CN104592111B - A kind of synthetic method of montelukast sodium intermediate - Google Patents
A kind of synthetic method of montelukast sodium intermediate Download PDFInfo
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- CN104592111B CN104592111B CN201510080010.5A CN201510080010A CN104592111B CN 104592111 B CN104592111 B CN 104592111B CN 201510080010 A CN201510080010 A CN 201510080010A CN 104592111 B CN104592111 B CN 104592111B
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- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical compound [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 0.000 title claims abstract description 16
- 229960001951 montelukast sodium Drugs 0.000 title claims abstract description 16
- 238000010189 synthetic method Methods 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 150000004756 silanes Chemical class 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- 230000000694 effects Effects 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 59
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 42
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical group C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 3
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 claims description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 229940050176 methyl chloride Drugs 0.000 claims description 2
- -1 chloro-2-quinolyl Chemical group 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 abstract description 4
- 229920002554 vinyl polymer Polymers 0.000 abstract description 4
- 229940095102 methyl benzoate Drugs 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- 238000003756 stirring Methods 0.000 description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 239000002994 raw material Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 6
- 239000007789 gas Substances 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- GWNVDXQDILPJIG-CCHJCNDSSA-N 11-trans-Leukotriene C4 Chemical compound CCCCC\C=C/C\C=C\C=C\C=C\[C@H]([C@@H](O)CCCC(O)=O)SC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O GWNVDXQDILPJIG-CCHJCNDSSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000001650 tertiary alcohol group Chemical group 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of synthetic method of montelukast sodium intermediate, belong to medical chemistry synthesis field.The method is that chemical compounds I reacts with halogenated silanes under the effect of alkaline reagents, obtains compound ii; Compound ii and form reagent react, obtain compound III; Compound III is reacted under acid effect, obtains compounds Ⅳ.The present invention is Material synthesis montelukast sodium intermediate with (α S)-α-[3-[(1E)-2-(the chloro-2-quinolyl of 7-) vinyl] phenyl]-2-(1-hydroxyl-1-methylethyl)-methyl benzoate, not only production technique is easy, and product yield is high, purity is high.
Description
Technical field
The invention belongs to medical chemistry synthesis field, be specifically related to a kind of synthetic method of montelukast sodium intermediate.
Background technology
Asthma is a kind of common disease, and it shows as recurrent exerbation, does not prolongedly heal, and is a kind of chronic disease.Some asthma patients, from teenager's onset, still often show effect after entering old age, so there is the saying of " internal medicine is not controlled and breathed heavily ".Menglusitena is a kind of oral LTRA, specificity can suppress in air flue cysteinyl leukotriene (CysLT1) acceptor, thus reaches and improve airway inflammation, effective Control of asthma symptom.
Compounds Ⅳ is the important intermediate preparing Menglusitena, and its Chinese name is called (α S)-α-[3-[(1E)-2-(the chloro-2-quinolyl of 7-) vinyl] phenyl]-2-(1-hydroxyl-1-methylethyl)-phenylpropyl alcohol; Chemical structural formula is:
Several method preparing montelukast sodium intermediate is openly reported in the documents such as WO2008035086, US2005245569, WO2012123506.
Wherein, reporting with (S)-1-(3-bromophenyl)-3-[2-(1-hydroxyl-1-methylethyl)-phenyl] methyl-formiate in WO2008035086 open source literature is the synthetic method that montelukast sodium intermediate prepared by raw material, and its syntheti c route is as follows:
This method is when ester group is transformed into tertiary alcohol group by step 1, and transformation efficiency is lower; And step 2 linked reaction employs palladium catalyst, industrial cost is higher, and therefore this method is not suitable for suitability for industrialized production.
In addition, US2005245569 and WO2012123506 openly reports one with (α S)-α-[3-[(1E)-2-(the chloro-2-quinolyl of 7-) vinyl] phenyl]-2-(1-hydroxyl-1-methylethyl)-methyl benzoate for raw material, prepare the synthetic method of montelukast sodium intermediate, its syntheti c route is as follows:
The method adopts acetylthio substituted hydroxy, wherein, when ester group is changed into the tertiary alcohol by step 3, need to use cerous compounds to make catalyzer on the one hand and improve productive rate, this catalyzer can make two molecule intermediates combine and generate ether on the other hand, reduces yield and the purity of product; And step 4 when acetylthio being converted into sulfydryl difficulty comparatively large, yield is not high yet, adds length and the complexity of technique.Therefore, this method is not suitable for suitability for industrialized production equally.
Summary of the invention
This Fa Ming is the synthetic method providing a kind of brand-new montelukast sodium intermediate for the problems referred to above.This synthetic method not only increases the purity of product, and reduce process costs, simultaneous reactions mild condition, easy and simple to handle, conversion rate of products is high, is of value to industrialization scale operation.
Object of the present invention can be achieved through the following technical solutions:
A synthetic method for montelukast sodium intermediate, the synthetic route of the method is as follows:
Wherein, RX is halogenated silanes; Preferred RX is trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE, tert-butyl diphenyl chlorosilane or tri isopropyl chlorosilane; Most preferably RX is trimethylchlorosilane.
The method comprises the steps:
In the first step reaction, chemical compounds I reacts with halogenated silanes under the effect of alkaline reagents, obtains compound ii.
In the first step reaction, reaction solvent is selected from least one in acetonitrile, methylene dichloride and tetrahydrofuran (THF); Preferred reaction solvent is tetrahydrofuran (THF), and alkaline reagents is selected from N-methylmorpholine, K
2cO
3, Et
3at least one in N, pyridine and 4-DMAP; Preferred alkaline reagents is N-methylmorpholine, and temperature of reaction is-20 ~ 50 DEG C; Preferable reaction temperature is-10 ~ 35 DEG C, chemical compounds I: alkaline reagents: the mol ratio of halogenated silanes is 1:1 ~ 2:1 ~ 2; Preferred compound I: halogenated silanes: the mol ratio of alkaline reagents is 1:1 ~ 1.5:1.5 ~ 2.
A kind of process of synthetic compound II is: slowly joined by halogenated silanes in the mixed solution of chemical compounds I and alkaline reagents and be obtained by reacting compound ii.A kind of process of preferred synthetic compound II is: in reaction system, be filled with nitrogen or rare gas element as shielding gas; and halogenated silanes is slowly joined in the mixed solution of chemical compounds I and alkaline reagents under temperature is-20 ~ 0 DEG C of condition; react under temperature is-10 ~ 50 DEG C of conditions after adding, obtain compound ii.
In second step reaction, compound ii and grignard reagent methyl chloride reactive magnesium, obtain compound ii.
In second step reaction, reaction solvent is selected from least one in tetrahydrofuran (THF), toluene and methylene dichloride; Preferred reaction solvent is tetrahydrofuran (THF); Temperature of reaction is-30 ~ 30 DEG C; Preferable reaction temperature is-15 ~ 30 DEG C, and the mol ratio of compound ii, methylmagnesium-chloride is 1:3 ~ 10; The mol ratio of preferred compound II, methylmagnesium-chloride is 1:5 ~ 6.
A kind of process of synthetic compound III is: be dissolved in by compound ii in organic solvent; be filled with nitrogen or rare gas element as shielding gas; and under temperature is-30 ~ 0 DEG C of condition, Grignard reagent is slowly joined in the system of compound ii; react under temperature is-10 ~ 30 DEG C of conditions after adding, obtain compound III.
Three-step reaction is compound III and reacts under acid effect, obtains compounds Ⅳ.
In three-step reaction, reaction solvent is selected from least one in tetrahydrofuran (THF), methyl alcohol, methylene dichloride, acetone, pyridine and water, and preferred reaction solvent is the mixed solvent of methyl alcohol and water; Acid is selected from methylsulfonic acid, trifluoroacetic acid, hydrochloric acid or hydrofluoric acid, and preferred acid is methylsulfonic acid; Temperature of reaction is-30 ~ 50 DEG C, and preferable reaction temperature is-20 ~ 30 DEG C.
The detailed process of synthetic compound IV is: in reaction system, be filled with nitrogen or a rare gas element, under temperature is-30 ~ 0 DEG C of condition, is joined by slow acid in compound III, reacts, obtain compounds Ⅳ after adding 0 ~ 50 DEG C of condition.
Beneficial effect of the present invention:
The present invention is Material synthesis montelukast sodium intermediate with (α S)-α-[3-[(1E)-2-(the chloro-2-quinolyl of 7-) vinyl] phenyl]-2-(1-hydroxyl-1-methylethyl)-methyl benzoate.The present invention by use silylation protection compound and form reagent react, without the need to using catalyzer, not only production cost is lower, and product yield and purity all higher.
Embodiment
Below in conjunction with embodiment, the invention will be further described, but protection scope of the present invention is not limited thereto:
Embodiment 1
The preparation of compound ii: by chemical compounds I (10g in 500ml reaction flask; 21.84mmol) be dissolved in THF (100ml); add N-methylmorpholine (3.31g; 32.76mmol); under nitrogen protection; system is cooled to-10 ~-5 DEG C; slow dropping trimethylchlorosilane (3.08g; 28.39mmol); keep temperature in dropping process to be no more than-5 DEG C, after dropwising, stir 15min; slowly be warming up to 30 ~ 35 DEG C and stir 0.5h, then stirring at room temperature 5h.Vapor detection raw material complete reaction.After adding toluene 250mL dilution, be cooled to 0 ~ 5 DEG C, add water (100ml), control temperature is lower than 10 DEG C, stir 15min, separatory, add 1mol/LHCl (50ml) washing in organic phase, separatory, organic phase drying is concentrated, obtains compound ii 11.23g, yield 97%.
The preparation of compound III: by compound ii (10g in 250ml reaction flask; 18.86mmol) be dissolved in anhydrous THF (100ml); under nitrogen protection; stir 15min; and be cooled to-10 DEG C, drip the tetrahydrofuran solution (30ml) of methylmagnesium-chloride (7.05g, 94.32mmol); after about 30min dropwises, control temperature-5 ~ 5 DEG C reaction 6h.TLC point plate, raw material complete reaction.In system, add the water (50ml) of precooling, stir 20min, add toluene (100ml) extraction, separatory, aqueous phase toluene (50ml*3) extraction, merges organic phase, organic phase drying is concentrated, obtains compound III 9.5g, yield 95%.
The preparation of compounds Ⅳ: add compound III (10g in 250ml reaction flask; 18.86mmol); add methyl alcohol (100ml) stirring and dissolving; nitrogen protection; be cooled to-20 DEG C; drip 20% methanesulfonic acid solution (20ml), slowly rise to room temperature subsequently, reaction 3h.TLC point plate is monitored, raw material complete reaction.Add saturated NaHCO
3solution (20ml) cancellation is reacted, and adds water (50ml) diluting reaction system, rises to stirring at room temperature 30min, with ethyl acetate (100ml*3) extraction, separatory, underpressure distillation organic phase, obtain compounds Ⅳ 8.47g, productive rate 98%, HPLC detects purity 98%.
Embodiment 2
The preparation of compound ii: by chemical compounds I (9.8g in 500ml reaction flask; 21.40mmol) be dissolved in methylene dichloride (100ml); add N-methylmorpholine (3.24g; 32.10mmol); under nitrogen protection; system is cooled to-10 ~-5 DEG C; slow dropping TERT-BUTYL DIMETHYL CHLORO SILANE (4.19g; 27.82mol); keep temperature in dropping process to be no more than-5 DEG C, after dropwising, stir 15min; slowly be warming up to 30 ~ 35 DEG C and stir 0.5h, then stirring at room temperature 5h.Vapor detection raw material complete reaction.After adding toluene (200ml) dilution, be cooled to 0 ~ 5 DEG C, add water (100ml), control temperature, lower than 10 DEG C, stirs 15min, separatory, add 1mol/LHCl (50ml) washing in organic phase, separatory, organic phase drying is concentrated, obtain compound ii 11.51g, yield 94%.
The preparation of compound III: by compound ii (8g in 250ml reaction flask; 15.09mmol) be dissolved in dry toluene (80ml); under nitrogen protection; stir 15min; and be cooled to-10 DEG C, drip the toluene solution (30ml) of methylmagnesium-chloride (5.64g, 75.46mmol); after about 30min dropwises, control temperature-5 ~ 5 DEG C reaction 6h.TLC point plate, raw material complete reaction.In system, add the water (30ml) of precooling, stir 20min, add toluene (80ml) extraction, separatory, aqueous phase toluene (50ml*3) extraction, merges organic phase, organic phase drying is concentrated, obtains compound III 7.52g, yield 94%.
The preparation of compounds Ⅳ: add compound III (8g, 13.98mmol) in 250ml reaction flask, adds acetone (80ml) stirring and dissolving; nitrogen protection, is cooled to-15 DEG C, drips 20% hydrochloric acid soln (20ml); delay subsequently and rise to room temperature, reaction 3h.TLC point plate is monitored, raw material complete reaction.Add saturated NaHCO
3solution (20ml) cancellation is reacted, and adds water (50ml) diluting reaction system, rises to stirring at room temperature 30min, with ethyl acetate (100ml*3) extraction, separatory, underpressure distillation organic phase, obtain compounds Ⅳ 5.95g, productive rate 93%.
Embodiment 3
The preparation of compound ii: be dissolved in 110mLTHF by chemical compounds I (11g, 24.02mmol) in 500ml reaction flask, adds triethylamine (3.65g; 36.03mmol); under nitrogen protection, system is cooled to-10 ~-5 DEG C, slowly drips tert-butyl diphenyl chlorosilane (8.58g; 31.23mol); keep temperature in dropping process to be no more than-5 DEG C, after dropwising, stir 15min; slowly be warming up to 30 ~ 35 DEG C and stir 0.5h, then stirring at room temperature 5h.Vapor detection raw material complete reaction.After adding toluene 200mL dilution, be cooled to 0 ~ 5 DEG C, add water (100ml), control temperature is lower than 10 DEG C, stir 15min, separatory, add 1mol/LHCl (50ml) washing in organic phase, separatory, organic phase drying is concentrated, obtains compound ii 13.19g, yield 96%.
The preparation of compound III: by compound ii (10g in 250ml reaction flask; 18.86mmol) be dissolved in anhydrous THF (100ml); under nitrogen protection; stir 15min; and be cooled to-10 DEG C, drip the tetrahydrofuran solution (30ml) of methylmagnesium-chloride (8.46g, 113.18mmol); after about 30min dropwises, control temperature-5 ~ 5 DEG C reaction 6h.TLC point plate, raw material complete reaction.In system, add the water (50ml) of precooling, stir 20min, add toluene (100ml) extraction, separatory, aqueous phase toluene (50ml*3) extraction, merges organic phase, organic phase drying is concentrated, obtains compound III 9.5g, yield 95%.
The preparation of compounds Ⅳ: add compound III (10g in 250ml reaction flask; 14.36mmol); add pyridine (60ml) stirring and dissolving; nitrogen protection; be cooled to-15 DEG C; drip 20% hydrofluoric acid solution (20ml), slowly rise to room temperature subsequently, reaction 3h.TLC point plate is monitored, raw material complete reaction.Add saturated NaHCO
3solution (20ml) cancellation is reacted, and adds water (50ml) diluting reaction system, rises to stirring at room temperature 30min, with ethyl acetate (100ml*3) extraction, separatory, underpressure distillation organic phase, obtain compounds Ⅳ 6.12g, productive rate 93%.
Embodiment 4
The preparation of compound ii: by chemical compounds I (10g in 500ml reaction flask; 21.84mmol) be dissolved in acetonitrile (100ml); add salt of wormwood (4.53g; 32.75mmol); under nitrogen protection; system is cooled to-10 ~-5 DEG C; slow dropping tri isopropyl chlorosilane (5.47g; 28.39mol); keep temperature in dropping process to be no more than-5 DEG C, after dropwising, stir 15min; slowly be warming up to 30 ~ 35 DEG C and stir 0.5h, then stirring at room temperature 5h.Vapor detection raw material complete reaction.After adding toluene 250mL dilution, be cooled to 0 ~ 5 DEG C, add water (100ml), control temperature is lower than 10 DEG C, stir 15min, separatory, add 1mol/LHCl (50ml) washing in organic phase, separatory, organic phase drying is concentrated, obtains compound ii 12.20g, yield 91%.
The preparation of compound III: by compound ii (9.8g in 250ml reaction flask; 18.48mmol) be dissolved in anhydrous THF (100ml); under nitrogen protection; stir 15min; and be cooled to-10 DEG C, drip the THF solution (30ml) of methylmagnesium-chloride (6.91g, 92.43mmol); after about 30min dropwises, control temperature 10 ~ 20 DEG C reaction 6h.TLC point plate, raw material complete reaction.In system, add the water (50ml) of precooling, stir 20min, add toluene (100ml) extraction, separatory, aqueous phase toluene (50ml*3) extraction, merges organic phase, organic phase drying is concentrated, obtains compound III 9.51g, yield 97%.
The preparation of compounds Ⅳ: add compound III (10g in 250ml reaction flask; 16.28mmol); add methylene dichloride (100ml) stirring and dissolving; nitrogen protection; be cooled to-20 DEG C; drip 20% trifluoroacetic acid solution (20ml), slowly rise to room temperature subsequently, reaction 3h.TLC point plate is monitored, raw material complete reaction.Add saturated NaHCO
3solution (20ml) cancellation is reacted, and adds water (50ml) diluting reaction system, rises to stirring at room temperature 30min, with ethyl acetate (100ml*3) extraction, separatory, underpressure distillation organic phase, obtain compounds Ⅳ 7.0g, productive rate 94%.
Claims (5)
1. a synthetic method for montelukast sodium intermediate, is characterized in that:
Wherein, RX is trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE, tert-butyl diphenyl chlorosilane or tri isopropyl chlorosilane.
2. the synthetic method of montelukast sodium intermediate according to claim 1, is characterized in that: the method comprises the steps:
The first step is reacted, and chemical compounds I reacts with halogenated silanes under the effect of alkaline reagents, obtains compound ii;
Second step reacts, and compound ii and methyl chloride reactive magnesium, obtain compound III;
Three-step reaction, compound III with react under acid effect, obtain compounds Ⅳ;
3. the synthetic method of montelukast sodium intermediate according to claim 2, is characterized in that: in the first step reaction, reaction solvent is selected from least one in acetonitrile, methylene dichloride and tetrahydrofuran (THF), and alkaline reagents is selected from N-methylmorpholine, K
2cO
3, Et
3n, pyridine or 4-DMAP, temperature of reaction is-20 ~ 50 DEG C.
4. the synthetic method of montelukast sodium intermediate according to claim 1, is characterized in that: in the first step reaction, RX is trimethylchlorosilane.
5. the synthetic method of montelukast sodium intermediate according to claim 2, it is characterized in that: in three-step reaction, reaction solvent is selected from least one in tetrahydrofuran (THF), methyl alcohol, methylene dichloride, acetone, pyridine and water, acid is selected from methylsulfonic acid, hydrochloric acid, trifluoroacetic acid or hydrofluoric acid, and temperature of reaction is-30 ~ 50 DEG C.
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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 |
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