CN105541710B - A kind of synthetic method of montelukast - Google Patents
A kind of synthetic method of montelukast Download PDFInfo
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- CN105541710B CN105541710B CN201610096340.8A CN201610096340A CN105541710B CN 105541710 B CN105541710 B CN 105541710B CN 201610096340 A CN201610096340 A CN 201610096340A CN 105541710 B CN105541710 B CN 105541710B
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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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Abstract
The invention discloses a kind of synthetic methods of montelukast.It is to add in 1 (mercapto methyl) cyclopropaneacetic acid and alkali in organic solvent, and two anion aqueous slkalis are stirred to react to obtain at 10 30 DEG C；Quinoline diol compound and triethylamine are dissolved in organic solvent and obtain quinoline diol solution；Paratoluensulfonyl chloride is dissolved in organic solvent and obtains tolysulfonyl solutions of chlorine；Then quinoline diol solution and tolysulfonyl solutions of chlorine are passed through in microreactor by coutroi velocity respectively, hybrid reaction at 10 30 DEG C, obtain p-methyl benzenesulfonic acid ester compounds solution；Then it with 1 (mercapto methyl) cyclopropaneacetic acid, the two anion aqueous slkali hybrid reaction at 10 30 DEG C being passed through, obtains montelukast feed liquid and goes out microreactor, it is post-treated to obtain montelukast solid.The present invention is easy to operate, and each step byproduct of reaction is few, and high income, products obtained therefrom purity is fabulous, and each step reactor product is easily isolated purification, is suitble to industrialized production.
Description
Technical field
The invention belongs to medical chemistries to synthesize field, and in particular to a kind of synthetic method of montelukast.
Background technology
Montelukast Sodium (Montelukast Sodium), chemistry are entitled：(+)-1-[[[(1R)-1-[3-[(1E)-2-
(the chloro- 2- quinolyls of 7-)-vinyl] phenyl] -3- [2- (1- hydroxyl -1- Methylethyls) phenyl] propyl] sulphur] methyl] cyclopropane
Acetic acid mono-sodium salt, molecular formula：C35H35ClNNaO3S, molecular weight：608.18 structural formula is：
Montelukast Sodium (trade name：Singulair) it is researched and developed by United States Merck company, 2 months 1998 for the first time in Finland and Mo Xi
Brother lists, and obtains within 1999 state food and drug administration's approval official listing.The compound is a kind of oral
Leukotriene receptor antagonists, energy specificity inhibits the cysteinyl leukotriene receptor in air flue, so as to reach improvement airway inflammation,
Effective Control of asthma symptom, additionally suitable for the treatment of allergic rhinitis.
It is synthesized in the prior art about Montelukast Sodium, mostly with compound 2- [2- [3- (R)-[3- [2- (the chloro- 2- quinoline of 7-
Base) vinyl] phenyl] -3- hydroxyls] propyl phenyl] and -2- propyl alcohol (hereinafter referred to as quinoline diol class compound) be raw material system
It is standby.
Original grinds the preparation method that Canadian Mike's fluorine Ross spy company discloses the compound in CN1061407A, it is adopted
It is reacted in the presence of diisopropyl ethyl amine with methylsufonyl chloride with quinoline diol compound, isolated intermediate 2- [2- [3-
(R)-[3- [2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- sulfonyloxy methyls oxygroup] propyl phenyl] (the following letter of -2- propyl alcohol
Claim mesylate compound), after then being reacted with 1- (mercapto methyl)-cyclopropylacetate Meng Lu is obtained through hydrolysis, into salt
The special sodium of department, specific route is as shown in reaction equation 1.The preparation of mesylate compound is needed at -35 DEG C or so in this method
In a low temperature of carry out, the reaction is more demanding to production equipment, considerably increases production cost.And the mesylate compound needs
It is preserved under -18 DEG C of drying conditions, it is all unstable to moisture and air.Therefore, this kind of method carries out large-scale production control
Difficulty it is very big.
The method that another synthesis Montelukast Sodium is disclosed in CN1139429A, this method is disclosed in CN1061407A
The improved method of synthetic method, this method is first in organic solvent by 1- (mercapto methyl)-cyclopropaneacetic acid and a kind of lithium alkali
Reaction generation 1- (mercapto methyl)-two anion of cyclopropaneacetic acid, two lithium, then by two anion, two lithium compound and methylsulphur
Montelukast is prepared in ester compound reaction, further obtains Montelukast Sodium into salt.Specific 2 institute of route reaction equation
Show.The alkaline butyl lithium reagent used in the method is dangerous and expensive, and excessive butyl lithium present in reaction mixture causes
A large amount of by-products, eventually reduce product purity and yield.
Pct international patent WO2005/105751 discloses a kind of method for preparing Montelukast Sodium, the method includes
The methyl esters of 1- (mercapto methyl) cyclopropaneacetic acid is reacted with mesylate compound in the presence of solvent/co-solvent/alkali, more
Montelukast acid is made, and the acid is converted to Montelukast Sodium in the presence of kind solvent, specific route is shown in reaction equation 3.
In approach described above, all refer to using quinoline diol compound synthesis mesylate compound, preparation process
It need to generally be carried out under -30 DEG C or so low temperature, higher to equipment requirement, control difficulty is larger.And it is used in entire synthesis
A variety of a large amount of organic solvents, are unfavorable for environmental protection.
Invention content
In view of the above-mentioned problems, the present invention provides a kind of synthetic methods of montelukast.The synthetic method uses micro- reaction
Device is reacted and in reaction process using same organic solvent, and simple for process, reaction condition is mild, environmental-friendly, gained
The purity of montelukast is suitable for industrialized production up to more than 99.8%.
The specific reaction equation of the present invention is as follows.
The technical scheme is that：A kind of synthetic method of montelukast, it is characterized in that, include the following steps：
(1) 1- (mercapto methyl)-cyclopropaneacetic acid and alkali are added in organic solvent, is stirred to react at 10-30 DEG C of temperature control
1-3h obtains two anion aqueous slkali of 1- (mercapto methyl)-cyclopropaneacetic acid (referred to as two anion aqueous slkalis)；The alkali and 1-
The molar ratio of (mercapto methyl)-cyclopropaneacetic acid is 1.5-2.5：1, preferably 2.05:1；
Quinoline diol class compound and triethylamine are dissolved in organic solvent and obtain quinoline diol solution；The triethylamine and quinoline
The molar ratio of diol moiety class compound is 1.0-2.0:1, preferably 1.2:1；
Paratoluensulfonyl chloride is dissolved in organic solvent and obtains tolysulfonyl solutions of chlorine；
The molar ratio 1 of the quinoline diol class compound, 1- (mercapto methyl)-cyclopropaneacetic acid and paratoluensulfonyl chloride:
1.0-1.5:1.0-1.5 preferably 1:1.1:1.0；
(2) quinoline diol solution and tolysulfonyl solutions of chlorine are passed through in microreactor by coutroi velocity respectively, in temperature
Hybrid reaction (reaction 1) 10-20 minutes, obtain p-methyl benzenesulfonic acid ester compounds solution at 10-30 DEG C (as shown in formula II)；
(3) p-methyl benzenesulfonic acid ester compounds solution flow rate obtained by rate-determining steps (2) and 1- (the mercapto methyl)-ring third being passed through
Two anion aqueous slkali of guanidine-acetic acid hybrid reaction (reaction 2) 20-40 minute at 10-30 DEG C, obtain montelukast feed liquid go out it is micro- instead
Answer device；
(4) montelukast feed liquid is instilled in purified water, added with solvent extracting impurities；Water phase acid adding adjusts pH5.0-
6.9 (preferably pH5.5-6.0), then stirring and crystallizing, filtering, dry montelukast solid.
Microreactor used in the present invention includes three control temperature units (two anion aqueous slkali control temperature units, quinoline diols
Solution control temperature unit and tolysulfonyl solutions of chlorine control temperature unit), reaction Unit 1 and reaction Unit 2, wherein paratoluensulfonyl chloride
Solution control temperature unit, quinoline diol solution control temperature unit are connected with reacting Unit 1, react Unit 1 and two anion aqueous slkalis
Control temperature unit is connected with reacting Unit 2.Quinoline diol solution and tolysulfonyl solutions of chlorine first respectively enter microreactor
Quinoline diol solution control temperature unit and tolysulfonyl solutions of chlorine control temperature unit, 10-30 DEG C of temperature control, subsequently into microreactor
React 1 unit hybrid reaction 10-20 minutes (T1=10-20 minutes)；Then again with enter microreactor two anion alkali solubles
Liquid control temperature unit enters reaction Unit 2 together controlled at 10-30 DEG C of two anion solutions, is reacting 2 unit process 20-
After 40 minutes (T2=20-40 minutes), go out microreactor and carry out next step operation.The present invention microreactor using it is healthy and free from worry (on
Sea) Management Co., Ltd production healthy and free from worry low discharge micro passage reaction LFR.
Alkali can be sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, potassium tert-butoxide, sodium ethoxide etc. in the step (1)
In one or more, preferably sodium hydroxide and sodium methoxide.
The organic solvent that three kinds of solution use in the step (1) is identical.It can be dimethylformamide, dimethyl
One kind in sulfoxide, tetrahydrofuran, acetone and acetonitrile, preferably dimethylformamide or dimethyl sulfoxide (DMSO).
Organic solvent and 1- (mercapto methyl)-cyclopropaneacetic acid amount ratio in two anion aqueous slkalis in the step (1)
For 1-6ml/g, preferably 2-3ml/g.Organic solvent and quinoline diol class compound amount ratio are 1- in the quinoline diol solution
6ml/g, preferably 2-3ml/g.The amount ratio of organic solvent and paratoluensulfonyl chloride is 1- in the tolysulfonyl solutions of chlorine
2ml/g。
The controlling reaction temperature of reaction 1 is preferably 10-15 DEG C in the step (2).Quinoline diol is molten in the step (2)
The flow velocity of liquid into microreactor is 3-12ml/min, preferably 6ml/min.The tolysulfonyl solutions of chlorine is into the stream of microreactor
Speed is 1-3ml/min, preferably 1.5ml/min.
The controlling reaction temperature of reaction 2 is preferably 20-25 DEG C in the step (3).The two anion aqueous slkali is into micro-
The flow velocity of reactor is 1-3ml/min, preferably 2ml/min.The flow velocity of the p-methyl benzenesulfonic acid ester compounds solution is 5-15ml/
Min, preferably 10ml/min.
The dosage of purified water is 10-20ml/g (in terms of quinoline diol class compound), preferably 12ml/ in the step (4)
g。
Extraction is ethyl acetate, methyl acetate, butyl acetate, chloroform, dichloro with organic solvent in the step (4)
One kind in methane, toluene, ether, diethyl ether, ethyl methyl ether, methyl tertiary butyl ether(MTBE), methyl iso-butyl ketone (MIBK), ethyl acetate and
Dichloromethane.The once used amount of extraction solvent is 2-10ml/g (in terms of quinoline diol class compound), preferably 3-4ml/
g。
Acid in the step (4) can be the nothings such as formic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, sodium hydrogensulfite
It is one or more in machine acid and organic acid, preferably acetic acid and tartaric acid.
Beneficial effects of the present invention are：
1st, it is reacted using microreactor, it can be achieved that each reaction member reaction mass is sufficiently mixed and to reaction
Accurate control, greatly reduces the generation of side reaction, so as to obtain the continuity in high yield and high-purity product, realizing reaction process
And automation, compared to traditional reactive mode, there is the advantages that time is short, and safety is easily-controllable, and production efficiency is high；
2nd, using same solvent in reaction process, solvent is easy to recycling, environmental-friendly；
3rd, synthetic reaction condition is mild, without low-temp reaction, greatly reduces reaction controlling difficulty；
4th, raw material used in synthetic method of the invention is easy to get, easy to operate, and each byproduct of reaction that walks is few, high income
(>=93.0%), products obtained therefrom purity is fabulous (>=99.8%), and each step reactor product is easily isolated purification, is suitble to industry metaplasia
Production.
Description of the drawings
Fig. 1 is the structure diagram of microreactor of the present invention.
Specific embodiment
With reference to specific embodiment, the present invention is further illustrated, but protection scope of the present invention is not limited to
This：Quinoline diol class compound used, 1- (mercapto methyl)-cyclopropaneacetic acid and other reagents and solvent can be straight in the present invention
Buying from the market is connect to obtain.
Embodiment 1
As shown in Figure 1, the microreactor of the present invention includes three control temperature units (two anion aqueous slkali control temperature units, quinolines
Diol moiety solution control temperature unit and tolysulfonyl solutions of chlorine control temperature unit), reaction Unit 1 and reaction Unit 2, wherein to toluene
Sulfonic acid chloride control temperature unit, quinoline diol solution control temperature unit are connected with reacting Unit 1, react Unit 1 and two anion alkali solubles
Liquid control temperature unit is connected with reacting Unit 2.
Quinoline diol solution and tolysulfonyl solutions of chlorine first respectively enter the quinoline diol solution temperature control list of microreactor
Member and tolysulfonyl solutions of chlorine control temperature unit, 10-30 DEG C of temperature control, subsequently into the 1 unit hybrid reaction of reaction of microreactor
10-20 minutes (T1=10-20 minutes)；Then temperature is controlled with entering two anion aqueous slkali control temperature units of microreactor again
Enter reaction Unit 2 together for 10-30 DEG C of two anion solutions, react (T2=20-40 points of 2 unit process 20-40 minutes
Clock) after, go out microreactor and carry out next step operation.
The preparation of 2 montelukast of embodiment
(1) 9.8g (0.246mol) sodium hydroxides and 1- (mercapto methyl) cyclopropaneacetic acid 17.5g (0.12mol) are added in
In 35ml dimethylformamides, 3h is stirred to react at 10-30 DEG C and obtains two anion alkali soluble of 1- (mercapto methyl) cyclopropaneacetic acid
Liquid；
(2) 50g (0.11mol) quinoline diol class compound and 13.4g (0.13mol) triethylamine are dissolved in 100ml diformazans
In base formamide；Paratoluensulfonyl chloride 21g (0.11mol) is dissolved in 21ml dimethylformamides, respectively coutroi velocity
6.0ml/min and 1.5ml/min enter in microreactor, and 10 points are reacted at 10-15 DEG C after reacting in Unit 1 through control temperature unit
Clock；
(3) and then under coutroi velocity 10ml/min Unit 2 are being reacted with the two anion aqueous slkalis that flow velocity is 2.0ml/min
It is reacted 20 minutes at middle 20-25 DEG C, gained montelukast feed liquid goes out microreactor；
(4) montelukast feed liquid is instilled in 500ml purified waters, with 150ml*3 ethyl acetate extracting impurities 3 times；Water phase
Adjust pH=5.5-6.0 with 50% acetic acid, stirring and crystallizing, filtering, at 50-60 DEG C forced air drying obtain faint yellow solid 61.4g, receive
Rate 95.1%, HPLC detection purity are more than 99.8%, and chiral purity is more than 99.9%.
ESI (+) MS=586.2.
1HNMR(CD3OD)：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 3 montelukast of embodiment
(1) 10.0g (0.25mol) sodium hydroxides and 1- (mercapto methyl)-cyclopropaneacetic acid 17.5g (0.12mol) are added
Enter in 35ml dimethyl sulfoxide (DMSO)s, 2h is stirred to react at 10-30 DEG C and obtains two anion alkali soluble of 1- (mercapto methyl)-cyclopropaneacetic acid
Liquid；
(2) 50g (0.11mol) quinoline diol class compound and 13.4g (0.13mol) triethylamine are dissolved in 100ml diformazans
In base sulfoxide, paratoluensulfonyl chloride 21g (0.11mol) is dissolved in 21ml dimethyl sulfoxide (DMSO)s, respectively coutroi velocity 6.0ml/min
Enter in microreactor with 1.5ml/min, reacted 10 minutes at 10-15 DEG C through control temperature unit after reacting in Unit 1.Then it controls
Under flow velocity 10ml/min processed 20 are reacted at 20-25 DEG C with the two anion aqueous slkalis that flow velocity is 2.0ml/min in Unit 2 are reacted
Minute, gained montelukast feed liquid goes out microreactor；
(3) montelukast feed liquid is instilled in 500ml purified waters, with 150ml*3 ethyl acetate extracting impurities 3 times；Water phase
Adjust pH=5.5-6.0 with 50% acetic acid, stirring and crystallizing, filtering, at 50-60 DEG C forced air drying obtain faint yellow solid 60.4g, receive
Rate 93.5%, HPLC detection purity are more than 99.8%, and chiral purity is more than 99.9%.ESI (+) MS=586.2.
The preparation of 4 montelukast of embodiment
(1) 13.3g (0.246mol) sodium methoxides and 1- (mercapto methyl)-cyclopropaneacetic acid 17.5g (0.12mol) are added in
3h is stirred to react in 35ml dimethylformamides at 10-30 DEG C and obtains two anion aqueous slkali of 1- (mercapto methyl)-cyclopropaneacetic acid；
(2) 50g (0.11mol) quinoline diol class compound and 13.4g (0.13mol) triethylamine are dissolved in 100ml diformazans
In base formamide, paratoluensulfonyl chloride 21g (0.11mol) is dissolved in 21ml dimethylformamides, respectively coutroi velocity
6.0ml/min and 1.5ml/min enter in microreactor, and 15 points are reacted at 10-15 DEG C after reacting in Unit 1 through control temperature unit
Clock；
(3) and then under coutroi velocity 10ml/min Unit 2 are being reacted with the two anion aqueous slkalis that flow velocity is 2.0ml/min
It is reacted 25 minutes at middle 20-25 DEG C, gained montelukast feed liquid goes out microreactor；
(4) montelukast feed liquid is instilled in 500ml purified waters, with 150ml*3 ethyl acetate extracting impurities 3 times；Water phase
Adjust water phase pH=5.5-6.0 with 50% acetic acid, stirring and crystallizing, filtering, at 50-60 DEG C forced air drying obtain faint yellow solid
61.2g, yield 94.8%, HPLC detection purity are more than 99.8%, and chiral purity is more than 99.9%.ESI (+) MS=586.2.
Comparative example：
Using methylsufonyl chloride 12.6g (0.11mol) instead of paratoluensulfonyl chloride 21g (0.11mol), remaining same embodiment
2.Faint yellow solid 58.0g, yield 89.9% are obtained, HPLC detection purity is more than 99.5%, and chiral purity is more than 99.5%.
ESI (+) MS=586.2.It can be seen that using the synthetic method of paratoluensulfonyl chloride, yield and product purity, which have, significantly to be carried
It is high.
Claims (7)
1. a kind of synthetic method of montelukast, it is characterized in that, include the following steps：
(1) 1- (mercapto methyl)-cyclopropaneacetic acid and alkali are added in organic solvent, 1-3h are stirred to react at 10-30 DEG C of temperature control,
Obtain two anion aqueous slkali of 1- (mercapto methyl)-cyclopropaneacetic acid；Mole of the alkali and 1- (mercapto methyl)-cyclopropaneacetic acid
Than for 1.5-2.5：1；
Quinoline diol class compound and triethylamine are dissolved in organic solvent and obtain quinoline diol solution；The triethylamine and quinoline two
The molar ratio of alcohol compound is 1.0-2.0:1；
Paratoluensulfonyl chloride is dissolved in organic solvent and obtains tolysulfonyl solutions of chlorine；
The molar ratio 1 of the quinoline diol class compound, 1- (mercapto methyl)-cyclopropaneacetic acid and paratoluensulfonyl chloride:1.0-
1.5:1.0-1.5；
Identical organic solvent is used in the step (1), is dimethylformamide or dimethyl sulfoxide (DMSO)；The alkali is hydrogen-oxygen
Change sodium or sodium methoxide；
(2) quinoline diol solution and tolysulfonyl solutions of chlorine are passed through in microreactor by coutroi velocity respectively, in temperature 10-30
Hybrid reaction 10-20 minutes at DEG C, p-methyl benzenesulfonic acid ester compounds solution is obtained；
(3) p-methyl benzenesulfonic acid ester compounds solution flow rate obtained by rate-determining steps (2) and be passed through the 1- (mercapto methyl) of microreactor-
Two anion aqueous slkali of cyclopropaneacetic acid obtains montelukast feed liquid and goes out micro- reaction hybrid reaction 20-40 minutes at 10-30 DEG C
Device；
(4) montelukast feed liquid is instilled in purified water, added with solvent extracting impurities；Water phase acid adding adjusts pH5.0-6.9, so
Stirring and crystallizing afterwards, filtering, dry montelukast solid；
The quinoline diol class compound is：
The p-methyl benzenesulfonic acid ester compounds are：
The two anion aqueous slkali of 1- (mercapto methyl)-cyclopropaneacetic acid referred to as two anion aqueous slkalis；The microreactor
Including three control temperature units, reaction Unit 1 and reaction Unit 2, three control temperature units are two anion aqueous slkali temperature control lists
Member, quinoline diol solution control temperature unit and tolysulfonyl solutions of chlorine control temperature unit；Wherein tolysulfonyl solutions of chlorine temperature control list
Member, quinoline diol solution control temperature unit are connected with reacting Unit 1, react Unit 1 and two anion aqueous slkali control temperature units are equal
It is connected with reacting Unit 2；The quinoline diol that quinoline diol solution and tolysulfonyl solutions of chlorine first respectively enter microreactor is molten
Liquid control temperature unit and tolysulfonyl solutions of chlorine control temperature unit, 10-30 DEG C of temperature control, subsequently into reaction Unit 1 of microreactor
Hybrid reaction obtains p-methyl benzenesulfonic acid ester compounds solution；Then again with enter microreactor two anion aqueous slkali temperature control lists
Member enters reaction Unit 2 together controlled at 10-30 DEG C of two anion solutions, and montelukast is obtained reacting 2 unit processes
Feed liquid goes out microreactor.
2. a kind of synthetic method of montelukast as described in claim 1, it is characterized in that, quinoline diol in the step (2)
The flow velocity of solution into microreactor is 3-12ml/min；The flow velocity of tolysulfonyl solutions of chlorine into microreactor is 1-3ml/min.
3. a kind of synthetic method of montelukast as claimed in claim 2, it is characterized in that, quinoline diol in the step (2)
The flow velocity of solution into microreactor is 6ml/min；The flow velocity of tolysulfonyl solutions of chlorine into microreactor is 1.5ml/min.
4. a kind of synthetic method of montelukast as described in claim 1, it is characterized in that, (3) the two anion alkali of step
The flow velocity of solution into microreactor is 1-3ml/min；The flow velocity of p-methyl benzenesulfonic acid ester compounds solution is 5-15ml/min.
5. a kind of synthetic method of montelukast as claimed in claim 4, it is characterized in that, (3) the two anion alkali of step
The flow velocity of solution into microreactor is 2ml/min；The flow velocity of p-methyl benzenesulfonic acid ester compounds solution is 10ml/min.
6. a kind of synthetic method of montelukast as described in claim 1, it is characterized in that, with quinoline diol class compound amount
It counts, the dosage of purified water is 10-20ml/g in the step (4).
7. a kind of synthetic method of montelukast as described in claim 1, it is characterized in that, extraction is with having in the step (4)
Solvent for ethyl acetate, methyl acetate, butyl acetate, chloroform, dichloromethane, toluene, ether, diethyl ether, ethyl methyl ether,
One kind in methyl tertiary butyl ether(MTBE), methyl iso-butyl ketone (MIBK).
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| 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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| GB0614485D0 (en) * | 2006-07-21 | 2006-09-27 | Pliva Istrazivanje I Razvoj D | Process |
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|---|---|---|---|---|
| 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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