CN116332839A - Preparation method of montelukast sodium drug intermediate - Google Patents
Preparation method of montelukast sodium drug intermediate Download PDFInfo
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- CN116332839A CN116332839A CN202310307396.3A CN202310307396A CN116332839A CN 116332839 A CN116332839 A CN 116332839A CN 202310307396 A CN202310307396 A CN 202310307396A CN 116332839 A CN116332839 A CN 116332839A
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- 229960001951 montelukast sodium Drugs 0.000 title claims abstract description 26
- 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 26
- 239000003814 drug Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229940079593 drug Drugs 0.000 title claims description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 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 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 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 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000008096 xylene Substances 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 6
- 229940043279 diisopropylamine Drugs 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 6
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims 8
- 239000012450 pharmaceutical intermediate Substances 0.000 claims 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 238000007039 two-step reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- WQZQFYRSYLXBGP-UHFFFAOYSA-N 7-chloro-2-methylquinoline Chemical compound C1=CC(Cl)=CC2=NC(C)=CC=C21 WQZQFYRSYLXBGP-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- SWGQITQOBPXVRC-UHFFFAOYSA-N methyl 2-bromobenzoate Chemical compound COC(=O)C1=CC=CC=C1Br SWGQITQOBPXVRC-UHFFFAOYSA-N 0.000 description 1
- JAVRNIFMYIJXIE-UHFFFAOYSA-N methyl 2-chlorobenzoate Chemical compound COC(=O)C1=CC=CC=C1Cl JAVRNIFMYIJXIE-UHFFFAOYSA-N 0.000 description 1
- BXXLTVBTDZXPTN-UHFFFAOYSA-N methyl 2-iodobenzoate Chemical compound COC(=O)C1=CC=CC=C1I BXXLTVBTDZXPTN-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Quinoline Compounds (AREA)
Abstract
The invention belongs to the technical field of medicine synthesis, in particular to the field of synthesis of the medicine montelukast sodium, and more particularly relates to a preparation method of a montelukast sodium medicine intermediate. The invention takes the compound IV and the compound V as raw materials, and prepares the target product compound I through two-step reaction. The synthesis method disclosed by the invention has the advantages of mild reaction conditions, low cost of used reagents, high safety, simple preparation process, high yield and high purity of the target compound, and is suitable for industrial mass production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, in particular to the field of synthesis of the medicine montelukast sodium, and more particularly relates to a preparation method of a montelukast sodium medicine intermediate.
Background
Montelukast sodium (montelukast sodium), chemical name [ R- (E) ] -1- [ [ [1- [3- [2- (7-chloro-2-quinolinyl) vinyl ] phenyl ] -3- [2- (1-hydroxy-1-methylethyl) phenyl ] propyl ] thio ] methyl ] cyclopropylacetate, developed by Merck, USA, for the first time in Finland and Mexico in 1998, was marketed for 2 months. Montelukast sodium is selectively combined with leukotriene in the airway, so that the effect of allergic medium is blocked, the airway inflammation is improved, the airway is smooth, and the preparation method is an anti-asthma anti-inflammatory and antiallergic drug with high efficiency, low toxicity and high safety, and has wide application prospect.
Compound I is an important intermediate for the synthesis of the drug montelukast sodium. The prior art discloses a method for synthesizing the important intermediate, wherein the compound A is used as a raw material in the literature, and a series of reactions are carried out to prepare the montelukast sodium drug intermediate compound I, and the synthetic route is as follows:
the method has the advantages of long synthetic route, harsh reaction conditions, low yield and long production period, and is not suitable for industrial production.
Therefore, it is a hot spot and difficult problem to provide a preparation method which is simple to operate, low in cost, high in yield, safe and environment-friendly for those skilled in the art.
Disclosure of Invention
The invention aims to provide a preparation method of a montelukast sodium drug intermediate, aiming at the problems of long synthesis route, low yield, high cost, harsh conditions and the like in the prior art, so that a new thought can be provided for the synthesis of the montelukast sodium drug intermediate, and the industrial production and application of the montelukast sodium drug intermediate are promoted.
In order to achieve the aim of the invention, the invention discloses a preparation method of a montelukast sodium drug intermediate, which comprises the following synthetic route:
wherein X is any one of Cl, br and I;
the method specifically comprises the following steps:
(1) Reacting the compound IV with a compound V in a solvent I in the presence of a palladium catalyst, diisopropylamine or triethylamine to obtain a compound III;
(2) And reacting the compound III with the compound II in a solvent II in the presence of acetic anhydride to obtain the compound I.
Further preferably, in the step (1), the palladium catalyst is one of palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium.
Further preferably, in the step (1), the solvent one is one of toluene, ethylbenzene, xylene, N-dimethylformamide, tetrahydrofuran, and acetonitrile.
Further, in the step (1), the molar ratio of the compound IV to the compound V to the diisopropylamine or the triethylamine is 1 (1-1.5): 1-1.5.
Further, in the step (1), the mass ratio of the compound IV to the palladium catalyst is 1:0.05-0.2.
Further, in the step (1), the reaction temperature is 50 to 100 ℃.
Further, in the step (2), the molar ratio of the compound III to the compound II is 1-2:1.
Further, in the step (2), the molar ratio of the acetic anhydride to the compound II is 1.5-3:1.
Further, in the step (2), the solvent xylene is toluene or xylene.
Further, in the step (2), the reaction temperature is 80-160 ℃.
Further, in the step (2), the reaction time is 6-16 h.
By adopting the technical scheme of the invention, the advantages are as follows:
the invention provides a preparation method of a novel montelukast sodium drug intermediate, which takes a compound IV and a compound V as raw materials, and a target product compound I can be prepared by only two steps of reactions. Compared with the synthesis mode of gradually synthesizing and prolonging the side chain of 7-chloro-2-methylquinoline serving as a raw material to obtain the target compound I in the prior art, the method has the advantages of low cost of the used reagent, high safety, simple preparation process, high yield and high purity of the target compound, and meanwhile, the synthesis method disclosed by the invention has mild reaction conditions, and is suitable for industrial mass production.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
EXAMPLE 1 Synthesis of Compound III
To the reaction flask, compound IV (20 g,123 mmol), diisopropylamine (14.9 g,147.6 mmol) and 100ml toluene were added under nitrogen protection, stirred and dissolved, then 2g palladium acetate was added, the temperature was raised to 80℃and methyl o-iodobenzoate (35.5 g,135.5 mmol) was added dropwise at the temperature, the reaction was completed at 80℃with the completion of the dropwise incubation, and TLC monitored the completion of the reaction of the starting material. Filtering, adding 70 ℃ hot water into the filtrate, stirring and washing at the temperature of 70 ℃, standing for layering, decompressing and desolventizing the organic layer, stirring, cooling for crystallization, centrifuging and drying to obtain the compound III, wherein the yield is 94.7%, and the purity is 99.3%.
EXAMPLE 2 Synthesis of Compound III
Under the protection of nitrogen, compound IV (20 g,123 mmol), triethylamine (12.5 g,123.5 mmol) and 100ml of xylene are added into a reaction bottle, stirred and dissolved, then 4g of palladium acetate is added, the temperature is raised to 100 ℃, methyl o-bromobenzoate (26.5 g,123 mmol) is added dropwise at the temperature, the reaction is completed at the temperature of 100 ℃ after the dropwise, and TLC monitors that the raw materials are completely reacted. Filtering, adding 70 ℃ hot water into the filtrate, stirring and washing at the temperature of 70 ℃, standing for layering, decompressing and desolventizing the organic layer, stirring, cooling for crystallization, centrifuging and drying to obtain the compound III, wherein the yield is 91.2%, and the purity is 99.1%.
EXAMPLE 3 Synthesis of Compound III
To the reaction flask were added compound IV (20 g,123 mmol), diisopropylamine (18.6 g,183.8 mmol) and 100ml acetonitrile under nitrogen protection, dissolved with stirring, then 1g tetrakis (triphenylphosphine) palladium was added, the temperature was raised to 50 ℃, methyl o-chlorobenzoate (31.4 g,184 mmol) was added dropwise at a temperature of 50℃and the reaction was completed with dropwise completion of the reaction, as monitored by TLC. Filtering, adding 70 ℃ hot water into the filtrate, stirring and washing at the temperature of 70 ℃, standing for layering, decompressing and desolventizing the organic layer, stirring, cooling for crystallization, centrifuging and drying to obtain the compound III, wherein the yield is 89.6%, and the purity is 99.2%.
EXAMPLE 4 Synthesis of Compound I
To the reaction flask were added compound III (62.7 g,211.5 mmol), compound II (25 g,141 mmol), acetic anhydride (29.6 g,290 mmol) and 200ml toluene under nitrogen, and the resulting reaction mixture was heated to 120℃and stirred for 10 hours. After the reaction was completed, the reaction mass was cooled to 30℃and 200ml of n-hexane was added thereto and stirred for about 2 hours. The solid separated was filtered and washed with 100ml of n-hexane to give a crude product. 200ml of ethyl acetate was added thereto and stirred for 1 hour. Filtering, and distilling the obtained filtrate. The solid isolated by filtration was washed with 100ml of ethyl acetate and dried to give compound I in 96.5% yield and 99.4% purity.
EXAMPLE 5 Synthesis of Compound I
To the reaction flask were added compound III (83.5 g,282 mmol), compound II (25 g,141 mmol), acetic anhydride (21.6 g,212 mmol) and 200ml toluene under nitrogen, and the resulting reaction mixture was heated to 160℃and stirred for 6 hours. After the reaction was completed, the reaction mass was cooled to 30℃and 200ml of n-hexane was added thereto and stirred for about 2 hours. The solid separated was filtered and washed with 100ml of n-hexane to give a crude product. 200ml of ethyl acetate was added thereto and stirred for 1 hour. Filtering, and distilling the obtained filtrate. The solid isolated by filtration was washed with 100ml of ethyl acetate and dried to give compound I in 92.7% yield and 99.2% purity.
EXAMPLE 6 Synthesis of Compound I
To the reaction flask were added compound III (41.8 g,141 mmol), compound II (25 g,141 mmol), acetic anhydride (43.1 g,422 mmol) and 200ml of xylene under nitrogen, and the resulting reaction mixture was heated to 80℃and stirred for 16 hours. After the reaction was completed, the reaction mass was cooled to 30℃and 200ml of n-hexane was added thereto and stirred for about 2 hours. The solid separated was filtered and washed with 100ml of n-hexane to give a crude product. 200ml of ethyl acetate was added thereto and stirred for 1 hour. Filtering, and distilling the obtained filtrate. The solid isolated by filtration was washed with 100ml of ethyl acetate and dried to give compound I in a yield of 90.4% and a purity of 99.1%.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments may be modified or some technical features may be replaced equivalently; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. The preparation method of the montelukast sodium drug intermediate is characterized by comprising the following synthetic route:
wherein X is any one of Cl, br and I;
the method specifically comprises the following steps:
(1) Reacting the compound IV with a compound V in a solvent I in the presence of a palladium catalyst, diisopropylamine or triethylamine to obtain a compound III;
(2) And reacting the compound III with the compound II in a solvent II in the presence of acetic anhydride to obtain the compound I.
2. The method for preparing a montelukast sodium drug intermediate according to claim 1, wherein in the step (1), the palladium catalyst is one of palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, and 1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride.
3. The method for preparing a montelukast sodium pharmaceutical intermediate according to claim 1, wherein in the step (1), the solvent one is one of toluene, ethylbenzene, xylene, N-dimethylformamide, tetrahydrofuran, and acetonitrile.
4. The preparation method of the montelukast sodium drug intermediate according to claim 1, wherein in the step (1), the molar ratio of the compound IV to the compound V to the diisopropylamine to the triethylamine is 1 (1-1.5): 1-1.5.
5. The preparation method of the montelukast sodium drug intermediate according to claim 1, wherein in the step (1), the mass ratio of the compound IV to the palladium catalyst is 1:0.05-0.2.
6. The method for preparing the montelukast sodium drug intermediate according to claim 1, wherein in the step (1), the reaction temperature is 50 to 100 ℃.
7. The method for preparing the montelukast sodium drug intermediate according to claim 1, wherein in the step (2), the molar ratio of the compound III to the compound II is 1-2:1.
8. The method for preparing a montelukast sodium drug intermediate according to claim 1, wherein in the step (2), the molar ratio of the acetic anhydride to the compound II is 1.5-3:1.
9. The method for preparing a montelukast sodium pharmaceutical intermediate according to claim 1, wherein in step (2), the solvent xylene is toluene or xylene.
10. The method for preparing a montelukast sodium drug intermediate according to claim 1, wherein in the step (2), the reaction temperature is 80-160 ℃; the reaction time is 6-16 h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936671A (en) * | 2014-05-06 | 2014-07-23 | 启东东岳药业有限公司 | Preparation method for montelukast sodium intermediate |
| CN112724082A (en) * | 2020-12-17 | 2021-04-30 | 江苏阿尔法药业有限公司 | Preparation method of montelukast sodium drug intermediate |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936671A (en) * | 2014-05-06 | 2014-07-23 | 启东东岳药业有限公司 | Preparation method for montelukast sodium intermediate |
| CN112724082A (en) * | 2020-12-17 | 2021-04-30 | 江苏阿尔法药业有限公司 | Preparation method of montelukast sodium drug intermediate |
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| LIANG HE等: ""Practical synthesis of methyl (E)-2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-oxopropyl)benzoate, a key intermediate of Montelukast"", CHINESE CHEMICAL LETTERS, vol. 23, no. 5, 31 December 2012 (2012-12-31), pages 518 - 520, XP028421601, DOI: 10.1016/j.cclet.2012.03.023 * |
| PARTHA GHOSH等: ""Acid-Catalyzed Air-Oxidative Fragmentation of the Carbon-Carbon Bond in 2-Aryl-1-tetralones"", ACS OMEGA, vol. 4, no. 5, 31 December 2019 (2019-12-31), pages 8065 - 8070 * |
| ROBERT D. LARSEN等: ""Practical Route to a New Class of LTD4 Receptor Antagonists"", JOURNAL OF ORGANIC CHEMISTRY, vol. 61, no. 10, 31 December 1996 (1996-12-31), pages 3398 - 3405, XP002462200, DOI: 10.1021/jo952103j * |
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