Method for recovering β isomer from CME solution containing β isomer and α isomer

Abstract

The present application belongs to the technical field of recovery and purification, and particularly relates to a method for recovering a β isomer from a CME solution containing a β isomer and an α isomer. The method for recovering a β isomer from a CME solution containing a β isomer and an α isomer of the present application comprises the following steps: concentrating the CME solution containing a β isomer and an α isomer, then dissolving same and trichloroacetic acid in methanol for a salt forming reaction, and after cooling and crystallization, filtering same, so as to obtain a trichloroacetate of the β isomer of CME; and dissociating the trichloroacetate of the β isomer of CME in methanol by using ammonia water, so as to obtain the β isomer of CME. By reacting trichloroacetic acid with the α isomer and β isomer of CME to form a salt, the trichloroacetate of the β isomer of CME is separated out by utilizing the different dissolvability of the trichloroacetate of the α isomer and the trichloroacetate of the β isomer, and the trichloroacetate of the β isomer of CME is then dissociated by using ammonia water, thereby achieving the recovery of the β isomer of CME.

Description

A method for recovering β isomer from CME solution containing β and α isomers

[0001] This application claims priority to a Chinese patent application filed with the Patent Office of China on October 24, 2024, with application number 202411487460.1 and invention name “A method for recovering β isomer from a CME solution containing both β and α isomers”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present application belongs to the field of recovery and purification technology, and specifically relates to a method for recovering β isomer from a CME solution containing both β and α isomers. Background Art

[0003] CME, also known in Chinese as (2R)-5-(5-cytosin-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester, includes the β-isomer of CME as (2R,5S)-5-(5-cytosin-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester, and the α-isomer of CME as (2R,5R)-5-(5-cytosin-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester. The β-isomer of CME is a key intermediate in the preparation of lamivudine, which can be reduced with sodium borohydride to yield lamivudine.

[0004] Lamivudine is a pharmaceutical ingredient with excellent antiviral activity, primarily used to treat hepatitis B and HIV. It is the main active ingredient in cocktail therapies currently used to treat hepatitis B and HIV. It is clinically used to treat chronic hepatitis B, decompensated cirrhosis, and HIV infection, also known as AIDS, in cocktail therapies. It is widely used due to its convenient oral administration, rapid antiviral effect, high safety, and relatively low treatment costs.

[0005] The current industrial synthesis process for lamivudine primarily involves preparing the lamivudine intermediate CME β-isomer, which is then reduced to produce lamivudine. During the reaction to prepare the lamivudine intermediate CME β-isomer, two CME isomers, β and α, are generated. After the reaction, the β-isomer is separated and purified. However, the residual liquid after separation and purification still contains some β-isomer, which is difficult to separate from the α-isomer. Directly disposing of the residual liquid after separation and purification as wastewater not only wastes resources but also exacerbates environmental pollution.

[0006] Summary of the Invention

[0007] In view of this, the present application provides a method for recovering β isomer from a CME solution containing both β and α isomers. The preparation method provided in the present application can separate a small amount of CME β isomer contained in the waste liquid, realize the resource utilization of the waste liquid, and reduce the discharge of the waste liquid.

[0008] In order to solve the above technical problems, the present application provides a method for recovering β isomer from a CME solution containing both β and α isomers, comprising the following steps:

[0009] The CME solution containing β and α isomers and trichloroacetic acid are dissolved in methanol to form a salt, and the salt is cooled, crystallized, and filtered to obtain the trichloroacetate salt of the CME β isomer.

[0010] The trichloroacetate of the CMEβ isomer is liberated with aqueous ammonia in methanol to obtain the CMEβ isomer.

[0011] Preferably, the temperature of the salt-forming reaction is 35-45° C., and the time is 1.8-2.2 h.

[0012] Preferably, the temperature of the cooling crystallization is -5 to 2°C, and the holding time of the cooling crystallization is 1.8 to 2.2 hours.

[0013] Preferably, after the filtration, the process further comprises: rinsing the solid obtained by filtration with methanol and then drying it to obtain the trichloroacetate of the CMEβ isomer.

[0014] Preferably, the methanol used for elution is low-temperature methanol, and the temperature of the low-temperature methanol is -5 to 5°C.

[0015] Preferably, the mass concentration of the ammonia water is 20-30%.

[0016] Preferably, the molar ratio of the trichloroacetate of the CMEβ isomer to the ammonia in the ammonia water is 1:1.1-1.3.

[0017] Preferably, the mass ratio of the trichloroacetate salt of the CMEβ isomer to methanol may be 1:5.5-6.5.

[0018] Preferably, the free time is 1 to 2 hours.

[0019] Preferably, the method further comprises: concentrating the freed system and dispersing it in water, and filtering it; and washing the solid obtained by filtration with water to obtain the CMEβ isomer.

[0020] Preferably, the dispersion temperature is 15-25°C.

[0021] Preferably, the mass ratio of α isomer to β isomer in the CME solution containing β and α isomers is 1:0.9-1.1.

[0022] Preferably, the CME solution containing both β and α isomers is waste liquid generated during the preparation of the lamivudine intermediate CME β isomer.

[0023] The present application provides a method for recovering the β isomer from a CME solution containing both β and α isomers, comprising the following steps: dissolving the CME solution containing both β and α isomers and trichloroacetic acid in methanol for a salt-forming reaction, cooling and crystallizing, and filtering to obtain the trichloroacetate salt of the CME β isomer; and liberating the trichloroacetate salt of the CME β isomer in methanol with aqueous ammonia to obtain the CME β isomer. The present application involves reacting trichloroacetic acid with the α and β isomers of CME to form salts, separating the trichloroacetate salt of the CME β isomer by utilizing the different solubilities of the trichloroacetate salts of the α and β isomers, and then liberating the trichloroacetate salt of the CME β isomer with aqueous ammonia to obtain the CME β isomer. The recovery method provided in the present application is simple and easy to operate, capable of separating a small amount of CME β isomer from waste liquid, thereby realizing resource utilization of the waste liquid while reducing waste liquid discharge. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] FIG1 is a hydrogen nuclear magnetic resonance spectrum of the trichloroacetate salt of the compound CMEβ isomer prepared in Example 1;

[0025] FIG2 is an LC-MS mass spectrum of the trichloroacetate salt of the compound CMEβ isomer prepared in Example 1;

[0026] FIG3 is a GC-MS mass spectrum of the trichloroacetate salt of the compound CMEβ isomer prepared in Example 1 after acidification and release;

[0027] FIG4 is an infrared spectrum of the trichloroacetate salt of the compound CMEβ isomer prepared in Example 1. DETAILED DESCRIPTION

[0028] The present application provides a method for recovering β isomer from a CME solution containing both β and α isomers, comprising the following steps:

[0029] The CME solution containing β and α isomers and trichloroacetic acid are dissolved in methanol to form a salt, and the salt is cooled, crystallized, and filtered to obtain the trichloroacetate salt of the CME β isomer.

[0030] The trichloroacetate of the CMEβ isomer is liberated with aqueous ammonia in methanol to obtain the CMEβ isomer.

[0031] In the present application, a CME solution containing both β and α isomers and trichloroacetic acid are dissolved in methanol to form a salt, and the mixture is cooled and crystallized before filtration to obtain the trichloroacetate salt of the CME β isomer. As one embodiment of the present application, the mass ratio of the α isomer to the β isomer in the CME solution containing both β and α isomers can be 1:0.9 to 1.1, specifically 1:1; the CME solution containing both β and α isomers can be waste liquid generated during the preparation of the lamivudine intermediate CME β isomer.

[0032] As one embodiment of the present application, before dissolving the CME solution containing both β and α isomers and trichloroacetic acid in methanol, the process may further include concentrating the CME solution containing both β and α isomers. This application does not specify the method for concentrating the CME solution containing both β and α isomers, as long as the solvent in the solution can be removed. This application does not specify the amount of methanol used, as long as it can completely dissolve the CME. This application does not specify the amount of trichloroacetic acid used, as long as it can fully react with the β and α isomers of CME to form salts. As one embodiment of the present application, the temperature of the salt-forming reaction can be 35-45°C, specifically 35°C, 40°C, or 45°C; the reaction time can be 1.8-2.2 hours, specifically 2 hours. As one embodiment of the present application, the temperature of the cooling crystallization can be -5-2°C, specifically -2°C, 0°C, or 1°C; and the holding time of the cooling crystallization can be 1.8-2.2 hours, specifically 2 hours.

[0033] The present application has no special limitation on the filtration, and conventional methods in the art can be used. As an embodiment of the present application, the filtration may further 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 application, the temperature of the low-temperature methanol may be -5 to 5°C, specifically -5°C, 0°C or 5°C. The present application can remove a small amount of trichloroacetate of the CMEα isomer that has not been filtered out by rinsing. The present application has no special limitation on the drying, as long as the solvent in the solid can be removed.

[0034] After obtaining the trichloroacetate of the CME β isomer, the present application liberates the trichloroacetate of the CME β isomer in methanol with aqueous ammonia to obtain the CME β isomer. As one embodiment of the present application, the mass concentration of the aqueous ammonia can be 20-30%, specifically 20%, 22%, 25% or 30%. As one embodiment of the present application, the mass ratio of the trichloroacetate of the CME β isomer to methanol can be 1:5.5-6.5, specifically 1:6. As one embodiment of the present application, the molar ratio of ammonia in the trichloroacetate of the CME β isomer and aqueous ammonia can be 1:1.1-1.3, specifically 1:1.1, 1:1.2 or 1:1.3. As one embodiment of the present application, the pH value of the methanol system after the trichloroacetate of the CME β isomer is liberated with aqueous ammonia can be 7-8.

[0035] As an embodiment of the present application, the free time may be 1 to 2 hours, specifically 1 hour, 1.5 hours or 2 hours.

[0036] As an embodiment of the present application, the freeing process may further include: concentrating the freed system and dispersing it in water, filtering; washing the filtered solid with water to obtain the CME β isomer. The present application 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 application, the mass ratio of the trichloroacetate salt of the CME β isomer to water can be 1:3 to 3.5, or 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 the dispersion process can be accompanied by stirring.

[0037] This application has no special requirements for the filtering and washing, and conventional methods in the art can be used.

[0038] As an embodiment of the present application, the equations for the salt formation reaction, crystallization and release are shown in formula a:

[0039] The present application can successfully separate the CMEβ isomer with higher purity from the waste liquid of preparing the CMEβ isomer for use in preparing lamivudine, thereby reducing the cost of lamivudine products and reducing waste liquid discharge.

[0040] In order to further illustrate the present application, the technical solutions provided in the present application are described in detail below in conjunction with the embodiments, but they should not be understood as limiting the scope of protection of the present application.

[0041] Example 1

[0042] Step 1: Prepare the intermediate CMEβ isomer used to synthesize lamivudine according to the reaction equation shown in formula b:

[0043] Preparation of compound 5: 144 g (0.5 mol) of HME (compound 1), 40.2 g (0.55 mol) of N,N-dimethylformamide (compound 3, DMF), 0.96 g (0.01 mol) of methanesulfonic acid (compound 4) and 432 g of dichloromethane were mixed and cooled to 5°C. 71.4 g (0.6 mol) of thionyl chloride (compound 2) was added dropwise with stirring. The mixture was heated and refluxed for 3 h. The thionyl chloride was distilled at atmospheric pressure until no flow was observed. 288 g of dichloromethane was added and stirred to dissolve to obtain a dichloromethane solution of HME chloride (compound 5);

[0044] Preparation of Compound 8: 55.5 g (0.5 mol) of cytosine (Compound 6), 0.96 g (0.01 mol) of methanesulfonic acid (Compound 4), 112.7 g (0.7 mol) of hexamethyldisilazane (Compound 7), and 111 g of toluene were mixed, and the mixture was heated and refluxed for 8 h until the system was clear. The toluene and excess hexamethyldisilazane were evaporated under reduced pressure to obtain Compound 8, and 222 g of dichloromethane was added and stirred to dissolve the mixture to obtain a dichloromethane solution of Compound 8;

[0045] Preparation of CMEβ isomer: A dichloromethane solution of compound 8 and 60.6 g (0.6 mol) of triethylamine (compound 9) were mixed, and the dichloromethane solution of compound 5 was added dropwise to the mixed solution at a temperature of 40°C. The mixture was condensed at 45°C for 15 h (the content of the main product no longer increased as tracked by HPLC), and then post-treated as follows: the condensation reaction system was washed twice with 150 g of water, the organic layer was separated and concentrated, 500 g of isopropyl acetate was added to the concentrated system, the temperature was raised to 70°C and kept warm for 1 h, cooled to 5°C, kept warm for 2 h, filtered, and rinsed with 100 g of 5°C isopropyl acetate and 100 g of water in sequence; the washed solid was dried to give 144.2 g of an off-white solid product CMEβ isomer (compound 10β). The melting point of the off-white solid CMEβ isomer was detected to be 214.9-216.1°C, and the specific rotation value (1% methanol) was -113.6°. The yield of CMEβ isomer was 75.7% based on HME, and the HPLC purity was 99.46%.

[0046] The filtrate obtained by filtration is combined with the eluting isopropyl acetate feed solution to form a residual liquid to be recovered.

[0047] HLPC analysis showed that the mass ratio of α-isomer to β-isomer of CME in the residual liquid was 49.6:50.4.

[0048] Step 2: Recovery of CMEβ isomer from the residual solution

[0049] The residual liquid was concentrated, mixed with 150 g of methanol and 19.6 g (0.12 mol) of trichloroacetic acid, and stirred at 40° C. for 1 h to form a salt; the mixture was cooled to 0° C. and kept warm for 2 h for cooling crystallization; the filtered solid was washed with 15 g of 0° C. methanol, and dried to obtain 21.2 g of CMEβ isomer trichloroacetate as a white solid. The specific rotation value (1% methanol) was -83.0°, the melting point was 208° C. (decomposition), and the mass percentage of CMEα isomer trichloroacetate in the solid was 0.12% as determined by HLPC;

[0050] 21.2 g (0.039 mol) of CMEβ isomer trichloroacetate, 127.2 g of methanol, and 3.2 g (0.047 mol) of 25% ammonia water were mixed at 20°C (pH of the mixed system was about 8), allowed to dissociate for 1 hour, and then concentrated to a paste. 63.6 g of water was added and stirred and dispersed at 20°C for 1 hour. The mixture was filtered and rinsed with 21.2 g of water to obtain 13.7 g of CMEβ isomer as a white solid. The yield of this step was 92.2%.

[0051] The melting point of the CMEβ isomer was detected to be 215.6-216.3°C, and the specific rotation value (1% methanol) was -115.3°.

[0052] HLPC analysis showed that the purity of the white solid CMEβ isomer was 99.86%, of which the mass percentage of the CMEα isomer was 0.03%.

[0053] The CMEβ isomer was recovered from the residual mother liquor with an increased yield of 7.2% based on the HME input into the reaction.

[0054] The compound CMEβ isomer trichloroacetate (C 18 H 27 N3O4S.C2HCl3O2) was subjected to nuclear magnetic resonance detection, liquid chromatography-mass spectrometry (LC-MS) detection, gas chromatography-mass spectrometry (GC-MS) detection and infrared detection, and the spectra were shown in Figures 1 to 4, wherein: Figure 1 is the nuclear magnetic resonance hydrogen spectrum of the trichloroacetate salt of the compound CMEβ isomer, and 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 .02-1.07(m,2H,CH2),1.40-1.49(m,2H,CH2),1.65(d,2H,CH2),1.91(m,2H,CH2 ),3.12(dd,1H,CH),3.53(dd,1H,CH),4.67(m,1H,CH),5.69(s,1H,CH),5.79(d ,1H,CH),6.34(t,1H,CH),7.35(d,2H,NH2),7.95(d,1H,CH),8.32(s,1H,COOH).

[0055] Figure 2 is the mass spectrum of the trichloroacetate salt of the β-isomer of compound CME in the positive ion mode of LC-MS, showing that C 18 H 27 C of N3O4S.C2HCl3O2 18 H 27 [M+H] of N3O4S + (i.e. C 18 H 27 N3O4S (M=381);

[0056] Figure 3 is the GC-MS mass spectrum of the trichloroacetate salt of the compound CMEβ isomer after acidification and release, showing that C 18 H 27 The mass spectrometry of C2HCl3O2 of N3O4S.C2HCl3O2, i.e., trichloroacetic acid, matches the mass spectrometry of trichloroacetic acid in the database (no molecular ion peak).

[0057] FIG4 is an infrared spectrum of the trichloroacetic acid salt of the compound CMEβ isomer. The infrared spectrum data are as follows: (IR, KBr, cm -1 ):(IR,KBr,cm -1 ): 3346(ν O-H ), 3131(ν N-H ), 2955(ν CH3 ), 2869(ν CH2 ), 1734(ν C＝O ), 1663(δ N-H ), 1522(δ N-H ), 1485(δ O-H ), 1369(ν CH3 ), 1284(ν C-N ), 1177(ν C-N ), 1076(ν C-H ), 981(ν ＝CH), 837(ν C-Cl ), 784(ν C-H ), 717(ν C-Cl ), 676(γ NH2 ), 596(γ NH2 ).

[0058] Elemental analysis of trichloroacetate of compound CMEβ isomer (C 18 H 27 N3O4S.C2HCl3O2, %) (found / calculated): C 43.95 / 44.09, H 5.23 / 5.18, N 7.66 / 7.71.

[0059] The HPLC detection of three batches of CMEβ isomer trichloroacetate showed that the external standard contents of Cl3CCOOH were 30.12%, 30.26%, 29.86%, and C 18 H 27 In the molecular structure of N3O4S.C2HCl3O2, the calculated content of Cl3CCOOH is 29.99%, indicating that the molecular ratio of the two salts is 1:1, which is consistent with the above molecular structure.

[0060] From the results of Example 1, it can be seen that the method provided in this application can recover CMEβ isomer with relatively high purity from the residual liquid generated during the preparation of CMEβ isomer, and can be used to prepare lamivudine.

[0061] Although the above embodiment provides a detailed description of the present application, it is only a part of the embodiments of the present application, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the scope of protection of the present application.

Claims

1. A method for recovering β isomer from a CME solution containing β and α isomers, comprising the following steps: The CME solution containing β and α isomers and trichloroacetic acid are dissolved in methanol to form a salt, and then cooled and crystallized, and filtered to obtain the trichloroacetate salt of the CME β isomer; The trichloroacetate of the CMEβ isomer is liberated with aqueous ammonia in methanol to obtain the CMEβ isomer.

2. The method according to claim 1, characterized in that: The temperature of the salt-forming reaction is 35-45° C. and the time is 1.8-2.2 hours.

3. The 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.

4. The method according to any one of claims 1 to 3, characterized in that: After the filtration, the method further comprises: rinsing the solid obtained by filtration with methanol and then drying it to obtain the trichloroacetate of the CMEβ isomer.

5. The method according to claim 4, characterized in that: The methanol used for elution is low-temperature methanol, and the temperature of the low-temperature methanol is -5 to 5°C.

6. The method according to claim 1, characterized in that: The mass concentration of the ammonia water is 20-30%.

7. The method according to claim 1 or 6, characterized in that: The molar ratio of the trichloroacetate of the CMEβ isomer to the ammonia in the ammonia water is 1:1.1-1.

3.

8. The method according to claim 1, characterized in that: The mass ratio of the trichloroacetate of the CMEβ isomer to methanol may be 1:5.5-6.

5.

9. The method according to claim 1 or 8, characterized in that: The free time is 1 to 2 hours.

10. The method according to claim 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.

11. The method according to claim 10, characterized in that: The dispersion temperature is 15-25°C.

12. The method according to claim 1, characterized in that: The mass ratio of the α isomer to the β isomer in the CME solution containing the β and α isomers is 1:0.9-1.

1.

13. The method according to claim 1 or 12, characterized in that: The CME solution containing β and α isomers is waste liquid generated during the preparation of lamivudine intermediate CME β isomer.

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