CN104395286A - A kind of preparation method of lactam compound - Google Patents

Abstract

The invention discloses a method for preparing pregabalin and an amide substance in an important intermediate thereof. The method does not require the use of hydrogen, high pressure equipment. By selecting proper catalyst and reducer, the product with high purity can be prepared by simple steps by using conventional equipment. The method is simple, safe, high in yield and suitable for industrial production.

Description

A kind of preparation method of lactam compound

technical field

The invention relates to a method for preparing pregabalin and its intermediate lactam compound.

Background technique

Pregabalin has analgesic, anticonvulsant and anxiolytic activity, and has a preventive effect on epileptic seizures.

The lactam compound 4-isobutyl-2-pyrrolidone (02) is a key intermediate for the synthesis of pregabalin, and the qualified 4-isobutyl-2-pyrrolidone (02) is easily obtained for the synthesis of pregabalin. Significance.

There are various methods for preparing 4-isobutyl-2-pyrrolidone in the prior art. For example, patent application CN200910266661.8 or WO2006110783 discloses related methods for preparing 4-isobutyl-2-pyrrolidone; but these methods need to use hydrogen and/or high-pressure equipment or use other substrates to go through multiple steps to obtain, the reaction The time is long, the process is cumbersome and/or there are major unsafe factors. Therefore, there is a need for a method with low requirements on equipment, safety, simple operation process and high yield, so as to be suitable for industrial production.

Contents of the invention

The invention provides a method for preparing pregabalin, comprising: converting a nitro compound (01) into a lactam compound 4-isobutyl-2-pyrrolidone (02), and then hydrolyzing and resolving the compound (02) , to obtain pregabalin (03),

Wherein, R is halogen, OR ¹ or N R ² R ³ ; R ¹ , R ² and R ³ are each independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, aryl, methanesulfonate Acyl, benzenesulfonyl or p-toluenesulfonyl; wherein, the (C1-C6) alkyl, (C3-C6) cycloalkyl or aryl is optionally unsubstituted or substituted by one or more substituents ; (C1-C6) alkyl includes without limitation methyl, ethyl, isopropyl, tert-butyl, etc., (C3-C6) cycloalkyl includes without limitation cyclopropyl, cyclohexyl; aryl Non-limiting include phenyl, tolyl, halogen is fluorine, chlorine, bromine or iodine; the aforementioned substituents are non-limiting halogen, trifluoromethyl, nitro, cyano, mercapto, alkylthio one or more.

The present invention provides a method for preparing a lactam compound (02). The method does not require the use of hydrogen (H ₂ ) and/or high-pressure equipment, and the lactam compound (02) can be obtained through simple reaction steps. The preparation method comprises converting the nitro compound shown in formula (01) into 4-isobutyl-2-pyrrolidone shown in formula (02) in the presence of a metal halide,

wherein R is as defined above.

The nitro compound (01) can be prepared by known methods, for example, the method reported by Li Jing et al. in Chinese Journal of Medicinal Chemistry, Vol. 17, No. 1 in 2007.

In some embodiments, the method for preparing the lactam compound (02) from the nitro compound (01) comprises: in the presence of a metal halide, the nitro compound (01) is converted into the lactam compound ( 02),

Or in some embodiments, the nitro compound (01) is converted into a lactam compound (02) through an intermediate (I-II), wherein the definition of R in the formula (I-II) is the same as that of the formula (01),

In the process of converting the nitro compound (01) to the lactam compound (02), the intermediate (I-I) or (I-II) may or may not be isolated. In some embodiments, intermediates are not isolated.

In some embodiments, a reducing agent is used in addition to the metal halide during the conversion of the nitro compound (01) to the lactam compound (02).

In some embodiments, in the process of converting the nitro compound (01) into the lactam compound (02), in addition to the presence of metal halides, reducing agents and metal catalysts can also be used.

In some embodiments, the nitro compound (01) is converted into a lactam compound (02) through a reducing agent in the presence of a metal halide; or the nitro compound (01) is converted into a lactam compound (02) through a metal catalyst and a reducing In the presence of halides, it can be transformed into lactam compound (02) by reducing agent.

In some embodiments, the metal halide is nickel halide, copper halide, tin halide, cobalt halide, palladium halide, or hydrates thereof, or any combination thereof. In other embodiments, the metal halide is nickel halide, tin halide, or hydrates thereof, or any combination thereof. In some embodiments, the nickel halide is nickel chloride (NiCl ₂ ), nickel chloride dihydrate (NiCl ₂ ·2H ₂ O), nickel chloride hexahydrate (NiCl ₂ ·6H ₂ O), bromide Nickel (NiBr ₂ ), nickel bromide trihydrate (NiBr ₂ ·3H ₂ O), or any combination thereof; the copper halide is cuprous iodide (CuI), cuprous bromide (CuBr), or their The combination; the tin halide is stannous chloride dihydrate (SnCl ₂ ·2H ₂ O), stannous chloride (SnCl ₂ ), or their combination; the cobalt halide is cobalt dichloride (CoCl ₂ ); the palladium halide is palladium dichloride (PdCl ₂ ).

In some embodiments, the reducing agent is formic acid or a salt thereof, a metal borohydride, a metal hydride, or any combination thereof. In some embodiments, the reducing agent is ammonium formate, sodium formate, formic acid, ammonium acetate, potassium borohydride, sodium borohydride, lithium aluminum hydride, sodium hydride, diisobutylaluminum hydride, dimethylaminoborane , or any combination of them. In some embodiments, the reducing agent is ammonium formate, potassium borohydride, sodium borohydride, or any combination thereof. In some embodiments, the reducing agent is potassium borohydride, sodium borohydride, or a combination thereof.

In some embodiments, the metal catalyst is palladium on carbon (Pd/C), palladium hydroxide (Pd(OH) ₂ ), platinum (Pt), platinum on carbon (Pt/C), nickel (Ni), or their any combination of . In other embodiments, the metal catalyst is palladium on carbon (Pd/C). In some embodiments, the metal catalyst is nickel (Ni).

The molar ratio of the nitro compound (01) to the metal halide is 1:0.1 to 1:2.0. In some embodiments, the molar ratio is from 1:0.3 to 1:1.0. In some embodiments, the molar ratio is from 1:0.3 to 1:0.8.

The molar ratio of the nitro compound (01) to the reducing agent is 1:0.5 to 1:6. In some embodiments, the molar ratio is from 1:1.0 to 1:6. In some embodiments, the molar ratio is from 1:1.1 to 1:4.5. In some embodiments, the molar ratio is from 1:1.3 to 1:4.5. In some embodiments, the molar ratio is from 1:1.3 to 1:4.

The weight ratio of the nitro compound (01) to the metal catalyst is 1:0.01 to 1:0.2. In some embodiments, the weight ratio is from 1:0.01 to 1:0.1. In some embodiments, the weight ratio is 1:0.01 to 1:0.05.

In some embodiments, the pH value of the system can be controlled to be lower than 6, or lower than 5, or lower than 4.5, or lower than 4 after the reaction, so as to eliminate excess reagents. In some embodiments, pH=2-3 is controlled by adjusting with aqueous hydrochloric acid. In some embodiments, pH = 1-2 is controlled.

During the preparation of the nitro compound (01) into the lactam compound (02), the reaction solvent is an alcohol solvent, a nitrile solvent, a ketone solvent, an ether solvent, an ester solvent, or any combination thereof; The alcohol solvent is methanol, ethanol, isopropanol, or any combination thereof; the nitrile solvent is acetonitrile; the ketone solvent is acetone; the ether solvent is tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether or any combination thereof; the ester solvent is trimethyl orthoformate, triethyl orthoformate or a combination thereof. In some embodiments, the reaction solvent is methanol, ethanol, trimethyl orthoformate, or any combination thereof.

During the preparation of the nitro compound (01) into the lactam compound (02), the reaction temperature is -40°C to 65°C. In some embodiments, the reaction temperature is from 0°C to 45°C. The reaction time of the reaction is 0.5 hours to 20 hours.

In some embodiments, the process of preparing the nitro compound (01) into a lactam compound ( ₀₂ ) comprises: in a solvent, in the presence of NiCl , reacting the nitro compound (01) with sodium borohydride to obtain the lactam compound ( 02).

In some embodiments, the nitro compound (01) is first reacted with ammonium formate, potassium borohydride, sodium borohydride, or any combination thereof in the presence of Pd/C in a solvent, and then reacted in NiCl ₂ or SnCl ₂ In the presence of , react with potassium borohydride or sodium borohydride to prepare lactam compound (02).

In the context of the present invention, all numbers disclosed herein are approximations, whether or not the word "about" or "approximately" is used. The value of each figure may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%. Whenever a number with a value of N is disclosed, any number with N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8%, N+ Figures for /-10%, N+/-15% or N+/-20% values are explicitly disclosed, where "+/-" means plus or minus. Whenever a lower limit, AL, and an upper limit, AU, of a numerical range are disclosed, any numerical value within that disclosed range is expressly disclosed. In particular, the following values are included in the range: A=AL+k*(AU-AL), where k is a variable from 1% to 100% in increments of 1%. Such as: 1%, 2%, 3%, 4%, 5%...50%, 51%, 52%...95%, 96%, 97%, 98%, 99% or 100%. In addition, the above-mentioned numerical ranges defined by two A numbers disclosed herein are also specifically included.

Detailed ways

In order to further understand the present invention, the present invention will be described in detail below in conjunction with examples.

In the following examples, R is ethoxy. If R is other groups, please refer to the following examples to prepare lactam compound (02).

Example 1

In 600 ml of methanol, add 50.00 g of nitro compound (01), 18.04 g of NiCl ₂ ·6H ₂ O; cool the solution to 0°C-5°C, and add 18.2 g of sodium borohydride. After the addition, the temperature was raised to 40°C-45°C and stirred for 12 hours. Then the mixture was cooled to room temperature, and aqueous hydrochloric acid was added dropwise to adjust the pH to 2-3. The reaction solution was concentrated under reduced pressure until no obvious methanol was found in the system (detected by gas chromatography), ethyl acetate was added for extraction, washed with water, the organic layer was dried and concentrated to obtain lactam compound (02), 31.20 g of light yellow oil, yield 96.0% , 99.10% purity. Mass Spectrum: m/z=142[M+1], m/z=283[2M+1]; NMR Proton Spectrum: (CDCl ₃ ,400MHz)0.91(m,6H),1.33(m,2H),1.61( m,1H), 1.99(m,1H), 2.17(m,1H), 2.44(m,1H), 3.01(m,1H), 3.50(m,1H), 6.71(br,1H).

Example 2

50.00 g of nitro compound (01) was dissolved in 600 ml of methanol solution, cooled to -15°C; 22.05 g of potassium borohydride and 10.93 g of NiCl ₂ ·6H ₂ O were added; after addition, the temperature was raised to 45°C and stirred for 12 hours. Then the mixture was cooled to 0°C-5°C, and hydrochloric acid solution was added to adjust the pH to 2-3. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with water, and the organic layer was dried and concentrated to obtain lactam compound (02), 32.00 g of light yellow oil, yield 98.5%, purity 96.50%; mass spectrum: m/z= 142[M+1], m/z=283[2M+1].

Example 3

To 500 ml of methanol, add 50.00 g of nitro compound (01), 31.35 g of NiBr ₂ ·3H ₂ O; cool down to -5°C, and add 27.50 g of sodium hydride. After the addition, the temperature was raised to 40°C-45°C and stirred for 10 hours. Then the temperature of the reaction mixture was lowered to 0°C-5°C, and aqueous hydrochloric acid was added to adjust the pH=2-3. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with water, and the organic layer was dried and concentrated to give lactam compound (02), 31.10 g of light yellow oil, yield 95.7%, purity 99.11%; mass spectrum: m/z =142[M+1], m/z=283[2M+1].

Example 4

To 900 ml of methanol, add 50.00 g of nitro compound (01), 24.65 g of NiCl ₂ ·6H ₂ O; cool down to 0°C-5°C, and add 18.20 g of sodium borohydride. After the addition, the temperature was raised to 40°C-45°C and stirred for 10 hours. Then the temperature of the reaction mixture was lowered to 5°C-25°C, and aqueous hydrochloric acid was added to adjust the pH to 2-3. The reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with water, and the organic layer was dried and concentrated to give lactam compound (02), 31.22 g of light yellow oil, yield 96.0%, purity 99.10%; mass spectrum: m/ z=142[M+1], m/z=283[2M+1].

Example 5

50.00 g of nitro compound (01), 5.20 g of SnCl ₂ ·2H ₂ O were added to 600 ml of methanol; the temperature was lowered to 0°C-5°C, and 18.20 g of sodium borohydride was added. After the addition was complete, the temperature of the reaction mixture was raised to 40°C-45°C and stirred for 10 hours. Then the temperature of the reaction mixture was lowered to 5°C-15°C, and aqueous hydrochloric acid was added to adjust the pH to 2-3. Then the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated brine, and the organic layer was dried and concentrated to obtain lactam compound (02), 31.30 g of light yellow oil, yield 96.4%, purity 99.10%; mass spectrometry : m/z=142[M+1], m/z=283[2M+1].

Example 6

In 50 milliliters of ethanol, add 5 grams of nitro compound (01), 6.50 grams of ammonium formate and 0.25 grams of 5% Pd/C, stir at room temperature for 6.5 hours; filter, concentrate the filtrate, extract with ethyl acetate, wash the organic layer with water, After drying and concentrating, 3.30 g of a yellow oily substance was obtained. The yellow oil was dissolved in 40 ml of methanol, cooled to -10°C, 2.51 g of potassium borohydride and 1.37 g of NiCl ₂ ·6H ₂ O were added, then heated to 45°C and stirred for 12 hours. Cool the mixed solution to -5°C-0°C, add hydrochloric acid aqueous solution dropwise to adjust pH = 1-2; concentrate the mixed solution under reduced pressure until no methanol is detected in the gas phase, add ethyl acetate for extraction, wash with water, dry the organic layer and concentrate to obtain Amide compound (02), light yellow oil 2.71g, purity 99.12%, yield 82.6%; mass spectrum: m/z=142[M+1], m/z=283[2M+1].

Example 7

In 60 ml of methanol, add 5 g of nitro compound (01), 6.50 g of ammonium formate and 0.15 g of 10% Pd/C, stir at room temperature for 6.5 hours; then cool the reaction mixture to 0°C, add 1.09 g of sodium borohydride and 3.01 g of NiCl ₂ ·6H ₂ O, after the addition, the temperature was raised to 45°C and stirred for 12 hours. Then the temperature of the reaction mixture was lowered to 0°C-5°C, and aqueous hydrochloric acid was added dropwise to adjust the pH to 1-2. Then the reaction mixture was concentrated under reduced pressure until there was no obvious methanol, extracted with ethyl acetate, washed with saturated brine, dried and concentrated to give lactam compound (02), 3.05 g of light yellow oil; yield 94%, purity 99.10%; Mass spectrum: m/z = 142 [M+1], m/z = 283 [2M+1].

Example 8

In 60 milliliters of methanol, add 5 grams of nitro compound (01), 6.50 grams of ammonium formate and 0.25 grams of 5% Pd/C, stir at room temperature for 6.5 hours; then cool the reaction mixture to 0°C, add 1.84 grams of sodium borohydride and 4.93 grams of SnCl ₂ ·2H ₂ O. The reaction mixture was warmed to 45°C and stirred for 12 hours. Then the temperature of the reaction mixture was lowered to 0°C-5°C, and aqueous hydrochloric acid was added to adjust the pH to 1-2. Then the reaction mixture was concentrated under reduced pressure until there was no obvious methanol, extracted with ethyl acetate, washed with saturated NaCl solution, and the organic layer was dried and concentrated to give lactam compound (02), 3.04 g of light yellow oil; yield 93.6%, purity 99.20%; mass spectrum: m/z = 142 [M+1], m/z = 283 [2M+1].

The descriptions of the above embodiments are only used to help understand the method and core idea of the present invention. It should be pointed out that for those skilled in the art, without departing from the principle of the present invention, some improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (11)

1. A method for preparing 4-isobutyl-2-pyrrolidone, comprising: the nitro compound shown in formula (01) reacts in the presence of a metal halide, and is prepared into 4-isobutyl-2-pyrrolidone shown in (02) 2-pyrrolidone, in: R is halogen, OR ¹ or NR ² R ³ ; R ¹ , R ² and R ³ are each independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, aryl, methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl, wherein said (C1-C6)alkyl, (C3-C6)cycloalkyl or aryl are optionally unsubstituted or substituted by one or more substituents such as halogen, trifluoromethyl, nitro , one or more of cyano, mercapto, and alkylthio. 2. The method according to claim 1, wherein the metal halide is a nickel halide or a hydrate thereof, a copper halide or a hydrate thereof, a tin halide or a hydrate thereof, a cobalt halide or a hydrate thereof , palladium halide or hydrate thereof, or any combination thereof; or the metal halide is NiCl ₂ or hydrate thereof, SnCl ₂ or hydrate thereof, or any combination thereof. 3. The method according to claim 1 or 2, wherein the reaction is carried out in the presence of a reducing agent. 4. The method of claim 3, wherein the reaction is performed in the presence of a metal catalyst. 5. The method according to claim 3 or 4, wherein the reducing agent is formic acid or its salt, metal borohydride, metal hydride, or any combination thereof; or the reducing agent is ammonium formate, sodium formate , formic acid, ammonium acetate, potassium borohydride, sodium borohydride, lithium aluminum hydride, sodium hydride, diisobutylaluminum hydride, dimethylaminoborane, or any combination thereof. 6. The method according to claim 4, wherein the metal catalyst is Pd/C, Pd(OH) ₂ , Pt, Pt/C, Ni, or any combination thereof; or the metal catalyst is Pd/ C, Ni or their combination. 7. according to the method described in any one of claim 1-6, in the process that nitro compound shown in formula (01) is prepared into lactam compound shown in formula (02), reaction solvent is alcoholic solvent, nitriles Solvent, ketone solvent, ether solvent, ester solvent or any combination thereof; The alcohol solvent is methanol, ethanol, isopropanol or any combination thereof; The nitrile solvent is acetonitrile; The ketone The solvent is acetone; the ether solvent is tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether or any combination thereof; the ester solvent is trimethyl orthoformate, triethyl orthoformate or their combination. 8. The method according to claim 7, wherein the reaction solvent is methanol, ethanol or a combination thereof. 9. The method according to any one of claims 2-3, wherein, in the presence of NiCl ₂ , SnCl ₂ , or hydrates thereof, in a solvent, the nitro compound shown in formula (01) is mixed with sodium borohydride or Potassium borohydride reaction prepares the lactam compound shown in formula (02). 10. The method according to any one of claims 2-3, wherein, in the presence of NiCl ₂ , SnCl ₂ , or hydrates thereof, in methanol or ethanol, the nitro compound shown in formula (01) is reacted with hydroboration The lactam compound shown in formula (02) is prepared by reacting sodium or potassium borohydride. 11. The method according to any one of claims 4-8, wherein, in a solvent, the nitro compound shown in formula (01) is first mixed with ammonium formate, potassium borohydride, sodium borohydride or The composition is reacted, and then reacted with potassium borohydride or sodium borohydride in the presence of NiCl ₂ , SnCl ₂ or hydrates thereof to prepare the lactam compound represented by formula (02).