CN101323589B - Preparation of novel compound and montelukast sodium - Google Patents
Preparation of novel compound and montelukast sodium Download PDFInfo
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- CN101323589B CN101323589B CN2008100831989A CN200810083198A CN101323589B CN 101323589 B CN101323589 B CN 101323589B CN 2008100831989 A CN2008100831989 A CN 2008100831989A CN 200810083198 A CN200810083198 A CN 200810083198A CN 101323589 B CN101323589 B CN 101323589B
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Abstract
The invention provides a method for preparing Montelukast sodium, which includes the following steps that sodium alcoholate and Montelukast acid react in an organic solvent; wherein, the Montelukast acid is obtained from acidification of Montelukast cyclohexane. The invention provides a new method for preparing the Montelukast sodium without impurities of cinnamene and lactone; the overall yield of the Montelukast sodium can be on a par with the yields of the methods disclosed by European patent No.737 and No.186. In addition, the invention also provides a method, by which a subsequent coupling reaction can be operated more easily at relatively high reaction temperature, without separating unstable methanesulfonic acid.
Description
Technical field
The present invention relates to the preparation method of new compound and Menglusitena (montelukast sodium).
Background technology
The chemistry of Menglusitena is called 1-[[[(1R)-1-[3-[(1E)-and 2-(7-chloro-2-quinoline) vinyl] phenyl]-3-[2-(1-hydroxyl-1-methylethyl) phenyl] propyl group] sulfo-] methyl] cyclopropaneacetic acid sodium, its structural formula is as follows:
Menglusitena is a kind of LTRA, and it suppresses the biosynthesizing of leukotriene.Menglusitena is a kind of being white in color to linen powder, dissolves in methyl alcohol, second alcohol and water, but is insoluble in acetonitrile.
European patent the 480th, disclosed Menglusitena and preparation method thereof No. 717, this method at first is hydrolyzed into rough sodium salt with its ester derivative, again this rough thing acidifying is become montelukast acid (montelukastacid), utilize column chromatography that this crude acid purifying is become the buttery montelukast acid at last.This oily montelukast acid is in ethanol, by sodium hydroxide solution processing changing into the Menglusitena of equimolar amount.After removing ethanol, Menglusitena is dissolved in the water, is frozen drying treatment subsequently.The Menglusitena that finally obtains is an amorphous hydrated state as shown in Figure 2.
Pointed in No. the 737th, 186, European patent as the contriver, the synthetic method of this Menglusitena is not suitable for scale operation, and productive rate is very low.And the amorphous solid sodium salt that obtains at last is not suitable for pharmaceutical preparation usually.Therefore, they have disclosed the method for an effectively synthetic Menglusitena, promptly use 2-(2-(3-(S)-(3-(7-chloro-2-quinoline) vinyl) phenyl)-3-methylsulfonyl propoxy-) phenyl)-the lithium salts coupling of 2-propyl alcohol and 1-(thiomethyl alcohol base) cyclopropaneacetic acid, the montelukast acid that is produced is converted to the dicyclohexyl amine salt into correspondence, and from the mixture recrystallize of toluene and acetonitrile, to prepare crystalloid Menglusitena.This method has improved productive rate greatly, is convenient to large-scale production, and the product sodium salt is a crystalline form.
According to the 737th, No. 186 described preparation method of European patent, the chemical purity of Menglusitena and optical purity depend on the reaction conditions of methylsulfonylization between quinoline diol and the methylsulfonyl chloride to a great extent.For example, the increase of temperature of reaction has caused methylsulfonylization that secondary alcohol is optionally reduced, so temperature of reaction has determined the chemical purity of coupling product (Singulair lithium).The methylsulfonylization of the tertiary alcohol that takes place when higher temperatures especially under acidic conditions, will produce impurity, as styrene derivatives.This vinylbenzene impurity is difficult to remove by the purge process of using DCHA salt to generate (DCHA salt formation); And the excess base that exists in the reaction mixture, butyllithium cause forming the cyclisation by product, reduces the productive rate of product the most at last.
WO2005/105751 has disclosed the another kind of method for preparing Menglusitena, and it is that methylsulfonic acid (with in No. the 737th, 186, the European patent identical) is prepared with 1-(thiomethyl alcohol base) cyclopropane base ester coupling under alkaline state.In this patent, dangerous and expensive alkaline butyllithium reagent is replaced by other relatively mild organic or inorganic alkali.Yet a relevant difficult problem that forms vinylbenzene impurity still can't solve.
Summary of the invention
The invention provides the method that a kind of new preparation does not contain the Menglusitena of vinylbenzene and lactone impurity, its overall yield can compare favourably with the productive rate of the 737th, No. 186 method that discloses of European patent.In addition, the present invention also provides a kind of method, and it need not separate unsettled methylsulfonic acid and can more easily operate follow-up coupled reaction under higher reaction temperatures.The deprotection of oxazoline functional group (deprotection) provide rough Menglusitena.After acidifying gradually, formed rough montelukast acid, and by forming and its corresponding cyclohexylamine salt of crystallization and purifying.This crystal salt can release hydrogen ions and be dissolved in tetrahydrofuran (THF) or methyl alcohol in, then with equimolar sodium methylate processing, to change Menglusitena into.After most of solvent was removed in distillation, rough Menglusitena diluted with water, and spraying drying produces amorphous Menglusitena as shown in Figure 3 then.
Therefore, the invention provides a kind of method for preparing Menglusitena, it comprises sodium alkoxide and montelukast acid is reacted that wherein said montelukast acid obtains by acidifying Singulair hexahydroaniline in organic solvent.
In the method for the invention, described sodium alkoxide includes but not limited to sodium methylate, sodium ethylate, sodium propylate and sodium butylate.In preferred embodiment, described sodium alkoxide is a sodium methylate.
In the method for the invention, described Singulair hexahydroaniline includes but not limited to the form of crystal salt, and it produces montelukast acid.
In the method for the invention, described organic solvent includes but not limited to tetrahydrofuran (THF) and methyl alcohol.
For ease of dry Menglusitena, the inventive method comprises that further (i) removes organic solvent; (ii) add water and form the aqueous solution; And the (iii) dry aqueous solution, with production amorphous Menglusitena.
In the method for the invention, by hexahydroaniline and Singulair acid-respons are produced the Singulair hexahydroaniline.And described montelukast acid is by following formula I V compound
Oxazoline functional group deprotection and acidifying produce.
In preferred embodiment, described deprotection carries out in organic solvent (for example ethylene glycol) with alkali (for example sodium hydroxide).
In the method for the invention, the compound of formula IV is the compound by formula III
React in containing the tetrahydrofuran (THF) of Cerium II Chloride with methylmagnesium-halide and prepare.
In preferred embodiment, the compound of formula III is by preparing containing to surpass to react in the tetrahydrofuran (THF) of 1.0 normal Cerium II Chlorides with the normal methylmagnesium-halide of 2.5-4.0.
In the method for the invention, the compound of formula III is the compound by formula B
Compound with formula II
Coupling produces.
In preferred embodiment, described coupling carries out in-5-25 ℃ temperature range.
The present invention also provides { 1-[(4,4-dimethyl-4,5-dihydro-1,3-oxazoles-2-yl) methyl] cyclopropyl } thiomethyl alcohol.
The present invention further provides the compound of formula III:
The present invention further provides the compound of formula IV:
The present invention further provides the compound of formula V:
The x-ray diffractogram of powder of the compound of formula V as shown in Figure 4.
Description of drawings
Fig. 1 is a synthetic route chart of the present invention;
Fig. 2 has shown the X-ray powder diffraction figure of the amorphous Menglusitena of producing by freeze-drying;
Fig. 3 has shown the X-ray powder diffraction figure of the amorphous Menglusitena of producing by spray-drying process;
Fig. 4 has shown the X-ray powder diffraction figure of crystalloid Singulair hexahydroaniline.
Embodiment
Following embodiment will further specify the present invention.They only are used to illustrate the present invention, and illustrate the various advantages of specific embodiment of the present invention, but do not represent that the present invention only is confined to this kind mode.
Embodiment 1
The preparation of methylsulfonic acid II and oxazoline III:
Under nitrogen atmosphere,, add the wet block Compound I (11 parts) in the toluene in the chemical reactor of agent of thermopair high temperature and charging tank to mechanical stirrer.Behind the component distillation (6 parts), water content test (KF＜0.1%) is done in its mixture sampling.After being cooled to room temperature, in the mixture of output, add DMF (1.7 parts) and triethylamine (2 equivalent).After adding, chemical reactor is cooled to-5-5 ℃.Dropwise add methylsulfonyl chloride (1.5 equivalent) (with the dilution of the toluene (2 parts) in the charging tank) in the mixture of output, and during adding, the control vessel temp is at-5.0-5.0 ℃.Add finish after, continue to stir the mixture at-5.0-5.0 ℃, up to the methylsulfonyl end.
At this moment, under nitrogen atmosphere, in another SS reactor, add toluene (2 parts), DMF (0.5 part), sodium hydride (60%, 3.0 equivalent) and oxazoline B (1.2 equivalent), during vessel temp remain on below 20.0 ℃.Methylsulfonic acid in the GL reactor adds to via transfer lime in the SS reactor of the sodium salt that contains oxazoline B.After interpolation two hours, sampling is used for HPLC and analyzes (compound III＞95.0%) in mixture.With icy water (5 parts) reaction mixture, so organic layer can be separated and with salt water washing organic layer.Organic layer is concentrated into drying, with the oily compound III (seeing Table 1) that the 80-96% productive rate is provided.
1H NMR (600MHz, CDCl3) δ 7.12-7.97 (15H, Ar), 3.84 (t, J=7.3Hz, SCH, 1H), 3.76 (s.CH2O, 2H), 3.73 (s, OCH3,3H), 3.00 and 2.85 (m, SCHCH2,2H), 2.42 and 2.39 (ABq,,
2J=13.0Hz, 2H), 2.34 and 2.29 (ABq, SCH2,
2J=14.9Hz, 2H), 2.06-2.18 (m, 2H), 1.13 (s, CH3,6H), 0.28-0.48 (m, 4H).
13C NMR (150MHz, CDCl3): δ 167.8,164.2.0,156.8,148.6,143.6,143.3,136.4,136.0,135.4,135.0,132.0,131.0,130.8,129.4,128.9,128.8,128.7,128.61,128.58,128.1,127.0,126.9,126.0,125.6,119.5, (Ar), 78.7,66.7,51.9,50.0,39.2,38.6,34.1,32.8,28.4 (CH3), 17.5 (Cy-C), 12.5,12.2 (Cy-CH2) .FABMS (m/z, intensity): M
+(639,63.01%), M
+-C 10H17NOS (B) (440,8.69%), B
+-H (198,100.00%).
Other conditions that are used for preparing compound III are listed in the table 1.
The preparation condition of table 1. compound III:
| Group | Compound I (eq.) | Methylsulfonyl chloride (eq.) | Triethylamine (eq.) | NaH (eq.) | Temperature (℃) | Time (h) | Purity (%) | Productive rate (%) |
| 1 | 1.0 | 1.5 | 2.0 | 4.0 | 15-20 | 5 | 96 | 85 |
| 2 | 1.0 | 1.2 | 1.5 | 2.5 | 15-20 | 2 | 98 | 91 |
| 3 | 1.0 | 1.5 | 2.0 | 3.0 | 5-10 | 2 | 99 | 86 |
| 4 | 1.0 | 1.5 | 2.0 | 2.2 | 5-10 | 4 | 96 | 96 |
| 5 | 1.0 | 1.2 | 1.5 | 3.0 | 0-5 | 2 | 98 | 80 |
Embodiment 2
The preparation method of formula IV:
Under nitrogen atmosphere,, add tetrahydrofuran (THF) (12 parts) and anhydrous cerium chloride (2.5 equivalents, KF＜1.0%) in the SS reactor of thermopair and charging tank to mechanical stirrer.Stirred suspension at room temperature, and add methylmagnesium-chloride (3.0-3.5 equivalent) by the Teflon pump.After interpolation is finished, continued to stir the mixture 60 minutes, and be cooled to 10-25 ℃.Compound III in the tetrahydrofuran (THF) is added in the mixture via charging tank.After interpolation, mixture further reacted 2-4 hour and detected (compound IV＞95.0%) with HPLC.Reactor is cooled to 5.0-15.0 ℃, and adds entry carefully.Institute's precipitated solid is by centrifugal and with tetrahydrofuran (THF) washing, filtrate is concentrated into drying, is the oily compound IV (seeing Table 2) of 80-95% so that productive rate to be provided.
1H NMR (600MHz, CDCl3): δ 7.05-8.00 (15H, Ar), 3.93 (t, J=7.3Hz, SCH, 1H), 3.78 (s, OCH2,2H), 3.15 and 2.94 (m, SCH2CH2,2H), 2.43 and 2.35 (dd, 2H), 2.33 and 2.29 (dd, 2H), 2.16-2.27 (m, 2H), 1.57 (s, 3H), 1.56 (s, 3H), 1.15 (s, CH3,6H), 0.31-0.49 (m, 4H).
13C NMR (150MHz, CDCl3): δ 164.6,156.8, and 148.6,145.7,144.0,140.2,136.4,136.1,135.5,135.1,131.4,128.9,128.7,128.58,128.56,128.1,127.03,126.97,126.92,126.0,125.62,15.57,125.4,119.6 (alkene classes), 78.9,73.3,66.8,50.2,39.6,39.2,34.0,32.1,32.0,31.9,28.42,28.41,17.5,12.6,12.3.FABMS (m/z, relative intensity): M
+(639,68.63%), M+
-H2O (621,10.37%), M
+-B (440,20.71%), M
+-B-H2O (424,20.71%), B
+-H (198,93.32%).
The preparation condition of table 2. compound IV
| Group | Compound I I (eq.) | Cerium II Chloride (eq.) | Methylmagnesium-chloride (eq.) | Tetrahydrofuran (THF) (part) | Time (branch) | Temperature (℃) | The result |
| Purity (%) | Vinylbenzene (%) | Residue II |
| 1 | 1.0 | 2.0 | 3.5 | 15 | 30 | 18-22 | 95.6 | ND | 0.11 |
| 2 | 1.0 | 0.5 | 2.5 | 15 | 60 | 13-17 | 77.1 | ND | 19.4 |
| 3 | 1.0 | 0.1 | 2.6 | 15 | 40 | 18-22 | 37.2 | ND | 53.2 |
| 4 | 1.0 | 1.2 | 2.6 | 15 | 30 | 18-22 | 80.3 | ND | 0.4 |
| 5 | 1.0 | 2.1 | 3.5 | 15 | 30 | 18-22 | 96.4 | ND | 0.0 |
| 6 | 1.0 | 2.1 | 2.5 | 12 | 120 | 20-25 | 96.5 | ND | 0.0 |
Embodiment 3
Menglusitena rough:
Add in the compound IV in ethylene glycol (10 parts) as aqueous sodium hydroxide solution (1-3N, 2.0 equivalents), the suspension that heating is produced, carried out HPLC and analyzes (Menglusitena＞94.0%) after 12 hours to 120-150 ℃.Reaction mixture is cooled to 60-70 ℃, and concentrating so that productive rate to be provided under vacuum then is the oily Menglusitena (seeing Table 3) of 60-80%.
1H NMR (600MHz, CD3OD): δ 6.94-8.44 (15H, Ar), 3.92 (t, J=6.66Hz, 1H), 2.97 (dt, J=4.68Hz, 12.0Hz, 1H), 2.71 (dt, J=4.56Hz, 12.0Hz, 1H), 2.53 and 2.41 (ABq,
2J=12.8Hz, 2H), 2.28 and 2.20 (ABq,
2J=14.6Hz, 2H), 2.13 (m, 1H), 2.03 (m, 1H), 1.41 (s, 3H), 1.40 (s, 3H), 0.42 (m, 1H), 0.35 (m, 1H), 0.28 (m, 1H), 0.20 (m, 1H).
13C NMR (150MHz, CDCl3): δ 180.9 (CO2), 170.6,158.9,149.4,147.2,145.8,141.4,138.3,137.9,137.5,137.0,132.6,130.6,130.22,130.19,128.9,128.4,128.3,128.1,128.0,127.4,127.1,126.7,126.6,120.97,74.0 (Ar C (CH3) 2OH), 51.6 (SCH), 44.8,41.5,41.2,32.5,32.0 (CH3), 18.7 (Cy-C), 13.5,13.0 (Cy-CH2).
The reaction conditions of table 3. preparation compound V
| Group | Compound IV (eq.) | NaOH (concentration and equivalent) | EG (part) | Time (h) | Temperature (℃) | Product purity (%) |
| 1 | 1.0 | 1N, 2 |
10 | 25 | 120 | 97.2 |
| 2 | 1.0 | 1N, 2 |
10 | 12 | 130 | 97.5 |
| 3 | 1.0 | 3N, 2 |
10 | 5 | 150 | 94.0 |
| 4 | 1.0 | 4N, 2 equivalents | 5 | 4 | 160 | 90.8 |
| 5 | 1.0 | 3N, 2 |
10 | 3 | 195 | 62.0 |
Embodiment 4: the purifying of Menglusitena is with dry
PH value to 5 with 5% aqueous acetic acid is regulated the raw oil of Menglusitena extracts with toluene then.The flushing of gained toluene extraction liquid water.Handle the organic layer that contains montelukast acid with hexahydroaniline (1.1-1.5 equivalent), add acetonitrile again and precipitate.After stirring was spent the night, filtration was collected salt and is washed with acetonitrile.Gained salt is with toluene/hexane or toluene/acetonitrile recrystallize, up to reaching ideal purity (seeing Table 4).Analyze crystalline solid with X-ray powder diffractometer, analyze spectrum as shown in Figure 4.
1H NMR (600MHz, CDCl3): δ 7.06-8.04 (15H, Ar), 6.41 (bs, cy-NH
3+), 3.96 (t, J=7.08Hz, 1H), 3.15 (m, 1H), 2.77-2.87 (m, 2H), 2.57 and 152.51 (ABq,
2J=11.1Hz, 2H), 2.31 and 2.27 (ABq,
2J=15.0Hz, 2H), 2.22 (m, 1H), 2.12 (m, 1H), 1.95 (d, J=10.6Hz, 2H), 1.68 (d, J=12.9Hz, 2H), 1.56 (s, 3H), 1.54 (s, 3H), 1.28 (m, 2H), 1.14 (m, 2H), 1.08 (m, 2H), 0.49 (m, 1H), 0.42 (m, 1H), 0.34 (m, 1H), 0.27 (m, 1H) .13C NMR (150MHz, CDCl3): δ 179.0 (CO2), 157.0,148.7,145.6,144.1,140.5,136.6,136.3,135.7,135.4,131.7,129.1,128.8,128.7,128.6,128.2,127.2,127.1,127.0,126.2,125.8,125.7,125.6,119.7 (alkene classes), 73.7,50.3,50.2,43.7,40.3,40.1,32.5,32.1,32.0,31.8,25.1,24.7,17.7,13.1,12.4.
The recrystallize of table 4 Singulair hexahydroaniline
| Group | Solvent | Solvent volume (part) | Purity HPLC% |
| 1 | Toluene/ |
5，10 | 99.22 |
| 2 | Toluene/ |
10，15 | 99.03 |
| 3 | Toluene/hexane | 15，15 | 99.17 |
| 4 | Toluene/ |
20，10 | 99.25 |
| 5 | Toluene/ |
10，10 | 99.40 |
Embodiment 5
Handle the Singulair cyclohexylamine salt that is suspended in the toluene (5 parts) with aqueous acetic acid (5 parts), reach between the 5.0-5.5 up to the pH value.Isolate organic layer and water (5 parts) flushing twice, concentrate organic layer then so that rough oily montelukast acid to be provided.(100.0 grams 170.2mMol) are dissolved in 500 milliliters of tetrahydrofuran (THF)s, and under nitrogen atmosphere, add the NaOH solution of 78 milliliters the about 2N of concentration with consequent montelukast acid.After stirring several minutes, reduce pressure gradually with except that desolvating, rough oily Menglusitena is provided at 30 ℃.
Raw oil added in 2.5 literss of water and concentrate reach about 2.7 liters (residual quantity that GC analyzes tetrahydrofuran (THF) is 1.7%) up to cumulative volume to remove residual tetrahydrofuran (THF).Filter the Singulair sodium water solution, measure its purity (99.7%) with HPLC.The solution that is filtered is spraying drying under various different conditions, the results are shown in Table 5.
The Menglusitena of table 5 spraying drying in the aqueous solution
| Group | Interpolation speed mL/min | Inlet air temperature (℃) | Air outlet temperature (℃) | The result | |||
| Purity HPLC% | Tetrahydrofuran (THF) (ppm) | KF (％) | Productive rate % | ||||
| 1 | 20 | 140 | 100 | 99.7 | 92 | 1.9 | 60 |
| 2 | 20 | 150 | 100 | 99.7 | 89 | 1.7 | 60 |
| 3 | 28 | 140 | 85 | 99.1 | ND | 2.1 | 60 |
| 4 | 28 | 140 | 85 | 99.7 | ND | 1.6 | 60 |
| 5 | 28 | 150 | 84 | 99.6 | ND | 2.8 | 67 |
| 6 | 38 | 140 | 80 | 99.7 | ND | 2.7 | 50 |
A. spraying drying is to carry out on the model L-8 of Ohkawara Kakohki Co.Ltd;
B. solids content (being defined as the amount of solute) is 4%;
C. the solid volume density is 0.16g/mL;
D.4% solids content is 5.63 centistokes 30 ℃ viscosity;
E. solution density approximately is 1.0g/mL;
F. particle size dispersion: d (50)=10 micron and d (90)=30 micron
Embodiment 6
Methanol solution (degasification in advance) with the sodium methylate of the 0.31N (77mmol) of 248mL is handled the montelukast acid (85mmol) that purifying is crossed, and additionally adds the sodium methylate of 16.5mL, reaches 8.43 up to the pH value.Can remove most methyl alcohol being lower than under 50 ℃ the decompression state.In the raw oil product, add entry, with the methyl alcohol distillation of remnants.Additionally add and add water to final volume and reach 1,060mL.Filtering solution, GC detect the residual methanol amount be 3.0% and HPLC to detect purity be 99.8%.Spraying drying Singulair sodium water solution, the result is as shown in table 6.
Menglusitena in table 6 spray drying aqueous solution
| Group | Interpolation speed mL/min | Inlet air temperature (℃) | Air outlet temperature (℃) | The result | |||
| Purity HPLC% | Methyl alcohol (ppm) | KF (％) | Productive rate % | ||||
| 1 | 20 | 120 | 80-85 | 99.8 | 0.00 | 1.8 | 80 |
| 2 | 30 | 140 | 78-80 | 99.7 | 0.00 | 2.2 | 90 |
Though the present invention discloses as above with preferred embodiment, it is not in order to limit the present invention.Those of ordinary skill in the art, without departing from the spirit and scope of the present invention, change of being done or modification all belong to protection scope of the present invention.
Claims (12)
1. method for preparing Menglusitena; it comprises sodium alkoxide and montelukast acid is reacted in organic solvent; wherein said montelukast acid is produced by the Singulair hexahydroaniline acidifying of crystalline salt form; the Singulair hexahydroaniline produces by the reaction of hexahydroaniline and montelukast acid, and montelukast acid is that acidifying forms behind the deprotection of through type IVization He Wu oxazoline functional group
2. the method for claim 1 is characterized in that, described sodium alkoxide is a sodium methylate.
3. the method for claim 1 is characterized in that, described organic solvent is tetrahydrofuran (THF) or methyl alcohol.
4. the method for claim 1 is characterized in that, this method further comprises
(a) remove organic solvent;
(b) add water to form the aqueous solution; And
(c) the dry aqueous solution is to produce the amorphous Menglusitena.
5. the method for claim 1 is characterized in that, the deprotection effect of described functional group is finished in organic solvent by alkali.
6. method as claimed in claim 5 is characterized in that, described alkali is sodium hydroxide.
7. method as claimed in claim 5 is characterized in that, described organic solvent is an ethylene glycol.
8. the method for claim 1 is characterized in that, compound IV is the compound by formula III
React in containing the tetrahydrofuran (THF) of Cerium II Chloride with methylmagnesium-halide and to produce.
9. method as claimed in claim 8 is characterized in that, this method has been used the methylmagnesium-halide of 2.5-4.0 molar equivalent.
10. method as claimed in claim 8 is characterized in that, this method is to carry out under the situation that has the Cerium II Chloride that surpasses 1.0 molar equivalents.
11. method as claimed in claim 8 is characterized in that, the compound of formula III is the compound by formula B
Compound with formula II
Coupling produces.
12. method as claimed in claim 11 is characterized in that, described coupling is carried out in-5～25 ℃ temperature range.
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| KR20130041664A (en) * | 2011-10-17 | 2013-04-25 | 주식회사 엘지생명과학 | Process for preparation of highly pure montelukast sodium |
| CN102442948B (en) * | 2011-11-01 | 2013-10-16 | 上海璎黎科技有限公司 | Method for preparing montelukast sodium intermediate |
| CN104370810B (en) * | 2013-08-13 | 2016-10-05 | 天津汉瑞药业有限公司 | Montelukast sodium compound |
| CN103570619B (en) * | 2013-11-08 | 2015-12-09 | 南京靖龙药物研发有限公司 | A kind of preparation method of montelukast sodium derivative |
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| CN1139429A (en) * | 1993-12-28 | 1997-01-01 | 麦克公司 | Process for the preparation of leukotriene antagonists |
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| CN1139429A (en) * | 1993-12-28 | 1997-01-01 | 麦克公司 | Process for the preparation of leukotriene antagonists |
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