Preparation method of lamivudine intermediate

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a lamivudine intermediate. The preparation method of the lamivudine intermediate provided by the invention comprises the following steps: mixing a compound 1, a compound 2, triethylamine and an organic solvent for condensation reaction to obtain a mixed solution containing a CMEbeta isomer and a CMEalpha isomer; concentrating the mixed solution containing the CMEbeta isomer and the CMEalpha isomer, dissolving the concentrated mixed solution and trichloroacetic acid in methanol for salt forming reaction, cooling, crystallizing, and filtering to obtain trichloroacetate of the CMEbeta isomer; and dissociating trichloroacetate of the CMEbeta isomer in methanol by using an alkaline solution to obtain the lamivudine intermediate CMEbeta isomer. The trichloroacetate of the CMEbeta isomer is separated by utilizing different dissolvability of trichloroacetate of alpha and beta isomers, and the CMEbeta isomer with high purity and high yield is obtained by utilizing an alkaline solution to carry out dissociation.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a lamivudine intermediate. Background Art

[0002] Lamivudine is called Lamivudine in English, and its chemical name is (2R)-hydroxymethyl-(5S)-(cytosine-1′-yl)-1,3-oxathiolane, codenamed 3-TC. It is a drug raw material with good antiviral activity, mainly used to fight hepatitis B virus and HIV. It is the main active ingredient in the cocktail therapy for treating hepatitis B and AIDS. It is clinically used to treat chronic hepatitis B, decompensated liver cirrhosis, and HIV infection in cocktail therapy. It is widely used because of its advantages such as convenient oral administration, rapid antiviral effect, high safety, and relatively low treatment cost.

[0003] At present, the industrial synthesis process of lamivudine mainly involves first preparing the intermediate CMEβ isomer of lamivudine. Then it is reduced to prepare lamivudine; in the process of preparing the lamivudine intermediate CME β isomer, two isomers of CME, β and α, are generated. The Chinese name of CME is: (2R)-5-(5-cytosine-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester, wherein the β isomer of CME is: (2R,5S)-5-(5-cytosine-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester, and the α isomer of CME is: (2R,5R)-5-(5-cytosine-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester. The β isomer is obtained by separation and purification. However, the yield and purity of the CME β isomer obtained by the existing separation and purification method are low, which directly affects the production efficiency of lamivudine. Summary of the invention

[0004] In view of this, the present invention provides a method for preparing a lamivudine intermediate. According to the preparation method provided by the present invention, a CMEβ isomer with higher purity and higher yield can be prepared, which is beneficial to the production and preparation of lamivudine.

[0005] In order to solve the above technical problems, the present invention provides a method for preparing a lamivudine intermediate, comprising the following steps:

[0006] Compound 1, compound 2, triethylamine and an organic solvent are mixed for condensation reaction to obtain a mixed solution containing CMEβ isomer and CMEα isomer;

[0007] The mixed solution containing the CMEβ isomer and the CMEα isomer is concentrated and dissolved in methanol with trichloroacetic acid to form a salt, and then cooled and crystallized and filtered to obtain the trichloroacetate salt of the CMEβ isomer;

[0008] The trichloroacetate of the CMEβ isomer is freed in methanol using an alkaline solution to obtain the lamivudine intermediate CMEβ isomer;

[0009]

[0010] Preferably, the molar ratio of the compound 1 to the compound 2 is 1:1-1.2, and the molar ratio of the compound 1 to triethylamine is 1:1.1-1.3;

[0011] The organic solvent includes dichloromethane.

[0012] Preferably, the condensation reaction temperature is 43-47° C. and the reaction time is 13-17 h.

[0013] Preferably, the molar ratio of the compound 1 to trichloroacetic acid is 1:1.1-1.3;

[0014] The temperature of the salt-forming reaction is 35-45° C. and the time is 1.8-2.2 hours.

[0015] Preferably, the temperature of the cooling crystallization is -5 to 2°C, and the insulation time of the cooling crystallization is 1.8 to 2.2 hours.

[0016] Preferably, after the filtration, the process further comprises: rinsing the solid obtained by filtration with low-temperature methanol and then drying it to obtain the trichloroacetate salt of the CMEβ isomer; the temperature of the low-temperature methanol is -5 to 5°C.

[0017] Preferably, the alkaline solution includes sodium carbonate solution, potassium carbonate solution, ammonia water or triethylamine solution;

[0018] The mass concentration of the alkaline solution is 20-30%.

[0019] Preferably, the molar ratio of the trichloroacetate of the CMEβ isomer to the alkaline compound in the alkaline solution is 1:1.1-1.3.

[0020] Preferably, the dissociation temperature is 15-25°C and the time is 1-2 hours.

[0021] Preferably, the method further comprises: concentrating the free system and dispersing it in water, filtering it; and washing the solid obtained by filtration with water to obtain the CMEβ isomer.

[0022] The preparation method of a lamivudine intermediate provided by the present invention comprises the following steps: mixing a compound 1, a compound 2, triethylamine and an organic solvent for a condensation reaction to obtain a mixed solution containing a CMEβ isomer and a CMEα isomer; concentrating the mixed solution containing the CMEβ isomer and the CMEα isomer, dissolving the mixed solution with trichloroacetic acid in methanol for a salt-forming reaction, cooling and crystallizing, and filtering to obtain a trichloroacetate salt of the CMEβ isomer; and freeing the trichloroacetate salt of the CMEβ isomer in methanol with an alkaline solution to obtain a lamivudine intermediate CMEβ isomer; The invention relates to a method for preparing a CME beta isomer by reacting trichloroacetic acid with an α isomer and a β isomer of CME to form a salt, and the trichloroacetate of the α isomer and the trichloroacetate of the β isomer are separated by using different solubilities, and then the trichloroacetate of the CME beta isomer is freed by an alkaline solution to obtain the CME beta isomer. The preparation method provided by the invention is simple and easy to operate, and can improve the yield and purity of the CME beta isomer. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the CMEβ isomer of the compound prepared in Example 1;

[0024] Figure 2 This is the LC-MS mass spectrum of the compound CMEβ isomer prepared in Example 1;

[0025] Figure 3 This is the infrared spectrum of the CMEβ isomer of the compound prepared in Example 1. DETAILED DESCRIPTION

[0026] The present invention provides a method for preparing a lamivudine intermediate, comprising the following steps:

[0027] Compound 1, compound 2, triethylamine and an organic solvent are mixed for condensation reaction to obtain a mixed solution containing CMEβ isomer and CMEα isomer;

[0028] The mixed solution containing the CMEβ isomer and the CMEα isomer is concentrated and dissolved in methanol with trichloroacetic acid to form a salt, and then cooled and crystallized and filtered to obtain the trichloroacetate salt of the CMEβ isomer;

[0029] The trichloroacetate of the CMEβ isomer is freed in methanol using an alkaline solution to obtain the lamivudine intermediate CMEβ isomer;

[0030]

[0031] In the present invention, compound 1, compound 2, triethylamine and an organic solvent are mixed for condensation reaction to obtain a mixed solution containing CMEβ isomer and CMEα isomer. As a specific embodiment of the present invention, the preparation method of compound 1 may include the following steps:

[0032] HME, N,N-dimethylformamide, methanesulfonic acid and dichloromethane are mixed to obtain a first mixed solution; the structural formula of the HME is

[0033] Thionyl chloride is added dropwise to the first mixed solution to carry out a first reflux reaction, thereby obtaining the compound 1.

[0034] As a specific embodiment of the present invention, the molar ratio of the HME, N,N-dimethylformamide (DMF) and methanesulfonic acid can be 1:1-1.2:0.01-0.02, specifically 1:1.1:0.02; the mass ratio of the HME and dichloromethane can be 1:2.5-3.5, specifically 1:3. The present invention has no special requirements for the mixing, as long as it can be mixed evenly. The present invention has no special requirements for the rate of the dropwise addition, as long as it is added dropwise. As a specific embodiment of the present invention, the molar ratio of the HME and thionyl chloride can be 1:1.1-1.3, specifically 1:1.2; the first reflux time can be 2-4h, specifically 3h.

[0035] As a specific embodiment of the present invention, the first reflux may further include: distilling the system after the first reflux. The present invention removes the unreacted thionyl chloride by distillation.

[0036] In the present invention, the reaction equation of the first reflux is shown in Formula 1:

[0037]

[0038] As a specific embodiment of the present invention, the preparation method of the compound 2 may include the following steps: mixing cytosine, methanesulfonic acid, hexamethyldisilazane and toluene, and performing a second reflux to obtain the compound 2. As a specific embodiment of the present invention, the molar ratio of cytosine, methanesulfonic acid and hexamethyldisilazane may be 1:0.01-0.02:1.3-1.4, and may be specifically 1:0.02:1.4; the mass ratio of cytosine and toluene may be 1:1.5-2.5, and may be specifically 1:2. As a specific embodiment of the present invention, the second reflux time may be 7-9h, and may be specifically 8h.

[0039] As a specific embodiment of the present invention, the second reflux may further include: distilling the system after the second reflux. The present invention removes toluene and excess hexamethyldisilazane by distillation.

[0040] In the present invention, the reaction equation of the second reflux is shown in Formula 2:

[0041]

[0042] As a specific embodiment of the present invention, the mixing of compound 1, compound 2, triethylamine and an organic solvent may include the following steps:

[0043] Dissolving the compound 1 in a portion of an organic solvent to obtain a solution of the compound 1;

[0044] Dissolving the compound 2 in the remaining organic solvent to obtain a solution of the compound 2;

[0045] Triethylamine is added to the solution of the compound 1, and then the solution of the compound 2 is added dropwise to obtain a reaction solution.

[0046] As a specific embodiment of the present invention, the organic solvent may include dichloromethane; the molar ratio of compound 1 to compound 2 may be 1:1-1.2, specifically 1:1, and the molar ratio of compound 1 to triethylamine may be 1:1.1-1.3, specifically 1:1.2. The present invention has no special requirements for the dosage ratio of the organic solvent and the remaining organic solvent, as long as they can be completely dissolved.

[0047] As a specific embodiment of the present invention, the temperature of the condensation reaction can be 43-47°C, and can be specifically 45°C; the time of the condensation reaction can be 13-17h, and can be specifically 14h, 15h or 16h.

[0048] As a specific embodiment of the present invention, after the condensation reaction, the following steps may be further performed: washing the system after the condensation reaction with water, and taking the organic layer to obtain a mixed solution containing CMEβ isomer and CMEα isomer.

[0049] After obtaining a mixed solution containing CMEβ isomer and CMEα isomer, the present invention concentrates the mixed solution containing CMEβ isomer and CMEα isomer and dissolves it in methanol with trichloroacetic acid to carry out salt-forming reaction, cools and crystallizes, and filters to obtain trichloroacetate salt of CMEβ isomer. The present invention has no special requirements for the concentration method, as long as the solvent can be removed. As a specific embodiment of the present invention, the molar ratio of compound 1 to trichloroacetic acid can be 1:1.1-1.3, and can be specifically 1:1.2. As a specific embodiment of the present invention, the mixed solution containing CMEβ isomer and CMEα isomer can be concentrated and dissolved in methanol to obtain a CME methanol solution; trichloroacetic acid is added to the CME methanol solution in batches to carry out salt-forming reaction. As a specific embodiment of the present invention, the dissolution temperature can be 25-35°C, and can be specifically 30°C; the dissolution can be carried out under stirring. As a specific embodiment of the present invention, the temperature of the salt-forming reaction can be 35 to 45°C, specifically 35°C, 40°C or 45°C; the time of the salt-forming reaction can be 1.8 to 2.2 hours, specifically 2 hours. As an embodiment of the present invention, the temperature of the cooling crystallization can be -5 to 2°C, specifically -2°C, 0°C or 1°C; the insulation time of the cooling crystallization can be 1.8 to 2.2 hours, specifically 2 hours.

[0050] The present invention has no special limitation on the filtration, and the conventional methods in the art can be used. As an embodiment of the present invention, the filtration may also include: rinsing the filtered solid with low-temperature methanol and then drying it to obtain the trichloroacetate of the CMEβ isomer. As an embodiment of the present invention, the temperature of the low-temperature methanol can be -5 to 5°C, and can be specifically: -3°C, 0°C or 1°C. In the present invention, the trichloroacetate of the CMEβ isomer is almost insoluble in low-temperature methanol, while the trichloroacetate of the CMEα isomer has a large solubility in low-temperature methanol. The present invention can remove the residual trichloroacetate of the CMEα isomer by rinsing. The present invention has no special limitation on the drying, as long as the solvent in the solid can be removed.

[0051] After obtaining the trichloroacetate of the CMEβ isomer, the present invention frees the trichloroacetate of the CMEβ isomer in methanol with an alkaline solution to obtain the lamivudine intermediate CMEβ isomer. As an embodiment of the present invention, the alkaline solution may include sodium carbonate solution, potassium carbonate solution, ammonia water or triethylamine solution, which may be specifically ammonia water; the mass concentration of the alkaline solution may be 20-30%, which may be specifically 23%, 25% or 28%. As an embodiment of the present invention, the mass ratio of the trichloroacetate of the CMEβ isomer to methanol may be 1:6-6.5, which may be specifically 1:6; the molar ratio of the trichloroacetate of the CMEβ isomer to the alkaline compound in the alkaline solution may be 1:1.1-1.3, which may be specifically 1:1.1, 1:1.2 or 1:1.3. As an embodiment of the present invention, the pH value of the methanol system after the trichloroacetate of the CMEβ isomer is freed by ammonia water may be 7-8.

[0052] As an embodiment of the present invention, the dissociation temperature may be 15-25°C, and may be specifically 18°C, 20°C or 23°C; the dissociation time may be 1-2h, and may be specifically 1h, 1.5h or 2h.

[0053] As a specific embodiment of the present invention, the freeing process may further include: concentrating the free system and dispersing it in water, filtering it; washing the filtered solid with water to obtain the CMEβ isomer. The present invention has no special requirements for the concentration, as long as most of the solvent in the system can be removed, and the system becomes a paste after concentration. As an embodiment of the present invention, the mass ratio of the trichloroacetate salt of the CMEβ isomer to water can be 1:3-3.5, or 1:3-3.3; the dispersion temperature can be 15-25°C, specifically 15°C, 20°C or 25°C; the dispersion time can be 0.8-1.2h, specifically 1h; the dispersion process can be accompanied by stirring.

[0054] The present invention has no special requirements for the filtering and washing, and conventional methods in the art can be used.

[0055] As an embodiment of the present invention, taking the alkaline solution as aqueous ammonia as an example, the equations of the condensation reaction, salt formation reaction, crystallization precipitation and liberation are shown in Formula 3; in the reaction equation, CME includes CMEβ isomers and CMEα isomers.

[0056]

[0057] According to the preparation method provided by the present invention, CMEβ isomer with higher purity and higher yield can be prepared for preparing lamivudine, thereby facilitating the efficient production of lamivudine and reducing the cost of lamivudine products.

[0058] In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0059] Example 1

[0060] Preparation of compound 1: 144 g (0.5 mol) of HME, 40.2 g (0.55 mol) of N,N-dimethylformamide, 0.96 g (0.01 mol) of methanesulfonic acid and 432 g of dichloromethane were mixed and cooled to 5°C, 71.4 g (0.6 mol) of thionyl chloride was added dropwise under stirring, the temperature was raised and refluxed for 3 h, thionyl chloride was distilled at normal pressure until there was no flow, 288 g of dichloromethane was added, and the mixture was stirred and dissolved to obtain a dichloromethane solution of compound 1;

[0061] Preparation of compound 2: 55.5 g (0.5 mol) of cytosine, 0.96 g (0.01 mol) of methanesulfonic acid, 112.7 g (0.7 mol) of hexamethyldisilazane (HMDS) and 111 g of toluene were mixed and refluxed for 8 h until the system was clear, and toluene and excess hexamethyldisilazane were evaporated under reduced pressure to obtain compound 2;

[0062] Preparation of CMEβ isomer: Compound 2 was dissolved in 222g of dichloromethane to obtain a solution of Compound 2; 60.6g (0.6mol) of triethylamine was added to the solution of Compound 2, and the dichloromethane solution of Compound 1 was added dropwise at 40°C, followed by condensation reaction at 45°C for 15h (the content of the main product no longer increased as tracked by HPLC), and then washed twice with 150g of water, the organic layer was separated, 1300g of methanol was added after concentrating the organic layer, and the temperature was raised to 30°C and stirred to dissolve, thereby obtaining a methanol solution of CME (a mixed solution containing CMEβ isomer and CMEα isomer);

[0063] To a mixed solution containing CMEβ isomer and CMEα isomer, 98.1 g (0.6 mol) of trichloroacetic acid was added in batches at 30°C, and the mixture was heated to 40°C for salt formation reaction (with stirring) for 1 h, then cooled to 0°C and cooled for crystallization for 2 h, filtered, rinsed with 250 g of low-temperature methanol at 0°C, filtered, and dried to obtain 236.5 g of white solid CMEβ isomer trichloroacetate. After testing, the specific rotation value (1% methanol) was -82.9° and the melting point was 208°C (decomposition).

[0064] The yield of CMEβ-isomer trichloroacetate was 86.7% based on HME.

[0065] 236.5 g (0.434 mol) of trichloroacetate of CMEβ isomer, 1419 g of methanol and 35.4 g (0.521 mol) of ammonia water with a mass concentration of 25% were mixed at 20°C (the pH value of the mixed system was about 8), concentrated to a paste after freeing for 1 hour, added with 709.5 g of water and stirred and dispersed at 20°C for 1 hour, filtered, and then rinsed with 236.5 g of water to obtain 157.2 g of CMEβ isomer as a white solid. The yield of this step was 95.1% based on the trichloroacetate of CMEβ isomer. The melting point of the CMEβ isomer was detected to be 215.8-216.5°C, and the specific rotation value (1% methanol) was -115.4°.

[0066] The total yield of CMEβ isomer was 82.5% based on HME, and the HPLC purity was 99.83%, of which the content of CMEα isomer was 0.03%.

[0067] Comparative Example 1

[0068] According to the method of Example 1, a dichloromethane solution of compound 1 and compound 2 were prepared;

[0069] According to the method of Example 1, a condensation reaction is carried out with compound 1, compound 2 and triethylamine as raw materials, except that the treatment steps after the condensation reaction are as follows: the system after the condensation reaction is washed twice with 150g of water, the organic layer is separated, the organic layer is concentrated and 500g of isopropyl acetate is added, the temperature is raised to 70°C and kept warm for 1h, cooled to 5°C, kept warm for 2h, filtered, rinsed with 100g of cold isopropyl acetate and 100g of water; filtered and dried to obtain 144.2g of off-white solid CMEβ isomer. The melting point of the off-white solid CMEβ isomer is detected to be 214.9-216.1°C, and the specific rotation value (1% methanol) is -113.6°.

[0070] The yield of off-white solid CMEβ isomer was 75.7% based on HME, and the HPLC purity was 99.46%, wherein the content of CMEα isomer was 0.42%.

[0071] The CMEβ isomer (C 18 H 27 N3O4S) was tested by nuclear magnetic resonance, liquid chromatography-mass spectrometry (LC-MS) and infrared detection to obtain the spectrum as shown in Figures 1 to 3 As shown, where: Figure 1 This is the nuclear magnetic resonance hydrogen spectrum of the compound CMEβ isomer. The hydrogen spectrum data are as follows: ( 1H-NMR)(DMSO-d6),600MHz): δ0.73(d,3H,CH3),0.87–0.90(m,7H,CH,2*CH3),1.02–1.06(m,2H,CH2),1.40-1.49(m,2H,CH2),1.65(d,2H,CH2),1.89-1. 94(m,2H,CH2),3.12(dd,1H,CH),3.53(dd,1H,CH),4.67(m,1H,CH),5.68(s, 1H,CH),5.78(d,1H,CH),6.34(t,1H,CH),7.32(d,2H,NH2),7.96(d,1H,CH).

[0072] Figure 2 This is the LC-MS mass spectrum of CMEβ isomer, [M+H] in positive ion mode + =382 (i.e. M = 381), and C 18 H 27 The molecular composition of N3O4S is consistent;

[0073] Figure 3 This is the infrared spectrum of the compound CMEβ isomer. The infrared spectrum data are as follows: (IR, KBr, cm -1 ): (IR, KBr, cm -1 ): 3356(ν N-H ), 3179(ν N-H ), 2955(ν CH3 ), 2928(ν CH3 ), 2867(ν CH2 ), 1752(ν C＝O ), 1640(δ N-H ), 1521(δ N-H ), 1489(δ CH2 ), 1369(ν CH3 ), 1289(ν C-N ), 1178(ν C-N ), 1100(ν C-H ), 981(ν ＝C－H ), 785(ν C-H ), 678(γ NH2 ), 629(γ NH2 ).

[0074] Elemental analysis of the β-isomer of compound CME (C 18 H 27 N3O4S, %) (found / calculated): C 56.59 / 56.67, H 7.18 / 7.13, N 11.12 / 11.01.

[0075] The above test results show that the product prepared in Example 1 is the CMEβ isomer.

[0076] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing a lamivudine intermediate, comprising the following steps: Compound 1, compound 2, triethylamine and an organic solvent are mixed for condensation reaction to obtain a mixed solution containing CMEβ isomer and CMEα isomer; The mixed solution containing the CMEβ isomer and the CMEα isomer is concentrated and dissolved in methanol with trichloroacetic acid to form a salt, and then cooled and crystallized and filtered to obtain the trichloroacetate salt of the CMEβ isomer; The trichloroacetate of the CMEβ isomer is freed in methanol using an alkaline solution to obtain the lamivudine intermediate CMEβ isomer; 2. The preparation method according to claim 1, characterized in that: The molar ratio of the compound 1 to the compound 2 is 1:1-1.2, and the molar ratio of the compound 1 to triethylamine is 1:1.1-1.3; The organic solvent includes dichloromethane.

3. The preparation method according to claim 1 or 2, characterized in that: The temperature of the condensation reaction is 43-47° C., and the time is 13-17 hours.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the compound 1 to trichloroacetic acid is 1:1.1-1.3; The temperature of the salt-forming reaction is 35-45° C. and the time is 1.8-2.2 hours.

5. The preparation method according to claim 1, characterized in that: The temperature of the cooling crystallization is -5 to 2°C, and the insulation time of the cooling crystallization is 1.8 to 2.2 hours.

6. The preparation method according to claim 1, characterized in that: After the filtration, the method further comprises: rinsing the solid obtained by filtration with low-temperature methanol and then drying it to obtain the trichloroacetate of the CMEβ isomer; the temperature of the low-temperature methanol is -5 to 5°C.

7. The preparation method according to claim 1, characterized in that: The alkaline solution includes sodium carbonate solution, potassium carbonate solution, ammonia water or triethylamine solution; The mass concentration of the alkaline solution is 20-30%.

8. The preparation method according to claim 1 or 7, characterized in that: The molar ratio of the trichloroacetate of the CMEβ isomer to the alkaline compound in the alkaline solution is 1:1.1-1.

3.

9. The preparation method according to claim 1, characterized in that: The temperature of the dissociation is 15-25° C., and the time is 1-2 hours.

10. The preparation method according to claim 1 or 9, characterized in that: The method further comprises: concentrating the free system and dispersing it in water, filtering it, and washing the solid obtained by filtering it with water to obtain the CMEβ isomer.

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