CN103073481A - Preparation method for 4-azaspiro [2.4] heptane hydrochloride - Google Patents
Preparation method for 4-azaspiro [2.4] heptane hydrochloride Download PDFInfo
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- CN103073481A CN103073481A CN2013100477444A CN201310047744A CN103073481A CN 103073481 A CN103073481 A CN 103073481A CN 2013100477444 A CN2013100477444 A CN 2013100477444A CN 201310047744 A CN201310047744 A CN 201310047744A CN 103073481 A CN103073481 A CN 103073481A
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Abstract
The invention relates to a preparation method for 4-azaspiro [2.4] heptane hydrochloride and mainly aims to solve the technical problem that a suitable industrial synthesis method does not exist at present. The preparation method comprises the following steps of: firstly, preparing 4-benzyl-4-azaspiro [2.4] heptane by taking 1-benzylpyrrolidine-2-ketone and an ethylmagnesium bromide reagent as raw materials, and then, preparing the 4-azaspiro [2.4] heptane hydrochloride by using chloroethyl chloroformate. The reaction formula is shown as follows: the 4-azaspiro [2.4] heptane hydrochloride obtained by the preparation method is a useful midbody or product used for synthesizing plenty of drugs.
Description
Technical field
The present invention relates to the synthetic method of 4-azaspiro [2.4] heptane hydrochloride.
Background technology
4-azaspiro [2.4] heptane hydrochloride and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.4-azaspiro [2.4] heptane hydrochloride is synthetic comparatively difficult at present.Therefore, need raw material of exploitation to be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is fit to.
Summary of the invention
The objective of the invention is to develop and a kind ofly have raw material and be easy to get, easy to operate, reaction is easy to control, the synthetic method of 4-azaspiro [2.4] the heptane hydrochloride that yield is higher.Mainly solve the technical problem that is not fit at present Industrialized synthesis method.
Technical scheme of the present invention: the preparation method of a kind of 4-azaspiro [2.4] heptane hydrochloride; may further comprise the steps; the present invention in two steps; at first; ethylmagnesium bromide reagent is placed anhydrous tetrahydro furan; under the nitrogen protection; at-80 to-50 degrees centigrade; drip titanium isopropylate; then at-80 to-50 degrees centigrade 1-benzyl-pyrrole alkane-2-ketone is joined in the reaction system; the lower stirring of room temperature (20-30 ℃) obtained 4-benzyl-4-azaspiro [2.4] heptane in 60-80 hour, preferred stirring at room 72 hours, and reaction formula is as follows:
Then, 4-benzyl-4-azaspiro [2.4] heptane is placed methylene dichloride, under-20 to 10 degrees centigrade, drip ethyl chloroformate, then stirred overnight at room temperature (12-16 hour) added methanol eddy 1 to 8 hour at last, obtain 4-azaspiro [2.4] heptane hydrochloride, reaction formula is as follows:
Beneficial effect of the present invention: the invention provides the method for a kind of synthetic 4-azaspiro [2.4] heptane hydrochloride, the method route is short, and yield can be up to more than 90%, and reaction is easy to amplify convenient experimental operation.
Embodiment
Reaction formula of the present invention is as follows:
Embodiment 1:a, with ethylmagnesium bromide reagent (4.8 mL; 1.7 mmol) place anhydrous tetrahydro furan (100 mL); under the nitrogen protection; at-65 degrees centigrade, drip titanium isopropylate (1.62 g, 5.72 mmol); stirred 30 minutes; then at-65 degrees centigrade 1-benzyl-pyrrole alkane-2-ketone (1.0 g, 5.72 mmol) is joined in the reaction system stirring at room 72 hours.The TLC(sherwood oil: the ethyl acetate volume ratio=3:1) following the tracks of reaction finishes, and adds entry (10 mL) in reaction system, and adding salt of wormwood is basified to pH and equals 8, then uses ethyl acetate extraction, and each 10mL extracts three times.After acetic acid ethyl acetate extract merges, use the saturated common salt water washing, each 10mL, washed twice, ethyl acetate solution arrives 4-benzyl-4-azaspiro [2.4] heptane (2 g, yield 93%) with anhydrous sodium sulfate drying, and product is directly used in next step operation.
Compound 4-benzyl-4-azaspiro [2.4] heptane (1.0 g, 5.35 mmol) is placed methylene dichloride (100 mL), and then 4 degrees centigrade of lower ethyl chloroformates (2.29 g, 16 mmol) that drip at room temperature stir and spend the night.The TLC(sherwood oil: the ethyl acetate volume ratio=5:1) following the tracks of reaction finishes.Reaction soln is spin-dried for revolving to steam, and residuum adding methyl alcohol (20 mL) and reflux 3 hours are spin-dried for reaction solution, obtain product 4-azaspiro [2.4] heptane hydrochloride (0.7 g, yield 99%).
1 T00412603?TH05653-029-1?MeOD?400MHz
δ?4.525-4.510?(m,?2H),?2.810-2.651?(m,?4H),?0.530-0.471?(m,?2H)。
B, at-50 degrees centigrade, drip titanium isopropylate, at-50 degrees centigrade 1-benzyl-pyrrole alkane-2-ketone is joined in the reaction system, under-20 degrees centigrade, drip ethyl chloroformate, added methyl alcohol and reflux 1 hour, all the other same a obtain product yield 90%.
C, at-80 degrees centigrade, drip titanium isopropylate, at-80 degrees centigrade 1-benzyl-pyrrole alkane-2-ketone is joined in the reaction system, under 10 degrees centigrade, drip ethyl chloroformate, added methyl alcohol and reflux 8 hours, all the other same a obtain product yield 92%.
Embodiment 2: with ethylmagnesium bromide reagent (48 mL; 17 mmol) place anhydrous tetrahydro furan (1 L); under the nitrogen protection; at-65 degrees centigrade, drip titanium isopropylate (16.2 g, 57.2 mmol); stirred 30 minutes; then at-65 degrees centigrade 1-benzyl-pyrrole alkane-2-ketone (10 g, 57.2 mmol) is joined in the reaction system stirring at room 72 hours.The TLC(sherwood oil: the ethyl acetate volume ratio=3:1) following the tracks of reaction finishes, and adds entry (100 mL) in reaction system, and adding salt of wormwood is basified to pH and equals 8, then uses ethyl acetate extraction, and each 200mL extracts three times.After acetic acid ethyl acetate extract merges, use the saturated common salt water washing, each 100mL, washed twice, ethyl acetate solution arrives 4-benzyl-4-azaspiro [2.4] heptane (19 g, yield 87.4%) with anhydrous sodium sulfate drying, and product is directly used in next step.
Compound 4-benzyl-4-azaspiro [2.4] heptane (19 g, 0.1 mol) is placed methylene dichloride (1.0 L), and then 4 degrees centigrade of lower ethyl chloroformates (43.5 g, 0.3 mol) that drip at room temperature stir and spend the night.The TLC(sherwood oil: the ethyl acetate volume ratio=5:1) following the tracks of reaction finishes.Reaction soln is spin-dried for revolving to steam, and residuum adding methyl alcohol (200 mL) and reflux 3 hours are spin-dried for reaction solution, obtain product 4-azaspiro [2.4] heptane hydrochloride (13.3 g, yield 99%).
1 T00412603?TH05653-029-1?MeOD?400MHz
δ?4.525-4.510?(m,?2H),?2.810-2.651?(m,?4H),?0.530-0.471?(m,?2H)。
Embodiment 3: with ethylmagnesium bromide reagent (480 mL; 1.7 mol) place anhydrous tetrahydro furan (1.5 L); under the nitrogen protection; at-70 degrees centigrade, drip titanium isopropylate (162 g, 572 mmol); stirred 30 minutes; then at-65 degrees centigrade 1-benzyl-pyrrole alkane-2-ketone (100 g, 572 mmol) is joined in the reaction system stirring at room 72 hours.The TLC(sherwood oil: the ethyl acetate volume ratio=3:1) following the tracks of reaction finishes, and adds entry (1.0 L) in reaction system, and adding salt of wormwood is basified to pH and equals 8, then uses ethyl acetate extraction, and each 1.0 L extract three times.After acetic acid ethyl acetate extract merges, use the saturated common salt water washing, each 1.0 L, washed twice, ethyl acetate solution arrives 4-benzyl-4-azaspiro [2.4] heptane (200 g, yield 93%) with anhydrous sodium sulfate drying, and product is directly used in next step.
Compound 4-benzyl-4-azaspiro [2.4] heptane (100 g, 535 mmol) is placed methylene dichloride (1.5 L), and then 4 degrees centigrade of lower ethyl chloroformates (229 g, 1.6 mol) that drip at room temperature stir and spend the night.The TLC(sherwood oil: the ethyl acetate volume ratio=5:1) following the tracks of reaction finishes.Reaction soln is spin-dried for revolving to steam, and residuum adding methyl alcohol (2.0 L) and reflux 3 hours are spin-dried for reaction solution, obtain product 4-azaspiro [2.4] heptane hydrochloride (70 g, yield 99%).
1 T00412603?TH05653-029-1?MeOD?400MHz
δ?4.525-4.510?(m,?2H),?2.810-2.651?(m,?4H),?0.530-0.471?(m,?2H)。
Claims (2)
1. the preparation method of a 4-azaspiro [2.4] heptane hydrochloride, it is characterized in that may further comprise the steps: the first step, ethylmagnesium bromide reagent is placed anhydrous tetrahydro furan, under the nitrogen protection, at-80 to-50 degrees centigrade, drip titanium isopropylate, then 1-benzyl-pyrrole alkane-2-ketone is joined in the reaction system, stirring reaction obtains 4-benzyl-4-azaspiro [2.4] heptane under the room temperature; Second step places methylene dichloride with 4-benzyl-4-azaspiro [2.4] heptane, under-20 to 10 degrees centigrade, drips ethyl chloroformate, and then stirred overnight at room temperature adds methanol eddy at last, obtains 4-azaspiro [2.4] heptane hydrochloride, and reaction formula is as follows:
2. the preparation method of a kind of 4-azaspiro according to claim 1 [2.4] heptane hydrochloride is characterized in that, the first step reaction room temperature churning time is 60 to 80 hours, second step methanol eddy reaction 1 to 8 hour.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109485648A (en) * | 2018-12-17 | 2019-03-19 | 无锡合全药业有限公司 | The preparation method of tert-butyl -1- methyl -5- oxygen subunit thriazaspiro [5.5] hendecane -8- formic acid base ester |
| CN110092753A (en) * | 2018-01-31 | 2019-08-06 | 南京药石科技股份有限公司 | A kind of preparation method synthesizing 3- azabicyclic [4.1.0] heptane -2- formic acid and its hydrochloride |
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| CN1100095A (en) * | 1988-08-31 | 1995-03-15 | 第一制药株式会社 | Preparation of a sprio compound |
| CN102863373A (en) * | 2012-09-07 | 2013-01-09 | 苏州康润医药有限公司 | Method for synthesizing 5-benzylazaspiro[2,4]heptane |
| WO2013013505A1 (en) * | 2011-07-26 | 2013-01-31 | 山东亨利医药科技有限责任公司 | 9-aminomethyl substituted tetracycline compound |
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2013
- 2013-02-06 CN CN2013100477444A patent/CN103073481A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1100095A (en) * | 1988-08-31 | 1995-03-15 | 第一制药株式会社 | Preparation of a sprio compound |
| WO2013013505A1 (en) * | 2011-07-26 | 2013-01-31 | 山东亨利医药科技有限责任公司 | 9-aminomethyl substituted tetracycline compound |
| CN102863373A (en) * | 2012-09-07 | 2013-01-09 | 苏州康润医药有限公司 | Method for synthesizing 5-benzylazaspiro[2,4]heptane |
Non-Patent Citations (3)
| Title |
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| KUO-WEI LIN, ET AL: "Unusual Ambiphilic Carbenoid Equivalentin Amide Cyclopropanation", 《ORG. LETT.》 * |
| PHILIPPE BERTUS AND JAN SZYMONIAK: "Titanium- and Lewis Acid-Mediated Cyclopropanation of Imides", 《ORG.LETT.》 * |
| 姚其正: "《药物合成反应》", 30 September 2012, 北京：中国医药科技出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110092753A (en) * | 2018-01-31 | 2019-08-06 | 南京药石科技股份有限公司 | A kind of preparation method synthesizing 3- azabicyclic [4.1.0] heptane -2- formic acid and its hydrochloride |
| CN110092753B (en) * | 2018-01-31 | 2022-04-26 | 南京药石科技股份有限公司 | Preparation method for synthesizing 3-azabicyclo [4.1.0] heptane-2-formic acid and hydrochloride thereof |
| CN109485648A (en) * | 2018-12-17 | 2019-03-19 | 无锡合全药业有限公司 | The preparation method of tert-butyl -1- methyl -5- oxygen subunit thriazaspiro [5.5] hendecane -8- formic acid base ester |
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Owner name: TIANJIN YAOMING KANGDE NEW MEDICINE DEVELOPMENT CO Free format text: FORMER OWNER: TIANJIN YAOMING KANGDE NEW MEDICINE DEVELOPMENT CO., LTD. WUHAN YAOMING KANGDE NEW DRUGS DEVELOPMENT CO., LTD. YAOMINGKANGDE NEW MEDICINE DEVELOPMENT CO., LTD., WUXI SHANGHAI SYNTHEALL PHARMACEUTICAL CO., LTD. SHANGHAI STA PHARMACEUTICAL R + D CO., LTD. Effective date: 20141216 |
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Effective date of registration: 20141216 Address after: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant after: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Applicant after: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. Applicant after: Wuhan AppTec New Drug Development Co., Ltd. Address before: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Applicant before: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. Applicant before: Wuhan AppTec New Drug Development Co., Ltd. Applicant before: Yaomingkangde New Medicine Development Co., Ltd., Wuxi Applicant before: Shanghai SynTheAll Pharmaceutical Co., Ltd. Applicant before: Shanghai STA Pharmaceutical R & D Co., Ltd. |
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Application publication date: 20130501 |