CN109503624A - The synthetic method of 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formate - Google Patents
The synthetic method of 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formate Download PDFInfo
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- CN109503624A CN109503624A CN201811539645.7A CN201811539645A CN109503624A CN 109503624 A CN109503624 A CN 109503624A CN 201811539645 A CN201811539645 A CN 201811539645A CN 109503624 A CN109503624 A CN 109503624A
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- Prior art keywords
- compound
- oxa
- nonane
- butyl formate
- diaza spiro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
Abstract
The present invention relates to a kind of synthetic methods of 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formate, the technical issues of mainly solution currently without suitable Industrialized synthesis method.The present invention divides three steps, paraformaldehyde is added in solvent n,N-Dimethylformamide by compound 1 first in the first step, tetrabutyl ammonium fluoride reacts to obtain compound 2, second step, compound 2 and bromoacetate, cesium carbonate reacts in acetone obtains compound 3, third step, compound 3 and iron, ammonium chloride reacts in second alcohol and water obtains final compound 4, and reaction equation is as follows:
Description
Technical field
The present invention relates to compound 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formates
Synthetic method.
Background technique
Compound 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formate (CAS:1251000-
12-0) and relevant derivative has extensive use in pharmaceutical chemistry and organic synthesis.Oxa- -2 6- oxygen subunit -8- at present,
5- diaza spiro [3.5] nonane -2- t-butyl formate synthetic method rarely has document report.It is easy therefore, it is necessary to develop a raw material
, it is easy to operate, react easily controllable, overall yield is suitble to, and is suitble to the synthetic method of industrialized production.
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 6- of yield
The synthetic method of oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formate.It mainly solves currently without suitable
The technical issues of closing Industrialized synthesis method.
A kind of technical solution of the present invention: the tertiary fourth of 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- formic acid
The synthetic method of ester, the present invention divide three steps, and the first step is added in solvent n,N-Dimethylformamide by compound 1 more first
Polyformaldehyde, tetrabutyl ammonium fluoride react to obtain compound 2, second step, compound 2 and bromoacetate, and cesium carbonate is in acetone
Reaction obtains compound 3, third step, compound 3 and iron, and ammonium chloride reacts in second alcohol and water obtains final compound 4.Reaction
Formula is as follows:
First step reaction temperature is 0 DEG C-room temperature, is reacted 16 hours；Second step reaction temperature is 60 DEG C, and the reaction time is 1 hour；
Third step reaction temperature is that 80 DEG C of reactions are stayed overnight.
The Chinese paraphrase that the present invention abridges: TLC: thin-layered chromatography.
Beneficial effects of the present invention: reaction process of the present invention design rationally, which employs be easy to get, can large-scale production original
Expect 3- nitro azetidine -1- t-butyl formate, synthesizes 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonyl by three steps
Alkane -2- t-butyl formate, this method route is short, and yield may be up to 56%, and reaction is easy to amplify, easy to operate.
Specific embodiment
Reaction equation of the present invention is as follows:
Embodiment:
Step 1: compound 1 (45 g, 0.22 mol) is dissolved in n,N-Dimethylformamide (500 mL), poly is added
Formaldehyde (60.2 g, 0.66 mol), this is that reaction is cooled to 0 DEG C, and tetrabutyl ammonium fluoride (5.8 g, 0.02 mol) adds
Entering into reaction solution the reaction is kept for 0 DEG C react 30 minutes, is then warming up to room temperature and is reacted 30 minutes 15 hours.TLC is aobvious
Show that reaction is over.Diatomite filtering is added in the reaction, and filtrate, which is poured into water, is added ethyl acetate extraction, organic to be added to anhydrous sulphur
Take solid chemical compound 2 (47 g, 90% purity) yield of white after sour sodium is dry: 90%.
1(400 M; CDCl3)
δ4.43-4.40 (d, J = 10 Hz, 2 H), 4.20-4.18 (d, J = 9.2 Hz, 2 H), 4.15-4.12
(d, J = 10 Hz, 2 H), ,1.46 (s, 9 H)。
Step 2: compound 2 (200 g, 0.86 mol) is dissolved in acetone (1.5L), sequentially add at room temperature
Cesium carbonate (561 g, 1.72 mol) and bromoacetate (172 g, 1.03 mol), at this moment reaction is warming up to 60 DEG C of reactions
1 hour.TLC display reaction is over.The reaction, which is poured into water, is added ethyl acetate extraction, organic to be added to anhydrous sodium sulfate drying
After take crude product, gained crude product is obtained colourless with silica gel column purification (gradient elution: petrol ether/ethyl acetate volume ratio=8:1)
Oily compound 3 (170 g, 62% purity) yield: 80%.
1(400 M; CDCl3)
δ 4.44 (2 H, d, J=10.14 Hz), 4.16 - 4.25 (6 H, m), 4.12 (2 H, s), 1.45 (9
H, s), 1.24 - 1.32 (3 H, m)。
Step 3: compound 3 (55 g, 0.17 mol) is dissolved in ethyl alcohol (500 mL) and water (100 mL),
At room temperature be added ammonium chloride (27.7 g, 0.52 mol), this be reaction be warming up to 80 DEG C of addition iron (48.2 g, 0.86
Mol) the reaction is maintained at 80 DEG C overnight.LCMS display reaction is over.It is cooled to room temperature, filter and filtrate is spin-dried for
After be dissolved in ethyl acetate, water extraction is added three times, it is organic be added to anhydrous sodium sulfate it is dry after take crude product, gained crude product is used
Silica gel column purification (gradient elution: petrol ether/ethyl acetate volume ratio=1:2) obtain white solid chemical compound 4 (30 g,
71.6% purity) yield 78%.
1(400 M; CDCl3)
δ7.51 (1 H, br. s.), 4.15 (2 H, s), 3.94 - 4.00 (2 H, m), 3.88 - 3.92 (4
H, m), 1.43 (9 H, s)。
Claims (4)
1. a kind of synthetic method of 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formate, feature
It is: includes the following steps, paraformaldehyde, four fourths is added by compound 1 first in the first step in solvent n,N-Dimethylformamide
Base ammonium fluoride reacts to obtain compound 2, second step, compound 2 and bromoacetate, and cesium carbonate reacts in acetone obtains chemical combination
Object 3, third step, compound 3 and iron, ammonium chloride reacts in second alcohol and water obtains final compound 4, and reaction equation is as follows:
。
2. 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formate according to claim 1
Synthetic method, it is characterized in that: the first step maintains 0 DEG C to arrive room temperature reaction 16 hours.
3. 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formate according to claim 1
Synthetic method, it is characterized in that: second step reaction temperature is 60 DEG C, the reaction time is 1 hour.
4. 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formate according to claim 1
Synthetic method, it is characterized in that: 80 DEG C of third step reactions are overnight.
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| CN201811539645.7A CN109503624A (en) | 2018-12-17 | 2018-12-17 | The synthetic method of 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formate |
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| CN201811539645.7A CN109503624A (en) | 2018-12-17 | 2018-12-17 | The synthetic method of 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formate |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111574537A (en) * | 2020-05-20 | 2020-08-25 | 成都药明康德新药开发有限公司 | Synthesis method of tert-butyl-8-oxa-3, 11-diazaspiro [5.6] dodecane-3-formylate |
| CN113200997A (en) * | 2021-05-07 | 2021-08-03 | 上海合全医药有限公司 | Synthesis method of 2, 5-dioxa-8-azaspiro [3.5] nonane and salt thereof |
| CN113278021A (en) * | 2021-05-29 | 2021-08-20 | 天津全和诚科技有限责任公司 | Preparation method of 1, 7-diazaspiro [3.5] nonane-7-tert-butyl formate and oxalate thereof |
| CN116082359A (en) * | 2022-11-08 | 2023-05-09 | 南通药明康德医药科技有限公司 | Method for preparing 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tert-butyl ester |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111574537A (en) * | 2020-05-20 | 2020-08-25 | 成都药明康德新药开发有限公司 | Synthesis method of tert-butyl-8-oxa-3, 11-diazaspiro [5.6] dodecane-3-formylate |
| CN111574537B (en) * | 2020-05-20 | 2022-11-15 | 成都药明康德新药开发有限公司 | Synthesis method of tert-butyl-8-oxa-3,11-diazaspiro [5.6] dodecane-3-formylate |
| CN113200997A (en) * | 2021-05-07 | 2021-08-03 | 上海合全医药有限公司 | Synthesis method of 2, 5-dioxa-8-azaspiro [3.5] nonane and salt thereof |
| CN113200997B (en) * | 2021-05-07 | 2023-10-03 | 上海合全医药有限公司 | Synthesis method of 2, 5-dioxa-8-azaspiro [3.5] nonane and salt thereof |
| CN113278021A (en) * | 2021-05-29 | 2021-08-20 | 天津全和诚科技有限责任公司 | Preparation method of 1, 7-diazaspiro [3.5] nonane-7-tert-butyl formate and oxalate thereof |
| CN116082359A (en) * | 2022-11-08 | 2023-05-09 | 南通药明康德医药科技有限公司 | Method for preparing 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tert-butyl ester |
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