Process for the preparation of a lamivudine intermediate

Abstract

The application 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 application comprises the following steps: mixing compound 1, compound 2, triethylamine and an organic solvent to perform a condensation reaction, so as to obtain a mixed solution containing CME beta isomer and CME alpha isomer; dissolving the mixed solution containing CME beta isomer and CME alpha isomer in methanol to perform a salt formation reaction after concentration, and then performing cooling crystallization and filtration, so as to obtain a trichloroacetic acid salt of CME beta isomer; and using an alkaline solution to free the trichloroacetic acid salt of CME beta isomer in methanol, so as to obtain the lamivudine intermediate CME beta isomer. The trichloroacetic acid salt of CME beta isomer is separated by using different solubilities of the trichloroacetic acid salts of alpha and beta isomers, and the CME beta isomer with high purity and high yield is obtained by using the alkaline solution to free.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a lamivudine intermediate. BACKGROUND

[0002] Lamivudine is also known as Lamivudine in English, and its chemical name is (2R)-hydroxymethyl-(5S)-(cytosine-1'-yl)-1,3-oxathiolane, and its code is 3-TC. It is a drug material with good antiviral activity, and is mainly used for anti-hepatitis B virus and anti-AIDS virus. It is the main active ingredient in the current treatment of hepatitis B and AIDS cocktail therapy, and is used in the treatment of chronic hepatitis B, decompensated cirrhosis, and HIV infection in the cocktail therapy. It is widely used due to its advantages of convenient oral administration, rapid inhibition of virus, high safety, and relatively low treatment cost.

[0003] Currently, the synthesis process of lamivudine in industry mainly comprises the following steps: first, a lamivudine intermediate CME β isomer is prepared Then, the lamivudine is prepared by reduction; in the preparation of the lamivudine intermediate CME β isomer, CME β and α isomers are generated, and the CME is (2R)-5-(5-cytosine-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester in Chinese. 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, but the yield and purity of the CME β isomer obtained by the existing separation and purification method are low, which directly affects the generation efficiency of the lamivudine. SUMMARY

[0004] Therefore, the present application provides a preparation method of a lamivudine intermediate, and the preparation method can be used to prepare CME β isomer with high purity and high yield, which is beneficial to the production of lamivudine.

[0005] In order to solve the above technical problems, the present application provides a preparation method of a lamivudine intermediate, comprising the following steps:

[0006] Compound 1, compound 2, triethylamine and an organic solvent are mixed to perform a condensation reaction, so as to obtain a mixed solution containing CME β isomer and CME α isomer;

[0007] The mixture solution containing CME beta isomer and CME alpha isomer is concentrated, and then a salt reaction is carried out by dissolving trichloroacetic acid in methanol, and after cooling and crystallization, the trichloroacetic acid salt of CME beta isomer is obtained by filtration;

[0008] The trichloroacetic acid salt of CME beta isomer is freed with an alkaline solution in methanol to obtain the CME beta isomer of lamivudine intermediate;

[0009]

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

[0011] The organic solvent includes dichloromethane.

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

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

[0014] The temperature of the salt reaction is 35-45℃, and the time is 1.8-2.2h.

[0015] Preferably, the temperature of the cooling and crystallization is -5-2℃, and the holding time of the cooling and crystallization is 1.8-2.2h.

[0016] Preferably, after the filtration, the obtained solid is rinsed with low-temperature methanol and then dried to obtain the trichloroacetic acid salt of CME beta isomer; the temperature of the low-temperature methanol is -5-5℃.

[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 trichloroacetic acid salt of CME beta isomer and the alkaline compound in the alkaline solution is 1:1.1-1.3.

[0020] Preferably, the temperature of the freeing is 15-25℃, and the time is 1-2h.

[0021] Preferably, after the freeing, the system is concentrated and then dispersed in water, and then filtered; the obtained solid is washed with water to obtain the CME beta isomer.

[0022] The application provides a preparation method of a lamivudine intermediate, and comprises the following steps: mixing compound 1, compound 2, triethylamine and an organic solvent to perform a condensation reaction, so as to obtain a mixed solution containing CME beta isomer and CME alpha isomer; dissolving the mixed solution containing CME beta isomer and CME alpha isomer in methanol to perform a salt formation reaction after concentration, and then performing cooling crystallization and filtration, so as to obtain a trichloroacetic acid salt of CME beta isomer; performing dissociation of the trichloroacetic acid salt of CME beta isomer in methanol by using an alkaline solution, so as to obtain a lamivudine intermediate CME beta isomer. The application separates the trichloroacetic acid salt of CME beta isomer by using the different solubilities of the trichloroacetic acid salt of CME alpha isomer and the trichloroacetic acid salt of CME beta isomer, and then dissociates the trichloroacetic acid salt of CME beta isomer by using an alkaline solution to obtain CME beta isomer. BRIEF DESCRIPTION OF DRAWINGS

[0023] Fig. 1 A nuclear magnetic resonance hydrogen spectrum of the compound CME beta isomer prepared in Example 1 is shown in the figure.

[0024] Fig. 2 An LC-MS mass spectrum of the compound CME beta isomer prepared in Example 1 is shown in the figure.

[0025] Fig. 3 An infrared spectrum of the compound CME beta isomer prepared in Example 1 is shown in the figure. DETAILED DESCRIPTION

[0026] The application provides a preparation method of a lamivudine intermediate, and comprises the following steps:

[0027] Mixing compound 1, compound 2, triethylamine and an organic solvent to perform a condensation reaction, so as to obtain a mixed solution containing CME beta isomer and CME alpha isomer;

[0028] Dissolving the mixed solution containing CME beta isomer and CME alpha isomer in methanol to perform a salt formation reaction after concentration, and then performing cooling crystallization and filtration, so as to obtain a trichloroacetic acid salt of CME beta isomer;

[0029] Performing dissociation of the trichloroacetic acid salt of CME beta isomer in methanol by using an alkaline solution, so as to obtain a lamivudine intermediate CME beta isomer;

[0030]

[0031] The present application mixes compound 1, compound 2, triethylamine and an organic solvent to carry out a condensation reaction, to obtain a mixed solution containing CME beta isomer and CME alpha isomer. As a specific embodiment of the present application, the preparation method of the compound 1 can comprise the following steps:

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

[0033] Add dropwise chlorosulfuric acid to the first mixed solution to carry out a first reflux reaction, to obtain the compound 1.

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

[0035] As a specific embodiment of the present application, after the first reflux, the system after the first reflux can further comprise distillation. The present application removes the unreacted chlorosulfuric acid by distillation.

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

[0037]

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

[0039] As a specific embodiment of the present application, the second refluxing can further comprise distilling the second refluxing system. The present application removes toluene and excess hexamethyldisilazane by distillation.

[0040] In the present application, the reaction equation of the second refluxing is shown as formula 2:

[0041]

[0042] As a specific embodiment of the present application, the mixing of compound 1, compound 2, triethylamine and organic solvent can comprise the following steps:

[0043] dissolving the compound 1 in part of the organic solvent to obtain a solution of compound 1;

[0044] dissolving the compound 2 in the rest of the organic solvent to obtain a solution of compound 2;

[0045] adding triethylamine to the solution of compound 1 and then adding the solution of compound 2 dropwise to obtain a reaction solution.

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

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

[0048] As a specific embodiment of the present application, the condensation reaction can further comprise washing the condensation reaction system with water, and taking the organic layer to obtain a mixed solution containing CME β isomer and CME α isomer.

[0049] After obtaining the mixed solution containing CME β isomer and CME α isomer, the present application concentrates the mixed solution containing CME β isomer and CME α isomer, and then dissolves trichloroacetic acid in methanol to carry out a salting reaction, and then filters after cooling and crystallization to obtain the trichloroacetate of CME β isomer. The present application does not have special requirements for the concentration method, as long as the solvent can be removed. As a specific embodiment of the present application, the molar ratio of the compound 1 and trichloroacetic acid can be 1:1.1-1.3, and can be specifically 1:1.2. As a specific embodiment of the present application, the mixed solution containing CME β isomer and CME α isomer can be concentrated and then dissolved in methanol to obtain a CME methanol solution; trichloroacetic acid is added to the CME methanol solution in batches to carry out a salting reaction. As a specific embodiment of the present application, the temperature of the dissolution 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 application, the temperature of the salting reaction can be 35-45°C, and can be specifically 35°C, 40°C or 45°C; the time of the salting reaction can be 1.8-2.2h, and can be specifically 2h. As a specific embodiment of the present application, the temperature of the cooling and crystallization can be -5-2°C, and can be specifically -2°C, 0°C or 1°C; the holding time of the cooling and crystallization can be 1.8-2.2h, and can be specifically 2h.

[0050] The present application does not have special requirements for the filtration, and a conventional method in the art can be used. As a specific embodiment of the present application, after the filtration, the obtained solid can be washed with low-temperature methanol and then dried to obtain the trichloroacetate of CME β isomer. As a specific embodiment of the present application, the temperature of the low-temperature methanol can be -5-5°C, and can be specifically -3°C, 0°C or 1°C. In the present application, the trichloroacetate of CME β isomer is almost insoluble in low-temperature methanol, while the solubility of the trichloroacetate of CME α isomer in low-temperature methanol is very large, and the residual trichloroacetate of CME α isomer can be removed by washing. The present application does not have special requirements for the drying, as long as the solvent in the solid can be removed.

[0051] After obtaining the trichloroacetic acid salt of the CMEβ isomer, this invention further liberates the trichloroacetic acid salt of the CMEβ isomer in methanol using an alkaline solution to obtain the lamivudine intermediate CMEβ isomer. In one embodiment of this invention, the alkaline solution may include sodium carbonate solution, potassium carbonate solution, ammonia water, or triethylamine solution, specifically ammonia water; the mass concentration of the alkaline solution may be 20-30%, specifically 23%, 25%, or 28%. In another embodiment of this invention, the mass ratio of the trichloroacetic acid salt of the CMEβ isomer to methanol may be 1:6-6.5, specifically 1:6; the molar ratio of the trichloroacetic acid salt of the CMEβ isomer to the alkaline compound in the alkaline solution may be 1:1.1-1.3, specifically 1:1.1, 1:1.2, or 1:1.3. In another embodiment of this invention, the pH value of the methanol system after the trichloroacetic acid salt of the CMEβ isomer is liberated in ammonia water may be 7-8.

[0052] In one embodiment of the present invention, the free temperature can be 15-25°C, specifically 18°C, 20°C or 23°C; the free time can be 1-2 hours, specifically 1 hour, 1.5 hours or 2 hours.

[0053] In one specific embodiment of the present invention, the process of dispersing the system may further include: concentrating the dispersed system and dispersing it in water, then filtering; washing the filtered solid with water to obtain the CMEβ isomer. The present invention does not have special requirements for the concentration process, as long as most of the solvent in the system can be removed, and the concentrated system becomes a paste. In one embodiment of the present invention, the mass ratio of the trichloroacetic acid salt of the CMEβ isomer to water can be 1:3 to 3.5, or even 1:3 to 3.3; the dispersion temperature can be 15 to 25°C, specifically 15°C, 20°C, or 25°C; the dispersion time can be 0.8 to 1.2 hours, specifically 1 hour; and stirring may be present during the dispersion process.

[0054] The present invention does not have any special requirements for the filtration and washing processes; conventional methods in the field can be used.

[0055] As one embodiment of the present invention, taking ammonia water as an alkaline solution as an example, the equations for the condensation reaction, salt formation reaction, crystallization and release are shown in Equation 3; in the reaction equation, CME includes CMEβ isomer and CMEα isomer.

[0056]

[0057] The preparation method provided by this invention can prepare CMEβ isomers with high purity and high yield for the preparation of lamivudine, thereby facilitating the efficient production of lamivudine and reducing the cost of lamivudine products.

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

[0059] Example 1

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

[0061] Preparation of Compound 2: Cytosine 55.5 g (0.5 mol), methyl sulfonic acid 0.96 g (0.01 mol), hexamethyldisilazane (HMDS) 112.7 g (0.7 mol) and toluene 111 g were mixed and heated to reflux for 8 h until the system was clear, and the toluene and excess hexamethyldisilazane were distilled off under reduced pressure, to obtain Compound 2;

[0062] Preparation of CME β isomer: Compound 2 was dissolved in 222 g of dichloromethane to obtain a solution of Compound 2; 60.6 g (0.6 mol) of triethylamine was added to the solution of Compound 2, and the dichloromethane solution of Compound 1 was added dropwise at 40°C, and then the condensation reaction was carried out at 45°C for 15 h (HPLC tracking showed that the content of the main product no longer increased), and the solution was washed twice with 150 g of water, and the organic layer was separated, and then concentrated, and 1300 g of methanol was added, and the temperature was raised to 30°C, and the solution was stirred to dissolve, to obtain a methanol solution of CME (a mixed solution containing CME β isomer and CME α isomer);

[0063] To the mixed solution containing CME β isomer and CME α isomer, 98.1 g (0.6 mol) of trichloroacetic acid was added in batches at 30°C, and the salt formation reaction was carried out at 40°C for 1 h with stirring, and then the temperature was cooled to 0°C, and the crystallization was carried out for 2 h, and then filtered, and washed with 250 g of low-temperature methanol at 0°C, and filtered, and dried, to obtain white solid CME β isomer trichloroacetate 236.5 g, which was detected to have a specific rotation (1% methanol) of -82.9° and a melting point of 208°C (decomposition).

[0064] The yield of CME β isomer trichloroacetate was 86.7% based on HME.

[0065] 236.5 g (0.434 mol) of trichloroacetic acid salt of CMEβ isomer, 1419 g of methanol, and 35.4 g (0.521 mol) of 25% ammonia solution were mixed at 20 °C (pH of the mixture was approximately 8). After being free for 1 h, the mixture was concentrated to a paste. 709.5 g of water was added and the mixture was stirred and dispersed at 20 °C for 1 h. The mixture was filtered and then washed with 236.5 g of water to obtain 157.2 g of white solid CMEβ isomer. The yield of this step was 95.1% based on the trichloroacetic acid salt of CMEβ isomer. The melting point of the CMEβ isomer was determined to be 215.8–216.5 °C, and the specific rotation (1% methanol) was -115.4°.

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

[0067] Comparative Example 1

[0068] A dichloromethane solution of compound 1 and compound 2 were prepared according to the method of Example 1;

[0069] The condensation reaction was carried out using compounds 1, 2, and triethylamine as raw materials according to the method of Example 1, with the difference being the post-condensation treatment steps: the system after the condensation reaction was washed twice with 150g of water, the organic layer was separated, the organic layer was concentrated, and 500g of isopropyl acetate was added. The mixture was heated to 70°C and held at that temperature for 1 hour, then cooled to 5°C and held at that temperature for 2 hours. After filtration, the mixture was rinsed with 100g of cold isopropyl acetate and 100g of water. After filtration and drying, 144.2g of a white solid CMEβ isomer was obtained. The melting point of the white solid CMEβ isomer was determined to be 214.9–216.1°C, and the specific rotation (1% methanol) was -113.6°.

[0070] Based on HME, the yield of the off-white solid CMEβ isomer was 75.7%, with an HPLC purity of 99.46%, of which the content of CMEα isomer was 0.42%.

[0071] The CMEβ isomer (C) prepared in Example 1 18 H 27 N3O4S) was detected by nuclear magnetic resonance, liquid chromatography-mass spectrometry (LC-MS), and infrared spectroscopy to obtain the following spectra: Figs. 1-3 As shown, where: Fig. 1 The following is the 1H NMR spectrum of the CMEβ isomer of compound CME. The 1H NMR data are as follows: 1H-NMR) (DMSO-d6), 600 MHz): δ 0.73 (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] Fig. 2 LC-MS mass spectrum of the CME β isomer, [M+H] in positive mode + = 382 (i.e.: M = 381), in agreement with the C 18 H 27 N3O4S molecular composition;

[0073] Fig. 3 IR spectrum of the compound CME β isomer, infra-red spectral data as follows: (IR, KBr, cm -1 ) : (IR, KBr, cm -1 ) : 3356 (v N-H ), 3179 (v N-H ), 2955 (v CH3 ), 2928 (v CH3 ), 2867 (v CH2 ), 1752 (v C＝O ), 1640 (δ N-H ), 1521 (δ N-H ), 1489 (δ CH2 ), 1369 (v CH3 ), 1289 (v C-N ), 1178 (v C-N ), 1100 (v C-H ), 981 (v ＝C－H ), 785 (v C-H ), 678 (γ NH2 ), 629 (γ NH2 ).

[0074] Elemental analysis (C 18 H 27 N3O4S, %) (found / calc): C 56.59 / 56.67, H 7.18 / 7.13, N 11.12 / 11.01.

[0075] The product prepared in Example 1 is CME β isomer according to the above detection results.

[0076] Although the above embodiments have been described in detail, they are only some embodiments of the present application, not all embodiments. Other embodiments can be obtained according to the above embodiments without creativity, and these embodiments also belong to the protection scope of the present application.

Claims

1. A method for preparing a lamivudine intermediate, comprising the following steps: mixing compound 1, compound 2, triethylamine and an organic solvent to perform a condensation reaction, to obtain a mixed solution containing CME β isomer and CME α isomer; concentrating the mixed solution containing CME β isomer and CME α isomer, dissolving trichloroacetic acid in methanol to perform a salting reaction, cooling and crystallizing, filtering to obtain a trichloroacetate of CME β isomer; the salting reaction is performed at a temperature of 35-45℃ for 1.8-2.2h; the cooling and crystallizing is performed at a temperature of -5-2℃, and the cooling and crystallizing is maintained for 1.8-2.2h; after the filtering, the filtered solid is rinsed with low-temperature methanol and dried to obtain the trichloroacetate of CME β isomer; the low-temperature methanol is at a temperature of -5-5℃; dissolving the trichloroacetate of CME β isomer in methanol with an alkaline solution to obtain a lamivudine intermediate CME β isomer; the alkaline solution comprises a sodium carbonate solution, a potassium carbonate solution, ammonia water or a triethylamine solution; the dissolving is performed at a temperature of 15-25℃ for 1-2h; 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 the triethylamine is 1:1.1-1.3; the organic solvent comprises dichloromethane; the condensation reaction is performed at a temperature of 43-47℃ for 13-17h; the molar ratio of the compound 1 to the trichloroacetic acid is 1:1.1-1.3; the mass concentration of the alkaline solution is 20-30%; the molar ratio of the trichloroacetate of CME β isomer to the alkaline compound in the alkaline solution is 1:1.1-1.3; after the dissolving, the system is concentrated and dispersed in water, and then filtered; the filtered solid is washed with water to obtain the CME β isomer. ​ ​ ​ 、 。 2. The method of claim 1, wherein, ​ ​ 3. The method of claim 1 or 2, wherein the method further comprises, ​ 4. The preparation method according to claim 1, characterized in that, ​ 5. The method of claim 1, wherein the step of forming the first and second layers is performed by a process selected from the group consisting of: sputtering, evaporation, and chemical vapor deposition. ​ 6. The method of claim 1 or 5, wherein the step of preparing the mixture is performed at a temperature of 20 to 30°C. ​ 7. The method of claim 1, wherein the step of forming the first and second layers is performed by a process selected from the group consisting of: sputtering, evaporation, and chemical vapor deposition. ​

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