CN111170939A - Preparation method of high-purity montelukast sodium and intermediate thereof - Google Patents
Preparation method of high-purity montelukast sodium and intermediate thereof Download PDFInfo
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- CN111170939A CN111170939A CN201911328148.7A CN201911328148A CN111170939A CN 111170939 A CN111170939 A CN 111170939A CN 201911328148 A CN201911328148 A CN 201911328148A CN 111170939 A CN111170939 A CN 111170939A
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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 60
- 229960001951 montelukast sodium Drugs 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000002253 acid Substances 0.000 claims abstract description 35
- 229960005127 montelukast Drugs 0.000 claims abstract description 30
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound 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 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 claims abstract description 26
- VFAXPOVKNPTBTM-UHFFFAOYSA-N 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid Chemical compound OC(=O)CC1(CS)CC1 VFAXPOVKNPTBTM-UHFFFAOYSA-N 0.000 claims abstract description 24
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims abstract description 17
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims abstract description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- ZLOLVGQQYDQBMP-HKHDRNBDSA-N 2-[1-[[(1r)-1-[3-[(e)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetic acid;n-cyclohexylcyclohexanamine Chemical class C1CCCCC1NC1CCCCC1.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 ZLOLVGQQYDQBMP-HKHDRNBDSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 22
- 239000012535 impurity Substances 0.000 claims description 19
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- 238000002425 crystallisation Methods 0.000 claims description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 11
- 239000012266 salt solution Substances 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 239000013078 crystal Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 235000002906 tartaric acid Nutrition 0.000 claims description 7
- 239000011975 tartaric acid Substances 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 3
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 238000005119 centrifugation Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000001914 filtration Methods 0.000 description 15
- 238000000926 separation method Methods 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- XBVRITAEUIMAPP-NDEPHWFRSA-N (1S)-1-[2-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propan-1-ol Chemical compound CC(C)(C1=CC=CC=C1CC[C@@H](C2=CC=CC=C2C=CC3=NC4=C(C=CC(=C4)Cl)C=C3)O)O XBVRITAEUIMAPP-NDEPHWFRSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000001308 synthesis method Methods 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
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- -1 montelukast di-n-propylamine salt Chemical class 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 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 1
- FBHGMUULBJCCCG-LJAQVGFWSA-N 2-[2-[(3S)-3-[2-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-hydroxypropyl]phenyl]propan-2-yl methanesulfonate Chemical compound S(C)(=O)(=O)OC(C)(C)C1=C(C=CC=C1)CC[C@H](O)C1=C(C=CC=C1)C=CC1=NC2=CC(=CC=C2C=C1)Cl FBHGMUULBJCCCG-LJAQVGFWSA-N 0.000 description 1
- JCBPETKZIGVZRE-UHFFFAOYSA-N 2-aminobutan-1-ol Chemical class CCC(N)CO JCBPETKZIGVZRE-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- SMBQBQBNOXIFSF-UHFFFAOYSA-N dilithium Chemical compound [Li][Li] SMBQBQBNOXIFSF-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 238000007038 hydrochlorination reaction Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- CHMBIJAOCISYEW-UHFFFAOYSA-N n-(4-aminophenyl)acetamide Chemical class CC(=O)NC1=CC=C(N)C=C1 CHMBIJAOCISYEW-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Quinoline Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a high-purity montelukast sodium intermediate and a preparation method of montelukast sodium, wherein the preparation method of the montelukast sodium comprises the following steps: the preparation method comprises the steps of preparing the disodium salt of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid, preparing montelukast free acid, preparing the dicyclohexylamine salt of montelukast, and preparing montelukast sodium. The preparation method can effectively improve the purity and quality of the montelukast sodium product, reduce the manufacturing cost, reduce the synthesis steps, remove high-risk operation in the synthesis process and reduce the environmental pollution.
Description
Technical Field
The invention belongs to the field of organic chemistry and pharmaceutical chemistry, and particularly relates to a preparation method of high-purity montelukast sodium and an intermediate thereof.
Background
Montelukast sodium is a prescription drug developed and produced by the american company moendong (also called merck corporation) for treating asthma, and can be used for treating respiratory diseases such as asthma, allergic rhinitis and the like. Pathologically, montelukast sodium is an oral leukotriene receptor antagonist, and can specifically inhibit cysteinyl leukotriene (CysLT1) receptors in airways, so that airway inflammation is improved, and asthma symptoms are effectively controlled.
The chemical structural formula of montelukast sodium is as follows:
the prior art methods for synthesizing montelukast sodium have several approaches: one is the preparation of montelukast sodium salt from the free acid by hydrochlorination of dicyclohexylamine to prepare montelukast to obtain the montelukast free acid. For example, montelukast sodium is synthesized by reacting dilithium dianion of 1- (mercaptomethyl) cyclopropylacetic acid with methanesulfonate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolinyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol, treating the reaction solution, reacting with dicyclohexylamine to obtain dicyclohexylamine salt, and purifying. One is by conversion of the montelukast free acid to the montelukast organic group protecting salt, which is then converted to the montelukast sodium salt. For example, Zhejiang Takeda pharmaceuticals, Inc. (publication No. CN103570618A) has adopted the conversion of montelukast free acid to montelukast dicyclohexylamine salt; converting the montelukast dicyclohexylamine salt to the montelukast di-n-propylamine salt; a synthetic process for converting montelukast di-n-propylamine salt to montelukast sodium salt. And Shandong New times pharmaceutical Co., Ltd (publication Nos. CN105585524A, CN105924392A) used to synthesize a montelukast acid p-aminoacetanilide salt by using montelukast free acid or a montelukast acid 2-amino-1-butanolate salt, acidify the salt protected by the transition group, and add a base to prepare montelukast sodium.
However, the first synthesis method has disadvantages in controlling several impurities of montelukast sodium, in which sulfoxide impurities (usp impurities a), disulfide impurities (usp impurities c and d), and styrene impurities (usp impurity f) are not well removed, and n-butyllithium having a very high activity and a very high risk is used in the synthesis process. The product quality and the production safety can not meet the current requirements. The second synthesis method for converting the montelukast free acid into the montelukast organic group protective salt has the problems that the organic protective group is not easy to select, a large amount of byproducts are introduced, the purity of the prepared montelukast sodium is low, and the production cost is overhigh. Therefore, a synthesis method of montelukast sodium with high purity, good safety and less pollution needs to be solved urgently.
Disclosure of Invention
In order to improve the quality of montelukast sodium products, improve the industry and degree and reduce the cost; the synthesis steps are reduced, high-risk operation in the synthesis process is removed, the safety risk is reduced, and the environmental pollution is reduced; the invention provides a preparation method of high-purity montelukast sodium and an intermediate thereof. The specific scheme is as follows:
a preparation method of a montelukast sodium intermediate, which is characterized by comprising the following steps:
step A, preparing disodium salt of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid;
step B, reacting (2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol mesylate) with the disodium salt in the step A to prepare a crude montelukast sodium salt, and reacting the crude salt with a weak acid after extraction and impurity removal to prepare montelukast free acid;
and C, reacting the montelukast free acid in the step B with dicyclohexylamine to prepare the montelukast dicyclohexylamine salt.
Preferably, the step a is specifically performed according to the following method: dissolving 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid (compound I) in a reagent a, cooling to low temperature, adding an alkaline solution, and reacting for several hours at low temperature to obtain the disodium salt (compound II) of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid.
Preferably, the reagent a is one or more of tetrahydrofuran, toluene, and ketone solvent of C3-C5.
Preferably, the alkaline solution is an ethanol solution of sodium hydroxide or a solution of sodium methoxide.
Preferably, the low temperature is-40 to 0 ℃, and the reaction time is 0.5 to 10 hours.
Preferably, the step B is specifically performed according to the following method: the mesylate of (2- (2- (3S) - (3- (2- (7-chloro-2-quinolinyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol) (compound iii) was added to a solution of the disodium salt of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid, reacted at low temperature for several hours, after the reaction was completed, water and dichloromethane were added, stirred and extracted, after which reagent b was added to the aqueous phase and treated with tartaric acid to give the montelukast free acid, protected with nitrogen for further use.
And C: and C, reacting the montelukast free acid obtained in the step B with dicyclohexylamine, and crystallizing, centrifuging and drying the obtained product to obtain the montelukast dicyclohexylamine salt so as to prepare the high-purity montelukast sodium intermediate.
Preferably, the reagent b is ethyl acetate or dichloromethane, the low temperature is-40 to 0 ℃, and the reaction time is 1 to 20 hours.
Preferably, the step C is specifically performed according to the following method: adding dicyclohexylamine into the montelukast free acid, adjusting the reaction temperature and time to react to obtain crude dicyclohexylamine salt of the montelukast free acid, then adding a montelukast dicyclohexylamine salt seed crystal, crystallizing, centrifuging, and drying to obtain the montelukast dicyclohexylamine salt.
Preferably, the reaction temperature is 0 to 40 ℃, and the time is 10 minutes to 6 hours.
The invention also provides a preparation method of the high-purity montelukast sodium, wherein the high-purity montelukast sodium intermediate obtained by the preparation method is selected to be subjected to reverse acid treatment and reacts with sodium hydroxide to form crude salt, and the crude salt is subjected to concentration crystallization and centrifugal drying treatment, so that the high-purity montelukast sodium is prepared.
Preferably, the inverse acid treatment is to dissolve the montelukast dicyclohexylamine salt by using a reagent c, acidify, wash and separate the solution to obtain an intermediate solution; the concentration crystallization method is to add sodium hydroxide into the intermediate solution to form sodium salt, and add the sodium salt into a reagent d for crystallization after concentration.
Preferably, the reagent c is one or more of toluene, ethyl acetate and dichloromethane; the reagent d is one or more of petroleum ether, n-hexane and n-heptane.
The invention obtains the following beneficial effects:
the preparation method can effectively improve the purity and quality of the montelukast sodium product, the yield of the montelukast dicyclohexylamine salt is more than 94%, the yield of the montelukast sodium is more than 95%, the manufacturing cost is reduced, meanwhile, the synthesis steps are reduced, high-risk operation in the synthesis process is eliminated, and the environmental pollution is reduced.
Drawings
Figure 1 nuclear magnetic resonance spectrum of montelukast sodium synthesized in the present application.
Figure 2 infrared spectrum of montelukast sodium synthesized herein.
Figure 3 high resolution mass spectrum of the acid moiety of montelukast sodium synthesized in the present application.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that the preparation methods of the examples are illustrative only and not limiting, and that modifications to the preparation methods of the invention that are within the spirit of the invention are within the scope of the claimed invention.
Example 1
Adding 20g (0.137mol) of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid and 200ml of tetrahydrofuran into a 500ml three-necked bottle, stirring to dissolve, cooling to-10 ℃, adding 30g of sodium methoxide solution, keeping the temperature at-10-0 ℃ for reaction for 3 hours to obtain a disodium salt solution of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid for later use.
Adding the prepared disodium salt solution of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid into a 2000ml three-necked bottle, adding 54g (0.1mol) of mesylate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol, reacting at 10-0 ℃ for 10 hours, adding 200ml of dichloromethane and 400ml of water, stirring for 30 minutes, standing for 30 minutes for liquid separation, adding 40g of tartaric acid into an aqueous phase, stirring for 30 minutes, adding 500ml of ethyl acetate, stirring for 30 minutes, and standing for liquid separation to obtain montelukast free acid with the purity of more than 99% for later use.
The montelukast sodium free acid prepared above was added to a 1000ml three-necked flask. Adding 11g of dicyclohexylamine, reacting for 2 hours at 10-30 ℃, adding 0.2g of montelukast dicyclohexylamine salt seed crystal, carrying out heat preservation and crystallization for 10 hours at 10-30 ℃, filtering, and drying for 12 hours at 60 ℃ to obtain 21g of montelukast dicyclohexylamine salt with single impurity less than 0.03%, wherein the yield is 94%.
10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene are added into a 250ml three-necked flask, and after the mixture is stirred and dissolved, 100ml of water and 2g of glacial acetic acid are added, the mixture is stirred for 30 minutes, and the mixture is kept stand and separated. Adding a sodium hydroxide/ethanol solution (prepared by adding 15g of ethanol into 0.5g of sodium hydroxide), reacting at room temperature for 30 minutes, adding 1g of activated carbon, decoloring at room temperature for 30 minutes, filtering, distilling 20g of solvent from the filtrate at 50 ℃, adding into 100ml of n-heptane, crystallizing for 2 hours, filtering, and drying at 60 ℃ for 24 hours to obtain 7.5g of montelukast sodium with single impurity less than 0.03%, purity more than 99.9%, and yield of 95%.
Example 2
Adding 20g (0.137mol) of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid and 200ml of toluene into a 500ml three-necked bottle, stirring for dissolving, cooling to-20 ℃, adding 30g of ethanol solution of sodium hydroxide, and reacting at the temperature of-10-0 ℃ for 5 hours to obtain the disodium salt solution of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid for later use.
Adding the prepared disodium salt solution of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid into a 2000ml three-necked bottle, adding 54g (0.1mol) of mesylate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol, reacting at 10-0 ℃ for 10 hours, adding 200ml of dichloromethane and 400ml of water, stirring for 30 minutes, standing for 30 minutes for liquid separation, adding 40g of tartaric acid into an aqueous phase, stirring for 30 minutes, adding 500ml of dichloromethane, stirring for 30 minutes, and standing for liquid separation to obtain montelukast free acid with the purity of more than 99% for later use.
The montelukast sodium free acid prepared above was added to a 1000ml three-necked flask. Adding 11g of dicyclohexylamine, reacting for 2 hours at 10-30 ℃, adding 0.2g of montelukast dicyclohexylamine salt seed crystal, carrying out heat preservation and crystallization for 10 hours at 10-30 ℃, filtering, and drying for 12 hours at 60 ℃ to obtain 21g of montelukast dicyclohexylamine salt with single impurity less than 0.03%, wherein the yield is 94%.
10g of the prepared montelukast dicyclohexylamine salt and 60ml of ethyl acetate are added into a 250ml three-necked flask, and after the mixture is stirred and dissolved, 100ml of water and 2g of glacial acetic acid are added, the mixture is stirred for 30 minutes, and the mixture is kept stand and separated. Adding a sodium hydroxide/ethanol solution (prepared by adding 15g of ethanol into 0.5g of sodium hydroxide), reacting at room temperature for 30 minutes, adding 1g of activated carbon, decoloring at room temperature for 30 minutes, filtering, distilling 20g of solvent from the filtrate at 50 ℃, adding into 100ml of n-hexane, crystallizing for 2 hours, filtering, and drying at 60 ℃ for 24 hours to obtain 7.5g of montelukast sodium with the single impurity of less than 0.03 percent and the purity of more than 99.9 percent, wherein the yield is 95 percent.
Example 3
Adding 20g (0.137mol) of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid and 200ml of acetone into a 500ml three-necked bottle, stirring to dissolve, cooling to-30 ℃, adding 30g of sodium methoxide solution, keeping the temperature at-30 to-10 ℃ for 10 hours, and reacting to obtain the disodium salt solution of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid for later use.
The prepared disodium salt solution of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid is added into a 2000ml three-necked bottle, 54g (0.1mol) of mesylate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol is added, the mixture is incubated at 30 to-10 ℃ for 20 hours, 200ml of dichloromethane and 400ml of water are added, the mixture is stirred for 30 minutes, the mixture is kept still for 30 minutes for liquid separation, 40g of tartaric acid is added into the water phase, the mixture is stirred for 30 minutes, 500ml of ethyl acetate is added, the mixture is stirred for 30 minutes and kept still for liquid separation, and montelukast free acid with the purity of more than 99 percent is obtained for standby.
The montelukast sodium free acid prepared above was added to a 1000ml three-necked flask. Adding 11g of dicyclohexylamine, reacting for 2 hours at 10-30 ℃, adding 0.2g of montelukast dicyclohexylamine salt seed crystal, carrying out heat preservation and crystallization for 10 hours at 10-30 ℃, filtering, and drying for 12 hours at 60 ℃ to obtain 21g of montelukast dicyclohexylamine salt with single impurity less than 0.03%, wherein the yield is 94%.
10g of the prepared montelukast dicyclohexylamine salt and 60ml of dichloromethane are added into a 250ml three-necked flask, and after the mixture is stirred and dissolved, 100ml of water and 2g of glacial acetic acid are added, the mixture is stirred for 30 minutes, and the mixture is kept stand for liquid separation. Adding a sodium hydroxide/ethanol solution (prepared by adding 15g of ethanol into 0.5g of sodium hydroxide), reacting at room temperature for 30 minutes, adding 1g of activated carbon, decoloring at room temperature for 30 minutes, filtering, distilling 20g of solvent from the filtrate at 50 ℃, adding into 100ml of n-hexane, crystallizing for 2 hours, filtering, and drying at 60 ℃ for 24 hours to obtain 7.5g of montelukast sodium with the single impurity of less than 0.03 percent and the purity of more than 99.9 percent, wherein the yield is 95 percent.
Example 4
Adding 20g (0.137mol) of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid and 200ml of butanone into a 500ml three-necked bottle, stirring to dissolve, cooling to-40 ℃, adding 30g of sodium methoxide solution, keeping the temperature at-40 ℃ and reacting for 3 hours to obtain the disodium salt solution of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid for later use.
The prepared disodium salt solution of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid is added into a 2000ml three-necked flask, 54g (0.1mol) of mesylate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol is added, the mixture is kept at 40 ℃ for 20 hours, 200ml of dichloromethane and 400ml of water are added, the mixture is stirred for 30 minutes, the mixture is kept still for 30 minutes for liquid separation, 40g of tartaric acid is added into the water phase, the mixture is stirred for 30 minutes, 500ml of ethyl acetate is added, the mixture is stirred for 30 minutes, and the liquid separation is kept still to obtain montelukast free acid with the purity of more than 99 percent for standby.
The montelukast sodium free acid prepared above was added to a 1000ml three-necked flask. Adding 11g of dicyclohexylamine, reacting for 2 hours at 0-30 ℃, adding 0.2g of montelukast dicyclohexylamine salt seed crystal, carrying out heat preservation and crystallization for 10 hours at 0-30 ℃, filtering, and drying for 12 hours at 60 ℃ to obtain 21g of montelukast dicyclohexylamine salt with single impurity less than 0.03%, wherein the yield is 94%.
10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene are added into a 250ml three-necked flask, and after the mixture is stirred and dissolved, 100ml of water and 2g of glacial acetic acid are added, the mixture is stirred for 30 minutes, and the mixture is kept stand and separated. Adding sodium methoxide solution (prepared by adding 15g of methanol into 0.5g of sodium hydroxide), reacting at room temperature for 30 minutes, adding 1g of activated carbon, decoloring at room temperature for 30 minutes, filtering, distilling 20g of solvent from filtrate at 50 ℃, adding into 100ml of n-heptane, crystallizing for 2 hours, filtering, and drying at 60 ℃ for 24 hours to obtain the montelukast sodium with the single impurity of less than 0.03 percent, the purity of more than 99.9 percent, 7.5g and the yield of 95 percent.
Example 5
Adding 20g (0.137mol) of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid and 200ml of cyclopentanone into a 500ml three-necked bottle, stirring to dissolve, cooling to 0 ℃, adding 30g of sodium methoxide solution, and keeping the temperature at 0 ℃ for reaction for 3 hours to obtain the disodium salt solution of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid for later use.
The prepared disodium salt solution of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid was added to a 2000ml three-necked flask, 54g (0.1mol) of mesylate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol was added thereto, the mixture was reacted at 0 ℃ for 2 hours, 200ml of dichloromethane and 400ml of water were added thereto, the mixture was stirred for 30 minutes, and the mixture was allowed to stand for 30 minutes for liquid separation, 40g of tartaric acid was added to the aqueous phase, and then stirred for 30 minutes, 500ml of ethyl acetate was added thereto, stirred for 30 minutes, and then allowed to stand for liquid separation to obtain montelukast free acid having a purity of more than 99% for use.
The montelukast sodium free acid prepared above was added to a 1000ml three-necked flask. Adding 11g of dicyclohexylamine, reacting for 2 hours at 0 ℃, adding 0.2g of montelukast dicyclohexylamine salt seed crystal, carrying out heat preservation and crystallization for 10 hours at 0-30 ℃, filtering, and drying for 12 hours at 60 ℃ to obtain 21g of montelukast dicyclohexylamine salt with single impurity less than 0.03%, wherein the yield is 94%.
10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene are added into a 250ml three-necked flask, and after the mixture is stirred and dissolved, 100ml of water and 2g of glacial acetic acid are added, the mixture is stirred for 30 minutes, and the mixture is kept stand and separated. Adding sodium methoxide solution (prepared by adding 15g of methanol into 0.5g of sodium hydroxide), reacting at room temperature for 30 minutes, adding 1g of activated carbon, decoloring at room temperature for 30 minutes, filtering, distilling 20g of solvent from filtrate at 50 ℃, adding into 100ml of n-hexane for crystallization for 2 hours, filtering, and drying at 60 ℃ for 24 hours to obtain 7.5g of montelukast sodium with single impurity less than 0.03%, purity more than 99.9% and yield of 95%.
The characterization results of montelukast sodium synthesized by the methods described in examples 1-5 are shown in fig. 1-3. Referring to fig. 1-2, characteristic peaks in the nmr spectrum and the ir spectrum of the montelukast sodium sample may correspond to characteristic peaks in the standard spectrum in a one-to-one correspondence; referring to fig. 3, [ M + H ] in the high resolution mass spectrometry data of the acid moiety of the montelukast sodium sample]+Measured value (M/z) of 586.2165, and [ M + H]+Has a molecular ion peak molecular composition of C in the acid radical part of the sample, and has a theoretical value (m/z)586.2177 very close to each other35H37NO3SCl, molecular formula C35H36NO3SCl. From the above characterization, it can be seen that montelukast sodium can be synthesized in high purity by the methods described herein.
Although the present invention has been described with reference to the above embodiments, the present invention is not limited to the above embodiments, which are only illustrative and not restrictive, and those skilled in the art can make various modifications without departing from the spirit and scope of the present invention as claimed in the claims.
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| CN112409252A (en) * | 2019-12-20 | 2021-02-26 | 牡丹江恒远药业股份有限公司 | A kind of preparation method of high-purity montelukast sodium and intermediate thereof |
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