CN102424673A - Montelukast sodium intermediate and method for synthesizing montelukast sodium thereof - Google Patents
Montelukast sodium intermediate and method for synthesizing montelukast sodium thereof Download PDFInfo
- Publication number
- CN102424673A CN102424673A CN2011102829523A CN201110282952A CN102424673A CN 102424673 A CN102424673 A CN 102424673A CN 2011102829523 A CN2011102829523 A CN 2011102829523A CN 201110282952 A CN201110282952 A CN 201110282952A CN 102424673 A CN102424673 A CN 102424673A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- reaction
- gained
- milliliters
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- RHXXYWBMAWLSOS-XNTDXEJSSA-N CC(C)(c1c(CCC(c2cccc(/C=C/c(cc3)nc4c3ccc(Cl)c4)c2)=O)cccc1)O Chemical compound CC(C)(c1c(CCC(c2cccc(/C=C/c(cc3)nc4c3ccc(Cl)c4)c2)=O)cccc1)O RHXXYWBMAWLSOS-XNTDXEJSSA-N 0.000 description 1
- QDSJAAAHFVOTSB-WEVVVXLNSA-N CC(c1cc(/C=C/c(cc2)nc3c2ccc(Cl)c3)ccc1)O Chemical compound CC(c1cc(/C=C/c(cc2)nc3c2ccc(Cl)c3)ccc1)O QDSJAAAHFVOTSB-WEVVVXLNSA-N 0.000 description 1
Classifications
-
- 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
Abstract
The invention relates to a chemical synthesis drug technology, especially relates to a novel technology for synthesizing montelukast sodium, the invention also relates to a novel intermediate of the synthesized montelukast sodium. The method has the advantages of cheap raw material and easy acquisition, short synthesis route and simple operation, and is suitable for industrial production.
Description
Technical field
The present invention relates to the synthetic field of medicine, relate in particular to the new midbody of a kind of Menglusitena and utilize this midbody to synthesize the method for Menglusitena.
Background technology
The chemical name of Menglusitena (Montelukast Sodium) is: [R-(E)]-1-[[[1-[3-[2-[7-chloro-2-quinoline] vinyl] phenyl]-3-[2-(1-hydroxyl-1-methylethyl) phenyl] propyl group] sulphur] methyl] cyclopropaneacetic acid list sodium salt, and its structural formula is following:
Menglusitena is a kind of LTRA, can suppress the biosynthesizing of leukotriene, pharmaceutically can be used as Zhichuan agent, anti-allergic agent etc.This compound is open first in the CN1061407A patent by Canadian Mike's Dan Frost company; The preparation method of this compound of describing in this patent is that product acidifying after hydrolysis obtains montelukast free acid with 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(hydroxyl) propyl group) phenyl) propyl alcohol and 1-(thiopurine methyltransferase)-cyclopropaneacetic acid ester reaction.
Synthesizing about Menglusitena in the prior art; How with compound 2-(2-3 (R)-(3-2 (7-chloro-2-quinolyl)-vinyl) phenyl)-3-(hydroxyl) propyl group) phenyl) propyl alcohol or 2-(2-3 (S)-(3-2 (7-chloro-2-quinolyl)-vinyl) phenyl)-3-(hydroxyl) propyl group) phenyl) propyl alcohol is raw material, this compound is again a synthetic on the basis of midbody 2-(2-(3-(2-(7-chloro-2-quinolyl) vinyl) phenyl)-3-oxopropyl) oil of Niobe or 2-(2-(3-(2-(7-chlorine 2-quinolyl) vinyl) phenyl)-3-hydroxypropyl) oil of Niobe.About synthesizing of this type of midbody, several kinds of approach below the report in the prior art:
As at J.Org.Chem.Vol.61; No.10; 1996; Among the 3398-3405, be starting raw material, obtain 2-(2-(3-(2-(7-chloro-2-quinolyl) vinyl) phenyl)-3-oxopropyl) oil of Niobe through the palladium catalytic coupling with 7-chloro-2-vinylquinoline and 2-(3-(3-2-bromomethylphenyl)-3-oxopropyl) oil of Niobe.
In the preparation method F that european patent document EP480717 provides; Be that decarboxylize obtains 2-(2-(3-(2-(7-chloro-2-quinolyl) vinyl) phenyl)-3-oxopropyl) oil of Niobe then with 3-(3-(2-(7-chloro-2-quinolyl) vinyl) phenyl)-3-oxo ethyl propionate and the reaction of iodomethyl oil of Niobe.
Be where to sting with the 7-chloroquine to be raw material and m-terephthal aldehyde reaction generation 3-(2 (E)-2-(7-chloro-quinazoline base) vinyl) phenyl aldehyde in the preparation method k that EP480717 provides; Carry out grignard reaction with vinyl bromination azoviolet; With the reaction of 2-bromo-benzoic acid ethyl ester, obtain 2-(2-(3-(2-(7-chloro-2-quinolyl) vinyl) phenyl)-3-oxopropyl) oil of Niobe then.
Some need use valuable metallic palladium reagent in the compound method of above-mentioned midbody, has strengthened production cost; Some need repeatedly carry out grignard reaction, and complicated condition is harsh, needs strict control, and by product is more; Exist the product that generates to be inappropriate for the problem of long placement simultaneously, be inappropriate for scale operation.
In the prior art; About another important intermediate of Singulair 2-(2-3-(3-2 (7-chloro-2-quinolyl)-vinyl) phenyl)-3-oxopropyl) phenyl) the rare report of compound method of propyl alcohol; This midbody is under the effect of chiral reduction agent; Can optionally obtain needed chirality parent nucleus, so midbody is with a wide range of applications.
The professor Robert H.Crabtree of Yale was at Green Chemistry in 2010; 2010; 12, the 1362-1364 report utilizes benzyl secondary alcohol β position at the benzyl primary alconol under Pottasium Hydroxide or sodium hydroxide effect that good alkylated reaction takes place, and this reaction does not need severe toxicity, expensive heavy metal to make catalyzer; Yield is good, and this reaction formula is following:
Wherein, R
1Be the chlorine atom of para-orientation or the methyl of para-orientation, R
2Be the chlorine atom or the bromine atoms of para-orientation, or the methyl of para-orientation.
The contriver explores through the effort to the Singulair synthesis technique, has found a kind of starting raw material cheap and easy to get, and synthetic route is short, and is simple to operate, can be fit to the synthesis technique that industrialization is produced.
Summary of the invention
The new intermediate and this intermediates preparation that the purpose of this invention is to provide synthetic Menglusitena.
Another object of the present invention provides the novel method of utilizing above-mentioned intermediate preparation Menglusitena.
Adopt route method of the present invention, can synthesize Menglusitena midbody and Menglusitena economical, easily.
The objective of the invention is to realize through following method:
The invention provides new intermediate of a kind of synthetic Menglusitena as shown in the formula I and preparation method thereof,
R wherein
1Be CH
2OH or CHO, preferred CH
2OH; P is a hydroxyl protecting group, is selected from THP trtrahydropyranyl, C
1-C
6Alkyl, C
1-C
6Alkoxyalkyl.
The present invention has also further comprised the preparation method of formula I compound, and this method comprises the steps:
(a). with phthalide and the form reagent C H of formula IV
3The MgX reaction obtains formula V compound:
The reaction medium of this step reaction is selected from C
6～C
8Aromatic hydrocarbons, C
2～C
6Ether or THF, the grignard reagent CH of use
3X is selected from Cl, Br or I among the MgX, phthalide IV and form reagent C H
3The ratio of the amount of substance of MgX is 1: 2.1～3.0, and temperature of reaction is-25 ℃～25 ℃.
(b). with blocking group P ' on the primary hydroxyl of formula V compound, obtain compound as shown in the formula VI:
Wherein, P ' is a hydroxyl protecting group, is selected from C
1-C
4Alkyloyl, benzoyl-or tertiary butyl dimethyl-are silica-based, preferred ethanoyl.
The reaction medium of this step reaction is selected from C
1～C
4Halohydrocarbon; The alkali that uses is organic bases; Be selected from 4-dimethylamino pyridine, 2.6-dimethylamino pyridine, triethylamine, N; N-diisopropylethylamine or Isopropylamine use acetic anhydride, Benzoyl chloride 99min., TERT-BUTYL DIMETHYL CHLORO SILANE that primary hydroxyl is protected, preferred acetic anhydride; Formula V compound is 1: 1.0～3.0 with the amount of substance ratio of acetic anhydride, and temperature of reaction is-25 ℃～25 ℃.
(c). with blocking group P on the tert-hydroxyl of formula VI compound, obtain formula VII compound:
Wherein, the definition of hydroxyl protecting group P ' as previously mentioned, P is a hydroxyl protecting group, is selected from THP trtrahydropyranyl, C
1-C
6Alkyl or C
1-C
6Alkoxyalkyl, preferred THP trtrahydropyranyl.
In this reaction, when hydroxyl protecting group P was THP trtrahydropyranyl, reaction medium was C
1-C
4Halohydrocarbon, use 3,4-dihydro-2H-pyrans is protected tert-hydroxyl, formula VI compound and 3, the ratio of the amount of substance of 4-dihydro-2H-pyrans is 1: 1.2～5.0, temperature of reaction is 20 ℃～30 ℃; When P is C
1-C
6Alkyl or C
1-C
6During alkoxyalkyl, reaction medium is N, and dinethylformamide or THF use C
1-C
6Halogenated alkane, C
1-C
6The alcoxyl halogenated alkane is protected tert-hydroxyl.
(d). the primary hydroxyl of sloughing formula VII compound is protected basic P ', obtains the compound of formula I:
Wherein, R
1Be CH
2OH, the definition of hydroxyl protecting group P is as previously mentioned;
In this step reaction, working as P ' is C
1-C
4When alkyloyl or benzoyl-, reaction medium is the C that contains alkali
1～C
4Alcohol, said alkali is selected from salt of wormwood, saleratus or yellow soda ash, formula VII compound is 1: 1.2～2.0 with the ratio of the amount of substance of alkali, temperature of reaction is 20 ℃～30 ℃; When P ' is that tertiary butyl dimethyl-is when silica-based; Reaction medium is a THF; Deprotecting regent is selected from the hydrochloric acid of tetrabutyl ammonium fluoride or 2-6 mol; The hydrochloric acid of preferred 4 mol, the mass volume ratio of the hydrochloric acid of formula VII compound and 4 mol are 1: 0.2～2 (grams per milliliters), and temperature of reaction is 0 ℃～30 ℃.
(e). optionally, the primary hydroxyl oxidation with step (d) gained formula I compound obtains formula I compound:
Wherein, R
1Be CHO, the definition of hydroxy-protective group P as previously mentioned.
The present invention also further provides the method by the compound of the following formula III of formula I intermediate preparation, and wherein the formula III compound can be further used for preparing Menglusitena,
This method comprises:
(a). with the compound of formula I
Compound with formula IIa
Or the compound of formula IIb
In the presence of alkali, react, obtain containing mixture as shown in the formula IIc and formula IId:
Wherein, R
1Be CH
2OH, P is a hydroxyl protecting group, is selected from THP trtrahydropyranyl, C
1-C
6Alkyl or C
1-C
6Alkoxyalkyl; The reaction medium of this reaction is C
6～C
8Aromatic hydrocarbons, preferred toluene; The alkali that uses is sodium hydroxide, Pottasium Hydroxide, sodium tert-butoxide or potassium tert.-butoxide, preferred Pottasium Hydroxide; The compound of reaction Chinese style I is 1: 1.0～1.1 with the ratio of the amount of substance of formula IIa or formula IIb compound, and temperature of reaction is 110 ℃～175 ℃.
(b). step (a) gained mixture is further carried out oxidizing reaction through oxygenant, obtain compound as shown in the formula IIc:
The reaction medium of this reaction is C
1～C
4Halohydrocarbon, preferred methylene dichloride, the oxidizing reaction oxygenant is selected from silver suboxide, Manganse Dioxide, methyl-sulphoxide, 2-iodoxy phenylformic acid, Dai Si-Martin's oxygenant, 2; 2; 6,6-tetramethyl piperidine-oxyradical, Rosensthiel's green, Textone or chromium trioxide, preferred Dai Si-Martin's oxygenant; Step (a) gained formula IId compound is 1: 1.2～3.0 with the ratio of the amount of substance of Dai Si-Martin's oxygenant, and temperature of reaction is 0 ℃～40 ℃.
(c). step (b) gained formula II c compound is sloughed hydroxyl protecting group P, obtain the compound of following formula III;
In this step reaction; Can adopt conventional method to slough hydroxyl protecting group; For example add deprotecting regent, deprotecting regent can be selected from toluene pyridine-sulfonic acid drone salt, acetic acid, hydrochloric acid, tosic acid, triphenylphosphine hydrobromate, magnesium bromide, boric acid, BFEE or borine, also can use acid macroporous resin; Preferably to toluene pyridine-sulfonic acid drone salt, step (b) gained formula IIc compound is 1: 0.2～0.5 with ratio to the amount of substance of toluene pyridine-sulfonic acid drone salt.
The present invention also provides the method for midbody compound of the Menglusitena of other a kind of intermediate preparation formula III that utilizes formula I,
This method comprises:
(a). with the compound of formula I
Compound with formula IIa
In the presence of alkali, react, obtain containing mixture as shown in the formula IIc and formula IId:
Wherein, R
1Be CHO, P is a hydroxyl protecting group, is selected from THP trtrahydropyranyl, C
1-C
6Alkyl or C
1-C
6Alkoxyalkyl.The reaction medium of this reaction is C
6～C
8Aromatic hydrocarbons, preferred toluene; The alkali that uses is sodium hydroxide, Pottasium Hydroxide, sodium tert-butoxide or potassium tert.-butoxide, preferred Pottasium Hydroxide; The compound of reaction Chinese style I is 1: 1.0～1.1 with the ratio of the amount of substance of formula IIa compound, and temperature of reaction is 110 ℃～175 ℃.
(b). step (a) gained mixture is further carried out oxidizing reaction through oxygenant, obtain compound as shown in the formula IIc:
The reaction medium of this reaction is C
1～C
4Halohydrocarbon or C
6～C
8Aromatic hydrocarbons; The oxidizing reaction oxygenant is selected from silver suboxide, Manganse Dioxide, methyl-sulphoxide, 2-iodoxy phenylformic acid, Dai Si-Martin's oxygenant, 2,2,6; 6-tetramethyl piperidine-oxyradical, Rosensthiel's green, Textone or chromium trioxide, preferred Dai Si-Martin's oxygenant; Step (a) gained formula IId compound is 1: 1.2～3.0 with the ratio of the amount of substance of Dai Si-Martin's oxygenant, and temperature of reaction is 0 ℃～40 ℃.
(c). step (b) gained formula IIc compound thing is sloughed hydroxyl protecting group P, obtain the compound of formula III;
Can adopt conventional method to slough hydroxyl protecting group; For example add deprotecting regent; Deprotecting regent is optional to toluene pyridine-sulfonic acid drone salt, acetic acid, hydrochloric acid, tosic acid, triphenylphosphine hydrobromate, magnesium bromide, boric acid, BFEE or borine; Also can use acid macroporous resin, preferably to toluene pyridine-sulfonic acid drone salt, step (b) gained formula IIc compound is 1: 0.2～0.5 with ratio to the amount of substance of toluene pyridine-sulfonic acid drone salt.
The present invention also provides-kind of the novel method that will be synthesized Menglusitena by the midbody compound of formula III, and this method may further comprise the steps:
Wherein, L is a leavings group, preferred methylsulfonyl or p-toluenesulfonyl.
This method is to be raw material with formula (III) compound; Obtain chipal compounds (VIII) through the reductive agent selective reduction; The secondary hydroxyl of compound (VIII) is converted into leavings group; Obtain formula (IX) compound; Formula (IX) compound and 1-thiopurine methyltransferase cyclopropyl acetate (X) reaction obtain 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) cyclopropyl acetate (XI), and montelukast acid that obtains (XI) and sodium hydroxide reaction are further changed into target compound Menglusitena (XII).
Further specify in the face of this method down:
Method of the present invention comprises the steps:
(a). prepare the formula III compound according to preceding method:
(b). step (a) gained formula III compound through the reductive agent selective reduction, is obtained formula VIII compound:
(c). the secondary hydroxyl in the formula VIII compound is converted into leavings group, obtains formula IX compound
Wherein, L is a leavings group, preferred methylsulfonyl or p-toluenesulfonyl;
(d). with formula IX compound and the reaction of formula X compound, obtain formula XI compound:
(e). formula XI compound and NaOH reaction are obtained the XII compound:
Reductive agent is selected from (-)-diisopinocampheylchloroborane base chloroborane in this method steps (b), and compound (III) is 1: 1.0～3.0 with the ratio of the amount of substance of (-)-diisopinocampheylchloroborane base chloroborane, and preferred 1: 2.0～2.5.Temperature of reaction is-25 ℃～80 ℃, and preferred-15 ℃～25 ℃, reaction medium is C
1～C
4Halohydrocarbon, preferred methylene dichloride.
In the step of the present invention (c), compound (VIII) is 1: 1.05～2.0 with the amount of substance ratio of methylsulfonyl chloride or Tosyl chloride, preferred 1: 1.1～1.5; Compound in the reaction (VIII) and alkali N, the amount of substance ratio of N-diisopropylethylamine is 1: 1.2～2.5, preferred 1: 1.5～2.0; Reaction medium is C
1～C
4Halohydrocarbon, C
6～C
8Aromatic hydrocarbons or C
2～C
6Nitrile; Temperature of reaction is-50 ℃～80 ℃, preferred-25 ℃～25 ℃.
In the step of the present invention (d), compound (IX) is 1: 1.05～2.0 with the amount of substance ratio of formula (X) compound, preferred 1: 1.1～1.2; Compound in the reaction (IX) is 1: 2.5～5.0 with the amount of substance of cesium carbonate, preferred 1: 2.5～3.5; Catalysts is polyoxyethylene glycol-400, polyoxyethylene glycol-600 or 18-hat-6 ethers, preferred polyoxyethylene glycol-400, and compound in the reaction (IX) is 1: 0.1～10 with the mass ratio of catalyzer, preferred 1: 0.5～2.0; Reaction medium is C
2-C
6Alkane ether or C
1～C
4Alkane acid amides, temperature of reaction are-50 ℃～25 ℃.
In the step of the present invention (e), reaction Chinese style (XI) compound is 1: 1.05～1.1 with the amount of substance ratio of NaOH, preferred 1: 1.05; Solvent is selected from C
1～C
4Alcohol, particular methanol; Temperature of reaction is 0～50 ℃.
Further specify the present invention through embodiment below.Mandatory declaration, following embodiment is used to explain the present invention rather than limitation of the present invention.
Embodiment 1: [2-[1-methyl isophthalic acid-(tetrahydropyrans-2-oxygen base) ethyl] phenyl]-methyl alcohol synthetic
The first step: in-15 ℃ of ice baths, in three mouthfuls of round-bottomed flasks of 2000 milliliters, add 50 gram phthalides, 200 milliliters of THFs, nitrogen protection slowly drips 400 milliliters of CH then
3The tetrahydrofuran solution of MgCl (2.0 mol) dripped off in 2 hours, slowly was warming up to room temperature then, after 4 hours reaction solution was poured in the flask that 500 milliliters of saturated ammonium chloride frozen water solution are housed; Stir, with ETHYLE ACETATE (4 * 200 milliliters) extraction, combined ethyl acetate layer; With 10% salt solution (3 * 200 milliliters) washing, add dried over mgso, the rotation solvent evaporated; Vacuum-drying 4 hours gets white waxy solid 57 grams, yield 92.0%.
1H?NMR(400MHz，CDCl
3)：δ1.59(s，6H)，4.52(s，2H)，4.71(s，2H)，7.27-7.17(m，4H)。
Second step: waxy solid 55 grams that the first step reaction is obtained are dissolved in 115 milliliters of methylene dichloride, add 100 milliliters of triethylamines, slowly splash into 38 milliliters of acetic anhydride then under the ice bath; Reacted 2 hours, reaction is finished, and dry dichloromethane is revolved in decompression earlier; Add 200 milliliters of saturated sodium hydrogen carbonate solutions then, with ETHYLE ACETATE (4 * 200 milliliters) extraction, combined ethyl acetate layer; Wash with saturated brine (3 * 200 milliliters); Add dried over mgso, the rotation solvent evaporated gets oily matter, directly is used for next step.
1H?NMR(400M?Hz，CDCl
3)：δ1.64(s，6H)，2.08(s，3H)，5.53(s，2H)，7.24-7.27(m，2H)，7.35-7.41(m，2H)。
The 3rd step: under the room temperature, oily matter 17 grams that the second step reaction is obtained are dissolved in 34 milliliters of methylene dichloride, add 3,11.2 milliliters of 4-dihydros-2H-pyrans; Add again toluene pyridine-sulfonic acid drone salt 1.0 grams, react after 4 hours, add 100 ml waters, standing demix; Water is with methylene dichloride (2 * 50 milliliters) extraction, and the combined dichloromethane layer washs with saturated brine (3 * 200 milliliters); Add dried over mgso, the rotation solvent evaporated gets oily matter, directly is used for next step.
1H?NMR(400M?Hz，CDCl
3)：δ1.41-1.55(m，6H)，1.63(s，3H)，1.73(s，3H)，2.10(s，3H)，3.34-3.40(m，1H)，3.89-3.94(m，1H)，4.71-4.49(m，1H)，5.49-5.59(m，2H)，7.25-7.30(m，2H)，7.31-7.41(m，2H)。
The 4th step: the oily matter that three-step reaction is obtained is dissolved in 35 milliliters of anhydrous methanols, adds salt of wormwood 7.3 grams under the room temperature, reacts 2 hours; The first evaporate to dryness methyl alcohol that reduces pressure adds 50 ml waters then, extracts with ETHYLE ACETATE (3 * 40 milliliters); The combined ethyl acetate layer; With the saturated brine washing, add dried over mgso, the rotation solvent evaporated gets the oily title compound.
1H?NMR(400MHz，CDCl
3)：δ1.41-1.55(m，6H)，1.65(s，3H)，1.69(s，3H)，3.33-3.38(m，1H)，3.89-3.92(m，1H)，4.58-4.65(m，1H)，4.62-4.65(d，1H，J＝11.7Hz)，5.15-5.18(d，1H，J＝11.7Hz)，7.25-7.30(m，2H)，7.31-7.41(m，2H)。
Embodiment 2: [2-[1-methyl isophthalic acid-(methoxyl group) ethyl] phenyl]-methyl alcohol synthetic
The first step: with the first step of embodiment 1.
Second step: resulting waxy solid 55 grams of the first step are dissolved in 115 milliliters of methylene dichloride, add 100 milliliters of triethylamines, 4-Dimethylamino pyridine 0.4 gram; Slowly splash into TERT-BUTYL DIMETHYL CHLORO SILANE 62.5 grams that are dissolved in 50 milliliters of methylene dichloride then under the ice bath, reacted 4 hours, reaction is finished; Add 200 milliliters of saturated sodium hydrogen carbonate solutions, layering, water layer is used methylene dichloride (2 * 150 milliliters) extraction again; The combined dichloromethane layer with saturated brine (3 * 200 milliliters) washing, adds dried over mgso; The rotation solvent evaporated gets oily matter, directly is used for next step.
The 3rd step: under the room temperature, get oily matter 28 grams that part second step obtains and be dissolved in 100 milliliters of N, in the dinethylformamide, slowly add sodium hydride 8 grams (60% sodium hydride) under the ice bath; Stirring is 30 minutes after adding, and slowly drips 7.0 milliliters of methyl iodide again, reacts to add 100 milliliters of entry, layering after 10 hours; Water merges with ETHYLE ACETATE (2 * 150 milliliters) extraction, washs with saturated brine (3 * 200 milliliters); Add dried over mgso, the rotation solvent evaporated gets oily matter, directly is used for next step.
The 4th step: get oily matter 30 grams that part the 3rd step obtains and be dissolved in 100 milliliters of THFs, add 14 milliliters of the hydrochloric acid of 4 mol under the room temperature, reacted 8 hours; Add 100 ml waters then; With ETHYLE ACETATE (3 * 100 milliliters) extraction, merge, wash with saturated brine; Add dried over mgso, the rotation solvent evaporated gets oily matter.Column chromatography silica gel separates to such an extent that title product [2-[1-methyl isophthalic acid-(methoxyl group) ethyl] phenyl]-methyl alcohol 5.0 restrains.
Synthesizing of embodiment 3:1-[3-[2-(7-chloro-2-quinolyl)-vinyl] phenyl]-3-[2-(1-hydroxyl-1-methyl) ethylphenyl]-propane-1-ketone (formula III compound)
[3-[2-(7-chloro-2-quinolyl) ethenylphenyl]-ethanol 3.09 grams is dissolved in 20 milliliters of toluene, adds [2-[1-methyl isophthalic acid-(tetrahydropyrans-2-oxygen base) ethyl] phenyl]-methyl alcohol 3.0 grams again to get 1-; Pottasium Hydroxide 1.2 grams, reflux 6 hours is after the reaction; Add 100 milliliters of saturated NH4Cl solution, with ETHYLE ACETATE (3 * 40 milliliters) extraction, combined ethyl acetate layer; With the saturated brine washing, add dried over mgso, solvent evaporated gets oily matter.This oily matter is dissolved in 20 milliliters of methylene dichloride, adds Dai Si-Martin's oxygenant 4.2 grams under the room temperature, react after 4 hours diatomite filtration; Revolve dried solvent, add 20 ml methanol again, add 0.75 gram to toluene pyridine-sulfonic acid drone salt, room temperature reaction is evaporate to dryness methyl alcohol after 10 hours; Add 30 milliliters of entry again, with ETHYLE ACETATE (3 * 30 milliliters) extraction, combined ethyl acetate layer; With saturated brine (3 * 20 milliliters) washing, add dried over mgso, the rotation solvent evaporated gets oily matter.Add 6 milliliters of ETHYLE ACETATE again and dissolve clearly, slowly splash into 6 ml n-hexanes then, separate out white solid 3.0 grams, yield is 65%,
1HNMR (400MHz, CDCl
3): δ 1.72 (s, 6H), 2.47 (s, 1H), 3.45 (s, 4H), 7.18-8.30 (m, 15H).
Synthesizing of embodiment 4:2-(2-(3-(2-(7-chloro-2-quinolyl)-ethenylphenyl)-3-hydroxypropyl) phenyl)-2-propyl alcohol (formula VIII)
With 1-[3-[2-(7-chloro-2-quinolyl)-vinyl] phenyl]-3-[2-(1-hydroxyl-1-methyl) ethylphenyl]-propane-1-ketone 45.5 grams, 900 milliliters of methylene dichloride, N is in 35 milliliters of adding reaction flasks of N-diisopropylethylamine; Place reaction flask-15 ℃ of ice baths to stir 30 minutes, slowly splash into 148 milliliters of (-)-diisopinocampheylchloroborane base chloroboranes (60% n-heptane solution) again, drip off in 30 minutes, drip and finish; Continue reaction 8 hours, reaction slowly is warming up to 25 ℃ after finishing, and adds 25 milliliters of triethylamines and stirs 2 hours; Add 500 milliliters of saturated nacl aqueous solutions, leave standstill, tell dichloromethane layer, water layer extracts with methylene dichloride (2 * 300 milliliters); The combined dichloromethane layer, with saturated brine (2 * 200 milliliters) washing, the rotation solvent evaporated gets oily matter, adds 250 milliliters of toluene under the room temperature; 55 ℃ dissolve and slowly to be cooled to stirring at room again 12 hours after clear, filter, and filter cake is washed 2 times with 50 milliliters of normal heptanes; 45～50 ℃ of drying under reduced pressure get title product 43.5 grams, and yield is 95.2%.
Embodiment 5: montelukast acid (formula XI compound) synthetic
2-(2-(3-(2-(7-chloro-2-quinolyl)-ethenylphenyl)-3-hydroxypropyl) phenyl)-2-propyl alcohol 15 grams are added in the reaction flask after being dissolved in 80 milliliters of toluene, add N, 8.0 milliliters of N-diisopropylethylamine; Be cooled to-25 ℃, slowly splash into 3.3 milliliters of methylsulfonyl chlorides again, dripped off in 20 minutes; After dripping off, temperature of reaction slowly rises to room temperature, reacts after 4 hours; Filter, filter cake is washed with 20 milliliters of ice acetonitriles, then solid is dissolved in 40 milliliters of THFs.
In another flask, add 1-thiopurine methyltransferase cyclopropyl acetate 4.8 grams, cesium carbonate 32 grams and 7.5 gram polyoxyethylene glycol-400, add 40 milliliters of N again, dinethylformamide; Stir under the room temperature after 1 hour, under-15 ℃ of temperature, above-mentioned 40 milliliters tetrahydrofuran solution is added in this reaction flask then; Temperature of reaction slowly rises to room temperature then, reacts after 8 hours, adds 100 milliliters of 1M hydrochloric acid; With ETHYLE ACETATE (3 * 50 milliliters) extraction, the combined ethyl acetate layer is with the washing of ice saturated brine; Add anhydrous magnesium sulfate drying, filter, solvent evaporated gets oily matter.This oily matter is dissolved in 90 milliliters of ETHYLE ACETATE, 50 ℃ dissolve clear after, be cooled to room temperature, slowly splash into 90 ml n-hexanes again, separate out yellow solid compound 15.4 grams, yield is 80.2%, HPLC detects the content of montelukast acid greater than 96.7%.
Above-mentioned montelukast acid 15 grams are used toluene respectively, behind the methyl alcohol purifying, get product 10.2 grams, yield is 68.2%, and HPLC detects the content of montelukast acid greater than 99.5%.
Embodiment 6: Menglusitena (formula XII compound) synthetic
Under the room temperature, with sodium hydroxide 0.35 gram, methyl alcohol adds in the round-bottomed flask for 25 milliliters, stirs 15 minutes.Then this alkali lye is joined in 25 ml methanol that are dissolved with 5 gram montelukast acids, stirring reaction 30 minutes adds activated carbon 0.5 gram then; Stirred 30 minutes, diatomite filtration then, filtrating is revolved dried; 70 ℃ of vacuum-dryings got product 5.1 grams in 7 hours; Yield is 98.0%, HPLC >=99.5%, isomer >=99.5%.
Claims (13)
1. compound of representing with formula I:
Wherein, R
1Be selected from CH
2OH or CHO, P is a hydroxyl protecting group, is selected from THP trtrahydropyranyl, C
1-C
6Alkyl or C
1-C
6Alkoxyalkyl.
2. formula I compound according to claim 1, wherein, R
1Be CH
2OH, P are THP trtrahydropyranyls.
3. method for preparing the described formula I compound of claim 1, this method comprises:
(a). with phthalide and the grignard reagent CH of formula IV
3The MgX reaction obtains formula V compound:
Wherein, X is selected from Cl, Br or I by oneself;
(b). with blocking group P ' on the primary hydroxyl of formula V compound, obtain formula VI compound:
Wherein, P ' is a hydroxyl protecting group, is selected from C
1-C
4Alkyloyl, benzoyl-or tertiary butyl dimethyl-are silica-based;
(c). with blocking group P on the tert-hydroxyl of formula VI compound, obtain formula VII compound:
Wherein, the definition of hydroxyl protecting group P ' as previously mentioned, P is a hydroxyl protecting group, is selected from THP trtrahydropyranyl, C
1-C
6Alkyl or C
1-C
6Alkoxyalkyl;
(d). slough the primary hydroxyl blocking group P ' of formula VII compound, obtain formula I compound:
Wherein, R
1Be CH
2OH, the definition of hydroxy-protective group P is as previously mentioned;
(e). optionally, the primary hydroxyl oxidation with step (d) gained formula I compound obtains formula I compound:
Wherein, R
1Be CHO, the definition of hydroxy-protective group P as previously mentioned.
4. according to the method for claim 3, wherein, P ' is an ethanoyl, and P is a THP trtrahydropyranyl.
5. according to the method for claim 3 or 4, wherein, reactions step (b) is carried out in the presence of solvent and alkali.
6. method according to claim 5, wherein, said solvent is C
1～C
4Halohydrocarbon, said alkali is selected from 4-dimethylamino pyridine, 2,6-dimethylamino pyridine, triethylamine, N, N-diisopropylethylamine or Isopropylamine.
7. method for preparing the compound of formula III,
This method comprises:
(a). with the compound of formula I
Compound with formula IIa
Or the compound of formula IIb
In the presence of alkali, react, obtain containing mixture as shown in the formula IIc and formula IId:
(b). step (a) gained mixture is further carried out oxidizing reaction through oxygenant, obtain compound as shown in the formula IIc:
(c). step (b) gained formula IIc compound is sloughed hydroxyl protecting group P, obtain the compound of formula III;
Wherein, R
1Be CH
2OH, P is a hydroxyl protecting group, is selected from THP trtrahydropyranyl, C
1-C
6Alkyl or C
1-C
6Alkoxyalkyl.
8. method for preparing the compound of formula III
This method comprises:
(a). with the compound of formula I
Compound with formula IIa
In the presence of alkali, react, obtain containing mixture as shown in the formula IIc and formula IId:
(b). step (a) gained mixture is further carried out oxidizing reaction through oxygenant, obtain compound as shown in the formula IIc:
(c). step (b) gained formula IIc compound is sloughed hydroxyl protecting group P, obtain the compound of formula III;
Wherein, R
1Be selected from CHO, P is a hydroxyl protecting group, is selected from THP trtrahydropyranyl, C
1-C
6Alkyl or C
1-C
6Alkoxyalkyl.
9. according to the method for claim 7 or 8, wherein, said alkali is selected from sodium hydroxide, Pottasium Hydroxide, sodium tert-butoxide or potassium tert.-butoxide, preferred Pottasium Hydroxide.
10. according to the method for claim 7 or 8; Wherein, Said oxygenant is selected from silver suboxide, Manganse Dioxide, methyl-sulphoxide, 2-iodoxy phenylformic acid, Dai Si-Martin's oxygenant, 2,2,6; 6-tetramethyl piperidine-oxyradical, Rosensthiel's green, Textone or chromium trioxide, preferred Dai Si-Martin's oxygenant.
11. a method for preparing the Menglusitena of formula XII,
This method comprises:
(a). prepare the formula III compound according to claim 7 or 8 said methods:
(b). step (a) gained formula III compound through the reductive agent selective reduction, is obtained formula VIII compound:
(c). the secondary hydroxyl in step (b) the gained formula VIII compound is converted into leavings group, obtains formula IX compound:
Wherein, L is a leavings group;
(d). with step (c) gained formula IX compound and the reaction of formula X compound, obtain formula XI compound:
(e). step (d) gained formula XI compound and NaOH are reacted the Menglusitena that obtains formula XII:
12. according to the method for claim 11, wherein, said reductive agent is (-)-diisopinocampheylchloroborane base chloroborane, said leavings group L is selected from methylsulfonyl or p-toluenesulfonyl.
13. the purposes of the described formula I compound of claim 1 in preparation Singulair or its pharmacy acceptable salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102829523A CN102424673B (en) | 2011-09-14 | 2011-09-14 | Montelukast sodium intermediate and method for synthesizing montelukast sodium thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102829523A CN102424673B (en) | 2011-09-14 | 2011-09-14 | Montelukast sodium intermediate and method for synthesizing montelukast sodium thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102424673A true CN102424673A (en) | 2012-04-25 |
| CN102424673B CN102424673B (en) | 2013-12-04 |
Family
ID=45958709
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011102829523A Active CN102424673B (en) | 2011-09-14 | 2011-09-14 | Montelukast sodium intermediate and method for synthesizing montelukast sodium thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102424673B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103073492A (en) * | 2013-02-04 | 2013-05-01 | 中国科学院上海有机化学研究所 | Synthesis method of 2-(3-(S)-(3-(2-7-chlorine-2-quinolyl) vinyl) phenyl)-3-hydroxypropyl) benzoate |
| CN104592111A (en) * | 2015-02-13 | 2015-05-06 | 江苏欧信医药化工有限公司 | Synthesis method of montelukast intermediate |
| CN105541711A (en) * | 2016-02-22 | 2016-05-04 | 齐鲁天和惠世制药有限公司 | Preparation method of montelukast |
| CN105541710A (en) * | 2016-02-22 | 2016-05-04 | 齐鲁天和惠世制药有限公司 | Synthesis method for montelukast |
| CN108069863A (en) * | 2016-11-17 | 2018-05-25 | 武汉武药制药有限公司 | A kind of method for synthesizing norepinephrine |
| CN109970822A (en) * | 2017-12-27 | 2019-07-05 | 上海科胜药物研发有限公司 | A kind of preparation method synthesizing the net intermediate of Ai Gelie |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5525736A (en) * | 1991-11-06 | 1996-06-11 | Ciba-Geigy Corporation | Process for the production of cyclic sulfonium salts |
| WO2010148209A2 (en) * | 2009-06-19 | 2010-12-23 | Dr. Reddy's Laboratories Ltd. | Preparation of montelukast |
-
2011
- 2011-09-14 CN CN2011102829523A patent/CN102424673B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5525736A (en) * | 1991-11-06 | 1996-06-11 | Ciba-Geigy Corporation | Process for the production of cyclic sulfonium salts |
| WO2010148209A2 (en) * | 2009-06-19 | 2010-12-23 | Dr. Reddy's Laboratories Ltd. | Preparation of montelukast |
Non-Patent Citations (3)
| Title |
|---|
| 《Green Chem.》 20100629 Laura J. Allen et al. Green alcohol coupling without transition metal catalysts：base-mediated beta-alkylation of alcohols in aerobic conditions 第1362-1364页 第12卷, * |
| LAURA J. ALLEN ET AL.: "Green alcohol coupling without transition metal catalysts：base-mediated β-alkylation of alcohols in aerobic conditions", 《GREEN CHEM.》 * |
| 陈瀛等: "孟鲁司特纳合成路线图解", 《中国医药工业杂志》 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103073492A (en) * | 2013-02-04 | 2013-05-01 | 中国科学院上海有机化学研究所 | Synthesis method of 2-(3-(S)-(3-(2-7-chlorine-2-quinolyl) vinyl) phenyl)-3-hydroxypropyl) benzoate |
| CN104592111A (en) * | 2015-02-13 | 2015-05-06 | 江苏欧信医药化工有限公司 | Synthesis method of montelukast intermediate |
| CN104592111B (en) * | 2015-02-13 | 2015-11-11 | 江苏欧信医药化工有限公司 | A kind of synthetic method of montelukast sodium intermediate |
| CN105541711A (en) * | 2016-02-22 | 2016-05-04 | 齐鲁天和惠世制药有限公司 | Preparation method of montelukast |
| CN105541710A (en) * | 2016-02-22 | 2016-05-04 | 齐鲁天和惠世制药有限公司 | Synthesis method for montelukast |
| CN105541711B (en) * | 2016-02-22 | 2018-06-19 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of montelukast |
| CN105541710B (en) * | 2016-02-22 | 2018-06-19 | 齐鲁天和惠世制药有限公司 | A kind of synthetic method of montelukast |
| CN108069863A (en) * | 2016-11-17 | 2018-05-25 | 武汉武药制药有限公司 | A kind of method for synthesizing norepinephrine |
| CN108069863B (en) * | 2016-11-17 | 2020-08-11 | 武汉武药制药有限公司 | Method for synthesizing norepinephrine |
| CN109970822A (en) * | 2017-12-27 | 2019-07-05 | 上海科胜药物研发有限公司 | A kind of preparation method synthesizing the net intermediate of Ai Gelie |
| CN109970822B (en) * | 2017-12-27 | 2023-03-28 | 上海科胜药物研发有限公司 | Preparation method for synthesizing emamectin benzoate intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102424673B (en) | 2013-12-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102424673B (en) | Montelukast sodium intermediate and method for synthesizing montelukast sodium thereof | |
| JP4114754B2 (en) | Process for producing 1-substituted-3-fluoroalkylpyrazole-4-carboxylic acid ester | |
| CN102952157A (en) | Intermediates for synthesis of benzindene prostaglandins and preparations thereof | |
| CN101945861A (en) | A kind of preparation method of benzamide compound | |
| CN106928227A (en) | The synthetic method and its midbody compound of Entecavir | |
| JP2007326784A (en) | Method for producing 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester | |
| CN107250102A (en) | The method that benzidine is prepared by azobenzene is catalyzed by ruthenium | |
| EP2298756B1 (en) | Method for producing 3-methyl-2-thiophenecarboxylic acid | |
| CN107629064B (en) | A kind of synthetic method of Azacyclooctane and Furanones compound | |
| CN113788777A (en) | Method for preparing 1-substituted-3-carbonyl pyrrole | |
| CN106831863A (en) | Montelukast sodium intermediate and its preparation method and application | |
| JPS6357580A (en) | 2,3-dihydrofuran derivative, manufacture and use for manufacturing tetrahydrofuran as intermediate | |
| CN105732339B (en) | Dapoxetine hydrochloride intermediate and preparation method thereof | |
| JP2000169407A (en) | Production of 3-butene-1-ol derivative | |
| Azzena et al. | Reductive lithiation of alkoxy-substituted benzyl methyl ethers and connection with cross-coupling reactions | |
| CN105646414A (en) | Synthetic method of 6-hydroxyl-2-methylbenzofuran type compound | |
| JP4159784B2 (en) | Method for producing 2,3-disubstituted thiophene derivatives | |
| JP4162891B2 (en) | Method for producing tetrahydrothiophene derivative | |
| JP4374287B2 (en) | Process for producing (Z) -1-phenyl-1-diethylaminocarbonyl-2-hydroxymethylcyclopropane | |
| WO2021038586A1 (en) | Improved process for the preparation of tezacaftor intermediate | |
| JP2000336066A (en) | Preparation of 2-(4-methylphenyl)benzoic acid derivative | |
| JP4038837B2 (en) | Process for producing fluorine-containing indole, benzofuran and benzothiophene derivatives | |
| CN111848552A (en) | Preparation method and application of 3- (substituted phenyl) oxetane-3-carboxylic acid and intermediate thereof | |
| CN104109123B (en) | For midbody compound synthesizing montelukast and preparation method thereof | |
| TW202316967A (en) | Process for preparing isoxazolinecarboxylic acid derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |