CN108774153A - The preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile - Google Patents
The preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile Download PDFInfo
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- CN108774153A CN108774153A CN201810418217.2A CN201810418217A CN108774153A CN 108774153 A CN108774153 A CN 108774153A CN 201810418217 A CN201810418217 A CN 201810418217A CN 108774153 A CN108774153 A CN 108774153A
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- chloro
- preparation
- epoxychloropropane
- butyronitrile
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/16—Preparation of carboxylic acid nitriles by reaction of cyanides with lactones or compounds containing hydroxy groups or etherified or esterified hydroxy groups
Abstract
The invention discloses the preparation methods of one kind (S) -4- chloro-3-hydroxyl butyronitrile, S- epoxychloropropane puts into reactor with solvent, it keeps suitable under reaction temperature, a certain amount of hydrogen cyanide is added dropwise thereto in certain time, rear insulation reaction is added dropwise to terminating, 5% sodium hydroxide solution is added, stirring a period of time, stratification, (S) -4- chloro-3-hydroxyl butyronitrile is concentrated under reduced pressure in organic phase, the invention avoids the uses of a large amount of Cymags, to greatly reduce wastewater flow rate and wherein cyaniding sodium content, wastewater treatment expense is low, reaction yield of the present invention is high, preparation process is simple, it is suitble to industrialized production.
Description
Technical field
The present invention relates to synthesis technical fields, and in particular to the preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile.
Background technology
Atorvastatin calcium is the drug of Pfizer pharmaceutical developments, can effectively reduce blood fat, has high-efficiency low-toxicity
Side effect, receive the favor in market.1 synthetic method of existing Atorvastatin side chain intermediate A is as follows：
Prior art is that a certain amount of water is added in reactor, S- epoxychloropropane is added, while sodium cyanide solution is added dropwise
And dilute dilute sulfuric acid, it keeps PH and temperature in a certain range, uses solvent extraction after reaction, solvent is concentrated under reduced pressure and obtains A1.
The technique uses large excess of sodium cyanide solution, produces a large amount of cyanide wastewater, industrial processing is expensive, is unfavorable for existing
The theory for the green production that country advocates.
Invention content
The content of present invention is directed to the deficiency of prior art, provides the preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile, directly
It connects using hydrogen cyanide and S- epoxychloropropane single step reactions, both obtains A1, reaction yield is high, and easy to operate, cyanide wastewater is significantly
It reduces.
The technical scheme is that：
The preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile, 1 part of S- epoxychloropropane are reacted with 2-6 parts of solvent inputs
Device is kept under suitable reaction temperature, wherein 0.8-2 part hydrogen cyanide are added dropwise, rear insulation reaction is added dropwise to terminating, addition
10% sodium hydroxide solution, stirring a period of time, (S) -4- chloro-3-hydroxyl butyronitrile is concentrated under reduced pressure in stratification, organic phase.
Further, the suitable reaction temperature is at 20-60 DEG C, preferably 40-45 DEG C.
Further, the solvent is toluene, and toluene is 2-6, preferably 3-4 with S- epoxychloropropane charged material weight ratio.
Further, the time for adding that hydrogen cyanide is added is 2-8h, preferably 3-4h.
Further, the molar ratio of the S- epoxychloropropane and hydrogen cyanide is 0.8-2, preferably 1.1-1.2.
Beneficial effects of the present invention are：
The content of present invention is directed to the deficiency of prior art, directly uses hydrogen cyanide and S- epoxychloropropane single step reactions, both
A1 is obtained, reaction yield is high, and easy to operate, cyanide wastewater greatly reduces.
Specific implementation mode
The specific implementation mode of the present invention is described further below, the present embodiment is not construed as limiting the invention.
Embodiment 1
By in 200kgS- epoxychloropropane (2.16mol, 1eq) and 600kg toluene input reactor, 40 DEG C are warming up to, drop
It is 4h to add 65kg hydrogen cyanide (2.4mol, 1.11eq) (flowmeter metering), control time for adding.Insulation reaction, on-line monitoring are anti-
It should be flowed into reaction kettle and 10% sodium hydroxide solutions of 100kg are added completely, stirring 30min, stratification, organic phase decompression is dense
Contract to obtain 234kg A1, purity 98.2%.
Embodiment 2
By in 200kgS- epoxychloropropane (2.16mol, 1eq) and 600kg toluene input reactor, 55 DEG C are warming up to, drop
It is 8h to add 65kg hydrogen cyanide (2.4mol, 1.11eq) (flowmeter metering), control time for adding.Insulation reaction, on-line monitoring are anti-
Should be complete, into reaction kettle, 10% sodium hydroxide solutions of 100kg are added in stream, stir 30min, stratification, organic phase decompression
It is concentrated to give 221kg A1, purity 97.9%.
Embodiment 3
By in 200kgS- epoxychloropropane (2.16mol, 1eq) and 600kg toluene input reactor, 35 DEG C are warming up to, drop
Add 80kg hydrogen cyanide (2.96mol, 1.37eq) (flowmeter metering), time for adding 4h.Insulation reaction, on-line monitoring have reacted
Entirely, into reaction kettle, 10% sodium hydroxide solutions of 100kg are added in stream, stir 30min, stratification, and organic phase is concentrated under reduced pressure
204kg A1, purity 96.3%.
Embodiment 4
By in 200kgS- epoxychloropropane (2.16mol, 1eq) and 800kg toluene input reactor, 45 DEG C are warming up to, drop
Add 58kg hydrogen cyanide (2.16mol, 1eq) (flowmeter metering), time for adding 3h.Insulation reaction, the reaction was complete for on-line monitoring,
Into reaction kettle, 10% sodium hydroxide solutions of 100kg are added in stream, stir 30min, stratification, and organic phase is concentrated under reduced pressure
231kg A1, purity 98.1%.
Comparative example 1
700kg water is added into reactor, 200kg S- epoxychloropropane (2.16mol, 1eq) keeps 30 DEG C of left sides of temperature
The right side, while 30% sulfuric acid of 30% sodium cyanide solutions of 800kg (4.9mol, 2.27eq) and 800kg is added dropwise, keep PH on 7 left sides
The right side, the reaction was complete for GC monitoring, and ethyl acetate extracting and demixing is added, and 219kg A1, purity 97.3% is concentrated under reduced pressure to obtain in organic phase.
The above described is only a preferred embodiment of the present invention, being not used in the limitation present invention, those skilled in the art can
It is this to change or equally replace within the spirit and scope of the present invention, various modifications or equivalent replacements are made to the present invention
It changes and also should be regarded as falling in the protection domain of technical solution of the present invention.
Claims (5)
1. the preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile, it is characterised in that：1 part of S- epoxychloropropane and 2-6 parts of solvents
Reactor is put into, is kept under suitable reaction temperature, wherein 0.8-2 part hydrogen cyanide are added dropwise, rear insulation reaction is added dropwise to knot
10% sodium hydroxide solution is added in beam, and stirring a period of time, (S) -4- chloro-3-hydroxyls are concentrated under reduced pressure in stratification, organic phase
Butyronitrile.
2. according to the preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile described in claim 1, it is characterised in that：It is described
Suitable reaction temperature at 20-60 DEG C, preferably 40-45 DEG C.
3. according to the preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile described in claim 1, it is characterised in that：It is described
Solvent is toluene, and toluene is 2-6, preferably 3-4 with S- epoxychloropropane charged material weight ratio.
4. according to the preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile described in claim 1, it is characterised in that：It is described
The time for adding that hydrogen cyanide is added is 2-8h, preferably 3-4h.
5. according to the preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile described in claim 1, it is characterised in that：It is described
The molar ratio of S- epoxychloropropane and hydrogen cyanide is 0.8-2, preferably 1.1-1.2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810418217.2A CN108774153A (en) | 2018-05-03 | 2018-05-03 | The preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810418217.2A CN108774153A (en) | 2018-05-03 | 2018-05-03 | The preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile |
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| Publication Number | Publication Date |
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| CN108774153A true CN108774153A (en) | 2018-11-09 |
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| CN201810418217.2A Pending CN108774153A (en) | 2018-05-03 | 2018-05-03 | The preparation method of one kind (S) -4- chloro-3-hydroxyl butyronitrile |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1764636A (en) * | 2003-04-16 | 2006-04-26 | 株式会社Lg生命科学 | Process for preparing 4-chloro-3-hydroxybutanoic acid ester |
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2018
- 2018-05-03 CN CN201810418217.2A patent/CN108774153A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1764636A (en) * | 2003-04-16 | 2006-04-26 | 株式会社Lg生命科学 | Process for preparing 4-chloro-3-hydroxybutanoic acid ester |
Non-Patent Citations (1)
| Title |
|---|
| HUBER, JOEL E.等: "《e-EROS Encyclopedia of Reagents for Organic Synthesis 》", 31 December 2011, JOHN WILEY & SONS, LTD., CHICHESTER, UK. * |
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Application publication date: 20181109 |