CN113999126B - Preparation method of trimebutine - Google Patents
Preparation method of trimebutine Download PDFInfo
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- CN113999126B CN113999126B CN202111470165.1A CN202111470165A CN113999126B CN 113999126 B CN113999126 B CN 113999126B CN 202111470165 A CN202111470165 A CN 202111470165A CN 113999126 B CN113999126 B CN 113999126B
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- phenylbutanol
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- 229960005345 trimebutine Drugs 0.000 title claims abstract description 36
- LORDFXWUHHSAQU-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid [2-(dimethylamino)-2-phenylbutyl] ester Chemical compound C=1C=CC=CC=1C(CC)(N(C)C)COC(=O)C1=CC(OC)=C(OC)C(OC)=C1 LORDFXWUHHSAQU-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 39
- UTUOJASDCBCXIL-UHFFFAOYSA-N 2-amino-2-phenylbutan-1-ol Chemical compound CCC(N)(CO)C1=CC=CC=C1 UTUOJASDCBCXIL-UHFFFAOYSA-N 0.000 claims abstract description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 26
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002994 raw material Substances 0.000 claims abstract description 24
- JDCWNZJOVSBOLK-UHFFFAOYSA-N 2-(dimethylamino)-2-phenylbutan-1-ol Chemical compound CCC(CO)(N(C)C)C1=CC=CC=C1 JDCWNZJOVSBOLK-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 20
- UBXUDSPYIGPGGP-UHFFFAOYSA-N 2-azaniumyl-2-phenylbutanoate Chemical compound CCC(N)(C(O)=O)C1=CC=CC=C1 UBXUDSPYIGPGGP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000001412 amines Chemical class 0.000 claims abstract description 13
- 235000019253 formic acid Nutrition 0.000 claims abstract description 13
- 239000011230 binding agent Substances 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 238000007069 methylation reaction Methods 0.000 claims abstract description 12
- 238000005886 esterification reaction Methods 0.000 claims abstract description 10
- 239000012467 final product Substances 0.000 claims abstract description 8
- BUHYMJLFRZAFBF-UHFFFAOYSA-N 3,4,5-trimethoxybenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=CC(OC)=C1OC BUHYMJLFRZAFBF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 6
- 238000006722 reduction reaction Methods 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 80
- 150000001875 compounds Chemical class 0.000 claims description 46
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical group 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003799 water insoluble solvent Substances 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- 238000005902 aminomethylation reaction Methods 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical group CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 125000005587 carbonate group Chemical group 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 21
- 239000012535 impurity Substances 0.000 abstract description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 7
- 150000001336 alkenes Chemical class 0.000 abstract description 5
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 65
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 239000000243 solution Substances 0.000 description 19
- 239000000203 mixture Substances 0.000 description 18
- 230000001276 controlling effect Effects 0.000 description 17
- 238000010438 heat treatment Methods 0.000 description 15
- 235000011121 sodium hydroxide Nutrition 0.000 description 14
- 238000010992 reflux Methods 0.000 description 13
- 238000001816 cooling Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- 238000005070 sampling Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- 238000004821 distillation Methods 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 230000011987 methylation Effects 0.000 description 8
- 239000003513 alkali Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000013067 intermediate product Substances 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- 239000012265 solid product Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000002699 waste material Substances 0.000 description 5
- SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002351 wastewater Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- FSRLGULMGJGKGI-BTJKTKAUSA-N Trimebutine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=CC=1C(CC)(N(C)C)COC(=O)C1=CC(OC)=C(OC)C(OC)=C1 FSRLGULMGJGKGI-BTJKTKAUSA-N 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- CREXVNNSNOKDHW-UHFFFAOYSA-N azaniumylideneazanide Chemical group N[N] CREXVNNSNOKDHW-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000003912 environmental pollution Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 208000002551 irritable bowel syndrome Diseases 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- -1 sulfoxide iodide Chemical class 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- IWPZKOJSYQZABD-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Natural products COC1=CC(OC)=CC(C(O)=O)=C1 IWPZKOJSYQZABD-UHFFFAOYSA-N 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000005176 gastrointestinal motility Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- GUXPELMEYCDGIS-UHFFFAOYSA-N 3,4,5-trimethylbenzoyl chloride Chemical compound CC1=CC(C(Cl)=O)=CC(C)=C1C GUXPELMEYCDGIS-UHFFFAOYSA-N 0.000 description 1
- 206010000060 Abdominal distension Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010015137 Eructation Diseases 0.000 description 1
- 206010067715 Gastrointestinal sounds abnormal Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 208000027687 belching Diseases 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- ORVACBDINATSAR-UHFFFAOYSA-N dimethylaluminum Chemical compound C[Al]C ORVACBDINATSAR-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 230000008673 vomiting Effects 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
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of 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
- 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
- C07C213/08—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 not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of trimebutine, and belongs to the technical field of drug synthesis. In order to solve the problems of high pollution and low yield in the prior art, the preparation method of trimebutine comprises the steps of carrying out reduction reaction on 2-amino-2-phenylbutyric acid in an organic solvent under the action of a catalyst to obtain an intermediate 2-amino-2-phenylbutanol; and the catalyst is selected from protonic acid or Lewis acid; carrying out an amine methylation reaction on 2-amino-2-phenylbutanol, formaldehyde and formic acid to obtain 2- (dimethylamino) -2-phenylbutanol; in the presence of an acid binding agent, the raw material 3,4, 5-trimethoxybenzoyl chloride and 2- (dimethylamino) -2-phenylbutanol are subjected to esterification reaction to obtain a final product. Can selectively introduce methyl on amino, keep the methyl not introduced on alcohol hydroxyl, effectively avoid ether and double bond olefin impurities, and realize the effects of high product yield and purity.
Description
Technical Field
The invention relates to a preparation method of trimebutine, and belongs to the technical field of drug synthesis.
Background
Trimebutine maleate (Trimebutine Maleate) was the gastrointestinal motility drug developed by french Jouveinal and was first marketed in france in 1970. Trimebutine maleate was marketed in china in 2000. Is mainly suitable for improving symptoms such as inappetence, nausea, vomiting, belching, abdominal distension, borborygmus, abdominal pain, diarrhea, constipation and the like caused by gastrointestinal motility dysfunction. Irritable bowel syndrome (Irritable Bowel Syndrome, IBS) is a common functional bowel disorder with abdominal pain or abdominal discomfort as the principal symptom, which is ameliorated after defecation, often accompanied by changes in bowel habits, and lack of morphological and biochemical abnormalities explaining the symptoms.
At present, the reported synthesis method of trimebutine at home and abroad mainly comprises the following two synthesis routes: among them, document [ Bull.Korean chem.Soc.2005, vol.26, no.2] reports that 1-ethyl-1-phenyl-oxirane is produced by reacting propiophenone as a raw material with trimethyliodinated sulfoxide, then 2-dimethylamino-2-phenyl-butanol is obtained by ring opening by reacting with trimethylaluminum and dimethylamine, and finally trimebutine is produced by reacting with 3,4, 5-trimethylbenzoyl chloride (see scheme 1). The synthetic route has low yield, harsh reaction conditions, expensive raw materials of trimethyl sulfoxide iodide and dimethyl aluminum, high cost and is not suitable for industrialization.
Another document (publication No. CN 102276487A) reports that 2-amino-2-phenylbutyric acid is taken as a raw material, is firstly esterified by dimethyl sulfate and simultaneously subjected to amino nitrogen atom methylation, and is then reduced to 2- (dimethylamino) -2-phenylbutanol, and is reacted with 3,4, 5-trimethoxybenzoic acid in an organic solvent by using protonic acid as a catalyst to prepare the trimebutine. The synthetic route uses the highly toxic product dimethyl sulfate, has higher production safety requirement, and the waste water generated by the reaction contains higher sulfide ions, so that the three wastes are treated with higher cost and lack of cost advantages.
And the reaction process adopts p-toluenesulfonic acid as a catalyst to carry out high-temperature reflux water diversion for esterification reaction. In the water separation process, at high temperature, the intermediate 2- (dimethylamino) -2-phenyl butanol can be subjected to intermolecular dehydration under the catalysis of a catalyst such as p-toluenesulfonic acid to generate ether impurities, and because the hydrogen at the benzyl position is active, the intramolecular dehydration is easy to generate olefin impurities containing double bonds, and the impurities are more, so that the product quality and the yield are influenced, the post-treatment difficulty is high, and the operation is not easy.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of trimebutine, and solves the problems of providing a novel synthetic route which has less environmental pollution and high product yield.
The invention aims at realizing the following technical scheme, and discloses a preparation method of trimebutine, which is characterized by comprising the following steps of:
A. under the action of a catalyst, carrying out reduction reaction on the 2-amino-2-phenylbutyric acid of the compound of the formula II under the action of borohydride in an organic solvent to obtain an intermediate compound of the formula III, namely 2-amino-2-phenylbutanol; and the catalyst is selected from a protic acid or a lewis acid;
B. Carrying out an aminomethylation reaction on a compound 2-amino-2-phenylbutanol, formaldehyde and formic acid in the formula III to obtain an intermediate compound 2- (dimethylamino) -2-phenylbutanol in the formula IV;
C. In the presence of an acid binding agent, carrying out esterification reaction on a raw material 3,4, 5-trimethoxybenzoyl chloride of a formula V compound and an intermediate 2- (dimethylamino) -2-phenylbutanol of a formula IV compound to obtain a final product of the formula I compound;
The carboxyl of the initial raw material 2-amino-2-phenylbutyric acid is reduced into the alcoholic hydroxyl, and the activity of amino nitrogen atoms is improved by utilizing the characteristic that the alcoholic hydroxyl is electron donating, so that in the subsequent amine methylation process, an intermediate 2- (dimethylamino) -2-phenylbutanol can be obtained by adopting a formaldehyde/formic acid system for amine methylation reaction, the methyl esterification of the carboxyl of 2-amino-2-phenylbutyric acid (2) by using virulent dimethyl sulfate and the methylation of the amino nitrogen atoms are avoided, the emission of sulfur-containing wastewater is reduced, the production operation is safer, the pollution to the environment is reduced, and the requirements on green production are more favorably met. Meanwhile, in the existing amine methylation process, methyl is introduced into carboxyl to form ester bond, so that the dosage of dimethyl sulfate is quite large, the cost is increased, a large amount of sulfur-containing wastewater is generated, and the environmental pollution is high. The invention can change the reaction system by reducing the carboxyl into the alcohol hydroxyl and then carrying out the amine methylation process, can realize the amine methylation by adopting a formic acid/formaldehyde system, selectively introduces methyl on the amino, keeps the alcohol hydroxyl free from introducing methyl, and is more beneficial to the reaction and improves the yield of the product. And the raw materials 3,4, 5-trimethoxybenzoyl chloride and the intermediate 2- (dimethylamino) -2-phenylbutanol are adopted for esterification reaction, and as the carboxyl of the 3,4, 5-trimethoxybenzoic acid is activated into acyl chloride, the activity of the acyl chloride is far greater than that of the carboxyl, so that the reaction does not need to adopt acid catalysts such as p-toluenesulfonic acid and the like, but the better reaction can be realized at a lower temperature (0-10 ℃) in the presence of an acid binding agent, the problems of ether impurities and double bond olefin impurities in the high-temperature reaction process under a p-toluenesulfonic acid system are effectively avoided, the advantage of less product impurities is realized, and the effects of high product yield and purity can also be realized.
In the preparation method of the trimebutine, the reaction in the step C is carried out in an organic solvent containing water, and the water is contained in a solvent system, so that small molecular salt formed in the reaction process can be better removed, and the purity and quality requirements of the product can be improved. The organic solvent may be an alcohol solvent, a ketone solvent, or an ether solvent such as dioxane. Preferably, the esterification reaction in step C is carried out in an aqueous alcohol solution, an aqueous acetone solution or an aqueous dioxane solution. The alcohols can be low molecular weight alcohol solvents such as isopropanol, ethanol or propanol, and the reaction is carried out under an aqueous system, so that the reaction is more facilitated, and small molecular inorganic matters and the like formed in the reaction process can be effectively dissolved in water for effective removal, so that the reaction is more facilitated and the purity and quality requirements of the product are improved; and the adopted solvent system is more beneficial to post-treatment, reduces the generation of three wastes and is beneficial to better realizing the green production. The amount of the solvent used may be adjusted according to the reaction requirement to make the reaction more gentle, and it is preferable that the mass ratio of the organic solvent, i.e., alcohol, acetone or dioxane, to the intermediate compound 2- (dimethylamino) -2-phenylbutanol of formula IV is 3 to 7:1, preferably, the mass ratio of the organic solvent to the intermediate compound 2- (dimethylamino) -2-phenylbutanol of formula IV is 5:1, a step of; the mass ratio of water to the intermediate compound 2- (dimethylamino) -2-phenylbutanol in the reaction system is 1-5: 1, preferably 2 to 3:1.
In the above-mentioned preparation method of trimebutine, preferably, the temperature of the esterification reaction in the step C is 0 to 10 ℃. The method improves the selection of raw materials in the reaction process, and enables the reaction to be carried out in the presence of an acid binding agent, so that the reaction can be carried out at low temperature, the problem that ether impurities and double bond olefin impurities are easy to form in the high temperature process is avoided, the product yield and purity quality are better, and the method is easier to operate and safe to produce. Further preferably, the temperature of the esterification reaction is 0 to 5 ℃.
In the preparation method of the trimebutine, the acid-binding agent in the step C can be inorganic base or organic base, wherein the inorganic base can be alkali metal hydroxide or alkali metal carbonate or bicarbonate, the organic base can be piperidine, pyridine, pyrrole or organic amine, and the like, and the organic amine can be triethylamine, diethylamine, and the like. Preferably, the acid-binding agent in the step C is one or more selected from sodium hydroxide, potassium carbonate, sodium bicarbonate and triethylamine. The small molecular acid formed in the reaction process can be effectively neutralized, the reaction is more favorable to be carried out in the forward direction, and the conversion rate of the product is improved; and the formed inorganic salt can be effectively dissolved in water to be more beneficial to removal, and the method is beneficial to improving the purity of the product.
In the above preparation method of trimebutine, preferably, after the amine methylation reaction in the step B is finished, an alkaline reagent is added to the reaction solution to adjust the pH of the system to 10-11, then a water-insoluble solvent capable of dissolving the compound of formula iv, 2- (dimethylamino) -2-phenylbutanol, is added to extract, and the collected organic phase is distilled to remove the solvent, so as to obtain the intermediate compound of formula iv, 2- (dimethylamino) -2-phenylbutanol. After the reaction is finished, the acid added in the reaction system can be removed by adding an alkaline reagent for adjustment, the nonaqueous solvent can be used for extraction, the intermediate product can be extracted into an organic solvent for separation, and the purity and the yield of the product are better ensured. The alkaline agent is preferably an aqueous alkaline solution, for example, an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution, or an aqueous sodium carbonate solution or an aqueous sodium bicarbonate solution, and most preferably an aqueous sodium bicarbonate solution or an aqueous sodium carbonate solution, and the water-insoluble solvent is selected from toluene, methylene chloride, and the like. Preferably, the compound of formula III: the molar ratio of the alkali is 1:0.8 to 1.3, and ensuring the pH value of the system to be 10 to 11; the compounds of formula III may also be reacted: the mass ratio of the water-insoluble organic solvent is 1:1.3 to 1.6.
In the above-mentioned preparation method of trimebutine, preferably, the protonic acid in the step a is selected from sulfuric acid; the Lewis acid is selected from one or more of aluminum trichloride, zinc chloride, boron trifluoride and calcium chloride. The method can be matched with borohydride to jointly reduce carboxylic acid groups in raw materials to form alcoholic hydroxyl groups, and sulfuric acid is preferably adopted as the catalyst, so that the three wastes can be reduced while the reaction is ensured, and the pollution to the environment is reduced.
In the above preparation method of trimebutine, preferably, the borohydride in the step a is one or more selected from lithium borohydride, sodium borohydride and potassium borohydride. The catalytic reduction is preferably carried out by adopting the combined action of borohydride and sulfuric acid, so that a large amount of aluminum-containing wastewater is avoided from being easily generated by adopting Lewis acid such as aluminum trichloride, and the cost for treating three wastes is reduced.
In the above-mentioned preparation method of trimebutine, preferably, the organic solvent in the step a is selected from ether solvents. As a further preferable aspect, the ether solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, diethyl ether, ethylene glycol dimethyl ether and ethylene glycol monomethyl ether. Furthermore, the above-mentioned ether solvent is preferably used in an amount 8 to 10 times by mass as much as the amount of the 2-amino-2-phenylbutyric acid compound of formula II, i.e., the mass ratio of the 2-amino-2-phenylbutyric acid compound of formula II to the ether solvent is 1: 8-10.
In the above-mentioned preparation method of trimebutine, the amount of the raw materials may be controlled according to molar reaction equivalent. Of course, in order to better ensure that the starting materials proceed adequately and reduce waste of the starting materials, it is preferable that the compound of formula II in step A is 2-amino-2-phenylbutyric acid: catalyst: the molar ratio of borohydride is 1:1.2 to 1.5:2.0 to 2.5; is favorable for promoting the reaction to be fully carried out, ensuring the reaction of the raw materials to be fully carried out and improving the utilization rate of the raw materials. Further subjecting the compound of formula iii described in step B to 2-amino-2-phenylbutanol: formaldehyde: the molar ratio of formic acid is 1:2.0 to 4.5:2.0 to 3.0; the intermediate compound of formula iv, 2- (dimethylamino) -2-phenylbutanol, as described in step C, may be further reacted: 3,4, 5-trimethoxybenzoyl chloride compound of formula v: the mole ratio of the acid binding agent is 1:1.1 to 1.5:1.2 to 1.6.
In the above-mentioned preparation method of trimebutine, the temperature of the reduction reaction in the step A is preferably 10 to 30 ℃, so that the mild reaction can be ensured, and the temperature is preferably controlled to 10 to 20 ℃. It is further preferable to control the time of the reduction reaction to 10 to 14 hours.
And C, after the reduction reaction in the step A is finished, adding alkali liquor into the reaction liquid for adjustment, heating to reflux conditions for reflux for 1-3 hours, stopping heating, standing and layering to obtain the corresponding intermediate compound of the formula III. The alkali content in the alkaline aqueous solution is preferably 5 to 20% by mass. The mass ratio of the compound of the formula II, namely 2-amino-2-phenyl butanol to the alkali is 1:2 to 4. Aims to better remove impurities and unreacted raw materials and improve the purity and quality of the intermediate.
In summary, compared with the prior art, the invention has the following advantages:
1. Through reducing carboxyl into alcohol hydroxyl and then carrying out an amine methylation process, and adopting a formic acid/formaldehyde system for amine methylation, methyl can be selectively introduced into amino groups, methyl can not be introduced into alcohol hydroxyl, the reaction is more facilitated, the yield of a product is improved, and ether impurities and double bond olefin impurities can be effectively avoided in the esterification process, so that the effects of high product yield and purity can be realized.
2. The activity of the adopted raw material 3,4, 5-trimethoxybenzoyl chloride is far greater than that of carboxyl, so that the step of reaction does not need to adopt acid catalysts such as p-toluenesulfonic acid, and the like, and the better reaction can be realized at a lower temperature (0-10 ℃) in the presence of an acid binding agent, so that the effects of high product yield and purity can be realized, the product purity reaches more than 99%, and the environmental pollution is less.
Detailed Description
The technical scheme of the present invention will be further specifically described by means of specific examples, but the present invention is not limited to these examples.
Example 1
Preparation of 2-amino-2-phenylbutanol as compound of formula III
Adding 134.3g of solvent tetrahydrofuran into a clean four-neck flask, starting stirring, sequentially adding 17.9g (0.1 mol) of raw material 2-amino-2-phenylbutyric acid and 8.3g (0.22 mol) of sodium borohydride, slowly dropwise adding 12.7g (0.13 mol) of sulfuric acid under the condition of stirring at the temperature of 10-20 ℃, keeping the temperature at room temperature for reaction for 12h after the dropwise adding is finished, sampling and centrally controlling the reaction process, cooling the system temperature of the reaction solution to 10 ℃ after the centrally controlling the reaction is qualified, dropwise adding 53.7g (0.27 mol) of 20% sodium hydroxide aqueous solution by mass percent, controlling the dropwise adding temperature to 10-15 ℃, heating to reflux for 2h after the dropwise adding, stopping heating and standing for layering, collecting an upper organic phase, concentrating the collected organic phase under reduced pressure to recover tetrahydrofuran, and obtaining 14.2g of intermediate product 2-amino-2-phenylbutanol, wherein the GC content is 98.0%, and the GC yield is 86%.
Example 2
Preparation of 2-amino-2-phenylbutanol as Compound of formula IV
Taking 14.5g (0.086 mol) of the compound 2-amino-2-phenylbutanol of the formula III obtained in the example 1, 11.6g (0.22 mol) of formic acid with the mass fraction of 85% and 20.9g (0.26 mol) of formaldehyde with the mass fraction of 37% sequentially, putting the obtained mixture into a clean four-necked flask, heating and refluxing the mixture for 6 hours, sampling and centrally controlling the mixture in the reaction process, cooling the mixture to room temperature after the mixture is qualified in the central control, adding 12.6g (0.095 mol) of liquid alkali, regulating the pH value of the reaction solution to be 10-11, extracting the mixture with toluene (20 g multiplied by 2) twice, merging toluene layers obtained by the two extractions, washing the toluene layer with water twice (15 g multiplied by 2), and distilling the obtained toluene layer under reduced pressure to remove the solvent to obtain 15.8g of the corresponding intermediate compound 2-amino-2-phenylbutanol of the formula IV, wherein the GC content is 95%, and the yield is 95%.
Example 3
Preparation of the Compound trimebutine of formula I
31.6G of water, 9.61g (0.12 mol) of sodium bicarbonate, 50g of acetone and 15.8g (0.082 mol) of 2-amino-2-phenylbutanol of a compound shown in a formula IV are sequentially added into a clean four-port reaction bottle, the system is cooled to 5-10 ℃, then a mixed solution prepared by 22.62g (0.098 mol) of the compound shown in the formula V and 29g of acetone is slowly added dropwise, the temperature is controlled to 5-10 ℃ in the dropwise adding process, the heat preservation reaction is continued for 2 hours after the dropwise adding is finished, the acetone is recovered by reduced pressure distillation after the reaction is finished, the acetone is filtered, the obtained wet product solid product is leached twice (15 g is multiplied by 2) by water, and is dried, so that the final product trimebutine 29.14g is obtained, the product is white to pale yellow crystalline powder, the HPLC purity is 99.5%, and the single impurity is less than 0.1%, and the yield is 92%.
Example 4
Adding 150g of solvent tetrahydrofuran into a clean four-neck flask, starting stirring, sequentially adding 17.9g (0.1 mol) of raw material 2-amino-2-phenylbutyric acid and 9.4g (0.25 mol) of sodium borohydride, slowly dropwise adding 14.7g (0.15 mol) of sulfuric acid at 15-20 ℃ under the stirring state, keeping the temperature at room temperature for reaction for 14h after the dropwise adding is finished, sampling and centrally controlling the reaction process, cooling the system temperature of the reaction solution to 10 ℃ after the central control is qualified, dropwise adding 60g (the adding amount of sodium hydroxide is 0.3 mol) of 20% sodium hydroxide aqueous solution by mass percent, controlling the dropwise adding temperature to 10-15 ℃, heating to reflux for 2h after the dropwise adding, stopping heating and standing for layering, collecting an upper organic phase, concentrating the collected organic phase under reduced pressure to recover tetrahydrofuran, and obtaining 14.3g of intermediate product 2-amino-2-phenylbutanol, and obtaining light yellow viscous liquid with the GC content of 98.3%, wherein the GC content is 86.8%.
Taking 14.3g (0.085 mol) of the obtained 2-amino-2-phenylbutanol, 14.1g (0.26 mol) of formic acid with the mass fraction of 85% and 24.3g (0.3 mol) of formaldehyde with the mass fraction of 37% sequentially, putting the obtained mixture into a clean four-necked flask, heating and refluxing the mixture for 5 hours, sampling and centrally controlling the mixture in the reaction process, cooling the mixture to room temperature after the mixture is qualified, adding 13g (0.01 mol) of caustic soda liquid, regulating the pH value of the reaction solution system to be 10-11, extracting the mixture twice by toluene (20 g multiplied by 2), combining the toluene layers obtained by the two extractions, washing the toluene layer twice (15 g multiplied by 2), and carrying out reduced pressure distillation on the toluene layer obtained to remove the solvent to obtain 15.66g of the corresponding intermediate compound 2-amino-2-phenylbutanol with the formula IV, wherein the brown viscous liquid has the GC content of 95.4% and the yield of 95.5%.
Sequentially adding 32g of water, 10g of sodium bicarbonate, 60g of acetone and 15.9g of the obtained 2-amino-2-phenylbutanol into a clean four-port reaction bottle, cooling to 5-10 ℃, slowly dropwise adding a mixed solution prepared by 27.7g of a raw material formula V compound and 30g of acetone, controlling the temperature to 5-10 ℃ in the dropwise adding process, continuously carrying out heat preservation reaction for 3h after dropwise adding, carrying out reduced pressure distillation to recover acetone after the reaction is finished, filtering, leaching the obtained wet solid product with water twice (15 g is multiplied by 2), and drying to obtain 29.4g of final product trimebutine, wherein the purity of the product is 99.6%, the single impurity is less than 0.1%, and the yield is 92.3%.
Example 5
Adding 150g of solvent 1, 4-dioxane into a clean four-neck flask, starting stirring, sequentially adding 17.9g (0.1 mol) of raw material 2-amino-2-phenylbutyric acid and 11g (0.2 mol) of potassium borohydride, slowly dropwise adding 10.8g (0.11 mol) of sulfuric acid at 15-20 ℃ under the stirring state, keeping the temperature at room temperature for 11h after the dropwise adding, sampling and centrally controlling the reaction process, after the centrally controlling, cooling the system temperature of the reaction solution to 10 ℃ after the reaction is finished, dropwise adding 60g (the adding amount of sodium hydroxide is 0.3 mol) of 20% sodium hydroxide aqueous solution by mass percent, controlling the dropwise adding temperature to 10-15 ℃, heating to reflux for 2h after the dropwise adding, stopping heating and standing for layering, collecting an upper organic phase, concentrating the collected organic phase under reduced pressure to recover tetrahydrofuran, and obtaining 14.5g of intermediate product 2-amino-2-phenylbutanol, and obtaining light yellow viscous liquid with the GC content of 98.2%, wherein the GC content is 88%.
Taking 14.3g (0.085 mol) of the obtained 2-amino-2-phenylbutanol, 9.7g (0.18 mol) of formic acid with the mass fraction of 85% and 24.3g (0.3 mol) of formaldehyde with the mass fraction of 37% sequentially, putting the obtained mixture into a clean four-necked flask, heating and refluxing the mixture for 5 hours, sampling and centrally controlling the mixture in the reaction process, cooling the mixture to room temperature after the mixture is qualified, adding 13g (0.01 mol) of caustic soda liquid, regulating the pH value of the reaction solution system to be 10-11, extracting the mixture twice by toluene (20 g multiplied by 2), combining the toluene layers obtained by the two extractions, washing the toluene layer twice (15 g multiplied by 2), and carrying out reduced pressure distillation on the toluene layer obtained to remove the solvent to obtain 15.8g of the corresponding intermediate compound 2-amino-2-phenylbutanol with the formula IV, wherein the GC content is 95.4%, and the yield is 96.3%.
Sequentially adding 30g of water, 10g of sodium bicarbonate, 50g of acetone and 15.8g of the obtained 2-amino-2-phenylbutanol into a clean four-port reaction bottle, cooling to 5-10 ℃, slowly dropwise adding a mixed solution prepared by 27.7g of a raw material formula V compound and 30g of acetone, controlling the temperature to 5-10 ℃ in the dropwise adding process, continuously carrying out heat preservation reaction for 3h after dropwise adding, carrying out reduced pressure distillation to recover acetone after the reaction is finished, filtering, leaching the obtained wet solid product with water twice (15 g is multiplied by 2), and drying to obtain 29.4g of final product trimebutine, wherein the purity of the product is 99.4%, the single impurity is less than 0.1%, and the yield is 92.5%.
Example 6
180G of solvent ethylene glycol dimethyl ether is put into a clean four-neck flask, stirring is started, 17.9g (0.1 mol) of raw material 2-amino-2-phenylbutyric acid and 13g (0.24 mol) of potassium borohydride are sequentially put into the four-neck flask, then 12.7g (0.13 mol) of sulfuric acid is slowly added dropwise under the condition of stirring at 15-20 ℃, after the dropwise addition is finished, the reaction is carried out at room temperature for 10 hours, sampling and central control can be carried out in the reaction process, after the central control is finished, the system temperature of the reaction solution is cooled to 10 ℃,60 g (the adding amount of sodium hydroxide is 0.3 mol) of 20 percent by mass of sodium hydroxide aqueous solution is dropwise added, the dropwise addition temperature is controlled to be 10-15 ℃, the dropwise addition is finished, the temperature is raised to reflux for 2 hours, heating is stopped, the upper organic phase is collected in a standing layering mode, the collected organic phase is decompressed, the intermediate product 2-amino-2-phenylbutanol is 14.4g, the viscous liquid is obtained, and the GC content is 98.3 percent, and the yield is 87.6 percent.
Taking 14.3g (0.085 mol) of 2-amino-2-phenylbutanol obtained by the method, 10.8g (0.2 mol) of formic acid with the mass fraction of 85% and 27.6g (0.34 mol) of formaldehyde with the mass fraction of 37% sequentially, putting the materials into a clean four-necked flask, heating and refluxing for reaction for 6h, sampling and centrally controlling the materials in the reaction process, cooling the materials to room temperature after the materials are qualified in the central control, adding 13g (the amount of sodium hydroxide is 0.01 mol) of liquid alkali, adjusting the pH value of a reaction solution system to be 10-11, extracting twice by toluene (20 g multiplied by 2), combining toluene layers obtained by the two extractions, washing the toluene layers twice (15 g multiplied by 2), and carrying out reduced pressure distillation on the toluene layers obtained by the water layers to remove the solvent to obtain 15.2g of the corresponding intermediate compound 2-amino-2-phenylbutanol with the formula IV, wherein the GC content is 95.4%, and the yield is 92.6%.
70G of water, 11g of sodium bicarbonate, 60g of acetone and 15.4g of the obtained 2-amino-2-phenylbutanol are sequentially added into a clean four-port reaction bottle, the temperature is reduced to 5-10 ℃, then a mixed solution prepared by 22.2g of a raw material formula V compound and 20g of acetone is slowly added dropwise, in the dropwise process, the temperature is controlled to 5-10 ℃, after the dropwise process is finished, the heat preservation reaction is continued for 2.5h, after the reaction is finished, acetone is recovered by reduced pressure distillation, the obtained wet solid product is filtered, leached twice (15 g is multiplied by 2) by water, and the final product trimebutine 29g is obtained by drying, the white-like to light yellow crystal powder has the HPLC purity of 99.6%, the single impurity is less than 0.1%, and the yield is 94%.
Example 7
170G of solvent 2-methyltetrahydrofuran is put into a clean four-neck flask, stirring is started, 17.9g (0.1 mol) of raw material 2-amino-2-phenylbutyric acid and 8.3g (0.22 mol) of sodium borohydride are sequentially put into the four-neck flask, then 11.8g (0.12 mol) of sulfuric acid is slowly added dropwise under the condition of stirring at 15-20 ℃ under the condition of controlling the system temperature, after the dropwise adding is finished, the reaction is carried out at room temperature for 10 hours, sampling and central control can be carried out in the reaction process, after the central control is qualified, the system temperature of the reaction solution is cooled to 10 ℃, 58g of sodium hydroxide aqueous solution with the mass percent of 20% is dropwise added, the dropwise adding temperature is controlled to be 10-15 ℃, after the dropwise adding is finished, the dropwise adding is heated to reflux for 2 hours, heating and standing layering are stopped, an upper organic phase is collected, the collected organic phase is decompressed, concentrated and the solvent is recovered, and the intermediate product 2-amino-2-phenylbutanol 14.3g, light yellow viscous liquid with the GC content of 98.5% is obtained, and the yield is 87.1%.
Taking 14.3g (0.085 mol) of 2-amino-2-phenylbutanol obtained by the method, 10.8g (0.2 mol) of formic acid with the mass fraction of 85% and 27.6g (0.34 mol) of formaldehyde with the mass fraction of 37% sequentially, putting the materials into a clean four-necked flask, heating and refluxing for reaction for 6h, sampling and centrally controlling the materials in the reaction process, cooling the materials to room temperature after the materials are qualified in the central control, adding 13g (the amount of sodium hydroxide is 0.01 mol) of liquid alkali, adjusting the pH value of a reaction solution system to be 10-11, extracting twice by toluene (20 g multiplied by 2), combining toluene layers obtained by the two extractions, washing the toluene layers twice (15 g multiplied by 2), and carrying out reduced pressure distillation on the toluene layers obtained by the toluene layers to remove the solvent to obtain 15.1g of the corresponding intermediate compound 2-amino-2-phenylbutanol with the formula IV, wherein the GC content is 95.4%, and the yield is 92.2%.
Adding 65g of water, 11g of sodium bicarbonate, 65g of isopropanol and 15.1g of the obtained 2-amino-2-phenylbutanol into a clean four-port reaction bottle in sequence, cooling to 0-5 ℃, slowly dropwise adding a mixed solution prepared by 23g of a raw material formula V compound and 25g of isopropanol, controlling the temperature to 0-5 ℃ in the dropwise adding process, continuously carrying out heat preservation reaction for 2.5h after dropwise adding, carrying out reduced pressure distillation to recover solvent isopropanol and water after the reaction is finished, filtering, leaching the obtained wet solid product twice (15 g is multiplied by 2) with water, drying to obtain the final product trimebutine 28.3g, which is white to light yellow crystalline powder, wherein the HPLC purity is 99.5%, single impurity is less than 0.1%, and the yield is 93.6%.
The specific embodiments described herein are offered by way of illustration only. Those skilled in the art may make various modifications or additions to the described embodiments or substitutions thereof without departing from the spirit of the invention or exceeding the scope of the invention as defined in the accompanying claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (8)
1. A method for preparing trimebutine, which is characterized by comprising the following steps:
A. under the action of a catalyst, carrying out reduction reaction on the 2-amino-2-phenylbutyric acid of the compound of the formula II under the action of borohydride in an organic solvent to obtain an intermediate compound of the formula III, namely 2-amino-2-phenylbutanol; and the catalyst is selected from a protic acid or a lewis acid;
B. carrying out an aminomethylation reaction on a compound 2-amino-2-phenylbutanol, formaldehyde and formic acid in the formula III to obtain an intermediate compound 2- (dimethylamino) -2-phenylbutanol in the formula IV;
C. In the presence of an acid binding agent, carrying out esterification reaction on raw material 3,4, 5-trimethoxybenzoyl chloride of a formula V compound and an intermediate compound 2- (dimethylamino) -2-phenylbutanol of a formula IV compound, and controlling the temperature to be between 0 and 10 ℃ to obtain a final product of the compound of the formula I; the reaction is carried out in an organic solvent containing water, and the organic solvent is selected from an alcohol solvent or an acetone solvent; the mass ratio of the compound of the formula IV, namely 2- (dimethylamino) -2-phenylbutanol to water is 1:1 to 5; the acid-binding agent is selected from organic base or inorganic base, and the inorganic base is selected from carbonate or bicarbonate of alkali metal; the organic base is selected from piperidine, pyridine, pyrrole or organic amine; the alcohol solvent is selected from propanol, ethanol or isopropanol;
2. The preparation method of trimebutine according to claim 1, wherein in the step C, the acid binding agent is one or more selected from potassium carbonate, sodium bicarbonate and triethylamine.
3. The preparation method of trimebutine according to claim 1, wherein after the amine methylation reaction in the step B is finished, the preparation method further comprises the steps of adding an alkaline reagent into a reaction solution to adjust the pH value of the reaction solution to 10-11, then adding a water-insoluble solvent capable of dissolving the compound 2- (dimethylamino) -2-phenylbutanol of the formula IV for extraction, and distilling the collected organic phase to remove the solvent to obtain the compound 2- (dimethylamino) -2-phenylbutanol of the formula IV.
4. A process for the preparation of trimebutine according to any one of claims 1-3, characterized in that in step a the protic acid is selected from sulfuric acid; the Lewis acid is selected from one or more of aluminum trichloride, zinc chloride, boron trifluoride and calcium chloride.
5. A process for the preparation of trimebutine according to any one of claims 1-3, wherein in step a the borohydride is selected from one or more of lithium borohydride, sodium borohydride and potassium borohydride.
6. A process for the preparation of trimebutine according to any one of claims 1 to 3, characterized in that in step a the organic solvent is selected from the group of ethereal solvents.
7. The preparation method of trimebutine according to claim 6, wherein the ether solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, diethyl ether, ethylene glycol dimethyl ether and ethylene glycol monomethyl ether.
8. A process for the preparation of trimebutine according to any one of claims 1-3, wherein in step a the compound of formula ii is 2-amino-2-phenylbutyric acid: catalyst: the molar ratio of borohydride is 1:1.2 to 1.5:2.0 to 2.5; the compound of formula III described in step B is 2-amino-2-phenylbutanol: formaldehyde: the molar ratio of formic acid is 1:2.0 to 4.5:2.0 to 3.0; the intermediate compound of formula iv in step C, 2- (dimethylamino) -2-phenylbutanol: 3,4, 5-trimethoxybenzoyl chloride compound of formula v: the mole ratio of the acid binding agent is 1:1.1 to 1.5:1.2 to 1.6.
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|---|---|---|---|---|
| JPS5516416B2 (en) * | 1974-05-11 | 1980-05-01 | ||
| WO2008012603A1 (en) * | 2006-07-26 | 2008-01-31 | Techfields Biochem Co. Ltd | Positively charged water-soluble prodrugs of diflunisal and related compounds with very fast skin penetration rate |
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2021
- 2021-12-03 CN CN202111470165.1A patent/CN113999126B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5516416B2 (en) * | 1974-05-11 | 1980-05-01 | ||
| WO2008012603A1 (en) * | 2006-07-26 | 2008-01-31 | Techfields Biochem Co. Ltd | Positively charged water-soluble prodrugs of diflunisal and related compounds with very fast skin penetration rate |
Non-Patent Citations (1)
| Title |
|---|
| X-ray crystallographic and NMR spectroscopical characterization of intermediates in the Pd-catalyzed allylic substitution reaction with 4-substituted phosphinooxazolines. Correlation between intermediate structure and product configuration;Margareta Zehnder，等;《Inorganica Chimica Acta》;第337卷;287-298 * |
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