CN107400075A - A kind of preparation method of pregabalin intermediate - Google Patents
A kind of preparation method of pregabalin intermediate Download PDFInfo
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- CN107400075A CN107400075A CN201610339023.4A CN201610339023A CN107400075A CN 107400075 A CN107400075 A CN 107400075A CN 201610339023 A CN201610339023 A CN 201610339023A CN 107400075 A CN107400075 A CN 107400075A
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- reaction
- pyrrolidone
- sodium
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- isobutyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a kind of method for preparing the pyrrolidones of 4 isobutyl group of pregabalin intermediate 2, with pyrrolidines 2,4 diketone are raw material, react to obtain compound 3 by wittig, compound 3 reacts to obtain compound 1, the i.e. pyrrolidones of 4 isobutyl group of target product pregabalin intermediate 2 by double-bond hydrogenation.This method is simple to operate, high income, is the technique for being suitable for industrial amplification production.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of preparation method of pregabalin intermediate.
Background technology
Pregabalin (Pregabalin) has analgesia, anticonvulsion and Antianxiety Activity, has prevention effect to epileptic attack.4- is different
Butyl -2-Pyrrolidone (1) synthesizes a key intermediate of Pregabalin, easily obtains qualified 4- isobutyl group -2- pyrroles
Synthesis of the pyrrolidone (02) to Pregabalin is significant.
There are a variety of methods to prepare 4- isobutyl groups -2-Pyrrolidone in the prior art.For example, patent application CN200910266661.8
Or the correlation technique for preparing 4- isobutyl groups -2-Pyrrolidone is disclosed in WO2006110783；But these methods need to use hydrogen
Gas and/or high-tension apparatus can just be obtained with other substrates by multi-step, and reaction time length, technique is cumbersome and/or exists
Larger unsafe factor.Therefore a kind of low for equipment requirements, safety is needed, operating procedure is easy and the method for high income, with suitable
In industrialized production.
The content of the invention
The invention provides a kind of preparation method of pregabalin intermediate 4- isobutyl groups -2-Pyrrolidone, with pyrrolidines -2,4- bis-
Ketone is raw material, reacts to obtain compound 3 by wittig, compound 3 reacts to obtain compound 1, i.e. mesh by double-bond hydrogenation
Mark product pregabalin intermediate 4- isobutyl groups -2-Pyrrolidone.Synthetic route is as follows：
Alkali used in wittig reaction prepare compound 3 be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate,
One or more of mixtures in potassium carbonate, n-BuLi, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or caustic alcohol, preferably
For potassium tert-butoxide.
Solvent used in the wittig reactions prepare compound 3 is selected from methanol, ethanol, acetonitrile, tetrahydrofuran, acetic acid second
One or more of mixtures in ester, toluene, dimethylbenzene or DMF, preferably N, N- dimethyl methyls
Acid amides.
The reaction temperature of the wittig reactions prepare compound 3 is -78 DEG C~room temperature, preferably 0 DEG C~room temperature.
Pyrrolidine-2,4-diketone and isobutyl group tri-phenyl-phosphorus bromide rubs in the reaction of described wittig reactions prepare compound 3
You are than being 1:0.7~1:1.5, preferably 1:0.9~1:1.2.
The reducing agent that described hydrogenation reaction prepares used in 4- isobutyl groups -2-Pyrrolidone is selected from sodium borohydride, potassium borohydride, cyanogen
One or more of mixtures in base sodium borohydride, sodium triacetoxy borohydride, preferably sodium triacetoxy borohydride.
The solvent that described hydrogenation reaction prepares used in 4- isobutyl groups -2-Pyrrolidone is selected from methanol, ethanol, acetonitrile, tetrahydrochysene furan
Mutter, one or more of mixtures in ethyl acetate, toluene, dimethylbenzene or DMF, preferably tetrahydrochysene
Furans.
The reaction temperature that described hydrogenation reaction prepares 4- isobutyl groups -2-Pyrrolidone is the reflux temperature of 0 DEG C~solvent, preferably
For 0 DEG C~room temperature.
Described hydrogenation reaction prepares compound 2 and the mol ratio of reducing agent in the reaction of 4- isobutyl groups -2-Pyrrolidone
1:1.5~1:3, preferably 1:1.5~1:2.
Beneficial effects of the present invention：The present invention solve need to use hydrogen and/or high pressure etc. in the synthetic method being currently known it is severe
Reaction condition, or multi-step, reaction time length are carved, technique is cumbersome and/or the problem of larger unsafe factor be present.Pass through 2
Step reaction, reaction condition is gentle, simple to operate, high income, is adapted to industrial amplification production.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described embodiment model
Among enclosing.
Initiation material pyrrolidine-2,4-diketone and the commercially available purchase of isobutyl group tri-phenyl-phosphorus bromide.
Embodiment 1
The preparation of compound 3
15g pyrrolidines -2,4- diketone and 26g isobutyl group tri-phenyl-phosphorus bromides are added to 200ml DMFs
In, 0 DEG C is cooled to, 17g potassium tert-butoxides are added portionwise, are warming up to room temperature, continues stirring 5 hours, TLC point board monitorings are anti-
It should finish, reaction solution is poured into 800ml water, add ethyl acetate and extract three times, merge organic phase, add anhydrous sodium sulfate
Dry, filtering, be concentrated under reduced pressure, obtain the crude product of 16.8g compounds 3, without being further purified, be directly used in anti-in next step
Should.
Embodiment 2
The preparation of 4- isobutyl groups -2-Pyrrolidone
The crude product of 16.8g compounds 3 is added in 150ml tetrahydrofurans, is cooled to 0 DEG C, is slowly added to the second of 15.2g tri-
Triacetoxyborohydride, it is stirred overnight at room temperature, TLC points board monitoring reaction finishes, and adds saturated ammonium chloride, adds water and second
Acetoacetic ester extracts, and obtains organic phase, adds anhydrous sodium sulfate, filtering, is concentrated under reduced pressure, gained residue is evaporated under reduced pressure, and is obtained
18.6g 4- isobutyl groups -2-Pyrrolidone.Total recovery 87%, purity 99.51%, m/z=142 [M+1].
Claims (9)
1. a kind of method for preparing 4- isobutyl groups -2-Pyrrolidone, with pyrrolidines -2,4- diketone for raw material, reacts by wittig
Compound 3 is obtained, compound 3 reacts to obtain compound 1 by double-bond hydrogenation, i.e. target product pregabalin intermediate 4- is different
Butyl -2-Pyrrolidone.Synthetic route is as follows：
2. according to the method for claim 1, wherein, alkali used in described wittig reaction prepare compounds 3 is selected from hydroxide
Sodium, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, n-BuLi, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or second
One or more of mixtures in sodium alkoxide.
3. according to the method for claim 1, wherein, the solvent used in described wittig reaction prepare compounds 3 is selected from first
One kind or several in alcohol, ethanol, acetonitrile, tetrahydrofuran, ethyl acetate, toluene, dimethylbenzene or DMF
The mixture of kind.
4. according to the method for claim 1, wherein, the reaction temperature of described wittig reaction prepare compounds 3 is -78
DEG C~room temperature.
5. the method according to claim 11, wherein, pyrrolidines -2,4- in the reaction of described wittig reaction prepare compounds 3
The mol ratio of diketone and isobutyl group tri-phenyl-phosphorus bromide is 1:0.7~1:1.5.
6. according to the method for claim 1, wherein, described hydrogenation reaction is prepared used in 4- isobutyl groups -2-Pyrrolidone
Reducing agent is one or more of mixed in sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride
Compound.
7. the method narrated according to claim 1, wherein, described hydrogenation reaction is prepared used in 4- isobutyl groups -2-Pyrrolidone
Solvent is in methanol, ethanol, acetonitrile, tetrahydrofuran, ethyl acetate, toluene, dimethylbenzene or DMF
One or more of mixtures.
8. the method narrated according to claim 1, wherein, described hydrogenation reaction prepares the reaction of 4- isobutyl groups -2-Pyrrolidone
Temperature is the reflux temperature of 0 DEG C~solvent.
9. the method narrated according to claim 1, wherein, described hydrogenation reaction prepares the reaction of 4- isobutyl groups -2-Pyrrolidone
Middle compound 2 and the mol ratio of reducing agent are 1:1.5~1:3.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610339023.4A CN107400075A (en) | 2016-05-19 | 2016-05-19 | A kind of preparation method of pregabalin intermediate |
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| CN201610339023.4A CN107400075A (en) | 2016-05-19 | 2016-05-19 | A kind of preparation method of pregabalin intermediate |
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| CN107400075A true CN107400075A (en) | 2017-11-28 |
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| CN201610339023.4A Pending CN107400075A (en) | 2016-05-19 | 2016-05-19 | A kind of preparation method of pregabalin intermediate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115475162A (en) * | 2022-10-18 | 2022-12-16 | 浙江震元制药有限公司 | Application of 4-isobutyl-2-pyrrolidone in preparation of analgesic and analgesic drug |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1583724A (en) * | 2004-06-01 | 2005-02-23 | 中国医学科学院医药生物技术研究所 | 7-(4,4-dimethyl 3-aminomethylpentazane-1-radicle) substituted, quinoline carboxylic acid derivative and its preparation |
| CN101300224A (en) * | 2005-04-11 | 2008-11-05 | 特瓦制药工业有限公司 | Process for making (s)-pregabalin |
| CN102115449A (en) * | 2009-12-31 | 2011-07-06 | 浙江华海药业股份有限公司 | Novel method for preparing pregabalin raceme hydrochloride |
-
2016
- 2016-05-19 CN CN201610339023.4A patent/CN107400075A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1583724A (en) * | 2004-06-01 | 2005-02-23 | 中国医学科学院医药生物技术研究所 | 7-(4,4-dimethyl 3-aminomethylpentazane-1-radicle) substituted, quinoline carboxylic acid derivative and its preparation |
| CN101300224A (en) * | 2005-04-11 | 2008-11-05 | 特瓦制药工业有限公司 | Process for making (s)-pregabalin |
| CN102115449A (en) * | 2009-12-31 | 2011-07-06 | 浙江华海药业股份有限公司 | Novel method for preparing pregabalin raceme hydrochloride |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115475162A (en) * | 2022-10-18 | 2022-12-16 | 浙江震元制药有限公司 | Application of 4-isobutyl-2-pyrrolidone in preparation of analgesic and analgesic drug |
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Application publication date: 20171128 |