CN114437022A - Preparation method of duloxetine intermediate - Google Patents
Preparation method of duloxetine intermediate Download PDFInfo
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- CN114437022A CN114437022A CN202111662305.5A CN202111662305A CN114437022A CN 114437022 A CN114437022 A CN 114437022A CN 202111662305 A CN202111662305 A CN 202111662305A CN 114437022 A CN114437022 A CN 114437022A
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- thienyl
- dimethyl
- propylamine
- hydroxy
- methanol
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- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 title claims abstract description 21
- 229960002866 duloxetine Drugs 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- WYJOVVXUZNRJQY-UHFFFAOYSA-N 2-Acetylthiophene Chemical compound CC(=O)C1=CC=CS1 WYJOVVXUZNRJQY-UHFFFAOYSA-N 0.000 claims abstract description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 47
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 29
- XWCNSHMHUZCRLN-UHFFFAOYSA-N 3-(dimethylamino)-1-thiophen-2-ylpropan-1-ol Chemical compound CN(C)CCC(O)C1=CC=CS1 XWCNSHMHUZCRLN-UHFFFAOYSA-N 0.000 claims abstract description 26
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 20
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 20
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 20
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000243 solution Substances 0.000 claims abstract description 15
- 239000011259 mixed solution Substances 0.000 claims abstract description 14
- 229930040373 Paraformaldehyde Natural products 0.000 claims abstract description 13
- 229920002866 paraformaldehyde Polymers 0.000 claims abstract description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006479 redox reaction Methods 0.000 claims abstract description 8
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims abstract description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract 2
- 239000007787 solid Substances 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 238000001035 drying Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 230000000171 quenching effect Effects 0.000 claims description 5
- HPVHJPMLORARSR-UHFFFAOYSA-N 3-(dimethylamino)-1-thiophen-2-ylpropan-1-one;hydron;chloride Chemical compound Cl.CN(C)CCC(=O)C1=CC=CS1 HPVHJPMLORARSR-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 18
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titanium dioxide Inorganic materials O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 abstract description 6
- 239000006227 byproduct Substances 0.000 abstract description 4
- 230000036632 reaction speed Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000011964 heteropoly acid Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 5
- 229960002496 duloxetine hydrochloride Drugs 0.000 description 5
- JFTURWWGPMTABQ-UHFFFAOYSA-N n,n-dimethyl-3-naphthalen-1-yloxy-3-thiophen-2-ylpropan-1-amine Chemical compound C=1C=CC2=CC=CC=C2C=1OC(CCN(C)C)C1=CC=CS1 JFTURWWGPMTABQ-UHFFFAOYSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 3
- YEJVVFOJMOHFRL-UHFFFAOYSA-N 3-(methylamino)-1-thiophen-2-ylpropan-1-ol Chemical compound CNCCC(O)C1=CC=CS1 YEJVVFOJMOHFRL-UHFFFAOYSA-N 0.000 description 3
- 238000006683 Mannich reaction Methods 0.000 description 3
- SHPBBNULESVQRH-UHFFFAOYSA-N [O-2].[O-2].[Ti+4].[Zr+4] Chemical compound [O-2].[O-2].[Ti+4].[Zr+4] SHPBBNULESVQRH-UHFFFAOYSA-N 0.000 description 3
- 238000005902 aminomethylation reaction Methods 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000002105 nanoparticle Substances 0.000 description 3
- 229960002748 norepinephrine Drugs 0.000 description 3
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001768 cations Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- QJOYDDZDFRTXPE-QRPNPIFTSA-N (1S)-3-(dimethylamino)-1-thiophen-2-ylpropan-1-ol hydrochloride Chemical compound Cl.CN(C)CC[C@H](O)C1=CC=CS1 QJOYDDZDFRTXPE-QRPNPIFTSA-N 0.000 description 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 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000240602 cacao Species 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 230000000742 histaminergic effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- -1 imine ion Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 229910052758 niobium Inorganic materials 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- RVTZCBVAJQQJTK-UHFFFAOYSA-N oxygen(2-);zirconium(4+) Chemical compound [O-2].[O-2].[Zr+4] RVTZCBVAJQQJTK-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
- 229910001928 zirconium oxide Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
The invention provides a preparation method of a duloxetine intermediate, which relates to the technical field of chemical synthesis and comprises the following steps; (1) mixing 2-acetylthiophene, concentrated hydrochloric acid, phosphotungstic acid loaded with zirconia-titanium oxide, paraformaldehyde and dimethyl methanol to obtain 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride; (2) dissolving 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride in a methanol solution to obtain a mixed solution 1, adding sodium borohydride to carry out redox reaction to obtain (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine; (3) dissolving (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine in a mixed solution of toluene and methanol, and dropwise adding S-mandelic acid to obtain S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine. The invention uses the phosphotungstic acid loaded with zirconia-titania as a catalyst, accelerates the reaction speed, improves the reaction yield and avoids the generation of byproducts.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of a duloxetine intermediate.
Background
Duloxetine is an anxiolytic, antidepressant drug, primarily a norepinephrine and 5-hydroxytryptamine reuptake inhibitor, with a dual channel, usually used as the hydrochloride salt. Because duloxetine is unstable and easily degraded in an acidic environment, duloxetine or a salt thereof is suitably formulated into an enteric preparation to resist the destruction of the drug by gastric juice.
The pharmacological mechanism of duloxetine hydrochloride is as follows: the exact mechanism of antidepressant and central analgesic effects of duloxetine hydrochloride is not clear, but it is thought to be involved in its potentiation of central nervous system 5-hydroxytryptamine energy and norepinephrine function. The results of preclinical studies show that duloxetine hydrochloride is a strong inhibitor of reuptake of 5-hydroxytryptamine and norepinephrine, and has a relatively weak inhibition effect on reuptake of dopamine. The results of in vitro studies show that duloxetine hydrochloride has no significant affinity with dopaminergic receptors, adrenergic receptors, cholinergic receptors, histaminergic receptors, opioid receptors, glutamate receptors, GABA receptors. Duloxetine hydrochloride does not inhibit monoamine oxidase.
The published patent application No. CN200710028364.0 discloses a preparation method of (S) -duloxetine key intermediate, which takes 3-dimethylamino-1- (2-thienyl) -1-lactone hydrochloride as a raw material, adopts chiral monosulfonyldiamide-ruthenium catalyst and formate as a hydrogen source reagent, and prepares (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine hydrochloride through asymmetric transfer hydrogenation reaction in a proper organic solvent. The method has the advantages of no need of nitrogen protection, mild reaction conditions, simple operation, high reaction yield and enantioselectivity, and is expected to provide a simple, convenient and effective new method for industrial production of (S) -duloxetine.
The preparation method of the duloxetine intermediate in the prior art has the advantages of long reaction time, cocoa reaction conditions, low yield and high cost.
Disclosure of Invention
In view of the above, the present application provides a method for preparing a duloxetine intermediate, which comprises preparing 3-dimethylamino 1- (2-thienyl) -1-propanone hydrochloride from 2-acetylthiophene by aminomethylation, reducing with sodium borohydride to obtain (RS) N, N-monomethyl 3-hydroxy 3- (2-thienyl) propylamine, and then resolving with S- (+) -mandelic acid to obtain (S) - (-) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine. By using the phosphotungstic acid loaded with the zirconium oxide-titanium oxide as a catalyst, the reaction speed is accelerated, the raw materials are saved, the reaction time is shortened, the reaction yield is improved, and meanwhile, the generation of byproducts can be avoided.
The invention relates to a preparation method of a duloxetine intermediate, which comprises the following steps;
(1) 2-acetylthiophene, concentrated hydrochloric acid and phosphotungstic acid loaded with zirconia-titanium oxide (as
The catalyst is added in an amount of 4-4.6 percent of 2-acetylthiophene), paraformaldehyde and dimethyl methanol (solvent) are mixed, the molar weight of the paraformaldehyde is 1.4 times of that of the 2-acetylthiophene, the mixture is stirred and reacted for 7-8 hours, and the molar ratio of the 2-acetylthiophene to concentrated hydrochloric acid is 13-14: 1, quenching and filtering, washing and drying a filter cake to obtain 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride with a structural formula
；
In this step, under the environment of concentrated hydrochloric acid, 2-acetylthiophene and paraformaldehyde carry out Mannich reaction, and the reaction mechanism is shown as follows. The protonation of carbonyl, nucleophilic addition of amine to carbonyl, deprotonation, electron transfer on nitrogen and water separation to obtain an imine ion intermediate. The addition amount of hydrochloric acid in the reaction determines the degree and the speed of the Mannich reaction, and the molar ratio of the 2-acetylthiophene to the concentrated hydrochloric acid is 13-14: 1, the effective proceeding of the reaction can be well ensured, and the yield is ensured.
The phosphotungstic acid loaded with zirconia-titania is used as a catalyst, zirconia and titania are particles with nanometer particle diameters, and the loaded catalyst is easy to separate reaction liquid, enlarges the specific surface area of the catalyst and improves the catalytic activity. The ratio of the number of surface atoms to the total number of atoms of the nanoparticles increases dramatically as the size of the nanoparticles decreases. This surface effect allows the nanomaterial to have a large specific surface area. The large specific surface area and the severely mismatched bonds can cause the appearance of a plurality of active centers, the surface steps and roughness are increased, and the surface has non-chemical equilibrium and non-integer coordination valency, so that the chemical property of the nano system is greatly different from that of a chemical equilibrium system. The nanometer material has wide application in the field of catalysis, and the metallic nanometer particles can greatly improve the catalytic effect when being used as a catalyst. The phosphotungstic acid in the application loads two nano-sized titanium oxide and zirconium oxide, and can achieve the purpose of improving the catalytic effect, the phosphotungstic acid is a heteropoly acid, and the heteropoly acid is a kind of oxygen-containing polyacid which is formed by coordination and bridging of heteroatoms (also called central atoms, such as P, Si, Fe, note Co and the like) and polyatomic atoms (also called coordinated atoms, such as Mo, W, V, Nb and the like) through oxygen atoms according to a certain structure. The heteropoly acid has a determined structure, the heteropolyanion is a primary structure, the heteropolyanion and the counter cation form a secondary structure, and the heteropolyanion, the counter cation and the crystal water are arranged in a three-dimensional space to form a tertiary structure. Of the traditional heteropolyacids, phosphotungstic acid is the highest in acidity, and another important property of heteropolyacids is its unique "quasi-liquid phase" behavior. Because the heteropoly acid has a cage structure like zeolite, certain gaps are reserved among heteropoly acid anions in a bulk phase, and a plurality of smaller polar molecules (such as water, alcohol, ammonia, pyridine and the like) can enter the bulk phase of the heteropoly acid. Therefore, the change occurring on the surface of the heteropoly-acid can be rapidly spread to various places in the bulk phase. Thus, besides the surface phase catalysis, the solid heteropoly acid catalyst can also have the characteristic of homogeneous phase catalytic reaction like a concentrated sulfuric acid catalyst, which greatly enhances the catalytic capability of the heteropoly acid.
The main application of the 2-acetylthiophene is as follows: used as solvent, extractant and medical intermediate. In the application, 2-acetylthiophene is used as a raw material for preparing a duloxetine intermediate (S) - (-) -N, N-dimethyl-3-hydroxy-3- (2-thiophene) propylamine, and generates a Mannich reaction with paraformaldehyde under the condition that phosphotungstic acid loaded with zirconia-titania is used as a catalyst.
(2) Dissolving 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride in methanol
And (3) obtaining a mixed solution 1 in the solution, adjusting the pH value to 11-12 by using sodium hydroxide, adding sodium borohydride, carrying out oxidation-reduction reaction for 5-6h, wherein the temperature of the oxidation-reduction reaction is 28-32 ℃, the sodium borohydride has strong selective reducibility, a small amount of sodium borohydride can reduce nitrile into aldehyde, and excessive sodium borohydride can reduce nitrile into amine. If the amount of sodium borohydride is small, aldehyde as an impurity is generated, the molar ratio of 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride to sodium borohydride in the application is 10: 6-6.5, adding acetone into the reaction solution after the reaction is finished, evaporating the solvent under reduced pressure, and then performing suction filtration, drying and recrystallization (using ethyl acetate which is a substance commonly used in the organic purification process) to obtain (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine;
the 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride is reduced by sodium borohydride to generate amine, the addition amount of the sodium borohydride in the reaction process can influence the generation of the amine, and the addition amount is strictly controlled to avoid the generation of byproducts.
(3) Dissolving (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine in methyl
And (2) dropwise adding S-mandelic acid (chiral resolving agent) into the mixed solution of benzene and methanol, and reacting at 80-84 ℃ for 50-65min to obtain a white solid (S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine.S- (+) -mandelate), (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine and S-mandelic acid, wherein the molar ratio of the S-mandelic acid to the N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine to the S-mandelic acid is 1: 1-1.2, dissolving the white solid in water, extracting, washing and drying to obtain S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine, wherein the extraction is to adjust the pH value to 11-12 after dissolving the white solid in water, extracting with ethyl acetate and washing with saturated saline solution; the S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine is recrystallized and purified by using a methanol solution. The structural formula of the S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine is shown in the specification;
the main function of this step is to carry out chiral resolution, dissolving (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine in the mixed solution of toluene and methanol, and racemizing S-mandelic acid as resolving agent. (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine is racemic and optically resolved by a diastereoisomeric salt formation method.
The invention adopts aminomethylation reaction to prepare 3-dimethylamino 1- (2-thienyl) -1-acetone hydrochloride by using 2-acetylthiophene as a raw material, obtains (RS) N, N-monomethyl 3-hydroxy 3- (2-thienyl) propylamine by reduction of sodium borohydride, and then obtains (S) - (-) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine by resolution of S- (+) -mandelic acid. By using the phosphotungstic acid loaded with the zirconium oxide-titanium oxide as a catalyst, the reaction speed is accelerated, the reaction time is shortened, and the reaction yield is improved.
Best mode for carrying out the invention
The present invention will be described in detail with reference to specific embodiments.
Example 1
A preparation method of a duloxetine intermediate comprises the following steps;
(1) 2-acetylthiophene, concentrated hydrochloric acid and phosphotungstic acid loaded with zirconia-titanium oxide (as
The catalyst is added, the adding amount of the catalyst is 4 percent of that of the 2-acetylthiophene), after the paraformaldehyde and the dimethyl methanol solvent are mixed, the molar weight of the paraformaldehyde is 1.4 times of that of the 2-acetylthiophene, the mixture is stirred and reacted for 7 hours, and the molar ratio of the 2-acetylthiophene to the concentrated hydrochloric acid is 13: 1, carrying out suction filtration after quenching, washing and drying a filter cake to obtain 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride;
(2) dissolving 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride in methanol
Obtaining a mixed solution 1 in the solution, adjusting the pH value to 11 by using sodium hydroxide, adding sodium borohydride, carrying out redox reaction for 5 hours at the temperature of 28 ℃, wherein the molar ratio of 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride to sodium borohydride is 10: 6, adding acetone into the reaction solution after the reaction is finished, evaporating the solvent under reduced pressure, and then carrying out suction filtration, drying and recrystallization to obtain (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine;
(3) dissolving (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine in methyl
And (2) dropwise adding S-mandelic acid into the mixed solution of benzene and methanol, and reacting at 80 ℃ for 50min to obtain a white solid (S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine, S- (+) -mandelate), (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine and S-mandelic acid, wherein the molar ratio of the S-mandelic acid to the N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine to the S-mandelic acid is 1: 1, dissolving the white solid in water, extracting, washing and drying to obtain S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine, wherein in the extraction, after the white solid is dissolved in the water, the pH value is adjusted to 11, the white solid is extracted by ethyl acetate, and the white solid is washed by saturated saline solution; the S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine is recrystallized and purified by using a methanol solution.
The overall yield of S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine in this example was calculated to be 67.6%.
Example 2
A preparation method of a duloxetine intermediate comprises the following steps;
(1) 2-acetylthiophene, concentrated hydrochloric acid and phosphotungstic acid loaded with zirconia-titanium oxide (as
The catalyst is added in an amount of 4.6 percent of 2-acetylthiophene), and after paraformaldehyde and dimethyl methanol (solvent) are mixed, the molar weight of the paraformaldehyde is 1.4 times of that of the 2-acetylthiophene, the mixture is stirred and reacted for 8 hours, and the molar ratio of the 2-acetylthiophene to concentrated hydrochloric acid is 14: 1, carrying out suction filtration after quenching, washing and drying a filter cake to obtain 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride;
(2) dissolving 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride in methanol
Obtaining a mixed solution 1 in the solution, adjusting the pH value to 12 by using sodium hydroxide, adding sodium borohydride, carrying out redox reaction for 6 hours at the temperature of 32 ℃, wherein the molar ratio of 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride to sodium borohydride is 10: 6.5, adding acetone into the reaction solution after the reaction is finished, evaporating the solvent under reduced pressure, and then carrying out suction filtration, drying and recrystallization to obtain (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine;
(3) dissolving (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine in methyl
And (2) dropwise adding S-mandelic acid into the mixed solution of benzene and methanol, and reacting at 84 ℃ for 65min to obtain a white solid (the white solid is S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine.S- (+) -mandelate), (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine and S-mandelic acid, wherein the molar ratio of the S-mandelic acid to the N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine is 1: 1.2, dissolving the white solid in water, extracting, washing and drying to obtain S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine, wherein in the extraction, after the white solid is dissolved in the water, the pH value is adjusted to 12, the white solid is extracted by ethyl acetate, and the white solid is washed by saturated saline solution; the S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine is recrystallized and purified by using a methanol solution.
The overall yield of S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine in this example was calculated to be 66.2%.
Example 3
A preparation method of a duloxetine intermediate comprises the following steps;
(1) 2-acetylthiophene, concentrated hydrochloric acid and phosphotungstic acid loaded with zirconia-titanium oxide (as
The catalyst is added, the addition amount of the catalyst is 4.3 percent of 2-acetylthiophene), and after paraformaldehyde and a dimethyl methanol solvent are mixed, the molar weight of the paraformaldehyde is 1.4 times of that of the 2-acetylthiophene, the mixture is stirred and reacted for 7.5 hours, and the molar ratio of the 2-acetylthiophene to concentrated hydrochloric acid is 13.5: 1, carrying out suction filtration after quenching, washing and drying a filter cake to obtain 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride;
(2) dissolving 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride in methanol
Obtaining a mixed solution 1 in the solution, adjusting the pH value to 11.5 by using sodium hydroxide, adding sodium borohydride, carrying out redox reaction for 5.5h at the temperature of 30 ℃, wherein the molar ratio of 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride to sodium borohydride is 10: 6.3, adding acetone into the reaction solution after the reaction is finished, evaporating the solvent under reduced pressure, and then carrying out suction filtration, drying and recrystallization (using ethyl acetate which is a substance commonly used in the organic purification process) to obtain (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine;
(3) dissolving (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine in methyl
And (2) dropwise adding S-mandelic acid into the mixed solution of benzene and methanol, reacting at 83 ℃ for 55min to obtain a white solid (S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine, S- (+) -mandelate), (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine and S-mandelic acid, wherein the molar ratio of the S-mandelic acid to the N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine to the S-mandelic acid is 1: 1.1, dissolving the white solid in water, extracting, washing and drying to obtain S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine, wherein in the extraction, after the white solid is dissolved in the water, the pH value is adjusted to 11.2, the white solid is extracted by ethyl acetate, and the white solid is washed by saturated saline solution; the S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine is recrystallized and purified by using a methanol solution.
The overall yield of S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine in this example was calculated to be 65.3%.
The invention adopts aminomethylation reaction to prepare 3-dimethylamino 1- (2-thienyl) -1-acetone hydrochloride by using 2-acetylthiophene as a raw material, obtains (RS) N, N-monomethyl 3-hydroxy 3- (2-thienyl) propylamine by reduction of sodium borohydride, and then obtains (S) - (-) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine by resolution of S- (+) -mandelic acid. By using the phosphotungstic acid loaded with the zirconium oxide-titanium oxide as a catalyst, the reaction speed is accelerated, the raw materials are saved, the reaction time is shortened, the reaction yield is improved, and meanwhile, the generation of byproducts can be avoided.
Claims (9)
1. A preparation method of a duloxetine intermediate is characterized by comprising the following steps;
mixing 2-acetylthiophene, concentrated hydrochloric acid, phosphotungstic acid loaded with zirconia-titanium oxide, paraformaldehyde and dimethyl methanol, stirring to react for 7-8h, quenching, performing suction filtration, washing and drying a filter cake to obtain 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride;
dissolving 3-dimethylamino-1- (2-thienyl) -1-acetone hydrochloride in a methanol solution to obtain a mixed solution 1, adjusting the pH value to be alkaline, adding sodium borohydride to carry out redox reaction, adding acetone into the reaction solution after the reaction is finished, removing the solvent, carrying out suction filtration, drying and recrystallization to obtain (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine;
dissolving (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine in a mixed solution of toluene and methanol, then dropwise adding S-mandelic acid, reacting at 80-84 ℃ for 50-65min to obtain a white solid, adding water to the white solid for dissolving, and then extracting, washing and drying to obtain the S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine.
2. A method for preparing duloxetine intermediate according to claim 1, wherein the molar ratio of 3-dimethylamino-1- (2-thienyl) -1-propanone hydrochloride to sodium borohydride in step (2) is 10: 6-6.5.
3. The process according to claim 1, wherein the pH of the mixed solution 1 in the step (2) is 11 to 12.
4. A process according to claim 3, wherein the time for said redox reaction is from 5 to 6 hours.
5. The process of claim 1, wherein step (3) further comprises purifying S-N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine by recrystallization from methanol.
6. A process for preparing a duloxetine intermediate according to claim 1, wherein the molar ratio of 2-acetylthiophene to concentrated hydrochloric acid in step (1) is 13-14: 1.
7. a process according to claim 6, wherein the molar amount of paraformaldehyde in step (1) is 1.4 times that of 2-acetylthiophene.
8. A process for the preparation of duloxetine intermediate as claimed in claim 1, wherein the molar Ratio of (RS) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine to S-mandelic acid in step (3) is 1: 1-1.2.
9. A duloxetine intermediate as claimed in claim 8, wherein the extraction is carried out by dissolving the white solid in water, adjusting pH to 11-12, extracting with ethyl acetate, and washing with saturated brine.
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