CN109503579A - The preparation method of tert-butyl -1- methyl -5- oxygen subunit thriazaspiro [5.5] hendecane -9- formic acid base ester - Google Patents
The preparation method of tert-butyl -1- methyl -5- oxygen subunit thriazaspiro [5.5] hendecane -9- formic acid base ester Download PDFInfo
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- CN109503579A CN109503579A CN201811539869.8A CN201811539869A CN109503579A CN 109503579 A CN109503579 A CN 109503579A CN 201811539869 A CN201811539869 A CN 201811539869A CN 109503579 A CN109503579 A CN 109503579A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The present invention relates to a kind of tert-butyl -1- methyl -5- oxygen subunit-Isosorbide-5-Nitrae, the preparation methods of 9- thriazaspiro [5.5] hendecane -9- formic acid base ester, the technical issues of mainly solution currently without suitable Industrialized synthesis method.The present invention is total in two steps: the first step, ethylenediamine and benzyltriethylammoinium chloride are added in methylene chloride；5-20 DEG C is added drop-wise to sodium hydrate aqueous solution in reaction solution；It is stirred to react, N- tertbutyloxycarbonyl -4- piperidones is then dissolved in the mixture that chlorination is imitative after methylene chloride and is added drop-wise in above-mentioned reaction solution, reaction obtains compound 2；Compound 2 is dissolved in methanol by second step, and formalin and acetic acid is added；Sodium cyanoborohydride is added at 0 DEG C；Mixture is stirred to react, and reaction terminates, and processing purifying obtains final product.The compound that the present invention obtains provides useful intermediate or product for the synthesis of many drugs.
Description
Technical field
The present invention relates to tert-butyl -1- methyl -5- oxygen subunit thriazaspiro [5.5] hendecane -9- formic acid base ester, i.e., tertiary fourths
Base -1- methyl -5- oxygen subunit -1,4,9- thriazaspiro [5.5] hendecane -9- formic acid base ester (CAS:1263177-81-6)
Preparation method.
Background technique
Tert-butyl -1- methyl -5- oxygen subunit -1,4,9- thriazaspiro [5.5] hendecane -9- formic acid base ester and relevant spread out
Biology has in pharmaceutical chemistry and organic synthesis to be widely applied.At present about tert-butyl -1- methyl -5- oxygen subunit -1,4,9-
Seldom, there are certain risk and roads for similar document reaction for the synthesis report of thriazaspiro [5.5] hendecane -9- formic acid base ester
Wire length, yield are lower.Therefore it needs to develop a raw material to be easy to get, it is easy to operate, react easily controllable, the suitable conjunction of overall yield
At method.
Summary of the invention
It is easy to operate the purpose of the present invention is developing one kind to be easy to get with raw material, react easily controllable, the higher uncle of yield
The preparation method of butyl -1- methyl -5- oxygen subunit -1,4,9- thriazaspiro [5.5] hendecane -9- formic acid base ester.Mainly solve
The technical issues of currently without suitable Industrialized synthesis method.
A kind of technical solution of the present invention: tert-butyl -1- methyl -5- oxygen subunit -1,4,9- thriazaspiro [5.5] 11
The preparation method of alkane -9- formic acid base ester, includes the following steps, the present invention in two steps, the first step, ethylenediamine and benzyl triethyl ammonium chlorine
Change ammonium to be added in methylene chloride；5-20 DEG C is added drop-wise to sodium hydrate aqueous solution in reaction solution；It is stirred to react, then by the tertiary fourth of N-
Oxygen carbonyl -4- piperidones is dissolved in the mixture that chlorination is imitative after methylene chloride and is added drop-wise in above-mentioned reaction solution, and reaction obtains compound
2.Compound 2 is dissolved in methanol by second step, and formalin and acetic acid is added；Sodium cyanoborohydride is added at 0 DEG C；Mixing
Object is stirred to react, and reaction terminates, and processing purifying obtains compound 3.Reaction equation is as follows:
For first step reaction temperature practical range at 5-25 DEG C, the reaction time is 8 hours；Second step reaction temperature practical range is in 0-
25 DEG C, the reaction time 16 hours.
Beneficial effects of the present invention: the present invention provides a kind of synthesizing tertiary butyl -1- methyl -5- oxygen subunit -1,4,9- three
The method of azaspiro [5.5] hendecane -9- formic acid base ester, this method synthetic route is short, and yield may be up to 70%, and reaction is easy to put
Greatly, easy to operate, there is industrial applications prospect.
Specific embodiment
Reaction equation of the present invention is as follows:
Embodiment 1:a, ethylenediamine (18.10 g, 301.13 mmol, 20.15 mL, 1.2eq) and benzyl triethyl ammonium chlorination
Ammonium (2.86 g, 12.55 mmol, 0.05eq) be added in DCM (200 mL)；Reaction cools to 5 degrees centigrades；It will
Sodium hydroxide (100.38 g, 2.51 mol, 10eq) aqueous solution that is dissolved in water (150 mL) is added drop-wise in reaction solution；Charging
Temperature maintains 5-20 degrees Celsius in the process, drips reaction and stirs 2 hours, N- tertbutyloxycarbonyl -4- piperidones (50 g,
250.95 mmol, 1 eq) be dissolved in methylene chloride (200 mL) afterwards chlorination it is imitative (44.94 g, 376.42 mmol, 30.36
mL, 1.5 eq) mixture be added drop-wise in the reaction solution of front, mixture stirs 6 hours under 25 degrees Celsius.TLC (dichloro
Methane/methanol volume ratio=20/1) display reaction terminates, with water (500 mL) quenching reaction, reaction solution saline solution later
It washes, water phase is extracted with dichloromethane, and merges organic phase and is dried over sodium sulfate, filters and be evaporated under reduced pressure, column chromatographic purifying obtains Huang
The compound 2 (40 g, crude) of color solid, yield 70%.
B, by compound 2(tert-butyl -5- oxygen subunit -1,4,9- thriazaspiro [5.5] hendecane -9- formic acid base ester) (10
g, 37.13 mmol, 1 eq) be dissolved in methanol (100 mL), 20 degrees Celsius of addition formalins (30.13 g, 371.28
mmol, 27.65 mL, 37% purity, 10 eq) and acetic acid (22.30 g, 371.28 mmol, 21.23 mL, 10eq)；Reaction under 0 degree Celsius be added sodium cyanoborohydride (4.67 g, 74.26 mmol, 2eq)；Mixture is Celsius 25
Degree lower stirring 16 hours, TLC (methylene chloride/methanol volume ratio=20/1) display reaction terminated, and reaction solution vacuum distillation is residual
Slag is extracted with ethyl acetate after being dissolved in water, and organic phase is washed with salt later, merges organic phase and is dried over sodium sulfate, filters and subtract
Pressure distillation, column chromatographic purifying obtain the compound 3 (8 g, crude) of yellow solid, yield 70%.
1H NMR (400MHz, CHLOROFORM-d) δ = 6.52 (br s, 1H), 3.92 (br s, 1H),
3.86 (br s, 1H), 3.34 (dt, J=2.4, 5.4 Hz, 2H), 3.09 (br s, 1H), 3.02 (br t, J
=5.3 Hz, 2H), 2.86 (br s, 1H), 2.49 (s, 3H), 2.10 (dt,J=4.8, 12.9 Hz, 2H),
1.57 (br s, 1H), 1.44 (s, 9H), 1.30 - 1.23 (m, 1H)。
Claims (3)
1. a kind of preparation side of tert-butyl -1- methyl -5- oxygen subunit -1,4,9- thriazaspiro [5.5] hendecane -9- formic acid base ester
Method, it is characterized in that: the following steps are included: the first step, ethylenediamine and benzyltriethylammoinium chloride are added in methylene chloride；5-20℃
Sodium hydrate aqueous solution is added drop-wise in reaction solution；It is stirred to react, N- tertbutyloxycarbonyl -4- piperidones is then dissolved in dichloromethane
The imitative mixture of chlorination is added drop-wise in above-mentioned reaction solution after alkane, and reaction obtains compound 2；Compound 2 is dissolved in methanol by second step
In, formalin and acetic acid is added；Sodium cyanoborohydride is added at 0 DEG C；Mixture is stirred to react, and reaction terminates, and is handled pure
Change obtains compound 3；Reaction equation is as follows:
。
2. a kind of tert-butyl -1- methyl -5- oxygen subunit -1,4,9- thriazaspiro according to claim 1 [5.5] 11
The preparation method of alkane -9- formic acid base ester, it is characterized in that: first step reaction temperature practical range at 5-25 DEG C, reacts 8 hours.
3. a kind of tert-butyl -1- methyl -5- oxygen subunit -1,4,9- thriazaspiro according to claim 1 [5.5] 11
The preparation method of alkane -9- formic acid base ester, it is characterized in that: second step reaction temperature practical range is at 0-25 DEG C, the reaction time 16 is small
When.
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| CN201811539869.8A CN109503579A (en) | 2018-12-17 | 2018-12-17 | The preparation method of tert-butyl -1- methyl -5- oxygen subunit thriazaspiro [5.5] hendecane -9- formic acid base ester |
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| CN201811539869.8A CN109503579A (en) | 2018-12-17 | 2018-12-17 | The preparation method of tert-butyl -1- methyl -5- oxygen subunit thriazaspiro [5.5] hendecane -9- formic acid base ester |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103608336A (en) * | 2011-02-01 | 2014-02-26 | 勃林格殷格翰国际有限公司 | 9-[4-(3-chlor-2-fluor-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one dimaleate, use thereof as a drug, and production thereof |
| CN106892928A (en) * | 2017-02-07 | 2017-06-27 | 上海药明康德新药开发有限公司 | A kind of synthetic method of the carboxylate of 8 hydroxyl of the tert-butyl group, 5 oxa- 2 azaspiro [3.5] nonane 2 |
| CN107216335A (en) * | 2017-06-29 | 2017-09-29 | 上海药明康德新药开发有限公司 | The formic acid base ester preparation method of 3 oxa- of a kind of tert-butyl group 1 (methylol) 9 azaspiro [5.5] hendecane 9 |
| CN108863958A (en) * | 2018-07-20 | 2018-11-23 | 南京药石科技股份有限公司 | A kind of preparation method of 4,7- diaza spiro [2.5] Octane derivatives |
-
2018
- 2018-12-17 CN CN201811539869.8A patent/CN109503579A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103608336A (en) * | 2011-02-01 | 2014-02-26 | 勃林格殷格翰国际有限公司 | 9-[4-(3-chlor-2-fluor-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one dimaleate, use thereof as a drug, and production thereof |
| CN106892928A (en) * | 2017-02-07 | 2017-06-27 | 上海药明康德新药开发有限公司 | A kind of synthetic method of the carboxylate of 8 hydroxyl of the tert-butyl group, 5 oxa- 2 azaspiro [3.5] nonane 2 |
| CN107216335A (en) * | 2017-06-29 | 2017-09-29 | 上海药明康德新药开发有限公司 | The formic acid base ester preparation method of 3 oxa- of a kind of tert-butyl group 1 (methylol) 9 azaspiro [5.5] hendecane 9 |
| CN108863958A (en) * | 2018-07-20 | 2018-11-23 | 南京药石科技股份有限公司 | A kind of preparation method of 4,7- diaza spiro [2.5] Octane derivatives |
Non-Patent Citations (2)
| Title |
|---|
| BELL: "[11C]MK-4232: The First Positron Emission Tomography Tracer for the Calcitonin Gene-Related Peptide Receptor", 《ACS MEDICINAL CHEMISTRY LETTERS》 * |
| RN:1263177-81-6: "Chemical Abstract Service", 《STNEXT REGISTRY 数据库》 * |
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