CN109503401A - A kind of preparation method of Pregabalin - Google Patents
A kind of preparation method of Pregabalin Download PDFInfo
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- CN109503401A CN109503401A CN201811571064.1A CN201811571064A CN109503401A CN 109503401 A CN109503401 A CN 109503401A CN 201811571064 A CN201811571064 A CN 201811571064A CN 109503401 A CN109503401 A CN 109503401A
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- 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
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- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/005—Amino acids other than alpha- or beta amino acids, e.g. gamma amino acids
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Abstract
The present invention provides a kind of preparation methods of Pregabalin, using Pregabalin raceme as starting material, Pregabalin chiral ester are made under the action of lipase, the Pregabalin chiral ester obtains Pregabalin through hydrolysis.The purity is high of Pregabalin obtained by the preparation method of Pregabalin of the present invention, preparation method is easy to operate, also safer environmental protection.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology more particularly to a kind of preparation methods of Pregabalin.
Background technique
Pregabalin is a kind of analog of neurotransmitter GABA, is the subsequent product of Gabapentin.The work of Pregabalin
It is similar to Gabapentin with mechanism, the effects of anticonvulsion and analgesic is shown in different animal models, but detailed effect
Mechanism is unclear.Pregabalin is similar to neurotransmitter GABA in structure, but directly plays work not by GABA mechanism
With, while this product is different from traditional antiepileptic and does not make mutually with GABAA or GABAB receptor in Valid concentration
With not being metabolized to GABA or gaba agonist, do not inhibit the intake and degradation of GABA yet, do not act on sodium, calcium channel and right
The release and intake of glutamate.Pregabalin does not show the parent with glutamic acid, GABA isoreactivity amino acid receptor simultaneously
And effect, but Pregabalin can replace the combination of GABA and calcium channel α 2, the Asia δ receptor by marking, inhibit maincenter mind
A kind of subunit α 2- δ albumen through system voltage dependent calcium channel reduces flow of calcium ions, to reduce glutamate, go first
The release of the excitatory neurotransmitters such as adrenaline and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, and influencing GABA can neurotransmission.Furthermore Pregabalin can be significant
Increase the level of GABA in vivo, the activity of glutamate decarboxylase can significantly be enhanced by increasing Pregabalin taking dose.
In the U.S., Pregabalin has been approved for adult's partial seizures diabetic peripheral nerve pain, band-like blister
The adjuvant treatment of neurogenic pain caused by rash post herpetic neuralgia, fibromyalgia and spinal cord injury.In August, 2003, Pfizer
Company proposes application for registration, in December, 2004 in the U.S. first, and U.S. FDA is ratified Pregabalin being used for diabetic peripheral
Neuralgia (DPN) and post-herpetic neuralgia (PHN), this is also that certification is used for US and European (in July, 2004) jointly
Treat 2 kinds of neuralgic first drugs；In June, 2005, Pregabalin are certified again as the auxiliary for the treatment of part epileptic attack
Help therapeutic agent；In June, 2007, Pregabalin continue to be approved by the FDA in the United States the medicine as first treatment fibromyalgia syndrome
Object；In June, 2012, FDA approval Pregabalin become first for treating neuralgic drug caused by spinal cord injury.
The preparation method of Pregabalin mainly has asymmetric syntheses and chemical resolution two types, and chemical resolution is to work as this life
The main stream approach of production, but yield is low, and reaction condition is violent, develops mild method for splitting with important application value.
Summary of the invention
It is an object of the invention to disclose a kind of preparation method of Pregabalin, the preparation method of Pregabalin is improved
Water solubility, convenient for the clinical expansion of drug.
To achieve the above object, the present invention provides a kind of preparation methods of Pregabalin, and the structural formula of Pregabalin is such as
Shown in lower:
Wherein, Pregabalin shown in structure above the preparation method comprises the following steps: using Pregabalin raceme as starting material,
Pregabalin chiral ester is made under the action of lipase, the Pregabalin chiral ester obtains Pregabalin through hydrolysis.
Further, the structural formula of Pregabalin chiral ester is as follows:
Wherein, it is methyl, ethyl or isopropyl that R, which is selected from,.
Further, the reaction process of Pregabalin chiral ester are as follows: solvent and Pregabalin raceme is added in reaction flask, so
After be added lipase, constant-temperature table, 200rpm reacts for 24 hours, filters, and silica gel column chromatography is concentrated in filtrate, collects corresponding eluent, dense
Pregabalin chiral ester is obtained after contracting.
Further, solvent is ethyl alcohol or isopropanol.
Further, the reaction process of Pregabalin are as follows: Pregabalin chiral ester and hydrolysising solvent is added in reaction flask, stirs
It mixes, is dissolved after concentration and dry, recrystallized through organic solvent, obtain Pregabalin.
Further, hydrolysising solvent includes one of sulfuric acid, hydrochloric acid or sodium hydroxide or two or more any ratios
The mixture of example.
Further, hydrolysising solvent include one of ethyl acetate, methylene chloride or tetrahydrofuran or two kinds with
The mixture of upper arbitrary proportion.
Further, organic solvent is the mixture of ethyl alcohol and acetone.
Compared with prior art, the beneficial effects of the present invention are: improving the purity of Pregabalin, preparation method safety
It is environmentally friendly, easy to operate.
Specific embodiment
Below with reference to each embodiment, the present invention is described in detail, but it should be stated that, these embodiments are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according to these embodiments in made function, method or structure
Equivalent transformation or substitution, all belong to the scope of protection of the present invention within.
The present invention provides a kind of preparation method of Pregabalin, the structural formula of Pregabalin is as follows:
Wherein, Pregabalin shown in structure above the preparation method comprises the following steps: using Pregabalin raceme as starting material,
Pregabalin chiral ester is made under the action of lipase, Pregabalin chiral ester obtains Pregabalin through hydrolysis.
The structural formula of Pregabalin chiral ester is as follows:
Wherein, it is methyl, ethyl or isopropyl that R, which is selected from,.
The reaction process of Pregabalin chiral ester are as follows: solvent and Pregabalin raceme is added in reaction flask, and rouge is then added
Fat enzyme, constant-temperature table, 200rpm are reacted for 24 hours, are filtered, and silica gel column chromatography is concentrated in filtrate, collects corresponding eluent, obtains after concentration
Pregabalin chiral ester.Solvent is ethyl alcohol or isopropanol.
The reaction process of Pregabalin are as follows: Pregabalin chiral ester and hydrolysising solvent is added in reaction flask, and stirring is molten after concentration
It solves and dries, recrystallized through organic solvent, obtain Pregabalin.Hydrolysising solvent includes in sulfuric acid, hydrochloric acid or sodium hydroxide
The mixture of one or two kinds of any of the above ratio.Hydrolysising solvent can also be including ethyl acetate, methylene chloride or four
The mixture of one of hydrogen furans or two or more arbitrary proportions.Organic solvent is the mixture of ethyl alcohol and acetone.
Embodiment one:
Present embodiment discloses a kind of Pregabalins obtained according to the method described above, and wherein R is selected from ethyl, specific reaction step
It is rapid as follows:
100ml ethyl alcohol and Pregabalin raceme 12.5g is added in 500ml round-bottomed flask, 1g lipase is then added, in 40
DEG C constant-temperature table, 200rpm are reacted for 24 hours, are filtered, and silica gel column chromatography is concentrated in filtrate, collects corresponding eluent, obtains after concentration general
Auspicious Bahrain's chiral ester 6.1g.
Pregabalin chiral ester 5g and concentrated hydrochloric acid 10ml is added in 50ml reaction flask, and return stirring 3h, 2M sodium hydroxide is adjusted to
PH5, methylene chloride is dissolved and is dried after concentration, and methylene chloride is then removed under reduced pressure, and ethanol/acetone recrystallization obtains high-purity
Pregabalin 3.2g.
The high-purity Pregabalin that the present embodiment is finally prepared measures Pregabalin using chemical analysis method
Purity is 99.75%.
Embodiment two
Present embodiment discloses a kind of Pregabalins obtained according to the method described above, and wherein R is selected from isopropyl, specific to react
Steps are as follows:
100ml isopropanol and Pregabalin raceme 12.5g is added in 500ml round-bottomed flask, and 1g lipase is then added, in
40 DEG C of constant-temperature tables, 200rpm react for 24 hours.It filters, silica gel column chromatography is concentrated in filtrate, collects corresponding eluent, obtains after concentration
Pregabalin chiral ester 6.2g.
Pregabalin chiral ester 5g and 2M sodium hydroxide 20ml, 80 DEG C of stirring 6h is added in 50ml reaction flask, and 6M hydrochloric acid is adjusted to
PH5, ethyl acetate is dissolved and is dried after concentration, and methylene chloride is then removed under reduced pressure, and ethanol/acetone recrystallization obtains high-purity
Pregabalin 3.3g.
The high-purity Pregabalin that the present embodiment is finally prepared measures Pregabalin using chemical analysis method
Purity is 99.72%.
The method that R is selected from the preparation method and embodiment one and embodiment two of methyl is same or similar, and details are not described herein.
The series of detailed descriptions listed above only for feasible embodiment of the invention specifically
Protection scope bright, that they are not intended to limit the invention, it is all without departing from equivalent implementations made by technical spirit of the present invention
Or change should all be included in the protection scope of the present invention.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiments being understood that.
Claims (8)
1. a kind of preparation method of Pregabalin, which is characterized in that the structural formula of the Pregabalin is as follows:
Wherein, Pregabalin shown in structure above the preparation method comprises the following steps: using Pregabalin raceme as starting material, in fat
Pregabalin chiral ester is made under the action of enzyme, the Pregabalin chiral ester obtains Pregabalin through hydrolysis.
2. preparation method according to claim 1, which is characterized in that the structural formula of the Pregabalin chiral ester is as follows:
Wherein, it is methyl, ethyl or isopropyl that R, which is selected from,.
3. preparation method according to claim 2, which is characterized in that the reaction process of the Pregabalin chiral ester are as follows:
Solvent and Pregabalin raceme is added in reaction flask, and lipase, constant-temperature table is then added, and 200rpm is reacted for 24 hours, filtered, filter
Silica gel column chromatography is concentrated in liquid, collects corresponding eluent, Pregabalin chiral ester is obtained after concentration.
4. preparation method according to claim 3, which is characterized in that the solvent is ethyl alcohol or isopropanol.
5. the preparation method according to claim 4, which is characterized in that the reaction process of the Pregabalin are as follows: reaction flask
Pregabalin chiral ester and hydrolysising solvent is added, stirring dissolves and dry after concentration, recrystallizes through organic solvent, obtain Puri
Bahrain.
6. preparation method according to claim 5, which is characterized in that the hydrolysising solvent includes sulfuric acid, hydrochloric acid or hydrogen
The mixture of one of sodium oxide molybdena or two or more arbitrary proportions.
7. preparation method according to claim 5, which is characterized in that the hydrolysising solvent includes ethyl acetate, dichloromethane
The mixture of one of alkane or tetrahydrofuran or two or more arbitrary proportions.
8. preparation method according to claim 7, which is characterized in that the organic solvent is the mixing of ethyl alcohol and acetone
Object.
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| CN201811571064.1A CN109503401A (en) | 2018-12-21 | 2018-12-21 | A kind of preparation method of Pregabalin |
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| CN201811571064.1A CN109503401A (en) | 2018-12-21 | 2018-12-21 | A kind of preparation method of Pregabalin |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009087650A2 (en) * | 2007-10-15 | 2009-07-16 | V.B. Medicare Pvt. Ltd. | A novel process for synthesis of pregabalin from substituted cyclopropane intermediate and a process for enzymatic resolution of racemic pregabalin |
| CN105348125A (en) * | 2015-11-26 | 2016-02-24 | 太仓运通生物化工有限公司 | Method for synthesizing Pregabalin by taking isovaleraldehyde as raw material |
-
2018
- 2018-12-21 CN CN201811571064.1A patent/CN109503401A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009087650A2 (en) * | 2007-10-15 | 2009-07-16 | V.B. Medicare Pvt. Ltd. | A novel process for synthesis of pregabalin from substituted cyclopropane intermediate and a process for enzymatic resolution of racemic pregabalin |
| CN105348125A (en) * | 2015-11-26 | 2016-02-24 | 太仓运通生物化工有限公司 | Method for synthesizing Pregabalin by taking isovaleraldehyde as raw material |
Non-Patent Citations (1)
| Title |
|---|
| 许建和等: "《生物催化工程》", 31 October 2008 * |
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