CN111153820A - Method for preparing pregabalin by photocatalysis - Google Patents

Method for preparing pregabalin by photocatalysis Download PDF

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Publication number
CN111153820A
CN111153820A CN201811324050.XA CN201811324050A CN111153820A CN 111153820 A CN111153820 A CN 111153820A CN 201811324050 A CN201811324050 A CN 201811324050A CN 111153820 A CN111153820 A CN 111153820A
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compound
pregabalin
reaction
organic solvent
alkali
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李恩民
姬东方
赵国磊
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Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
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Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/34—Preparation of optical isomers by separation of optical isomers

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Abstract

The invention discloses a preparation method of (3S) -3-aminomethyl-5-methylhexanoic acid (pregabalin), which is characterized by comprising the following steps of: 1) dissolving a compound I and a certain amount of alkali in an organic solvent, adding a compound II, and heating for reaction to obtain a compound III; 2) dissolving a compound III, a compound IV and a photocatalyst in an organic solvent, and preparing a compound V under the illumination condition; 3) and carrying out deprotection, ring opening, chiral resolution and recrystallization on the compound V to obtain the pregabalin. The raw materials used in the method are cheap and easy to obtain, the reaction condition of the photocatalytic oxidation method is mild, and the reagent is environment-friendly and environment-friendly, so that the method is an ideal industrial production process.

Description

Method for preparing pregabalin by photocatalysis
Technical Field
The invention belongs to the technical field of synthetic chemistry, and particularly relates to a method for preparing (S) -3-aminomethyl-5-methylhexanoic acid by photocatalytic oxidation.
Background
Pregabalin, chemical name (3S) -3-aminomethyl-5-methylhexanoic acid, trade name lerecan, is a neurotransmitter GABA (gamma-aminobutyric acid) analog. The structure is as follows:
Figure RE-35758DEST_PATH_IMAGE001
。
pregabalin has been approved in the united states for the adjunctive treatment of adult onset partial diabetic peripheral neuralgia, postherpetic neuralgia, fibromyalgia, and neuropathic pain resulting from spinal cord injury. In 8 months 2003, the registered application was first filed in the united states by the company pfeiri, and in 12 months 2004, the FDA in the united states approved the use of pregabalin for Diabetic Peripheral Neuralgia (DPN) and postherpetic neuralgia (PHN), which is also the first drug to be jointly approved in the united states and europe (7 months 2004) for the treatment of 2 types of neuralgia; in 6 months in 2005, pregabalin was approved as an adjuvant therapy for the treatment of partial seizures; in 6 months 2007, pregabalin continues to be approved by the FDA in the united states as the first drug to treat fibromyalgia syndrome; in 6 months 2012, the FDA approved pregabalin as the first drug for treating neuralgia caused by spinal cord injury. Pregabalin is currently approved for the treatment of neuropathic pain in 40 countries, europe, canada, mexico, and the united states.
At present, many documents and patents report the synthesis of pregabalin, but many routes often use highly toxic cyanide or Grignard reagents with harsh requirements on conditions, so that it is necessary to develop a synthesis method with atom economy, environmental friendliness and mild conditions.
In recent years, photocatalytic oxidation reaction is a green synthesis strategy in organic synthesis due to atom economy, environmental friendliness and mild conditions. The photocatalytic oxidation reaction has been widely used in the pharmaceutical, agricultural and chemical industriesJ. Am. Chem. Soc.2010,132, 1464 ；J. Org. Chem. 2012,77, 4425]
Disclosure of Invention
Based on the problems in the synthesis of pregabalin, the invention aims to provide a novel process which is green, efficient and good in selectivity to replace the traditional process. The invention provides a new green and efficient pregabalin synthesis process by utilizing a photocatalytic oxidation reaction.
The invention discloses a method for preparing (3S) -3-aminomethyl-5-methylhexanoic acid by photocatalytic oxidation, which specifically comprises the following steps:
1) dissolving the compound I and a certain amount of alkali in an organic solvent, adding the compound II, and heating for reaction to obtain a compound III. 2) Dissolving the compound III, the compound IV and the photocatalyst in an organic solvent, and preparing the compound V under the illumination condition. 3) And carrying out deprotection, ring opening, chiral resolution and recrystallization on the compound V to obtain the pregabalin.
As a better choice of the above technical solution, the base in step 1) is sodium hydride, diethylamine and/or pyridine.
As a better choice of the technical proposal, the organic solvent in the step 1) is anhydrous diethyl ether, methyl ethyl ether, anhydrous tetrahydrofuran, 2-methyltetrahydrofuran and/or 1, 4-dioxane.
As a better choice of the above technical solution, the photosensitizer in step 2) is: [ Ir (ppy)2(dtbbpy)]+Or Ir [ dF (CF)3)ppy]2(dtbbpy)+The amount of the photosensitizer is 0.1-20%.
The photocatalyst used above has the following structure:
serial number Shorthand writing Chemical formula (II)
Photocatalyst 1 [Ir(ppy)2(dtbbpy)]+
Figure RE-91438DEST_PATH_IMAGE002
Photocatalyst 2 Ir[dF(CF3)ppy]2(dtbbpy)+
Figure RE-DEST_PATH_IMAGE003
As a better choice of the above technical solution, the photochemical reactor in step 2) is an inner-immersion bubbling photochemical reactor, the inner-immersion bubbling photochemical reactor is made of borosilicate glass, a borosilicate glass jacketed sink well is arranged in the middle, a high-pressure mercury lamp or LED lamp is installed in the sink well, and the jacket is provided with an inlet and an outlet for cooling water.
As a better choice of the above technical scheme, the alkali in the step 2) is CsF and Cs2CO3、K2CO3、Na2CO3、NaHCO3、KHCO3、K2HPO4And/or Na2HPO4。
As a better choice of the technical proposal, the alkali is K2HPO4 and/or Na2HPO4。
As a better choice of the above technical solution, the wavelength range used by the photocatalytic reaction in step 2) is greater than 400 nm.
As a better choice of the technical proposal, the alkali used in the step 3) is NaOH and/or KOH, and the acid used is HCl and/or H2SO4。
As a better choice of the technical scheme, the pH value of the acid is adjusted to be 6.0-7.5 under the alkaline condition in the step 3).
As a better choice of the technical scheme, the pH value is adjusted to be 6.4-7.0.
As a better choice of the above technical scheme, the chiral resolving agent in step 3) is (S) - (+) -mandelic acid.
As a better choice of the above technical solution, the method further comprises: and after obtaining a crude product, purifying the crude product by adopting a recrystallization method, wherein the mixed solvent is isopropanol-water, the temperature is 75-85 ℃, the ice salt bath is used for crystallizing for 1 hour, and filtering to obtain the pregabalin.
As a better choice of the technical proposal, the volume ratio of the isopropanol to the water during the recrystallization is 5:1, 3:1 and/or 3: 1.
As a better choice of the technical proposal, the inorganic salt used by the ice salt bath is NaCl or CaCl2And the crystallization temperature is-5 to 0 ℃.
The key point of the invention is that the photocatalytic oxidation reaction is applied to the preparation of (3S) -3-aminomethyl-5-methylhexanoic acid, so that the reaction can be smoothly carried out under mild conditions, and the use of highly toxic reagents is avoided. The method has mild reaction conditions, and the reagent is environment-friendly and environment-friendly, thereby being an ideal industrial production process.
Detailed Description
The following are examples of the present invention, which are intended to be illustrative of the invention only and not limiting.
Example 1
The reaction scheme of the examples is as follows:
Figure RE-111347DEST_PATH_IMAGE004
1) adding 200mL of anhydrous tetrahydrofuran and 33mL of pyridine into a reaction bottle in sequence, cooling the mixture to-5-0 ℃ in an ice salt bath, stirring the mixture, dropwise adding 22.4g of a compound II, and heating the mixture to 35-45 ℃ to react for 1h after the dropwise adding is finished. And cooling the reaction liquid to-5-0 ℃ in an ice salt bath, dropwise adding 8.6g of isovaleraldehyde, continuously keeping the low temperature for 1 hour after dropwise adding, then heating to 45 ℃ and reacting for 1 hour. After cooling to room temperature, 100 mL of water was added, and extraction was performed 3 times with 150mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give 14.1g of a colorless liquid with a yield of 90%.
2) 0.6g Ir dF (CF) was added into an in-line bubbling photochemical reactor3)ppy]2(dtbbpy)+10.5g of Compound IV, 11.5g K2HPO411.5g of Compound III, 200mL of DMF, with constant bubbling of gas. And (3) illumination, wherein the reaction temperature is controlled to be 10-30 ℃ in the reaction process, and the illumination time is 5 h. After the reaction is finished, removing the solvent by rotary evaporation, separating and purifying the product by a silica gel column, wherein an eluent is n-hexane: ethyl acetate was 10:3, giving 16.6g of a pale yellow oil in 88.0% yield.
3) Adding 8.0g of sodium hydroxide into a 250mL three-neck round-bottom flask, adding 150mL of water, stirring and dissolving in an ice-water bath, adding 16.6g of a compound V, heating and refluxing for 12 hours, stopping heating, cooling to room temperature, adjusting the pH to about 7.0 by using 6M HCl, cooling to-5-0 ℃ by using an ice-salt bath, preserving heat and crystallizing for 1 hour, separating out a large amount of white solids, and filtering to obtain 7.8g of a filter cake, namely a crude pregabalin racemate. Adding the crude product into a 250mL three-neck round-bottom flask, adding 180mL isopropanol and 60mL water, adding 8.0g of (S) - (+) -mandelic acid, heating to 75 ℃, continuously refluxing for 30min after the system is dissolved, slowly cooling to room temperature, crystallizing at 0 ℃ for 1h, filtering, adding the obtained solid into a mixed system of THF (120 mL) and water (10 mL), heating and refluxing for 1h, cooling, crystallizing at-5-0 ℃ for 1h, filtering to obtain a white solid, continuously recrystallizing with isopropanol-water (volume ratio of 3: 1), cooling, crystallizing, and filtering to obtain 3.2g of the white solid with the yield of 41.0%.
Example 2
The reaction scheme of the examples is as follows:
Figure RE-265336DEST_PATH_IMAGE005
1) adding 200mL of anhydrous tetrahydrofuran and 33mL of pyridine into a reaction bottle in sequence, cooling the mixture to-5-0 ℃ in an ice salt bath, stirring the mixture, dropwise adding 16.0g of a compound II, and heating the mixture to 35-45 ℃ to react for 1h after the dropwise adding is finished. And cooling the reaction liquid to-5-0 ℃ in an ice salt bath, dropwise adding 8.6g of isovaleraldehyde, continuously keeping the low temperature for 1 hour after dropwise adding, then heating to 45 ℃ and reacting for 1 hour. After cooling to room temperature, 100 mL of water was added, and extraction was performed 3 times with 150mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give 19.8g of a colorless liquid with a yield of 86.8%.
2) 1.2g Ir dF (CF) was added to an internally immersed bubbling photochemical reactor3)ppy]2(dtbbpy)+10.6g of Compound IV, 11.5g K2HPO413.7g of Compound III, 200mL of DMF, with the gas being kept bubbling. And (3) illumination, wherein the reaction temperature is controlled to be 10-30 ℃ in the reaction process, and the illumination time is 5 h. After the reaction is finished, removing the solvent by rotary evaporation, separating and purifying the product by a silica gel column, wherein an eluent is n-hexane: ethyl acetate was 10:3, giving 16.8g of a pale yellow oil in 89.0% yield.
3) Adding 8.0g of sodium hydroxide into a 250mL three-neck round-bottom flask, adding 150mL of water, stirring and dissolving in an ice-water bath, adding 16.8g of a compound V, heating and refluxing for 12 hours, stopping heating, cooling to room temperature, adjusting the pH to about 7.0 by using 6M HCl, cooling to-5-0 ℃ by using an ice-salt bath, preserving heat and crystallizing for 1 hour, separating out a large amount of white solids, and filtering to obtain 7.7g of a filter cake, namely a crude pregabalin racemate. Adding the crude product into a 250mL three-neck round-bottom flask, adding 180mL isopropanol and 60mL water, adding 8.0g of (S) - (+) -mandelic acid, heating to 75 ℃, continuously refluxing for 30min after the system is dissolved, slowly cooling to room temperature, crystallizing at 0 ℃ for 1h, filtering, adding the obtained solid into a mixed system of THF (120 mL) and water (10 mL), heating to reflux for 1h, cooling, crystallizing at-5-0 ℃ for 1h, filtering to obtain a white solid, continuously recrystallizing with isopropanol-water (volume ratio of 3: 1), cooling, crystallizing, and filtering to obtain 3.5g of the white solid with the yield of 45.5%.
Example 3
The reaction scheme of the examples is as follows:
Figure RE-969298DEST_PATH_IMAGE007
1) adding 200mL of anhydrous tetrahydrofuran and 33mL of pyridine into a reaction bottle in sequence, cooling the mixture to-5-0 ℃ in an ice salt bath, stirring the mixture, dropwise adding 16.0g of a compound II, and heating the mixture to 35-45 ℃ to react for 1h after the dropwise adding is finished. And cooling the reaction liquid to-5-0 ℃ in an ice salt bath, dropwise adding 8.6g of isovaleraldehyde, continuously keeping the low temperature for 1 hour after dropwise adding, then heating to 45 ℃ and reacting for 1 hour. After cooling to room temperature, 100 mL of water was added, and the mixture was extracted 3 times with 150mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give 20.7g of a colorless liquid with a yield of 90.8%.
2) 1.2g Ir dF (CF) was added to an internally immersed bubbling photochemical reactor3)ppy]2(dtbbpy)+10.6g of Compound IV, 11.5g K2HPO413.8g of Compound III, 200mL of DMF, with the gas being kept bubbling. And (3) illumination, wherein the reaction temperature is controlled to be 10-30 ℃ in the reaction process, and the illumination time is 5 h. After the reaction is finished, removing the solvent by rotary evaporation, separating and purifying the product by a silica gel column, wherein an eluent is n-hexane: ethyl acetate was 10:3, giving 16.8g of a pale yellow oil in 89.0% yield.
3) Adding 8.0g of sodium hydroxide into a 250mL three-neck round-bottom flask, adding 150mL of water, stirring and dissolving in an ice-water bath, adding 16.8g of a compound V, heating and refluxing for 12 hours, stopping heating, cooling to room temperature, adjusting the pH to about 7.0 by using 6M HCl, cooling to-5-0 ℃ by using an ice-salt bath, preserving heat and crystallizing for 1 hour, separating out a large amount of white solids, and filtering to obtain 7.7g of a filter cake, namely a crude pregabalin racemate. Adding the crude product into a 250mL three-neck round-bottom flask, adding 180mL isopropanol and 60mL water, adding 7.9g of (S) - (+) -mandelic acid, heating to 75 ℃, continuously refluxing for 30min after the system is dissolved, slowly cooling to room temperature, crystallizing at 0 ℃ for 1h, filtering, adding the obtained solid into a mixed system of THF (120 mL) and water (10 mL), heating to reflux for 1h, cooling, crystallizing at-5-0 ℃ for 1h, filtering to obtain a white solid, continuously recrystallizing with isopropanol-water (volume ratio of 3: 1), cooling, crystallizing, and filtering to obtain 3.6g of the white solid with the yield of 46.8%.

Claims (10)

1. A method for preparing (3S) -3-aminomethyl-5-methylhexanoic acid (pregabalin) using photocatalytic oxidation, comprising:
1) dissolving the compound I and a certain amount of alkali in an organic solvent, adding the compound II, and heating for reaction to obtain a compound III. 2) Dissolving the compound III, the compound IV and the photocatalyst in an organic solvent, and preparing the compound V under the illumination condition. 3) Carrying out deprotection, ring opening, chiral resolution and recrystallization on the compound V to obtain pregabalin;
Figure RE-620046DEST_PATH_IMAGE001
wherein R is1Is CHO, COOMe, COOEt, COOPr or COOBu, R2Is COOMe, COOEt, COOPr, COOBu or COOBn, R3Is H, (C)2H5O)2PO or the same as R2. R4Cbz, Boc or Bz.
2. The method of claim 1, wherein: the alkali in the step 1) is sodium hydride, diethylamine and/or pyridine.
3. The method of claim 1, wherein: the organic solvent in the step 1) is anhydrous diethyl ether, methyl ethyl ether, anhydrous tetrahydrofuran, 2-methyltetrahydrofuran and/or 1, 4-dioxane.
4. The method of claim 1, wherein: the photosensitizer in the step 2) is as follows:
[Ir(ppy)2(dtbbpy)]+or Ir [ dF (CF)3)ppy]2(dtbbpy)+The amount of the photosensitizer is 0.1-20%.
5. The method of claim 1, wherein: the light source in the step 2) is an LED lamp, an incandescent lamp, a high-pressure mercury lamp and/or a fluorescent lamp.
6. The method of claim 1, wherein: the alkali in the step 2) is CsF and Cs2CO3、K2CO3、Na2CO3、NaHCO3、KHCO3、K2HPO4And/or Na2HPO4。
7. The method of claim 1, wherein: the wavelength used by the photocatalytic reaction in the step 2) is more than 400 nm.
8. The method of claim 1, wherein: and 3) adjusting the pH value of the acid to be 6.0-7.5 under the alkaline condition.
9. The method of claim 1, wherein: the chiral resolving agent in the step 3) is (S) - (+) -mandelic acid.
10. The method of claim 1, wherein: the solvent used for recrystallizing the crude pregabalin product is isopropanol and water, and the volume ratio of the isopropanol to the water is 3:1, 5:1 and/or 1: 1.
CN201811324050.XA 2018-11-08 2018-11-08 Method for preparing pregabalin by photocatalysis Pending CN111153820A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104140375A (en) * 2014-05-16 2014-11-12 南通常佑药业科技有限公司 Preparation method of pregabalin
CN105061235A (en) * 2015-08-18 2015-11-18 太仓运通生物化工有限公司 Method for synthesizing Pregabalin
CN107857710A (en) * 2017-11-23 2018-03-30 河南师范大学 A kind of preparation method of antiepileptic Pregabalin
CN108358799A (en) * 2018-04-24 2018-08-03 贵州师范大学 A kind of preparation method of Pregabalin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104140375A (en) * 2014-05-16 2014-11-12 南通常佑药业科技有限公司 Preparation method of pregabalin
CN105061235A (en) * 2015-08-18 2015-11-18 太仓运通生物化工有限公司 Method for synthesizing Pregabalin
CN107857710A (en) * 2017-11-23 2018-03-30 河南师范大学 A kind of preparation method of antiepileptic Pregabalin
CN108358799A (en) * 2018-04-24 2018-08-03 贵州师范大学 A kind of preparation method of Pregabalin

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHU, LINGLING 等: "Carboxylic Acids as A Traceless Activation Group for Conjugate Additions: A Three-Step Synthesis of (±)-Pregabalin", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 *

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Application publication date: 20200515