CN108586287A - A kind of preparation method of 2- phenyl -2- cyano butyramides - Google Patents
A kind of preparation method of 2- phenyl -2- cyano butyramides Download PDFInfo
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- CN108586287A CN108586287A CN201810059915.8A CN201810059915A CN108586287A CN 108586287 A CN108586287 A CN 108586287A CN 201810059915 A CN201810059915 A CN 201810059915A CN 108586287 A CN108586287 A CN 108586287A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/20—Preparation of carboxylic acid nitriles by dehydration of carboxylic acid amides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
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Abstract
A kind of preparation method of 2 phenyl, 2 cyano butyramide, preparation method are：Polar solvent is cooled down in ice-water bath, dehydrating agent is added dropwise, it is added dropwise and phenylethyl malonamide is added by several times, carry out dehydration, reaction, which finishes, is slowly added into reaction solution in ice water, stirring while adding, continues to stir 1h after adding, be precipitated white solid, white solid through filtering, wash, drain after obtain 2 phenyl, 2 cyano butyramide crude product；Organic solvent is added into crude product, dissolves by heating, activated carbon decolorizing flows back after dissolved clarification, heat filtering, mother liquor Temperature fall, then ice bath cooling, and white needle-like crystals are precipitated, obtain 2 phenyl, 2 cyano butyramide；Its synthetic route is：
Description
Technical field
The invention belongs to technical field of pharmaceuticals, are related to a kind of preparation of pharmaceutical intermediate, more particularly to a kind of 2- phenyl -2-
The preparation method of cyano butyramide.
Background technology
Primidone（No. CAS：125-33-7）It is a kind of scentless white crystalline powder, chemical name：5- ethyls -5-
Phenyl-dihydro -4,6（1H, 5H）Hybar X, molecular formula C12H14N2O2, molecular weight 325.42, taste slightly bitter is no acidic,
Slightly soluble in ethyl alcohol.Primidone is antiepileptic, is clinically mainly used for epilepsy Myoclonic seizures, simple partial seizure and complexity
The single medicine or drug combination of partial seizures are treated.It is also used for the treatment of idiopathic concussion and senile concussion.
There are six impurity of A, B, C, D, E, F, 2- phenyl -2- cyano in European Pharmacopoeia and United States Pharmacopeia Primidone quality standard
Butyramide is Primidone impurity D（Formula 1）, synthetic method reported without open source information so far.
Formula 1
Invention content
The technical problem to be solved in the present invention is to provide a kind of route is short, 2- phenyl -2- cyano butyramides easy to operate
Preparation method.
In order to solve the above technical problems, the technical scheme is that：A kind of preparation side of 2- phenyl -2- cyano butyramides
Method, innovative point are：The preparation method is that：After polar solvent is cooled to 10 DEG C in ice-water bath, dehydrating agent, drop is added dropwise
Phenylethyl malonamide is added after the completion of adding by several times, carries out dehydration, is slowly added into reaction solution after the completion of reaction
In 100g ice water, controls and added in 20-30min, it is stirring while adding, continue to stir 1h after adding, the mixing speed is
260rpm, be precipitated white solid, white solid through filtering, wash, drain after obtain 2- phenyl -2- cyano butyramide crude products；To
0.7-0.8 times of organic solvent of crude product quality is added in crude product, is heated to 65 DEG C of dissolvings, activated carbon decolorizing flows back after dissolved clarification
20min, heat filtering, mother liquor are naturally cooling to 22-25 DEG C, then ice bath is cooled to 0-5 DEG C, and white needle-like crystals are precipitated in heat preservation 2h,
Obtain 2- phenyl -2- cyano butyramides；
Further, the dehydrating agent is one kind in phosphorus oxychloride or thionyl chloride, the dehydrating agent and phenylethyl third
The ratio between amount of substance of diamides is 1.1-1.3：1, temperature is no more than 25 DEG C during the dehydrating agent is added dropwise.
Further, the phenylethyl malonamide feeding mode is to divide 2-3 time and feed intake, when the often minor tick
Between be 5min.
Further, the polar solvent is one kind in DMF or DMSO, the polar solvent and phenylethyl the third two
The amount ratio of amide material is 3.0-3.5：1.
Further, the dehydration temperature is 40-50 DEG C, reaction time 3-4h.
Further, the organic solvent is one kind in ethyl alcohol, 95% ethyl alcohol, ethyl acetate.
Beneficial effects of the present invention are as follows：The present invention provides a kind of route is short, post-processing is simple, preparation easy to operation
The method of 2- phenyl -2- cyano butyramides provides qualified reference substance as Primidone impurity D for the quality control of Primidone.
2- phenyl -2- cyano butyramide purity obtained is higher（HPLC reaches 98% or more）, can be applied to research of the chemical standard product.
Specific implementation mode
The following examples can make professional and technical personnel that the present invention be more fully understood, but therefore not send out this
It is bright to be limited among the embodiment described range.
Embodiment 1
It is dried in 250mL and DMF 25mL stirrings is added in four-hole bottle, ice bath is cooled to 10 DEG C and starts that 18g (0.117mol) is added dropwise
Phosphorus oxychloride, control dropping temperature is no more than 25 DEG C, by 20.6g（0.1mol）Phenylethyl malonamide puts into reaction in three times
In system, per minor tick 5min, charge temperature is no more than 25 DEG C.Fed intake end, in 40-50 DEG C of insulation reaction 3-4 hours.Reaction
Terminate, reaction solution is slowly added in 100g ice water, controls and added in 20-30min, stirring while adding, mixing speed is
260rpm continues to stir 1h after adding, white solid is precipitated, filter, wash, drain to obtain 2- phenyl -2- cyano butyramides it is thick
Product dry to obtain 16.1g, and crude product is dissolved in 15mL ethyl acetate, are heated to being completely dissolved, and activated carbon decolorizing flows back after dissolved clarification
30min, heat filtering, after mother liquor is naturally cooling to 22-25 DEG C, ice bath cools to 0-5 DEG C of crystallization 2h, and white needle is obtained by filtration
Shape crystal dries to obtain 13.2g 2- phenyl -2- cyano butyramides.
Embodiment 2
It is dried in 250mL and DMSO 25mL stirrings is added in four-hole bottle, ice bath is cooled to 10 DEG C and starts that 18g (0.117mol) is added dropwise
Phosphorus oxychloride, control dropping temperature are no more than 25 DEG C, are added dropwise, by 20.6g（0.1mol）Phenylethyl malonamide point three
In secondary input reaction system, per minor tick 5min, charge temperature is no more than 25 DEG C.Feed intake end, in 40-50 DEG C of insulation reaction 3-
4 hours.Reaction terminates, and reaction solution is slowly added in 100g ice water, controls and is added in 20-30min, stirring while adding, stirring
Speed is 260rpm, continues to stir 1h after adding, white solid is precipitated, filters, wash, draining to obtain 2- phenyl -2- cyano fourths
Crude amide dries to obtain 16.2g, and crude product is dissolved in 95% ethyl alcohol of 15mL, is heated to being completely dissolved, activated carbon decolorizing after dissolved clarification
Flow back 30min, and heat filtering, after mother liquor is naturally cooling to 22-25 DEG C, ice bath cools to 0-5 DEG C of crystallization 2h, is obtained by filtration white
Color acicular crystal dries to obtain 13.4g target products.
Embodiment 3
It is dried in 250mL and DMF 25mL stirrings is added in four-hole bottle, ice bath is cooled to 10 DEG C and starts that 15.5g (0.13mol) is added dropwise
Thionyl chloride, control dropping temperature are no more than 25 DEG C, are added dropwise, by 20.6g（0.1mol）Phenylethyl malonamide point three
In secondary input reaction system, per minor tick 5min, charge temperature is no more than 25 DEG C.Feed intake end, in 40-50 DEG C of insulation reaction 3-
4 hours.Reaction terminates, and reaction solution is slowly added in 100g ice water, stirring while adding, controls and is added in 20-30min, stirs
Speed is 260rpm, continues to stir 1h after adding, white solid is precipitated, filters, wash, draining to obtain 2- phenyl -2- cyano fourths
Crude amide dries to obtain 14.4g, and crude product is dissolved in 13mL ethyl acetate, is heated to being completely dissolved, activated carbon decolorizing after dissolved clarification
Flow back 30min, and heat filtering, after mother liquor is naturally cooling to 22-25 DEG C, ice bath cools to 0-5 DEG C of crystallization 2h, is obtained by filtration white
Color acicular crystal dries to obtain 11.7g target products.
Embodiment 4
It is dried in 250mL and DMSO 25mL stirrings is added in four-hole bottle, ice bath is cooled to 10 DEG C and starts that 15.5g is added dropwise
(0.13mol) thionyl chloride, control dropping temperature are no more than 25 DEG C, are added dropwise, by 20.6g（0.1mol）Phenylethyl the third two
Amide is put into reaction system in three times, and per minor tick 5min, charge temperature is no more than 25 DEG C.Feed intake end, in 40-50 DEG C of guarantor
Temperature reaction 3-4 hours.Reaction terminates, and reaction solution is slowly added in 100g ice water, controls and is added in 20-30min, side edged stirs
It mixes, mixing speed 260rpm, continues to stir 1h after adding, white solid is precipitated, filters, wash, draining to obtain 2- phenyl -2-
Cyano butyramide crude product, dries to obtain 14.2g, and crude product is dissolved in 12mL ethyl alcohol, is heated to being completely dissolved, and activated carbon is de- after dissolved clarification
Color reflux 30min, heat filtering, after mother liquor is naturally cooling to 22-25 DEG C, ice bath cools to 0-5 DEG C of crystallization 2h, is obtained by filtration
White needle-like crystals dry to obtain 11.3g target products.The physical and chemical index of 2- phenyl -2- cyano butyramides obtained by embodiment 1-4
It is as shown in table 1.
The physical and chemical index of 2- phenyl -2- cyano butyramides obtained by 1 embodiment 1-4 of table
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | |
| Appearance | White crystalline powder | White crystalline powder | White crystalline powder | White crystalline powder |
| Total recovery .% | 73.3% | 74.4% | 65% | 62.7% |
| Purity .% | 98.5% | 98.4% | 98.2% | 98.4% |
| DEG C of fusing point | 115.5-116.2℃ | 115.3-116.8℃ | 116.5-118.6℃ | 115.5-117.4℃ |
Note：Appearance is tested with eyesight；Purity passes through hplc determination；Fusing point is with GB/T 28724-2012 standard tests.
Conclusion：As shown in Table 1, the 2- phenyl -2- cyano butyramide purity made from embodiment 1-4 is higher（HPLC reaches
98% or more）, stable yield can be applied to research of the chemical standard product.
The basic principles and main features and advantages of the present invention of the present invention have been shown and described above.The skill of the industry
Art personnel it should be appreciated that the present invention is not limited to the above embodiments, the above embodiments and description only describe
The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these
Changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and
Its equivalent thereof.
Claims (6)
1. a kind of preparation method of 2- phenyl -2- cyano butyramides, it is characterised in that：The preparation method is that：By polar solvent
After being cooled to 10 DEG C in ice-water bath, dehydrating agent is added dropwise, is added dropwise and phenylethyl malonamide is added by several times, be dehydrated anti-
It answers, reaction solution is slowly added into 100g ice water after the completion of reaction, control and added in 20-30min, it is stirring while adding, it adds
After continue stir 1h, the mixing speed be 260rpm, be precipitated white solid, white solid through filtering, wash, drain after obtain
2- phenyl -2- cyano butyramide crude products；Into crude product be added crude product quality 0.7-0.8 times of organic solvent, be heated to 65 DEG C it is molten
It solving, activated carbon decolorizing reflux 20min after dissolved clarification, heat filtering, mother liquor is naturally cooling to 22-25 DEG C, then ice bath is cooled to 0-5 DEG C,
It keeps the temperature 2h and white needle-like crystals is precipitated, obtain 2- phenyl -2- cyano butyramides；Its synthetic route is：
。
2. a kind of preparation method of 2- phenyl -2- cyano butyramides according to claim 1, it is characterised in that：It is described de-
Aqua is one kind in phosphorus oxychloride or thionyl chloride, the ratio between the amount of substance of the dehydrating agent and phenylethyl malonamide
For 1.1-1.3：1, temperature is no more than 25 DEG C during the dehydrating agent is added dropwise.
3. a kind of preparation method of 2- phenyl -2- cyano butyramides according to claim 1, it is characterised in that：The benzene
Base ethyl malonamide feeding mode is to divide 2-3 times to feed intake, and each interval time is 5min.
4. a kind of preparation method of 2- phenyl -2- cyano butyramides according to claim 1, it is characterised in that：The pole
Property solvent be one kind in DMF or DMSO, the amount ratio of the polar solvent and phenylethyl malonamide substance is 3.0-
3.5：1.
5. a kind of preparation method of 2- phenyl -2- cyano butyramides according to claim 1, it is characterised in that：It is described de-
Water reaction temperature is 40-50 DEG C, reaction time 3-4h.
6. a kind of preparation method of 2- phenyl -2- cyano butyramides according to claim 1, it is characterised in that：It is described to have
Solvent is one kind in ethyl alcohol, 95% ethyl alcohol, ethyl acetate.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810059915.8A CN108586287A (en) | 2018-01-22 | 2018-01-22 | A kind of preparation method of 2- phenyl -2- cyano butyramides |
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| CN201810059915.8A CN108586287A (en) | 2018-01-22 | 2018-01-22 | A kind of preparation method of 2- phenyl -2- cyano butyramides |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030144538A1 (en) * | 2000-02-10 | 2003-07-31 | Johannes Bartek | Method for producing alkoxy malonic acid dinitriles |
| CN107089929A (en) * | 2017-06-22 | 2017-08-25 | 广西科技大学 | It is trans（4 cyanogen methyl）The preparation method of Cyclohexylamino t-butyl formate |
-
2018
- 2018-01-22 CN CN201810059915.8A patent/CN108586287A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030144538A1 (en) * | 2000-02-10 | 2003-07-31 | Johannes Bartek | Method for producing alkoxy malonic acid dinitriles |
| CN107089929A (en) * | 2017-06-22 | 2017-08-25 | 广西科技大学 | It is trans（4 cyanogen methyl）The preparation method of Cyclohexylamino t-butyl formate |
Non-Patent Citations (1)
| Title |
|---|
| W.R.BOON ET AL: "Some Derivatives of Tetra- and Hexa-hydro-4:6-dioxopyrimidine", 《JOURNAL OF THE CHEMICAL SOCIETY》 * |
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