CN102617460A - Compounding method of midbody required in compounding of montelukast sodium - Google Patents
Compounding method of midbody required in compounding of montelukast sodium Download PDFInfo
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- CN102617460A CN102617460A CN2012100884840A CN201210088484A CN102617460A CN 102617460 A CN102617460 A CN 102617460A CN 2012100884840 A CN2012100884840 A CN 2012100884840A CN 201210088484 A CN201210088484 A CN 201210088484A CN 102617460 A CN102617460 A CN 102617460A
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Abstract
The invention provides a compounding method of an important midbody (E)-3-(2-(7-Cl-2- quinolyl)) vinyl-benzoate required in compounding of montelukast sodium. Raw materials of the method are simple to obtain, and the method is suitable for large scale production. A product is the important midbody in compounding of the montelukast sodium which is an anti-asthmatic agent.
Description
Technical field
The invention belongs to the synthetic of medical middleware, relate in particular to a kind of midbody (E)-3-(compound method of 2-(7-chloro-2-quinolyl) vinyl benzoic acid ester of anti-asthmatic medicament Menglusitena.
Background technology
Menglusitena (montelukast sodium); Chemistry [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolyl) vinyl] phenyl]-3-[2-(1-hydroxyl-1-methylethyl) phenyl] propyl group] sulfo-] methyl] cyclopropyl sodium acetate by name; It is a kind of medicine by Merck & Co., Inc.'s Development and Production; Trade(brand)name " pleasing to the ear peaceful Singulair ", in 1998 in America and Europe listing, went on the market in China in 2002.This compound is a kind of highly selective cysteinyl leukotriene receptor antagonist, can effectively treat asthma, non-evident effect.
Synthesizing of relevant Menglusitena has report (US4851409, EP480717, US5565473, WO 2006/021974A1, WO2008035086, WO9518107 etc.) more.Wherein (2-(7-chloro-2-quinolyl) vinyl benzoic acid ester is as a midbody of synthetic Menglusitena, and its compound method report is less for (E) 3-.Mainly obtain in the condensation of diacetyl oxide condition refluxed on the patent (WO2008035379) at present from 7-chlorine quinaldine red and a formaldehyde methyl-formiate or ethyl ester.Wherein formaldehyde methyl-formiate or ethyl ester by m-methyl benzoic acid methyl esters or ethyl ester bromination then oxidation obtain.The subject matter that exists is that condensation need be used diacetyl oxide, and price is higher, and bromide is oxidized to aldehyde and need uses acetate, production unit is required high.
There is mass preparation 7-chlorine quinaldine red with crotonic aldehyde in we in acid from m-chloro aniline, and wherein we use the zinc chloride purifying, can obtain the purity high product.M-methyl benzoic acid methyl esters or ethyl ester obtain a formaldehyde methyl-formiate or an ethyl ester through bromination under the illumination heating condition through the Kornblum oxidation, and be little to equipment corrosion.A 7-chlorine quinaldine red and a formaldehyde methyl-formiate or ethyl ester can be at other piperidines, sodium acetate, sodium methylate or 4-N, condensation under the N-Dimethylamino pyridine condition, and these alkali are cheap and easy to get, practiced thrift production cost.This is a complete synthetic intermediate (E)-3-(method of 2-(7-chloro-2-quinolyl) vinyl benzoic acid ester.
This clearly demarcated method raw material is simple and easy to, and is fit to scale operation.
Summary of the invention
In the method for numerous synthetic Menglusitenas, wherein to use an important midbody.The present invention is a kind of method of synthetic following compound, is the synthetic required midbody of anti-asthmatic medicament Menglusitena.
Compound 1
The present invention adopts the 7-chlorine quinaldine red of one of m-chloro aniline and the synthetic initial feed of crotonic aldehyde, is raw material with the m-methyl benzoic acid then, through esterification, and bromination, oxidation, aldehyde benzoic acid ester between having obtained is followed and the condensation of 7-chlorine quinaldine red obtains target compound.Whole process is raw materials used all to be cheap and easy to get, and reaction process is simple, and mild condition relatively is fit to amplify scale prodn.
The present invention adopts following synthesis step following:
(a) with m-chloro aniline and crotonic aldehyde synthetic compound (4) 7-chlorine quinaldine red under the acid effect, in purifying, zinc chloride need be used, highly purified product can be obtained.React as follows:
M-chloro aniline and crotonic aldehyde were refluxed 1～4 hour in the two phase solvent system that acid exists, add zinc chloride backflow complexing product then and carried out purifying in 0.1～1 hour.Thereby product can dissociate product with ammoniacal liquor again and go out to obtain purer compound (4) 7-chlorine quinaldine red; Described m-chloro aniline, crotonic aldehyde, acid and ZnCl
2Mol ratio be 1: 1: 6～12; 1.1; Solvent is methyl alcohol, benzene, toluene, chloroform or their mixed solvent in the described two-phase solvent, and described acid is hydrochloric acid.
It is 2～12 moles every liter that the volumetric molar concentration of hydrochloric acid is adopted in suggestion; The volume ratio of hydrochloric acid and solvent is 1: 0～4.Use zinc chloride after the reaction and carry out processing purified.
(b) be raw material with m-methyl benzoic acid and ethanol, add the acid (acid) of catalytic amount, reflux water-dividing, esterification obtains compound (6) m-methyl benzoic acid ethyl ester, reacts as follows:
Can recovery set after reaction finishes with the used acid of catalysis.
In organic solvent, reflux temperature and catalyst acid exist down, and the esterification in 5-20 hour of m-methyl benzoic acid and alcohol reaction obtains compound m-methyl benzoic acid methyl esters or ethyl ester; The mol ratio of described m-methyl benzoic acid, pure and mild catalyzer is 1: 1: 0.1; Described alcohol is methyl alcohol or ethanol; Described organic solvent is toluene or benzene.
Recommending catalyst acid is the vitriol oil or tosic acid.
(c) compound (6) and NBS are in tetracol phenixin, and illumination (hv) heating condition produces compound (7) down, reacts as follows:
M-methyl benzoic acid methyl esters or ethyl ester and N-bromo-succinimide (NBS) are in tetracol phenixin, and the illumination condition refluxed is reacted chloro oil of Niobe or ethyl ester 7 between generation in 10～24 hours; The mol ratio of described m-methyl benzoic acid methyl esters or ethyl ester and NBS is 1: 1.
(d) in the presence of reflux temperature and acetonitrile and Glacial acetic acid min. 99.5, vulkacit H (urotropine, (CH
2)
6N
4) and compound (7) between chloro oil of Niobe or ethyl ester oxidizing reaction obtained aldehyde cpd (8) in 1～5 hour, described solvent is methyl alcohol, ethanol, water, acetonitrile or their mixed solvent; React as follows:
(e) compound (7) also can obtain aldehyde cpd (8) through the Kornblum oxidation; In organic solvent; Reflux temperature and alkali exist down, and a chloro oil of Niobe or ethyl ester obtained a formaldehyde methyl-formiate or an ethyl ester in 0.5～4 hour through the Kornblum oxidation: the mol ratio of described formaldehyde methyl-formiate or ethyl ester and alkali is 1: 2; Described alkali is the mineral alkali of yellow soda ash, sodium hydrogencarbonate or is the organic bases of piperidines, triethylamine; Described organic solvent is DMSO 99.8MIN. (DMSO); React as follows:
The alkali (base) of reaction is yellow soda ash, sodium hydrogencarbonate, salt of wormwood, saleratus, sodium methylate, triethylamine or piperidines.
The concentration that feeds intake of chloro oil of Niobe or ethyl ester 7 is 0.1～1 mole every liter between recommendation.
It is very short that this reacts the used reaction times, and yield is high, is fit to amplify produce.
(f) compound (4) and compound (8) be under the effect of catalyzer, reacting by heating, obtain compound (1) target molecule (E)-3-(2-(7-chloro-2-quinolyl) vinyl benzoic acid ester, reaction as follows:
In organic solvent, a 7-chlorine quinaldine red and a formaldehyde methyl-formiate or ethyl ester compound are under the effect of catalyzer, and reacting by heating obtained (E)-3-(2-(7-chloro-2-quinolyl) vinyl benzoic acid ester in 18 hours; The mol ratio of described 7-chlorine quinaldine red, a formaldehyde methyl-formiate or ethyl ester and catalyzer is 1: 1: 0.05～0.6;
Described organic solvent is benzene,toluene,xylene or sym-trimethylbenzene; Described catalyzer is diacetyl oxide, piperidines, sodium acetate, sodium methylate or 4-N, the N-Dimethylamino pyridine.
The product of described a)～f) step can pass through organic solvent extraction separation, washing, drying or recrystallization purifying.
This clearly demarcated method is that a kind of raw material is simple and easy to, and is fit to the method for the important intermediate of the synthetic anti-asthmatic medicament Menglusitena of scale operation.
Embodiment
Through embodiment the present invention is carried out concrete description below, be necessary to be pointed out that at this present embodiment only is used for the present invention is further specified, can not be interpreted as restriction protection domain of the present invention.
Embodiment 1:
The 250mL there-necked flask is installed reflux condensing tube, mechanical stirring oar, nitrogen protection.Under the room temperature, in bottle, add 3N hydrochloric acid 40mL, ethanol 40mL, stir.Add m-chloro aniline 10.4mL, stir and be white pulpous state liquid.Oil bath is heated to 85-100 ℃, drips crotonic aldehyde 10.32mL, drips and finishes, and system becomes yellow turbid solution, refluxes 2 hours.Be cooled to room temperature, extract 2 times, discard organic phase with sherwood oil 40mL.The gained water adds and has in the 250mL there-necked flask of stirring rake and reflux condensing tube, and high-speed stirring under the room temperature adds zinc chloride 13.6g.Oil bath is heated to 120 ℃ and refluxes half a hour.Keep high-speed stirring, be cooled to room temperature, have throw out to occur, mother liquor is near water white transparency.Discard mother liquor, the gained throw out stays in there-necked flask, adds ethanol 100mL, high-speed stirring half a hour.Suction filtration, filter cake are the fine and smooth powder of rice white, and filter cake divides with ethanol 100mL that to be washed till washing lotion three times colourless basically.Merging filtrate and washing lotion can heavily be steamed the recovery solvent.Filter cake is washed once with sherwood oil 30mL again, drains, and is transferred to the 250mL separating funnel, adds water 50mL, strong aqua 20mL, and ETHYLE ACETATE 30mL, fully shake extraction, standing demix, separatory, water are again with sherwood oil 20mL extraction once.Merge organic phase, 50mL washes once with saturated aqueous ammonium chloride.Behind the separatory, organic phase is used anhydrous sodium sulfate drying, revolves dried solvent, obtains compound 4 and is pale yellow crystals 11.34g.Obtain colourless tabular crystal 9.8g, yield 55.2% with the sherwood oil recrystallization.
1H?NMR(CDCl
3)δ(ppm)：2.76(s，3H)；7.28(d，1H)；7.46(d，1H)；7.7(d，1H)；8.04(d，1H)。MS?m/z(％(：178(M+H
+)。
Embodiment 2:
The 250mL there-necked flask is installed the reflux water-dividing device.Under the room temperature, in bottle, add m-methyl benzoic acid 30g, tosic acid 5g (perhaps vitriol oil 2.16g), ethanol 40mL, benzene 90mL stirs, and is achromaticity and clarification liquid.Oil bath is heated to 120 ℃, about 16 hours of reflux water-dividing.Be cooled to room temperature; Benzene and unnecessary ethanol are removed in distillation, obtain brown thickness turbid solution, add ETHYLE ACETATE 100mL dissolving; Water 30mL, saturated sodium bicarbonate solution 30mL*2, saturated nacl aqueous solution 30mL wash successively; ETHYLE ACETATE is used anhydrous sodium sulfate drying mutually behind the separatory, revolves and desolvates, and obtains yellow clarification viscous fluid.Underpressure distillation obtains compound 6 and is the achromaticity and clarification thick liquid, special odor is arranged, yield 86%.
1H?NMR(CDCl
3)δ(ppm)：1.40～1.44(t，3H)；2.43(s，3H)；4.38～4.43(dd，2H)；7.34～7.37(m，2H)；7.89(d，2H)。
Embodiment 3:
The 250mL there-necked flask is installed reflux condensing tube.Under the room temperature, in bottle, add compound (6) 8.2g, tetracol phenixin 160mL, NBS 9g stirs, and is light yellow suspension liquid.Oil bath is heated to 80 ℃ of backflows, after waiting to reflux, from the irradiation of reaction flask 2 centimeters, turns down oil bath temperature with the bulb of a 200W simultaneously, keeps the mild backflow of reaction system 16 hours.Sampling TLC shows that raw material disappears, and has a tangible novel substance point.Stop illumination and be cooled to room temperature.Go out throw out wherein with the zeyssatite suction filtration, the gained stillness of night, water 50mL*2, saturated nacl aqueous solution 50mL washed successively.Organic phase behind the separatory is used anhydrous sodium sulfate drying, and solvent is reclaimed in underpressure distillation, obtains the tawny oily liquids.Underpressure distillation obtains compound 7 and is light yellow oily liquid 10g, yield 82%.
1H?NMR(CDCl
3)δ(ppm)：1.31～1.35(t，3H)；4.29～4.34(dd，2H)；4.45(s，2H)；7.33～7.99(m，4H)。
Embodiment 4:
The 50mL there-necked flask is installed reflux condensing tube.Under the room temperature, in bottle, add compound (7) 3.64g, acetonitrile 6.5mL, Glacial acetic acid min. 99.5 6.5mL, urotropine 4.2g stirs fast, and system is yellow turbid solution, backflow 2.5h.Stop heating, visible have yellow oil to suspend.When treating that system temperature is reduced to about 50 ℃, add hydrochloric acid 5mL acidifying, stir and be cooled to room temperature.Add water 20mL, with ETHYLE ACETATE 10mL*2 extracted twice, merge organic phase, water 20mL*3, saturated sodium carbonate solution 20mL wash successively, and organic phase is used anhydrous sodium sulfate drying behind the separatory.TLC shows that raw material disappears, and has a tangible novel substance point.Solvent is removed in decompression, and obtaining compound (8) is light yellow oily liquid, and ETHYLE ACETATE and sherwood oil mixed solvent recrystallization get 1.8g yield 67%.
1H?NMR(CDCl
3)δ(ppm)：1.41～1.44(t，3H)；4.40～4.45(dd，2H)；7.6(t，1H)；8.09(d，1H)；8.31(d，1H)；8.5(s，1H)；10.09(s，1H)。
Embodiment 5:
The 250mL there-necked flask is installed reflux condensing tube.Under the room temperature, in bottle, add compound (7) 4.2g, DMSO 99.8MIN. 58mL; Add 2 normal alkali, be heated to 120 degrees centigrade of reaction 30min, add the dilution of 30mL water; With 20mL petroleum ether extraction 3 times, merge organic phase, with 20mL deionized water wash 2 times; The saturated common salt water washing once, anhydrous sodium sulfate drying.Decompression and solvent recovery.Residuum gets 2.15g with ethyl acetate petroleum ether mixed solvent recrystallization, yield 70%.
Embodiment 6
The 250mL there-necked flask is installed reflux condensing tube.Add compound (8) and compound (4) under the room temperature, add acetonitrile and catalyzer, reflux is 5 hours then; Separate out yellow mercury oxide, filter, filter cake washs with little solvent; After all filtratings concentrate; With the sherwood oil re-crystallizing in ethyl acetate, it is faint yellow solid (methyl esters) that the merging all solids obtains product, yield 82%.
1H?NMR(CDCl
3)δ(ppm)：3.95～3.97(s，3H)，7.4～8.4(m，11H)。
MS?m/z(％)：324(M+H
+)
Fusing point: 140～142 ℃
Claims (8)
- An anti-asthmatic medicament Menglusitena midbody (E)-3-(compound method of 2-(7-chloro-2-quinolyl) vinyl benzoic acid ester, described midbody has following structural formula:be R=Me or Et wherein, it is characterized in that obtaining through following steps:
(a) m-chloro aniline and crotonic aldehyde were refluxed 1～4 hour in the two phase solvent system that acid exists, add zinc chloride backflow complexing product then and carried out purifying in 0.1～1 hour, to obtain purer compound (4) 7-chlorine quinaldine red thereby with ammoniacal liquor product is dissociated again; Described m-chloro aniline, crotonic aldehyde, acid and ZnCl 2Mol ratio be 1: 1: 6～12; 1.1; Solvent is methyl alcohol, benzene, toluene, chloroform or their mixed solvent in the described two-phase solvent, and described acid is hydrochloric acid;(b) in organic solvent, reflux temperature and catalyst acid exist down, and the esterification in 5-20 hour of m-methyl benzoic acid and alcohol reaction obtains compound m-methyl benzoic acid methyl esters or ethyl ester; The mol ratio of described m-methyl benzoic acid, pure and mild catalyzer is 1: 1: 0.1; Described alcohol is methyl alcohol or ethanol; Described organic solvent is toluene or benzene;(c) m-methyl benzoic acid methyl esters or ethyl ester and N-bromo-succinimide NBS are in tetracol phenixin, and the illumination condition refluxed is reacted chloro oil of Niobe or ethyl ester 7 between generation in 10～24 hours; The mol ratio of described m-methyl benzoic acid methyl esters or ethyl ester and NBS is 1: 1;(d) in solvent, under the reflux temperature and in the presence of acetonitrile and the Glacial acetic acid min. 99.5, a vulkacit H and a chloro oil of Niobe or ethyl ester oxidizing reaction 1～5 hour obtain a formaldehyde methyl-formiate or ethyl ester compound 8:; Described solvent is methyl alcohol, ethanol, water, acetonitrile or their mixed solvent;(e) in organic solvent, reflux temperature and alkali exist down, and a chloro oil of Niobe or ethyl ester obtained a formaldehyde methyl-formiate or an ethyl ester in 0.5～4 hour through the Kornblum oxidation: the mol ratio of described formaldehyde methyl-formiate or ethyl ester and alkali is 1: 2; Described alkali is the mineral alkali of yellow soda ash, sodium hydrogencarbonate or is the organic bases of piperidines, triethylamine; Described organic solvent is a DMSO 99.8MIN.;(f) in organic solvent, a 7-chlorine quinaldine red and a formaldehyde methyl-formiate or ethyl ester compound are under the effect of catalyzer, and reacting by heating obtained (E)-3-(2-(7-chloro-2-quinolyl) vinyl benzoic acid ester in 18 hours; The mol ratio of described 7-chlorine quinaldine red, a formaldehyde methyl-formiate or ethyl ester and catalyzer is 1: 1: 0.05～0.6;Described organic solvent is benzene,toluene,xylene or sym-trimethylbenzene; Described catalyzer is diacetyl oxide, piperidines, sodium acetate, sodium methylate or 4-N, the N-Dimethylamino pyridine. - 2. according to the said method of claim 1, it is characterized in that the volumetric molar concentration of hydrochloric acid in the step (a) is 2～12 moles every liter.
- 3. according to the said method of claim 1, it is characterized in that in the step (a), the volume ratio of hydrochloric acid and solvent is 1: 0～4.
- 4. according to the said method of claim 1, it is characterized in that in the step (a), aftertreatment need be used zinc chloride and carried out processing purified.
- 5. according to the said method of claim 1, it is characterized in that catalyst acid is the vitriol oil or tosic acid in the step (b).
- 6. according to the said method of claim 1, it is characterized in that in the step (e), the alkali of reaction is yellow soda ash, sodium hydrogencarbonate, salt of wormwood, saleratus, sodium methylate, triethylamine or piperidines.
- 7. according to the said method of claim 1, it is characterized in that in the step (e), the concentration that feeds intake of a chloro oil of Niobe or ethyl ester 7 is 0.1～1 mole every liter.
- 8. method according to claim 1, the product that it is characterized in that described a)～f) step is through organic solvent extraction separation, washing, drying or recrystallization purifying.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104109122A (en) * | 2013-04-16 | 2014-10-22 | 浙江奥翔药业有限公司 | Intermediate compound for synthesizing montelukast, and preparation method thereof |
| CN106928138A (en) * | 2017-05-04 | 2017-07-07 | 威海迪素制药有限公司 | A kind of preparation method of montelukast sodium impurity D |
| CN108727261A (en) * | 2018-06-21 | 2018-11-02 | 济南大学 | A kind of preparation method of that pyridine of nitro substitution quinoline |
| CN115010661A (en) * | 2022-07-18 | 2022-09-06 | 江西省化学工业研究所 | Preparation method of 7-chloroquinaldine |
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| WO2008035379A2 (en) * | 2006-09-19 | 2008-03-27 | Aptuit Laurus Private Limited | Process for and intermediates of leukotriene antagonists |
| CN102070420A (en) * | 2011-01-04 | 2011-05-25 | 常州大学 | Method for preparing 2-bromo-6-fluorobenzaldehyde |
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2012
- 2012-03-29 CN CN2012100884840A patent/CN102617460A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008035379A2 (en) * | 2006-09-19 | 2008-03-27 | Aptuit Laurus Private Limited | Process for and intermediates of leukotriene antagonists |
| CN102070420A (en) * | 2011-01-04 | 2011-05-25 | 常州大学 | Method for preparing 2-bromo-6-fluorobenzaldehyde |
Non-Patent Citations (2)
| Title |
|---|
| CHARLES M. LEIR: "An Improvement in the Doebner-Miller Synthesis of Quinaldines", 《J. ORG. CHEM.》, vol. 42, no. 5, 31 December 1977 (1977-12-31) * |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104109122A (en) * | 2013-04-16 | 2014-10-22 | 浙江奥翔药业有限公司 | Intermediate compound for synthesizing montelukast, and preparation method thereof |
| CN104109122B (en) * | 2013-04-16 | 2017-03-29 | 浙江奥翔药业股份有限公司 | For synthesizing midbody compound of montelukast and preparation method thereof |
| CN106928138A (en) * | 2017-05-04 | 2017-07-07 | 威海迪素制药有限公司 | A kind of preparation method of montelukast sodium impurity D |
| CN106928138B (en) * | 2017-05-04 | 2019-08-16 | 威海迪素制药有限公司 | A kind of preparation method of montelukast sodium impurity D |
| CN108727261A (en) * | 2018-06-21 | 2018-11-02 | 济南大学 | A kind of preparation method of that pyridine of nitro substitution quinoline |
| CN108727261B (en) * | 2018-06-21 | 2021-09-24 | 济南大学 | Preparation method of nitro-substituted quinaldine |
| CN115010661A (en) * | 2022-07-18 | 2022-09-06 | 江西省化学工业研究所 | Preparation method of 7-chloroquinaldine |
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Application publication date: 20120801 |