A method for recovering the β isomer from a CME solution containing both β and α isomers.

Abstract

This invention belongs to the field of recycling and purification technology, specifically relating to a method for recovering the β isomer from a CME solution containing both β and α isomers. The method includes the following steps: concentrating the CME solution containing both β and α isomers and dissolving it in methanol with trichloroacetic acid to form a salt, followed by cooling and crystallization and filtration to obtain the trichloroacetic acid salt of the CME β isomer; then, ionizing the trichloroacetic acid salt of the CME β isomer in methanol with ammonia to obtain the CME β isomer. By reacting trichloroacetic acid with the α and β isomers of CME to form a salt, the different solubilities of the trichloroacetic acid salts of the α and β isomers are utilized to separate the trichloroacetic acid salt of the CME β isomer, and then ionizing the trichloroacetic acid salt of the CME β isomer with ammonia, the CME β isomer is recovered.

Description

Technical Field

[0001] This invention belongs to the field of recycling and purification technology, specifically relating to a method for recovering the β isomer from a CME solution containing both β and α isomers. Background Technology

[0002] CME, whose Chinese name is (2R)-5-(5-cytosine-1-yl)-1,3-oxothiacyclopentane-2-carboxylic acid-L-menthyl ester, has two isomers: the β-isomer is (2R,5S)-5-(5-cytosine-1-yl)-1,3-oxothiacyclopentane-2-carboxylic acid-L-menthyl ester, and the α-isomer is (2R,5R)-5-(5-cytosine-1-yl)-1,3-oxothiacyclopentane-2-carboxylic acid-L-menthyl ester. The β-isomer of CME is a key intermediate in the preparation of lamivudine; lamivudine is obtained by reducing the β-isomer of CME with sodium borohydride.

[0003] Lamivudine is a pharmaceutical raw material with good antiviral activity, mainly used to treat hepatitis B and HIV. It is the main active ingredient in current cocktail therapy for hepatitis B and HIV, and is used clinically for the treatment of chronic hepatitis B, decompensated cirrhosis, and HIV infection (AIDS) under cocktail therapy. It is widely used due to its advantages such as convenient oral administration, rapid viral inhibition, high safety, and relatively low treatment cost.

[0004] Currently, the industrial synthesis of lamivudine mainly involves first preparing the lamivudine intermediate CMEβ isomer, and then reducing it to obtain lamivudine. During the preparation of the lamivudine intermediate CMEβ isomer, two isomers, β and α, of CME are generated. After separation and purification, the β isomer is obtained. However, the residual liquid after separation and purification still contains some β isomer, which is difficult to separate from the α isomer. Directly treating the residual liquid after separation and purification as waste not only wastes resources but also exacerbates environmental pollution. Summary of the Invention

[0005] In view of this, the present invention provides a method for recovering the β isomer from a CME solution containing both β and α isomers. The preparation method provided by the present invention can separate a small amount of CME β isomer from the waste liquid, thereby realizing the resource utilization of the waste liquid and reducing the discharge of waste liquid.

[0006] To address the aforementioned technical problems, this invention provides a method for recovering the β isomer from a CME solution containing both β and α isomers, comprising the following steps:

[0007] The CME solution containing both β and α isomers was concentrated and dissolved in methanol with trichloroacetic acid to form a salt. After cooling and crystallization, the solution was filtered to obtain the trichloroacetic acid salt of the CME β isomer.

[0008] The trichloroacetic acid salt of the CMEβ isomer was released in methanol with ammonia to obtain the CMEβ isomer.

[0009] Preferably, the salt-forming reaction is carried out at a temperature of 35–45°C for a time of 1.8–2.2 h.

[0010] Preferably, the temperature for cooling crystallization is -5 to 2°C, and the holding time for cooling crystallization is 1.8 to 2.2 hours.

[0011] Preferably, the filtration process further includes: rinsing the filtered solid with methanol and then drying it to obtain the trichloroacetic acid salt of the CMEβ isomer.

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

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

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

[0015] Preferably, the process further includes: concentrating and dispersing the freed system in water, and filtering; washing the filtered solid with water to obtain the CMEβ isomer.

[0016] Preferably, the mass ratio of α isomer to β isomer in the CME solution containing both β and α isomers is 1:0.9 to 1.1.

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

[0018] This invention provides a method for recovering the β isomer from a CME solution containing both β and α isomers, comprising the following steps: concentrating the CME solution containing both β and α isomers, dissolving it in methanol with trichloroacetic acid to form a salt, cooling and crystallizing, and then filtering to obtain the trichloroacetic acid salt of the CME β isomer; and then relieving the trichloroacetic acid salt of the CME β isomer in methanol with ammonia to obtain the CME β isomer. This invention utilizes the reaction of trichloroacetic acid with the α and β isomers of CME to form a salt, taking advantage of the different solubilities of the trichloroacetic acid salts of the α and β isomers to separate the trichloroacetic acid salt of the CME β isomer, and then relieving the trichloroacetic acid salt of the CME β isomer with ammonia to obtain the CME β isomer. The recovery method provided by this invention is simple and easy to operate, capable of separating small amounts of CME β isomers from waste liquid, realizing the resource utilization of waste liquid, and reducing waste liquid discharge. Attached Figure Description

[0019] Figure 1 The 1H NMR spectrum of trichloroacetate, the CMEβ isomer of the compound prepared in Example 1;

[0020] Figure 2 The LC-MS mass spectrum of the trichloroacetic acid salt, the CMEβ isomer of the compound prepared in Example 1;

[0021] Figure 3 The image shows the GC-MS mass spectrum of the trichloroacetate, the CMEβ isomer obtained in Example 1, after acidification and release.

[0022] Figure 4 The infrared spectrum of trichloroacetate, the CMEβ isomer of the compound prepared in Example 1. Detailed Implementation

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

[0024] The CME solution containing both β and α isomers was concentrated and dissolved in methanol with trichloroacetic acid to form a salt. After cooling and crystallization, the solution was filtered to obtain the trichloroacetic acid salt of the CME β isomer.

[0025] The CMEβ isomer was obtained by ionizing the trichloroacetic acid salt of the CMEβ isomer in methanol with ammonia.

[0026] This invention involves concentrating a CME solution containing both β and α isomers, dissolving it in methanol with trichloroacetic acid, and then reacting the solution with the resulting solution to form a salt. After cooling and crystallization, the solution is filtered to obtain the trichloroacetic acid salt of the CME β isomer. In one embodiment of this invention, the mass ratio of the α isomer to the β isomer in the CME solution containing both β and α isomers can be 1:0.9–1.1, 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.

[0027] This invention does not have specific requirements for the concentration method of the CME solution containing both β and α isomers, as long as the solvent in the solution can be removed. This invention does not have specific requirements for the amount of methanol used, as long as it can be completely dissolved. This invention does not have specific requirements for the amount of trichloroacetic acid used, as long as it can fully react with the β and α isomers of CME to form a salt. As one embodiment of this invention, the temperature of the salt-forming reaction can be 35–45°C, specifically 35°C, 40°C, or 45°C; the time of the salt-forming reaction can be 1.8–2.2 h, specifically 2 h. As one embodiment of this invention, the temperature of the cooling crystallization can be -5–2°C, specifically -2°C, 0°C, or 1°C; the holding time for the cooling crystallization can be 1.8–2.2 h, specifically 2 h.

[0028] This invention does not impose any particular limitation on the filtration process; conventional methods in the art can be used. In one embodiment of this invention, the filtration process may further include: rinsing the filtered solid with low-temperature methanol followed by drying to obtain the trichloroacetic acid salt of the CMEβ isomer. In another embodiment of this invention, the temperature of the low-temperature methanol can be -5 to 5°C, specifically -5°C, 0°C, or 5°C. This invention can remove small amounts of unfiltered CMEα isomer trichloroacetic acid salt through rinsing. This invention does not impose any particular limitation on the drying process, as long as the solvent in the solid is removed.

[0029] After obtaining the trichloroacetic acid salt of the CMEβ isomer, this invention further liberates the trichloroacetic acid salt of the CMEβ isomer in methanol with ammonia water to obtain the CMEβ isomer. In one embodiment of this invention, the mass concentration of the ammonia water can be 20-30%, specifically 20%, 22%, 25%, or 30%. In another embodiment of this invention, the mass ratio of the trichloroacetic acid salt of the CMEβ isomer to methanol can be 1:5.5-6.5, specifically 1:6. In another embodiment of this invention, the molar ratio of the trichloroacetic acid salt of the CMEβ isomer to ammonia in the ammonia water can 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 with ammonia water can be 7-8.

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

[0031] In one 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.

[0032] The present invention does not have any special requirements for the filtration and washing processes; conventional methods in the field can be used.

[0033] As one embodiment of the present invention, the equations for the salt-forming reaction, crystallization, and freeing are shown in equation a:

[0034]

[0035] This invention can successfully separate high-purity CMEβ isomers from waste liquid used in the preparation of CMEβ isomers for the preparation of lamivudine, thereby reducing the cost of lamivudine products and reducing waste liquid discharge.

[0036] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0037] Example 1

[0038] Step 1: Prepare the intermediate CMEβ isomer for the synthesis of lamivudine according to the reaction equation shown in equation 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 with stirring. The mixture was heated to reflux 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 the mixture, resulting in a dichloromethane solution of the chlorinated HME (compound 5).

[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 refluxed for 8 h until the system was clear. The toluene and excess hexamethyldisilazane were evaporated under reduced pressure to obtain compound 8. 222 g of dichloromethane was added and stirred to dissolve the compound 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. The mixture was heated to 40 °C. A dichloromethane solution of compound 5 was added dropwise to the mixture. The mixture was then subjected to a condensation reaction at 45 °C for 15 h (HPLC monitoring showed that the content of the main product no longer increased). The mixture was then post-processed 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 held for 1 h. After cooling to 5 °C, the temperature was held for 2 h. The mixture was filtered and then rinsed with 100 g of isopropyl acetate at 5 °C and 100 g of water. The solid after rinsing was dried to obtain 144.2 g of the off-white solid product CMEβ isomer (compound 10β). The melting point of the off-white solid CMEβ isomer was found to be 214.9–216.1 °C, and the specific rotation (1% methanol) was -113.6°.

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

[0044] The filtrate obtained from filtration is combined with the washing solution of isopropyl acetate to form a residual liquid, which is to be recovered.

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

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

[0047] The residual liquid was concentrated and mixed with 150g of methanol and 19.6g (0.12mol) of trichloroacetic acid. The mixture was stirred at 40℃ for 1h to carry out a salt formation reaction. After cooling to 0℃, the mixture was kept at this temperature for 2h to carry out cooling crystallization. The solid obtained by filtration was washed with 15g of methanol at 0℃ and dried to obtain 21.2g of white solid CMEβ isomer trichloroacetate. The specific rotation value (1% methanol) was -83.0° and the melting point was 208℃ (decomposition). The mass percentage of CMEα isomer trichloroacetate in the solid obtained by HLPC analysis 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 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. 63.6 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 21.2 g of water to obtain 13.7 g of white solid CMEβ isomer. The yield of this step was 92.2%.

[0049] The melting point of the CMEβ isomer was found to be 215.6–216.3 °C, and the specific rotation (1% methanol) was -115.3 °C.

[0050] 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%.

[0051] Based on the reaction input HME, the recovery of the CMEβ isomer from the residual mother liquor increased the yield by 7.2%.

[0052] For the compound CMEβ isomer trichloroacetate (C 18 H 27 The N3O4S.C2HCl3O2) was detected by nuclear magnetic resonance, liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), and infrared spectroscopy, and the resulting spectra are shown below. Figures 1-4 As shown, where: Figure 1 The following is the 1H NMR spectrum of the trichloroacetate salt, an isomer of compound CMEβ. The 1H NMR 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 The LC-MS mass spectrum in positive ion mode for the CMEβ isomer trichloroacetate shows the C... 18 H 27 N3O4S.C2HCl3O2 of 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 acidified free trichloroacetate salt, an isomer of compound CMEβ, showing C. 18 H 27 The gas chromatography-mass spectra of N3O4S.C2HCl3O2, i.e., C2HCl3O2, are trichloroacetic acid. The spectrum matches the trichloroacetic acid gas chromatography-mass spectra in the database (no molecular ion peak).

[0055] Figure 4 The infrared spectrum of the CMEβ isomer trichloroacetate is shown below. The infrared spectral data are as follows: (IR, KBr, cm⁻¹) -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 trichloroacetic acid salt, the CMEβ isomer of compound C 18 H 27 N3O4S.C2HCl3O2, %)(Measured / Calculated): C 43.95 / 44.09, H 5.23 / 5.18, N 7.66 / 7.71.

[0057] HPLC analysis of three batches of the CMEβ isomer trichloroacetate showed that the external standard contents of Cl3CCOOH were 30.12%, 30.26%, and 29.86%, respectively. 18 H 27 In the N3O4S.C2HCl3O2 molecular structure, the calculated content of Cl3CCOOH is 29.99%, indicating that the ratio of the two salt-forming molecules is 1:1, which is consistent with the above molecular structure.

[0058] As can be seen from the results of Example 1, the method provided by the present invention can recover high-purity CMEβ isomers from the residual liquid generated during the preparation of CMEβ isomers, which can be used to prepare lamivudine.

[0059] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for recovering the β isomer from a CME solution containing both β and α isomers, comprising the following steps: The CME solution containing both β and α isomers was concentrated and dissolved in methanol with trichloroacetic acid to form a salt. After cooling and crystallization, the solution was filtered to obtain the trichloroacetic acid salt of the CME β isomer. The trichloroacetic acid salt of the CMEβ isomer was released in methanol with ammonia to obtain the CMEβ isomer.

2. The recycling method according to claim 1, characterized in that, The salt formation reaction is carried out at a temperature of 35–45°C for a time of 1.8–2.2 h.

3. The recycling method according to claim 1, characterized in that, The cooling crystallization temperature is -5 to 2°C, and the cooling crystallization holding time is 1.8 to 2.2 hours.

4. The recycling method according to any one of claims 1 to 3, characterized in that, The filtration process further includes: rinsing the filtered solid with methanol and then drying it to obtain the trichloroacetic acid salt 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 ammonia in ammonia water is 1:1.1 to 1.

3.

7. The recycling method according to claim 1, characterized in that, The time for the free tissue to be released is 1 to 2 hours.

8. The recycling method according to claim 1 or 7, characterized in that, The process after ionization further includes: concentrating and dispersing the ionized system in water, and filtering; washing the filtered solid with water to obtain the CMEβ isomer.

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

1.

10. The recycling method according to claim 1 or 9, characterized in that, The CME solution containing both β and α isomers is a waste liquid generated during the preparation of the lamivudine intermediate CMEβ isomer.

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