CN104293850A - Montelukast sodium preparation technology and intermediates - Google Patents
Montelukast sodium preparation technology and intermediates Download PDFInfo
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- CN104293850A CN104293850A CN201410395068.4A CN201410395068A CN104293850A CN 104293850 A CN104293850 A CN 104293850A CN 201410395068 A CN201410395068 A CN 201410395068A CN 104293850 A CN104293850 A CN 104293850A
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Abstract
The present invention discloses a montelukast sodium preparation technology and intermediates; 7-chloro-2-methylquinine and 3-bromobenzaldehyde are used as raw materials for condensation reaction to obtain a compound A2; by carbon-carbon coupling of the compound A2 and 1-tetralone in the presence of a catalyst, an intermediate compound A3 is obtained; an important intermediate compound A4 is obtained by bio-enzyme catalyzed asymmetric Baeyer-villiger reaction, a chiral center is highly selectively constructed, an important intermediate compound A5 is prepared from the compound A4 by grignard reaction by use of methylmagnesium chloride, finally montelukast sodium (A6) is obtained; according to the technology, the highly chiral important intermediate compound A4 is obtained by bio-enzyme catalyzed asymmetric reaction, the catalyst can be effectively repeatedly used, and the kind of used solvents is less, and the montelukast sodium preparation technology has the characteristics of safety and environmental protection, greatly saves the production cycle, is low in production cost, high in total yield, and simple in operation of production units, and is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation technology and intermediate product thereof of Menglusitena, belong to technical field of medicine synthesis.
Background technology
The chemical name of Menglusitena (Montelukast Sodium) is: 1-(((1-(R)-(3-(2-(the chloro-2-quinolyl of 7-)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl)) methyl) cyclopropaneacetic acid sodium, structural formula is as follows:
Singulair is the strong selectivity LTRA taken once current unique a kind of every day, is applicable to the treatment of adult and childhood asthma and allergic rhinitis asthmatic syndrome.First this compound is disclosed chemical structure and the preparation method of Singulair at US5565473 by Merck & Co., Inc., and in technique patent CN1046712 and CN1139429 the play-by-play preparation method of this compound. because its range of application is wider, easy administration, has obtained extensive approval and the clinical application of clinicist at present.
Various defect is all there is in the preparation method of current report, at Chinese Journal of Pharmaceuticals (Chinese Journal of Pharmaceticals 2009,40 (1), the chirality can summarizing Singulair in the Singulair synthesis route reported 64-67) obtains primarily of the reduction preparation of (+) DIP-Cl of costliness, greatly have impact on the production cost of Singulair.Such as in the synthetic route of Merck & Co., Inc.'s patent report, 7-chloro-2-methyl quinine and m-terephthal aldehyde is adopted to be that raw material gained obtains Compound C 1, then Compound C 2 is obtained by reacting with vinyl magnesium bromide grignard reagent, then intermediate compound C3 is obtained by reacting with 2-methyl-bromobenzoate by heck, using very expensive asymmetric reduction reagent (-)-DIP-Cl to reduce ketone group is again the alkylol cpd C4 of chirality, and then obtain A5 with methylmagnesium-chloride grignard reaction again, last and 1-(mercapto methyl)-cyclopropaneacetic acid is obtained by reacting product Menglusitena (compd A 6).In this operational path, repeatedly apply grignard reaction, and use can only nonrecoverablely cannot recycle go back original reagent (-)-DIP-Cl, synthetic route is shown below:
Merck company Singulair synthesis route
In the operational path of patent CN 101638381 disclosed in southern Shandong pharmacy, 7-chloro-2-methyl quinine and 3-cyanobenzaldehyde is adopted to be material construction parent nucleus B7, again with 2-methyl acetophenone (B1) for raw material obtains intermediate B 2 by methylmagnesium-chloride grignard reaction, rear for the alcoholic extract hydroxyl group THP of B2 protection and formaldehyde condensation are obtained intermediate B 4, grignard reagent B6 is prepared into again after intermediate B 4 chlorination, gained grignard reagent B6 reacts gained intermediate B 8 with compd B 7 again, then chiral centre is built with method of asymmetrically reducing again, whole operational path is tediously long, unit operation step is complicated, be unfavorable for suitability for industrialized production, synthetic route is shown below:
The synthesis route of southern Shandong pharmacy group company
By the synthesis route of Singulair, we are not difficult to find, the structure of Menglusitena chiral centre depends on method of asymmetrically reducing, and this type of method of asymmetrically reducing greatly adds production cost in industry is produced greatly, cause the price of Menglusitena higher, add the medical treatment cost of patient.
summary of the invention
The object of this invention is to provide a kind of preparation technology and intermediate product thereof of Menglusitena, the alternative of Menglusitena is prepared in applicable scale operation, specifically, with 7-chloro-2-methyl quinine and 3-bromobenzaldehyde for raw material obtains compd A 2 through condensation reaction, under catalyst action, the coupling of carbon carbon obtains compound A-13 with ALPHA-tetralone again, then important intermediate compd A 4 is obtained by the asymmetric Bayer-Wei Lige oxidizing reaction (baeyer-villiger reaction) of biological enzyme again, highly selective builds chiral centre, compd A 4 obtains important intermediate compound A-45 with methylmagnesium-chloride grignard reaction again, finally obtain Menglusitena (A6), synthetic route is shown below:
Comprise the steps:
1) 7-chloro-2-methyl quinine and 3-halogenated benzaldehyde are dissolved in a solvent, reacting by heating under acid and acid anhydrides effect, reaction solution, through washing, phase-splitting, recrystallization, obtains compd A 2;
2) by step 1) synthesize the compd A 2 and ALPHA-tetralone, transition-metal catalyst, part and alkali reacting by heating in a solvent that obtain, after reaction terminates, suction filtration removing insolubles, is separated and obtains compound A-13;
3) by step 2) synthesize the compound A-13 that obtains and be dissolved in solvent, then add pH buffered soln, hydrogen peroxide and biological enzyme reacts at 20-45 DEG C, transform completely, are separated organic phase, obtain the compd A 4 with highly chirality;
4) by step 3) synthesize the compd A 4 that obtains and be dissolved in toluene or tetrahydrofuran (THF), under Cerium II Chloride effect, obtain A5 in-10 DEG C to 25 DEG C through methylmagnesium-chloride grignard reaction;
5) by step 4) synthesize A5 and the 1-thiopurine methyltransferase cyclopropaneacetic acid that obtains and butyllithium reacts in a solvent, react terminate rear separation, salify obtains Menglusitena A6.
Step 1) described in solvent be toluene or dimethylbenzene, described 3-halogenated benzaldehyde is 3-bromobenzaldehyde or 3-benzaldehyde iodine, and described acid is acetic acid, and described acid anhydrides is the one in acetic anhydride or propionic anhydride.
Step 1) described in 7-chloro-2-methyl quinine, 3-halogenated benzaldehyde, acid and acid anhydrides molar ratio be 1:(1 ~ 3): (0.1 ~ 0.5): (1 ~ 3).
Step 2) described in transition-metal catalyst be palladium, Pd (DBA)
2or the one in Palladous chloride, part is the one in triphenylphosphine, 2-dicyclohexyl phosphorus-2 '-methyl diphenyl or BINAP, and alkali is the one in potassiumphosphate, potassium tert.-butoxide or sodium tert-butoxide, and solvent is toluene or dimethylbenzene.
Step 2) described in each material be compd A 2:1-Tetralone an intermediate of Sertraline with magnitude relation: transition-metal catalyst: part: the mol ratio of alkali is 1:(1-5): (0.001-0.02): (0.002-0.05): (1-5).
Step 2) reacting by heating temperature is 70 ~ 130 DEG C, the reaction times is 3 ~ 24 hours.
Step 3) described in biological enzyme be one in M-01, M-02, pH buffered soln is the aqueous solution of potassiumphosphate, and solvent is the one in toluene, dimethylbenzene.
Step 3) described in the molar ratio of compound A-13, biological enzyme and hydrogen peroxide be 1:(0.001 ~ 0.003): (1 ~ 10), the pH of pH buffered soln is 4 ~ 10; The mass ratio of compound A-13 and pH buffered soln is 1:(10-20).
Step 3) biological enzyme M-01 or M-02 catalysis Baeyer-villiger reaction has highly selective and high efficiency, and temperature of reaction is 20 ~ 45 DEG C, obtains having the product A 4 of height chirality.Chirality ee value is characterized with chiral column.Step 4) described in the molar ratio of compd A 4, Cerium II Chloride and methylmagnesium-chloride be 1:(2 ~ 5): (2 ~ 6), step 4) temperature of reaction is-10 DEG C ~ 25 DEG C, the reaction times is 3 ~ 24 hours.
Step 4) in products therefrom A5 have height chiral purity.Chirality ee value is characterized with chiral column.
Step 5) described in the molar ratio of compound A-45,1-thiopurine methyltransferase cyclopropaneacetic acid and butyllithium be 1:(1.2 ~ 4): (1.2 ~ 4).
Step 2) in excessive metalcatalyzing mechanism in, described compd A 2 forms A2 complex compound under metal catalyst and part effect, ALPHA-tetralone is in alkaline condition dehydrogenation, then halogen is sloughed with the coupling of A2 complex compound generation carbon-carbon bond, final generation intermediate compound A3, the structural formula of compound A-13 is shown below:
Compound A-13 is made up of two kinds of configurations, and structural formula is shown below:
Mechanism is shown below:
Step 3) biological enzyme asymmetric Baeyer-Villiger synthesis is the committed step producing chiral intermediate, described compound A-13 to be discharged in aqueous phase under the catalysis of biological enzyme by hydrogen peroxide oxidation from organic phase, discharge compd A 4, then absorb from aqueous phase again and enter organic phase, transform completely until compound A-13, be separated organic phase and can obtain compd A 4.Mechanism as shown in Figure 8.
Beneficial effect: this operational path adopts asymmetric biological enzymatic reaction method to obtain having the midbody compound A4 of height chirality, then the Singulair important intermediate compound A-45 with height chirality is prepared by grignard reaction, biological enzyme agent can effectively be reused, and use solvent species few, there is the feature of safety and environmental protection, and greatly save the production cycle, low production cost, total recovery is high, productive unit is simple to operate, final product Menglusitena is obtained by reacting by five steps, total recovery is more than 35%, whole technique is applicable to suitability for industrialized production.
Accompanying drawing explanation
Figure 1A 2 mass spectrum;
Fig. 2 A3 mass spectrum;
Fig. 3 A4 mass spectrum;
Fig. 4 A5 mass spectrum;
Fig. 5 A6 mass spectrum;
Fig. 6 A4 chirality test pattern;
Fig. 7 A5 chirality test pattern;
Fig. 8 compd A 4 synthesis mechanism figure.
Embodiment
7-chloro-2-methyl quinine, 3-bromobenzaldehyde, ALPHA-tetralone are from Aladdin Reagent Company; BINAP part, biological enzyme liquid are purchased from Sigma Reagent Company.
In following examples, the liquid phase detection method of chirality sees the following form.
The preparation of embodiment 1 compd A 2
In 1000ml there-necked flask, first add toluene 300ml and Glacial acetic acid 4.8ml (0.084mol, 0.3eq), under mechanical stirring, add 7-chloro-2-methyl quinine 50g (0.28mol, 1eq), 3-bromobenzaldehyde 77.7g (0.42mol, 1.5eq), after reinforced, be warming up to 70 DEG C, diacetyl oxide 45ml (0.48mol is added after raw material all dissolves, 1.71eq), then refluxing toluene is warming up to, control temperature 120-125 DEG C, reflux 10 hours, TLC detection reaction disappears to 7-chloro-2-methyl quinine raw material point, reaction terminates, stop heating, reaction solution is cooled to room temperature, stir after 2 hours, leave standstill 1 hour, suction filtration, filter cake is with dry after 30ml toluene wash.Obtain product compound A286.8g, yield 90%, MS m/z:346 (M+1)
+.
The preparation of embodiment 2 compd A 2
In 1000ml there-necked flask, first add toluene 300ml and Glacial acetic acid 8ml (0.14mol, 0.5eq), under mechanical stirring, add 7-chloro-2-methyl quinine 50g (0.28mol, 1eq), 3-bromobenzaldehyde 62.16g (0.34mol, 1.2eq), after reinforced, be warming up to 70 DEG C, diacetyl oxide 45ml (0.48mol is added after raw material all dissolves, 1.71eq), then refluxing toluene is warming up to, control temperature 120-125 DEG C, reflux 11 hours, TLC detection reaction disappears to 7-chloro-2-methyl quinine raw material point, reaction terminates, stop heating, reaction solution is cooled to room temperature, stir after 2 hours, leave standstill 1 hour, suction filtration, filter cake is with dry after 30ml toluene wash.Obtain product compound A282.9g, yield 86%, MS m/z:346 (M+1)
+.
The preparation of embodiment 3 compd A 2
In 1000ml there-necked flask, first add dimethylbenzene 350ml and Glacial acetic acid 4.8ml (0.084mol, 0.3eq), under mechanical stirring, add 7-chloro-2-methyl quinine 50g (0.28mol, 1eq), 3-bromobenzaldehyde 62.16g (0.34mol, 1.2eq), after reinforced, be warming up to 70 DEG C, propionic anhydride 54.6ml (0.42mol is added after raw material all dissolves, 1.5eq), then refluxing toluene is warming up to, control temperature 120-125 DEG C, reflux 12 hours, TLC detection reaction disappears to 7-chloro-2-methyl quinine raw material point, reaction terminates, stop heating, reaction solution is cooled to room temperature, stir after 2 hours, leave standstill 1 hour, suction filtration, filter cake is with dry after 30ml toluene wash.Obtain product A 284.4g, yield 87.5%, MS m/z:346 (M+1)
+.
The preparation of embodiment 4 compound A-13
In 100ml there-necked flask; under nitrogen protection; add A2 raw material 500mg (1.45mmol; 1eq), ALPHA-tetralone 424mg (2.90mmol; 2.0eq), palladium 4mg (0.015mmol; 0.01eq), BINAP ligand 1 8mg (0.029mmol, 0.02eq), potassiumphosphate 788mg (3.63mmol, 2.5eq), toluene 10ml.Reaction solution was heated to 100 DEG C of reactions after 18 hours, TLC detection reaction disappears to A2 raw material point, be cooled to room temperature, add 10ml dilution with toluene reaction solution, suction filtration removing inorganic salt, filtrate is with 50ml water washing twice, and after concentrated organic phase, pillar layer separation (sherwood oil: ethyl acetate=20:1 and 10:1 rinses pillar) obtains product compound A3493mg, yield 83%.MS?m/z:409(M-1)
-。
The preparation of embodiment 5 compound A-13
In 100ml there-necked flask; under nitrogen protection; add A2 raw material 500mg (1.45mmol; 1eq), ALPHA-tetralone 318mg (2.18mmol; 1.5eq), Pd (DBA) 2 (two (dibenzalacetone) palladium) 9mg (0.015mmol, 0.01eq), BINAP ligand 1 8mg (0.029mmol; 0.02eq), potassiumphosphate 788mg (3.63mmol, 2.5eq), toluene 10ml.Reaction solution was heated to 100 DEG C of reactions after 18 hours, TLC detection reaction disappears to A2 raw material point, be cooled to room temperature, add 10ml dilution with toluene reaction solution, suction filtration removing inorganic salt, filtrate is with 50ml water washing twice, and after concentrated organic phase, pillar layer separation (sherwood oil: ethyl acetate=20:1 and 10:1 rinses pillar) obtains product compound A3422mg, yield 71%.MS?m/z:409(M-1)
-。
The preparation of embodiment 6 compound A-13
In 100ml there-necked flask; under nitrogen protection; add A2 raw material 500mg (1.45mmol; 1eq), ALPHA-tetralone 318mg (2.18mmol; 1.5eq), two (dibenzalacetone) palladium 9mg (0.015mmol, 0.01eq), 2-dicyclohexyl phosphorus-2 '-methyl diphenyl 11mg (0.029mmol; 0.02eq), potassiumphosphate 788mg (3.63mmol, 2.5eq), toluene 10ml.Reaction solution was heated to 100 DEG C of reactions after 18 hours, TLC detection reaction disappears to A2 raw material point, be cooled to room temperature, add 10ml dilution with toluene reaction solution, suction filtration removing inorganic salt, filtrate is with 50ml water washing twice, and after concentrated organic phase, pillar layer separation (sherwood oil: ethyl acetate=20:1 and 10:1 rinses pillar) obtains product compound A3375mg, yield 63%.MS?m/z:409(M-1)
-。
The preparation of embodiment 7 compound A-13
In 100ml there-necked flask; under nitrogen protection; add A2 raw material 500mg (1.45mmol; 1eq), ALPHA-tetralone 318mg (2.18mmol; 1.5eq), two (dibenzalacetone) palladium 19mg (0.029mmol, 0.02eq), 2-dicyclohexyl phosphorus-2 '-methyl diphenyl 22mg (0.06mmol; 0.04eq), sodium tert-butoxide 537mg (7.26mmol, 5eq), toluene 10ml.Reaction solution was heated to 110 DEG C of reactions after 18 hours, TLC detection reaction disappears to A2 raw material point, be cooled to room temperature, add 10ml dilution with toluene reaction solution, suction filtration removing inorganic salt, filtrate is with 50ml water washing twice, and after concentrated organic phase, pillar layer separation (sherwood oil: ethyl acetate=20:1 and 10:1 rinses pillar) obtains product compound A3398mg, yield 67%.MS?m/z:409(M-1)
-。
The preparation of embodiment 8 compd A 4
1000mg compound A-13 (2.44mmol is added at reaction flask, 1eq) and 20ml toluene stirring and dissolving after, add pH aqueous buffer solution 10ml, the M-01 biological enzyme liquid of 0.001 equivalent and 1g hydrogen peroxide (8.8mmol again, 3.61eq), control temperature stirs 24 hours, after detection compound A3 complete reaction at 30 DEG C, be separated, obtain the organic phase of compd A 4, organic phase underpressure distillation removes desolventizing and obtains product 987mg, yield 95%.MS m/z:426 (M)
+, 458 (M+ACN)
+,
1h NMR (DMSO-d6,500MHz): 2.25 (m, 1H), 2.44 (m, 1H), 3.00 (m, 2H), 5.12 (dd, J=12.2,4.9Hz; 1H), 7.1-8.4 (m, 15H, Ar-H & vinyl CH); Chirality ee value=99.0%, chirality Liquid Detection the results are shown in Figure 6.
The preparation of embodiment 9 compd A 4
1000mg compound A-13 (2.44mmol is added at reaction flask, 1eq) and 20ml toluene stirring and dissolving after, add pH aqueous buffer solution 15ml, the M-01 biological enzyme liquid of 0.001 equivalent and 0.5g hydrogen peroxide (4.4mmol again, 1.8eq), control temperature stirs 24 hours, after detection compound A3 complete reaction at 35 DEG C, be separated, obtain the organic phase of compd A 4, organic phase underpressure distillation removes desolventizing and obtains product Compound A4945mg, yield 91%.MS m/z:426 (M)
+, 458 (M+ACN)
+,
1h NMR (DMSO-d6,500MHz): 2.25 (m, 1H), 2.44 (m, 1H), 3.00 (m, 2H), 5.12 (dd, J=12.2,4.9Hz; 1H), 7.1-8.4 (m, 15H, Ar-H & vinyl CH); Chirality ee value=99.0%.
The preparation of embodiment 10 compd A 4
1000mg compound A-13 (2.44mmol is added at reaction flask, 1eq) and 20ml toluene stirring and dissolving after, add pH aqueous buffer solution 10ml, the M-02 biological enzyme liquid of 0.001 equivalent and 0.33g hydrogen peroxide (2.93mmol again, 1.2eq), control temperature stirs 24 hours, after detection compound A3 complete reaction at 37 DEG C, be separated, obtain the organic phase of compd A 4, organic phase underpressure distillation removes desolventizing and obtains compd A 41007mg, yield 97%.MS m/z:426 (M)
+, 458 (M+ACN)
+,
1h NMR (DMSO-d6,500MHz): 2.25 (m, 1H), 2.44 (m, 1H), 3.00 (m, 2H), 5.12 (dd, J=12.2,4.9Hz; 1H), 7.1-8.4 (m, 15H, Ar-H & vinyl CH); Chirality ee value=99.0%.
The preparation of embodiment 11 compd A 4
1000mg compound A-13 (2.44mmol is added at reaction flask, 1eq) and 20ml toluene stirring and dissolving after, add pH aqueous buffer solution 10ml, the M-02 biological enzyme liquid of 0.002 equivalent and 0.38g hydrogen peroxide (3.41mmol again, 1.4eq), control temperature stirs 18 hours at 35 DEG C, after detecting A3 complete reaction, be separated, obtain the organic phase of A4, organic phase underpressure distillation removes desolventizing and obtains A4 compound 996mg, yield 96%.MS m/z:426 (M)
+, 458 (M+ACN)
+,
1h NMR (DMSO-d6,500MHz): 2.25 (m, 1H), 2.44 (m, 1H), 3.00 (m, 2H), 5.12 (dd, J=12.2,4.9Hz; 1H), 7.1-8.4 (m, 15H, Ar-H & vinyl CH); Chirality ee value=99.0%.
The preparation of embodiment 12 compound A-45
In reaction flask, add 3g compd A 4 (7.04mmol, 1eq), 3.5g Cerium II Chloride (14.19mmol, 2.01eq), 30ml tetrahydrofuran (THF) and 70ml toluene under nitrogen protection, be cooled to 0 DEG C.Dripped 12.5ml methyl magnesium chloride solution (the THF solution of 1.7M, 21.25mmol, 3.01eq) at 45 minutes, react at 0 DEG C after 4 hours and be warming up to 25 DEG C, till TLC detection reaction is complete.Add ammonium chloride solution cancellation reaction, then add 50ml toluene extractive reaction liquid, be separated organic phase, organic phase aqueous sodium carbonate washs, wash organic phase with water again, concentrated organic phase, adds sherwood oil, separate out solid, suction filtration obtains compound A-45 2.90g, yield 90%.MS m/z:458 (M)
+,
1h NMR (DMSO-d6,500MHz): 1.4 (s, 6H, CH3); 2.0 (m, 2H, CH2-CH2); 3.0 (m, 2H, CH2-CH2); 4.7 (m, 1H, CH-OH); 4.9 (s, 1H, OH of t-OH); 5.3 (s, 1H, OH of CH-OH); 7.1-8.4 (m, 15H, Ar-H & vinyl CH), chirality ee value=99.2%.
The preparation of embodiment 13 compound A-45
In reaction flask, add 3g compd A 4 (7.04mmol, 1eq), 5.2g Cerium II Chloride (21.28mmol, 3.0eq), 30ml tetrahydrofuran (THF) and 70ml toluene under nitrogen protection, be cooled to 0 DEG C.Dripped 16.6ml methyl magnesium chloride solution (the THF solution of 1.7M, 28.3mmol, 4.0eq) at 45 minutes, react at 0 DEG C after 4 hours and be warming up to 25 DEG C, till TLC detection reaction is complete.Add ammonium chloride solution cancellation reaction, then add 50ml toluene extractive reaction liquid, be separated organic phase, organic phase aqueous sodium carbonate washs, wash organic phase with water again, concentrated organic phase, adds sherwood oil, separate out solid, suction filtration obtains compound A-45 2.80g, yield 87%.MS m/z:458 (M)
+,
1h NMR (DMSO-d6,500MHz): 1.4 (s, 6H, CH3); 2.0 (m, 2H, CH2-CH2); 3.0 (m, 2H, CH2-CH2); 4.7 (m, 1H, CH-OH); 4.9 (s, 1H, OH of t-OH); 5.3 (s, 1H, OH of CH-OH); 7.1-8.4 (m, 15H, Ar-H & vinyl CH), chirality ee value=99.2%, is shown in Fig. 7.
The preparation of embodiment 14 Menglusitena A6
Step one:
To mechanical stirrer is housed, thermopair, the 100ml round-bottomed flask purging with nitrogen gas of nitrogen inlet and dropping funnel.The toluene solution (17.7ml, 0.35g/ml, 6.17g, 13.5mmol, 1eq) of compound A-45 is added, acetonitrile 45ml and N, N-diisopropyl ethyl amine 2.01g (15.6mmol, 1.16eq) in flask.This solution is cooled to-25 DEG C, added Methanesulfonyl chloride 1.70g (14.8mmol, 1.1eq) with 2.5 hours and maintain the temperature at-25 ± 2 DEG C.Reaction solution stirs 3 hours at-25 DEG C, filters cold suspension separation under nitrogen blanket and obtains product.Filter cake cold acetonitrile (20ml ,-30 DEG C) washing, then washs with cold hexane (20ml, 5 DEG C).After washing, at 5 DEG C, blow 20 hours drying products with nitrogen, obtain faint yellow solid.
Step 2:
To mechanical stirrer is housed, thermopair, the 250ml round-bottomed flask purging with nitrogen gas of nitrogen inlet and dropping funnel.40ml tetrahydrofuran (THF) and 1-(mercapto methyl) cyclopropaneacetic acid 1.32g (16.2mmol, 1.2eq) is added in flask.Mixture is stirred 10 minutes, solution is cooled to-15 DEG C, with the t-BuLi hexane solution (purchased from Aladdin Reagent Company) (10.5ml, the 16.4mmol that within 75 minutes, add 1.56M, 1.21eq), keep the temperature <-5 DEG C of reaction mixture simultaneously.Solution is stirred 30 minutes at-5 DEG C.
In another 100ml flask, add 30mL tetrahydrofuran (THF), solution is cooled to-5 DEG C, add the faint yellow solid in step one, stirring and dissolving, obtain the yellow solution clarified.
By the yellow solution of clarification by the 250ml reaction flask in nitrogen press-in step 2, maintain the temperature at-5 ± 2 DEG C, stir 8.5 hours at-5 DEG C, then reaction solution is added cancellation reaction in the mixing solutions 50ml of ethyl acetate 50ml and 10%NaCl, stir static after 30 minutes, removing water layer, washs organic phase 0.5M tartaric acid solution 36ml, wash with water 2 times (40ml*2), above-mentioned organic phase is concentrated into 15ml.Solution after concentrated adds 44ml ethyl acetate and 1.8ml dicyclohexyl amine, at room temperature stirs 1 hour.At room temperature in above-mentioned solution, add 120ml hexane, at room temperature aged overnight.Filter above-mentioned solid, the filter cake ethyl acetate of 0 DEG C: hexane=1:2 mixing solutions washing.Product is dry at 40 DEG C.Obtain the salt of montelukast dicyclohexylamine.
Step 3:
To mechanical stirrer is housed, well heater, by purging with nitrogen gas in the 250ml reaction flask of nitrogen inlet and dropping funnel, adds toluene 95ml, the salt of water 10ml and montelukast dicyclohexylamine.The acetic acid solution 4.5ml of 2M is added in above-mentioned mixed solution.Stir after 10 minutes stop stir, isolate aqueous phase, organic phase with 70ml water washing once.In organic phase, add the 1% aqueous ethanol solution of 12.5mlNaOH, stir 30 minutes.Above-mentioned solution is filtered, uses toluene as cleaning solvent.The filtrate obtained is concentrated into oily matter, adds 30ml acetonitrile, 40 DEG C are stirred after 1.5 hours, then add 30ml acetonitrile, and the suspension liquid obtained stirs 12 hours at 40 DEG C, to be cooled to after room temperature ageing 1 hour, to filter out product, filter cake 40ml acetonitrile wash.By the product that obtains 40 DEG C of oven dry, obtain 3.6g Menglusitena (44%).
Claims (10)
1. the preparation technology of Menglusitena, is characterized in that comprising the steps:
1) 7-chloro-2-methyl quinine and 3-halogenated benzaldehyde are dissolved in a solvent, reacting by heating under acid and acid anhydrides effect, reaction solution, through washing, phase-splitting, recrystallization, obtains compd A 2;
2) step 1) is synthesized the compd A 2 obtained and ALPHA-tetralone, transition-metal catalyst, part and alkali reacting by heating in a solvent, after reaction terminates, suction filtration removing insolubles, is separated and obtains compound A-13;
3) by step 2) synthesize the compound A-13 that obtains and be dissolved in solvent, then add pH buffered soln, hydrogen peroxide and biological enzyme and react at 20-45 DEG C, transform completely, separation organic phase, obtains compd A 4;
4) being dissolved in toluene or tetrahydrofuran (THF) by synthesizing the compd A 4 obtained in step 3), under Cerium II Chloride effect, at-10 DEG C to 25 DEG C, obtaining A5 through methylmagnesium-chloride grignard reaction;
5) step 4) is synthesized the compound A-45 and 1-thiopurine methyltransferase cyclopropaneacetic acid obtained and butyllithium reacts in toluene or tetrahydrofuran (THF), the molar ratio of compound A-45,1-thiopurine methyltransferase cyclopropaneacetic acid and butyllithium is 1:(1.2 ~ 4): (1.2 ~ 4), reaction terminates rear separation, salify obtains Menglusitena.
2. the preparation technology of Menglusitena according to claim 1, it is characterized in that: solvent described in step 1) is toluene or dimethylbenzene, described 3-halogenated benzaldehyde is 3-bromobenzaldehyde or 3-benzaldehyde iodine, described acid is acetic acid, and described acid anhydrides is the one in acetic anhydride or propionic anhydride.
3. the preparation technology of Menglusitena according to claim 1, is characterized in that: the molar ratio of the chloro-2-methyl of 7-described in step 1) quinine, 3-halogenated benzaldehyde, acid, acid anhydrides is 1:(1 ~ 3): (0.1 ~ 0.5): (1 ~ 3).
4. the preparation technology of Menglusitena according to claim 1, is characterized in that: step 2) described in transition-metal catalyst be palladium, Pd(DBA)
2or the one in Palladous chloride, part is the one in triphenylphosphine, 2-dicyclohexyl phosphorus-2 '-methyl diphenyl or BINAP, and alkali is the one in potassiumphosphate, potassium tert.-butoxide or sodium tert-butoxide, and solvent is toluene or dimethylbenzene.
5. the preparation technology of Menglusitena according to claim 1, is characterized in that: step 2) described in each material with magnitude relation be: compd A 2:1-Tetralone an intermediate of Sertraline: transition-metal catalyst: part: the mol ratio of alkali is 1:(1 ~ 5): (0.001 ~ 0.02): (0.002 ~ 0.05): (1 ~ 5).
6. the preparation technology of Menglusitena according to claim 1, is characterized in that: step 2) reacting by heating temperature is 70 ~ 130 DEG C, the reaction times is 3 ~ 24 hours.
7. the preparation technology of Menglusitena according to claim 1, is characterized in that: biological enzyme described in step 3) is the one in M-01, M-02, and pH buffered soln is the aqueous solution of potassiumphosphate, and solvent is the one in toluene, dimethylbenzene.
8. the preparation technology of Menglusitena according to claim 1, is characterized in that: the molar ratio of compound A-13 described in step 3), biological enzyme and hydrogen peroxide is 1:(0.001 ~ 0.003): (1 ~ 10), the pH of pH buffered soln is 4-10; The mass ratio of compound A-13 and pH buffered soln is 1:(10 ~ 20).
9. the preparation technology of Menglusitena according to claim 1, is characterized in that: the molar ratio of compd A 4 described in step 4), Cerium II Chloride, methylmagnesium-chloride is 1:(2 ~ 5): (2 ~ 6), temperature of reaction is-10 DEG C ~ 25 DEG C.
10. the intermediate product that the preparation technology of the Menglusitena in claim 1 ~ 9 described in any one prepares, it is characterized in that, structural formula is shown below:
。
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| CN104745652A (en) * | 2015-03-25 | 2015-07-01 | 苏州汉酶生物技术有限公司 | Preparation method of Montelukast intermediate |
| CN111474260A (en) * | 2020-04-23 | 2020-07-31 | 中山奕安泰医药科技有限公司 | Detection method of montelukast sodium intermediate |
| CN113521044A (en) * | 2021-06-04 | 2021-10-22 | 中国人民解放军南部战区总医院 | Application of 2- (1- (mercaptomethyl) cyclopropyl) acetic acid as and/or in preparation of beta-lactamase inhibitor |
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| CN101356157A (en) * | 2005-11-18 | 2009-01-28 | 斯索恩有限公司 | Process for making montelukast and intermediates therefor |
| CN101558042A (en) * | 2006-12-14 | 2009-10-14 | 韩美药品株式会社 | Method of preparing montelukast and intermediates used therein |
| CN101774990A (en) * | 2010-02-09 | 2010-07-14 | 上海应用技术学院 | Method for preparing dihydrocoumarin without phenol |
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| CN101356157A (en) * | 2005-11-18 | 2009-01-28 | 斯索恩有限公司 | Process for making montelukast and intermediates therefor |
| CN101558042A (en) * | 2006-12-14 | 2009-10-14 | 韩美药品株式会社 | Method of preparing montelukast and intermediates used therein |
| CN101774990A (en) * | 2010-02-09 | 2010-07-14 | 上海应用技术学院 | Method for preparing dihydrocoumarin without phenol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104745652A (en) * | 2015-03-25 | 2015-07-01 | 苏州汉酶生物技术有限公司 | Preparation method of Montelukast intermediate |
| CN111474260A (en) * | 2020-04-23 | 2020-07-31 | 中山奕安泰医药科技有限公司 | Detection method of montelukast sodium intermediate |
| CN113521044A (en) * | 2021-06-04 | 2021-10-22 | 中国人民解放军南部战区总医院 | Application of 2- (1- (mercaptomethyl) cyclopropyl) acetic acid as and/or in preparation of beta-lactamase inhibitor |
| CN113521044B (en) * | 2021-06-04 | 2022-09-16 | 中国人民解放军南部战区总医院 | Application of 2- (1- (mercaptomethyl) cyclopropyl) acetic acid as and/or in preparation of beta-lactamase inhibitor |
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