CN105541710A - Synthesis method for montelukast - Google Patents
Synthesis method for montelukast Download PDFInfo
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- CN105541710A CN105541710A CN201610096340.8A CN201610096340A CN105541710A CN 105541710 A CN105541710 A CN 105541710A CN 201610096340 A CN201610096340 A CN 201610096340A CN 105541710 A CN105541710 A CN 105541710A
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- XBPCUCUWBYBCDP-UHFFFAOYSA-N C(CC1)CCC1NC1CCCCC1 Chemical compound C(CC1)CCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)(c1ccccc1CC[C@@](CSCC1(C*=C)CC1)c1cccc(C=Cc(cc2)nc3c2ccc(Cl)c3)c1)O Chemical compound CC(C)(c1ccccc1CC[C@@](CSCC1(C*=C)CC1)c1cccc(C=Cc(cc2)nc3c2ccc(Cl)c3)c1)O 0.000 description 1
- FUDLXHPHMMCWRB-GUOCTKQSSA-N C[C@H](CCc1ccccc1C(C)(C)O)c1cc(/C=C/c2nc(cc(cc3)Cl)c3cc2)ccc1 Chemical compound C[C@H](CCc1ccccc1C(C)(C)O)c1cc(/C=C/c2nc(cc(cc3)Cl)c3cc2)ccc1 FUDLXHPHMMCWRB-GUOCTKQSSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
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- Chemical & Material Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
The invention discloses a synthesis method for montelukast. 1-(mercaptomethyl)- cyclopropaneacetic acid and alkali are added into organic solvent, and the mixture is subjected to a stirred reaction at 10 DEG C-30 DEG C to obtain a dianion alkaline solution; a quinolinediol compound and triethylamine are dissolved into organic solvent to obtain a quinolinediol solution; paratoluensulfonyl chloride is dissolved into organic solvent to obtain a paratoluensulfonyl chloride solution; then flow speed is controlled to inject the quinolinediol solution and the paratoluensulfonyl chloride into a micro-reactor for a mixed reaction at 10 DEG C-30 DEG C to obtain a tosylate compound solution; then the tosylate compound solution and the injected 1-(mercaptomethyl)-cyclopropaneacetic acid dianion alkaline solution are subjected to a mixed reaction at 10 DEG C-30 DEG C to obtain montelukast feed liquid which is discharged out of the micro-reactor, and the montelukast solid is obtained through post-treatment. The synthesis method is easy to operate, few by-products are generated in all the steps of reactions, the yield is high, the purity of the obtained product is quite high, the products generated by all the steps of reactions are easily subjected to separation and purification, and the synthesis method is suitable for industrialized production.
Description
Technical field
The invention belongs to medical chemistry synthesis field, be specifically related to a kind of synthetic method of Singulair.
Background technology
Menglusitena (MontelukastSodium), chemistry is by name: (+)-1-[[[(1R)-1-[3-[(1E)-2-(the chloro-2-quinolyl of 7-)-vinyl] phenyl]-3-[2-(1-hydroxyl-1-methylethyl) phenyl] propyl group] sulphur] methyl] cyclopropaneacetic acid list sodium salt, molecular formula: C
35h
35clNNaO
3s, molecular weight: 608.18, structural formula is:
Menglusitena (trade(brand)name: Singulair) is researched and developed by Merck company, and in February, 1998, first in Finland and Mexico's listing, obtains state food and drug administration's approval official listing for 1999.This compound is a kind of oral LTRA, specificity can suppress in air flue cysteinyl leukotriene receptor, thus reaches and improve airway inflammation, and effective Control of asthma symptom, is applicable to the treatment of allergic rhinitis in addition.
About Menglusitena synthesis in prior art, mainly with compound 2-[2-[3-(R)-[3-[2-(the chloro-2-quinolyl of 7-) vinyl] phenyl]-3-hydroxyl] propyl group phenyl]-2-propyl alcohol (hereinafter referred to as quinoline diol compounds) for raw material is prepared.
Formerly grind the preparation method that Canadian Mike's fluorine Luo Site company discloses this compound in CN1061407A, it adopts quinoline diol compound to react with Methanesulfonyl chloride under diisopropyl ethyl amine exists, separation obtains intermediate 2-[2-[3-(R)-[3-[2-(the chloro-2-quinolyl of 7-) vinyl] phenyl]-3-sulfonyloxy methyl oxygen base] propyl group phenyl]-2-propyl alcohol (hereinafter referred to as mesylate compound), then through being hydrolyzed after reacting with 1-(mercapto methyl)-cyclopropylacetate, salify obtains Menglusitena, concrete route is as shown in reaction equation 1.In the method, the preparation of mesylate compound needs to carry out under the low temperature of about-35 DEG C, and this reaction requires higher to production unit, considerably increases production cost.And this mesylate compound need be preserved under-18 DEG C of drying conditionss, its to moisture and air all unstable.Therefore, this kind of method difficulty of carrying out scale operation control is very large.
The method of another kind of synthesis Menglusitena is disclosed in CN1139429A, the method is improving one's methods of synthetic method disclosed in CN1061407A, 1-(mercapto methyl)-cyclopropaneacetic acid and a kind of lithium alkali reaction are generated 1-(mercapto methyl)-cyclopropaneacetic acid two negatively charged ion two lithium by the method first in organic solvent, then two negatively charged ion two lithium compounds and mesylate compound are reacted and prepare Singulair, further salify obtains Menglusitena.Shown in concrete route reaction equation 2.The alkaline butyllithium reagent used in this method is dangerous and expensive, and the excessive butyllithium existed in reaction mixture causes a large amount of by product, eventually reduces product purity and productive rate.
Pct international patent WO2005/105751 discloses a kind of method preparing Menglusitena, the methyl esters of 1-(mercapto methyl) cyclopropaneacetic acid and mesylate compound react under being included in the existence of solvent/co-solvent/alkali by described method, obtained montelukast acid under multi-solvents exists, and described acid is changed into Menglusitena, concrete route is shown in reaction equation 3.
In the above method, all relate to and adopt quinoline diol compou nd synthesis mesylate compound, its preparation process generally need be carried out under about-30 DEG C low temperature, higher to equipment requirements, controls difficulty larger.And in whole synthesis, employ multiple a large amount of organic solvent, be unfavorable for environmental protection.
Summary of the invention
For the problems referred to above, the invention provides a kind of synthetic method of Singulair.This synthetic method adopts microreactor carry out reacting and adopt same organic solvent in reaction process, and technique is simple, and reaction conditions is gentle, and environmental friendliness, the purity of gained Singulair reaches more than 99.8%, is suitable for suitability for industrialized production.
Concrete reaction equation of the present invention is as follows.
Technical scheme of the present invention is: a kind of synthetic method of Singulair, is characterized in that, comprises the following steps:
(1) 1-(mercapto methyl)-cyclopropaneacetic acid and alkali are added in organic solvent, stirring reaction 1-3h at temperature control 10-30 DEG C, obtains 1-(mercapto methyl)-cyclopropaneacetic acid two anion base solution (being called for short two anion base solution); The mol ratio of described alkali and 1-(mercapto methyl)-cyclopropaneacetic acid is 1.5-2.5:1, preferred 2.05:1;
Quinoline diol compounds and triethylamine are dissolved in organic solvent and obtain quinoline diol solution; The mol ratio of described triethylamine and quinoline diol compounds is 1.0-2.0:1, preferred 1.2:1;
Tosyl chloride is dissolved in organic solvent and obtains tolysulfonyl chlorine solution;
The mol ratio 1:1.0-1.5:1.0-1.5 of described quinoline diol compounds, 1-(mercapto methyl)-cyclopropaneacetic acid and Tosyl chloride, preferred 1:1.1:1.0;
(2) quinoline diol solution and tolysulfonyl chlorine solution pass in microreactor by coutroi velocity respectively, at temperature 10-30 DEG C, hybrid reaction (reaction 1) 10-20 minute, obtains p-toluenesulfonic esters compound solution (as shown in formula II);
(3) rate-determining steps (2) gained p-toluenesulfonic esters compound solution flow velocity and 1-(mercapto methyl)-cyclopropaneacetic acid two anion base solution hybrid reaction (the reacting 2) 20-40 minute at 10-30 DEG C passed into, obtain Singulair feed liquid and go out microreactor;
(4) by Singulair feed liquid instillation purified water, organic solvent extraction impurity is added; Aqueous phase acid adding regulates pH5.0-6.9 (preferred pH5.5-6.0), then stirring and crystallizing, filters, dry Singulair solid.
The present invention's microreactor used comprises three control temperature units (two anion base solution control temperature units, quinoline diol solution control temperature unit and tolysulfonyl chlorine solution control temperature unit), reacts Unit 1 and reaction Unit 2, wherein tolysulfonyl chlorine solution control temperature unit, quinoline diol solution control temperature unit are all connected with reaction 1 unit, react Unit 1 and are all connected with reaction 2 unit with two anion base solution control temperature units.Quinoline diol solution and tolysulfonyl chlorine solution first enter quinoline diol solution control temperature unit and the tolysulfonyl chlorine solution control temperature unit of microreactor respectively, temperature control 10-30 DEG C, then enters reaction 1 unit hybrid reaction 10-20 minute (T1=10-20 minute) of microreactor; And then enter reaction 2 unit together with two anion solutions being 10-30 DEG C with the two anion base solution control temperature unit control temperature entering microreactor, after reaction 2 unit process 20-40 minute (T2=20-40 minute), go out microreactor and carry out next step operation.The healthy and free from worry low flow micro passage reaction LFR that microreactor of the present invention adopts healthy and free from worry (Shanghai) Management Co., Ltd to produce.
In described step (1), alkali can be one or more in sodium hydroxide, potassium hydroxide, sodium hydride, sodium methylate, potassium tert.-butoxide, sodium ethylate etc., preferred sodium hydroxide and sodium methylate.
In described step (1), the organic solvent of three kinds of solution uses is identical.It can be the one in dimethyl formamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetone and acetonitrile, is preferably dimethyl formamide or dimethyl sulfoxide (DMSO).
In described step (1), in two anion base solution, organic solvent and 1-(mercapto methyl)-cyclopropaneacetic acid amount ratio are 1-6ml/g, preferred 2-3ml/g.In described quinoline diol solution, organic solvent and quinoline diol compounds amount ratio are 1-6ml/g, preferred 2-3ml/g.In described tolysulfonyl chlorine solution, the amount ratio of organic solvent and Tosyl chloride is 1-2ml/g.
In described step (2), the control temperature of reaction of reaction 1 is preferably 10-15 DEG C.In described step (2), quinoline diol solution enters the flow velocity of microreactor is 3-12ml/min, preferred 6ml/min.The flow velocity that described tolysulfonyl chlorine solution enters microreactor is 1-3ml/min, preferred 1.5ml/min.
In described step (3), the control temperature of reaction of reaction 2 is preferably 20-25 DEG C.The flow velocity that described two anion base solution enter microreactor is 1-3ml/min, preferred 2ml/min.The flow velocity of described p-toluenesulfonic esters compound solution is 5-15ml/min, preferred 10ml/min.
In described step (4), the consumption of purified water is 10-20ml/g (in quinoline diol compounds), preferred 12ml/g.
In described step (4), extraction organic solvent is one, ethyl acetate and the methylene dichloride in ethyl acetate, methyl acetate, butylacetate, trichloromethane, methylene dichloride, toluene, ether, diethyl ether, methyl ethyl ether, methyl tertiary butyl ether, methyl iso-butyl ketone (MIBK).The once used amount of described extraction solvent is 2-10ml/g (in quinoline diol compounds), preferred 3-4ml/g.
Acid in described step (4) can be one or more in the mineral acids such as formic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, tartrate, sodium bisulfite and organic acid, preferred acetic acid and tartrate.
Beneficial effect of the present invention is:
1, microreactor is adopted to react, the abundant mixing of each reaction member reaction mass and the accurate control to reaction can be realized, greatly reduce the generation of side reaction, thus obtain high yield and high-purity product, the continuity of realization response process and automatization, compare traditional reactive mode, have the time short, safety is control easily, production efficiency advantages of higher;
2, use same solvent in reaction process, solvent is easy to recycling, environmental friendliness;
3, synthetic reaction condition is gentle, does not have low-temp reaction, greatly reduces reaction controlling difficulty;
4, used in synthetic method of the present invention raw material is easy to get, simple to operate, and each step byproduct of reaction is few, yield high (>=93.0%), products obtained therefrom purity fabulous (>=99.8%), and each step reactor product is easy to separating-purifying, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the structural representation of microreactor of the present invention.
Embodiment
Below in conjunction with specific embodiment, the present invention is further illustrated, but protection scope of the present invention is not limited thereto: in the present invention, quinoline diol compounds used, 1-(mercapto methyl)-cyclopropaneacetic acid and other reagent and solvent all directly can be purchased from the market and obtain.
Embodiment 1
As shown in Figure 1, microreactor of the present invention comprises three control temperature units (two anion base solution control temperature units, quinoline diol solution control temperature unit and tolysulfonyl chlorine solution control temperature unit), reacts Unit 1 and reaction Unit 2, wherein Tosyl chloride control temperature unit, quinoline diol solution control temperature unit are all connected with reaction 1 unit, react Unit 1 and are all connected with reaction 2 unit with two anion base solution control temperature units.
Quinoline diol solution and tolysulfonyl chlorine solution first enter quinoline diol solution control temperature unit and the tolysulfonyl chlorine solution control temperature unit of microreactor respectively, temperature control 10-30 DEG C, then enters reaction 1 unit hybrid reaction 10-20 minute (T1=10-20 minute) of microreactor; And then enter reaction 2 unit together with two anion solutions being 10-30 DEG C with the two anion base solution control temperature unit control temperature entering microreactor, after reaction 2 unit process 20-40 minute (T2=20-40 minute), go out microreactor and carry out next step operation.
The preparation of embodiment 2 Singulair
(1) add in 35ml dimethyl formamide by 9.8g (0.246mol) sodium hydroxide and 1-(mercapto methyl) cyclopropaneacetic acid 17.5g (0.12mol), at 10-30 DEG C, stirring reaction 3h obtains 1-(mercapto methyl) cyclopropaneacetic acid two anion base solution;
(2) 50g (0.11mol) quinoline diol compounds and 13.4g (0.13mol) triethylamine are dissolved in 100ml dimethyl formamide; Be dissolved in 21ml dimethyl formamide by Tosyl chloride 21g (0.11mol), coutroi velocity 6.0ml/min and 1.5ml/min enters in microreactor respectively, reacts 10 minutes after control temperature unit in reaction 1 unit at 10-15 DEG C;
(3) the two anion base solution being then 2.0ml/min with flow velocity under coutroi velocity 10ml/min react 20 minutes at 20-25 DEG C in reaction 2 unit, and gained Singulair feed liquid goes out microreactor;
(4) by Singulair feed liquid instillation 500ml purified water, with 150ml*3 extraction into ethyl acetate impurity 3 times; Aqueous phase 50% acetic acid regulates pH=5.5-6.0, stirring and crystallizing, and filter, at 50-60 DEG C, forced air drying obtains faint yellow solid 61.4g, and yield 95.1%, HPLC detects purity and is greater than 99.8%, and chiral purity is greater than 99.9%.
ESI(+)MS＝586.2。
1HNMR(CD
3OD)：δ/ppm＝8.335(d,1H),8.021(brs,1H),8.012(d,1H),7.954(d,1H),7.803(d,1H),7.751(brs,1H),7.628(d,1H),7.578(d,1H),7.522(d,1H),7.414(m,1H),7.412(m,1H),7.355(d,1H),7.123(m,1H),7.105(m,1H),7.079(m,1H),5.158(brs,1H),4.033(t,1H),3.178-2.752(m,2H),2.724-2.549(d,2H),2.227-2.115(m,2H),2.139-2.027(d,2H),1.469-1.459(s,6H),0.459-0.254(m,4H)。
The preparation of embodiment 3 Singulair
(1) add in 35ml dimethyl sulfoxide (DMSO) by 10.0g (0.25mol) sodium hydroxide and 1-(mercapto methyl)-cyclopropaneacetic acid 17.5g (0.12mol), at 10-30 DEG C, stirring reaction 2h obtains 1-(mercapto methyl)-cyclopropaneacetic acid two anion base solution;
(2) 50g (0.11mol) quinoline diol compounds and 13.4g (0.13mol) triethylamine are dissolved in 100ml dimethyl sulfoxide (DMSO), Tosyl chloride 21g (0.11mol) is dissolved in 21ml dimethyl sulfoxide (DMSO), coutroi velocity 6.0ml/min and 1.5ml/min enters in microreactor respectively, reacts 10 minutes after control temperature unit in reaction 1 unit at 10-15 DEG C.Then be that the two anion base solution of 2.0ml/min react 20 minutes at 20-25 DEG C in reaction 2 unit with flow velocity under coutroi velocity 10ml/min, gained Singulair feed liquid goes out microreactor;
(3) by Singulair feed liquid instillation 500ml purified water, with 150ml*3 extraction into ethyl acetate impurity 3 times; Aqueous phase 50% acetic acid regulates pH=5.5-6.0, stirring and crystallizing, and filter, at 50-60 DEG C, forced air drying obtains faint yellow solid 60.4g, and yield 93.5%, HPLC detects purity and is greater than 99.8%, and chiral purity is greater than 99.9%.ESI(+)MS＝586.2。
The preparation of embodiment 4 Singulair
(1) 13.3g (0.246mol) sodium methylate and 1-(mercapto methyl)-cyclopropaneacetic acid 17.5g (0.12mol) to be added in 35ml dimethyl formamide stirring reaction 3h at 10-30 DEG C and obtain 1-(mercapto methyl)-cyclopropaneacetic acid two anion base solution;
(2) 50g (0.11mol) quinoline diol compounds and 13.4g (0.13mol) triethylamine are dissolved in 100ml dimethyl formamide, Tosyl chloride 21g (0.11mol) is dissolved in 21ml dimethyl formamide, coutroi velocity 6.0ml/min and 1.5ml/min enters in microreactor respectively, reacts 15 minutes after control temperature unit in reaction 1 unit at 10-15 DEG C;
(3) the two anion base solution being then 2.0ml/min with flow velocity under coutroi velocity 10ml/min react 25 minutes at 20-25 DEG C in reaction 2 unit, and gained Singulair feed liquid goes out microreactor;
(4) by Singulair feed liquid instillation 500ml purified water, with 150ml*3 extraction into ethyl acetate impurity 3 times; Aqueous phase 50% acetic acid regulates aqueous phase pH=5.5-6.0, stirring and crystallizing, and filter, at 50-60 DEG C, forced air drying obtains faint yellow solid 61.2g, and yield 94.8%, HPLC detects purity and is greater than 99.8%, and chiral purity is greater than 99.9%.ESI(+)MS＝586.2。
Comparative example:
Adopt Methanesulfonyl chloride 12.6g (0.11mol) to replace Tosyl chloride 21g (0.11mol), all the other are with embodiment 2.Obtain faint yellow solid 58.0g, yield 89.9%, HPLC detects purity and is greater than 99.5%, and chiral purity is greater than 99.5%.ESI(+)MS＝586.2。The synthetic method of visible employing Tosyl chloride, its yield and product purity tool are significantly improved.
Claims (10)
1. a synthetic method for Singulair, is characterized in that, comprises the following steps:
(1) 1-(mercapto methyl)-cyclopropaneacetic acid and alkali are added in organic solvent, stirring reaction 1-3h at temperature control 10-30 DEG C, obtain 1-(mercapto methyl)-cyclopropaneacetic acid two anion base solution; The mol ratio of described alkali and 1-(mercapto methyl)-cyclopropaneacetic acid is 1.5-2.5:1;
Quinoline diol compounds and triethylamine are dissolved in organic solvent and obtain quinoline diol solution; The mol ratio of described triethylamine and quinoline diol compounds is 1.0-2.0:1;
Tosyl chloride is dissolved in organic solvent and obtains tolysulfonyl chlorine solution;
The mol ratio 1:1.0-1.5:1.0-1.5 of described quinoline diol compounds, 1-(mercapto methyl)-cyclopropaneacetic acid and Tosyl chloride;
(2) quinoline diol solution and tolysulfonyl chlorine solution pass in microreactor by coutroi velocity respectively, and hybrid reaction 10-20 minute at temperature 10-30 DEG C obtains p-toluenesulfonic esters compound solution;
(3) rate-determining steps (2) gained p-toluenesulfonic esters compound solution flow velocity and 1-(the mercapto methyl)-cyclopropaneacetic acid two anion base solution hybrid reaction 20-40 minute at 10-30 DEG C passing into microreactor, obtain Singulair feed liquid and go out microreactor;
(4) by Singulair feed liquid instillation purified water, organic solvent extraction impurity is added; Aqueous phase acid adding regulates pH5.0-6.9, then stirring and crystallizing, filters, dry Singulair solid;
Described quinoline diol compounds is:
Described tosic acid ester cpds is:
Described 1-(mercapto methyl)-cyclopropaneacetic acid two anion base solution is called for short two anion base solution.
2. the synthetic method of a kind of Singulair as claimed in claim 1, it is characterized in that, described microreactor comprises three control temperature units, reacts Unit 1 and reaction Unit 2, and described three control temperature units are two anion base solution control temperature units, quinoline diol solution control temperature unit and tolysulfonyl chlorine solution control temperature unit; Wherein tolysulfonyl chlorine solution control temperature unit, quinoline diol solution control temperature unit are all connected with reaction 1 unit, react Unit 1 and are all connected with reaction 2 unit with two anion base solution control temperature units; Quinoline diol solution and tolysulfonyl chlorine solution first enter quinoline diol solution control temperature unit and the tolysulfonyl chlorine solution control temperature unit of microreactor respectively, temperature control 10-30 DEG C, the reaction 1 unit hybrid reaction then entering microreactor obtains p-toluenesulfonic esters compound solution; And then enter reaction 2 unit together with two anion solutions being 10-30 DEG C with the two anion base solution control temperature unit control temperature entering microreactor, obtain Singulair feed liquid in reaction 2 unit process and go out microreactor.
3. the synthetic method of a kind of Singulair as claimed in claim 1 or 2, is characterized in that, in described step (1) alkali be in sodium hydroxide, potassium hydroxide, sodium hydride, sodium methylate, potassium tert.-butoxide, sodium ethylate one or more.
4. the synthetic method of a kind of Singulair as claimed in claim 1 or 2, is characterized in that, adopting identical organic solvent in described step (1), is the one in dimethyl formamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetone and acetonitrile.
5. the synthetic method of a kind of Singulair as claimed in claim 1 or 2, is characterized in that, in described step (2), quinoline diol solution enters the flow velocity of microreactor is 3-12ml/min; The flow velocity that tolysulfonyl chlorine solution enters microreactor is 1-3ml/min.
6. the synthetic method of a kind of Singulair as claimed in claim 5, is characterized in that, in described step (2), quinoline diol solution enters the flow velocity of microreactor is 6ml/min; The flow velocity that tolysulfonyl chlorine solution enters microreactor is 1.5ml/min.
7. the synthetic method of a kind of Singulair as claimed in claim 1 or 2, is characterized in that, the flow velocity that described step (3) two anion base solution enters microreactor is 1-3ml/min; The flow velocity of p-toluenesulfonic esters compound solution is 5-15ml/min.
8. the synthetic method of a kind of Singulair as claimed in claim 7, is characterized in that, the flow velocity that described step (3) two anion base solution enters microreactor is 2ml/min; The flow velocity of p-toluenesulfonic esters compound solution is 10ml/min.
9. the synthetic method of a kind of Singulair as claimed in claim 1 or 2, is characterized in that, with quinoline diol compounds gauge, in described step (4), the consumption of purified water is 10-20ml/g.
10. the synthetic method of a kind of Singulair as claimed in claim 1 or 2, it is characterized in that, in described step (4), extraction organic solvent is the one in ethyl acetate, methyl acetate, butylacetate, trichloromethane, methylene dichloride, toluene, ether, diethyl ether, methyl ethyl ether, methyl tertiary butyl ether, methyl iso-butyl ketone (MIBK).
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114950299A (en) * | 2022-04-27 | 2022-08-30 | 浙江海昇药业股份有限公司 | Preparation device and method of pirstine bromide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005105751A1 (en) * | 2004-04-21 | 2005-11-10 | Teva Pharmaceutical Industries Ltd. | Processes for preparing montelukast sodium |
| WO2008009970A2 (en) * | 2006-07-21 | 2008-01-24 | Pliva Hrvatska D.O.O. | Process for the preparation of montelukast |
| CN102424673A (en) * | 2011-09-14 | 2012-04-25 | 浙江海正药业股份有限公司 | Montelukast sodium intermediate and method for synthesizing montelukast sodium thereof |
| CN104119270A (en) * | 2014-08-12 | 2014-10-29 | 牡丹江恒远药业有限公司 | Method for preparing Montelukast sodium |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005105751A1 (en) * | 2004-04-21 | 2005-11-10 | Teva Pharmaceutical Industries Ltd. | Processes for preparing montelukast sodium |
| WO2008009970A2 (en) * | 2006-07-21 | 2008-01-24 | Pliva Hrvatska D.O.O. | Process for the preparation of montelukast |
| CN102424673A (en) * | 2011-09-14 | 2012-04-25 | 浙江海正药业股份有限公司 | Montelukast sodium intermediate and method for synthesizing montelukast sodium thereof |
| CN104119270A (en) * | 2014-08-12 | 2014-10-29 | 牡丹江恒远药业有限公司 | Method for preparing Montelukast sodium |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114950299A (en) * | 2022-04-27 | 2022-08-30 | 浙江海昇药业股份有限公司 | Preparation device and method of pirstine bromide |
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