A preparation method of pregabalin intermediate

Abstract

The invention belongs to the technical field of pharmaceutical intermediate synthesis, and particularly relates to a method for preparing a pregabalin intermediate. Under the protection of an inert gas, diethyl malonate and (1E)-4-methyl-1-nitro-1-pentene are added in an organic solvent at a molar ratio of 1:0.8-1.6, and a quaternary ammonium salt catalyst whose amount is 0.005-0.025 times that of diethyl malonate and a base are reacted at 10°C-25°C for 4-6 hours to obtain a pregabalin intermediate 1,3-diethyl 2-[(1S)-3-methyl-1-(nitromethyl)butyl]malonate, wherein the quaternary ammonium salt catalyst is

Description

Technical Field

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

[0002] Epilepsy is a common chronic neurological disease and the second most common neurological disease after headache. Drug therapy is the main treatment for controlling epileptic seizures. Common anti-epileptic drugs include Lyrica, carbamazepine, phenobarbital, phenytoin sodium, sodium valproate, etc.

[0003] Lyrica, also known as Pregabalin Capsules, is a new, highly effective and long-lasting nervous system drug developed by Pfizer, USA. It can be used to treat post-herpetic neuralgia, partial-onset epilepsy, anxiety and other diseases. It was approved for marketing in China in 2010. Compared with the previous generation of nervous system drugs, Gabapentin Capsules, Lyrica has the advantages of easy absorption, significant effect, high bioavailability, low dosage, and low resistance to drugs. At the same time, it has the characteristics of linear pharmacokinetics and can accurately control the effect of the course of treatment. At present, Lyrica, as a nervous system drug with significant effects, has very good market and application prospects.

[0004] Pregabalin intermediates are often prepared by asymmetric conjugate addition reactions. In asymmetric conjugate addition reactions, although products can be obtained with excellent enantioselectivity and yield under metal catalysis, disadvantages such as harsh reaction conditions, high toxicity or expensive catalysts cannot be avoided.

[0005] The asymmetric conjugate addition synthesis of pregabalin intermediates without the use of metal catalysts has been reported:

[0006] (1) N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(1R,2R)-2-(dimethylamino)cyclohexyl]thiourea (Cheminform, 2011, 67(3):636-640):

[0007]

[0008] The catalyst is complex to prepare, expensive, and the reaction time is as long as 24 hours.

[0009] (2) N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(3aR,5S,6S,6aR)-tetrahydro-2,2-dimethyl-6-[(phenylmethyl)amino]furo[2,3-d]-1,3-dioxol-5-yl]thiourea (Organic & Biomolecular Chemistry, 2016, 14(48):11454-11461.):

[0010]

[0011] This method has strict reaction conditions and a long reaction time, and also has the problems of expensive catalysts and high synthesis costs.

[0012] (3) (1S,2S)-N1,N2-bis(phenylmethyl)-1,2-cyclohexanediamine (RU2555370):

[0013]

[0014] This method also has the problems of expensive catalyst and high synthesis cost.

[0015] It can be seen that the current asymmetric catalytic synthesis of pregabalin intermediates generally has the disadvantages of high cost, long reaction time, low efficiency, etc., which brings great trouble to practical applications. Therefore, it is of great value to develop a synthesis process of pregabalin intermediates with low cost, simple operation and high product purity. Summary of the invention

[0016] In order to solve the above technical problems, the present invention provides a method for preparing a pregabalin intermediate:

[0017] The quaternary ammonium salt catalyst is used to catalyze the conjugate addition reaction of diethyl malonate and (1E)-4-methyl-1-nitro-1-pentene to generate the pregabalin intermediate 1,3-diethyl 2-[(1S)-3-methyl-1-(nitromethyl)butyl]malonate, wherein the quaternary ammonium salt catalyst is

[0018] The catalytic reaction formula is:

[0019]

[0020] As a preference: the quaternary ammonium salt catalyst is prepared by the following method:

[0021] (1) Preparation of (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol

[0022] Under a nitrogen atmosphere, a tetrahydrofuran solution of BH3·SMe2 was added dropwise to a THF / B(OMe)3 solution of (S)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dicarboxylic acid. After stirring for 5 hours, methanol was added thereto to quench the reaction, and then the solvent was removed under reduced pressure. Hydrochloric acid was added to the residue, and ethyl acetate was added to extract after sufficient mixing. After sufficient stratification, an organic layer was separated to obtain a layer, which was dried and concentrated under reduced pressure. Pyridine, THF and liquid bromine were added to the concentrated organic layer, and the reaction was stirred for 1 hour. The resulting reaction system was poured into a saturated Na2SO3 aqueous solution and ethyl acetate. After sufficient stratification, an organic layer was separated to obtain a layer, which was dried and concentrated under reduced pressure. The (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol was purified by silica gel column chromatography.

[0023] (2) Preparation of (S)-3,3'-bis(3,4,5-trifluorophenyl)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol

[0024] Under a nitrogen atmosphere, add the (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol obtained in step (1), 3,4,5-trifluorophenylboric acid, palladium acetate, tri(o-methylphenyl)phosphine, K3PO4-nH2O, and tetrahydrofuran solution into a flask, mix thoroughly and heat to react, monitor the reaction by thin layer chromatography until the signal of the raw material (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol disappears, filter the obtained reaction system, concentrate the filtrate in vacuo, and purify by silica gel column chromatography to obtain (S)-3,3'-bis(3,4,5-trifluorophenyl)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol;

[0025] (3) PBr3 and (S)-3,3'-bis(3,4,5-trifluorophenyl)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol obtained in step (2) are added to CH2Cl2, and after stirring for reaction, water is added thereto to quench the reaction, and then ether is added thereto for extraction. After sufficient stratification, an organic layer is separated to obtain a organic layer, and the organic layer is washed with brine, dried, and concentrated under reduced pressure. Under an argon atmosphere, the system after reduced pressure concentration is put into a suspension of K2CO3 and Bu2NH in acetonitrile, and after sufficient mixing and heating for reaction, the obtained mixed system is poured into an aqueous HBr solution to quench the reaction, and CH2Cl2 is added for extraction. After sufficient stratification, an organic layer is separated to obtain a organic layer, and the organic layer is dried, concentrated under reduced pressure, and purified by silica gel column chromatography.

[0026] Further: in step (1), after adding pyridine and THF to the concentrated organic layer, the resulting mixture is first cooled to -20°C, and then liquid bromine is added thereto, and then the temperature is raised to 0°C and stirred for reaction for 1 hour.

[0027] Furthermore: in step (2), the temperature of the heating reaction is 88°C.

[0028] Furthermore: in step (3), the temperature of the temperature-raising reaction is 80° C. and the reaction time is 10 h.

[0029] Preferably, the molar ratio of diethyl malonate, (1E)-4-methyl-1-nitro-1-pentene and quaternary ammonium salt catalyst is 1:0.8-1.6:0.005-0.025.

[0030] Preferably, under the protection of inert gas, diethyl malonate and (1E)-4-methyl-1-nitro-1-pentene are reacted in an organic solvent in the presence of a quaternary ammonium salt catalyst and a base to undergo a conjugate addition reaction.

[0031] Furthermore: the organic solvent is toluene, DMF or acetonitrile.

[0032] Furthermore: the reaction temperature of the conjugate addition reaction is -10°C to 25°C, and the reaction time is 4 to 6 hours.

[0033] When the quaternary ammonium salt catalyst of this scheme catalyzes the synthesis of diethyl malonate and (1E)-4-methyl-1-nitro-1-pentene, the diethyl malonate, one of the reactants, is converted into an enol and exhibits negative charge, forming an ion pair with the quaternary ammonium salt functional group. The negatively charged oxygen atom on the nitro group of (1E)-4-methyl-1-nitro-1-pentene biphenyl also has a mutual attraction of opposite charges with the nitrogen on the quaternary ammonium salt, thereby playing a role in fixing the relative positions of the reaction molecules. When the addition reaction occurs, the partially negatively charged carbon atom on the enol form attacks the double bond of (1E)-4-methyl-1-nitro-1-pentene to undergo a Michael addition reaction, and the two large sterically hindered trifluorophenyl groups on the chiral biphenyl make the carbon atom attacking from one side in the above reaction occupy an absolute advantage, thereby effectively improving the enantioselectivity of the reaction and making the proportion of highly active configurations in the product higher. The mechanism is as follows:

[0034]

[0035] At the same time, the catalyst used in the present invention is low in dosage and cheap, has high industrial value, is safe and environmentally friendly, has high yield, and is easy to operate, so the cost of the prepared pregabalin intermediate is also relatively low. DETAILED DESCRIPTION

[0036] The present invention will be further described below in conjunction with the examples (the raw materials used in the following examples are all industrial grade products):

[0037] The preparation method of the quaternary ammonium salt catalyst is:

[0038] (1) Preparation of (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol

[0039] Under nitrogen atmosphere, a 0°C solution of BH3·SMe2 (4.0 mmol) in tetrahydrofuran (4.0 mL) was added dropwise to a 0°C solution of (S)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dicarboxylic acid (1.0 mmol) in THF / B(OMe)3 (4 mL / 2 mL). The temperature of the resulting mixed system was raised to room temperature (25°C, the same below) and the reaction was continued with stirring for 5 hours. Then, 1 mL of methanol was slowly added thereto to quench the reaction. The solvent was then removed under reduced pressure. 8.0 mL of 1N hydrochloric acid was added to the residue. After sufficient mixing, ethyl acetate was added for extraction. After sufficient stratification, the organic layer was separated and dried over Na2SO4. The organic layer was concentrated under reduced pressure, pyridine (0.57 mL) and THF (5 mL) were added to the concentrated organic layer, the mixture was mixed thoroughly and then cooled to -20°C, liquid bromine (0.36 mL, 7.0 mmol) was added to the mixture, the mixture was heated to 0°C and stirred for reaction for 1 hour, the obtained reaction system was poured into saturated aqueous Na2SO3 solution and ethyl acetate, after sufficient stratification, the organic layer was separated, the organic layer was dried over Na2SO4, the organic layer was concentrated under reduced pressure, and then purified by silica gel column chromatography (petroleum ether / ethyl acetate volume ratio of 1:1 as eluent) to obtain (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol;

[0040] (2) Preparation of (S)-3,3'-bis(3,4,5-trifluorophenyl)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol:

[0041] Under nitrogen atmosphere, (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol (0.276 g) obtained in step (1), 3,4,5-trifluorophenylboric acid (0.440 g, 2.5 mmol), palladium acetate (0.0225 g, 0.10 mmol), tri(o-methylphenyl)phosphine (0.122 g, 0.40 mmol), K3PO4-nH2O (1.056 g, 5.0 mmol), tetrahydrofuran solution (5 mL) were added to a flask and mixed. The mixture was fully post-heated to 88° C. and stirred for reaction. The reaction was monitored by thin layer chromatography (TLC) until the signal of the raw material (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol disappeared. The obtained reaction system was filtered, and the filtrate was concentrated in vacuo. Then, the filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate volume ratio of 2:1 as eluent) to obtain (S)-3,3'-bis(3,4,5-trifluorophenyl)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol.

[0042] (3) PBr3 (0.038 mL, 0.4 mmol) and (S)-3,3'-bis(3,4,5-trifluorophenyl)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol (0.2 mmol) obtained in step (2) were added to CH2Cl2 (5 mL) at 0°C. The mixture was heated to room temperature and stirred for 1 hour. Water was added to quench the reaction. Ether was then added to extract the mixture. After sufficient separation, an organic layer was separated. The organic layer was washed with brine, dried with Na2SO4, and concentrated under reduced pressure. Under a carbonyl atmosphere, the system after reduced pressure concentration was put into a suspension of K2CO3 (0.0553 g, 0.40 mmol) and Bu2NH (0.037 mL, 0.22 mmol) in acetonitrile (5 mL), mixed thoroughly and heated to 80°C for reaction for 10 h. The resulting mixed system was poured into 5.0 mL of 1N HBr aqueous solution for quenching, and CH2Cl2 was added for extraction. After sufficient stratification, the organic layer was separated and dried over Na2SO4. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH / CH2Cl2 volume ratio of 1:10 as eluent).

[0043] Example 1

[0044] Synthesis of 1,3-Diethyl 2-[(1S)-3-methyl-1-(nitromethyl)butyl]malonate

[0045] Under argon protection, (1E)-4-methyl-1-nitro-1-pentene (563.82 mg, 4.37 mmol) and diethyl malonate (500 mg, 3.12 mmol) were added to a flask, and 20 mL of toluene was added to fully dissolve the mixture. The quaternary ammonium salt catalyst prepared above (252.1 mg, 0.0312 mmol) was then added thereto, and the reaction was started at room temperature with stirring. The reaction was monitored by TLC. After stirring for 6 hours, the resulting reaction system was concentrated under vacuum conditions and purified by silica gel column chromatography (hexane / ethyl acetate volume ratio of 5:1 as eluent) to obtain a colorless oily target product (794 mg, 88.0%, "88.0%" here is the yield, calculated by the number of moles of the target product ÷ the number of moles of diethyl malonate in the reactant × 100%, the same below), with an ee value of 92%.

[0046] Product structure characterization: 1 H NMR(400MHz, CDCl3) δ4.71(dd,J=13.3,5.0Hz,1H),4.53(dd,J=13.3,6.6Hz,1H),4.31-4.14(m,4H),3.62(d ,J=5.5Hz,1H),3.07-2.82(m,1H),1.73-1.57(m,1H),1.36-1.25(m,8H),0.95-0.89(m,6H)ppm; ESI-MS[M+H + ]:290.

[0047] Examples 2 to 5

[0048] On the basis of Example 1, other experimental conditions remained unchanged, and only the molar ratio of diethyl malonate and (1E)-4-methyl-1-nitro-1-pentene was changed to investigate the effect on the reaction results, and compared with Example 1. The results are shown in Table 1:

[0049] Table 1

[0050]

[0051] It can be found from Table 1 that the most suitable molar ratio of diethyl malonate to (1E)-4-methyl-1-nitro-1-pentene is 1:1.4. Further increasing the molar ratio does not change much the yield.

[0052] Examples 6 to 9

[0053] On the basis of Example 1, other experimental conditions remain unchanged, and only the influence on the reaction result is investigated by changing the percentage of the amount of substance of the quaternary ammonium salt catalyst relative to diethyl malonate, and compared with Example 1, the obtained results are shown in Table 2:

[0054] Table 2

[0055]

[0056]

[0057] It can be found from Table 2 that the most suitable amount of catalyst is 1%, and the yield does not change much when the amount is further increased.

[0058] Examples 10 to 13

[0059] On the basis of Example 1, other experimental conditions remain unchanged, and only the reaction temperature is changed to examine the effect on the reaction results, and compared with Example 1, the obtained results are shown in Table 3:

[0060] Table 3

[0061] Reaction temperature Yield ee value Example 1 25℃ 88.0％ 92％ Example 10 -10℃ 80.2％ 92％ Embodiment 11 0℃ 80.4％ 91％ Example 12 10℃ 83.5％ 88％ Example 13 35℃ 87.3％ 87％

[0062] It can be found from Table 3 that when the reaction temperature is 25°C, a higher yield and ee value can be obtained simultaneously.

[0063] Examples 14 to 16

[0064] On the basis of Example 1, other experimental conditions remained unchanged, and only the reaction solvent was changed to examine the effect on the reaction results. The results were compared with those of Example 1, and the obtained results are shown in Table 4:

[0065] Table 4

[0066] Reaction solvent Yield ee value Example 1 Toluene 88.0％ 92％ Example 10 Acetonitrile 80.2％ 90％ Embodiment 11 DMF 84.4％ 85％ Example 12 DMSO 82.5％ 87％

[0067] It can be found from Table 4 that when the solvent is toluene, high yield and ee value can be obtained.

[0068] Embodiment 17

[0069] On the basis of Example 1, other experimental conditions remain unchanged, and only the influence on the reaction results is investigated by changing the molecular structure composition of the catalyst, and compared with Example 1, the obtained results are shown in Table 5:

[0070] In this embodiment, 3,4,5-trifluorophenylboric acid is not added in the preparation method of the quaternary ammonium salt catalyst, and the remaining operations are the same as in Example 1:

[0071] (1) Under nitrogen atmosphere, a 0°C solution of BH3·SMe2 (4.0 mmol) in tetrahydrofuran (4.0 mL) was added dropwise to a 0°C solution of (S)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dicarboxylic acid (1.0 mmol) in THF / B(OMe)3 (4 mL / 2 mL). The temperature of the resulting mixed system was raised to room temperature (25°C, the same below) and stirred for 5 hours. Then, 1 mL of methanol was slowly added thereto to quench the reaction. The solvent was then removed under reduced pressure. 8.0 mL of 1N hydrochloric acid was added to the residue. After sufficient mixing, ethyl acetate was added for extraction. After sufficient separation, the organic layer was separated and dried over Na2SO4. The organic layer was concentrated under reduced pressure, pyridine (0.57 mL) and THF (5 mL) were added to the concentrated organic layer, the mixture was mixed thoroughly and then cooled to -20°C, liquid bromine (0.36 mL, 7.0 mmol) was added to the mixture, the mixture was heated to 0°C and stirred for reaction for 1 hour, the obtained reaction system was poured into saturated aqueous Na2SO3 solution and ethyl acetate, and after sufficient stratification, the organic layer was separated and dried over Na2SO4, the organic layer was concentrated under reduced pressure, and then purified by silica gel column chromatography (petroleum ether / ethyl acetate volume ratio of 1:1 as eluent) to obtain (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol;

[0072] (2) PBr3 (0.038 mL, 0.4 mmol) and (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol (0.2 mmol) obtained in step (1) were added to CH2Cl2 (5 mL) at 0°C. The mixture was heated to room temperature and stirred for 1 hour. Water was added to quench the reaction. Ether was then added to extract the mixture. After sufficient separation, an organic layer was separated. The organic layer was washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The system after concentration under reduced pressure was put into a suspension of K2CO3 (0.0553 g, 0.40 mmol) and Bu2NH (0.037 mL, 0.22 mmol) in acetonitrile (5 mL), mixed thoroughly and heated to 80°C for reaction for 10 h, then the resulting mixed system was poured into 5.0 mL of 1N HBr aqueous solution for quenching, and CH2Cl2 was added for extraction. After sufficient stratification, the organic layer was separated and dried over Na2SO4. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH / CH2Cl2 volume ratio of 1:10 as eluent).

[0073] Table 5

[0074] Yield ee value Example 1 88.0％ 92％ Embodiment 17 82.1％ 78％

[0075] As shown in the table above, in this embodiment, after the benzene ring side group is lost on the biphenyl structure of the quaternary ammonium salt catalyst, when the Michael addition reaction occurs, the restriction effect of the corresponding carbon atom on the enol on the attack direction of (1E)-4-methyl-1-nitro-1-pentene is greatly weakened, so that the controllability of the reaction is correspondingly reduced, resulting in an increase in by-products and a decrease in the selectivity of the product.

[0076] Embodiment 18

[0077] On the basis of Example 1, other experimental conditions remain unchanged, and only the influence on the reaction results is investigated by changing the molecular structure composition of the catalyst, and compared with Example 1, the obtained results are shown in Table 6:

[0078] In this embodiment, in the preparation method of the quaternary ammonium salt catalyst, "Bu2NH" in step (3) is replaced by "diethylamine", and the remaining operations are the same as in Example 1:

[0079] (1) Preparation of (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol

[0080] Under nitrogen atmosphere, a 0°C solution of BH3·SMe2 (4.0 mmol) in tetrahydrofuran (4.0 mL) was added dropwise to a 0°C solution of (S)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dicarboxylic acid (1.0 mmol) in THF / B(OMe)3 (4 mL / 2 mL). The temperature of the resulting mixed system was raised to room temperature (25°C, the same below) and the reaction was continued with stirring for 5 hours. Then, 1 mL of methanol was slowly added thereto to quench the reaction. The solvent was then removed under reduced pressure. 8.0 mL of 1N hydrochloric acid was added to the residue. After sufficient mixing, ethyl acetate was added for extraction. After sufficient stratification, the organic layer was separated and dried over Na2SO4. The organic layer was concentrated under reduced pressure, pyridine (0.57 mL) and THF (5 mL) were added to the concentrated organic layer, the mixture was mixed thoroughly and then cooled to -20°C, liquid bromine (0.36 mL, 7.0 mmol) was added to the mixture, the mixture was heated to 0°C and stirred for reaction for 1 hour, the obtained reaction system was poured into saturated aqueous Na2SO3 solution and ethyl acetate, after sufficient stratification, the organic layer was separated, the organic layer was dried over Na2SO4, the organic layer was concentrated under reduced pressure, and then purified by silica gel column chromatography (petroleum ether / ethyl acetate volume ratio of 1:1 as eluent) to obtain (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol;

[0081] (2) Preparation of (S)-3,3'-bis(3,4,5-trifluorophenyl)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol:

[0082] Under nitrogen atmosphere, (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol (0.276 g) obtained in step (1), 3,4,5-trifluorophenylboric acid (0.440 g, 2.5 mmol), palladium acetate (0.0225 g, 0.10 mmol), tri(o-methylphenyl)phosphine (0.122 g, 0.40 mmol), K3PO4-nH2O (1.056 g, 5.0 mmol), tetrahydrofuran solution (5 mL) were added to a flask and mixed. The mixture was fully post-heated to 88° C. and stirred for reaction. The reaction was monitored by thin layer chromatography (TLC) until the signal of the raw material (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol disappeared. The obtained reaction system was filtered, and the filtrate was concentrated in vacuo. Then, the filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate volume ratio of 2:1 as eluent) to obtain (S)-3,3'-bis(3,4,5-trifluorophenyl)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol.

[0083] (3) PBr3 (0.038 mL, 0.4 mmol) and (S)-3,3'-bis(3,4,5-trifluorophenyl)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol (0.2 mmol) obtained in step (2) were added to CH2Cl2 (5 mL) at 0°C. The mixture was heated to room temperature and stirred for 1 hour. Water was added to quench the reaction. Ether was then added to extract the mixture. After sufficient separation, an organic layer was separated. The organic layer was washed with brine, dried with Na2SO4, and concentrated under reduced pressure. Under a gas atmosphere, the system after reduced pressure and concentration was put into a suspension of K2CO3 (0.0553 g, 0.40 mmol) and diethylamine (0.023 mL, 0.22 mmol) in acetonitrile (5 mL), mixed thoroughly and heated to 80°C for reaction for 10 h, then the resulting mixed system was poured into 5.0 mL of 1N HBr aqueous solution for quenching, and CH2Cl2 was added for extraction. After sufficient stratification, the organic layer was separated and dried over Na2SO4. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH / CH2Cl2 volume ratio of 1:10 as eluent).

[0084] Table 6

[0085] Yield ee value Example 1 88.0％ 92％ Embodiment 18 84.6％ 87％

[0086] As shown in the table above, in this embodiment, after the butyl segment on the catalyst that is close to the reactant molecule is changed into a shorter ethyl group, the controllability of the reaction decreases. This may be because the butyl segment on the catalyst structure has a certain restrictive effect on the attack direction between the reactants based on its own chain length, but its influence is less than that caused by the large steric hindrance trifluorophenyl on biphenyl.

[0087] Embodiment 19

[0088] On the basis of Example 1, other experimental conditions remain unchanged, and only the influence on the reaction results is investigated by changing the molecular structure composition of the catalyst, and compared with Example 1, the obtained results are shown in Table 7:

[0089] In the present embodiment, the preparation method of the quaternary ammonium salt catalyst is:

[0090] After adding dialdehyde compound (440 mg, 1 mmol), methylamino acid hydrochloride (1.5 mmol), sodium cyanoborohydride (330 mg, 3 mmol) and 20 mL of methanol to a 50 mL flask, the mixture was stirred at room temperature for 4 hours. The reaction system mixture was diluted with EtOAc and washed with brine. After washing, it was allowed to stand for sufficient stratification. The organic phase was separated and retained. The organic phase was dried with anhydrous Na2SO4 and concentrated. Then, it was purified by silica gel column chromatography to obtain the corresponding N, N-disubstituted amine. The obtained N, N-disubstituted amine (0.2 mmol) and allyl bromide (0.4 mmol) were dissolved in 5 mL of acetonitrile and stirred at room temperature for 2 days. Then, the reaction system mixture was diluted with CH2Cl2 and concentrated in vacuo to remove the solvent and allyl bromide. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH volume ratio 10:1 as eluent). The preparation formula is:

[0091]

[0092] Among them, by changing the structure of R on the methyl amino acid hydrochloride molecule, quaternary ammonium salt 1 and quaternary ammonium salt 2 are obtained, and their molecular structures are as follows:

[0093] Quaternary ammonium salt 1:

[0094] 1H NMR (300 MHz, CDCl3) δ 3.26 (t, 1H, J = 12.0 Hz), 3.61 (s, 3H), 3.72 - 3.81 (m, 7H), 3.90 - 4.00 (m, 14H), 4.51 - 4.66 (m, 2H), 4.80 (d, 1H, J = 9.0 Hz), 5.40 (d, 1H, J = 13.2 Hz), 5.56 - 5.64 (m, 3H), 6.30 - 6.43 (m, 1H), 7.24 - 7.30 (m, 5H), 7.53 (s, 1H), 7.67 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 32.8, 52.8, 55.9, 56.4, 60.45, 60.46, 60.57, 60.62 62.9, 64.1, 73.0, 110.3, 111.1, 121.9, 122.8, 124.8, 127.2, 127.6, 128.2, 129.0, 132.6, 143.2, 143.3, 151.18, 151.24, 153.3, 166.3 ppm. ESI-MS: 578.1 (M+-Br); HRMS (ESI) for C 33 H 40 N1O2 (M+-Br): calcd 578.2754, found 578.275;

[0095] Quaternary ammonium salt 2:

[0096] H NMR (300MHz, CDCl3) δ0.68 (d, 3H, J = 6.3Hz), 0.72 (d, 3H, J = 6.6Hz), 1.37 (br, 1H),1.85-2.05(m,2H),3.31(d,1H,J=12.6Hz),3.51(s,6H),3.57(d,1H,13. 8Hz),3.73(s,3H),3.75(s,6H),3.80(d,6H,J=1.5Hz),4.12(d,1H,J=12.9Hz ),4.22-4.29(m,1H),4.39-4.46(m,1H),4.67(d,1H,J=13.5Hz),5.34-5.45(m ,3H),6.02-6.16(m,1H),7.02(s,1H),7.50(s,1H);13CNMR(100MHz,CDCl3)δ 20.8,22.7,25.4,34.6,53.6,55.9,56.5,60.5,60.56,60.61,62.7,63.2,70 .9,110.0,111.3,122.1,122.3,122.7,123.0,125.4,127.5,143.3,143.4,1 51.1,151.3,153.0,153.4,167.1ppm.ESI-MS:544.1(M+-Br); HRMS(ESI)forC 30 H 42 N1O8(M+-Br):calcd 544.2910,found544.2896.

[0097] Table 7

[0098]

[0099]

[0100] As shown in the table above, in this embodiment, after the benzene ring side group is lost on the biphenyl structure of the quaternary ammonium salt catalyst, when the Michael addition reaction occurs, the restriction effect of the corresponding carbon atom on the enol on the attack direction of (1E)-4-methyl-1-nitro-1-pentene is greatly weakened, so that the controllability of the reaction is correspondingly reduced, resulting in an increase in by-products and a decrease in the selectivity of the product.

Claims

1. A method for preparing a pregabalin intermediate, characterized in that: The preparation method is: The pregabalin intermediate is generated by catalyzing a conjugate addition reaction between diethyl malonate and (1E)-4-methyl-1-nitro-1-pentene under organic solvent conditions using a quaternary ammonium salt catalyst. Wherein, the quaternary ammonium salt catalyst is Wherein, the organic solvent is any one of toluene, acetonitrile, DMF or DMSO.

2. The method for preparing a pregabalin intermediate according to claim 1, wherein: The molar ratio of the diethyl malonate, the (1E)-4-methyl-1-nitro-1-pentene and the quaternary ammonium salt catalyst is 1:0.8-1.6:0.005-0.

025.

3. The method for preparing a pregabalin intermediate according to claim 1, wherein: The reaction temperature of the conjugate addition reaction is -10°C to 25°C, and the reaction time is 4 to 6 hours.

4. The method for preparing a pregabalin intermediate according to claim 1, wherein: The preparation method of the quaternary ammonium salt catalyst is: (1) Preparation of (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol Under a nitrogen atmosphere, a tetrahydrofuran solution of BH3·SMe2 is added dropwise to a THF / B(OMe)3 solution of (S)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dicarboxylic acid. After stirring for 5 hours, methanol is added thereto to quench the reaction, and then the solvent is removed under reduced pressure. Hydrochloric acid is added to the residue, and after sufficient mixing, ethyl acetate is added for extraction. After sufficient stratification, an organic layer is separated to obtain a layer, which is dried and concentrated under reduced pressure. Pyridine, THF and liquid bromine are added to the concentrated organic layer, and the reaction is stirred for 1 hour. The resulting reaction system is poured into a saturated Na2SO3 aqueous solution and ethyl acetate. After sufficient stratification, an organic layer is separated to obtain a layer, which is dried and concentrated under reduced pressure. The (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol is purified by silica gel column chromatography. (2) Preparation of (S)-3,3'-bis(3,4,5-trifluorophenyl)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol Under a nitrogen atmosphere, add the (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol obtained in step (1), 3,4,5-trifluorophenylboric acid, palladium acetate, tri(o-methylphenyl)phosphine, K3PO4-nH2O, and tetrahydrofuran solution into a flask, mix thoroughly and heat to react, monitor the reaction by thin layer chromatography until the signal of the raw material (S)-3,3'-dibromo-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol disappears, filter the obtained reaction system, concentrate the filtrate in vacuo, and purify by silica gel column chromatography to obtain the (S)-3,3'-bis(3,4,5-trifluorophenyl)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol; (3) PBr3 and the (S)-3,3'-bis(3,4,5-trifluorophenyl)-4,5,6,4',5',6'-hexamethoxybiphenyl-2,2'-dimethanol obtained in step (2) are added to CH2Cl2, stirred for reaction, water is added thereto to quench the reaction, and then ether is added thereto for extraction. After sufficient stratification, an organic layer is separated to obtain a organic layer, the organic layer is washed with brine, dried, and concentrated under reduced pressure. Under an argon atmosphere, the system after reduced pressure concentration is put into a suspension of K2CO3 and Bu2NH in acetonitrile, mixed sufficiently and heated for reaction, and the obtained mixed system is poured into an aqueous HBr solution to quench the reaction, CH2Cl2 is added for extraction, and after sufficient stratification, an organic layer is separated to obtain a organic layer, dried, and concentrated under reduced pressure, and then purified by silica gel column chromatography.

5. The method for preparing a pregabalin intermediate according to claim 4, characterized in that: In step (1), pyridine and THF are added to the concentrated organic layer, the resulting mixture is cooled to -20°C, the liquid bromine is added thereto, the temperature is raised to 0°C, and the mixture is stirred for reaction for 1 hour.

6. The method for preparing a pregabalin intermediate according to claim 4, characterized in that: In step (2), the temperature of the heating reaction is 88°C.

7. The method for preparing a pregabalin intermediate according to claim 4, characterized in that: In step (3), the temperature of the temperature-raising reaction is 80° C. and the reaction time is 10 h.

Images