CN106892862A - A kind of lacidipine compound and preparation method thereof - Google Patents
A kind of lacidipine compound and preparation method thereof Download PDFInfo
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- CN106892862A CN106892862A CN201710072743.3A CN201710072743A CN106892862A CN 106892862 A CN106892862 A CN 106892862A CN 201710072743 A CN201710072743 A CN 201710072743A CN 106892862 A CN106892862 A CN 106892862A
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- lacidipine
- dichloromethane
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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
- C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
- C07D211/84—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 two 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 directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a kind of lacidipine compound crystal and preparation method thereof, it is characterized in that with triphenylphosphine and chloroacetic acid tert-butyl ester as raw material, chemical synthesis is carried out under microwave, crystallization is carried out under the conditions of high frequency ultrasound, a kind of lacidipine compound crystal is obtained, product yield is improved, and the reaction time shortens, cost reduction, product stability increases, and keeping life extension, dissolving out capability is improved, curative effect is improve, promising result is achieved.
Description
Technical field
The present invention relates to chemicals preparation field, and in particular to a kind of lacidipine compound and preparation method thereof.
Background technology
It is special, potent lasting dihydropyridine calcium channel blocker, the retardance blood of substantial selectivity that lacidipine is
The calcium channel of pipe smooth muscle, expands peripheral arterial, lowers peripheral vascular resistance, lowers cardiac afterload, reduces blood pressure, and is a kind of
Preferable drug for hypertension, with dosage it is small, rapid-action, antihypertensive effect is strong, the low obvious advantage of adverse reaction rate.Mesh
Before, using being chemically synthesized, synthetic method has that yield is low, the production cycle is long to lacidipine, and production cost is high, and product is inadequate
Stabilization, the term of validity is short to wait not enough, and proterties is amorphous powder, and dissolving out capability is bad, affects the treatment.
The content of the invention
The present invention is explored and optimized to overcome above-mentioned deficiency to lacidipine synthesis technique, is adopted in committed step
It is catalyst with titanium dioxide, is synthesized under microwave, crystallized under ultrasound condition, obtains a kind of new drawing
Western Horizon dihydrochloride dihydrate crystal, reaction condition is gentle, and product yield is improved, and the reaction time shortens, cost reduction, product stability
Increase, keeping life extension, dissolving out capability is improved, and improves curative effect, achieves promising result.
Invention embodiment is as follows：
52.4 parts of triphenylphosphine and 45.0 parts of chloroacetic acid tert-butyl ester are put in microwave reaction kettle, add 200 parts of toluene, two
1 part of titanium oxide, selects microwave frequency 2250MHz, is warming up to 105~110 DEG C, reacts 1 hour, cooling, and filtering, filter cake is used appropriate
Isopropyl ether is washed, and is dried to obtain white solid, is added water 100 parts, is stirred 10 minutes, and sodium hydroxide solution is added dropwise, and filtering is dried,
White solid is obtained, dichloromethane is added, triphen phosphinidene tert-butyl acetate dichloromethane solution is made；By OPA 5.0
Part adds 50 parts of dichloromethane, in ice salt bath, triphen phosphinidene tert-butyl acetate dichloromethane solution is added dropwise, and reacts 40 minutes,
Dichloromethane is steamed, filter cake is washed with appropriate isopropyl ether, steam isopropyl ether and obtain yellow oil, add amino ethyl crotonate 12
Part, 1 part of ammonium sulfate is dissolved in appropriate absolute ethyl alcohol, in ice salt bath, is reacted 1.5 hours, and reactant is added into sodium bicarbonate water
In solution, Tan solid is obtained, filtered, dried, in putting ultrasonic reaction kettle, add 200 parts of ethyl acetate, heating for dissolving, while hot
Filtering, selects supersonic frequency 15kHz, and cooling has crystalline solid to separate out, and suction filtration is dried, and obtains lacidipine dihydrochloride dihydrate crystal.
The present invention program compared to the prior art, the characteristics of substantial and significant progress is：
1 is catalyst from titanium dioxide, ammonium sulfate, improves reaction yield, reduces production cost.
2 carry out chemosynthesis reaction from microwave, shorten the reaction time, reduce production cost.
3, from ultrasonic crystallization, obtain new lacidipine dihydrochloride dihydrate crystal, increased product stability, extend product
The product term of validity, enhances dissolving out capability, improves curative effect.
In the present invention program involved term unless otherwise specified, with Chinese Pharmacopoeia, state food drug surveilance pipe
The medicine related specifications such as reason office standard are explained and are defined.
" part " described in foregoing invention scheme refers to weight portion.
The power selection of equipment determines according to the size of institute's production sample amount in foregoing invention scheme, by manufacturer's equipment
Specification regulation is capable of achieving the present invention.
As do not indicated temperature, pressure in foregoing invention scheme, all refer to normal temperature, normal pressure, cooling does not indicate chilling temperature, refers to cold
To room temperature.
Solution all refers to saturated solution as do not indicated concentration in foregoing invention scheme.
The raw material that the embodiment above is previously mentioned is as follows：
Triphenylphosphine:No. CAS: 603-35-0；Company standard；
Chloroacetic acid tert-butyl ester:No. CAS: 107-59-5；Company standard；
Toluene:No. CAS: 108-88-3；The Chinese Pharmacopoeia ministerial standard of version four in 2015；
Titanium dioxide：No. CAS: 1317-80-2；The Chinese Pharmacopoeia ministerial standard of version four in 2015；
NaOH：No. CAS:1310-73-2；The Chinese Pharmacopoeia ministerial standard of version four in 2015；
Dichloromethane：No. CAS: 75-09-2；The Chinese Pharmacopoeia ministerial standard of version four in 2015；
OPA：No. CAS: 643-79-8；Company standard；
Amino ethyl crotonate：No. CAS: 7318-00-5；Company standard；
Ammonium sulfate：No. CAS: 7783-20-2；The Chinese Pharmacopoeia ministerial standard of version four in 2015；
Ethanol：No. CAS: 64-17-5；The Chinese Pharmacopoeia ministerial standard of version four in 2015；
Sodium acid carbonate：No. CAS: 144-55-8；The Chinese Pharmacopoeia ministerial standard of version four in 2015；
Raw material used in above lacidipine can be commercially available without particular/special requirement from pharmaceuticals, as long as meeting quality mark
Standard can be used to implement the present invention.
The key equipment that the embodiment above is previously mentioned is as follows：
Sonochemistry reacts instrument：Frequency 5kHz~100kHz, 50~5000W of power；
Microwave chemical reaction instrument：Frequency 2000MHz~3000 MHz, 1000~5000W of power；
Without particular/special requirement, there is sale in market to equipment used in above lacidipine, as long as meet parameter area can be used to
Implement the present invention.
Four specific embodiments
Specific embodiment of the invention
The triphenylphosphine of 52.4g and the chloroacetic acid tert-butyl ester of 45.0g are put in microwave reaction kettle, add toluene 200g, titanium dioxide
Titanium 1g, selects microwave frequency 2450MHz, is warming up to 105~110 DEG C, reacts 1 hour, cooling, filtering, the appropriate isopropyl of filter cake
Ether is washed, and is dried to obtain white solid, and add water 100g, is stirred 10 minutes, and sodium hydroxide solution is added dropwise, and filtering is dried, and obtains white
Color solid, adds dichloromethane, is made triphen phosphinidene tert-butyl acetate dichloromethane solution；OPA 5.0g is added two
Chloromethanes 50g, in ice salt bath, is added dropwise triphen phosphinidene tert-butyl acetate dichloromethane solution, reacts 40 minutes, steams dichloromethane
Alkane, filter cake is washed with appropriate isopropyl ether, is steamed isopropyl ether and is obtained yellow oil, adds amino ethyl crotonate 12g, ammonium sulfate
1g, is dissolved in appropriate absolute ethyl alcohol, in ice salt bath, reacts 1.5 hours, by reactant addition sodium bicarbonate aqueous solution, obtains
Tan solid, filtering is dried, and is put in ultrasonic reaction kettle, adds ethyl acetate 200g, and heating for dissolving is filtered while hot, and selection is super
Acoustic frequency 15kHz, cooling, has crystalline solid to separate out, suction filtration, dries, and obtains lacidipine dihydrochloride dihydrate crystal, yield 82.45%.
Above example illustrate, lacidipine dihydrochloride dihydrate crystal can be made using embodiment of the present invention, below with
Lacidipine dihydrochloride dihydrate crystal obtained in embodiment investigates actual effect of the invention：
Lacidipine molecular formula prepared by 1 the present invention program is determined with crystalline form.
Determined by Chinese Pharmacopoeia four 0661 thermogravimetries of version in 2015, as a result show drawing west prepared by the present invention program
Horizon is dihydrate, and molecular formula is C26H33NO6.2H2O, molecular weight 491.59；
Determined by Chinese Pharmacopoeia four 0451X ray diffraction methods of version in 2015, show that lacidipine prepared by the present invention program is
Crystalline structure.
2 the present invention program prepare lacidipine and prepare the contrast of lacidipine production cycle with using art methods.
1 production cycle of table contrast table
The above results show, the present invention prepares lacidipine ratio and prepares the lacidipine production cycle using art methods and shows
Write and shorten.
3 the present invention program prepare lacidipine and prepare the contrast of lacidipine production cost with using art methods.
The production cost contrast table of table 2
The above results show, the present invention prepares lacidipine ratio and prepares lacidipine production cost using art methods and shows
Writing reduces.
4 the present invention program prepare lacidipine and prepare the contrast of lacidipine total recovery with using art methods.
The total recovery contrast table of table 3
The above results show, the present invention prepares lacidipine ratio, and to prepare lacidipine total recovery using art methods notable
Improve, further reduce production cost.
5 the present invention program prepare lacidipine and prepare the contrast of the lacidipine term of validity with using prior art.
By Chinese Pharmacopoeia four annex of version in 2015, the lacidipine sample and prior art system of the present invention program preparation are taken
Standby lacidipine sample is placed in 25 DEG C ± 2 DEG C of temperature, in RH60% ± 10% environment, in the 0th, 3,6,9,12,18,24,36
The end of month samples, and is detected according to lacidipine standard.
As a result：
The term of validity contrast table of table 4
The above results show, the present invention prepares lacidipine ratio and prepares lacidipine period of validity using prior art and significantly prolongs
Long, stability increases.
6 the present invention program prepare lacidipine and prepare the dissolving out capability contrast of drawing west ground with using art methods.
Method：Using the raw material of embodiment one and commercially available lacidipine raw material, identical prescription is respectively adopted and is made lacidipine
Piece, by Chinese Pharmacopoeia four 0931 measure dissolution rates of version in 2015.
The dissolution rate contrast table of table 5
The above results show that the present invention prepares Lacidipine tablets ratio and prepares Lacidipine tablets dissolution rate using art methods
Significantly improve, p≤0.01.
Lacidipine safety testing prepared by 7 scheme of the invention.
Announced according to State Food and Drug Administration《Chemicals is acute, long term toxicity investigative technique instructs former
Then》Appended method is tested.
As a result：
Lacidipine prepared by the present invention program does not find acute, long term toxicity reaction to experiment white mouse, acts on safe and reliable.
Claims (2)
1. the hydrate crystal of a kind of lacidipine two, it is characterized in that taking 52.4 parts of triphenylphosphine and 45.0 parts of monoxone uncle
Butyl ester, in putting microwave reaction kettle, adds 200 parts of toluene, 1 part of titanium dioxide to select microwave frequency 2450MHz, it is warming up to 105~
110 DEG C, react 1 hour, cooling, filtering, filter cake is washed with appropriate isopropyl ether, is dried to obtain white solid, is added water 100 parts, is stirred
Mix 10 minutes, sodium hydroxide solution is added dropwise, filtering is dried, and obtains white solid, adds dichloromethane, is made triphen phosphinidene
Tert-butyl acetate dichloromethane solution；By 5.0 parts of 50 parts of dichloromethane of addition of OPA, in ice salt bath, triphen is added dropwise sub-
Phosphino- tert-butyl acetate dichloromethane solution, is reacted 40 minutes, steams dichloromethane, and filter cake is washed with appropriate isopropyl ether, is steamed different
Propyl ether obtains yellow oil, adds 12 parts of amino ethyl crotonate, and 1 part of ammonium sulfate is dissolved in appropriate absolute ethyl alcohol, in ice salt bath
In, react 1.5 hours, by reactant addition sodium bicarbonate aqueous solution, Tan solid is obtained, filter, dry, put ultrasonic reaction
In kettle, 200 parts of ethyl acetate is added, heating for dissolving is filtered while hot, selects supersonic frequency 15kHz, cooling has crystalline solid to separate out,
Suction filtration, dries, and obtains the hydrate crystal of lacidipine two.
2. the preparation method of the hydrate crystal of lacidipine two according to claim 1, it is characterized in that taking the three of 52.4 parts
Phenylphosphine and 45.0 parts of chloroacetic acid tert-butyl ester, put in microwave reaction kettle, add 200 parts of toluene, 1 part of titanium dioxide to select micro-
Wave frequency rate, 2450MHz, is warming up to 105~110 DEG C, reacts 1 hour, and cooling, filtering, filter cake is washed with appropriate isopropyl ether, dries
White solid is obtained, is added water 100 parts, stirred 10 minutes, sodium hydroxide solution is added dropwise, filtering is dried, and obtains white solid, plus
Enter dichloromethane, be made triphen phosphinidene tert-butyl acetate dichloromethane solution；By 5.0 parts of addition dichloromethane 50 of OPA
Part, in ice salt bath, triphen phosphinidene tert-butyl acetate dichloromethane solution is added dropwise, react 40 minutes, steam dichloromethane, filter cake
Washed with appropriate isopropyl ether, steam isopropyl ether and obtain yellow oil, add 12 parts of amino ethyl crotonate, 1 part of ammonium sulfate is dissolved in
In appropriate absolute ethyl alcohol, in ice salt bath, react 1.5 hours, by reactant addition sodium bicarbonate aqueous solution, obtain yellowish-brown and consolidate
Body, filtering is dried, and is put in ultrasonic reaction kettle, adds 200 parts of ethyl acetate, and heating for dissolving is filtered while hot, selects supersonic frequency
15kHz, cooling, has crystalline solid to separate out, suction filtration, dries, and obtains the hydrate crystal of lacidipine two.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710072743.3A CN106892862A (en) | 2017-02-10 | 2017-02-10 | A kind of lacidipine compound and preparation method thereof |
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| CN201710072743.3A CN106892862A (en) | 2017-02-10 | 2017-02-10 | A kind of lacidipine compound and preparation method thereof |
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| CN106892862A true CN106892862A (en) | 2017-06-27 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201710072743.3A Pending CN106892862A (en) | 2017-02-10 | 2017-02-10 | A kind of lacidipine compound and preparation method thereof |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420887A (en) * | 2013-08-30 | 2013-12-04 | 孙威 | Levosulpiride compound and preparation method thereof |
-
2017
- 2017-02-10 CN CN201710072743.3A patent/CN106892862A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420887A (en) * | 2013-08-30 | 2013-12-04 | 孙威 | Levosulpiride compound and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| A.JOHN BLACKER等: "《制药工艺开发—目前的化学与工程挑战》", 31 January 2016 * |
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Application publication date: 20170627 |