CN103772257A - Method for preparing 2-((3s)-3-hydroxy pyrrolidine-1-yl)-(1s)-1-phenethyl carbamate - Google Patents
Method for preparing 2-((3s)-3-hydroxy pyrrolidine-1-yl)-(1s)-1-phenethyl carbamate Download PDFInfo
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- CN103772257A CN103772257A CN201310748887.8A CN201310748887A CN103772257A CN 103772257 A CN103772257 A CN 103772257A CN 201310748887 A CN201310748887 A CN 201310748887A CN 103772257 A CN103772257 A CN 103772257A
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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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/10—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 no double bonds between ring members or between ring members and non-ring members 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
- C07D207/12—Oxygen or sulfur atoms
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Abstract
The invention belongs to the technical field of organic synthesis method design and crude drug and intermediate preparation, and particularly relates to a method for preparing 2-((3s)-3-hydroxy pyrrolidine-1-yl)-(1s)-1-phenethyl carbamate (I). The method comprises the steps of dissolving 2-oxo-((3s)3-hydroxy pyrrolidine-1-yl)-(1s)-1-phenethyl carbamate in an aprotic solvent; adding a reducing agent by batches; stirring for reacting for 8-10 hours at certain temperature to obtain a target compound. The 2-((3s)-3-hydroxy pyrrolidine-1-yl)-(1s)-1-phenethyl carbamate (I) is one of the major technological impurities inevitably generated in a preparation process of asimadoline. In order to better study the quality conditions of the crude drug and preparation of asimadoline, the development of a preparation method of the compound (I) is of very important significance.
Description
technical field
The invention belongs to methodology of organic synthesis design and bulk drug and intermediate preparing technical field, be specifically related to the preparation technology of 2-((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl carbamate.
Background technology
Asimadoline is a kind of κ-opioid receptor agonist, is the active drug for the treatment of irritable bowel syndrome (IBS), is at present the clinical study stage three phases.Clinical study shows can raise IBS patient's sensitivity threshold of Asimadoline, and tolerance is good, has a good application prospect.
2-((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl carbamate (I) is one of main technique impurity certainly leading in Asimadoline preparation process, its residual meeting has a strong impact on the quality of finished product, and current disclosed document yet there are no the synthetic report of this impurity.But in order to study better the quality condition of Asimadoline bulk drug and preparation, in the urgent need to obtaining the reference substance of compound (I), for the detection and localization of high performance liquid chromatography (HPLC), (I) preparation method who therefore develops compound has very important significance.
Summary of the invention
The present invention relates to a kind of method of the better simply 2-of preparation (s-3-hydroxyl pyrrolidine-1-yl)-s-1-styroyl carbamate (I), be dissolved in non-protonic solvent by 2-oxo-((3s) 3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl carbamate, add reductive agent in batches, under certain temperature, stirring reaction 8-10 h obtains target compound (I).Reaction equation is as follows:
Wherein: R is H, C1-C3 straight or branched alkyl, benzyl, the phenyl that phenyl or alkyl replace etc.
Temperature of reaction is 0-30 ℃, preferably room temperature reaction.
Solvent is aprotic solvent or their mixed solvents such as methylene dichloride, chloroform, toluene, ether, tetrahydrofuran (THF) (THF), preferably THF.
Reductive agent is the metal hydrides such as lithium aluminum hydride, aluminum hydride, preferably lithium aluminum hydride.
Embodiment
Following example is to describe in detail the present invention, but is not construed as limiting the invention.
The preparation of embodiment: 2-((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl urethanum.
Embodiment one
In 100 mL there-necked flasks, add 0.585 g (15.4 mmol) lithium aluminum hydride and the anhydrous THF of 20 mL, stir and form suspension liquid.Weighing 2-oxo-((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl urethanum 3.0 g (10.5 mmol) is dissolved in 30 mL THF.Under condition of ice bath, 2-oxo-(s-3-hydroxyl pyrrolidine-1-yl)-s-1-styroyl urethanum is added dropwise in reaction flask, ice bath stirring reaction 8 h, are slowly added dropwise to 5 mL deionized water cancellation reactions.Filter, the concentrated yellow oil that obtains of filtrate, dissolves oily matter with methylene dichloride, uses deionized water washed twice.Concentrated yellow oil 2.480 g, the yield 86.81% of obtaining of organic phase.
1H NMR(DMSO-
d 6 ) δ 1.503-1.553(m，3H)，4.422-4.445(m，2H)，5.210-5.235(s，1H)，3.715-3.730(m，1H)，3.025-3.251(m，2H)，7.551-7.815(m，5H)。
Embodiment two
In 100 mL there-necked flasks, add 0.959 g (25.3 mmol) lithium aluminum hydride and the anhydrous DCM of 30 mL, stir and form suspension liquid.Weighing 2-oxo-((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl urethanum 5.0 g (17.1 mmol) is dissolved in the anhydrous DCM of 30 mL.Under condition of ice bath, 2-oxo-((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl urethanum is added dropwise in reaction flask, stirring at room temperature is reacted 8 h, is added dropwise to 5 mL deionized water cancellation reactions.Filter, the concentrated yellow oil that obtains of filtrate, dissolves oily matter with methylene dichloride, uses deionized water washed twice.Concentrated yellow oil 3.810 g, the yield 80.24% of obtaining of organic phase.
1H NMR(DMSO-
d 6 ) δ 1.503-1.557(m，3H)，4.426-4.451(m，2H)，5.210-5.239(s，1H)，3.718-3.730(m，1H)，3.031-3.259(m，2H)，7.554-7.824(m，5H)。
The preparation of embodiment: 2-((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl phenyl carbamate
Embodiment three:
In 100 mL there-necked flasks, add 0.788 g (26.3 mmol) aluminum hydride and 50 mL THF, stir and form suspension liquid.Weighing 2-oxo-((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl phenyl carbamate 3.574 g (10.5 mmol) is dissolved in 30 mL THF.Under condition of ice bath, 2-oxo-(s-3-hydroxyl pyrrolidine-1-yl)-s-1-styroyl urethanum is added dropwise in reaction flask, ice bath stirring reaction 12 h, are added dropwise to 5 mL deionized water cancellation reactions.Filter, filtrate separatory, organic phase deionized water washed twice, with concentrated yellow oil 2.823 g, the yield 86.50% of obtaining after anhydrous magnesium sulfate drying.
1H NMR(DMSO-
d 6 ) δ 1.643-1.872(m，2H)，2.931-3.157(m，2H)，3.685-3.730(m，1H)，4.830-4.854(m，1H)，5.513-5.539(s，1H)，7.259-7.378(m，8H)，7.476-7.513(m，2H)。
The preparation of embodiment: 2-(s-3-hydroxyl pyrrolidine-1-yl)-s-1-styroyl benzyl carbamate
Embodiment four
In 100 mL there-necked flasks, add 0.968 g (25.5 mmol) lithium aluminum hydride and the anhydrous THF of 30mL, stir and form suspension liquid.Weighing 2-oxo-((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl benzyl carbamate 5.0 g (14.1 mmol) is dissolved in the anhydrous THF of 30 mL.Under condition of ice bath, 2-oxo-((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl benzyl carbamate solution is added dropwise in reaction flask, ice bath stirring reaction 10 h, are added dropwise to 5 mL deionized water cancellation reactions.Filter, the concentrated yellow oil that obtains of filtrate, dissolves oily matter with methylene dichloride, uses deionized water washed twice.Concentrated yellow oil 4.088 g, the yield 85.11% of obtaining of organic phase.
1H NMR(DMSO-
d 6 ) δ 5.537-5.551(m，2H)，5.419-5.440(s，1H)，3.419-3.433(m，1H)，3.029-3.251(m，2H)，7.556-7.823(m，10H)。
Embodiment five
In 100 mL there-necked flasks, add in 0.835g (22.0 mmol) lithium aluminum hydride and 30mL dry toluene, stir and form suspension liquid.Weighing ((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl benzyl carbamate 5.0 g (14.1 mmol) is dissolved in 30 mL dry toluenes.Under condition of ice bath, 2-oxo-((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl benzyl carbamate solution is added dropwise in reaction flask, after dripping 0.5 h, remove ice bath, stirring at room temperature is added dropwise to 5 mL deionized water cancellation reactions after reacting 10 h.Filter, the concentrated yellow oil that obtains of filtrate, dissolves oily matter with methylene dichloride, uses deionized water washed twice.Concentrated yellow oil 2.155 g, the yield 60.32% of obtaining of organic phase.
1H NMR(DMSO-
d 6 ) δ 5.545-5.549(m，2H)，5.419-5.442(s，1H)，3.420-3.432(m，1H)，3.027-3.252(m，2H)，7.852-7.820(m，10H)。
Claims (7)
1. prepare the method for 2-((3s)-3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl carbamate (I) for one kind, it is characterized in that 2-oxo-((3s) 3-hydroxyl pyrrolidine-1-yl)-(1s)-1-styroyl carbamate to be dissolved in non-protonic solvent, add reductive agent in batches, at the temperature of 0-30 ℃, stirring reaction 8-10 h obtains target compound (I)
Wherein: R is H, C1-C3 straight or branched alkyl, benzyl, the phenyl that phenyl or alkyl replace.
2. preparation method according to claim 1, its temperature of reaction is 0-5 ℃.
3. preparation method according to claim 1, wherein said non-protonic solvent is one or more mixed solvents in methylene dichloride, chloroform, toluene, ether, tetrahydrofuran (THF) (THF).
4. preparation method according to claim 3, wherein said non-protonic solvent is THF.
5. preparation method according to claim 1, wherein said reductive agent is metal hydride.
6. preparation method according to claim 5, the metal hydride described in it is lithium aluminum hydride, aluminum hydride.
7. preparation method according to claim 6, reductive agent is lithium aluminum hydride.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1079219A (en) * | 1992-05-09 | 1993-12-08 | 默克专利股份有限公司 | Arylacetamide |
| CN1297435A (en) * | 1998-04-20 | 2001-05-30 | 默克专利股份公司 | Method for producing enantiomer-free N-methyl-N-[(1S)-1-phenyl-2-[(3S)-3-hydroxypyrrolidine-1-y1)ethyl]-2, 2-diphenyl acetamide |
| WO2012012410A2 (en) * | 2010-07-19 | 2012-01-26 | Dr. Reddy's Laboratories Ltd. | Kappa opioid receptor agonists |
| WO2013131408A1 (en) * | 2012-03-05 | 2013-09-12 | Dr.Reddy's Laboratories Ltd. | Substituted heterocyclic acetamides as kappa opioid receptor (kor) agonists |
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2013
- 2013-12-31 CN CN201310748887.8A patent/CN103772257A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1079219A (en) * | 1992-05-09 | 1993-12-08 | 默克专利股份有限公司 | Arylacetamide |
| CN1297435A (en) * | 1998-04-20 | 2001-05-30 | 默克专利股份公司 | Method for producing enantiomer-free N-methyl-N-[(1S)-1-phenyl-2-[(3S)-3-hydroxypyrrolidine-1-y1)ethyl]-2, 2-diphenyl acetamide |
| WO2012012410A2 (en) * | 2010-07-19 | 2012-01-26 | Dr. Reddy's Laboratories Ltd. | Kappa opioid receptor agonists |
| WO2013131408A1 (en) * | 2012-03-05 | 2013-09-12 | Dr.Reddy's Laboratories Ltd. | Substituted heterocyclic acetamides as kappa opioid receptor (kor) agonists |
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Application publication date: 20140507 |