CN111807976A - Novel method for preparing sarpogrelate hydrochloride - Google Patents
Novel method for preparing sarpogrelate hydrochloride Download PDFInfo
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- CN111807976A CN111807976A CN202010744153.2A CN202010744153A CN111807976A CN 111807976 A CN111807976 A CN 111807976A CN 202010744153 A CN202010744153 A CN 202010744153A CN 111807976 A CN111807976 A CN 111807976A
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- solvent
- sarpogrelate
- sarpogrelate hydrochloride
- hydrochloride
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- FFYNAVGJSYHHFO-UHFFFAOYSA-N sarpogrelate Chemical compound COC1=CC=CC(CCC=2C(=CC=CC=2)OCC(CN(C)C)OC(=O)CCC(O)=O)=C1 FFYNAVGJSYHHFO-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 229950005789 sarpogrelate Drugs 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims abstract description 10
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940014800 succinic anhydride Drugs 0.000 claims abstract description 10
- 239000012458 free base Substances 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims abstract description 8
- HGQQRAXOBYWKDV-UHFFFAOYSA-N 2-[2-(3-methoxyphenyl)ethyl]phenol Chemical compound COC1=CC=CC(CCC=2C(=CC=CC=2)O)=C1 HGQQRAXOBYWKDV-UHFFFAOYSA-N 0.000 claims abstract description 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000013078 crystal Substances 0.000 claims abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 13
- 238000009833 condensation Methods 0.000 claims description 10
- 230000005494 condensation Effects 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000012267 brine Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 3
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 239000012047 saturated solution Substances 0.000 claims 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 abstract description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000006561 solvent free reaction Methods 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract 1
- 239000004593 Epoxy Substances 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 150000001983 dialkylethers Chemical class 0.000 description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010043540 Thromboangiitis obliterans Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 150000002924 oxiranes Chemical group 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- UUCCCPNEFXQJEL-UHFFFAOYSA-L strontium dihydroxide Chemical compound [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 description 1
- 229910001866 strontium hydroxide Inorganic materials 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/27—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms
- C07D301/28—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms by reaction with hydroxyl radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention aims to disclose a convenient and environment-friendly method for preparing sarpogrelate hydrochloride. It relates to a solvent which is freely condensed by 2- [2- (3-methoxyphenyl) ethyl ] phenol and epichlorohydrin (2- [2- (3-methoxyphenylyl) ethyl ] phenol with epoxy chloride). The oxirane of the resulting intermediate was ring-opened with dimethylamine at atmospheric pressure and then reacted with succinic anhydride to give sarpogrelate. The obtained free base is treated by isopropanol IPA.HCl to obtain the salpory hydrochloride. Crystals of the hydrochloride salt were formed in acetone to give the pure product. The preparation method adopts a solvent-free reaction in the first step and an atmospheric pressure reaction in the second step, so that the preparation method is suitable for industrial production.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a convenient and environment-friendly novel method for preparing sarpogrelate hydrochloride.
Background
Sarpogrelate hydrochloride (Sarpogrelate) was developed and sold by mitsubishi in japan in 1993. It is a platelet aggregation inhibitor with a novel mechanism of action, selectively antagonizing the serotonin receptor (5-HT 2). The sarpogrelate can inhibit platelet aggregation and vasoconstriction, and has antithrombotic effect and microcirculation improving effect. The indications are to improve all ischemic symptoms caused by chronic arterial occlusive diseases, such as ulcers, pain and peristaltic coldness. It also has potential for use in the treatment of diabetes, thromboangiitis obliterans (buerger's disease), raynaud's syndrome, coronary artery disease, angina and atherosclerosis.
The initial synthesis of sarpogrelate hydrochloride is disclosed in US 4485258. It involves the condensation of 2- [2- (3-methoxyphenyl) ethyl ] phenol and epichlorohydrin (2- [2- (3-methoxyphenylyl) ethyl ] phenol with epichlorohydrin) in anhydrous N, N-dimethylformamide in the presence of 60% sodium hydride, which process uses a hazardous sodium hydride reagent and is therefore inconvenient to operate.
Another process is disclosed in CN103965063, wherein a phase transfer catalyst is used and a high pressure reaction is also required to open the epoxide ring. This method uses an additional catalyst and also involves a high-pressure reaction, and thus is inconvenient to operate.
CN103242179 focuses more on solving the crystallization difficulties of the final product, but the synthesis problem is not yet solved.
Therefore, a more convenient, environmentally friendly process for preparing sarpogrelate hydrochloride is needed.
Disclosure of Invention
In view of the problems of the prior art, the present invention is a convenient and environmentally friendly new process for the preparation of sarpogrelate hydrochloride.
The invention is realized by the following technical scheme, which specifically comprises the following steps:
the first step involves the solvent-free condensation of 2- [2- (3-methoxyphenyl) ethyl ] phenol with epichlorohydrin (2- [2- (3-methoxyphenyl) ethyl ] phenol with epichlorohydrin) in the presence of a suitable base at a suitable temperature.
As a preferred embodiment of the present invention, the base may be selected from inorganic or organic bases, and usable bases such as lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), rub hydroxide (rboh), cesium hydroxide (CsOH), magnesium hydroxide (mg (oh)2), calcium hydroxide (ca (oh)2), strontium hydroxide (sr (oh)2), barium hydroxide (ba (oh)2), and the like, wherein sodium hydroxide (NaOH) is preferably used.
As a preferred embodiment of the present invention, the reaction temperature in the first step may be 25 ℃ to 200 ℃, preferably 48 ℃ to 52 ℃.
As a preferred embodiment of the present invention, after the condensation reaction, the reaction mass is diluted with a suitable solvent selected from, but not limited to, C1-C10 haloalkanes such as chloroform, dichloromethane, dichloroethane; C1-C10 dialkyl ethers, such as diethyl ether, isopropyl ether, propyl ether, methyl tert-butyl ether; carboxylic acid esters such as methyl acetate, ethyl acetate, propyl acetate; aromatic or chlorinated aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, bromobenzene and the like, the preferred solvent being toluene.
As a preferred embodiment of the present invention, the solution thus formed is filtered through a bed of celite and, after washing with brine, distillation of the solvent is carried out to obtain the intermediate of the first step.
The second step involves ring opening of the ethylene oxide of the primary intermediate with 40% aqueous dimethylamine in a suitable solvent at a suitable temperature.
As a preferred embodiment of the present invention, the solvent may be selected from C1-C10 dialkyl ethers such as but not limited to diethyl ether, isopropyl ether, propyl ether, methyl tert-butyl ether or cyclic ethers such as but not limited to tetrahydrofuran, 1, 4-dioxane, 2-methyltetrahydrofuran. Preference is given to using 2-methyltetrahydrofuran.
The second reaction temperature may be between 25 ℃ and 200 ℃, preferably between 25 ℃ and 30 ℃. Solvent distillation was performed after brine wash to obtain crude second step intermediate. Preferably, a saturated hydrogen chloride solution is added to the isopropyl alcohol IPA. Crystallization of the salt may be carried out in a suitable solvent at a suitable temperature. Preferably, isopropanol IPA between 25 deg.C and 30 deg.C is used to obtain the pure second step intermediate hydrochloride salt.
The third step involves condensation of the free base of the intermediate of step two with succinic anhydride, thereby forming crystallization of the product in the form of sarpogrelate hydrochloride.
As a preferred embodiment of the present invention, the free base of the intermediate of the second step can be obtained by treatment with an inorganic or organic base. The toluene solution is preferably treated with an aqueous sodium hydroxide solution.
As a preferred embodiment of the present invention, the condensation of step three intermediate free base with succinic anhydride can be carried out in a suitable solvent at a suitable temperature. The solvent of choice may be any organic solvent, with acetone being preferred.
The reaction temperature in the third step may be between 25 ℃ and 200 ℃, preferably between 50 ℃ and 55 ℃. Salt formation of the product can be accomplished by either passing HCl gas into the reaction mixture or by adding saturated hydrogen chloride solution. Preferably, a saturated hydrogen chloride solution is added to the isopropyl alcohol IPA.
Crystallization of the salt may be carried out in a suitable solvent at a suitable temperature. To obtain pure sarpogrelate hydrochloride, acetone is preferably used at 25 ℃ to 30 ℃.
The specific reaction formula is as follows:
step one (solvent-free condensation)
Step two (ethylene oxide open)
Step three (succinic anhydride reaction and formation of hydrochloride salt)
Compared with the existing synthetic route, the invention has many advantages:
compared with the prior art, the method avoids catalyst, solvent, high pressure and gas channels as much as possible, so the method is harmless, easy to operate and environment-friendly.
Wherein the preparation method adopts a solvent-free reaction in the first step and an atmospheric pressure reaction in the second step, so that the preparation method is suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the invention are not limited thereto.
Example 1
Step one (solvent-free condensation)
Epichlorohydrin (303.9g) was added to a mixture of 2,3-MPP (150g) and NaOH (31.5g) in RB at room temperature and heated at 48 to 52 ℃ for 3 hours. Another batch of NaOH (5.3g) was added and heating continued for 1 h. The reaction was cooled to room temperature and toluene (300ml) was added. The resulting suspension was passed through a water flow bed and the filtrate was washed with brine solution (300 ml). The volatiles were evaporated in vacuo to give 186g of a brown oil.
And (3) analysis:
MS:284.3(M+H)+
step two (ethylene oxide open)
To a solution of step one intermediate (186g) in 2-methyl THF (600ml) at 5 ℃ was added 40% aqueous dimethylamine solution (588.7 g). The addition temperature was raised to room temperature and stirred for 3 h. The reaction mixture was washed with brine solution (300 ml). The volatiles were evaporated in vacuo and the resulting residue was stripped with isopropanol, IPA. The obtained crude material was dissolved in isopropanol IPA (450ml) and cooled to 5 ℃. Isopropanol ipa.hcl (164.1g) was added to the reaction over 15 to 20 minutes. After 45 minutes an off-white solid was observed to form and stirring was continued for an additional 2 hours. The solid obtained was filtered and washed with isopropanol IPA (150ml) and dried in vacuo to give 180 g. It was dissolved in isopropanol IPA (450ml) at 55 ℃ and cooled to room temperature. It was stirred for 4 hours, and the resulting precipitate was filtered and washed with isopropanol IPA (150 ml). It was dried under vacuum to obtain 160g of product.
And (3) analysis:
MS:330.2(M+H)+(free base)
Step three
The step two intermediate (150g) was dissolved in 20% NaOH solution (190ml) and stirred for 30 min. Toluene (450ml) was added and stirred for an additional 30 minutes. The organic layer was separated and the aqueous layer was extracted with another batch of toluene (150 ml). Toluene was distilled from the combined organic layers and the resulting residue was stripped with fresh toluene (2X 75 ml). The residue obtained was dissolved in acetone (300 ml). A solution of succinic anhydride (51.23g) in acetone (300ml) was added. The resulting mixture was heated at 55 ℃ for 2 hours. The reaction mixture was cooled to 5 ℃ and isopropanol ipa.hcl (104.2g) was added slowly over 30 to 60 minutes. Acetone (150ml) was added to the reaction mass and stirring was continued for 2h 2h at 5 ℃. The solid obtained was filtered and washed with myoketone (150 ml). The crude solid was dissolved in acetone (712ml) and water (38 ml). The suspension was heated to 55 ℃ for 1 hour. It was cooled to room temperature and stirred for 2 hours. The solid obtained was filtered and washed with acetone (2X 75 ml). It was dried under vacuum to obtain 180g of sarpogrelate hydrochloride.
And (3) analysis:
NMR(1H,DMSO-d6):10.95(bs,1H),7.29-6.80(m,9H),5.09(m,1H),4.30-4.05(m,2H),3.83(s,3H),3.61-3.35(m,2H),2.86(s,6H),2.83-2.82(m,6H),2.52(m,2H).
MS 430.52(M + H) (for free base)
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A novel process for the preparation of sarpogrelate hydrochloride, characterized in that it comprises the following steps:
(1) 2- [2- (3-methoxyphenyl) ethyl ] phenol and epichlorohydrin are subjected to solvent-free condensation at a temperature between 25 ℃ and 200 ℃, and the obtained intermediate is further used for preparing sarpogrelate hydrochloride.
2. The process of claim 1, further comprising the steps of: (2) the ethylene oxide of the resulting intermediate was ring-opened with 40% aqueous dimethylamine solution at atmospheric pressure.
3. The process of claim 1, further comprising the steps of: (3) and (3) reacting the intermediate obtained in the step two with succinic anhydride to obtain sarpogrelate free alkali, and further reacting with hydrochloric acid to obtain sarpogrelate hydrochloride.
4. The process of claim 2, further comprising the steps of: (3) and (3) reacting the intermediate obtained in the step two with succinic anhydride to obtain sarpogrelate free alkali, and further reacting with hydrochloric acid to obtain sarpogrelate hydrochloride.
5. The process according to claim 1, wherein the base used in step (1) is selected from alkali metal bases.
6. The novel process for the preparation of sarpogrelate hydrochloride in accordance with claim 5, wherein the base in step (1) is sodium hydroxide.
7. The process of claim 1, wherein the solvent-free condensation in step (1) is carried out at a temperature of between 48 and 52 ℃.
8. A novel process for the preparation of sarpogrelate hydrochloride, characterized in that it comprises the following steps:
(1) 2- [2- (3-methoxyphenyl) ethyl ] phenol and epichlorohydrin are subjected to solvent-free condensation at a temperature between 25 ℃ and 200 ℃, and the obtained intermediate is further used for preparing sarpogrelate hydrochloride.
(2) The ethylene oxide of the resulting intermediate was ring-opened with 40% aqueous dimethylamine solution at atmospheric pressure.
(3) And (3) reacting the intermediate obtained in the step two with succinic anhydride to obtain sarpogrelate free alkali, and further reacting with hydrochloric acid to obtain sarpogrelate hydrochloride.
9. The novel process for the preparation of sarpogrelate hydrochloride according to claim 8, wherein the second step reaction temperature is between 25 ℃ and 30 ℃, solvent distillation is performed after washing with brine to obtain crude second step intermediate, preferably saturated hydrogen chloride solution is added to isopropanol IPA, and crystallization of the salt can be carried out in a suitable solvent at a suitable temperature.
10. The process according to claim 8, wherein the third step involves condensing the free base of the intermediate of step two with succinic anhydride, thereby forming crystals of the product in the form of sarpogrelate hydrochloride;
the free base of the intermediate of the second step can be obtained by treatment with an inorganic or organic base, preferably by treatment of the toluene solution with aqueous sodium hydroxide;
the condensation of step three intermediate free base with succinic anhydride may be carried out in a suitable solvent at a suitable temperature. The solvent of choice may be any organic solvent, acetone being preferred;
between 50 ℃ and 55 ℃ the salt formation of the product can be achieved by bringing HCl gas into the reaction mixture or by adding a saturated solution of hydrogen chloride, preferably to isopropanol IPA.
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| CN101239920A (en) * | 2007-02-05 | 2008-08-13 | 南京康然医药科技有限公司 | Method for preparing sarpogrelate hydrochloride |
| JP2013148857A (en) * | 2011-12-22 | 2013-08-01 | Tokyo Ohka Kogyo Co Ltd | Photosensitive resin composition, color filter, and liquid crystal display device |
| CN103242179A (en) * | 2013-05-08 | 2013-08-14 | 深圳万乐药业有限公司 | Preparation method of high-purity sarpogrelate hydrochloride |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101239920A (en) * | 2007-02-05 | 2008-08-13 | 南京康然医药科技有限公司 | Method for preparing sarpogrelate hydrochloride |
| JP2013148857A (en) * | 2011-12-22 | 2013-08-01 | Tokyo Ohka Kogyo Co Ltd | Photosensitive resin composition, color filter, and liquid crystal display device |
| CN103242179A (en) * | 2013-05-08 | 2013-08-14 | 深圳万乐药业有限公司 | Preparation method of high-purity sarpogrelate hydrochloride |
Non-Patent Citations (4)
| Title |
|---|
| ISHRAT JABEEN ET AL.: "Structure-activity relationships，Ligand efficiency，and Lipoohilic efficiency profiles of benzoohenone-type ingibitors of the multidrug tansporter P-Glycoprotein", 《MEDICINAL CHEMISTRY》 * |
| 信颖等: "《有机化学 第2版》", 31 January 2017, 华中科技大学出版社 * |
| 王振等: "盐酸沙格雷酯的合成", 《广州化工》 * |
| 陈晓强: "盐酸沙格雷酯的合成工艺研究", 《中国优秀博硕士学位论文全文数据库(硕士)工程科技Ⅰ辑》 * |
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