CN117285402A - Preparation method of pregabalin intermediate - Google Patents

Preparation method of pregabalin intermediate Download PDF

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CN117285402A
CN117285402A CN202311187175.3A CN202311187175A CN117285402A CN 117285402 A CN117285402 A CN 117285402A CN 202311187175 A CN202311187175 A CN 202311187175A CN 117285402 A CN117285402 A CN 117285402A
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reaction
organic layer
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hexamethoxybiphenyl
dimethanol
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徐梦娇
沈介发
辜顺林
张跃
严生虎
马晓明
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Changzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0239—Quaternary ammonium compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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Abstract

The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of a pregabalin intermediate, which comprises the following steps of: in an organic solvent, under the action of a quaternary ammonium salt catalyst with the mass of 0.005-0.025 times of diethyl malonate and alkali, carrying out conjugated addition reaction for 4-6 hours at the temperature of minus 10-25 ℃ to obtain the pregabalin intermediate 1, 3-diethyl 2- [ (1S) -3-methyl-1- (nitromethyl) butyl]Malonic ester, wherein the quaternary ammonium salt catalyst is

Description

Preparation method of pregabalin intermediate
Technical Field
The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of a pregabalin intermediate.
Background
Epilepsy is a relatively common chronic neurological disorder, the second most common neurological disorder to headache. The drug therapy is the main therapeutic means for controlling epileptic seizure, and common antiepileptic drugs include Le Ruika, carbamazepine, phenobarbital, phenytoin sodium, valproate sodium and the like.
Le Ruika also called as pregabalin capsule, pregabalin is a novel, efficient and durable nervous system drug developed by the company Pfizer of the american type, and can be used for treating diseases such as postherpetic neuralgia, partial seizure epilepsy, anxiety and the like, and is approved to be marketed in China in 2010. Compared with the previous generation of nervous system medicine gabapentin capsules, the Lerui card has the advantages of easy absorption, obvious effect, high bioavailability, low medicine taking dosage, difficult generation of drug resistance, drug resistance and the like, and simultaneously has the characteristic of linear pharmacokinetics and can accurately control the effect of the treatment course. At present, le Ruika has very good market and application prospect as a nervous system medicament with remarkable effect.
Pregabalin intermediates are often prepared by asymmetric conjugate addition reactions in which, although products can be obtained with excellent enantioselectivities and yields under metal catalysis, disadvantages such as severe reaction conditions, high toxicity, or expensive catalysts are unavoidable.
Asymmetric conjugate addition of pregabalin intermediates without metal catalysts has been reported:
(1) N- [3, 5-bis (trifluoromethyl) phenyl ] -N' - [ (1R, 2R) -2- (dimethylamino) cyclohexyl ] thiourea (chemform, 2011,67 (3): 636-640):
the catalyst has complex preparation, high price and long reaction time of 24 hours.
(2) N- [3, 5-bis (trifluoromethyl) phenyl ] -N' - [ (3 aR,5S,6 aR) -tetrahydro-2, 2-dimethyl-6- [ (phenylmethyl) amino ] furo [2,3-d ] -1, 3-dioxo-5-yl ] thiourea (Organic & Biomolecular Chemistry,2016,14 (48): 11454-11461.):
the method has the advantages of harsh reaction conditions, long reaction time, high price of the catalyst and high synthesis cost.
(3) (1 s,2 s) -N1, N2-bis (phenylmethyl) -1, 2-cyclohexanediamine (RU 2555370):
the method also has the problems of high price of the catalyst and high synthesis cost.
Therefore, the prior asymmetric catalytic pregabalin intermediate synthesis has the defects of high cost, long reaction time, low efficiency and the like, and brings great trouble to practical application. Therefore, the synthesis process of the pregabalin intermediate with low development cost, simple operation and high product purity has important value.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of a pregabalin intermediate, which comprises the following steps:
diethyl malonate and (1E) -4-methyl-1-nitro-1-pentene are catalyzed to generate conjugated addition reaction by a quaternary ammonium salt catalyst to generate the pregabalin intermediate 1, 3-diethyl 2- [ (1S) -3-methyl-1- (nitromethyl) butyl]Malonic ester, wherein the quaternary ammonium salt catalyst is
The catalytic reaction formula is:
as preferable: the quaternary ammonium salt catalyst is prepared by the following steps:
(1) Preparation of (S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol
BH was added under nitrogen atmosphere 3 ·SMe 2 To (S) -4,5,6,4',5',6 '-hexamethoxybiphenyl-2, 2' -dicarboxylic acid in THF/B (OMe) 3 Stirring the solution for 5 hours, adding methanol to quench the reaction, removing the solvent under reduced pressure, adding hydrochloric acid into the residue, adding ethyl acetate for extraction after mixing, separating to obtain an organic layer after full layering, drying the organic layer, concentrating the organic layer under reduced pressure, adding pyridine, THF and liquid bromine into the concentrated organic layer, stirring the mixture for 1 hour, pouring the obtained reaction system into saturated Na 2 SO 3 Separating the aqueous solution and ethyl acetate after fully layering to obtain an organic layer, drying the organic layer, concentrating the organic layer under reduced pressure, and purifying by a silica gel column chromatography to obtain (S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol;
(2) Preparation of (S) -3,3' -bis (3, 4, 5-trifluorophenyl) -4,5,6,4',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol
Adding (S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol, 3,4, 5-trifluoro phenylboronic acid, palladium acetate, tris (o-methylphenyl) phosphorus and K obtained in the step (1) into a flask under the atmosphere of nitrogen 3 PO 4 -nH 2 O and tetrahydrofuran solution are fully mixed and then heated for reaction, the reaction is monitored 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, the obtained reaction system is filtered, the filtrate is concentrated in vacuum, and the filtrate is purified 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;
(3) PBr is put into 3 (S) -3,3' -bis (3, 4, 5-trifluorophenyl) 4,5,6,4',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol obtained in step (2) is added to CH 2 Cl 2 Adding water into the mixture to quench the reaction after stirring the reaction, adding diethyl ether into the mixture to extract the mixture,after sufficient delamination, the organic layer was separated, washed with brine, dried, concentrated under reduced pressure, and the concentrated system was put into K under argon atmosphere 2 CO 3 And Bu (Bu) 2 Adding the mixture into acetonitrile suspension of NH, fully mixing and heating for reaction, pouring the obtained mixed system into HBr aqueous solution for quenching, adding CH 2 Cl 2 Extraction is carried out, after sufficient delamination, an organic layer is separated, the organic layer is dried, and the organic layer is concentrated under reduced pressure and then purified by silica gel column chromatography.
Further: in the step (1), pyridine and THF are added into the concentrated organic layer, the obtained mixture is cooled to-20 ℃, liquid bromine is added into the mixture, and the mixture is heated to 0 ℃ and then stirred for reaction for 1 hour.
Further: in the step (2), the temperature of the heating reaction was 88 ℃.
Further: in the step (3), the temperature of the heating reaction is 80 ℃ and the reaction time is 10 hours.
As preferable: the mass ratio of the diethyl malonate to the (1E) -4-methyl-1-nitro-1-pentene to the quaternary ammonium salt catalyst is 1:0.8 to 1.6: 0.005-0.025.
As preferable: under the protection of inert gas, diethyl malonate and (1E) -4-methyl-1-nitro-1-pentene are subjected to conjugate addition reaction in an organic solvent under the action of a quaternary ammonium salt catalyst and alkali.
Further: the organic solvent is toluene, DMF or acetonitrile.
Further: the reaction temperature of the conjugate addition reaction is-10 ℃ to 25 ℃ and the reaction time is 4 hours to 6 hours.
When the quaternary ammonium salt catalyst is used for catalyzing synthesis of diethyl malonate and (1E) -4-methyl-1-nitro-1-pentene, electronegativity is reflected after diethyl malonate of one reactant is converted into enol, ion pair combination is formed with quaternary ammonium salt functional groups, and an oxygen atom with negative charges on nitro on (1E) -4-methyl-1-nitro-1-pentene biphenyl and nitrogen on the quaternary ammonium salt have interaction of heterogeneous charges, so that the effect of fixing the relative positions of reaction molecules is achieved. When the addition reaction occurs, the carbon atom with partial negative charge on enol type attacks the double bond of (1E) -4-methyl-1-nitro-1-pentene to generate Michael addition reaction, and two large steric hindrance trifluorophenyl groups on chiral biphenyl enable the situation that the carbon atom attacks from one side to occupy absolute advantages in the reaction, thereby effectively improving the enantioselectivity of the reaction and leading the proportion of high-activity configuration in the product to be higher, and the mechanism is as follows:
meanwhile, the catalyst of the invention has low dosage and low cost, has higher industrialized value, safe and environment-friendly process, high yield and simple operation, and therefore, the cost of the prepared pregabalin intermediate is relatively lower.
Detailed Description
The invention is further described in connection with the following examples (the raw materials used in the following examples are all technical grade products):
the preparation method of the quaternary ammonium salt catalyst comprises the following steps:
(1) Preparation of (S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol
BH at 0℃under nitrogen atmosphere 3 ·SMe 2 (4.0 mmol) in tetrahydrofuran (4.0 mL) was added dropwise to a solution of (S) -4,5,6,4',5',6 '-hexamethoxybiphenyl-2, 2' -dicarboxylic acid (1.0 mmol) in THF/B (OMe) at 0deg.C 3 (4 mL/2 mL) of the solution, the temperature of the resulting mixed system was raised to room temperature (25 ℃ C., the same applies hereinafter) and then the reaction was continued with stirring for 5 hours, 1mL of methanol was slowly added thereto to quench the reaction, then the solvent was removed under reduced pressure, 8.0mL of 1N hydrochloric acid was added to the residue, the mixture was thoroughly mixed and then ethyl acetate was added to extract, and after sufficient delamination, an organic layer was obtained by separation, and Na was used 2 SO 4 Drying the organic layer, concentrating under reduced pressure, adding pyridine (0.57 mL) and THF (5 mL) into the concentrated organic layer, mixing, cooling to-20deg.C, adding liquid bromine (0.36 mL,7.0 mmol) into the mixture, heating to 0deg.C, stirring, reacting for 1 hr, and pouring the obtained reaction systemInto saturated Na 2 SO 3 Separating the aqueous solution and ethyl acetate to obtain an organic layer, and separating the organic layer with Na 2 SO 4 Drying the organic layer, concentrating the organic layer under reduced pressure, and purifying by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 1:1 as eluent) to obtain (S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol;
(2) Preparation of (S) -3,3' -bis (3, 4, 5-trifluorophenyl) -4,5,6,4',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol:
(S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol (0.276 g), 3,4, 5-trifluorophenylboronic acid (0.440 g,2.5 mmol), palladium acetate (0.0225 g,0.10 mmol), tris (o-methylphenyl) phosphorus (0.122 g,0.40 mmol), K obtained in step (1) were charged to a flask under a nitrogen atmosphere 3 PO 4 -nH 2 O (1.056 g,5.0 mmol) and tetrahydrofuran solution (5 mL), heating to 88 ℃ after mixing fully, stirring and reacting, monitoring the reaction 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 disappears, filtering the obtained reaction system, concentrating the filtrate in vacuum, and purifying by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 2:1 is used as eluent) to obtain (S) -3,3' -bis (3, 4, 5-trifluorophenyl) -4,5,6,4',5',6 '-hexamethoxybiphenyl-2, 2' -dimethanol;
(3) PBr at 0deg.C 3 (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 CH 2 Cl 2 (5 mL) the resulting mixture was allowed to stand at room temperature for 1 hour with stirring, quenched with water, extracted with diethyl ether, separated to give an organic layer, washed with Na 2 SO 4 Drying the organic layer, concentrating the organic layer under reduced pressure, and charging the concentrated solution into K under argon atmosphere 2 CO 3 (0.0553 g,0.40 mmol) and Bu 2 In a suspension of NH (0.037 mL,0.22 mmol) in acetonitrile (5 mL), mixing was complete and warmed to 80 ℃After heating for 10 hours, the resulting mixture was poured into 5.0mL of 1N aqueous HBr solution and quenched, and CH was added 2 Cl 2 Extracting, fully layering, separating to obtain an organic layer, and using Na 2 SO 4 The organic layer was dried and concentrated under reduced pressure, followed by column chromatography on silica gel (MeOH/CH 2 Cl 2 Volume ratio 1:10 as eluent).
Example 1
Synthesis of 1, 3-diethyl 2- [ (1S) -3-methyl-1- (nitromethyl) butyl ] malonate
Under the protection of argon gas, (1E) -4-methyl-1-nitro-1-pentene (563.82 mg,4.37 mmol) and diethyl malonate (500 mg,3.12 mmol) were added to the flask, and after 20mL of toluene was added for sufficient dissolution, the reaction was started at room temperature after adding the above prepared quaternary ammonium salt catalyst (252.1 mg,0.0312 mmol) thereto, and the reaction was monitored by TLC under stirring for 6 hours, and after concentrating the obtained reaction system under vacuum, the obtained reaction system was purified by silica gel column chromatography (hexane/ethyl acetate volume ratio 5:1 as eluent) to obtain the objective product (794 mg,88.0% where "88.0%" is the yield, calculated by mol of diethyl malonate in the objective product × 100%, the same applies below) with an ee value of 92%.
Characterization of the product structure: 1 H NMR(400MHz,CDCl 3 )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.
examples 2 to 5
On the basis of example 1, other experimental conditions were kept unchanged, and the effect on the reaction results was examined only by changing the ratio of the amounts of the materials of diethyl malonate and (1E) -4-methyl-1-nitro-1-pentene and compared with example 1, and the results obtained are shown in table 1:
TABLE 1
From Table 1, it was found that the ratio of the amounts of the materials of diethyl malonate and (1E) -4-methyl-1-nitro-1-pentene was 1:1.4 is most preferable, and the molar ratio is further increased, and the yield does not change much.
Examples 6 to 9
On the basis of example 1, other experimental conditions were kept unchanged, and the effect on the reaction results was examined by merely changing the percentage of the amount of the quaternary ammonium salt catalyst with respect to the diethyl malonate, and compared with example 1, and the results obtained are shown in table 2:
TABLE 2
As can be seen from Table 2, the catalyst amount was most suitably 1%, and the yield was not greatly changed by further increasing the amount.
Examples 10 to 13
On the basis of example 1, other experimental conditions were kept unchanged, and the effect on the reaction results was examined by merely changing the reaction temperature and compared with example 1, and the results obtained are shown in table 3:
TABLE 3 Table 3
Reaction temperature Yield is good ee value
Example 1 25℃ 88.0％ 92％
Example 10 -10℃ 80.2％ 92％
Example 11 0℃ 80.4％ 91％
Example 12 10℃ 83.5％ 88％
Example 13 35℃ 87.3％ 87％
As can be seen from Table 3, when the reaction temperature was 25 ℃, higher yields and ee values were obtained at the same time.
Examples 14 to 16
On the basis of example 1, other experimental conditions were kept unchanged, and the effect on the reaction results was examined by merely changing the reaction solvent and compared with example 1, and the results obtained are shown in table 4:
TABLE 4 Table 4
Reaction solvent Yield is good ee value
Example 1 Toluene (toluene) 88.0％ 92％
Example 10 Acetonitrile 80.2％ 90％
Example 11 DMF 84.4％ 85％
Example 12 DMSO 82.5％ 87％
As can be seen from Table 4, when the solvent was toluene, high yields and ee values were obtained.
Example 17
On the basis of example 1, other experimental conditions were kept unchanged, and the effect on the reaction results was examined by merely changing the molecular structure composition of the catalyst and compared with example 1, and the results obtained are shown in table 5:
in this example, 3,4, 5-trifluorophenylboronic acid is not added in the preparation method of the quaternary ammonium salt catalyst, and the rest of the operations are the same as in example 1:
(1) BH at 0℃under nitrogen atmosphere 3 ·SMe 2 (4.0 mmol) in tetrahydrofuran (4.0 mL) was added dropwise to a solution of (S) -4,5,6,4',5',6 '-hexamethoxybiphenyl-2, 2' -dicarboxylic acid (1.0 mmol) in THF/B (OMe) at 0deg.C 3 (4 mL/2 mL) of the solution, the temperature of the resulting mixed system was raised to room temperature (25 ℃ C., the same applies hereinafter) and then the reaction was continued with stirring for 5 hours, 1mL of methanol was slowly added thereto to quench the reaction, then the solvent was removed under reduced pressure, 8.0mL of 1N hydrochloric acid was added to the residue, the mixture was thoroughly mixed and then ethyl acetate was added to extract, and after sufficient delamination, an organic layer was obtained by separation, and Na was used 2 SO 4 The organic layer was dried, concentrated under reduced pressure, pyridine (0.57 mL) and THF (5 mL) were added to the concentrated organic layer, the mixture was cooled to-20℃after sufficient mixing, liquid bromine (0.36 mL,7.0 mmol) was added to the mixture, the mixture was heated to 0℃again, and the mixture was stirred for 1 hour to allow the reaction system to react, and saturated Na was added to the reaction system 2 SO 3 Separating the aqueous solution and ethyl acetate to obtain an organic layer, and separating the organic layer with Na 2 SO 4 Drying the organic layer, concentrating the organic layer under reduced pressure, and purifying by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 1:1 as eluent) to obtain (S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol;
(2) PBr at 0deg.C 3 (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 CH 2 Cl 2 (5 mL) the resulting mixture was allowed to stand at room temperature for 1 hour with stirring, quenched with water, extracted with diethyl ether, separated to give an organic layer, washed with Na 2 SO 4 Drying the organic layerConcentrating the organic layer under reduced pressure, and introducing the concentrated solution into K under argon atmosphere 2 CO 3 (0.0553 g,0.40 mmol) and Bu 2 In a suspension of NH (0.037 mL,0.22 mmol) in acetonitrile (5 mL), the mixture was thoroughly mixed and heated to 80℃for 10 hours, the resulting mixture was poured into 5.0mL of 1N aqueous HBr solution and quenched, and CH was added 2 Cl 2 Extracting, fully layering, separating to obtain an organic layer, and using Na 2 SO 4 The organic layer was dried and concentrated under reduced pressure, followed by column chromatography on silica gel (MeOH/CH 2 Cl 2 Volume ratio 1:10 as eluent).
TABLE 5
Yield is good ee value
Example 1 88.0％ 92％
Example 17 82.1％ 78％
As shown in the table above, in this example, after the biphenyl structure of the quaternary ammonium salt catalyst loses the benzene ring side group, when the Michael addition reaction occurs, the limitation 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, the by-product is increased, and the selectivity of the product is also reduced.
Example 18
On the basis of example 1, other experimental conditions were kept unchanged, and the effect on the reaction results was examined by merely changing the molecular structure composition of the catalyst and compared with example 1, and the results obtained are shown in table 6:
in this example, the "Bu" in step (3) was used in the preparation method of the quaternary ammonium salt catalyst 2 NH "replaced with" diethylamine ", the rest of the procedure being the same as in example 1:
(1) Preparation of (S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol
BH at 0℃under nitrogen atmosphere 3 ·SMe 2 (4.0 mmol) in tetrahydrofuran (4.0 mL) was added dropwise to a solution of (S) -4,5,6,4',5',6 '-hexamethoxybiphenyl-2, 2' -dicarboxylic acid (1.0 mmol) in THF/B (OMe) at 0deg.C 3 (4 mL/2 mL) of the solution, the temperature of the resulting mixed system was raised to room temperature (25 ℃ C., the same applies hereinafter) and then the reaction was continued with stirring for 5 hours, 1mL of methanol was slowly added thereto to quench the reaction, then the solvent was removed under reduced pressure, 8.0mL of 1N hydrochloric acid was added to the residue, the mixture was thoroughly mixed and then ethyl acetate was added to extract, and after sufficient delamination, an organic layer was obtained by separation, and Na was used 2 SO 4 The organic layer was dried, concentrated under reduced pressure, pyridine (0.57 mL) and THF (5 mL) were added to the concentrated organic layer, the mixture was cooled to-20℃after sufficient mixing, liquid bromine (0.36 mL,7.0 mmol) was added to the mixture, the mixture was heated to 0℃again, and the mixture was stirred for 1 hour to allow the reaction system to react, and saturated Na was added to the reaction system 2 SO 3 Separating the aqueous solution and ethyl acetate to obtain an organic layer, and separating the organic layer with Na 2 SO 4 Drying the organic layer, concentrating the organic layer under reduced pressure, and purifying by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 1:1 as eluent) to obtain (S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol;
(2) Preparation of (S) -3,3' -bis (3, 4, 5-trifluorophenyl) -4,5,6,4',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol:
under nitrogen gasThe flask was charged with (S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol (0.276 g), 3,4, 5-trifluorophenylboronic acid (0.440 g,2.5 mmol), palladium acetate (0.0225 g,0.10 mmol), tris (o-methylphenyl) phosphorus (0.122 g,0.40 mmol), K obtained in step (1) under an atmosphere 3 PO 4 -nH 2 O (1.056 g,5.0 mmol) and tetrahydrofuran solution (5 mL), heating to 88 ℃ after mixing fully, stirring and reacting, monitoring the reaction 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 disappears, filtering the obtained reaction system, concentrating the filtrate in vacuum, and purifying by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 2:1 is used as eluent) to obtain (S) -3,3' -bis (3, 4, 5-trifluorophenyl) -4,5,6,4',5',6 '-hexamethoxybiphenyl-2, 2' -dimethanol;
(3) PBr at 0deg.C 3 (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 CH 2 Cl 2 (5 mL) the resulting mixture was allowed to stand at room temperature for 1 hour with stirring, quenched with water, extracted with diethyl ether, separated to give an organic layer, washed with Na 2 SO 4 Drying the organic layer, concentrating the organic layer under reduced pressure, and charging the concentrated solution into K under argon atmosphere 2 CO 3 (0.0553 g,0.40 mmol) and diethylamine (0.023 mL,0.22 mmol) in acetonitrile (5 mL), mixing thoroughly and heating to 80deg.C for reaction for 10h, pouring the resulting mixture into 5.0mL of 1N aqueous HBr for quenching, adding CH 2 Cl 2 Extracting, fully layering, separating to obtain an organic layer, and using Na 2 SO 4 The organic layer was dried and concentrated under reduced pressure, followed by column chromatography on silica gel (MeOH/CH 2 Cl 2 Volume ratio 1:10 as eluent).
TABLE 6
Yield is good ee value
Example 1 88.0％ 92％
Example 18 84.6％ 87％
As shown in the table above, in this example, after the butyl segment on the catalyst close to the molecular position of the reactant becomes a shorter ethyl group, the reaction controllability is reduced, probably because the butyl segment on the catalyst structure has a certain limited influence on the attack direction between the reactants based on the chain length of the butyl segment, but the influence is smaller than that of the large-steric-hindrance trifluorophenyl group on the biphenyl.
Example 19
On the basis of example 1, other experimental conditions were kept unchanged, and the effect on the reaction results was examined by merely changing the molecular structure composition of the catalyst and compared with example 1, and the results obtained are shown in table 7:
in this embodiment, the preparation method of the quaternary ammonium salt catalyst is as follows:
after a dialdehyde compound (440 mg,1 mmol), methylamino acid hydrogen chloride (1.5 mmol), sodium cyanoborohydride (330 mg,3 mmol) and 20mL methanol were added to a 50mL flask, the reaction was stirred at room temperature for 4 hours, the resultant reaction mixture was diluted with EtOAc, washed with brine, and left to stand until the layers were separatedSeparating, separating and retaining the organic phase, and subjecting the obtained organic phase to anhydrous Na 2 SO 4 Dried, concentrated, and purified by silica gel column chromatography to give the corresponding N, N-disubstituted amine, dissolving the resulting N, N-disubstituted amine (0.2 mmol) and allyl bromide (0.4 mmol) in 5mL acetonitrile, and reacting for 2 days at room temperature with stirring, then using CH 2 Cl 2 After diluting the resulting reaction system mixture, the solvent and allyl bromide were removed by vacuum concentration, and the residue was purified by silica gel column chromatography (CH 2 Cl 2 MeOH volume ratio 10:1 as eluent). The preparation formula is as follows:
wherein, by changing the structure of R on methyl amino acid hydrogen chloride molecule, respectively obtaining quaternary ammonium salt 1 and quaternary ammonium salt 2, the molecular structure is as follows:
quaternary ammonium salt 1:
H NMR(300MHz,CDCl3)δ3.26(t,1H,J＝12.0Hz),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＝9.0Hz),5.40(d,1H,J＝13.2Hz),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(100MHz,CDCl3)δ32.8,52.8,55.9,56.4,60.45,60.46,60.57,60.62 62.9,64.1,73.0,110.3,111.1,121.9,122.8,124.8,127.2,127.6,128.2,129.0,132.6,143.2,143.3,151.18,151.24,153.3,166.3ppm.ESI-MS:578.1(M+-Br)；HRMS(ESI)for C 33 H 40 N 1 O 2 (M+-Br):calcd 578.2754,found578.275；
quaternary ammonium salt 2:
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)δ20.8,22.7,25.4,34.6,53.6,55.9,56.5,60.5,60.56,60.61,62.7,63.2,70.9,110.0,111.3,122.1,122.3,122.7,123.0,125.4,127.5,143.3,143.4,151.1,151.3,153.0,153.4,167.1ppm.ESI-MS:544.1(M+-Br)；HRMS(ESI)for C 30 H 42 N 1 O 8 (M+-Br):calcd 544.2910,found544.2896.
TABLE 7
As shown in the table above, in this example, after the biphenyl structure of the quaternary ammonium salt catalyst loses the benzene ring side group, when the Michael addition reaction occurs, the limitation 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, the by-product is increased, and the selectivity of the product is also reduced.

Claims (9)

1. A method for preparing pregabalin intermediate, which is characterized in that: the preparation method is that,
through a quaternary ammonium salt catalyst, diethyl malonate and (1E) -4-methyl-1-nitro-1-pentene are catalyzed to generate conjugated addition reaction to generate the pregabalin intermediate 1, 3-diethyl 2- [ (1S) -3-methyl-1- (nitromethyl) butyl]Malonate, wherein the quaternary ammonium salt catalyst is
2. A process for the preparation of pregabalin intermediate according to claim 1, characterized in that: the preparation method of the quaternary ammonium salt catalyst comprises the following steps of,
(1) Preparation of (S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol
BH was added under nitrogen atmosphere 3 ·SMe 2 To (S) -4,5,6,4',5',6 '-hexamethoxybiphenyl-2, 2' -dicarboxylic acid in THF/B (OMe) 3 Stirring the solution for 5 hours, adding methanol to quench the reaction, removing the solvent under reduced pressure, adding hydrochloric acid into the residue, adding ethyl acetate for extraction after mixing, separating to obtain an organic layer after full layering, drying the organic layer, concentrating the organic layer under reduced pressure, adding pyridine, THF and liquid bromine into the concentrated organic layer, stirring the mixture for 1 hour, pouring the obtained reaction system into saturated Na 2 SO 3 Separating the aqueous solution and ethyl acetate after fully layering to obtain an organic layer, drying the organic layer, concentrating the organic layer under reduced pressure, and purifying by a silica gel column chromatography to obtain the (S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol;
(2) Preparation of (S) -3,3' -bis (3, 4, 5-trifluorophenyl) -4,5,6,4',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol
Adding the (S) -3,3' -dibromo-4,5,6,4 ',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol, 3,4, 5-trifluorophenylboronic acid, palladium acetate, tris (o-methylphenyl) phosphorus, K obtained in the step (1) into a flask under a nitrogen atmosphere 3 PO 4 -nH 2 O and tetrahydrofuran solution are fully mixed and then heated for reaction, the reaction is monitored 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, the obtained reaction system is filtered, the filtrate is concentrated in vacuum, and the (S) -3,3' -bis (3, 4, 5-trifluorophenyl) -4,5,6,4',5',6 '-hexamethoxybiphenyl-2, 2' -dimethanol is obtained by purifying the filtrate by silica gel column chromatography;
(3) PBr is put into 3 Adding the (S) -3,3' -bis (3, 4, 5-trifluorophenyl) 4,5,6,4',5',6' -hexamethoxybiphenyl-2, 2' -dimethanol obtained in the step (2) to CH 2 Cl 2 Adding water to quench the reaction after stirring the reaction, and then adding diethyl ether to extractTaking, fully layering, separating to obtain an organic layer, washing the organic layer with brine, drying the organic layer, concentrating the organic layer under reduced pressure, and putting the system after reduced pressure concentration into K under argon atmosphere 2 CO 3 And Bu (Bu) 2 Adding the mixture into acetonitrile suspension of NH, fully mixing and heating for reaction, pouring the obtained mixed system into HBr aqueous solution for quenching, adding CH 2 Cl 2 Extraction is carried out, after sufficient delamination, an organic layer is separated, the organic layer is dried, and the organic layer is concentrated under reduced pressure and then purified by silica gel column chromatography.
3. A process for the preparation of pregabalin intermediate according to claim 2, characterized in that: in the step (1), after pyridine and THF are added into the concentrated organic layer, the obtained mixture is cooled to-20 ℃, then the liquid bromine is added into the mixture, and the mixture is heated to 0 ℃ and then stirred for reaction for 1 hour.
4. A process for the preparation of pregabalin intermediate according to claim 2, characterized in that: in the step (2), the temperature of the heating reaction is 88 ℃.
5. A process for the preparation of pregabalin intermediate according to claim 2, characterized in that: in the step (3), the temperature of the heating reaction is 80 ℃ and the reaction time is 10 hours.
6. A process for the preparation of pregabalin intermediate according to claim 1, characterized in that: the mass ratio of the diethyl malonate, the (1E) -4-methyl-1-nitro-1-pentene and the quaternary ammonium salt catalyst is 1:0.8 to 1.6: 0.005-0.025.
7. A process for the preparation of pregabalin intermediate according to claim 1, characterized in that: under the protection of inert gas, diethyl malonate and (1E) -4-methyl-1-nitro-1-pentene are subjected to the conjugate addition reaction in an organic solvent under the action of the quaternary ammonium salt catalyst and alkali.
8. A process for the preparation of pregabalin intermediate according to claim 8, characterized in that: the organic solvent is toluene, DMF or acetonitrile.
9. A process for the preparation of pregabalin intermediate according to claim 8, characterized in that: the reaction temperature of the conjugate addition reaction is-10 ℃ to 25 ℃ and the reaction time is 4 hours to 6 hours.
CN202311187175.3A 2023-09-14 2023-09-14 Preparation method of pregabalin intermediate Pending CN117285402A (en)

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