CN114605282A - Preparation method of montelukast sodium side chain intermediate - Google Patents
Preparation method of montelukast sodium side chain intermediate Download PDFInfo
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- CN114605282A CN114605282A CN202210282384.5A CN202210282384A CN114605282A CN 114605282 A CN114605282 A CN 114605282A CN 202210282384 A CN202210282384 A CN 202210282384A CN 114605282 A CN114605282 A CN 114605282A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical group [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 71
- YAINYZJQSQEGND-UHFFFAOYSA-N [1-(hydroxymethyl)cyclopropyl]methanol Chemical compound OCC1(CO)CC1 YAINYZJQSQEGND-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 19
- WYOMLUMUVAPMKE-UHFFFAOYSA-N 2-[1-(hydroxymethyl)cyclopropyl]acetonitrile Chemical compound N#CCC1(CO)CC1 WYOMLUMUVAPMKE-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- 229940125782 compound 2 Drugs 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 14
- 229940126214 compound 3 Drugs 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 claims description 9
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims description 9
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 9
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 claims description 8
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229960001951 montelukast sodium Drugs 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 238000011282 treatment Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 4
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 3
- VFAXPOVKNPTBTM-UHFFFAOYSA-N 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid Chemical compound OC(=O)CC1(CS)CC1 VFAXPOVKNPTBTM-UHFFFAOYSA-N 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- MXCOXRCQSNVLRE-UHFFFAOYSA-M C(C)(=O)[O-].[Na+].C1CC1 Chemical compound C(C)(=O)[O-].[Na+].C1CC1 MXCOXRCQSNVLRE-UHFFFAOYSA-M 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 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
- 239000006227 byproduct Substances 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 208000024695 exercise-induced bronchoconstriction Diseases 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/16—Preparation of carboxylic acid nitriles by reaction of cyanides with lactones or compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/10—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms two oxygen atoms and one sulfur atom, e.g. cyclic sulfates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Toxicology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of medicines, in particular to the technical field of pharmacy, and more particularly relates to a preparation method of a montelukast sodium side chain intermediate, wherein 1-hydroxymethyl cyclopropyl acetonitrile can be prepared by taking 1, 1-cyclopropane dimethanol as a raw material only through two steps, so that the preparation process steps are greatly simplified, and the preparation method has important significance for industrial popularization. Meanwhile, in the synthetic route disclosed by the invention, the target product has high yield and high purity, does not need a complex post-treatment process, and is suitable for large-scale industrial production. Finally, the reaction conditions of the invention are simple and easy to realize, and the synthesis cost is low.
Description
Technical Field
The invention relates to the field of medicines, in particular to the technical field of pharmacy, and more particularly relates to a preparation method of a montelukast sodium side chain intermediate.
Background
Montelukast sodium, an antiasthmatic, anti-inflammatory and antiallergic agent, is used for the prevention and long-term treatment of asthma, including the prevention of daytime and nighttime asthma symptoms, the treatment of aspirin-sensitive asthmatics and the prevention of exercise-induced bronchoconstriction. The chemical name is 1- [ [ [ (1R) -1- [3- [ (1E) -2- (7-chloro-2-quinoline) ethenyl ] phenyl ] -3- [2- (1-hydroxy-1-methylethyl) phenyl ] propyl ] thio ] methyl ] cyclopropane sodium acetate, the structural formula is as follows:
it can be seen from the structural formula that 1- (mercaptomethyl) cyclopropylacetic acid or its derivative of the side chain moiety is a key intermediate for the synthesis of montelukast sodium. At present, the synthesis of 1- (mercaptomethyl) cyclopropylacetic acid by 1-hydroxymethylcyclopropylacetonitrile is a mature technology, so that the synthesis of 1-hydroxymethylcyclopropylacetonitrile serving as a key intermediate has important influence on the preparation of 1- (mercaptomethyl) cyclopropylacetic acid and the industrial synthesis of montelukast sodium.
How to improve the synthesis yield of the 1-hydroxymethyl cyclopropyl acetonitrile and reduce the synthesis cost is a research hotspot of technicians in the field. For example, US7271268 reports a process for the preparation of 1-hydroxymethylcyclopropylacetonitrile: 1, 1-cyclopropyl dimethanol is used as a raw material, and is subjected to HBr/HOAc esterification and two-step conversion to prepare 1-hydroxymethyl cyclopropyl acetonitrile, wherein the specific route is as follows:
in the reaction, because the esterification reaction product is a mixture, the product needs to be further separated by a rectification mode, so that the complexity of the synthesis process is increased, a large amount of reaction raw material glycol is lost, and the synthesis cost is increased.
Disclosure of Invention
The technical problem to be solved by the invention is how to improve the yield of a target product, reduce the raw material loss caused by byproducts, simplify the synthesis process and reduce the cost loss caused by the separation of a mixture product in the process of preparing 1-hydroxymethyl cyclopropyl acetonitrile by taking 1, 1-cyclopropane dimethanol as a raw material.
In order to solve the technical problem, the invention discloses a preparation method of a montelukast sodium side chain intermediate, which takes 1, 1-cyclopropane dimethanol (compound 3) as a raw material to prepare 1-hydroxymethyl cyclopropyl acetonitrile (compound 1) by a two-step method, and the preparation route is as follows:
the first step is as follows:
the second step is that:
wherein R is SO2、CMe2Or CO.
More preferably, the feeding molar ratio of the compound 2 to the cyaniding agent is 1 (0.5-1.8), and the preferred ratio is 1: 1.2. The feeding molar ratio includes, but is not limited to, 1:0.5, 1:0.6, 1:0.8, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.5, 1:1.6, and 1: 1.8.
Further preferably, compound 2 is reacted with a cyanating reagent in the presence of ethanol and tetrabutylammonium bromide.
Further preferably, the reaction temperature of the compound 2 and the cyanating agent is 60 to 150 ℃, and preferably 90 ℃. Here, the reaction temperature includes, but is not limited to, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃, 100 ℃, 105 ℃, 110 ℃, 115 ℃, 120 ℃, 125 ℃, 130 ℃, 135 ℃, 140 ℃, 145 ℃, 150 ℃.
Further preferably, the specific process flow of the second step reaction is as follows: adding the compound 2, a cyaniding reagent, ethanol and tetrabutylammonium bromide into a reaction bottle, slowly heating to 60-150 ℃, and reacting for 18-20 hours under the condition of heat preservation. After the reaction is finished, cooling to 50 ℃, dropwise adding toluene and water, and reacting for 1 hour at the temperature of 70 ℃. And (3) evaporating the solvent at the temperature of 70-75 ℃ under reduced pressure at 30-35 KPa, filtering out solids, and then carrying out high-pressure vacuum distillation at 270-275 Pa to collect the fraction at the temperature of 78-84 ℃ to obtain a light yellow oily substance, namely the product compound 1.
The invention further discloses a preparation method of three different compounds 2.
For convenience of explanation, when R is SO2When so, compound 2 a; when R is CMe2When so, is designated compound 2 b; when R is CO, compound 2c is named.
The chemical structural formulas of the compound 2a, the compound 2b and the compound 2c are as follows:
further, the invention also discloses that the compound 2a is prepared by reacting 1, 1-cyclopropane dimethanol (compound 3) with sulfonyl chloride, and the reaction route is as follows:
meanwhile, the invention further discloses a preparation process flow of the compound 2a as follows: adding toluene, 1-cyclopropane dimethanol and sodium methoxide into a reaction bottle, stirring and heating to a reflux state, cooling to room temperature after reflux reaction for about 15 hours, and adding dichloromethane to prepare a substance to be used; adding dichloromethane into a reaction kettle, keeping the internal temperature at-20 ℃ under the protection of nitrogen, adding sulfonyl chloride, dripping the prepared standby substance, keeping the temperature for reaction for more than 2 hours, adding water after the reaction is finished, layering the reaction liquid, decompressing and dissolving the organic phase to dryness, adding toluene and 15-crown-5, stirring for 1 hour at room temperature, filtering and drying to obtain the compound 2 a.
More preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the sulfonyl chloride is 1: 0.6-1: 1.6, and is preferably 1: 1.1. It should be noted that the molar ratio of 1, 1-cyclopropane dimethanol to sulfonyl chloride as used herein includes, but is not limited to, 1:0.6, 1:0.8, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.5, and 1: 1.6.
The reaction temperature of-20 ℃ to 20 ℃ as used herein includes, but is not limited to, temperatures of-20 ℃, 15 ℃, 10 ℃, 5 ℃, 0 ℃, 5 ℃, 10 ℃, 15 ℃ and 20 ℃. With 0 c being the most preferred temperature.
Further, the invention also discloses that the compound 2b is prepared by the reaction of 1, 1-cyclopropane dimethanol (compound 3) and 2, 2-dimethoxy propane, and the reaction route is as follows:
meanwhile, the invention further discloses a preparation process flow of the compound 2b as follows: adding 2, 2-dimethoxypropane and p-toluenesulfonic acid monohydrate to a mixture of 1, 1-cyclopropane dimethanol in Thour F, and stirring at room temperature for 5-15 hours. The reaction was quenched by addition of TEA and distilled under vacuum to afford compound 2 b.
More preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the 2, 2-dimethoxypropane is 1: 0.1-2.5, and preferably 1: 1.2. It is noted that the molar ratio of 1, 1-cyclopropanedimethanol to 2, 2-dimethoxypropane as used herein includes, but is not limited to, 1:0.1, 1:0.2, 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.7, 1:2, 1:2.3, and 1: 2.5.
More preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the p-toluenesulfonic acid monohydrate is 1: 0.01-1: 1, and preferably 1: 0.3. The molar ratios of 1, 1-cyclopropanedimethanol and p-toluenesulfonic acid monohydrate used herein include, but are not limited to, 1:0.1, 1:0.2, 1:0.3, 1:0.5, 1:0.7, 1:0.8, and 1: 9.
The stirring is carried out for 5 to 15 hours at room temperature, including but not limited to 5 hours, 7 hours, 10 hours, 12 hours and 15 hours; of these, 10 hours is preferable.
Meanwhile, the invention further discloses that the compound 2c is prepared by the reaction of 1, 1-cyclopropane dimethanol (compound 3) and dimethyl carbonate, and the reaction route is as follows:
meanwhile, the invention further discloses a preparation process flow of the compound 2c, which is as follows: 1, 1-cyclopropane dimethanol, dimethyl carbonate and THF are added into a reaction bottle and heated to reflux for reaction for 12 hours. After completion of the reaction, distillation was carried out at 30 ℃ under reduced pressure to obtain Compound 2 c.
More preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the dimethyl carbonate is 1:0.1 to 2.5, preferably 1:1. The molar ratio of 1, 1-cyclopropane dimethanol to dimethyl carbonate is not limited to 1:0.1, 1:0.2, 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.7, 1:2, 1:2.3, and 1: 2.5.
Further preferably, the heating reflux reaction is performed for 5 to 20 hours, including but not limited to 5 hours, 7 hours, 10 hours, 12 hours, 15 hours, 17 hours, 20 hours, and most preferably 12 hours.
The description of "about" in the present invention represents ± 2% on the basis of the designated numerical value.
According to the technical scheme disclosed by the invention, 1-hydroxymethyl cyclopropyl acetonitrile can be prepared by taking 1, 1-cyclopropane dimethanol as a raw material only through two steps, so that the preparation process steps are greatly simplified, and the method has important significance for industrial popularization. Meanwhile, in the synthetic route disclosed by the invention, the target product has high yield and high purity, does not need a complex post-treatment process, and is suitable for large-scale industrial production. Finally, the reaction conditions of the invention are simple and easy to realize, and the synthesis cost is low.
Detailed Description
In order that the invention may be better understood, we now provide further explanation of the invention with reference to specific examples.
Unless otherwise specified, all reagents used in the present invention are commercially available products. The room temperature of the invention is 20-30 ℃.
EXAMPLE group 1 preparation route with Compound 2a as intermediate product
Examples 1 to 1
The first step is as follows:
putting toluene (150ml), 1-cyclopropane dimethanol (1mol, 76g) and sodium methoxide (81g, 1.5mol) into a reaction bottle, stirring and heating to reflux, cooling to room temperature after 15h, and adding 150ml of dichloromethane to prepare sodium salt for later use;
dichloromethane (375ml) was added to the reaction vessel, the internal temperature was maintained at 0 ℃ under nitrogen protection, sulfuryl chloride (148g, 1.1mol) was added, the above sodium salt was added dropwise, and the reaction was allowed to proceed for 2 hours. After the reaction, water (150ml) was added, the reaction solution was partitioned, the organic phase was vacuum-desolventized to dryness, toluene (300ml) and 15-crown-5 (0.075g) were added, stirred at room temperature for 1 hour, filtered and dried to obtain Compound 2 a.
The second step is that:
a reaction flask was charged with Compound 2a (164.2g, 1mol), NaCN (58.8g, 1.2mol), ethanol (550mL), and 16g of tetrabutylammonium bromide, and the temperature was slowly raised to 90 ℃ and the reaction was maintained for 20 hours. After completion of the reaction, the reaction mixture was cooled to 50 ℃ and toluene (600mL) and water (54mL) were added dropwise, followed by reaction at 70 ℃ for 1 hour. And (3) evaporating the solvent at the temperature of 70-75 ℃ under reduced pressure at 30-35 KPa, filtering out solids, and then carrying out high-pressure vacuum distillation at 270-275 Pa to collect the fraction at the temperature of 78-84 ℃ to obtain a light yellow oily substance, namely the product compound 1.
The total yield of the two steps is 92.6 percent, and the purity of the target product is 99.5 percent.
Examples 1-2 to examples 1-11
In examples 1-2 to 1-11, part of the preparation conditions were changed to examine the changes in the product purity and the two-step total yield under different conditions, respectively.
Only the feed ratio or other conditions were changed, respectively, in the manner disclosed in example 1-1, as detailed in table 1.
Note: the white portion in the table represents that the conditions are the same as in example 1-1.
Table 1 different reaction conditions and results
Wherein n is3:n4Represents the feeding molar ratio of 1, 1-cyclopropane dimethanol (compound 3) to sulfonyl chloride; n is2a:nCyanidation reagentRepresents the molar ratio of compound 2a to the cyanating agent.
EXAMPLE group 2 preparation route with Compound 2b as intermediate product
Example 2-1
The first step is as follows:
2, 2-Dimethoxypropane (125g, 1.2mol), p-toluenesulfonic acid monohydrate (57g, 0.3mol) were added to a mixture of 1, 1-cyclopropanedimethanol (102g, 1mol) in THF (2L) and stirred at room temperature for 10 h. The reaction was quenched by addition of TEA and distilled under vacuum to afford compound 2 b.
The second step is that:
to a reaction flask were added compound 2b (142.2g, 1mol), sodium cyanide (58.8g, 1.2mol), ethanol (550mL), and 16g tetrabutylammonium bromide, and the reaction was incubated while slowly raising the temperature to 90 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to 50 ℃ and toluene (600mL) and water (54mL) were added dropwise, followed by reaction at 70 ℃ for 1 hour. The solvent was evaporated under reduced pressure, the solid was filtered off and the product compound 1 was evaporated under high vacuum.
The total yield of the two steps is 93.5 percent, and the purity of the target product is 99.5 percent.
Examples 2-2 to 2-13
In examples 2-2 to 2-13, part of the preparation conditions were changed to examine the changes in the product purity and the two-step total yield under different conditions, respectively.
Only the respective charge ratios or other conditions were changed in the manner disclosed in example 2-1, as detailed in Table 2.
Note: the white portion in the table represents that the conditions are the same as in example 2-1.
Table 2 different reaction conditions and results
Wherein n is3:n5Represents the feeding molar ratio of 1, 1-cyclopropane dimethanol (compound 3) to 2, 2-dimethoxypropane; n is2b:nCyanidation reagentRepresents the feeding molar ratio of the compound 2b and the cyaniding reagent; n is3:n6Represents the charged molar ratio of 1, 1-cyclopropanedimethanol (compound 3) to p-toluenesulfonic acid monohydrate.
EXAMPLE group 3 preparation route with Compound 2c as intermediate product
Example 3-1
The first step is as follows:
1, 1-cyclopropanedimethanol (92g, 1mol), dimethyl carbonate (90g, 1mol), 450ml THF were added to the reaction flask and refluxed at 80 ℃ for 12 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure at 30 ℃ using a rotary evaporator to obtain Compound 2 c.
The second step is that:
a reaction flask was charged with Compound 2c (128g, 1mol), NaCN (58.8g, 1.2mol), ethanol (550mL), and 16g tetrabutylammonium bromide, and the temperature was slowly raised to 90 ℃ and the reaction was maintained for 20 hours. After the reaction, the reaction mixture was cooled to 50 ℃ and toluene (600mL) and water (54mL) were added dropwise, followed by reaction at 70 ℃ for 1 hour. The solvent is distilled off under reduced pressure, the solid is filtered out, and the product compound 1 is distilled off under high vacuum, the total yield of the two steps is 92.8 percent, and the purity of the target product is 99.2 percent.
Example 3-2 to example 3-11
In examples 3-2 to 3-11, part of the preparation conditions were changed to examine the changes in the product purity and the two-step total yield under different conditions, respectively.
Only the feed ratio or other conditions were changed, respectively, in the manner disclosed in example 3-1, as specified in Table 3.
Note: the white portion in the table represents that the conditions are the same as in example 3-1.
Table 3 different reaction conditions and results
Wherein n is3:n7Represents the feeding molar ratio of 1, 1-cyclopropane dimethanol (compound 3) to dimethyl carbonate; n is2c:nCyanidation reagentRepresents the molar ratio of compound 2c to the cyanating agent charged.
What has been described above is a specific embodiment of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and such improvements and modifications are also considered to be within the scope of the present invention.
Claims (8)
1. A preparation method of a montelukast sodium side chain intermediate is characterized in that: the method takes 1, 1-cyclopropane dimethanol (compound 3) as a raw material to prepare the 1-hydroxymethyl cyclopropyl acetonitrile (compound 1) by a two-step method, and the preparation route is as follows:
the first step is as follows:
the second step is that:
wherein R is SO2、CMe2Or CO.
2. The method for preparing a side chain intermediate of montelukast sodium according to claim 1, comprising: the feeding molar ratio of the compound 2 to the cyaniding agent is 1 (0.5-1.8), and the preferable ratio is 1: 1.2.
3. The method for preparing a montelukast sodium side chain intermediate according to claim 1, wherein: compound 2 is reacted with a cyanating reagent in the presence of ethanol and tetrabutylammonium bromide.
4. The method for preparing a montelukast sodium side chain intermediate according to claim 1, wherein: the reaction temperature of the compound 2 and the cyaniding reagent is 60-150 ℃, wherein the reaction temperature is preferably 90 ℃.
5. The method for preparing a montelukast sodium side chain intermediate according to claim 1, wherein: the specific process flow of the cyanidation reaction is as follows: adding a compound 2, a cyaniding reagent, ethanol and tetrabutylammonium bromide into a reaction bottle, slowly heating to 60-150 ℃, carrying out heat preservation reaction for 18-20 hours, cooling to 50 ℃ after the reaction is finished, dropwise adding toluene and water, and carrying out heat preservation reaction for 1 hour at 70 ℃; and (3) evaporating the solvent at the temperature of 70-80 ℃ under reduced pressure at 30-40 KPa, filtering out solids, and then carrying out high-pressure vacuum distillation at 270-280 Pa to collect the fraction at the temperature of 78-88 ℃ to obtain a light yellow oily substance, namely the product compound 1.
6. The method for preparing a montelukast sodium side chain intermediate according to claim 1, wherein: the compound 2a is prepared by reacting 1, 1-cyclopropane dimethanol (compound 3) with sulfonyl chloride, and the reaction route is as follows:
preferably, the preparation process flow of the compound 2a is as follows: adding toluene, 1-cyclopropane dimethanol and sodium methoxide into a reaction bottle, stirring and heating to a reflux state, cooling to room temperature after reflux reaction for about 15 hours, and adding dichloromethane to prepare a substance to be used; adding dichloromethane into a reaction kettle, keeping the internal temperature at-20 ℃ under the protection of nitrogen, adding sulfonyl chloride, dripping the prepared standby substance, keeping the temperature for reaction for more than 2 hours, adding water after the reaction is finished, carrying out pressure-less desolventizing on the organic phase until the organic phase is dry after the reaction liquid is layered, adding toluene and 15-crown-5, stirring for 1 hour at room temperature, filtering and drying to obtain a compound 2 a;
further preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the sulfonyl chloride is 1: 0.6-1: 1.6, preferably 1: 1.1;
further preferably, the reaction temperature is 0 ℃ among-20 ℃ to 20 ℃.
7. The method for preparing a montelukast sodium side chain intermediate according to claim 1, wherein: the compound 2b is prepared by the reaction of 1, 1-cyclopropane dimethanol (compound 3) and 2, 2-dimethoxy propane, and the reaction route is as follows:
preferably, the preparation process of the compound 2b is as follows: adding 2, 2-dimethoxypropane and p-toluenesulfonic acid monohydrate into a mixture of 1, 1-cyclopropane dimethanol and THF, stirring at room temperature for 5-15 hours, adding TEA to quench the reaction, and distilling under a vacuum state to obtain a compound 2 b;
more preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the 2, 2-dimethoxypropane is 1: 0.1-2.5, preferably 1: 1.2;
more preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the p-toluenesulfonic acid monohydrate is 1: 0.01-1: 1, and preferably 1: 0.3;
more preferably, the stirring is carried out at room temperature for 5 to 15 hours, preferably 10 hours.
8. The method for preparing a montelukast sodium side chain intermediate according to claim 1, wherein: the compound 2c is prepared by reacting 1, 1-cyclopropane dimethanol (compound 3) with dimethyl carbonate, and the reaction route is as follows:
preferably, the preparation process of the compound 2c comprises the following steps: 1, 1-cyclopropane dimethanol, dimethyl carbonate and THF are added into a reaction bottle and heated to reflux for reaction for 12 hours. After the reaction is finished, carrying out reduced pressure distillation at 30 ℃ to obtain a compound 2 c;
more preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the dimethyl carbonate is 1: 0.1-2.5, preferably 1: 1;
further preferably, the heating reflux reaction is carried out for 5 to 20 hours, and most preferably for 12 hours.
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