CN109503403A - A kind of method for splitting of Pregabalin - Google Patents
A kind of method for splitting of Pregabalin Download PDFInfo
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- CN109503403A CN109503403A CN201811571061.8A CN201811571061A CN109503403A CN 109503403 A CN109503403 A CN 109503403A CN 201811571061 A CN201811571061 A CN 201811571061A CN 109503403 A CN109503403 A CN 109503403A
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- C—CHEMISTRY; METALLURGY
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The present invention provides a kind of method for splitting 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 method for splitting of Pregabalin of the present invention, method for splitting 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 method for splitting 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 of Pregabalin mainly has asymmetric syntheses and chemical resolution two types, and chemical resolution produces now
Main stream approach, 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 method for splitting of Pregabalin, the method for splitting 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 method for splitting of Pregabalin, and the structural formula of Pregabalin is such as
Shown in lower:
Wherein, the method for splitting of Pregabalin shown in structure above are as follows: using Pregabalin raceme as starting material, ring
It is combined into Pregabalin lactams, the Pregabalin lactams chiral hydrolysis under the action of lipase obtains Puri bar
Woods.
Further, the reaction process of Pregabalin lactams is divided into 2 steps, the specific steps are as follows:
A: being added Pregabalin raceme and catalyst in reaction flask, return stirring reacts 6h, is down to room temperature, refrigerator naturally
Recrystallization, filters to obtain white solid；
B: step a is added in reaction flask, white solid and dissolution solvent, stirring and dissolving, enriching sulfuric acid, return stirring is made
Reaction, is down to room temperature naturally, sodium hydroxide tune PH to 5, concentration, and hexamethylene is added after the extraction of residue ethyl alcohol under reflux state to micro-
Muddiness, then ethyl alcohol is added dropwise to dissolved clarification, ice bath stirring crystallization filters to obtain Pregabalin lactams.
Further, catalyst includes acetic anhydride or sulfuric acid.
Further, dissolution solvent is one of ethyl acetate, methylene chloride, chloroform or tetrahydrofuran or two kinds
The mixture of any of the above ratio.
Further, the reaction process of Pregabalin are as follows: the Pregabalin lactams is dissolved in organic solvent, and fat is added
Enzyme Novozym, constant-temperature table, for 24 hours, after room temperature filters concentration, dissolving-recrystallization obtains Pregabalin for reaction.
Further, shaking table temperature is 35 DEG C.
Further, shaking speed 200r/min.
Further, organic solvent is toluene.
Compared with prior art, the beneficial effects of the present invention are: improving the purity of Pregabalin, method for splitting 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 method for splitting of Pregabalin, the structural formula of Pregabalin is as follows:
Wherein, the method for splitting of Pregabalin shown in structure above are as follows: using Pregabalin raceme as starting material, ring
It is combined into Pregabalin lactams, the Pregabalin lactams chiral hydrolysis under the action of lipase obtains Puri bar
Woods.
The reaction process of Pregabalin lactams is divided into 2 steps, the specific steps are as follows:
A: being added Pregabalin raceme and catalyst in reaction flask, return stirring reacts 6h, is down to room temperature, refrigerator naturally
Recrystallization, filters to obtain white solid；
B: step a is added in reaction flask, white solid and dissolution solvent, stirring and dissolving, enriching sulfuric acid, return stirring is made
Reaction, is down to room temperature naturally, sodium hydroxide tune PH to 5, concentration, and hexamethylene is added after the extraction of residue ethyl alcohol under reflux state to micro-
Muddiness, then ethyl alcohol is added dropwise to dissolved clarification, ice bath stirring crystallization filters to obtain Pregabalin lactams.Catalyst include acetic anhydride or
Sulfuric acid.Dissolution solvent is one of ethyl acetate, methylene chloride, chloroform or tetrahydrofuran or two or more arbitrary proportions
Mixture.
The reaction process of Pregabalin are as follows: the Pregabalin lactams is dissolved in organic solvent, and lipase is added
Novozym, constant-temperature table, for 24 hours, after room temperature filters concentration, dissolving-recrystallization obtains Pregabalin for reaction.Shaking table temperature is 35
℃.Shaking speed 200r/min.Organic solvent is toluene.
Embodiment one:
Present embodiment discloses a kind of Pregabalin obtained according to the method described above, specific reaction step is as follows:
15.9g Pregabalin raceme and 300ml acetic anhydride are added in 1L reaction flask, return stirring reacts 6h, drops naturally
To room temperature, refrigerator recrystallization filters to obtain white solid 10.7g.15.9g white solid and 200ml acetic acid are added in 05L reaction flask
Ethyl ester, stirring and dissolving, concentrated sulfuric acid 5ml, return stirring react for 24 hours, are down to room temperature naturally, and 2M sodium hydroxide tune PH to 5 is concentrated,
Hexamethylene is added after the extraction of residue ethyl alcohol under reflux state to micro- muddiness, then ethyl alcohol is added dropwise to dissolved clarification, ice bath stirring crystallization 2h takes out
Filter to obtain Pregabalin lactams 11.5g.
Pregabalin lactams 14.1g is dissolved in 1.5L toluene, and lipase 1g is added, and lipase is Novozym435 fat
Enzyme, 35 DEG C of reaction temperature, reaction temperature for 24 hours, shaking speed 200r/min.Room temperature filters recrystallisation from isopropanol after concentration, obtains white
Color solid 9.6g, the i.e. Pregabalin of high-purity.
The high-purity Pregabalin that the present embodiment is finally prepared measures Pregabalin using chemical analysis method
Purity is 99.45%.
Embodiment two:
Present embodiment discloses a kind of Pregabalin obtained according to the method described above, specific reaction step is as follows:
15.9g white solid and 200ml ethyl acetate, stirring and dissolving, concentrated sulfuric acid 5ml, reflux are added in 0.5L reaction flask
It is stirred to react for 24 hours, is down to room temperature, 2M sodium hydroxide tune PH to 5 naturally, concentration is added under reflux state after the extraction of residue ethyl alcohol
Hexamethylene is to micro- muddiness, then ethyl alcohol is added dropwise to dissolved clarification, and ice bath stirring crystallization 2h filters to obtain Pregabalin lactams 11.5g.
Pregabalin lactams 14.1g is dissolved in 1.5L toluene, and lipase 1g is added, and lipase is Novozym435 fat
Enzyme, 35 DEG C of reaction temperature, reaction temperature for 24 hours, shaking speed 200r/min.Room temperature filters recrystallisation from isopropanol after concentration, obtains white
Color solid 9.6g, the i.e. Pregabalin of high-purity.
The high-purity Pregabalin that the present embodiment is finally prepared measures Pregabalin using chemical analysis method
Purity is 99.52%.
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 method for splitting of Pregabalin, which is characterized in that the structural formula of the Pregabalin is as follows:
Wherein, the method for splitting of Pregabalin shown in structure above are as follows: using Pregabalin raceme as starting material, cyclization is
Pregabalin lactams, the Pregabalin lactams chiral hydrolysis under the action of lipase obtain Pregabalin.
2. method for splitting according to claim 1, which is characterized in that the reaction process of the Pregabalin lactams is divided into
2 steps, the specific steps are as follows:
A: being added Pregabalin raceme and catalyst in reaction flask, return stirring reacts 6h, is down to room temperature naturally, refrigerator is tied again
Crystalline substance filters to obtain white solid；
B: being added the obtained white solid of step a in reaction flask and dissolution solvent, stirring and dissolving, enriching sulfuric acid, return stirring react,
Naturally it is down to room temperature, hexamethylene is added to micro- muddiness in sodium hydroxide tune PH to 5, concentration under reflux state after the extraction of residue ethyl alcohol,
Ethyl alcohol is added dropwise again to dissolved clarification, ice bath stirring crystallization filters to obtain Pregabalin lactams.
3. method for splitting according to claim 2, which is characterized in that the catalyst includes acetic anhydride or sulfuric acid.
4. method for splitting according to claim 3, which is characterized in that the dissolution solvent be ethyl acetate, methylene chloride,
The mixture of one of chloroform or tetrahydrofuran or two or more arbitrary proportions.
5. method for splitting according to claim 4, which is characterized in that the reaction process of the Pregabalin are as follows: described general
Auspicious Bahrain's lactams is dissolved in organic solvent, and lipase Novozym is added, and constant-temperature table reacts for 24 hours, molten after room temperature filters concentration
Solution recrystallization, obtains Pregabalin.
6. method for splitting according to claim 5, which is characterized in that the shaking table temperature is 35 DEG C.
7. method for splitting according to claim 5, which is characterized in that the shaking speed 200r/min.
8. method for splitting according to claim 5, which is characterized in that the organic solvent is toluene.
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| CN201811571061.8A CN109503403B (en) | 2018-12-21 | 2018-12-21 | Pregabalin splitting method |
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| CN201811571061.8A CN109503403B (en) | 2018-12-21 | 2018-12-21 | Pregabalin splitting method |
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