CN109627207A - A kind of preparation method of 3- (difluoro-methoxy) piperidine hydrochlorate - Google Patents
A kind of preparation method of 3- (difluoro-methoxy) piperidine hydrochlorate Download PDFInfo
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- CN109627207A CN109627207A CN201811539647.6A CN201811539647A CN109627207A CN 109627207 A CN109627207 A CN 109627207A CN 201811539647 A CN201811539647 A CN 201811539647A CN 109627207 A CN109627207 A CN 109627207A
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- difluoro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The present invention relates to a kind of preparation methods of 3- (difluoro-methoxy) piperidine hydrochlorate, the technical issues of mainly solution currently without suitable Industrialized synthesis method.The present invention is total in two steps: the first step; compound 1 is added in acetonitrile; cuprous iodide is added into above-mentioned solution again; heating; 2- (fluorosulfonyl) difluoroacetic acid being dissolved in acetonitrile in advance is added dropwise into reaction solution again, reaction terminates post-treated purifying and obtains compound 2, second step; compound 2 stirs to get compound 3 in hydrochloric ethyl acetate solution, and reaction equation is as follows:
Description
Technical field
The present invention relates to the synthetic methods of 3- (difluoro-methoxy) piperidine hydrochlorate (CAS:1638772-02-7).
Background technique
3- (difluoro-methoxy) piperidine hydrochlorate and relevant derivative have extensive in pharmaceutical chemistry and organic synthesis
Using.Seldom about the synthesis report of 3- (difluoro-methoxy) piperidine hydrochlorate at present, there are certain danger for similar document reaction
Dangerous and route is long, and yield is lower.Therefore it needs to develop a raw material to be easy to get, it is easy to operate, react easily controllable, overall yield
Suitable synthetic 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 3- of yield
The synthetic method of (difluoro-methoxy) piperidine hydrochlorate.It mainly solves to ask currently without the technology of suitable Industrialized synthesis method
Topic.
Technical solution of the present invention: a kind of preparation method of 3- (difluoro-methoxy) piperidine hydrochlorate includes the following steps,
In two steps, the first step compound 1 is added in acetonitrile the present invention, then cuprous iodide is added into above-mentioned solution, heats, then to
2- (fluorosulfonyl) difluoroacetic acid being dissolved in acetonitrile in advance is added dropwise in reaction solution, reaction terminates post-treated purifyingization
Object 2, second step are closed, compound 2 stirs to get compound 3 in hydrochloric ethyl acetate solution, and reaction equation is as follows:
50 DEG C of the first step are reacted 1 hour；15 DEG C of second step are reacted 2 hours.
Beneficial effects of the present invention: the present invention provides it is a kind of synthesize 3- (difluoro-methoxy) piperidine hydrochlorate method,
This method synthetic route is short, and reaction is easy to amplify, easy to operate, has industrial applications prospect.
Specific embodiment
Reaction equation of the present invention is as follows:
Embodiment 1:
Will compound 1 (50 g, 248.4 mmol) be added acetonitrile (70 mL) in, add cuprous iodide (9.5 g, 49.7
Mmol), reaction is heated to 50 DEG C, then the 2- (fluorosulfonyl) being dissolved in acetonitrile (30mL) in advance is added dropwise into reaction solution
Difluoroacetic acid, reaction persistently stir 1 hour at 50 DEG C.TLC (petrol ether/ethyl acetate volume ratio=3/1) display reaction knot
Beam.Solvent in reaction system is removed by concentration, is added water (50 mL), ethyl acetate extraction, anhydrous sodium sulfate drying
After be concentrated under reduced pressure to give crude product and pass through column chromatographic isolation and purification again and obtain 4.5 g compounds 2, yield 72.09%.
Compound 2(20 g, 79.6 mmol) is added in ethyl acetate (50 mL), hydrochloric ethyl acetate is added
Reaction is persistently stirred 2 hours by (4M, 300 mL) at 15 DEG C.LC (petrol ether/ethyl acetate volume ratio=3/1) is aobvious
Show that reaction terminates.Solvent in reaction system is removed by concentration, obtains compound 3(15 g).HNMR (400MHz,
MeOD) δ= 1.74 - 2.14 (m, 5 H) 3.05 - 3.16 (m, 1 H) 3.20 - 3.29 (m, 1 H) 4.62
(br s, 1 H) 6.31 - 6.84 (m, 1 H)。
Claims (3)
1. a kind of preparation method of tert-butyl 3- (difluoro-methoxy) piperidine hydrochlorate, it is characterized in that: the following steps are included:
One step compound 1 is added in acetonitrile, then cuprous iodide is added into above-mentioned solution, heats, then thing is added dropwise into reaction solution
2- (fluorosulfonyl) difluoroacetic acid being first dissolved in acetonitrile, reaction terminate post-treated purify and obtain compound 2, second step,
Compound 2 stirs to get compound 3 in hydrochloric ethyl acetate solution, and reaction equation is as follows:
。
2. the preparation method of a kind of 3- (difluoro-methoxy) piperidine hydrochlorate according to claim 1, it is characterized in that: first
50 DEG C are walked to react 1 hour.
3. the preparation method of a kind of 3- (difluoro-methoxy) piperidine hydrochlorate according to claim 1, it is characterized in that: second
15 DEG C are walked to react 2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201811539647.6A CN109627207A (en) | 2018-12-17 | 2018-12-17 | A kind of preparation method of 3- (difluoro-methoxy) piperidine hydrochlorate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811539647.6A CN109627207A (en) | 2018-12-17 | 2018-12-17 | A kind of preparation method of 3- (difluoro-methoxy) piperidine hydrochlorate |
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| CN109627207A true CN109627207A (en) | 2019-04-16 |
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| CN201811539647.6A Pending CN109627207A (en) | 2018-12-17 | 2018-12-17 | A kind of preparation method of 3- (difluoro-methoxy) piperidine hydrochlorate |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101835764A (en) * | 2007-10-24 | 2010-09-15 | 安斯泰来制药有限公司 | Azolecarboxamide compound or salt thereof |
| WO2013112323A1 (en) * | 2012-01-23 | 2013-08-01 | Eli Lilly And Company | Phenyl methanesulfonamide derivatives useful as mgat - 2 inhibitors |
| CN107735088A (en) * | 2015-05-07 | 2018-02-23 | Chdi基金会股份有限公司 | Histone deacetylase inhibitor and combinations thereof and application method |
| WO2018134685A2 (en) * | 2017-01-17 | 2018-07-26 | Liverpool School Of Tropical Medicine | Compounds |
-
2018
- 2018-12-17 CN CN201811539647.6A patent/CN109627207A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101835764A (en) * | 2007-10-24 | 2010-09-15 | 安斯泰来制药有限公司 | Azolecarboxamide compound or salt thereof |
| WO2013112323A1 (en) * | 2012-01-23 | 2013-08-01 | Eli Lilly And Company | Phenyl methanesulfonamide derivatives useful as mgat - 2 inhibitors |
| CN107735088A (en) * | 2015-05-07 | 2018-02-23 | Chdi基金会股份有限公司 | Histone deacetylase inhibitor and combinations thereof and application method |
| WO2018134685A2 (en) * | 2017-01-17 | 2018-07-26 | Liverpool School Of Tropical Medicine | Compounds |
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