CN109651368A - The preparation method of 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate - Google Patents
The preparation method of 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate Download PDFInfo
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- CN109651368A CN109651368A CN201811539643.8A CN201811539643A CN109651368A CN 109651368 A CN109651368 A CN 109651368A CN 201811539643 A CN201811539643 A CN 201811539643A CN 109651368 A CN109651368 A CN 109651368A
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- oxygen
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- C—CHEMISTRY; METALLURGY
- 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
- C07D471/10—Spiro-condensed systems
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Abstract
The present invention relates to a kind of preparation methods of 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate, the technical issues of mainly solution currently without suitable Industrialized synthesis method.In two steps, the first step, with compound 1 and dimethyl maleate under the action of tetrabutylammonium iodide and potassium fluoride, dimethyl sulfoxide makees solvent to the present invention, and reaction generates compound 2；Second step, compound 2 is under conditions of methanol as solvent, through Raney's nickel/H2Catalytic hydrogenation obtains compound 3, i.e. 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate；Reaction equation is as follows:
Description
Technical field
The present invention relates to the preparation sides of 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate
Method.
Background technique
4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate (PubChem ID:545357)
And relevant derivative has important application in pharmaceutical chemistry and organic synthesis, there is fabulous prospect.But at present there is no complete
Synthetic route report.Therefore, it develops a cheap raw material to be easy to get, easy to operate, reaction is easy to produce in batches control, overall yield
The great meaning of suitable synthetic method.
Summary of the invention
It is a kind of cheap with raw material the purpose of the present invention is developing, it is easy to operate, it can amplify, the synthesis of two step higher yields
The preparation method of 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate.It mainly solves at present should
The technical issues of compound is without rapidly and efficiently preparation method.
A kind of technical solution of the present invention: the tertiary fourth of 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- formic acid
The preparation method of ester, the present invention include 2 steps: the first step, with compound 1 and dimethyl maleate in tetrabutylammonium iodide and
Under the action of potassium fluoride, dimethyl sulfoxide makees solvent, and reaction generates compound 2；Second step, compound 2 is in methanol as solvent
Under the conditions of, through Raney's nickel/H2Catalytic hydrogenation obtains compound 3, i.e. 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] last of the ten Heavenly stems
Alkane -8- t-butyl formate.Reaction equation is as follows:
In above-mentioned technique, first step reaction temperature is 25-40 DEG C, and the reaction time is 22 hours；Second step reaction temperature is 50 DEG C,
Hydrogen Vapor Pressure is 50 psi, and the reaction time is 12 hours.
Beneficial effects of the present invention: rationally, which employs cheap and easy to get, energy large-scale productions for reaction process design of the present invention
Raw material 4- nitro piperidines -1- carboxylic acid tert-butyl ester, synthesized 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] by two steps
Decane -8- t-butyl formate has been saved synthesis cost, and can have been produced on a large scale.
Specific embodiment
Reaction equation of the present invention is as follows:
Embodiment:
Step 1: compound 1 (100 g, 434.29 mol) is dissolved in 25 DEG C of stirrings in dimethyl sulfoxide (500 mL),
Then tetrabutylammonium iodide (160.41 g, 434.29 mmol) and potassium fluoride (126.15 g, 2.17 mol) is added.10 points
Dimethyl maleate (312.96 g, 2.17 mol, 272.14 mL) is added after clock and temperature is risen to 40 DEG C
Reaction 22 hours.TLC (petrol ether/ethyl acetate volume ratio=3/1) shows end of reaction.Water is added into reaction system
(2.5 L) is then extracted with fert-butyidimethylsilyl ether (500 mL x 5), is depressurized after organic phase anhydrous sodium sulfate drying dense
Contracting obtains crude product, gained crude product silica gel column purification (gradient elution: petrol ether/ethyl acetate~petrol ether/ethyl acetate body
Product ratio=5:1 ~ 10:1) obtain the oily compound 2 (140.2 g, 374.48 mmol) of yellow, yield 86%.
1 CHLOROFORM-d, 400 MHz
δ 4.17 - 3.97 (m, 2H), 3.79 (s, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.36
(dd, J = 3.2, 11.6 Hz, 1H), 2.88 (dd, J = 11.7, 17.1 Hz, 2H), 2.68 - 2.41 (m,
4H), 2.03 (s, 1H), 1.93 - 1.82 (m, 1H), 1.74 (ddd, J = 4.8, 12.3, 14.4 Hz,
1H), 1.47 - 1.42 (m, 9H)。
Step 2: compound 2 (14 g, 37.39 mmol) is added to methanol (150 mL) in hydrogenation bottle,
Then Raney's nickel (Raney Ni) (7 g, 81.70 mmol) are added at 50 DEG C, 50 psi react 12 hours.TLC (petroleum
Ether/ethyl acetate volume ratio=1/1) display end of reaction.Reaction solution plus diatomite are filtered, filtrate decompression is concentrated to get slightly
Product, gained crude product with fert-butyidimethylsilyl ether be beaten, filtering, filtration cakes torrefaction can be obtained compound as white solid 3 (9.92 g,
31.76 mmol), yield 84.9%.
1DMSO-d6 400 MHz
δ 8.44 (s, 1H), 3.64 (s, 5H), 3.06 (br t, J = 8.3 Hz, 3H), 2.71 - 2.58
(m, 1H), 2.44 - 2.32 (m, 1H), 1.85 - 1.72 (m, 1H), 1.59 - 1.22 (m, 12H)。
Claims (3)
1. a kind of preparation method of 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate, feature
Be: the following steps are included: the first step, with compound 1 and dimethyl maleate tetrabutylammonium iodide and potassium fluoride work
Under, dimethyl sulfoxide makees solvent, and reaction generates compound 2；Second step, compound 2 is under conditions of methanol as solvent, through thunder
Buddhist nun's nickel/H2Catalytic hydrogenation obtains compound 3, i.e. 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- formic acid
The tert-butyl ester；Reaction equation is as follows:
。
2. 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate according to claim 1
Preparation method, it is characterized in that: 25-40 DEG C of the first step react 22 hours.
3. 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate according to claim 1
Preparation method, it is characterized in that: 50 DEG C of second step react 12 hours, Hydrogen Vapor Pressure be 50 psi.
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| CN201811539643.8A CN109651368A (en) | 2018-12-17 | 2018-12-17 | The preparation method of 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate |
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| CN201811539643.8A CN109651368A (en) | 2018-12-17 | 2018-12-17 | The preparation method of 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113121537A (en) * | 2021-04-13 | 2021-07-16 | 南通药明康德医药科技有限公司 | Synthesis method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102083832A (en) * | 2008-05-01 | 2011-06-01 | 葛兰素惠尔康制造有限公司 | Spiro (piperidine-4,2'-pyrrolidine)-1-(3,5-trifluoromethyl phenyl) methylcarboxamides as NK1 Tachikynin receptor antagonists |
-
2018
- 2018-12-17 CN CN201811539643.8A patent/CN109651368A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102083832A (en) * | 2008-05-01 | 2011-06-01 | 葛兰素惠尔康制造有限公司 | Spiro (piperidine-4,2'-pyrrolidine)-1-(3,5-trifluoromethyl phenyl) methylcarboxamides as NK1 Tachikynin receptor antagonists |
Non-Patent Citations (2)
| Title |
|---|
| NCBI: "《Database PubChem Compound [Online]》", 27 March 2005, PUBCHEM CID 545357 * |
| PHILIP MULLEN 等: "N-Boc 4-nitropiperidine: preparation and conversion into a spiropiperidine analogue of the eastern part of maraviroc", 《TETRAHEDRON LETTERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113121537A (en) * | 2021-04-13 | 2021-07-16 | 南通药明康德医药科技有限公司 | Synthesis method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate |
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Application publication date: 20190419 |