WO2014005494A1

WO2014005494A1 - Method of preparing lactam compound

Info

Publication number: WO2014005494A1
Application number: PCT/CN2013/078258
Authority: WO
Inventors: Fang He; Yaobin ZHANG; Jingping KOU
Original assignee: Sunshine Lake Pharma Co., Ltd.
Priority date: 2012-07-02
Filing date: 2013-06-28
Publication date: 2014-01-09
Also published as: CN104395286A

Abstract

Provided is a method of preparing pregabalin and its important intermediate lactam compound. This method does not use hydrogen or high pressure equipment. By a convenient process, high purity of product can be obtained from selecting the proper catalyst and reducing agent with normal equipments. This method is convenient, safe and is of high yield, which is suitable for industry manufacture.

Description

A METHOD OF PREPARING A LACTAM COMPOUND

FIELD OF THE INVENTION

[001] The present invention relates to a method of preparing pregabalin and the intermediate lactam compound.

BACKGROUD OF THE INVENTION

[002] Pregabalin has activities of analgesia, anticonvulsive and antianxiety, and can be used in preventing epilepsy.

[003] The lactam compound, 4-isobutyl-2- pyrrolidinone (02) is a key intermediate in the synthesis of pregabalin. A convenient process to get 4-isobutyl-2- pyrrolidinone (02) is very important for the preparation of pregabalin.

(02)

[004] There are many methods for the preparation of 4- isobutyl-2- pyrrolidinone in prior art. For example, the patent application CN20091026661.8 or WO2006110783 discloses a related method of preparation of 4- isobutyl-2- pyrrolidinone. But these methods relate to using hydrogen (¾) and/or high pressure equipments or using other reactants to go through many steps to obtain the product with long reaction time, tedious processes and/or existing dangerous factors. Therefore, a safe method with lower requirements of equipment, convenient process and higher yield is required for industry manufacture.

SUMMARY OF THE INVENTION

[005] Provided herein is a method of preparing pregabalin, comprises: transforming the nitro compound (01) to 4- isobutyl-2- pyrrolidinone (02), then hydro lyzing and resolving compound (02) to give pregabalin (03),

(01 ) (02) (03) [006] wherein R is halo, OR 1 or NR 2 R 3 ; each of R 1 , R2 and R 3 is independently hydrogen, (C l -C6)alkyl, (C3-C6)cycloalkyl, aryl, methanesulfonyl, benzenesulfonyl and 4-methyl benzenesulfonyl, wherein the (C I - C6)alkyl, (C3 - C6)cycloalkyl or aryl is optionally unsubstituted or substituted with one or more substituents; wherein the (C I - C6)alkyl is but not limited to methyl, ethyl, i-propyl, t-butyl, etc; the (C3 - C6)cycloalkyl is but not limited to cyclopropyl, cyclohexyl; the aryl is but not limited to phenyl, tolyl; and halo is fluo, chloro, bromo or iodo; wherein each of the substituents is but not limited to one or more of halo, trifluoromethyl, nitro, cyano, thio, or alkylthio.

[007] Provided herein is a method of preparing a lactam compound (02), which doesn't use hydrogen (¾) and/or high pressure equipments and just uses convenient steps to get the lactam compound (02). The method comprises transforming a nitro compound of formula (01) to 4-isobutyl-2-pyrrolidinone of formula (02) in the presence of a metal halide compound,

(01 ) (02)

wherein R is as defined above.

[008] The nitro compound (01) can be prepared by a known method such as reported by Li Jing, et al. Chinese Journal of Medicinal Chemistry. 2007, volume 17, issue 1.

[009] In some embodiments, the method of preparing the lactam compound (02) from the nitro compound (01) comprises: in the presence of a metal halide compound, the nitro compound (01) is transformed to the lactam compound (02) through an intermediate (l - l),

(01 ) (l-l) (02) or in some embodiments, the nitro compound (01) is transformed to the lactam compound (02) through an intermediate(I-II ), wherein the R of formula (I-II ) is as defined above,

(01 ) ₍|__N) (02)

[0010] In the process of transforming of the nitro compound (01) into the lactam compound (02), the intermediate (I-I) or (I-II) can be separated or not. In some embodiments, the intermediate is not separated.

[0011] In some embodiments, besides of a metal halide compound, a reducing agent also is used in the transformation of the nitro compound (01) to the lactam compound (02).

[0012] In some embodiments, besides of a metal halide, a reducing agent and a metal catalyst can be used in the transformation of the nitro compound (01) to the lactam compound (02).

[0013] In some embodiments, the nitro compound (01) is transformed to the lactam compound (02) by using a reducing agent in the presence of a metal halide; or the nitro compound (01) is reacted with a metal catalyst and a reducing agent, then transformed to the lactam compound (02) by using a reducing agent in the presence of a metal halide.

[0014] In some embodiments, the metal halide is nickel halide, copper halide, tin halide, cobalt halide, or palladium halide, or their hydrate, or a combination thereof. In other embodiments, the metal halide is nickel halide, tin halide, or their hydrate, or a combination thereof. In some embodiments, the nickel halide is nickel chloride (NiCl₂), nickel chloride dihydrate (ΝίΟ₂·2Η₂0), nickel chloride hexahydrate (NiCl₂ -6H₂0), nickel bromide (NiBr₂), nickel bromide trihdyrate (NiBr₂-3H₂0), or a combination thereof; the copper halide is cuprous iodide (Cul), cupros bromide (CuBr) or a

combination thereof; the tin halide is stannous chloride dihydrate (SnCl₂"2H₂0), stannous chloride (SnCl₂), or a combination thereof; the cobalt halide is cobalt chloride (CoCl₂) or its hydrate; and the palladium halide palladium chloride (PdCl₂).

[0015] In some embodiments, the reducing agent is formic acid or its salt, a metal borohydride reagent, a metal hydride reagent, or a 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, diisobutyl aluminium hydride, dimethylaminoborane, or a combination thereof. In some embodiments, the reducing agent is ammonium formate, potassium borohydride, sodium borohydride, or a combination thereof. In some embodiments, the reducing agent is potassium borohydride, sodium borohydride, or a combination thereof.

[0016] In some embodiments, the metal catalyst is palladium-carbon (Pd/C), palladium hydroxide (Pd(OH)₂), platinum (Pt), platinum-carbon (Pt/C), nickel (Ni) catalyst, or a combination thereof. In other embodiments, the metal catalyst is palladium-carbon catalyst (Pd/C). In some embodiments, the metal catalyst is nickel catalyst (Ni).

[0017] The molar ratio of the nitro compound (01) to the metal halide is from 1 :0.1 to 1 :2.0. In some embodiments, the ratio is from 1 :0.3 to 1 : 1.0. In some embodiments, the ratio is froml :0.3 to 1 :0.8.

[0018] The molar ratio of the nitro compound (01) to the reducing agent is froml :0.5 to 1 :6. In some embodiments, the ratio is from 1 : 1.0 to 1 :6. In some embodiments, the ratio is from 1 : 1.1 to 1 :4.5. In some embodiments, the ratio is from 1 : 1.3 to 1 :4.5. In other embodiments, the ratio is froml : 1.3 to 1 : 1.4.

[0019] The weight ratio of the nitro compound (01) to the metal catalyst is from 1 :0.01 to 1 :0.2. In some embodiments, the ratio is from 1 :0.01 to 1 :0.1. In other embodiments, the ratio is froml :0.01 to 1 :0.05.

[0020] In some embodiments, after complete reaction, the pH value of the reaction mixture is controlled to eliminate the excess reactant to be lower than 6, or lower than 5, or lower than 4.5, or lower than 4. In some embodiments, the pH is controlled at 2-3 with aqueous hydrochloric acid solution. In some embodiments, the pH is 1 -2.

[0021] In the process of transforming of the nitro compound (01) to the lactam compound (02), the reaction solvent is an alcohol solvent, a nitrile solvent, a ketone solvent, an ether solvent, an ester solvent, or a combination thereof. The alcohol solvent is methanol, ethanol, i-propanol or a combination thereof; the nitrile solvent is acetonitrile; the ketone solvent is ketone; the ether solvent is tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether or a combination thereof; and the ester solvent is trimethyl orthoformate, triethyl orthoformate or a combination thereof. In some embodiments, the reaction solvent is methanol, ethanol, trimethyl orthoformate or a combination thereof.

[0022] In the process of transforming of the nitro compound (01) to the lactam compound (02), the reaction temperature is from -40 °C to 65 °C. In some embodiments, the reaction temperature is from 0 °C to 45 °C. The reaction time is from 0.5 hour to 20 hours.

[0023] In some embodiments, the method that the nitro compound (01) is transformed to the lactam compound (02) comprises: reacting the nitro compound (01) with sodium borohydride in a solvent in the presence of NiCl₂ to give the lactam compound (02).

[0024] In some embodiments, the nitro compound (01) is reacted with ammonium formate, potassium borohydride, sodium borohydride or a combination in the presence of Pd/C, then reduced by potassium borohydride or sodium boro hydride in the presence of NiCl₂ or SnCl₂ to get the lactam compound (02).

[0025] In the present invention, all numbers disclosed herein are approximate values, regardless whether the word "about" or "approximate" is used in connection

therewith. The value of each number may differ by 1 %, 2%, 5%, 7%, 8%, 10%, 15% or 20%. Therefore, whenever a number having a value N is disclosed, any number having the value N+/-l %, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8%, N+/-10%, N+/-15% or N+/-20% is specifically disclosed, wherein "+/-" refers to plus or minus. Whenever a numerical range with a lower limit, AL, and an upper limit, AU, is disclosed, any number falling within the range is specifically disclosed. In particular, the following numbers within the range are specifically disclosed: A=AL+k*(AU-AL), wherein k is a variable ranging from 1% to 100% with a 1 % increment, i.e., k is 1 %, 2%, 3%, 4%, 5%,..., 50%, 51%, 52%,..., 95%, 96%, 97%, 98%, 99%, or 100%. Moreover, any numerical range defined by two R numbers as defined above is also specifically disclosed.

Examples

[0026] For further understanding of the present invention, disclosed herein is detailed description of the present invention with the examples.

[0027] In the following examples, R is ethoxy. If R is other group, please reference the following examples to obtain the lactam compound (02).

Example 1

[0028] To a solution of methanol (600 mL) were added 50.00 g nitro compound (01) and NiCl₂ 6H₂0 (18.04g). The solution was cooled to 0 ^aC - 5 °C, and sodium borohydride (18.2 g) was added. After addition, it was heated to 40 °C - 45 °C and stirred for 12 hours. Then the mixture was cooled to room temperature and an aqueous solution of

hydrochloride was added to adjust the pH of the solution to 2-3. The reaction mixture was concentrated until no obvious methanol was detected by gas chromatography (GC). The concentrate was extracted with ethyl acetate and the organic phase was washed with water, dried and concentrated to give the lactam compound (02), light yellow oil (31.20 g, yield 96.0%, purity 99.10%). Mass spectrum: m/z=142 [M+l ], m/z=283 [2M+1]; NMR spectrum: (CDC1₃, 400 MHz) 0.91 (m, 6H), 1.33(m,2H), 1.61 (m, lH), 1.99(m, lH),

2.17(m, lH), 2.44(m, lH), 3.01(m, lH), 3.50(m, lH), 6.71 (br, 1H).

Example 2 [0029] A solution of 50.00 g nitro compound (01) in methanol (600 mL) was cooled to -15°C. Then potassium borohydride (22.05g) and NiCl₂ 6H₂0 (10.93 g) were added.

After addition, the solution was heated to 45 °C and stirred for 12 hours. Then the mixture was cooled to 0°C-5°C and an aqueous solution of hydrochloride was added to adjust the pH of the solution to 2-3. The reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated to give the lactam compound (02), light yellow oil (32.00 g, yield 98.5%, purity 96.50%; Mass spectrum: m/z=142 [M+l], m/z=283 [2M+1]).

Example 3

[0030] To a solution of methanol (500 mL) were added 50.00 g nitro compound (01) and NiBr₂ ^'3H₂0 (31.35 g). The solution was cooled to -5°C, and sodium hydride (27.50 g) was added. After addition, it was heated to 40^*C - 45^*0 and stirred for 10 hours. Then the mixture was cooled to 0°C-5°C and an aqueous solution of hydrochloride was added to adjust the pH of the solution to 2-3. The reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated to give the lactam compound (02), light yellow oil (31.1 Og, yield 95.7%, purity 99.11 %; Mass spectrum: m/z=142 [M+l ], m/z=283 [2M+1]).

Example 4

[0031] To a solution of methanol (900 mL) were added 50.00 g nitro compound (01) and NiCl₂ ^'6H₂0 (24.65g). The solution was cooled to 0°C - 5^*C, and sodium borohydride (18.20 g) was added. After addition, it was heated to 40°C - 45°C and stirred for 10 hours. Then the mixture was cooled to 5°C-25°C and an aqueous solution of hydrochloride was added to adjust the pH of the solution to 2-3. The reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated to give the lactam compound (02), light yellow oil (31.22 g, yield 96.0%, purity 99.11 %; Mass spectrum: m/z=142 [M+l ], m/z=283 [2M+1]).

Example 5

[0032] To a solution of methanol (600 mL) were added 50.00 g nitro compound (01) and SnCl₂ ^'2H₂0 (5.20 g). The solution was cooled to 0° C- 5°C, and sodium borohydride (18.20 g) was added. After addition, it was heated to 40 °C - 45°C and stirred for 10 hours. Then the mixture was cooled to 5°C- 15°C and an aqueous solution of

hydrochloride was added to adjust the pH of the solution to 2- 3. The reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried and concentrated to give the lactam compound (02), light yellow oil (31.30 g, yield 96.4%, purity 99.10%; Mass spectrum: m/z=142 [M+l ], m/z=283 [2M+1]).

Example 6

[0033] To a solution of ethanol (50 mL) were added 5 g nitro compound (01), ammonium formate (6.50 g) and 5%> Pd/C (0.25 g). The solution was stirred at room temperature for 6.5 hours and filtered. The filtrate was concentrated and exacted with ethyl acetate. The organic phase was washed with water, dried and concentrated to give yellow oil (3.30 g). The oil was dissolved in methanol (40 mL) and cooled to -10°C. Then potassium borohydride (2.51 g) and NiCl₂ 6H₂0 (1.37 g) were added. The mixture was heated to 45°C and stirred for 12 hours. Then the mixture was cooled to -5°C-0°C and an aqueous solution of hydrochloride was added to adjust the pH of the solution to 1 -2. The reaction mixture was concentrated until no obvious methanol was detected by GC. Then it was extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated to give the lactam compound (02), light yellow oil (2.71 g, yield 82.6%>, purity 99.12%; Mass spectrum: m/z=142 [M+l ], m/z=283 [2M+1]).

Example 7

[0034] To a solution of methanol (60 mL) were added 5 g nitro compound (01),

ammonium formate (6.5 Og) and 10%Pd/C (0.15 g). The solution was stirred at room temperature for 6.5 hours and cooled to 0°C. Then sodium borohydride (1.09 g) and NiCl₂ ^'6H₂0 (3.01 g) were added. The mixture was heated to 45°C and stirred for 12 hours. Then the mixture was cooled to 0°C-5°C and an aqueous solution of hydrochloride was added to adjust the pH of the solution to 1 -2. The reaction mixture was concentrated until no obvious methanol was detected. Then it was extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated to give the lactam compound (02), light yellow oil (3.05 g, yield 94%, purity 99.12%; Mass spectrum: m/z=142 [M+l], m/z=283 [2M+1]).

Example 8

[0035] To a solution of methanol (60 mL)were added 5 g nitro compound (01),

ammonium formate (6.50 g) and 5%Pd/C (0.25 g). The solution was stirred at room temperature for 6.5 hours and cooled to 0°o. Then sodium borohydride (1.84 g) and SnCl₂ ^'2H₂0 (4.93 g) were added. The mixture was heated to 45°C and stirred for 12 hours. Then the mixture was cooled to 0°C-5°C and an aqueous solution of hydrochloride was added to adjust the pH of the solution to 1 -2. The reaction mixture was concentrated until no obvious methanol was detected. Then it was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried and concentrated to give the lactam compound (02), light yellow oil (3.04 g, yield 93.6%, purity 99.20%; Mass spectrum: m/z=142 [M+l], m/z=283 [2M+1]).

[0036] All above embodiments are just to help understanding the method of the present invention ant its core ideology. A skilled artisan in the field can conduct some

improvements and modifications without departing from the premise of principle of the present invention, which are also deemed to be within the scope of the present invention.

Claims

What is claimed is:

1. A method for preparing 4-isobutyl-2-pyrrolidinone comprising: preparing

4-isobutyl-2-pyrrolidinone of formula (02) with a nitro compound of formula (01)

presence of a metal halide,

(01 ) (02) wherein Ris halo, OR 1 or NR 2 R 3 ; each of R 1 , R2 and R 3 is independently hydrogen,

(Cl-C6)alkyl, (C3-C6)cycloalkyl, aryl, methanesulfonyl, benzenesulfonyl or 4-methyl benzenesulfonyl, wherein the (Cl-C6)alkyl, (C3-C6)cycloalkyl or aryl is optionally unsubstituted or substituted with one or more substituents, wherein each of the substituents is one or more of halo, trifluoromethyl, nitro, cyano, thio, alkylthio.

2. The method of claim 1, wherein the metal halide is nickel halide or its hydrate, copper halide or its hydrate, tin halide or its hydrate, cobalt halide or its hydrate, palladium halide or its hydrate, or a combination thereof; or wherein the metal halide is NiC12 or its hydrate, SnC12 or its hydrate, or a combination thereof.

3. The method of claim 1 or 2, wherein the reaction proceeds in the presence of a reducing agent.

4. The method of claim 3, wherein the reaction proceeds in the presence of a metal catalyst.

5. The method of claim 3 or 4, wherein the reducing agent is formic acid or its salt, a metal borohydride reagent, a metal hydride reagent or a combination thereof; or wherein the reducing agent is ammonium formate, sodium formate, formic acid, ammonium acetate, potassium borohydride, sodium borohydride, lithium aluminum hydride, sodium hydride, diisobutyl aluminium hydride, dimethylaminoborane or a combination thereof.

6. The method of claim 4, wherein the metal catalyst is Pd/C, Pd(OH)2, Pt, Pt/C, Ni or a combination thereof; or wherein the metal catalyst is Pd/C, Ni or a combination thereof.

7. The method of any one of claims 1-6, wherein in the transformation process of nitro compound (01) to the lactam compound (02), the reaction solvent is an alcohol solvent, a nitrile solvent, a ketone solvent, an ether solvent, an ester solvent, or a combination thereof; wherein the alcohol solvent is methanol, ethanol, i-propanol or a combination thereof; the nitrile solvent is acetonitrile; the ketone solvent is ketone; the ether solvent is tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether or a combination thereof; the ester solvent is trimethyl orthoformate, triethyl orthoformate or a combination thereof.

8. The method of claim 7, wherein the reaction solvent is methanol, ethanol or a combination thereof.

9. The method of any one of claims 2-3, wherein the nitro compound (01) is reacted with sodium borohydride or potassium borohrdride in a solvent to prepare the lactam compound (02) in the presence of NiC12, SnC12, or a hydrate thereof.

10. The method of any one of claims 2-3, wherein the nitro compound (01) is reacted with sodium borohydride or potassium borohrdride in methanol or ethanol to prepare the lactam compound (02) in the presence of NiC12, SnC12, or a hydrate thereof.

11. The method of any one of claims 4-8, wherein the nitro compound (01) is reacted with ammonium formate, potassium borohydride, sodium borohydride or a

combination in the presence of Pd/C, then it is reacted with potassium borohydride or sodium borohydride in the presence of NiC12, SnC12, or a hydrate thereof to prepare the lactam compound (02).