent, halogenating the trans-5-hydroxy-1, 3-oxathiolane-2-carboxylic acid menthyl ester to obtain the trans-5-chloro-1, 3-oxathiolane-2-carboxylic acid menthyl ester;
5) Coupling the trans-5-chloro-1, 3-oxathiolane-2-carboxylic acid menthyl ester with silanized 5-fluorocytosine under the conditions of a catalyst and a solvent to obtain 5S- (5' -fluorocytosine) -1, 3-oxathiolane-2R-carboxylic acid menthyl ester;
6) Under the condition of a solvent, reducing the 5S- (5' -fluorocytosine) -1, 3-oxathiolane-2R-carboxylic acid menthyl ester, and salifying the reduced menthyl ester with salicylic acid to obtain emtricitabine salicylate;
7) And (3) recrystallizing the emtricitabine salicylate under the conditions of a catalyst and a solvent to separate the emtricitabine.
Optionally, the molar ratio of the L-menthol to the dihaloacetic acid to the catalyst in the step 1) is 1 to (1-3) to (0.81-2.1); the ratio of the total mass of the L-menthol, the dihaloacetic acid and the catalyst to the mass of the solvent is 1 to (7-15); the reaction temperature of the first reaction stage of the esterification reaction in the step 1) is-10 to 20 ℃, the reaction time is 1 to 4 hours, the reaction temperature of the second reaction stage is 80 to 130 ℃, and the reaction time is 5 to 12 hours.
Alternatively, the dihaloacetic acid menthyl ester in step 2): the catalyst comprises the following components: the weight ratio of the hydrolyzed water is 1 to (0.001-0.03) to (2-5); the hydrolysis temperature of the hydrolysis in the step 2) is 70-130 ℃, and the hydrolysis time is 3-8h.
Optionally, the molar ratio of the menthyl glyoxylate to the 2, 5-dihydroxy-1, 4-dithiane in step 3) is 1: 0.5-1; the condensation temperature of the condensation in the step 3) is 50-100 ℃, and the condensation time is 1-4h.
Optionally, the molar ratio of the trans-5-hydroxy-1, 3-oxathiolane-2-carboxylic acid menthyl ester, the halogenating agent and the acid-binding agent in the halogenation in the step 4) is 1: 0.3-1: 1.2-3.
Optionally, the reaction temperature of the first reaction stage of halogenation in the step 4) is-10 to 20 ℃, the reaction time is 1 to 5 hours, and the reaction temperature of the second reaction stage is 0 to 50 ℃, and the reaction time is 4 to 18 hours.
Optionally, the coupling temperature of the coupling in the step 5) is 50-120 ℃, and the coupling time is 4-12h.
Optionally, the molar ratio of the menthyl 5S- (5' -fluorocytosine) -1, 3-oxathiolane-2R-carboxylate in the step 6) to the reducing agent in the reduction is 1: (1-5); the reduction temperature of the reduction in the step 6) is 0-40 ℃, and the reduction time is 2-6h.
Alternatively, the molar ratio of menthyl 5S- (5' -fluorocytosinyl) -1, 3-oxathiolane-2R-carboxylate to salicylic acid is 1: 1-2; the salifying temperature in the step 6) is 40-80 ℃, and the salifying time is 2-5h.
Optionally, the molar ratio of the emtricitabine salicylate to the catalyst in the step 7) is 1 to (1-3), the recrystallization temperature of the recrystallization is 40-80 ℃, and the recrystallization time is 1-5h.
Compared with the prior art, the method for synthesizing emtricitabine has the following advantages:
according to the invention, cheap and easily-obtained dihaloacetic acid is used as a raw material, is condensed with L-menthol, is hydrolyzed to obtain glyoxylic acid menthyl ester, is condensed with 2, 5-dihydroxy-1, 4-dithiane, is coupled with silanized 5-fluorocytosine after being halogenated, is reduced, and forms salt with salicylic acid to obtain emtricitabine salicylate, and finally is recrystallized to obtain the optically pure emtricitabine.
Detailed Description
It should be noted that the embodiments and features of the embodiments of the present invention may be combined with each other without conflict.
The present invention will be described in detail with reference to examples.
Example 1
A synthetic method of emtricitabine specifically comprises the following steps:
1) Preparation of menthyl dichloroacetate: adding 15.60 (0.1 mol) L-menthol, 15.36g (0.12 mol) dichloroacetic acid, 0.244g (0.002 mol) 4-dimethylaminopyridine and 130ml n-hexane into a reactor, stirring until the materials are completely dissolved, and cooling to-5 ℃; slowly dripping a mixed solution of 20.06g (0.1 mol) of dicyclohexylcarbodiimide and 40ml of normal hexane into a reactor, heating to room temperature, stirring for reaction for 1h, heating to 100 ℃, stirring for reaction for 7h, fully performing esterification reaction on L-menthol and dihaloacetic acid, washing an organic phase with dilute hydrochloric acid, saturated sodium bicarbonate and saturated salt water in sequence, drying an organic layer by anhydrous sodium sulfate, and finally, distilling under reduced pressure to remove the solvent to obtain 18.68g of solid menthyl dichloroacetate, wherein the yield is 87.1 percent by calculation and the nuclear magnetic resonance hydrogen spectrum data is shown as follows by the nuclear magnetic resonance test 1 H-NMR(CDCl 3 )δ：6.29(s，1H)，4.46(m，1H)，1.82(m，1H)，1.73(m，1H)，1.55(m，2H)，1.51(m，1H)，1.38(m，2H)，0.86(d，3H)，0.83(d，6H)；
2) Preparation of glyoxylic acid menthyl ester: 26.6 (0.1 mol) dichloroacetic acid solution is added into a reactorHeating the charged ester, 0.266g of tetrabutylammonium bromide and 55ml of water to 95 ℃, keeping the temperature and reacting for 5 hours, fully hydrolyzing the dihaloacetic acid menthyl ester, standing for liquid separation, cooling and crystallizing an organic layer, performing suction filtration by using a Buchner funnel, and drying to obtain 18.08g of solid glyoxylic acid menthyl ester, wherein the organic layer containing the catalyst obtained by liquid separation can be supplemented with a small amount of water and the catalyst for recycling, the yield is 85.3 percent by calculation, and the nuclear magnetic resonance hydrogen spectrum data is 1H-NMR (CDCl) by nuclear magnetic resonance test 3 )δ：9.69(s，2H)，4.67(s，2H)，4.51(m，1H)，2.10(m，1H)，2.00(m，1H)，1.70(m，2H)，1.51(m，2H)，1.28(m，1H)，1.12(m，2H)，0.9(m，6H)，0.81(d，3H)；
3) Preparation of trans-5-hydroxy-1, 3-oxathiolane-2-carboxylic acid menthyl ester: adding 21.2g (0.1 mol) of menthyl glyoxylate, 4.7ml of glacial acetic acid and 150ml of toluene into a reactor under the protection of nitrogen, stirring until the menthyl glyoxylate, 4.7ml of glacial acetic acid and 150ml of toluene are completely dissolved, heating to 100 ℃, reacting until no fraction is produced, distilling under reduced pressure to remove the solvent, cooling to room temperature, adding 8.36g (0.055 mol) of 2, 5-dihydroxy-1, 4-dithiane, heating to 80 ℃, keeping the temperature for 2h to ensure that the menthyl glyoxylate and the 2, 5-dihydroxy-1, 4-dithiane are fully condensed, cooling to 0 ℃, filtering, slowly dripping 50ml of mixed solution of triethylamine and normal hexane (volume ratio is 1: 100) into the filtrate, keeping the temperature and stirring for 8h, filtering and drying to obtain 26.27g of solid trans-5-hydroxy-1, 3-oxathiolane-2-menthyl carboxylate, wherein the yield is 86.4 percent by calculation and the nuclear magnetic resonance test, and the nuclear magnetic resonance data of the nuclear magnetic resonance data are 86.4 percent 1 H-NMR(CDCl 3 )δ：5.95-6.82(m，1H)，5.55(d，1H)，4.72-5.65(m，1H)，3.30(dd，1H)，3.05(dd，1H)，1.06-2.03(m，8H)，0.89(dd，6H)，0.72(d，3H)；
4) Preparation of trans-5-chloro-1, 3-oxathiolane-2-carboxylic acid menthyl ester: adding 15.2g (0.05 mol) of trans-5-hydroxy-1, 3-oxathiolane-2-carboxylic acid menthyl ester, 150ml of dichloromethane and 5.94g (0.02 mol) of triphosgene into a reactor, stirring to fully dissolve the menthyl ester, and cooling to-5 ℃; weighing 9.48g (0.12 mol) of pyridine, dissolving in 65ml of dichloromethane solution, shaking uniformly, slowly dripping into a three-neck flask through a constant pressure dropping funnel, finishing dripping for 1h, keeping the temperature for reaction for 2h, heating to 25 ℃, stirring for reaction for 3h to ensure that trans-5-hydroxy-1, 3-oxathiolane-2-menthyl carboxylate is fully halogenated by triphosgene, filtering, and directly using mother liquor (trans-5-chloro-1, 3-oxathiolane-2-menthyl carboxylate) for the next reaction
5) Preparation of 5S- (5' -fluorocytosine) -1, 3-oxathiolane-2R-carboxylic acid menthyl ester: adding 6.45g (0.05 mol) of 5-fluorocytosine, 0.025ml of methanesulfonic acid, 8.09g (0.05 mol) of hexamethyldisilazane and 75ml of dichloromethane into a reactor, and heating under reflux until the solution becomes transparent to obtain a solution of silylated cytosine, namely silylated 5-fluorocytosine; adding 7.3ml triethylamine to the methyl silanized cytosine solution, heating and refluxing, then slowly dropwise adding the reaction solution obtained in the previous step (trans 5-chloro-1, 3-oxathiolane-2-carboxylic acid menthyl ester), heating to 75 ℃, reacting for 7h, fully coupling the trans 5-chloro-1, 3-oxathiolane-2-carboxylic acid menthyl ester with silanized 5-fluorocytosine (methyl silanized cytosine solution), pouring the reaction solution into water, washing the organic layer with a saturated sodium bicarbonate solution, washing with saturated brine, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove the solvent, recrystallizing the obtained oil with a mixed solution of n-hexane, ethyl acetate, and methanol (volume ratio 1 1 H-NMR(DMSO-d 6 )δ：8.17(s，1H)，7.91(s，1H)，7.70(s，1H)，6.28(t，1H)，5.70(s，1H)，4.72(d，1H)，3.53(dd，1H)，3.32(s，1H)，3.20(d，1H)，1.71(m，2H)，1.02-1.95(m，8H)，0.91(dd，6H)，0.84(d，3H)；
6) Preparation of emtricitabine salicylate: 21.5g (0.05 mol) of 5S- (5' -fluorocytosine) -1, 3-oxathiolane-2R-carboxylic acid menthyl ester and 150ml of tetrahydrofuran were charged into a reactor, and 10% NaOH (1.2 ml) and 5.45g (0.11 mol) of KBH were slowly added dropwise at room temperature of 25% 4 Dissolving in 60ml water, after the dropwise addition, keeping the temperature for 2h to react so as to ensure that the 5S- (5' -fluorocytosine) -1, 3-oxathiolane-2R-carboxylic acid menthyl ester is subjected to KBH 4 Fully reducing, standing for layering, and making into organic productAdjusting the pH to 4.0-4.5 by using 10% dilute hydrochloric acid, adjusting the pH to 6.8-7.2 by using 2mol/LNaOH solution, distilling under reduced pressure to remove the solvent, adding 7.6g (0.055 mol) of salicylic acid, heating to 60 ℃, stirring for reacting for 2 hours, cooling to 0 ℃ after the salt forming reaction is fully carried out, keeping the temperature and stirring for 1 hour, filtering, drying to obtain 20.41 solid emtricitabine salicylate, wherein the yield is 89.72% by calculation;
7) Preparing emtricitabine: adding 40.3g (0.1 mol) of emtricitabine salicylate, 320ml of absolute ethyl alcohol and 15.15g (0.15 mol) of ethylamine into a reactor, heating to 50 ℃, preserving heat for reaction for 1h to fully recrystallize the emtricitabine salicylate, removing the solvent by reduced pressure distillation, adding 300ml of ethyl acetate, cooling to 10 ℃, preserving heat and stirring for 1h, filtering, washing twice by 100ml of ethyl acetate, and drying to obtain 22.69g of white powdery emtricitabine, wherein the yield is 91.88% by calculation and the nuclear magnetic resonance hydrogen spectrum data is mp:184-185 ℃ of the weight percentage, 1 H-NMR(DMSO-d 6 ) δ:7.81 (d, 1H), 7.12-7.17 (brs, 2H), 6.02 (t, 1H), 5.75 (d, 1H), 5.25 (dt, 1H), 5.18 (t, 1H), 3.74 (dt, 2H), 3.40 (dd, 1H), 3.10 (dd, 1H), and the nuclear magnetic resonance carbon spectrum data is C-NMR (DMSO-d) 6 )δ：157.4，153.2，137.6，134.3，125.8，86.5，62.2，39.2。
The synthetic route of emtricitabine of this example is shown as follows:
in the preparation process of the emtricitabine of the invention, the solvent, the catalyst, the reducing agent, the acid-binding agent and the like in each step are not limited to the chemical substances in example 1, and chemical substances capable of realizing the preparation of the emtricitabine of the invention may be added as needed.
As in step 1), dihaloacetic acid other than dichloroacetic acid of example 1 may be preferably dibromoacetic acid, and the catalyst other than dicyclohexylcarbodiimide and 4-dimethylaminopyridine of example 1 may be preferably N, N-dimethylformamide, N-dimethylaniline, pyridine, diisopropyl etherPhenylethylamine, 4-dimethylaminopyridine, thionyl chloride, dicyclohexylcarbodiimide, H 2 SO 4 And when the catalyst is the combination of dicyclohexylcarbodiimide and 4-dimethylaminopyridine, the molar ratio of L-menthol to dichloroacetic acid to 4-dimethylaminopyridine to dicyclohexylcarbodiimide can be preferably 1 to (1-3) to (0.01-0.1) to (0.8-2), and the solvent can be preferably one or more of n-hexane, n-heptane, cyclohexane, toluene, dichloromethane, ethyl acetate, tetrahydrofuran and acetonitrile besides the n-hexane in example 1;
the catalyst used in step 2) is preferably ZnCl in addition to the phase transfer catalyst tetrabutylammonium bromide of example 1 2 、SnCl 2 、ZnCO 3 、Zn(OH) 2 、Zn(NO 3 ) 2 Phase transfer catalyst, concentrated H 2 SO 4 Concentrated HCl, concentrated HNO 3 And wherein the phase transfer catalyst can also be preferably one or more of 18 crown 6, 15 crown 5, cyclodextrin, benzyltriethylammonium chloride, benzyltriethylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, hexadecyltriethylammonium bromide;
the solvent in the step 3) can also be preferably one or more of dichloromethane, tetrahydrofuran, ethanol, acetonitrile, benzene and toluene besides the toluene in the embodiment 1;
the halogenating agent halogenated in the step 4) can be preferably thionyl chloride besides triphosgene of the example 1, the acid-binding agent can be preferably one or more of pyridine, triethylamine, N-dimethylformamide and sodium carbonate besides pyridine of the example 1, and the solvent can be preferably one or more of dichloromethane, chloroform, tetrahydrofuran, toluene and acetonitrile besides dichloromethane of the example 1;
the coupling agent for preparing the silylated cytosine solution (5-fluorocytosine silylation) in the step 5) may preferably be hexamethyldisilazane, trimethylsilyl trifluoromethanesulfonate, triethylsilane/I, in addition to the hexamethyldisilazane of example 1 2 Polymethylhydrosiloxane I 2 One or more of trimethylsilane and 5-fluorocytosine can be not silanized in the invention, trans-5-chloro-1, 3-oxathiolane-2-carboxylic acid menthyl ester can be directly coupled with 5-fluorocytosine, and trifluoromethanesulfonic acid/pyridine and ZrCl can be added to accelerate the coupling reaction process 4 、SnCl 4 And the like, and the coupling reaction is promoted by using a solvent which is preferably one or more of dichloromethane, chloroform, toluene and acetonitrile, besides dichloromethane in example 1;
the solvent in step 6) may preferably be one or more of tetrahydrofuran, 1,4 dioxane, dichloromethane, ethanol and methanol in addition to the tetrahydrofuran of example 1, and the reducing agent may preferably be KBH of example 1 4 LiAlH may also be preferred 4 、NaBH 4 、KBH 4 One or more of;
in the step 7), the catalyst can be preferably one or more of triethylamine, pyridine and 4-dimethylaminopyridine besides the triethylamine in the example 1, and the solvent can be preferably one or more of dichloromethane, tetrahydrofuran, toluene and absolute ethanol besides the absolute ethanol in the example 1.
The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. The method for synthesizing emtricitabine is characterized by comprising the following steps:
1) Under the condition of a catalyst and a solvent, L-menthol and dihaloacetic acid are subjected to esterification reaction to obtain dihaloacetic acid menthyl ester;
2) Hydrolyzing the dihaloacetic acid menthyl ester under the condition of a catalyst to obtain glyoxylic acid menthyl ester;
3) Condensing the menthyl glyoxylate with 2, 5-dihydroxy-1, 4-dithiane under the condition of a solvent to obtain trans-menthyl 5-hydroxy-1, 3-oxathiolane-2-carboxylate;
4) Under the condition of an acid-binding agent and a solvent, halogenating the trans-5-hydroxy-1, 3-oxathiolane-2-carboxylic acid menthyl ester to obtain the trans-5-chloro-1, 3-oxathiolane-2-carboxylic acid menthyl ester;
5) Coupling the trans-5-chloro-1, 3-oxathiolane-2-carboxylic acid menthyl ester with silanized 5-fluorocytosine under the conditions of a catalyst and a solvent to obtain 5S- (5' -fluorocytosine) -1, 3-oxathiolane-2R-carboxylic acid menthyl ester;
6) Under the condition of a solvent, reducing the 5S- (5' -fluorocytosine) -1, 3-oxathiolane-2R-carboxylic acid menthyl ester, and salifying the reduced menthyl ester with salicylic acid to obtain emtricitabine salicylate;
7) Under the conditions of a catalyst and a solvent, recrystallizing the emtricitabine salicylate, and separating emtricitabine; the catalyst in the step 1) is dicyclohexylcarbodiimide and 4-dimethylaminopyridine, and the molar ratio of the L-menthol to the dihaloacetic acid to the catalyst is 1: 1-3: 0.81-2.1; the ratio of the total mass of the L-menthol, the dihaloacetic acid and the catalyst to the mass of the solvent is 1: 7-15; the reaction temperature of the first reaction stage of the esterification reaction in the step 1) is-10-20 ℃, the reaction time is 1-4h, the reaction temperature of the second reaction stage is 80-130 ℃, and the reaction time is 5-12h;
the catalyst in the step 2) is tetrabutylammonium bromide, and the dihaloacetic acid menthyl ester: the catalyst comprises the following components: the weight ratio of the hydrolyzed water is 1 to (0.001-0.03) to (2-5); the hydrolysis temperature of the hydrolysis in the step 2) is 70-130 ℃, and the hydrolysis time is 3-8h;
the molar ratio of the menthyl glyoxylate to the 2, 5-dihydroxy-1, 4-dithiane in the step 3) is 1 to (0.5-1); the condensation temperature of the condensation in the step 3) is 50-100 ℃, and the condensation time is 1-4h;
the reaction temperature of the first reaction stage of halogenation in the step 4) is-10-20 ℃, the reaction time is 1-5h, the reaction temperature of the second reaction stage is 0-50 ℃, and the reaction time is 4-18h;
the coupling temperature of the coupling in the step 5) is 50-120 ℃, and the coupling time is 4-12h;
the molar ratio of the 5S- (5' -fluorocytosine) -1, 3-oxathiolane-2R-carboxylic acid menthyl ester to the salicylic acid is 1: 1-2; the salifying temperature in the step 6) is 40-80 ℃, and the salifying time is 2-5h.
2. The method for synthesizing emtricitabine according to claim 1, wherein the molar ratio of the trans 5-hydroxy-1, 3-oxathiolane-2-carboxylic acid menthyl ester, the halogenating agent and the acid scavenger in the halogenation in the step 4) is 1 to (0.3-1) to (1.2-3).
3. The method for synthesizing emtricitabine according to claim 1, wherein the molar ratio of the menthyl 5S- (5' -fluorocytosine) -1, 3-oxathiolane-2R-carboxylate in the step 6) to the reducing agent in the reduction is 1 to (1-5); the reduction temperature of the reduction in the step 6) is 0-40 ℃, and the reduction time is 2-6h.
4. The method for synthesizing emtricitabine according to claim 1, wherein the molar ratio of the emtricitabine salicylate to the catalyst in the step 7) is 1 to (1-3), the recrystallization temperature of the recrystallization is 40-80 ℃, and the recrystallization time is 1-5h.
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| CN102516078A (en) * | 2011-12-31 | 2012-06-27 | 浙江先锋科技有限公司 | Preparation methods of glyoxylic acid L-menthyl alcohol ester and monohydrate of glyoxylic acid L-menthyl alcohol ester |
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| CN1563002A (en) * | 2004-03-17 | 2005-01-12 | 济南久创化学有限责任公司 | Suitqable to industrialized method for preparing emtricitabine |
| CN102516078A (en) * | 2011-12-31 | 2012-06-27 | 浙江先锋科技有限公司 | Preparation methods of glyoxylic acid L-menthyl alcohol ester and monohydrate of glyoxylic acid L-menthyl alcohol ester |
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