CN109776405A - A kind of preparation method of butyrate clevidipine impurity - Google Patents
A kind of preparation method of butyrate clevidipine impurity Download PDFInfo
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- CN109776405A CN109776405A CN201910173222.6A CN201910173222A CN109776405A CN 109776405 A CN109776405 A CN 109776405A CN 201910173222 A CN201910173222 A CN 201910173222A CN 109776405 A CN109776405 A CN 109776405A
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Abstract
The present invention provides a kind of preparation method of butyrate clevidipine impurity, and using butyrate clevidipine as raw material, butyrate clevidipine impurity is obtained under the action of ceric sulfate and strong acid.Operation of the present invention is easy, product purity is higher, and obtained target product can be used for drug quality research, has a good application prospect.
Description
Technical field
The present invention relates to butyrate clevidipines, and in particular to a kind of preparation method of butyrate clevidipine impurity belongs to medicine
Object synthesis technical field.
Background technique
Butyrate clevidipine (Clevidipine butyrate), entitled 4- (2, the 3- dichlorophenyl)-Isosorbide-5-Nitrae-dihydro-of chemistry
2,6- dimethyl -3,5- pyridinedicarboxylic acid methyl (1- butyryl acyloxy) methyl esters (Formulas I), are a kind of intravenous injection dihydro pyrroles
Pyridine class calcium channel blocker, can flow of calcium ions outside selective depression human arterial smooth muscle cells, to keep blood vessel loose
It relaxes, blood pressure reduces.It is developed by Medicines Company company, in 1 Nikkei U.S. FDA of August approval listing in 2008.It is
External first antihypertensive drugs used for intravenous injection nearly ten years is suitble to the case where being not suitable for or being not intended to using oral preparation
The lower treatment for carrying out hypertension, also has application in terms of acute blood pressure elevation treatment after openheart surgery.Butyrate clevidipine works
Fastly, effect is eliminated also fast, can ascending-dose accurately control blood pressure, and do not put aside in vivo, toxic side effect is small, and market prospects are wide
It is wealthy.
Patent WO2010014234A1 discloses a kind of medical composition, and it includes clevidipine or its pharmaceutical salts, and wait
In or less than 0.2 weight % oxidation impurities (Formula II), but its preparation method for not being provided with Formula II compound.It is looked into, it is existing
There is technology also not disclose the preparation method of Formula II compound.Since impurity research is conducive to medicinal substances quantifier elimination, and
CFDA declares the more demanding of middle impurity research to drug, therefore acquisition impurity reference substance is declared drug and drug quality control
Have great importance, so this field is badly in need of providing a kind of preparation method of butyrate clevidipine specific impurities (Formula II).
Summary of the invention
In order to solve the problems in the prior art, the purpose of the present invention is to provide a kind of butyrate clevidipine impurity (formulas
II preparation method), this method is simple, and process operability is strong.
The object of the present invention is achieved like this:
A kind of preparation method of butyrate clevidipine impurity (Formula II), with butyrate clevidipine (Formulas I) for raw material, in sulfuric acid
Formula II compound is obtained under the action of high cerium and strong acid；The strong acid is selected from one or more of sulfuric acid, phosphoric acid, perchloric acid group
It closes.
The preparation method of butyrate clevidipine impurity (Formula II) of the present invention, synthetic route are as follows:
During preparation formula II compound, inventor has found that the dosage of butyrate clevidipine and ceric sulfate is especially closed
Key, once the bad situation that butyrate clevidipine (Formulas I) open loop or ester linkage breaking may occur of control.Inventor is through excessive
Amount experiment, finds after studying repeatedly, and the molar ratio of butyrate clevidipine and ceric sulfate is that fourth can be effectively reduced in 1:1~1.5
Sour clevidipine open loop and the case where hydrolyze, while improving the yield of reaction.
Further, in preferably embodiment of the invention, the preparation of butyrate clevidipine impurity (Formula II) of the present invention
Method, using following steps: butyrate clevidipine (Formulas I) being dissolved with solvent, ceric sulfate is added, controls interior temperature 10 DEG C~50
DEG C, strong acid is added, reacts 1~4 hour, after quenching reaction, extract product, washed product to PH=8~9, concentration, column
Chromatographic purifying, it is dry to get butyrate clevidipine impurity (Formula II).
Further, in preferably embodiment of the invention, 15 DEG C~20 DEG C of reaction temperature, the reaction time 2~2.5 is small
When.
Further, in preferably embodiment of the invention, solvent is DMF or DMSO or organic acid；Organic acid is preferred
Glacial acetic acid, propionic acid, oxalic acid, sulfonic acid and combinations thereof.
Further, in preferably embodiment of the invention, the inorganic base is selected from potassium carbonate, sodium carbonate, bicarbonate
Sodium, sodium hydroxide, potassium hydroxide or combinations thereof；Preferably, the inorganic base is sodium bicarbonate.
Further, a kind of preparation method of butyrate clevidipine impurity (Formula II), using following route:
Specific steps are as follows: butyric acid butyrate clevidipine is dissolved in glacial acetic acid, ceric sulfate is added, wherein butyrate clevidipine
Molar ratio with ceric sulfate is 1:1~1.5, controls interior 15 DEG C~20 DEG C of temperature, the concentrated sulfuric acid is added, and it is small then to react 2~2.5
When, after reaction solution be poured into water and be quenched, ethyl acetate extraction, sodium bicarbonate washs PH=8~9, concentration, and column chromatography is pure
Change, anhydrous sodium sulfate or anhydrous magnesium sulfate are dry to get butyrate clevidipine impurity (Formula II).
Beneficial effect
The present invention provides a kind of preparation method of butyrate clevidipine impurity, using butyrate clevidipine as raw material, in sulfuric acid
Butyrate clevidipine impurity is obtained under the action of high cerium and strong acid.Preparation process of the present invention effectively reduces butyrate clevidipine and opens
The occurrence of ring and hydrolysis, while reaction yield and purity are greatly improved, obtained target product purity meets up to 95%
CFDA declares drug the requirement of middle impurity research.Operation of the present invention is easy, reaction condition is mild, reagent is easy to get, and has good
Application prospect.
Specific embodiment
In order to keep the purpose of the present invention and technical solution clearer, the preferred embodiment of the present invention is carried out below detailed
Description.It is noted that following embodiment is served only for that the present invention is further detailed, and should not be understood as to this hair
The limitation of bright protection scope.Those skilled in the art's above content according to the present invention make it is some it is nonessential improvement and
Adjustment all belongs to the scope of protection of the present invention.
Embodiment 1
It takes 1000ml there-necked flask, is added 270ml glacial acetic acid, 27.36g (0.06mol) butyrate clevidipine, under stirring condition
24.24g (0.06mol) ceric sulfate is added, finishes the dropwise addition concentrated sulfuric acid 36ml into reaction solution, system heat release, ice water bathes control outside
15-20 DEG C of temperature in system.There are a large amount of solids to dissolve during being added dropwise, is added dropwise；20 DEG C of reaction two and one-half- hours, reaction solution is fallen
Enter in 1500ml ice water, is extracted with 300ml ethyl acetate；Ethyl acetate is washed till PH=8 with saturated sodium bicarbonate 150ml, anhydrous
Sodium sulphate 80g is dry, and evaporated under reduced pressure ethyl acetate obtains red oil, crosses silica gel column chromatography, obtains 12g grease, i.e. butyric acid
Clevidipine impurity (Formula II).1HNMR(600MHz,CDCl3) δ 7.70 (m, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 5.65
(dd, 2H), 3.49 (s, 3H), 2.56 (d, 6H), 2.20 (t, 3H), 1.49 (m, 2H), 0.87 (t, 3H)；13C NMR (600MHz,
CDCl3) 171.036 δ, 166.376,164.820,156.612,156.336,143.614,136.380,131.697,
130.831,129.995,128.739,127.888,125.834,124.408,79.245,52.329,34.741,23.023,
17.405 13.243；m/z([M+H]+): 454.08103.
Embodiment 2
1000ml there-necked flask is taken, 270mlDMF, 27.36g (0.06mol) butyrate clevidipine is added.Add under stirring condition
Enter 36.36g (0.09mol) ceric sulfate, finish the dropwise addition concentrated sulfuric acid 36ml into reaction solution, system heat release, ice water bathes control outside
15-20 DEG C of interior temperature.There are a large amount of solids to dissolve during being added dropwise, is added dropwise.15 DEG C of reaction two and one-half- hours, reaction solution is poured into
In 1500ml ice water, extracted with 300ml ethyl acetate.Ethyl acetate is washed till PH=9, anhydrous sulphur with saturated sodium bicarbonate 150ml
Sour sodium 80g is dry.Evaporated under reduced pressure ethyl acetate obtains red oil.Silica gel column chromatography is crossed, 10.9g grease, i.e. butyric acid are obtained
Clevidipine impurity (Formula II).
Embodiment 3
1000ml there-necked flask is taken, 270mlDMSO, 27.36g (0.06mol) butyrate clevidipine is once added.Stirring condition
Under 24.24g (0.06mol) ceric sulfate is added portionwise, finish into reaction solution dropwise addition concentrated sulfuric acid 24ml, system heat release, ice water
15-20 DEG C of temperature in outer bath control.There are a large amount of solids to dissolve during being added dropwise, is added dropwise.It 15 DEG C of reaction two and one-half- hours, will be anti-
It answers liquid to pour into 1500ml ice water, is extracted with 300ml ethyl acetate.Ethyl acetate is washed till PH=8, nothing with saturated sodium carbonate solution
Aqueous sodium persulfate 80g is dry.Evaporated under reduced pressure ethyl acetate obtains red oil.Silica gel column chromatography is crossed, obtains 11.2g grease, i.e.,
Butyrate clevidipine impurity (Formula II).
Embodiment 4
1000ml there-necked flask is taken, it is primary that 270ml oxalic acid, 27.36g (0.06mol) butyrate clevidipine is added.Stirring condition
Under 24.24g (0.06mol) ceric sulfate is added portionwise, finish into reaction solution dropwise addition concentrated sulfuric acid 36ml, system heat release, ice water
15-20 DEG C of temperature in outer bath control.There are a large amount of solids to dissolve during being added dropwise, is added dropwise.It 20 DEG C of reaction two and one-half- hours, will be anti-
It answers liquid to pour into 1500ml ice water, is extracted with 300ml ethyl acetate.Ethyl acetate is washed till PH=9, anhydrous sulphur with saturated sodium carbonate
Sour sodium 80g is dry.Evaporated under reduced pressure ethyl acetate obtains red oil.Silica gel column chromatography is crossed, 9.6g grease, i.e. butyric acid chlorine are obtained
It ties up Horizon impurity (Formula II).
Embodiment 5
1000ml there-necked flask is taken, it is primary that 270ml glacial acetic acid, 27.36g (0.06mol) butyrate clevidipine is added.Stirring bar
29.09g (0.072mol) ceric sulfate is added portionwise under part, finishes and concentrated sulfuric acid 43.2ml is added dropwise into reaction solution, system heat release,
15-20 DEG C of temperature in control is bathed outside ice water.There are a large amount of solids to dissolve during being added dropwise, is added dropwise.20-25 DEG C of reaction two and half is small
When, reaction solution is poured into 1500ml ice water, is extracted with 300ml ethyl acetate.Ethyl acetate is washed till PH=with 2M sodium hydroxide
8, anhydrous magnesium sulfate 80g are dry.Evaporated under reduced pressure ethyl acetate obtains red oil.Silica gel column chromatography is crossed, 10.4g oily is obtained
Object, i.e. butyrate clevidipine impurity (Formula II).
Embodiment 6
1000ml there-necked flask is taken, 270mlDMF, 27.36g (0.06mol) butyrate clevidipine is once added.Stirring condition
Under 29.09g (0.072mol) ceric sulfate is added portionwise, finish into reaction solution dropwise addition concentrated sulfuric acid 43.2ml, system heat release, ice
15-20 DEG C of temperature in control is bathed outside water.There are a large amount of solids to dissolve during being added dropwise, is added dropwise.20-25 DEG C of reaction two and half is small
When, reaction solution is poured into 1500ml ice water, is extracted with 300ml ethyl acetate.Ethyl acetate is washed till PH=with 2M sodium hydroxide
8, anhydrous magnesium sulfate 80g are dry.Evaporated under reduced pressure ethyl acetate obtains red oil.Silica gel column chromatography is crossed, 7.6g grease is obtained,
That is butyrate clevidipine impurity (Formula II).
Embodiment 7
1000ml there-necked flask is taken, 270mlDMSO, 27.36g (0.06mol) butyrate clevidipine is once added.Stirring condition
Under 29.09g (0.072mol) ceric sulfate is added portionwise, finish into reaction solution dropwise addition concentrated sulfuric acid 43.2ml, system heat release, ice
15-20 DEG C of temperature in control is bathed outside water.There are a large amount of solids to dissolve during being added dropwise, is added dropwise.20-25 DEG C of reaction two and half is small
When, reaction solution is poured into 1500ml ice water, is extracted with 300ml ethyl acetate.Ethyl acetate is washed till PH=with 2M sodium hydroxide
8, anhydrous magnesium sulfate 80g are dry.Evaporated under reduced pressure ethyl acetate obtains red oil.Silica gel column chromatography is crossed, 8.4g grease is obtained,
That is butyrate clevidipine impurity (Formula II).
Embodiment 8
1000ml there-necked flask is taken, it is primary that 270ml glacial acetic acid, 27.36g (0.06mol) butyrate clevidipine is added.Stirring bar
24.24g (0.06mol) ceric sulfate is added portionwise under part, finishes dropwise addition perchloric acid 64ml, system heat release, ice into reaction solution
15-20 DEG C of temperature in control is bathed outside water.There are a large amount of solids to dissolve during being added dropwise, is added dropwise.15-20 DEG C of reaction two and half is small
When, reaction solution is poured into 1500ml ice water, is extracted with 300ml ethyl acetate.Ethyl acetate is washed with saturated sodium bicarbonate solution
It is dry to PH=8, anhydrous sodium sulfate 80g.Evaporated under reduced pressure ethyl acetate obtains red oil.Silica gel column chromatography is crossed, 7.2g is obtained
Grease, i.e. butyrate clevidipine impurity (Formula II).
Embodiment 9
1000ml there-necked flask is taken, it is primary that 270ml glacial acetic acid, 27.36g (0.06mol) butyrate clevidipine is added.Stirring bar
24.24g (0.06mol) ceric sulfate is added portionwise under part, finishes into reaction solution dropwise addition phosphoric acid 38g, system heat release, outside ice water
15-20 DEG C of temperature in bath control.There are a large amount of solids to dissolve during being added dropwise, is added dropwise.It 15-20 DEG C of reaction two and one-half- hours, will
Reaction solution pours into 1500ml ice water, is extracted with 300ml ethyl acetate.Ethyl acetate is washed till PH=with saturated sodium bicarbonate solution
8, anhydrous sodium sulfate 80g are dry.Evaporated under reduced pressure ethyl acetate obtains red oil.Silica gel column chromatography is crossed, 6.9g grease is obtained,
That is butyrate clevidipine impurity (Formula II).
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (9)
1. a kind of preparation method of butyrate clevidipine impurity (Formula II), with butyrate clevidipine (Formulas I) for raw material, in sulfuric acid height
Formula II compound is obtained under the action of cerium and strong acid；The strong acid is selected from one or more of sulfuric acid, phosphoric acid, perchloric acid group
It closes；Synthetic route is as follows:
2. the method as described in claim 1, it is characterised in that: the molar ratio of the butyrate clevidipine and ceric sulfate is 1:
1~1.5.
3. the method as described in claim 1, which is characterized in that use following steps: butyric acid butyrate clevidipine (Formulas I) is used
Solvent dissolution, is added ceric sulfate, control in 10 DEG C~50 DEG C of temperature, strong acid is added, reacts 1~4 hour, after be quenched it is anti-
It answers, extracts product, washed product to PH=8~9, concentration, column chromatographic purifying, drying is to get butyrate clevidipine impurity (formula
II)。
4. method as claimed in claim 3, it is characterised in that: 15 DEG C~20 DEG C of reaction temperature, the reaction time 2~2.5 hours.
5. the method as claimed in claim 3 or 4, it is characterised in that: the solvent is DMF or DMSO or organic acid.
6. method as claimed in claim 5, it is characterised in that: the organic acid be selected from acetic acid, propionic acid, oxalic acid, sulfonic acid and its
Combination.
7. the method as claimed in claim 3 or 4, it is characterised in that: the inorganic base is selected from potassium carbonate, sodium carbonate, bicarbonate
Sodium, sodium hydroxide, potassium hydroxide or combinations thereof.
8. the method for claim 7, it is characterised in that: the inorganic base is selected from sodium bicarbonate.
9. a kind of preparation method of butyrate clevidipine impurity (Formula II), using following route:
Specific steps are as follows: butyric acid butyrate clevidipine is dissolved in glacial acetic acid, ceric sulfate is added, wherein butyrate clevidipine and sulphur
The molar ratio of the high cerium of acid is 1:1~1.5, controls interior 15 DEG C~20 DEG C of temperature, the concentrated sulfuric acid is added, then react 2~2.5 hours, complete
Reaction solution, which is poured into water, after finishing is quenched, and ethyl acetate extraction, sodium bicarbonate washs PH=8~9, is concentrated, and column chromatographic purifying is anhydrous
Sodium sulphate or anhydrous magnesium sulfate are dry to get butyrate clevidipine impurity (Formula II).
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102186351A (en) * | 2008-08-01 | 2011-09-14 | 医药公司 | Pharmaceutical compositions and methods for stabilizing the same |
| CN103237446A (en) * | 2010-10-12 | 2013-08-07 | 医药公司 | Clevidipine emulsion formulations containing antimicrobial agents |
-
2019
- 2019-03-07 CN CN201910173222.6A patent/CN109776405A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102186351A (en) * | 2008-08-01 | 2011-09-14 | 医药公司 | Pharmaceutical compositions and methods for stabilizing the same |
| CN103237446A (en) * | 2010-10-12 | 2013-08-07 | 医药公司 | Clevidipine emulsion formulations containing antimicrobial agents |
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