CN110183371B - Preparation process of zafirlukast intermediate - Google Patents
Preparation process of zafirlukast intermediate Download PDFInfo
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- CN110183371B CN110183371B CN201910288764.8A CN201910288764A CN110183371B CN 110183371 B CN110183371 B CN 110183371B CN 201910288764 A CN201910288764 A CN 201910288764A CN 110183371 B CN110183371 B CN 110183371B
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- methyl
- indol
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- zafirlukast
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- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229960004764 zafirlukast Drugs 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910052901 montmorillonite Inorganic materials 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 14
- -1 (5-nitro-1-tosyl-1H-indol-3-yl) methyl Chemical group 0.000 claims abstract description 12
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 229940095102 methyl benzoate Drugs 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 239000012442 inert solvent Substances 0.000 claims abstract description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims abstract description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000004809 thin layer chromatography Methods 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 230000008034 disappearance Effects 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- DUKYPQBGYRJVAN-UHFFFAOYSA-N methyl 3-methoxybenzoate Chemical compound COC(=O)C1=CC=CC(OC)=C1 DUKYPQBGYRJVAN-UHFFFAOYSA-N 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 229960001701 chloroform Drugs 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- NOPAUNSVSBHVMP-UHFFFAOYSA-N COC(CC1=CN(C2=CC=C(C=C12)[N+](=O)[O-])S(=O)(=O)C1=CC=C(C)C=C1)=O Chemical compound COC(CC1=CN(C2=CC=C(C=C12)[N+](=O)[O-])S(=O)(=O)C1=CC=C(C)C=C1)=O NOPAUNSVSBHVMP-UHFFFAOYSA-N 0.000 claims description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 2
- 238000003828 vacuum filtration Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 20
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- 239000003199 leukotriene receptor blocking agent Substances 0.000 abstract description 2
- 229940127554 medical product Drugs 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- HPEJINFHDRHIMZ-UHFFFAOYSA-N 3-methoxy-4-[(5-nitro-1h-indol-3-yl)methyl]benzoic acid Chemical group COC1=CC(C(O)=O)=CC=C1CC1=CNC2=CC=C([N+]([O-])=O)C=C12 HPEJINFHDRHIMZ-UHFFFAOYSA-N 0.000 description 3
- OZFPSOBLQZPIAV-UHFFFAOYSA-N 5-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=C2NC=CC2=C1 OZFPSOBLQZPIAV-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 229910001923 silver oxide Inorganic materials 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NHMPXQYHDHIZEI-UHFFFAOYSA-N 4-[(5-amino-1-methylindol-3-yl)methyl]-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1CC1=CN(C)C2=CC=C(N)C=C12 NHMPXQYHDHIZEI-UHFFFAOYSA-N 0.000 description 1
- PHKYMSLVWLYDKP-UHFFFAOYSA-N 5-nitro-1h-indole-3-carbaldehyde Chemical compound [O-][N+](=O)C1=CC=C2NC=C(C=O)C2=C1 PHKYMSLVWLYDKP-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- UKSSYMDOQUSGRZ-UHFFFAOYSA-N methyl 4-carbonochloridoyl-2-methoxybenzoate Chemical compound COC(=O)C1=CC=C(C(Cl)=O)C=C1OC UKSSYMDOQUSGRZ-UHFFFAOYSA-N 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
A preparation process of zafirlukast intermediate, which is an important intermediate for preparing a leukotriene antagonist drug zafirlukast. Taking (5-nitro-1-tosyl-1H-indol-3-yl) methyl acetate and 3-methoxy methyl benzoate as raw materials, heating and reacting in an inert solvent under the action of acidified montmorillonite until the raw materials disappear, and filtering to obtain 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl ] methyl benzoate; the target product is obtained by hydrolyzing the compound under alkaline conditions. The invention provides a new process route for synthesizing important zafirlukast intermediates, has the technical advantages of simple and convenient operation, low reaction cost, high product yield and environmental friendliness, and can meet the requirement of large-scale production of medical products.
Description
Technical Field
The invention belongs to the production field of fine chemical products, and particularly relates to a preparation process of a zafirlukast intermediate for treating asthma.
Background
With the continuous development of industrialization process, the living environment of human beings is also continuously changed, the air quality is reduced, and the number of asthma patients in major cities in China is increased year by year together with hundreds of millions of smoking people. Zafirlukast (Zafirlukast), chemically known as cyclopentyl [3- [ 2-methoxy-4- [ (2-tolyl) sulfonylaminocarbonyl ] benzyl ] -1-methyl-1H-indole-5-methylene ] carbamate, is a leukotriene receptor antagonist developed by astrazen, uk, and is clinically used for the prevention and long-term treatment of asthma. At present, the market price of zafirlukast is relatively expensive, the preparation process is relatively complex, and the defects that the synthesis process of the intermediate of zafirlukast has low yield, complex post-treatment and more 'three wastes' generated, and causes great pollution to the environment are mainly reflected, so that the requirement of large-scale industrial production is not facilitated. Therefore, the development of the preparation process of zafirlukast and the important intermediate thereof can bring better economic and social benefits.
The structure of zafirlukast is shown below:
in the molecular structure of zafirlukast, 3-methoxy-4- [ (1-methyl-5-amino-1H-indol-3-yl) methyl ] benzoic acid is the core structural unit of the compound. The precursor compound of the structural unit is 3-methoxy-4- [ (5-nitro-1H-indol-3-yl) methyl ] benzoic acid, namely the compound shown in the formula (I), and the structure of the compound is shown in the specification. Therefore, the preparation of the intermediate becomes the technical key of the preparation process of zafirlukast.
At present, there are three main routes for synthesizing zafirlukast intermediates reported in the literature. Route one: 5-nitroindole is used as a raw material, 4-bromomethyl-3-methoxy methyl benzoate is used as an alkylating reagent, and under the action of silver oxide, Friedel-crafts alkylation reaction is carried out to obtain 3-methoxy-4- (5-nitroindole-3-methylene) methyl benzoate, wherein the total yield is about 45% (Lewei, Ningqi, Zafirlukast synthesis [ J ]. China journal of medical industry, 2004,35(8): 451-452; Brown FJ, Bemstein PR, Yee YK, et al, Heter ℃ C. alic amide derivatives, US, 4859692). In the reaction, the use of expensive silver oxide and toxic halogenated aromatics greatly limits the application of the method to large-scale production. And a second route: under the action of Lewis acid, 5-nitroindole is used as a raw material, 3-methoxy-4-methoxycarbonylbenzoyl chloride is used as an acylation reagent, and the 3-methoxy-4- (5-nitroindole-3-methylene) methyl benzoate is obtained through two steps of reactions of Friedel-crafts acylation and carbonyl reduction, wherein the total yield is about 70% (Yanglimin, a preparation method of a novel zafirlukast important intermediate, CN 101104601A). The reaction is carried out under the conditions of high temperature (180-200 ℃) and strong alkali, the reaction yield is high, but the requirements of the reaction conditions of high temperature and strong alkali on equipment are high, and the product quality is difficult to guarantee. And a third route: 5-nitroindole and 3-methoxy-4-formyl methyl benzoate are used as raw materials, and the reduction-alkylation reaction is carried out under the catalysis of boron trifluoride/diethyl ether to prepare the 3-methoxy-4- (5-nitroindole-3-methylene) methyl benzoate with the yield of 52% (Mahadevan A, Sard H, Gonzalez M, McKew JC, A general method for C3 reduction alkylation of alloys, Tetrahedron Letters,2003,44: 4589-4591). The reaction is prone to produce bis-indole by-products, which makes purification of the target product difficult. The zafirlukast intermediate methyl 3-methoxy-4- (5-nitroindole-3-methylene) benzoate can be further hydrolyzed to obtain the compound shown in the formula (I).
In summary, although there are many technical approaches to prepare zafirlukast intermediates, these methods all have certain disadvantages: the raw materials/reagents are too expensive, lewis acid as a catalyst causes increase of impurities, purification is difficult, and the like. Therefore, the preparation process of the zafirlukast intermediate, which has the advantages of high efficiency, simple operation, high product purity and good quality and is suitable for large-scale production, still needs to be developed in the field.
Disclosure of Invention
The technical problem to be solved is as follows: the invention aims to solve the defects of the background technology, provides the preparation process of the zafirlukast intermediate, has the technical advantages of simple and convenient operation, low reaction cost, high product yield and environmental friendliness, and can meet the requirement of large-scale production of medical products.
The technical scheme is as follows: a preparation process of zafirlukast intermediate, the structure of which is shown as formula (I),
the method comprises the following steps:
a. adding (5-nitro-1-tosyl-1H-indol-3-yl) methyl acetate and methyl 3-methoxybenzoate into an inert solvent, adding acidified montmorillonite, heating to 30-45 ℃, reacting for 1-6H, filtering to remove the acidified montmorillonite after TLC (thin layer chromatography) determination of raw material disappearance, and obtaining methyl 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl ] benzoate; the mass ratio of (5-nitro-1-tosyl-1H-indol-3-yl) acetic acid methyl ester: methyl 3-methoxybenzoate: acidified montmorillonite is 2.3:1: 2;
b. dissolving 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl ] methyl benzoate in methanol, adding 2M potassium hydroxide aqueous solution, heating to 60 ℃ for reaction for 4H, adjusting the pH to 7 after TLC (thin layer chromatography) determination raw materials disappear, precipitating a light yellow solid, and carrying out vacuum filtration to obtain a target product, namely a compound shown in formula (I); the dosage is calculated by molar ratio, 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl ] benzoic acid methyl ester and potassium hydroxide are 1 (2-10).
Preferably, the inert solvent in step a is dichloromethane, trichloromethane or 1, 2-dichloroethane.
Preferably, the acidified montmorillonite in step a is trifluoroacetic acid acidified montmorillonite, trichloroacetic acid acidified montmorillonite or concentrated hydrochloric acid acidified montmorillonite.
The synthetic route of the zafirlukast important intermediate compound shown as the formula (I) is as follows:
the invention provides a new process route for synthesizing important zafirlukast intermediates, which is completely different from the synthetic route of zafirlukast intermediates reported in the prior literature and is a new breakthrough in the field. The synthetic raw material (5-nitro-1-tosyl-1H-indol-3-yl) methyl acetate adopted by the invention can be prepared in a large scale by referring to the reported literature (CheZ, Zhang S, Shao Y., et al, J.Agric.food chem.2013,61,5696-5705), and the required chemical reagents are cheap and easy to obtain. The synthetic raw material 3-methoxy methyl benzoate adopted by the invention belongs to a conventional reagent and can be directly purchased. The acidified montmorillonite adopted by the invention is prepared in a large scale by treating cheap common montmorillonite with protonic acid, and has the advantages of safety, environmental protection and reusability.
Has the advantages that: because a new process route for synthesizing the important intermediate of zafirlukast is adopted, the use of toxic halogenating reagents and acyl chloride reagents is avoided; meanwhile, acidified montmorillonite is adopted to replace Lewis acid with large pollution and expensive silver oxide, and can be removed only by filtering after the reaction is finished; in addition, the preparation process provided by the invention needs two steps of reaction, and a high-purity product is obtained by a recrystallization method, so that the total yield reaches 73 percent and is superior to the reported synthetic method. In a word, the invention provides a new process route for synthesizing important zafirlukast intermediates, has the advantages of simple operation, simple and convenient post-treatment, low production cost, high product yield, high purity, safety and environmental protection, and is relatively suitable for large-scale industrial production.
Detailed Description
The present invention will be illustrated by the following specific examples, but is not limited thereto.
Example 1
Preparation of methyl (5-nitro-1-tosyl-1H-indol-3-yl) acetate:
5-Nitroindole-3-carbaldehyde (19g, 0.1mol) was added to a 250mL round-bottomed flask, and dissolved in 150mL dry dichloromethane, followed by the addition of p-toluenesulfonyl chloride (19.1g, 0.1mol) and potassium carbonate (27.6g, 0.2mol), followed by heating and refluxing for 12 hours. TLC determination of the disappearance of the starting material, cooling to room temperature, standing, suction filtration, vacuum distillation of the filtrate to remove the organic solvent and yield 29g of a yellow solid. In a 250mL round bottom flask, 29g of the above yellow solid was dissolved in 100mL ethanol, and sodium borohydride (6.4g, 0.17mol) was added in portions with stirring and reacted at room temperature for 6 hours. TLC determined disappearance of starting material, pH was adjusted to 7 with 1M aqueous hydrochloric acid, ethyl acetate extraction (3X 50mL) was performed, and the organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 28g of a pale yellow oil. In a 250mL round-bottom flask, 28g of the above pale yellow oil was dissolved in 60mL of acetic anhydride, and 4-dimethylaminopyridine (1.0g, 0.08mol) was added with stirring and reacted at room temperature for 2 hours. TLC determination of disappearance of starting material and removal under reduced pressureMost of the organic solvent was removed, water was added to precipitate a pale yellow solid, which was filtered under reduced pressure and recrystallized from ethyl acetate/cyclohexane to give methyl (5-nitro-1-tosyl-1H-indol-3-yl) acetate as a white solid (28g, 72% overall yield over 3 steps).1H NMR(400MHz,DMSO-d6)δ8.56(d,J＝2.1Hz,1H),8.20(dd,J＝9.2,2.2Hz,1H),8.16-8.11(m,2H),7.92(d,J＝8.4Hz,2H),7.40(d,J＝8.3Hz,2H),5.25(s,2H),2.29(s,3H),2.00(s,3H)；13C NMR(101MHz,DMSO-d6)δ170.9,147.0,144.3,137.7,134.1,131.1,129.9,129.7,127.5,120.7,118.9,117.2,114.5,57.3,21.6,21.2；ESI MS m/z 389.4[M+H]+.
Preparing acidified montmorillonite:
in a 2L round bottom flask, montmorillonite (200g) and 3% aqueous hydrochloric acid (1.2L) were added, heated to 100 ℃ and stirred for 24 hours. The mixture was filtered, and the filter cake was washed with distilled water (1.5L), activated in an oven at 100 ℃ for 6 hours, and placed in a desiccator for further use.
Preparation of methyl 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl ] benzoate:
in a 250mL round bottom flask, methyl (5-nitro-1-tosyl-1H-indol-3-yl) acetate (19.4g, 0.05mol) and methyl 3-methoxybenzoate (8.4g, 0.05mol) were added dissolved in 100mL of dichloromethane, and acidified montmorillonite (16.8g) was added with stirring and heated to 45 ℃ for 4 hours under reflux. TLC (thin layer chromatography) determination of disappearance of raw materials, cooling to room temperature, standing, suction filtration, reduced pressure distillation of filtrate to remove organic solvent to obtain yellow solid, and recrystallization of ethyl acetate/cyclohexane to obtain white solid 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl]Methyl benzoate (18.4g, 74% yield).1H NMR(400MHz,DMSO-d6)δ8.42(d,J＝2.0Hz,1H),8.17(dd,J＝9.1,2.1Hz,1H),8.03(d,J＝9.1Hz,1H),7.72(d,J＝8.3Hz,2H),7.59-7.51(m,2H),7.41(s,1H),7.24(d,J＝8.3Hz,2H),7.13-7.05(m,1H),4.04(s,2H),3.91(s,3H),3.90(s,3H),2.36(s,3H)；13C NMR(101MHz,DMSO-d6)δ166.9,157.0,145.9,144.1,138.2,134.7,132.2,130.8,130.2,129.8,126.9,126.7,122.3,120.0,116.5,113.9,111.3,55.7,52.3,25.4,21.8；ESI MS m/z 495.4[M+H]+.
Preparation of 3-methoxy-4- [ (5-nitro-1H-indol-3-yl) methyl ] benzoic acid:
in a 250mL round bottom flask, 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl was added]Methyl benzoate (15.0g, 0.03mol) was dissolved in 80mL of methanol, and 2M aqueous potassium hydroxide (40mL) was added with stirring and heated to 60 ℃ for 4 hours. TLC (thin layer chromatography) determination for disappearance of raw materials, adjusting pH to 7 with 1M hydrochloric acid aqueous solution, precipitating light yellow solid, vacuum filtering, and recrystallizing with ethyl acetate/cyclohexane to obtain white solid 3-methoxy-4- [ (5-nitro-1H-indol-3-yl) methyl]Benzoic acid (9.7g, 98% yield).1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.44(d,J＝2.0Hz,1H),7.92(dd,J＝8.9,2.2Hz,1H),7.48-7.37(m,5H),7.19(d,J＝7.8Hz,1H),4.07(s,2H),3.88(s,3H)；13C NMR(101MHz,DMSO-d6)δ167.7,157.1,140.8,139.9,134.8,130.6,130.2,127.9,126.8,122.3,116.9,116.3,116.2,112.4,111.4,56.0,25.1；ESI MS m/z 349.4[M+Na]+.
Example 2
Preparation of methyl 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl ] benzoate:
to a 250mL round bottom flask was added methyl (5-nitro-1-tosyl-1H-indol-3-yl) acetate (9.7g, 0.025mol) and methyl 3-methoxybenzoate (4.2g, 0.025mol) dissolved in 50mL of chloroform, acidified montmorillonite (8.4g) was added with stirring, and the mixture was heated to 45 ℃ for 4 hours under reflux. TLC determination of disappearance of the starting material, cooling to room temperature, standing, suction filtration, reduced pressure distillation of the filtrate to remove the organic solvent gave a yellow solid, which was recrystallized from ethyl acetate/cyclohexane to give methyl 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl ] benzoate (8.1g, 66% yield) as a white solid.
Example 3
Preparation of methyl 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl ] benzoate:
to a 250mL round bottom flask was added methyl (5-nitro-1-tosyl-1H-indol-3-yl) acetate (9.7g, 0.025mol) and methyl 3-methoxybenzoate (4.2g, 0.025mol) dissolved in 50mL1, 2-dichloroethane, and acidified montmorillonite (8.4g) was added with stirring and heated to 45 ℃ for 4 hours under reflux. TLC determination of disappearance of starting material, cooling to room temperature, standing, suction filtration, reduced pressure distillation of the filtrate to remove the organic solvent gave a yellow solid, which was recrystallized from ethyl acetate/cyclohexane to give methyl 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl ] benzoate as a white solid (7.8g, 63% yield).
Claims (2)
1. A preparation process of zafirlukast intermediate, the structure of which is shown as formula (I),
the method is characterized by comprising the following steps:
a. adding (5-nitro-1-tosyl-1H-indol-3-yl) methyl acetate and methyl 3-methoxybenzoate into an inert solvent, adding acidified montmorillonite, heating to 30-45 ℃, reacting for 1-6H, filtering to remove the acidified montmorillonite after TLC (thin layer chromatography) determination of raw material disappearance, and obtaining methyl 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl ] benzoate; the mass ratio of (5-nitro-1-tosyl-1H-indol-3-yl) acetic acid methyl ester: methyl 3-methoxybenzoate: the acidified montmorillonite is 2.3:1:2, and is trifluoroacetic acid acidified montmorillonite, trichloroacetic acid acidified montmorillonite or concentrated hydrochloric acid acidified montmorillonite;
b. dissolving 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl ] methyl benzoate in methanol, adding 2M potassium hydroxide aqueous solution, heating to 60 ℃ for reaction for 4H, adjusting the pH to 7 after TLC (thin layer chromatography) determination raw materials disappear, precipitating a light yellow solid, and carrying out vacuum filtration to obtain a target product, namely a compound shown in formula (I); the dosage is calculated by molar ratio, 3-methoxy-4- [ (5-nitro-1-tosyl-1H-indol-3-yl) methyl ] benzoic acid methyl ester and potassium hydroxide are 1 (2-10).
2. The process for preparing zafirlukast intermediate according to claim 1, characterized in that: in the step a, the inert solvent is dichloromethane, trichloromethane or 1, 2-dichloroethane.
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