CN104829515A - Pregabalin impurity preparation method - Google Patents
Pregabalin impurity preparation method Download PDFInfo
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- CN104829515A CN104829515A CN201510294634.7A CN201510294634A CN104829515A CN 104829515 A CN104829515 A CN 104829515A CN 201510294634 A CN201510294634 A CN 201510294634A CN 104829515 A CN104829515 A CN 104829515A
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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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Abstract
The invention provides a pregabalin impurity preparation method. The method includes the following steps: adding S-pregabalin into an acidic system at temperature of 60-80 DEG C, and stirring for reaction; depressurizing and concentrating solvent until no liquid flows out after reaction is finished; adding an extracting agent into a system concentrated in the previous step, and stirring well; adding a weak alkali solution for cleaning, and then using water to clean; concentrating an organic layer until no obvious fraction flows out, and then adding organic solvent; cooling to 0-10 DEG C, dropwise adding alkane solvent until a lot of solid is dissolved out, performing suction filtering, and continuing concentrating to obtain a pregabalin lactam impurity. The ppregabalin lactam impurity can be prepared in a high-yield and high-purity manner without special reagent and reaction conditions.
Description
Technical field
The invention provides a kind of preparation method preparing lyrica impurity, belong to field of medicine and chemical technology.
background of invention
Epilepsy has been the difficult problem that faced by current medical science is thorny, and it is a kind of neural system paroxysmal disease, and be one of neural system common disease, morbidity is only second to cerebro-vascular diseases.Medicine market being used for the treatment of epileptics is more, and the Antiepileptic Drugs such as Carbamzepine and phenytoin Sodium neuropathic pain has the history of more than 40 years, has certain curative effect.
Antiepileptic drug new in the last few years constantly comes out, new development space has been opened up to the treatment of neuropathic pain, gabapentin therapy neuropathic pain clinical report is more, after patient treatment, 39.1% pain degree reduces, lyrica structure is different from gabapentin, completed multinomial clinical trial shows, the analgesic effect of lyrica is better than gabapentin, and lyrica is in the granted listing in multiple countries and regions such as Britain, the U.S. simultaneously.
Lyrica undesirable lactam impurity produces in crude product operation, has lyrica to close ring and is formed, current file report preparation few, so prepare lyrica lactan standard substance or necessary, this impurity structural formula is as follows:
Summary of the invention
The object of this invention is to provide a kind of preparation method of lyrica undesirable lactam impurity, comprise the following steps:
1) in the acid system of 60 ~ 80 DEG C, pregabalin stirring reaction is added;
2) concentrating under reduced pressure solvent flows out to absence of liquid after completion of the reaction;
3) in the concentrated system of previous step, add extraction agent to stir;
4) wash with water again after adding weak caustic solution washing;
5) concentration of organic layers adds organic solvent again after flowing out without obvious cut;
6) drip alkane solvent after being cooled to 0 ~ 10 DEG C to separate out to there being a large amount of solid, suction filtration, continuation concentrate and obtain lyrica undesirable lactam impurity;
Its reaction formula is as follows:
Described step 1) acid system refers to the system of hydrochloric acid and aceticanhydride or acetic acid and aceticanhydride; Hydrochloric acid used or acetic acid, the volumetric usage of acid anhydrides is 1 ~ 3 times of pregabalin quality respectively.
Described step 2) react complete time and refer to 10 ~ 18 hours.
Add extraction agent in the system that described step 3) is concentrated and refer to methylene dichloride, ethyl acetate, toluene.
The weak base that described step 4) adds refers to sodium bicarbonate, saleratus, adds after weak caustic solution washs 2 times, then washes 1 time with water; The volume of added weak base is 1 ~ 1.2 times of pregabalin weight.
The organic solvent that described step 5) adds refers to ethyl acetate, toluene; The volume of added organic solvent is 1 ~ 2 times of pregabalin quality, and enriched material dissolves by the amount namely adding organic solvent.
Alkane solvent described in described step 6) refers to cyclohexane, normal hexane, normal heptane; Drip alkane solvent can stop dripping to there being a large amount of solid to separate out.
The invention provides the preparation method of an economy, simple lyrica lactan, do not need special reagent and reaction conditions namely can the lyrica undesirable lactam impurity prepared of high yield high purity.
Embodiment
Below in conjunction with example, the present invention is further elaborated, but these examples do not form any restriction to the present invention.
Example 1:
Room temperature is adjusted and is added 50g pregabalin in 500ml four-hole boiling flask, hydrochloric acid and aceticanhydride are respectively 150ml and 100ml, stirring is warming up to 75 DEG C, after 16 hours, monitoring after completion of the reaction, be evaporated to and flow out without obvious liquid, in the system concentrated, add methylene dichloride 200ml, the saturated sodium bicarbonate solution 50ml that the backward dropping that stirs configures washs twice, wash one time at the 50ml that adds water afterwards, concentrating under reduced pressure organic layer is to flowing out without obvious liquid.In concentrated dry system, add 80ml ethyl acetate again, be cooled to 5 DEG C after stirring, dripping hexanaphthene 100ml has the precipitation of a large amount of solid to stop dripping, suction filtration, afterwards concentrating under reduced pressure 1h.Products obtained therefrom 40g, yield 90.3%, purity 99.8%.Product
1the displacement of NMR related chemistry is as follows:
1nMR (400 MHz, CDCl3) δ 3.50-3.55 (dd, 1H), 3.05 (t, 1H), 2.39-2.59 (m, 2H), 1.99-2.04 (m, 1H), 1.53-1.62 (m, 1H), 1.35-1.39 (t, 2H), 0.90-0.93 (dd, 6H).
Example 2:
Room temperature is adjusted and is added 50g pregabalin in 500ml four-hole boiling flask, hydrochloric acid and aceticanhydride are respectively 75ml and 100ml, stirring is warming up to 75 DEG C, after 15 hours, monitoring after completion of the reaction, be evaporated to and flow out without obvious liquid, in the system concentrated, add ethyl acetate 150ml, the saturated sodium bicarbonate solution 50ml that the backward dropping that stirs configures washs twice, wash one time at the 50ml that adds water afterwards, concentrating under reduced pressure organic layer is to flowing out without obvious liquid.In concentrated dry system, add 100ml ethyl acetate again, after stirring, be cooled to 3 DEG C, drip hexanaphthene and stop dripping to there being a large amount of solid to separate out, suction filtration, afterwards concentrating under reduced pressure 1h.Products obtained therefrom 40.2g, yield 90.7%, purity 99.8%.Product
1the displacement of NMR related chemistry is as follows:
1nMR (400 MHz, CDCl3) δ 3.50-3.55 (dd, 1H), 3.05 (t, 1H), 2.39-2.59 (m, 2H), 1.99-2.04 (m, 1H), 1.53-1.62 (m, 1H), 1.35-1.39 (t, 2H), 0.90-0.93 (dd, 6H).
Example 3:
Room temperature is adjusted and is added 50g pregabalin in 500ml four-hole boiling flask, hydrochloric acid and aceticanhydride are respectively 75ml and 100ml, stirring is warming up to 75 DEG C, after 14 hours, monitoring after completion of the reaction, be evaporated to and flow out without obvious liquid, in the system concentrated, add toluene 200ml, the saturated sodium bicarbonate solution 50ml that the backward dropping that stirs configures washs twice, wash one time at the 50ml that adds water afterwards, concentrating under reduced pressure organic layer is to flowing out without obvious liquid.In concentrated dry system, add 90ml ethyl acetate again, after stirring, be cooled to 5 DEG C, drip hexanaphthene and stop dripping to there being a large amount of solid to separate out, suction filtration, afterwards concentrating under reduced pressure 1h.Products obtained therefrom 39.5g, yield 89.4%, purity 99.9%.Product
1the displacement of NMR related chemistry is as follows:
1nMR (400 MHz, CDCl3) δ 3.50-3.55 (dd, 1H), 3.05 (t, 1H), 2.39-2.59 (m, 2H), 1.99-2.04 (m, 1H), 1.53-1.62 (m, 1H), 1.35-1.39 (t, 2H), 0.90-0.93 (dd, 6H).
Example 4:
Room temperature is adjusted and is added 50g pregabalin in 500ml four-hole boiling flask, acetic acid and aceticanhydride are respectively 100ml and 100ml, stirring is warming up to 80 DEG C, after 10 hours, monitoring after completion of the reaction, be evaporated to and flow out without obvious liquid, in the system concentrated, add methylene dichloride 200ml, the saturated sodium bicarbonate solution 50ml that the backward dropping that stirs configures washs twice, wash one time at the 50ml that adds water afterwards, concentrating under reduced pressure organic layer is to flowing out without obvious liquid.In concentrated dry system, add 80ml ethyl acetate again, after stirring, be cooled to 5 DEG C, drip normal heptane and stop dripping to there being a large amount of solid to separate out, suction filtration, afterwards concentrating under reduced pressure 1h.Products obtained therefrom 41.0g, yield 92.7%, purity 99.7%.Product
1the displacement of NMR related chemistry is as follows:
1nMR (400 MHz, CDCl3) δ 3.50-3.55 (dd, 1H), 3.05 (t, 1H), 2.39-2.59 (m, 2H), 1.99-2.04 (m, 1H), 1.53-1.62 (m, 1H), 1.35-1.39 (t, 2H), 0.90-0.93 (dd, 6H).
Example 5:
Room temperature is adjusted and is added 50g pregabalin in 500ml four-hole boiling flask, hydrochloric acid and aceticanhydride are respectively 80ml and 50ml, stirring is warming up to 75 DEG C, after 10 hours, monitoring after completion of the reaction, be evaporated to and flow out without obvious liquid, in the system concentrated, add ethyl acetate 150ml, the saturated sodium bicarbonate solution 50ml that the backward dropping that stirs configures washs twice, wash one time at the 50ml that adds water afterwards, concentrating under reduced pressure organic layer is to flowing out without obvious liquid.In concentrated dry system, add 60ml toluene again, after stirring, be cooled to 5 DEG C, drip normal heptane and stop dripping to there being a large amount of solid to separate out, suction filtration, afterwards concentrating under reduced pressure 1h.Products obtained therefrom 40.6g, yield 91.8%, purity 99.9%.Product
1the displacement of NMR related chemistry is as follows:
1nMR (400 MHz, CDCl3) δ 3.50-3.55 (dd, 1H), 3.05 (t, 1H), 2.39-2.59 (m, 2H), 1.99-2.04 (m, 1H), 1.53-1.62 (m, 1H), 1.35-1.39 (t, 2H), 0.90-0.93 (dd, 6H).
Example 6:
Room temperature is adjusted and is added 50g pregabalin in 500ml four-hole boiling flask, hydrochloric acid and aceticanhydride are respectively 90ml and 50ml, stirring is warming up to 75 DEG C, after 10 hours, monitoring after completion of the reaction, be evaporated to and flow out without obvious liquid, in the system concentrated, add toluene 200ml, the saturated sodium bicarbonate solution 50ml that the backward dropping that stirs configures washs twice, wash one time at the 50ml that adds water afterwards, concentrating under reduced pressure organic layer is to flowing out without obvious liquid.In concentrated dry system, add 50ml toluene again, after stirring, be cooled to 5 DEG C, drip normal heptane and stop dripping to there being a large amount of solid to wash out, suction filtration, afterwards concentrating under reduced pressure 1h.Products obtained therefrom 40.3g, yield 91.1%, purity 99.7%.Product
1the displacement of NMR related chemistry is as follows:
1nMR (400 MHz, CDCl3) δ 3.50-3.55 (dd, 1H), 3.05 (t, 1H), 2.39-2.59 (m, 2H), 1.99-2.04 (m, 1H), 1.53-1.62 (m, 1H), 1.35-1.39 (t, 2H), 0.90-0.93 (dd, 6H).
Example 7:
Room temperature is adjusted and is added 50g pregabalin in 500ml four-hole boiling flask, hydrochloric acid and aceticanhydride are respectively 120ml and 120ml, stirring is warming up to 75 DEG C, after 12 hours, monitoring after completion of the reaction, be evaporated to and flow out without obvious liquid, in the system concentrated, add methylene dichloride 200ml, the saturated potassium hydrogen carbonate solution 60ml that the backward dropping that stirs configures washs twice, wash one time at the 50ml that adds water afterwards, concentrating under reduced pressure organic layer is to flowing out without obvious liquid.In concentrated dry system, add 75ml toluene again, after stirring, be cooled to 5 DEG C, drip normal hexane and stop dripping to there being a large amount of solid to separate out, suction filtration, afterwards concentrating under reduced pressure 1h.Products obtained therefrom 39.8g, yield 90.0%, purity 99.8%.Product
1the displacement of NMR related chemistry is as follows:
1nMR (400 MHz, CDCl3) δ 3.50-3.55 (dd, 1H), 3.05 (t, 1H), 2.39-2.59 (m, 2H), 1.99-2.04 (m, 1H), 1.53-1.62 (m, 1H), 1.35-1.39 (t, 2H), 0.90-0.93 (dd, 6H).
Example 8:
Room temperature is adjusted and is added 50g pregabalin in 500ml four-hole boiling flask, hydrochloric acid and aceticanhydride are respectively 75ml and 150ml, stirring is warming up to 75 DEG C, after 15 hours, monitoring after completion of the reaction, be evaporated to and flow out without obvious liquid, in the system concentrated, add methylene dichloride 200ml, the saturated potassium hydrogen carbonate solution 50ml that the backward dropping that stirs configures washs twice, wash one time at the 50ml that adds water afterwards, concentrating under reduced pressure organic layer is to flowing out without obvious liquid.In concentrated dry system, add 100ml toluene again, after stirring, be cooled to 10 DEG C, drip normal hexane and stop dripping to there being a large amount of solid to separate out, suction filtration, afterwards concentrating under reduced pressure 1h.Products obtained therefrom 41.2g, yield 93.2%, purity 99.9%.Product
1the displacement of NMR related chemistry is as follows:
1nMR (400 MHz, CDCl3) δ 3.50-3.55 (dd, 1H), 3.05 (t, 1H), 2.39-2.59 (m, 2H), 1.99-2.04 (m, 1H), 1.53-1.62 (m, 1H), 1.35-1.39 (t, 2H), 0.90-0.93 (dd, 6H).
Example 9:
Room temperature is adjusted and is added 50g pregabalin acetic acid and aceticanhydride is respectively 90ml and 150ml in 500ml four-hole boiling flask, stirring is warming up to 75 DEG C, after 10 hours, monitoring after completion of the reaction, be evaporated to and flow out without obvious liquid, ethyl acetate 200ml is added in the system concentrated, the saturated potassium hydrogen carbonate solution 50ml that the backward dropping that stirs configures washs twice, washes one time afterwards at the 50ml that adds water, and concentrating under reduced pressure organic layer is to flowing out without obvious liquid.In concentrated dry system, add 75ml toluene again, after stirring, be cooled to 5 DEG C, drip normal hexane and stop dripping to there being a large amount of solid to separate out, suction filtration, afterwards concentrating under reduced pressure 1h.Products obtained therefrom 40g, yield 90.3%, purity 99.8%.Product
1the displacement of NMR related chemistry is as follows:
1nMR (400 MHz, CDCl3) δ 3.50-3.55 (dd, 1H), 3.05 (t, 1H), 2.39-2.59 (m, 2H), 1.99-2.04 (m, 1H), 1.53-1.62 (m, 1H), 1.35-1.39 (t, 2H), 0.90-0.93 (dd, 6H).
Example 10:
Room temperature is adjusted and is added 50g pregabalin in 500ml four-hole boiling flask, hydrochloric acid and aceticanhydride are respectively 90ml and 120ml, stirring is warming up to 75 DEG C, after 8 hours, monitoring after completion of the reaction, be evaporated to and flow out without obvious liquid, in the system concentrated, add methylene dichloride 200ml, the saturated sodium bicarbonate solution 50ml that the backward dropping that stirs configures washs twice, wash one time at the 50ml that adds water afterwards, concentrating under reduced pressure organic layer is to flowing out without obvious liquid.In concentrated dry system, add 50ml toluene again, after stirring, be cooled to 5 DEG C, drip normal hexane and stop dripping to there being a large amount of solid to separate out, suction filtration, afterwards concentrating under reduced pressure 1h.Products obtained therefrom 39.5g, yield 89.3%, purity 99.7%.Product
1the displacement of NMR related chemistry is as follows:
1nMR (400 MHz, CDCl3) δ 3.50-3.55 (dd, 1H), 3.05 (t, 1H), 2.39-2.59 (m, 2H), 1.99-2.04 (m, 1H), 1.53-1.62 (m, 1H), 1.35-1.39 (t, 2H), 0.90-0.93 (dd, 6H).
Claims (6)
1. a preparation method for lyrica undesirable lactam impurity, is characterized in that comprising the following steps:
1) in the acid system of 60 ~ 80 DEG C, pregabalin stirring reaction is added;
2) the above-mentioned solvent of concentrating under reduced pressure after completion of the reaction flows out to absence of liquid;
3) in the concentrated system of previous step, add extraction agent to stir;
4) wash with water again after adding weak caustic solution washing;
5) concentration of organic layers adds organic solvent again after flowing out without obvious cut;
6) drip alkane solvent after being cooled to 0 ~ 10 DEG C to separate out to there being a large amount of solid, suction filtration, continuation concentrate and obtain lyrica undesirable lactam impurity; Described reaction formula is as follows.
2.
Method according to claim 1, the acid system that it is characterized in that described in step 1) refers to the system of hydrochloric acid and aceticanhydride or acetic acid and aceticanhydride; Hydrochloric acid used or acetic acid, the volumetric usage of acid anhydrides is 1 ~ 3 times of pregabalin quality respectively.
3. method according to claim 1, is characterized in that adding extraction agent in the system that step 3) is concentrated refers to methylene dichloride, ethyl acetate, toluene.
4. method according to claim 1, is characterized in that the weak base that step 4) adds refers to sodium bicarbonate, saleratus; The volume of added weak base is 1 ~ 1.2 times of pregabalin weight.
5. method according to claim 1, is characterized in that the organic solvent that step 5) uses refers to ethyl acetate, toluene.
6. method according to claim 1, is characterized in that the alkane solvent described in step 6) refers to cyclohexane, normal hexane, normal heptane.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503403A (en) * | 2018-12-21 | 2019-03-22 | 江苏卓和药业有限公司 | A kind of method for splitting of Pregabalin |
| CN109851543A (en) * | 2019-01-24 | 2019-06-07 | 浙江华海药业股份有限公司 | A method of preparing pregabalin lactams |
| CN110903228A (en) * | 2019-11-07 | 2020-03-24 | 南通常佑药业科技有限公司 | Preparation method of 4-isobutyl pyrrolidone by solvent-free method |
| WO2020093229A1 (en) * | 2018-11-06 | 2020-05-14 | 浙江华海药业股份有限公司 | Pregabalin lactam methylene dimer and preparation method therefor |
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| CN101300224A (en) * | 2005-04-11 | 2008-11-05 | 特瓦制药工业有限公司 | Process for making (s)-pregabalin |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020093229A1 (en) * | 2018-11-06 | 2020-05-14 | 浙江华海药业股份有限公司 | Pregabalin lactam methylene dimer and preparation method therefor |
| CN112752754A (en) * | 2018-11-06 | 2021-05-04 | 浙江华海药业股份有限公司 | Pregabalin lactam methylene dimer and preparation method thereof |
| EP3878849A4 (en) * | 2018-11-06 | 2021-11-03 | Zhejiang Huahai Pharmaceutical Co., Ltd. | Pregabalin lactam methylene dimer and preparation method therefor |
| CN109503403A (en) * | 2018-12-21 | 2019-03-22 | 江苏卓和药业有限公司 | A kind of method for splitting of Pregabalin |
| CN109851543A (en) * | 2019-01-24 | 2019-06-07 | 浙江华海药业股份有限公司 | A method of preparing pregabalin lactams |
| CN109851543B (en) * | 2019-01-24 | 2023-07-07 | 浙江华海药业股份有限公司 | Method for preparing S-pregabalin lactam |
| CN110903228A (en) * | 2019-11-07 | 2020-03-24 | 南通常佑药业科技有限公司 | Preparation method of 4-isobutyl pyrrolidone by solvent-free method |
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Application publication date: 20150812 |