CN114790146B - Preparation method of 3- (methylamino) -1-aryl acetone - Google Patents
Preparation method of 3- (methylamino) -1-aryl acetone Download PDFInfo
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- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 title claims abstract description 79
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- -1 aryl acetone Chemical compound 0.000 claims abstract description 50
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 13
- 238000005691 oxidative coupling reaction Methods 0.000 claims abstract description 13
- 230000008569 process Effects 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 21
- WYJOVVXUZNRJQY-UHFFFAOYSA-N 2-Acetylthiophene Chemical compound CC(=O)C1=CC=CS1 WYJOVVXUZNRJQY-UHFFFAOYSA-N 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 14
- 229910052723 transition metal Inorganic materials 0.000 claims description 12
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 11
- 239000007800 oxidant agent Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000005947 deacylation reaction Methods 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- 230000001590 oxidative effect Effects 0.000 claims description 9
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical group [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 claims description 7
- 229940078494 nickel acetate Drugs 0.000 claims description 7
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 claims description 6
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 claims description 6
- IQZLUWLMQNGTIW-UHFFFAOYSA-N acetoveratrone Chemical compound COC1=CC=C(C(C)=O)C=C1OC IQZLUWLMQNGTIW-UHFFFAOYSA-N 0.000 claims description 6
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 4
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 4
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 4
- WYECURVXVYPVAT-UHFFFAOYSA-N 1-(4-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C=C1 WYECURVXVYPVAT-UHFFFAOYSA-N 0.000 claims description 3
- BUZYGTVTZYSBCU-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1 BUZYGTVTZYSBCU-UHFFFAOYSA-N 0.000 claims description 3
- ZDPAWHACYDRYIW-UHFFFAOYSA-N 1-(4-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C=C1 ZDPAWHACYDRYIW-UHFFFAOYSA-N 0.000 claims description 3
- IEMMBWWQXVXBEU-UHFFFAOYSA-N 2-acetylfuran Chemical compound CC(=O)C1=CC=CO1 IEMMBWWQXVXBEU-UHFFFAOYSA-N 0.000 claims description 3
- XSAYZAUNJMRRIR-UHFFFAOYSA-N 2-acetylnaphthalene Chemical compound C1=CC=CC2=CC(C(=O)C)=CC=C21 XSAYZAUNJMRRIR-UHFFFAOYSA-N 0.000 claims description 3
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- MBHINSULENHCMF-UHFFFAOYSA-N n,n-dimethylpropanamide Chemical compound CCC(=O)N(C)C MBHINSULENHCMF-UHFFFAOYSA-N 0.000 claims description 3
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical class CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 3
- 125000002252 acyl group Chemical group 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 7
- LUCXVPAZUDVVBT-UNTBIKODSA-N atomoxetine hydrochloride Chemical compound Cl.O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C LUCXVPAZUDVVBT-UNTBIKODSA-N 0.000 description 7
- WDKDECVQWMKUQU-UHFFFAOYSA-N 1-(methylamino)-3-thiophen-2-ylpropan-2-one Chemical compound CNCC(=O)CC1=CC=CS1 WDKDECVQWMKUQU-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 229960002496 duloxetine hydrochloride Drugs 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 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 6
- 239000000243 solution Substances 0.000 description 6
- CAIKBWLFBLRPJU-UHFFFAOYSA-N 3-(methylamino)-1-phenylpropan-1-one Chemical compound CNCCC(=O)C1=CC=CC=C1 CAIKBWLFBLRPJU-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000006683 Mannich reaction Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 229960002430 atomoxetine Drugs 0.000 description 3
- 229960002828 atomoxetine hydrochloride Drugs 0.000 description 3
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 3
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- UBLAMGLZYYIDOI-UHFFFAOYSA-N N-methyl-N-(3-oxo-3-phenylpropyl)formamide Chemical compound CN(CCC(=O)c1ccccc1)C=O UBLAMGLZYYIDOI-UHFFFAOYSA-N 0.000 description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 2
- 229940011182 cobalt acetate Drugs 0.000 description 2
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 description 2
- 229940079721 copper chloride Drugs 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 229940071125 manganese acetate Drugs 0.000 description 2
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 2
- XVFWDBZVDQSOPX-UHFFFAOYSA-N n-methyl-n-(3-oxo-3-phenylpropyl)acetamide Chemical compound CC(=O)N(C)CCC(=O)C1=CC=CC=C1 XVFWDBZVDQSOPX-UHFFFAOYSA-N 0.000 description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 2
- LGQLOGILCSXPEA-UHFFFAOYSA-L nickel sulfate Chemical compound [Ni+2].[O-]S([O-])(=O)=O LGQLOGILCSXPEA-UHFFFAOYSA-L 0.000 description 2
- 229910000363 nickel(II) sulfate Inorganic materials 0.000 description 2
- KBJMLQFLOWQJNF-UHFFFAOYSA-N nickel(ii) nitrate Chemical compound [Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O KBJMLQFLOWQJNF-UHFFFAOYSA-N 0.000 description 2
- 238000007867 post-reaction treatment Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- KFGFVPMRLOQXNB-UHFFFAOYSA-N 3,5,5-trimethylhexanoyl 3,5,5-trimethylhexaneperoxoate Chemical compound CC(C)(C)CC(C)CC(=O)OOC(=O)CC(C)CC(C)(C)C KFGFVPMRLOQXNB-UHFFFAOYSA-N 0.000 description 1
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 1
- 229940122200 5 Hydroxytryptamine uptake inhibitor Drugs 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010066218 Stress Urinary Incontinence Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- OTYNBGDFCPCPOU-UHFFFAOYSA-N phosphane sulfane Chemical compound S.P[H] OTYNBGDFCPCPOU-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- 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
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
Abstract
The invention provides a preparation method of 3- (methylamino) -1-aryl acetone, and relates to the technical field of chemical synthesis. According to the invention, aryl acetone is used as a starting material, N-methyl-N- (3-oxo-3-aryl propyl) amide compounds are obtained through oxidative coupling decarboxylation reaction with N, N-dimethyl amide compounds, acyl groups are removed through a simple and easy-to-operate method, and finally 3- (methylamino) -1-aryl acetone is obtained. The method synthesizes the target product 3- (methylamino) -1-aryl acetone through two steps of reactions, has the advantages of simple process, low cost of raw materials, simple and convenient operation, mild reaction conditions, environment friendliness, no use of expensive catalysts, and high yield and purity of the obtained product, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of 3- (methylamino) -1-aryl acetone.
Background
The 3- (methylamino) -1-aryl acetone is an important compound and can be used as a key intermediate of medicines such as atomoxetine hydrochloride, duloxetine hydrochloride and the like.
Atomoxetine hydrochloride (atomoxetine hydrochloride), chemical name (R) -N-methyl-3- (2-methylphenoxy) -3-phenyl-1-propanamine hydrochloride, structural formula I, was developed by Lilly pharmaceutical company in the United states and was approved by the FDA in the United states for 11 months 2002, and was marketed in the United states for 1 month 2003. It is used for the treatment of attention deficit/hyperactivity disorder (ADHD) in children and adolescents (6-18 years).
Duloxetine hydrochloride (duloxetine hydrochloride/Cymbaha), a 5-hydroxytryptamine and norepinephrine reuptake inhibitor developed by Lilly corporation in the united states, is a third generation antidepressant drug of formula II, is useful for the treatment of major depression, and for the relief of central pain such as diabetic peripheral neuropathic pain and female fibromyalgia, and is also useful for the treatment of female stress urinary incontinence. It has the advantages of good chemical stability, safety, effectiveness, less side effects, low affinity to other nervous systems, etc.
The structural general formula of the 3- (methylamino) -1-aryl acetone is shown as a formula III, wherein the acetophenone corresponds to the derivative 3- (methylamino) -1-phenylpropane-1-ketone and can be used for preparing a key intermediate of tomoxetine hydrochloride; the 2-acetylthiophene corresponding derivative 3- (methylamino) -1- (thiophen-2-yl) acetone can be used for preparing a key intermediate of duloxetine hydrochloride.
The procedure for obtaining 3- (methylamino) -1-aryl-propanone by Mannich reaction of an acetyl aromatic compound (2-acetylthiophene) with dimethylamine hydrochloride and paraformaldehyde in isopropanol is reported by Lilly company in U.S. Pat. No. 3,182A, and the reaction process is shown in formula (1). Although the synthetic method is mature, the amount of paraformaldehyde and dimethylamine hydrochloride required in the method is large, the paraformaldehyde and the dimethylamine hydrochloride cannot be recycled, in addition, the N-methyl needs to be removed by chloroformate, the cost of using the chloroformate is high, and the post-reaction treatment is complex.
Chinese patent CN1742003a reports a method for obtaining 3- (methylamino) -1-aryl acetone by Mannich reaction of acetyl aromatic compound (2-acetylthiophene) with methylamine hydrochloride and paraformaldehyde in isopropanol, wherein the reaction process is shown in formula (2). Since methylamine belongs to a primary amine, the monosubstituted product compound I (3- (methylamino) -1-aryl-propanone) is less via the Mannich reaction, inevitably yielding a disubstituted compound (compound II) which either becomes waste or is converted to compound I under treatment with excess methylamine hydrochloride, gaseous methylamine or liquid methylamine. The method has higher cost and complex post-reaction treatment.
It has also been reported (El-Khagawa, ahmed μm.; el-Zohry, mahereF.; ismail, mohamed T.; PREDF; phosphorus Sulfur; EN;33;1987; 25-32.; chirality,2000,12 (1): 26-29; CA: 2513542) that 3-chloro-1- (2-aryl) -acetone is produced by a classical Friedel-Crafts acylation reaction using an aromatic compound and 3-chloropropionyl chloride, followed by reaction with aqueous methylamine to produce 3-methylamino-1- (2-aryl) -1-propanone as shown in formula (3). However, the yield of Friedel-crafts reaction is too low, and the post-treatment is also complicated. 3-chloro-1- (2-aryl) -acetone reacts with methylamine to easily produce a disubstituted product.
Chen et al (Shaorui Chen, aijun Li, mingming Chen, synthesis and dual-HT 1a/SSRI activitiesof some novel arylpiperazine derivatives of duloxetin. Asian Jounal ofChemistry, (2012) 4:1680-1684) reported the reaction of an acetyl aromatic compound (2-acetylthiophene) with N, N-dimethylformamide dimethyl acetal (DMF-DMA), N-Dimethylformamide (DMF), lithium aluminum hydride (LiAlH) 4 ) The method for obtaining the 3- (methylamino) -1-aryl acetone by reducing and removing one N-methyl group has the reaction process shown in the formula (4), and the DMF-DMA raw material in the route is relatively expensive, unstable and difficult to store.
The prior art for preparing 3- (methylamino) -1-aryl acetone has the problems of complex method, high cost and the like. With the increasing market demands of medicines such as tomoxetine hydrochloride and duloxetine hydrochloride, the pharmaceutical industry market is in urgent need of further research and development of the production process of key intermediates, and a novel efficient and simple 3- (methylamino) -1-aryl acetone synthesis method is needed.
Disclosure of Invention
The invention aims to provide a preparation method of 3- (methylamino) -1-aryl acetone, which is simple and low in synthesis cost, and the yield of a target product 3- (methylamino) -1-aryl acetone is higher.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of 3- (methylamino) -1-aryl acetone, which comprises the following steps:
mixing aryl acetone, N-dimethylamide compounds, an oxidant and transition metal salt, and performing oxidative coupling decarboxylation reaction to obtain N-methyl-N- (3-oxo-3-aryl propyl) amide compounds;
and mixing the N-methyl-N- (3-oxo-3-aryl propyl) amide compound with sodium hydroxide, manganese dioxide and a solvent, and performing deacylation reaction to obtain 3- (methylamino) -1-aryl acetone.
Preferably, the temperature of the oxidative coupling decarboxylation reaction is 90-120 ℃ and the time is 10-14 h.
Preferably, the mol ratio of the aryl acetone to the N, N-dimethylamide compound to the oxidant to the transition metal salt is 1:3-10:2-4:0.05-0.1.
Preferably, the aryl acetone comprises one or more of acetophenone, 4-chloroacetophenone, 4-bromoacetophenone, 4-fluoroacetophenone, 4-methylacetophenone, 4-methoxyacetophenone, 3, 4-dimethoxyacetophenone, 2-naphthylethanone, 2-acetylthiophene and 2-acetylfuran.
Preferably, the N, N-dimethylformamide compound comprises one or more of N, N-dimethylformamide, N-dimethylacetamide and N, N-dimethylpropionamide.
Preferably, the oxidant comprises one or more of potassium persulfate, ammonium persulfate, aqueous solution of tert-butyl peroxide, benzoyl peroxide and di-tert-butyl peroxide.
Preferably, the transition metal salt includes one or more of copper acetate, cobalt acetate, manganese acetate, nickel acetate, copper chloride, nickel chloride, copper nitrate, nickel nitrate and nickel sulfate.
Preferably, the deacylation reaction is carried out at a temperature of 10-40 ℃ for a time of 12-16 h.
Preferably, the solvent is a mixed solvent of an alcohol solvent and water.
Preferably, the volume ratio of the alcohol solvent to the water is 7-9:1.
The invention provides a preparation method of 3- (methylamino) -1-aryl acetone, which comprises the following steps: mixing aryl acetone, N-dimethylamide compounds, an oxidant and transition metal salt, and performing oxidative coupling decarboxylation reaction to obtain N-methyl-N- (3-oxo-3-aryl propyl) amide compounds; and mixing the N-methyl-N- (3-oxo-3-aryl propyl) amide compound with sodium hydroxide, manganese dioxide and a solvent, and performing deacylation reaction to obtain 3- (methylamino) -1-aryl acetone. According to the invention, aryl acetone is used as a starting material, N-methyl-N- (3-oxo-3-aryl propyl) amide compounds are obtained through oxidative coupling decarboxylation reaction with N, N-dimethyl amide compounds, acyl groups are removed through a simple and easy-to-operate method, and finally 3- (methylamino) -1-aryl acetone is obtained. The method synthesizes the target product 3- (methylamino) -1-aryl acetone through two steps of reactions, has the advantages of simple process, low cost of raw materials, simple and convenient operation, mild reaction conditions, environment friendliness, no use of expensive catalysts, and high yield and purity of the obtained product, and is suitable for industrial production. The results of the examples show that the 3- (methylamino) -1-aryl-acetone prepared by the invention has higher yield and purity, the total yield is 60-70%, and the purity is 98.5-99%.
Detailed Description
The invention provides a preparation method of 3- (methylamino) -1-aryl acetone, which comprises the following steps:
mixing aryl acetone, N-dimethylamide compounds, an oxidant and transition metal salt, and performing oxidative coupling decarboxylation reaction to obtain N-methyl-N- (3-oxo-3-aryl propyl) amide compounds;
and mixing the N-methyl-N- (3-oxo-3-aryl propyl) amide compound with sodium hydroxide, manganese dioxide and a solvent, and performing deacylation reaction to obtain 3- (methylamino) -1-aryl acetone.
In the present invention, all raw materials are commercially available products well known to those skilled in the art unless specified otherwise.
In the invention, the preparation flow of the 3- (methylamino) -1-aryl acetone is as follows:
the invention mixes aryl acetone, N-dimethyl amide compound, oxidant and transition metal salt, and carries out oxidative coupling decarboxylation reaction to obtain N-methyl-N- (3-oxo-3-aryl propyl) amide compound. In the invention, the molar ratio of the aryl acetone, the N, N-dimethylamide compound, the oxidant and the transition metal salt is preferably 1:3-10:2-4:0.05-0.1, more preferably 1:4-6:3-4:0.08-0.1.
In the present invention, the aromatic acetone preferably includes one or more of acetophenone, 4-chloroacetophenone, 4-bromoacetophenone, 4-fluoroacetophenone, 4-methylacetophenone, 4-methoxyacetophenone, 3, 4-dimethoxyacetophenone, 2-naphthylethanone, 2-acetylthiophene and 2-acetylfuran. In the present invention, the N, N-dimethylamide compound preferably includes one or more of N, N-dimethylformamide, N-dimethylacetamide and N, N-dimethylpropionamide. In the present invention, the oxidizing agent preferably includes one or more of potassium persulfate, ammonium persulfate, t-butyl peroxide (TBHP) aqueous solution, benzoyl Peroxide (BPO), and di-t-butyl peroxide (DTHP). In the present invention, the mass concentration of the aqueous t-butyl peroxide solution is preferably 70%. In the present invention, the transition metal salt preferably includes one or more of copper acetate, cobalt acetate, manganese acetate, nickel acetate, copper chloride, nickel chloride, copper nitrate, nickel nitrate and nickel sulfate. In the invention, the transition metal salt is used as a catalyst to catalyze the oxidative coupling decarboxylation reaction of the aryl acetone and the N, N-dimethylamide compounds.
In the present invention, the temperature of the oxidative coupling decarboxylation reaction is preferably 90 to 120 ℃, more preferably 100 to 110 ℃; the time of the oxidative coupling decarboxylation reaction is preferably 10 to 14 hours, more preferably 10 to 12 hours.
The invention preferably comprises the steps of standing and cooling an obtained system to room temperature after the oxidative coupling decarboxylation reaction, adding water for dilution, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, and performing column chromatography to obtain the N-methyl-N- (3-oxo-3-aryl propyl) amide compound. In the present invention, the reagents used for the column chromatography are preferably petroleum ether and ethyl acetate.
After obtaining N-methyl-N- (3-oxo-3-aryl propyl) amide compounds, the invention mixes the N-methyl-N- (3-oxo-3-aryl propyl) amide compounds with sodium hydroxide, manganese dioxide and a solvent to carry out deacylation reaction to obtain 3- (methylamino) -1-aryl acetone. In the present invention, the mass ratio of the N-methyl-N- (3-oxo-3-arylpropyl) amide compound, sodium hydroxide, manganese dioxide and the solvent is preferably 1:0.25 to 0.5:0.25 to 0.5:30, more preferably 1:0.25 to 0.3:0.25 to 0.3:30. In the present invention, the method of mixing is preferably mechanical stirring. The invention uses sodium hydroxide and manganese dioxide to remove formyl or acetyl.
In the present invention, the solvent is preferably a mixed solvent of an alcohol solvent and water. In the present invention, the volume ratio of the alcohol solvent to water is preferably 7 to 9:1, more preferably 8 to 9:1. In the present invention, the alcohol solvent is preferably methanol or ethanol.
In the present invention, the temperature of the deacylation reaction is preferably 10 to 40 ℃, more preferably 20 to 30 ℃; the time for the deacylation reaction is preferably 12 to 16 hours, more preferably 12 to 14 hours.
In the present invention, preferably, after the deacylation reaction, the obtained reaction system is filtered to remove manganese dioxide, the solvent is removed by spin-evaporation, and then the solid is recrystallized to obtain 3- (methylamino) -1-aryl acetone.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Into a three-necked flask equipped with a thermometer, 1.21g of acetophenone, 5.22g of N, N-dimethylacetamide, 3.85g of 70wt% aqueous solution of t-butyl peroxide and 0.25g of nickel acetate were added, the mixture was magnetically stirred, the temperature was raised to 100℃in an oil bath, the mixture was kept warm for 12 hours, and then the mixture was allowed to stand still and cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and then subjected to column chromatography to give 1.50g of N-methyl-N- (3-oxo-3-phenylpropyl) acetamide in 73% yield. The obtained N-methyl-N- (3-oxo-3-phenylpropyl) acetamide was dissolved in 45mL of ethanol, 5.5mL of an aqueous sodium hydroxide solution (containing 0.38g of sodium hydroxide) was added, 0.38g of manganese dioxide was mechanically stirred for 14 hours, acetyl groups were removed, manganese dioxide was removed by filtration after the reaction was completed, ethanol solvent was removed by rotary evaporation, and the remaining solid was recrystallized to obtain 3- (methylamino) -1-phenylpropan-1-one, and the total yield of the two steps was 66%. The purity of the 3- (methylamino) -1-phenylpropan-1-one prepared in this example was 99%.
Example 2
Into a three-necked flask equipped with a thermometer, 1.21g of acetophenone, 4.38g of N, N-dimethylformamide, 3.85g of 70wt% aqueous solution of t-butyl peroxide, 0.25g of nickel acetate, magnetic stirring, heating to 100℃in an oil bath, maintaining the temperature for 12 hours, then standing and cooling to room temperature, diluting with water, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, and then carrying out column chromatography to obtain 1.34g of N-methyl-N- (3-oxo-3-phenylpropyl) formamide with a yield of 70%. The obtained N-methyl-N- (3-oxo-3-phenylpropyl) formamide was dissolved in 40mL of ethanol, 5mL of an aqueous sodium hydroxide solution (containing 0.34g of sodium hydroxide) was added, 0.34g of manganese dioxide was mechanically stirred for 14h, the formyl group was removed, after the reaction was completed, manganese dioxide was removed by filtration, the solvent ethanol was removed by rotary evaporation, and the remaining solid was recrystallized to obtain 3- (methylamino) -1-phenylpropan-1-one, and the total yield of the two steps was 65%. The purity of the 3- (methylamino) -1-phenylpropan-1-one prepared in this example was 99%.
Example 3
1.26g of 2-acetylthiophene, 5.22g of N, N-dimethylacetamide, 3.85g of 70wt% of tert-butyl peroxide aqueous solution, 0.25g of nickel acetate, magnetic stirring, heating to 100 ℃ in an oil bath, preserving heat for 12 hours, standing and cooling to room temperature, adding water for dilution, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, and performing column chromatography to obtain 1.52g of N-methyl-N- (3-oxo-3- (thiophen-2-yl) propyl) acetamide with the yield of 72%. The obtained N-methyl-N- (3-oxo-3- (thiophen-2-yl) propyl) acetamide was dissolved in 45mL of ethanol, 5.5mL of an aqueous sodium hydroxide solution (containing 0.38g of sodium hydroxide) was added, 0.38g of manganese dioxide was mechanically stirred for 14h, acetyl groups were removed, the reaction was completed, manganese dioxide was removed by filtration, the solvent ethanol was removed by rotary evaporation, and the remaining solid was recrystallized to give 3- (methylamino) -1- (thiophen-2-yl) acetone, and the total yield of the two steps was 64%. The purity of the 3- (methylamino) -1- (thiophen-2-yl) propanone prepared in this example was 99%.
Example 4
1.26g of 2-acetylthiophene, 4.38g of N, N-dimethylformamide, 3.85g of 70wt% of tert-butyl peroxide aqueous solution, 0.25g of nickel acetate, magnetic stirring, heating to 100 ℃ in an oil bath, preserving heat for 12 hours, standing and cooling to room temperature, diluting with water, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, and performing column chromatography to obtain 1.38g of N-methyl-N- (3-oxo-3- (thiophen-2-yl) propyl) formamide with the yield of 70%. The N-methyl-N- (3-oxo-3- (thiophene-2-yl) propyl) formamide is dissolved in 42mL of ethanol, 5mL of sodium hydroxide aqueous solution (containing 0.35g of sodium hydroxide) is added, manganese dioxide is 0.35g, mechanical stirring is carried out for 14h, formyl groups are removed, after the reaction is finished, manganese dioxide is removed by filtration, solvent ethanol is removed by rotary evaporation, and the residual solid is recrystallized, so that 3- (methylamino) -1- (thiophene-2-yl) acetone is obtained, and the total yield is 63%. The purity of the 3- (methylamino) -1- (thiophen-2-yl) propanone prepared in this example was 99%.
The synthesis method of the 3- (methylamino) -1-aryl acetone provided by the invention simplifies the synthesis steps and reduces the synthesis cost. The results of the examples show that the 3- (methylamino) -1-aryl-acetone obtained by the method provided by the invention has higher yield and purity. It is emphasized that 3- (methylamino) -1-phenylpropane-1-one, wherein acetophenone is correspondingly derived, can be used for preparing tomoxetine hydrochloride key intermediates; the 2-acetylthiophene corresponding derivative 3- (methylamino) -1- (thiophen-2-yl) acetone can be used for preparing a key intermediate of duloxetine hydrochloride.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (8)
1. A method for preparing 3- (methylamino) -1-aryl acetone, which comprises the following steps:
mixing aryl acetone, N-dimethylamide compounds, an oxidant and transition metal salt, and performing oxidative coupling decarboxylation reaction to obtain N-methyl-N- (3-oxo-3-aryl propyl) amide compounds; the aryl acetone is selected from one or more of acetophenone, 4-chloroacetophenone, 4-bromoacetophenone, 4-fluoroacetophenone, 4-methylacetophenone, 4-methoxyacetophenone, 3, 4-dimethoxy acetophenone, 2-naphthyl ethanone, 2-acetyl thiophene and 2-acetyl furan; the transition metal salt is nickel acetate;
and mixing the N-methyl-N- (3-oxo-3-aryl propyl) amide compound with sodium hydroxide, manganese dioxide and a solvent, and performing deacylation reaction to obtain 3- (methylamino) -1-aryl acetone.
2. The preparation method according to claim 1, wherein the temperature of the oxidative coupling decarboxylation reaction is 90-120 ℃ for 10-14 hours.
3. The preparation method according to claim 1, wherein the molar ratio of the aryl acetone, the N, N-dimethylamide compound, the oxidant and the transition metal salt is 1:3-10:2-4:0.05-0.1.
4. The method according to claim 1, wherein the N, N-dimethylamide compound is one or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide and N, N-dimethylpropionamide.
5. The method according to claim 1, wherein the oxidizing agent is one or more selected from the group consisting of potassium persulfate, ammonium persulfate, aqueous t-butyl peroxide, benzoyl peroxide and di-t-butyl peroxide.
6. The process according to claim 1, wherein the deacylation reaction is carried out at a temperature of 10 to 40 ℃ for a period of 12 to 16 hours.
7. The method according to claim 1, wherein the solvent is a mixed solvent of an alcohol solvent and water.
8. The method according to claim 7, wherein the volume ratio of the alcohol solvent to water is 7 to 9:1.
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