Method for recovering beta isomer from CME solution containing beta isomer and alpha isomer

Abstract

The invention belongs to the technical field of recovery and purification, and particularly relates to a method for recovering a beta isomer from a CME solution containing beta and alpha isomers. The method for recovering the beta-isomer from the CME solution containing the beta-isomer and the alpha-isomer comprises the following steps: concentrating the CME solution containing the beta-isomer and the alpha-isomer, dissolving the concentrated CME solution and trichloroacetic acid in methanol for salt forming reaction, cooling, crystallizing, and filtering to obtain trichloroacetate of the CME beta-isomer; and dissociating the trichloroacetate of the CMEbeta isomer in methanol by using ammonia water to obtain the CMEbeta isomer. According to the method, trichloroacetic acid reacts with an alpha isomer and a beta isomer of CME to form salt, trichloroacetate of the CME beta isomer is separated out by utilizing different dissolvability of trichloroacetate of the alpha isomer and trichloroacetate of the beta isomer, and then trichloroacetate of the CME beta isomer is dissociated by ammonia water, so that the CME beta isomer is recycled.

Description

Technical Field

[0001] The invention belongs to the technical field of recovery and purification, and in particular relates to a method for recovering β isomer from a CME solution containing β and α isomers. Background Art

[0002] CME, Chinese name: (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 of CME is a key intermediate in the preparation of lamivudine, and the β-isomer of CME is reduced with sodium borohydride to obtain lamivudine.

[0003] Lamivudine is a drug raw material with good antiviral activity. It is mainly used to treat hepatitis B and HIV. It is the main active ingredient in the cocktail therapy for treating hepatitis B and AIDS. It is clinically used for the treatment of chronic hepatitis B, decompensated liver cirrhosis, and HIV infection, i.e. AIDS, 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.

[0004] At present, the synthesis process of lamivudine in industry mainly involves first preparing the intermediate CMEβ isomer of lamivudine, and then reducing it to prepare lamivudine; in the process of preparing the intermediate CMEβ isomer of lamivudine, two isomers of CME, β and α, are generated, and the β isomer is obtained by separation and purification after the reaction, but the residual liquid after separation and purification still contains some β isomers that are difficult to separate from the α isomer. Directly treating the residual liquid after separation and purification as waste liquid not only causes a waste of resources, but also aggravates environmental pollution. Summary of the invention

[0005] In view of this, the present invention provides a method for recovering β isomer from a CME solution containing β and α isomers. The preparation method provided by the present invention 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.

[0006] In order to solve the above technical problems, the present invention provides a method for recovering β isomer from a CME solution containing β and α isomers, comprising the following steps:

[0007] The CME solution containing β and α isomers 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 CME β isomer;

[0008] The trichloroacetate of the CMEβ isomer is liberated with aqueous ammonia in methanol to obtain the CMEβ isomer.

[0009] Preferably, the temperature of the salt-forming reaction is 35-45° C. and the time is 1.8-2.2 h.

[0010] 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.

[0011] Preferably, after the filtration, the process further comprises: rinsing the solid obtained by filtration with methanol and then drying it to obtain the trichloroacetate salt of the CMEβ isomer.

[0012] Preferably, the mass concentration of the ammonia water is 20-30%.

[0013] Preferably, the molar ratio of the trichloroacetate of the CMEβ isomer to the ammonia in the ammonia water is 1:1.1-1.3.

[0014] Preferably, the free time is 1 to 2 hours.

[0015] 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.

[0016] 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.

[0017] Preferably, the CME solution containing both β and α isomers is waste liquid generated during the preparation of lamivudine intermediate CME β isomer.

[0018] The present invention provides a method for recovering β isomer from CME solution containing β and α isomers, comprising the following steps: concentrating the CME solution containing β and α isomers and dissolving it in methanol with trichloroacetic acid to carry out salt-forming reaction, cooling and crystallizing, filtering to obtain trichloroacetate of CME β isomer; freeing the trichloroacetate of CME β isomer in methanol with ammonia water to obtain CME β isomer. The present invention forms salt by reacting trichloroacetic acid with α isomer and β isomer of CME, separating the trichloroacetate of CME β isomer by utilizing the different solubility of trichloroacetate of α isomer and trichloroacetate of β isomer, and then freeing the trichloroacetate of CME β isomer by ammonia water to obtain CME β isomer. The recovery method provided by the present invention is simple and easy to operate, and can separate a small amount of CME β isomer in waste liquid, realizes the resource utilization of waste liquid, and reduces the discharge of waste liquid at the same time. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the trichloroacetate salt of the compound CMEβ isomer prepared in Example 1;

[0020] Figure 2 This is the LC-MS mass spectrum of the trichloroacetate salt of the compound CMEβ isomer prepared in Example 1;

[0021] Figure 3 This is the GC-MS mass spectrum of the trichloroacetate salt of the compound CMEβ isomer prepared in Example 1 after being acidified and released;

[0022] Figure 4 This is the infrared spectrum of the trichloroacetate salt of the compound CMEβ isomer prepared in Example 1. DETAILED DESCRIPTION

[0023] The present invention provides a method for recovering β isomer from a CME solution containing β and α isomers, comprising the following steps:

[0024] The CME solution containing β and α isomers 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 CME β isomer;

[0025] The trichloroacetate of the CMEβ isomer is liberated in methanol with aqueous ammonia to obtain the CMEβ isomer.

[0026] The present invention concentrates a CME solution containing two isomers of β and α, dissolves the solution with trichloroacetic acid in methanol for salt formation reaction, cools and crystallizes, and filters to obtain trichloroacetate of CME β isomer. As an embodiment of the present invention, the mass ratio of α isomer to β isomer in the CME solution containing two isomers of β and α can be 1:0.9-1.1, specifically 1:1; the CME solution containing two isomers of β and α can be waste liquid generated in the process of preparing lamivudine intermediate CME β isomer.

[0027] The present invention has no special requirements for the concentration method of the CME solution containing β and α isomers, as long as the solvent in the solution can be removed. The present invention has no special requirements for the amount of methanol used, as long as it can be completely dissolved. The present invention has no special requirements for the amount of trichloroacetic acid used, as long as it can fully react with the β isomer and α isomer of CME to form a salt. As an 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 2.2h, specifically 2h. 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 2.2h, specifically 2h.

[0028] 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, specifically -5°C, 0°C or 5°C. The present invention can remove a small amount of trichloroacetate of the CMEα isomer that has not been filtered out by rinsing. The present invention has no special limitation on the drying as long as the solvent in the solid can be removed.

[0029] After obtaining the trichloroacetate of the CMEβ isomer, the present invention frees the trichloroacetate of the CMEβ isomer in methanol with ammonia water to obtain the CMEβ isomer. As an embodiment of the present invention, the mass concentration of the ammonia water can be 20-30%, specifically 20%, 22%, 25% or 30%. As an embodiment of the present invention, the mass ratio of the trichloroacetate of the CMEβ isomer to methanol can be 1:5.5-6.5, specifically 1:6. As an embodiment of the present invention, the molar ratio of ammonia in the trichloroacetate of the CMEβ isomer and ammonia water can be 1:1.1-1.3, 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 can be 7-8.

[0030] As an embodiment of the present invention, the free time may be 1 to 2 hours, specifically 1 hour, 1.5 hours or 2 hours.

[0031] As an 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.

[0032] The present invention has no special requirements for the filtering and washing, and conventional methods in the art can be used.

[0033] As an embodiment of the present invention, the equations for the salt formation reaction, crystallization and release are shown in formula a:

[0034]

[0035] The invention can successfully separate the CMEβ isomer with higher purity from the waste liquid in preparing the CMEβ isomer for preparing lamivudine, thereby reducing the product cost of lamivudine and reducing the discharge of waste liquid.

[0036] 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.

[0037] Example 1

[0038] Step 1: Prepare the intermediate CMEβ isomer used for synthesizing lamivudine according to the reaction equation shown in formula b:

[0039]

[0040] 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 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, stirred and dissolved, and a dichloromethane solution of HME chloride (compound 5) was obtained;

[0041] 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. Toluene and excess hexamethyldisilazane were evaporated under reduced pressure to obtain compound 8. 222 g of dichloromethane was added and stirred to dissolve to obtain a dichloromethane solution of compound 8;

[0042] Preparation of CMEβ isomer: A dichloromethane solution of compound 8 and 60.6 g (0.6 mol) of triethylamine (compound 9) were mixed, and a dichloromethane solution of compound 5 was added dropwise to the mixed solution at a temperature of 40°C, followed by a condensation reaction 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 system after the condensation reaction 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 turn; the washed solid was dried to obtain 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°.

[0043] The yield of CMEβ isomer was 75.7% based on HME, and the HPLC purity was 99.46%.

[0044] The filtrate obtained by filtration is combined with the eluting isopropyl acetate feed solution to form a residual liquid to be recovered.

[0045] HLPC analysis showed that the mass ratio of α-isomer to β-isomer of CME in the residual liquid was 49.6:50.4.

[0046] Step 2: Recovery of CMEβ isomer from the residual liquid

[0047] 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 perform a salt-forming reaction; after cooling to 0°C, the mixture was kept warm for 2 h for cooling crystallization, filtered, and the filtered solid was washed with 15 g of 0°C methanol, and dried to obtain 21.2 g of white solid CMEβ isomer trichloroacetate. After testing, 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 obtained by HLPC testing was 0.12%;

[0048] 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 value of the mixed system was about 8), freed 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, filtered, and then 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%.

[0049] 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°.

[0050] The purity of the white solid CMEβ isomer was 99.86% as determined by HLPC, and the mass percentage of the CMEα isomer was 0.03%.

[0051] Based on the HME input into the reaction, the CMEβ isomer was recovered from the residual mother liquor with an increased yield of 7.2%.

[0052] 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 to obtain the spectrum as shown in Figures 1 to 4 As shown, where: Figure 1 This is the nuclear magnetic resonance hydrogen spectrum of the trichloroacetate salt 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 .02–1.07(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).

[0053] Figure 2 This is the mass spectrum of the LC-MS positive ion mode of the trichloroacetate salt of the compound CMEβ isomer, showing C 18 H 27 N3O4S.C2HCl3O2 C 18 H 27 [M+H] of N3O4S + (i.e. C 18 H 27 N3O4S (M=381);

[0054] Figure 3 This is the GC-MS mass spectrum of the trichloroacetate salt of the compound CMEβ isomer after acidification and release, showing C 18 H 27 N3O4S.C2HCl3O2 of C2HCl3O2, i.e. the mass spectrum of trichloroacetic acid, matches the mass spectrum of trichloroacetic acid in the database (no molecular ion peak);

[0055] Figure 4 This is the infrared spectrum of the trichloroacetate 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 CH2 ), 1369(ν CH3 ), 1284(ν C-N ), 1177(ν C-N), 1076(ν C-H ), 981(ν ＝C-H ), 837(ν C-Cl ), 784(ν C-H ), 717(ν C-Cl ), 676(γ NH2 ), 596(γ NH2 ).

[0056] Elemental analysis of the trichloroacetate salt of the β-isomer of compound CME 18 H 27 N3O4S.C2HCl3O2, %) (measured value / calculated value): C 43.95 / 44.09, H 5.23 / 5.18, N 7.66 / 7.71.

[0057] 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.

[0058] From the results of Example 1, it can be seen that the method provided by the present invention can recover CMEβ isomer with higher purity from the residual liquid generated in the process of preparing CMEβ isomer, and can be used for preparing lamivudine.

[0059] 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 recovering β isomer from a CME solution containing β and α isomers, comprising the following steps: The CME solution containing β and α isomers is concentrated and dissolved in methanol with trichloroacetic acid to form a salt, and then filtered after cooling and crystallization to obtain the trichloroacetate salt of CME β isomer; The trichloroacetate of the CMEβ isomer is liberated with aqueous ammonia in methanol to obtain the CMEβ isomer.

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

6. The recycling method according to claim 1 or 5, 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.

7. The recycling method according to claim 1, characterized in that: The free time is 1 to 2 hours.

8. The recycling method according to claim 1 or 7, 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.

9. The recycling 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.

10. The recycling method according to claim 1 or 9, 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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