CN115286613A - Preparation method of duloxetine hydrochloride - Google Patents
Preparation method of duloxetine hydrochloride Download PDFInfo
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- CN115286613A CN115286613A CN202211219178.6A CN202211219178A CN115286613A CN 115286613 A CN115286613 A CN 115286613A CN 202211219178 A CN202211219178 A CN 202211219178A CN 115286613 A CN115286613 A CN 115286613A
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- 229960002496 duloxetine hydrochloride Drugs 0.000 title claims abstract description 51
- 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 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 110
- 238000003756 stirring Methods 0.000 claims abstract description 90
- 238000001914 filtration Methods 0.000 claims abstract description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 30
- XWCNSHMHUZCRLN-QMMMGPOBSA-N (1s)-3-(dimethylamino)-1-thiophen-2-ylpropan-1-ol Chemical compound CN(C)CC[C@H](O)C1=CC=CS1 XWCNSHMHUZCRLN-QMMMGPOBSA-N 0.000 claims abstract description 29
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 27
- 238000006722 reduction reaction Methods 0.000 claims abstract description 27
- 239000002131 composite material Substances 0.000 claims abstract description 25
- 238000001035 drying Methods 0.000 claims abstract description 25
- GMBHLHMRHUMBHU-UHFFFAOYSA-N butan-2-one;hydrochloride Chemical compound Cl.CCC(C)=O GMBHLHMRHUMBHU-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000006683 Mannich reaction Methods 0.000 claims abstract description 17
- 238000005406 washing Methods 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 14
- 238000010520 demethylation reaction Methods 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 239000008367 deionised water Substances 0.000 claims abstract description 7
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 41
- 239000007864 aqueous solution Substances 0.000 claims description 38
- WYJOVVXUZNRJQY-UHFFFAOYSA-N 2-Acetylthiophene Chemical compound CC(=O)C1=CC=CS1 WYJOVVXUZNRJQY-UHFFFAOYSA-N 0.000 claims description 34
- 235000019441 ethanol Nutrition 0.000 claims description 34
- 239000000243 solution Substances 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 238000001816 cooling Methods 0.000 claims description 24
- 238000010992 reflux Methods 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 18
- 239000011259 mixed solution Substances 0.000 claims description 18
- 239000012279 sodium borohydride Substances 0.000 claims description 17
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 claims description 16
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 16
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 16
- 238000000498 ball milling Methods 0.000 claims description 15
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 claims description 14
- 239000000176 sodium gluconate Substances 0.000 claims description 14
- 235000012207 sodium gluconate Nutrition 0.000 claims description 14
- 229940005574 sodium gluconate Drugs 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- CWLKTJOTWITYSI-UHFFFAOYSA-N 1-fluoronaphthalene Chemical compound C1=CC=C2C(F)=CC=CC2=C1 CWLKTJOTWITYSI-UHFFFAOYSA-N 0.000 claims description 11
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 11
- 238000001704 evaporation Methods 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 11
- 229920002866 paraformaldehyde Polymers 0.000 claims description 11
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 claims description 10
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- -1 1-naphthoxy Chemical group 0.000 claims description 9
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 claims description 8
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 8
- 235000010413 sodium alginate Nutrition 0.000 claims description 8
- 239000000661 sodium alginate Substances 0.000 claims description 8
- 229940005550 sodium alginate Drugs 0.000 claims description 8
- 239000012312 sodium hydride Substances 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- 235000010265 sodium sulphite Nutrition 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 6
- 230000001678 irradiating effect Effects 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- WGYKZJWCGVVSQN-UHFFFAOYSA-N mono-n-propyl amine Natural products CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 238000004140 cleaning Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 8
- 239000003054 catalyst Substances 0.000 abstract description 7
- 238000004821 distillation Methods 0.000 abstract description 6
- 230000035484 reaction time Effects 0.000 abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 230000003287 optical effect Effects 0.000 description 12
- 238000004811 liquid chromatography Methods 0.000 description 11
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- 229940122200 5 Hydroxytryptamine uptake inhibitor Drugs 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- GYVRJKAGZONKTB-UHFFFAOYSA-N N,N-dimethyl-2-thiophenepropanamine Chemical compound CN(C)CCCC1=CC=CS1 GYVRJKAGZONKTB-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010066218 Stress Urinary Incontinence Diseases 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
Images
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
The invention discloses a preparation method of duloxetine hydrochloride, belonging to the technical field of duloxetine hydrochloride, and the preparation method comprises the following steps: mannich reaction, reduction reaction, alkylation reaction and demethylation reaction; the reduction reaction comprises the steps of adding 2-thiophene-2-dimethylamine methylethylketone hydrochloride and a composite reducing agent into an ethanol solution, controlling the temperature to 25-28 ℃, starting stirring, simultaneously using ultraviolet rays for irradiation, then dropwise adding a sodium hydroxide solution until the pH value is 10-11, then continuously stirring for 40-45min, carrying out reduced pressure distillation, filtering to obtain filter residues, washing with deionized water, and drying to obtain (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine; the invention can simplify the production flow, shorten the reaction time, improve the purity and the yield of the product, avoid the use of expensive catalysts and raw materials and have mild reaction conditions.
Description
Technical Field
The invention relates to the technical field of duloxetine hydrochloride, and in particular relates to a preparation method of duloxetine hydrochloride.
Background
Duloxetine hydrochloride, the mesocultural name of which is (S) - (+) -N-methyl-3- (1-naphthoxy) -3- (2-thiophene) -propylamine hydrochloride, is a 5-hydroxytryptamine and norepinephrine reuptake inhibitor developed by Eli Lilly, and can inhibit the reuptake of neurons to 5-hydroxytryptamine and norepinephrine, thereby increasing the concentration of the two central neurotransmitters in brain and spinal cord, and thus can be used for treating certain mood diseases such as depression and anxiety, and relieving central pain such as diabetes, peripheral neuropathic pain, and female fibromyalgia. Duloxetine hydrochloride also acts on 5-hydroxytryptamine and norepinephrine receptors in the urinary tract to increase the nervous tone and contractile ability of the urethral sphincter, and is therefore also effective in treating stress urinary incontinence in women.
The existing preparation method of duloxetine hydrochloride comprises the following steps:
taking 2-acetylthiophene, dimethylamine hydrochloride and paraformaldehyde as raw materials, performing Mannich reaction, reduction reaction, salt forming reaction, hydrolysis reaction and alkylation reaction, and hydrolyzing by sodium hydroxide to remove N-methyl to obtain duloxetine hydrochloride, wherein the hydrolysis reaction has a plurality of byproducts, so that the purity and yield of the product are influenced, and the reaction route is complex;
the method comprises the following steps of (1) reacting 2-thiophenecarboxylic acid serving as a raw material with oxalyl chloride and vinyl tributyltin, adding HCl, carrying out reduction reaction, reacting with sodium iodide, reacting with methylamine, and reacting with 1-fluoronaphthalene to obtain duloxetine hydrochloride, wherein a catalyst used in the reduction reaction is expensive;
the method comprises the following steps of taking 3-chloro-1- (2-thiophene) -acetone as a raw material, carrying out reduction reaction, removing lipase, reacting with sodium iodide, reacting with methylamine, and then reacting with 1-fluoronaphthalene to obtain duloxetine hydrochloride, wherein by-products which are not easy to separate are generated in the route, so that the purity and yield of the product are reduced;
reacting 2-acetylthiophene with paraformaldehyde and N-methylbenzylamine, reacting with phenyl chloroformate, reducing by sodium borohydride, hydrolyzing by sodium hydroxide, splitting by S- (+) -mandelic acid, and carrying out a alkylation reaction with 1-fluoronaphthalene to obtain duloxetine hydrochloride, wherein a metal catalyst used in the route is expensive, so that the production cost is high;
the duloxetine hydrochloride is obtained by Mannich reaction, reduction reaction, hydroxylation reaction and demethylation reaction of 2-acetylthiophene, dimethylamine hydrochloride and paraformaldehyde which are taken as raw materials, but a chiral auxiliary agent sodium borohydride is required in the route, the cost of the sodium borohydride is high, and the optical purity of the prepared (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine is low.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of duloxetine hydrochloride, which can simplify the production process, shorten the reaction time, improve the purity and yield of the product, avoid the use of expensive catalysts and raw materials, and has mild reaction conditions.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of duloxetine hydrochloride comprises the following steps: mannich reaction, reduction reaction, alkylation reaction and demethylation reaction.
The Mannich reaction comprises the steps of adding 2-acetylthiophene, dimethylamine hydrochloride and paraformaldehyde into isopropanol, then adding concentrated hydrochloric acid, starting stirring, controlling the stirring speed to 80-100rpm, heating to reflux, cooling to room temperature after refluxing for 6-7h, filtering, taking filter residue, washing for 2-3 times by using absolute ethyl alcohol, and drying at 70-75 ℃ until the weight is unchanged to obtain 2-thiophene-2-dimethylamine methylethylketone hydrochloride;
in the Mannich reaction, the weight ratio of 2-acetylthiophene, dimethylamine hydrochloride and paraformaldehyde is 700-720;
in the Mannich reaction, the weight ratio of 2-acetylthiophene to isopropanol to concentrated hydrochloric acid is 70-72;
in the Mannich reaction, the mass concentration of the concentrated hydrochloric acid is 36-38%.
The reduction reaction comprises the steps of adding 2-thiophene-2-dimethylamine methylethylketone hydrochloride and a composite reducing agent into an ethanol solution, controlling the temperature to 25-28 ℃, starting stirring, controlling the stirring speed to 60-80rpm, simultaneously irradiating by using ultraviolet rays with the wavelength of 220-250nm, then dropwise adding a sodium hydroxide solution, controlling the dropwise adding speed to 10-12g/min, dropwise adding until the pH value is 10-11, continuously stirring for 40-45min, stopping stirring and ultraviolet irradiation, evaporating ethanol by reduced pressure distillation, filtering to obtain filter residues, washing with deionized water for 2-3 times, and drying at 65-70 ℃ until the weight is unchanged to obtain (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine;
in the reduction reaction, the weight ratio of 2-thiophene-2-dimethylamine methylethylketone hydrochloride, the composite reducing agent and the ethanol solution is 100;
in the reduction reaction, the mass concentration of ethanol in the ethanol solution is 31-34%;
in the reduction reaction, the preparation method of the composite reducing agent comprises the following steps: mixing a sodium alginate aqueous solution with the mass concentration of 0.4-0.6% and a n-pentylamine aqueous solution with the mass concentration of 2.5-2.8% to obtain a mixed solution, controlling the temperature of the mixed solution to 30-35 ℃, starting stirring, controlling the stirring speed to 100-120rpm, adjusting the pH of the mixed solution to 4-4.5 by using a hydrochloric acid aqueous solution with the mass concentration of 4-5%, then dropwise adding a silver nitrate aqueous solution with the mass concentration of 0.8-1%, controlling the dropwise adding speed to 11-13g/min, continuously stirring for 20-25min after the dropwise adding is finished, adding sodium sulfite, continuously stirring for 25-30min, then adding ethanol, continuously stirring for 40-45min, filtering to obtain filter residues, and drying at 65-70 ℃ until the weight is not changed to obtain a negative carrier; mixing a negative carrier, sodium gluconate and sodium borohydride, then carrying out ball milling, controlling the ball-material ratio during ball milling to be 10-12;
in the preparation of the composite reducing agent, the weight ratio of sodium alginate aqueous solution with mass concentration of 0.4-0.6%, n-pentylamine aqueous solution with mass concentration of 2.5-2.8%, silver nitrate aqueous solution with mass concentration of 0.8-1%, sodium sulfite and ethanol is 350-10-20;
in the preparation of the composite reducing agent, the weight ratio of the loading agent to the sodium gluconate to the sodium borohydride is (10-12).
The alkylation reaction comprises the steps of adding (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine into dimethyl sulfoxide, dropwise adding a sodium hydride water solution with the mass concentration of 59-61%, controlling the dropwise adding speed to be 20-22g/min, controlling the temperature to be 25-28 ℃ after dropwise adding is finished, starting stirring, controlling the stirring speed to be 80-100rpm, stirring for 20-25min, heating to 40-45 ℃, dropwise adding 1-fluoronaphthalene, controlling the dropwise adding speed to be 13-15g/min, reacting for 5-6 hours at 40-45 ℃ after dropwise adding is finished to obtain a reaction liquid, cooling the reaction liquid to 2-4 ℃, adding acetic acid to adjust the pH to be 4-4.5, taking a water phase, extracting for 3 times by using ethyl acetate, combining the extraction liquid to the organic phase, cleaning the organic phase for 2-3 times by using a sodium chloride water solution, adding anhydrous magnesium sulfate, drying, filtering, and removing the solvent in the obtained filtrate to obtain (S) -N, N-dimethyl-3- (1-thienyl) propylamine 2-naphthyl oxide;
in the alkylation reaction, the weight ratio of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine to dimethyl sulfoxide to 59-61% of sodium hydride aqueous solution to 1-fluoronaphthalene is 18-20.
The demethylation reaction comprises the steps of dissolving (S) -N, N-dimethyl-3- (1-naphthoxy) -2-thienyl propylamine in dichloromethane, cooling to 2-4 ℃, dropwise adding 1-chloroethyl chloroformate, controlling the dropwise adding speed to be 12-15g/min, heating to reflux after dropwise adding is finished, steaming out the solvent after refluxing for 2-2.5h, controlling the temperature to be 40-45 ℃ after residues are dissolved by using methanol, keeping the temperature for 1-1.2h, steaming out 85-90% of the total volume of methanol, adding acetone which is 8-9 times of the volume of the residual methanol, cooling to 1-3 ℃, stirring for 1.5-1.8h, filtering to obtain filter residues, and obtaining duloxetine hydrochloride;
in the demethylation reaction, the weight ratio of (S) -N, N-dimethyl-3- (1-naphthoxy) -2-thienylpropylamine to dichloromethane to 1-chloroethyl chloroformate to methanol is 38-40.
Compared with the prior art, the invention has the beneficial effects that:
(1) The preparation method of duloxetine hydrochloride can simplify the production process and shorten the reaction time, and only comprises four steps of Mannich reaction, reduction reaction, alkylation reaction and demethylation reaction;
(2) The preparation method of duloxetine hydrochloride can improve the purity and yield of the prepared duloxetine hydrochloride, the purity of the prepared duloxetine hydrochloride can reach 99.89-99.95%, and the total yield can reach 55.45-58.46%;
(3) According to the preparation method of duloxetine hydrochloride, the use of expensive catalysts and raw materials can be avoided, sodium borohydride and sodium gluconate are used for replacing lithium aluminum hydride, and then the sodium borohydride and the sodium gluconate are loaded on water-soluble silver ions as reducing agents, so that the reducibility of the sodium borohydride and the sodium gluconate can be improved, the cost of the catalysts and the raw materials is reduced, and the yield of the prepared (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine is improved;
(4) The preparation method of duloxetine hydrochloride has mild reaction conditions, does not need to carry out reaction at high temperature or low temperature, and reduces the reaction energy consumption.
Drawings
FIG. 1 is a liquid chromatography analysis of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine prepared in example 1;
FIG. 2 is a liquid chromatography analysis of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine prepared in example 2;
FIG. 3 is a liquid chromatography analysis of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine prepared in example 3;
FIG. 4 is a liquid chromatography analysis of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine prepared in example 4;
FIG. 5 is a diagram of liquid chromatography for the optical purity detection of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine prepared in example 1;
FIG. 6 is a diagram of liquid chromatography for optical purity measurement of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine prepared in example 2;
FIG. 7 is a diagram of liquid chromatography for optical purity measurement of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine prepared in example 3;
FIG. 8 is a liquid chromatography analysis chart for the optical purity detection of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine prepared in example 4.
Detailed Description
In order to more clearly understand the technical features, objects, and effects of the present invention, specific embodiments of the present invention will now be described.
Example 1
A preparation method of duloxetine hydrochloride comprises the following steps:
1. mannich reaction: adding 700g of 2-acetylthiophene, 670g of dimethylamine hydrochloride and 290g of paraformaldehyde into 1700g of isopropanol, then adding 40g of concentrated hydrochloric acid, starting stirring, controlling the stirring speed to 80rpm, heating to reflux, cooling to room temperature after refluxing for 6 hours, filtering, taking filter residue, washing for 2 times by using absolute ethanol, and drying at 70 ℃ until the weight is unchanged to obtain 1161g of 2-thiophene-2-dimethylamine methylethylketone hydrochloride with the yield of 95.68% (calculated by 2-acetylthiophene);
the mass concentration of the concentrated hydrochloric acid is 36%.
2. Reduction reaction: adding 100g of 2-thiophene-2-dimethylamine methylethylketone hydrochloride and 60g of composite reducing agent into 220g of ethanol solution, controlling the temperature to 25 ℃, starting stirring, controlling the stirring speed to 60rpm, simultaneously irradiating by using ultraviolet rays with the wavelength of 220nm, then dropwise adding a sodium hydroxide solution, controlling the dropwise adding speed to 10g/min, dropwise adding until the pH value is 10, then continuing to stir for 40min, stopping stirring and ultraviolet irradiation, distilling off the ethanol by reduced pressure distillation, filtering to obtain filter residue, washing for 2 times by using deionized water, and drying at 65 ℃ until the weight is unchanged to obtain 58g of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine, wherein the yield is 68.46% (calculated by 2-thiophene-2-dimethylamine methylethylketone hydrochloride);
the weight concentration of ethanol in the ethanol solution is 31 percent;
the preparation method of the composite reducing agent comprises the following steps: mixing 350g of a sodium alginate aqueous solution with the mass concentration of 0.4% and 10g of a n-pentylamine aqueous solution with the mass concentration of 2.5% to obtain a mixed solution, controlling the temperature of the mixed solution to 30 ℃, starting stirring and controlling the stirring speed to 100rpm, adjusting the pH of the mixed solution to 4 by using a hydrochloric acid aqueous solution with the mass concentration of 4%, then dropwise adding 18g of a silver nitrate aqueous solution with the mass concentration of 0.8%, controlling the dropwise adding speed to 11g/min, continuously stirring for 20min after dropwise adding, adding 0.08g of sodium sulfite, continuously stirring for 25min, then adding 100g of ethanol, continuously stirring for 40min, filtering to obtain filter residue, drying at 65 ℃ until the weight is not changed to obtain a negative carrier, mixing 10g of the negative carrier, 40g of sodium gluconate and 50g of sodium borohydride, and then carrying out ball-milling, controlling the ball-to-material ratio during ball-milling to be 10 1, rotating speed to be 300rpm, temperature to be 25 ℃, time to be 30min, and obtaining the composite reducing agent after ball-milling.
3. And (3) a alkylation reaction: adding 18g of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine into 145g of dimethyl sulfoxide, dropwise adding 21g of a 59% sodium hydride aqueous solution with the dropwise adding speed controlled to be 20g/min, controlling the temperature to be 25 ℃ after the dropwise adding is finished, starting stirring, controlling the stirring speed to be 80rpm, stirring for 20min, heating to 40 ℃, dropwise adding 26g of 1-fluoronaphthalene with the dropwise adding speed controlled to be 13g/min, reacting at 40 ℃ for 5h after the dropwise adding is finished to obtain a reaction liquid, cooling the reaction liquid to 2 ℃, adding acetic acid to adjust the pH to 4, taking a water phase, extracting for 3 times by using ethyl acetate, combining extract liquid into an organic phase, washing the organic phase for 2 times by using a sodium chloride aqueous solution, adding anhydrous magnesium sulfate, drying, filtering, and removing the solvent in the obtained filtrate to obtain 29g of (S) -N, N-dimethyl-3- (1-naphthyloxy) -2-thienyl (the yield is 95.85% (calculated by (S) -N, N-dimethyl-3-thienyl) propylamine).
4. And (3) demethylation reaction: dissolving 38g of (S) -N, N-dimethyl-3- (1-naphthoxy) -2-thienyl propylamine in 290g of dichloromethane, cooling to 2 ℃, dropwise adding 20g of 1-chloroethyl chloroformate at a speed of 12g/min, heating to reflux after dropwise adding, refluxing for 2h, evaporating the solvent, dissolving the residue with 80g of methanol, controlling the temperature to 40 ℃, keeping the temperature for 1h, evaporating to remove 85% of the total volume of methanol, adding acetone which is 8 times of the volume of the rest methanol, cooling to 1 ℃, stirring for 1.5h, filtering to obtain filter residue, obtaining 36g of duloxetine hydrochloride, and carrying out liquid chromatography on duloxetine hydrochloride, wherein the purity of the prepared duloxetine hydrochloride is 99.94% and the yield is 88.32% (calculated by (S) -N, N-dimethyl-3- (1-naphthoxy) -2-thienyl propylamine) and the total yield is 55.45% and 100% when the optical purity is detected, and a liquid chromatogram in optical purity detection is shown in figure 5.
Example 2
A preparation method of duloxetine hydrochloride comprises the following steps:
1. mannich reaction: adding 710g of 2-acetylthiophene, 675g of dimethylamine hydrochloride and 292g of paraformaldehyde into 1710g of isopropanol, then adding 52g of concentrated hydrochloric acid, starting stirring, controlling the stirring speed to 85rpm, heating to reflux, refluxing for 6.2h, cooling to room temperature, filtering, taking filter residue, washing with absolute ethyl alcohol for 2 times, and drying at 72 ℃ until the weight is unchanged to obtain 1184g of 2-thiophene-2-dimethylamine methylethylketone hydrochloride, wherein the yield is 96.20% (calculated on the basis of 2-acetylthiophene);
the mass concentration of the concentrated hydrochloric acid is 37%.
2. Reduction reaction: adding 100g of 2-thiophene-2-dimethylamine methylethylketone hydrochloride and 61g of composite reducing agent into 230g of ethanol solution, controlling the temperature to 26 ℃, starting stirring, controlling the stirring speed to 65rpm, simultaneously irradiating by using ultraviolet rays with the wavelength of 230nm, then dropwise adding sodium hydroxide solution, controlling the dropwise adding speed to 10.5g/min, dropwise adding until the pH value is 10, then continuing stirring for 42min, stopping stirring and ultraviolet irradiation, distilling off the ethanol by reduced pressure distillation, filtering to obtain filter residue, washing for 2 times by using deionized water, and drying at 66 ℃ until the weight is unchanged to obtain 62g of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine, wherein the yield is 73.18% (calculated by 2-thiophene-2-dimethylamine methylethylketone hydrochloride);
the mass concentration of ethanol in the ethanol solution is 32 percent;
the preparation method of the composite reducing agent comprises the following steps: mixing 360g of a sodium alginate aqueous solution with the mass concentration of 0.45% and 11g of an n-pentylamine aqueous solution with the mass concentration of 2.6% to obtain a mixed solution, controlling the temperature of the mixed solution to 31 ℃, starting stirring and controlling the stirring speed to 110rpm, adjusting the pH of the mixed solution to 4.2 by using a hydrochloric acid aqueous solution with the mass concentration of 4.2%, then dropwise adding 19g of a silver nitrate aqueous solution with the mass concentration of 0.8%, controlling the dropwise adding speed to be 12g/min, continuously stirring for 21min after the dropwise adding is finished, adding 0.09g of sodium sulfite, continuously stirring for 26min, then adding 105g of ethanol, continuously stirring for 42min, filtering to obtain filter residues, and drying at 66 ℃ until the weight is not changed to obtain a negative carrier; mixing 11g of a load carrier, 42g of sodium gluconate and 52g of sodium borohydride, and then carrying out ball milling, wherein the ball-material ratio during ball milling is controlled to be 11, the rotation speed is 305rpm, the temperature is 26 ℃, the time is 31min, and the composite reducing agent is obtained after ball milling.
3. And (3) a alkylation reaction: adding 19g of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine into 147g of dimethyl sulfoxide, dropwise adding 22g of a 59% sodium hydride aqueous solution at a dropwise adding speed of 21g/min, controlling the temperature to 26 ℃ after the dropwise adding is finished, starting stirring, controlling the stirring speed to 85rpm, stirring for 21min, heating to 41 ℃ after the stirring, dropwise adding 27g of 1-fluoronaphthalene at a dropwise adding speed of 14g/min, reacting at 41 ℃ for 5.2 hours after the dropwise adding is finished to obtain a reaction solution, cooling the reaction solution to 3 ℃, adding acetic acid to adjust the pH to 4.1, taking a water phase, extracting for 3 times by using ethyl acetate, combining the extraction solution to an organic phase, washing the organic phase for 2 times by using a sodium chloride aqueous solution, adding anhydrous magnesium sulfate, drying, filtering, and removing a solvent in the obtained filtrate to obtain 30g of (S) -N, N-dimethyl-3- (1-naphthoxy) -2-thienyl, wherein the yield is 93.94% (calculated by S) -N, N-dimethyl-3- (2-thienyl) propylamine).
4. And (3) demethylation reaction: dissolving 39g of (S) -N, N-dimethyl-3- (1-naphthyloxy) -2-thienyl propylamine in 295g of dichloromethane, cooling to 3 ℃, dropwise adding 21g of 1-chloroethyl chloroformate, controlling the dropwise adding speed to be 13g/min, heating to reflux after the dropwise adding is finished, refluxing for 2.1h, evaporating to remove the solvent, dissolving the residue by using 81g of methanol, controlling the temperature to 41 ℃, keeping the temperature for 1.1h, evaporating to remove 86% of the total volume of methanol, adding acetone accounting for 8 times of the volume of the residual methanol, cooling to 1.5 ℃, stirring for 1.6h, filtering to obtain filter residues, obtaining 37g of duloxetine hydrochloride, and carrying out liquid chromatography on the duloxetine hydrochloride, wherein the liquid chromatography is shown in figure 2, the purity of the prepared duloxetine hydrochloride is 99.89%, the yield is 88.40% (calculated by (S) -N, N-dimethyl-3- (1-naphthyloxy) -2-thienyl propylamine), the total yield is 58.46%, the optical purity is 99.96%, and the optical purity is shown in figure 6.
Example 3
A preparation method of duloxetine hydrochloride comprises the following steps:
1. mannich reaction: adding 715g of 2-acetylthiophene, 678g of dimethylamine hydrochloride and 298g of paraformaldehyde into 1740g of isopropanol, then adding 55g of concentrated hydrochloric acid, starting stirring, controlling the stirring speed to 90rpm, heating to reflux, refluxing for 6.8h, cooling to room temperature, filtering, taking filter residue, washing 3 times by using absolute ethyl alcohol, and drying at 74 ℃ until the weight is unchanged to obtain 1167g of 2-thiophene-2-dimethylamine methylethylketone hydrochloride, wherein the yield is 94.16% (calculated on the basis of 2-acetylthiophene);
the mass concentration of the concentrated hydrochloric acid is 37%.
2. Reduction reaction: adding 100g of 2-thiophene-2-dimethylamine methylethylketone hydrochloride and 61.5g of composite reducing agent into 235g of ethanol solution, controlling the temperature to 27 ℃, starting stirring, controlling the stirring speed to 70rpm, simultaneously irradiating by using ultraviolet rays with the wavelength of 240nm, then dropwise adding a sodium hydroxide solution, controlling the dropwise adding speed to 11g/min, dropwise adding until the pH value is 11, then continuing stirring for 43min, stopping stirring and ultraviolet irradiation, distilling off the ethanol by reduced pressure distillation, filtering to obtain filter residue, washing for 3 times by using deionized water, and drying at 67 ℃ until the weight is unchanged to obtain 60g of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine, wherein the yield is 70.82% (calculated by 2-thiophene-2-dimethylamine methylethylketone hydrochloride);
the mass concentration of ethanol in the ethanol solution is 32 percent;
the preparation method of the composite reducing agent comprises the following steps: 370g of sodium alginate aqueous solution with the mass concentration of 0.6% and 11.7g of n-pentylamine aqueous solution with the mass concentration of 2.7% are mixed to obtain a mixed solution, the temperature of the mixed solution is controlled to 34 ℃, stirring is started, the stirring speed is controlled to 115rpm, the pH of the mixed solution is adjusted to 4.3 by using hydrochloric acid aqueous solution with the mass concentration of 4.8%, then 19.4g of silver nitrate aqueous solution with the mass concentration of 0.9% is dropwise added, the dropwise adding speed is controlled to be 12g/min, stirring is continued for 24min after the dropwise adding is finished, 0.09g of sodium sulfite is added, stirring is continued for 28min, 108g of ethanol is added, stirring is continued for 44min, filter residue is obtained by filtration, and drying is carried out at 68 ℃ until the weight is not changed, so as to obtain a negative carrier; mixing 11.8g of a load carrier, 44g of sodium gluconate and 53g of sodium borohydride, and then carrying out ball milling, wherein the ball-material ratio during ball milling is controlled to be 11, the rotation speed is 310rpm, the temperature is 28 ℃, the time is 34min, and the composite reducing agent is obtained after ball milling.
3. And (3) a alkylation reaction: adding 19.5g of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine into 149g of dimethyl sulfoxide, dropwise adding 22.3g of a 60% sodium hydride aqueous solution at a controlled dropwise adding speed of 21g/min, controlling the temperature to 27 ℃ after the dropwise adding is finished, starting stirring, controlling the stirring speed to 90rpm, stirring for 24min, heating to 44 ℃, dropwise adding 28g of 1-fluoronaphthalene at a controlled dropwise adding speed of 14g/min, reacting at 44 ℃ for 5.8h after the dropwise adding is finished to obtain a reaction liquid, cooling the reaction liquid to 3 ℃, adding acetic acid to adjust the pH to 4.4, taking a water phase, extracting for 3 times by using ethyl acetate, combining the extraction liquid with an organic phase, washing the organic phase for 3 times by using a sodium chloride aqueous solution, adding anhydrous magnesium sulfate, drying, filtering, and removing the solvent in the obtained filtrate to obtain 31g of (S) -N, N-dimethyl-3- (1-naphthyloxy) -2-thienyl) propylamine, wherein the yield is 94.58% (based on the dimethyl-3- (2-thienyl) propylamine).
4. And (3) demethylation reaction: dissolving 39g of (S) -N, N-dimethyl-3- (1-naphthoxy) -2-thienyl propylamine in 298g of dichloromethane, cooling to 3 ℃, dropwise adding 21.7g of 1-chloroethyl chloroformate at a speed of 14g/min, heating to reflux after dropwise adding, refluxing for 2.4h, evaporating the solvent, dissolving the residue with 82.5g of methanol, controlling the temperature to 44 ℃, keeping the temperature for 1.1h, evaporating to remove 88% of the total volume of methanol, adding acetone which accounts for 8.8 times of the volume of the residual methanol, cooling to 2 ℃, stirring for 1.7h, filtering to obtain filter residue, obtaining 37g of duloxetine hydrochloride, and carrying out liquid chromatographic analysis on the duloxetine hydrochloride, wherein the chromatogram of the prepared duloxetine hydrochloride is 99.95% in purity and 88.45% in yield (calculated by (S) -N, N-dimethyl-3- (1-naphthoxy) -2-thienyl propylamine), the total yield is 55.79% and 100% in optical purity, and the chromatogram is shown in 7% in the liquid chromatogram when the optical purity is detected.
Example 4
A preparation method of duloxetine hydrochloride comprises the following steps:
1. mannich reaction: adding 720g of 2-acetylthiophene, 680g of dimethylamine hydrochloride and 300g of paraformaldehyde into 1750g of isopropanol, then adding 60g of concentrated hydrochloric acid, starting stirring, controlling the stirring speed to 100rpm, heating to reflux, refluxing for 7h, cooling to room temperature, filtering, taking filter residue, washing 3 times by using absolute ethyl alcohol, and drying at 75 ℃ until the weight is unchanged to obtain 1191g of 2-thiophene-2-dimethylamine methylethylketone hydrochloride, wherein the yield is 95.43% (calculated by 2-acetylthiophene);
the mass concentration of the concentrated hydrochloric acid is 38%.
2. Reduction reaction: adding 100g of 2-thiophene-2-dimethylamine methylethylketone hydrochloride and 62g of composite reducing agent into 240g of ethanol solution, controlling the temperature to 28 ℃, starting stirring, controlling the stirring speed to 80rpm, simultaneously irradiating by using ultraviolet rays with the wavelength of 250nm, then dropwise adding a sodium hydroxide solution, controlling the dropwise adding speed to 12g/min, dropwise adding until the pH value is 11, then continuing stirring for 45min, stopping stirring and ultraviolet irradiation, distilling off the ethanol by reduced pressure distillation, filtering to obtain filter residue, washing for 3 times by using deionized water, and drying at 70 ℃ until the weight is unchanged to obtain 61g of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine, wherein the yield is 72.00% (calculated by 2-thiophene-2-dimethylamine methylethylketone hydrochloride);
the mass concentration of ethanol in the ethanol solution is 33 percent;
the preparation method of the composite reducing agent comprises the following steps: 380g of sodium alginate aqueous solution with the mass concentration of 0.6% and 12g of n-pentylamine aqueous solution with the mass concentration of 2.8% are mixed to obtain a mixed solution, the temperature of the mixed solution is controlled to 35 ℃, stirring is started, the stirring speed is controlled to 120rpm, the pH of the mixed solution is adjusted to 4.5 by using hydrochloric acid aqueous solution with the mass concentration of 5%, then 20g of silver nitrate aqueous solution with the mass concentration of 1% is dropwise added, the dropwise adding speed is controlled to be 13g/min, stirring is continued for 25min after dropwise adding is finished, 0.1g of sodium sulfite is added, stirring is continued for 30min, then 110g of ethanol is added, stirring is continued for 45min, filtering is carried out to obtain filter residue, and drying is carried out at 70 ℃ until the weight is not changed, so as to obtain a negative carrier; mixing 12g of a load carrier, 45g of sodium gluconate and 55g of sodium borohydride, and then carrying out ball milling, wherein the ball-material ratio during ball milling is controlled to be 12.
3. And (3) a alkylation reaction: adding 20g of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine into 150g of dimethyl sulfoxide, dropwise adding 23g of a 61% sodium hydride aqueous solution with the mass concentration controlled at 22g/min, controlling the temperature to 28 ℃ after the dropwise addition, starting stirring, controlling the stirring speed to 100rpm, stirring for 25min, heating to 45 ℃, dropwise adding 29g of 1-fluoronaphthalene with the dropping speed controlled at 15g/min, reacting at 45 ℃ for 6h after the dropwise addition to obtain a reaction solution, cooling the reaction solution to 4 ℃, adding acetic acid to adjust the pH to 4.5, taking a water phase, extracting for 3 times by using ethyl acetate, combining the extract liquid into an organic phase, washing the organic phase for 3 times by using a sodium chloride aqueous solution, adding anhydrous magnesium sulfate, drying, filtering, and removing the solvent in the obtained filtrate to obtain 32g of (S) -N, N-dimethyl-3- (1-naphthoxy) -2-thienyl, wherein the yield is 95.19% (calculated by (S) -N, N-dimethyl-3- (2-thienyl) propylamine).
4. And (3) demethylation reaction: dissolving 40g of (S) -N, N-dimethyl-3- (1-naphthoxy) -2-thienyl propylamine in 300g of dichloromethane, cooling to 4 ℃, dropwise adding 22g of 1-chloroethyl chloroformate, controlling the dropwise adding speed to be 15g/min, heating to reflux after the dropwise adding is finished, refluxing for 2.5h, evaporating the solvent, dissolving the residue by using 83g of methanol, controlling the temperature to 45 ℃, keeping the temperature for 1.2h, evaporating to remove 90% of the total volume of methanol, adding acetone accounting for 9 times of the volume of the residual methanol, cooling to 3 ℃, stirring for 1.8h, filtering to obtain filter residue, obtaining 38g of duloxetine hydrochloride, and carrying out liquid chromatographic analysis on the duloxetine hydrochloride, wherein the liquid chromatographic analysis chart shows that the purity of the prepared duloxetine hydrochloride is 99.93%, the yield is 88.56% (based on (S) -N, N-dimethyl-3- (1-naphthoxy) -2-thienyl propylamine) and the total yield is 57.92%, the purity is 99.94%, and the optical detection shows that the liquid chromatographic purity of 8 is 8.
Comparative example 1
The 2 nd step reduction in the process for preparing duloxetine hydrochloride described in example 1 was repeated, except that in the 2 nd step reduction step, 60g of the complex reducing agent was replaced with 34g of lithium aluminum hydride;
the reduction reaction of the 2 nd step gave 45g of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine in a yield of 53.12% (based on 2-thiophene-2-dimethylaminomethylethanone hydrochloride).
Comparative example 2
The 2 nd step reduction reaction in the preparation method of duloxetine hydrochloride described in example 1 was repeated, except that in the 2 nd step reduction reaction, 60g of the composite reducing agent was replaced with 34g of lithium aluminum hydride, and after dropwise addition of the sodium hydroxide solution, the stirring time was continued to be extended from 40min to 80min;
the reduction reaction of the 2 nd step gave 52g of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine in a yield of 61.38% (based on 2-thiophene-2-dimethylaminomethylethanone hydrochloride).
It can be seen from this comparative example that, after the composite reducing agent is replaced with lithium aluminum hydride, the yield of the prepared (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine is greatly reduced, and the reaction rate is reduced, which indicates that the reducibility of sodium borohydride and sodium gluconate in the composite catalyst used in example 1 is not the same as that of lithium aluminum hydride, but the reducibility of sodium borohydride and sodium gluconate can be improved by loading the sodium borohydride and sodium gluconate on the water-soluble silver ions, so that the yield of the prepared (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine is improved.
All percentages used in the present invention are mass percentages unless otherwise indicated.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A preparation method of duloxetine hydrochloride is characterized by comprising the following steps: mannich reaction, reduction reaction, alkylation reaction and demethylation reaction;
the Mannich reaction comprises the steps of adding 2-acetylthiophene, dimethylamine hydrochloride and paraformaldehyde into isopropanol, then adding concentrated hydrochloric acid, starting stirring, heating to reflux, cooling to room temperature after refluxing for 6-7h, filtering, taking filter residue, washing with absolute ethyl alcohol, and drying to obtain 2-thiophene-2-dimethylamine methylethylketone hydrochloride;
the reduction reaction comprises the steps of adding 2-thiophene-2-dimethylamine methylethylketone hydrochloride and a composite reducing agent into an ethanol solution, controlling the temperature to be 25-28 ℃, starting stirring, simultaneously irradiating by using ultraviolet rays with the wavelength of 220-250nm, then dropwise adding a sodium hydroxide solution, controlling the dropwise adding speed to be 10-12g/min, dropwise adding until the pH value is 10-11, then continuing stirring for 40-45min, stopping stirring and ultraviolet irradiation, distilling under reduced pressure to remove ethanol, filtering to obtain filter residues, washing by using deionized water, and drying to obtain (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine;
in the reduction reaction, the preparation method of the composite reducing agent comprises the following steps: mixing a sodium alginate aqueous solution with the mass concentration of 0.4-0.6% and a n-pentylamine aqueous solution with the mass concentration of 2.5-2.8% to obtain a mixed solution, controlling the temperature of the mixed solution to 30-35 ℃, starting stirring, adjusting the pH of the mixed solution to 4-4.5, then dropwise adding a silver nitrate aqueous solution with the mass concentration of 0.8-1%, controlling the dropwise adding speed to be 11-13g/min, continuously stirring for 20-25min after dropwise adding is finished, adding sodium sulfite, continuously stirring for 25-30min, then adding ethanol, continuously stirring for 40-45min, filtering to obtain filter residues, and drying to obtain a negative carrier; mixing a load carrier, sodium gluconate and sodium borohydride, then carrying out ball milling, and obtaining a composite reducing agent after the ball milling is finished;
the alkylation reaction comprises the steps of adding (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine into dimethyl sulfoxide, dropwise adding a sodium hydride water solution with the mass concentration of 59-61%, controlling the dropwise adding speed to be 20-22g/min, controlling the temperature to be 25-28 ℃ after dropwise adding, starting stirring, heating to 40-45 ℃ after stirring for 20-25min, dropwise adding 1-fluoronaphthalene, controlling the dropwise adding speed to be 13-15g/min, reacting for 5-6h at 40-45 ℃ after dropwise adding to obtain a reaction liquid, cooling the reaction liquid to 2-4 ℃, adjusting the pH to 4-4.5, taking a water phase, extracting by using ethyl acetate, combining an extraction liquid into an organic phase, cleaning the organic phase by using a sodium chloride water solution, drying, filtering, and removing a solvent in the obtained filtrate to obtain (S) -N, N-dimethyl-3- (1-naphthyloxy) -2-thienyl;
the demethylation reaction comprises the steps of dissolving (S) -N, N-dimethyl-3- (1-naphthoxy) -2-thienyl propylamine in dichloromethane, cooling to 2-4 ℃, dropwise adding 1-chloroethyl chloroformate, controlling the dropwise adding speed to be 12-15g/min, heating to reflux after dropwise adding, refluxing for 2-2.5h, evaporating to remove the solvent, dissolving the residue by using methanol, controlling the temperature to 40-45 ℃, keeping the temperature for 1-1.2h, evaporating to remove the methanol accounting for 85-90% of the total volume, adding acetone accounting for 8-9 times of the volume of the residual methanol, cooling to 1-3 ℃, stirring for 1.5-1.8h, and filtering to obtain filter residues to obtain duloxetine hydrochloride.
2. A process for preparing duloxetine hydrochloride according to claim 1, wherein the weight ratio of 2-acetylthiophene, dimethylamine hydrochloride, paraformaldehyde in said Mannich reaction is 700-720.
3. A process for preparing duloxetine hydrochloride according to claim 1, wherein the weight ratio of 2-acetylthiophene, isopropanol, concentrated hydrochloric acid in the Mannich reaction is 70-72;
the mass concentration of the concentrated hydrochloric acid is 36-38%.
4. A method for preparing duloxetine hydrochloride according to claim 1, wherein the weight ratio of 2-thiophene-2-dimethylamine methylethylketone hydrochloride, the composite reducing agent and the ethanol solution in the reduction reaction is 100.
5. A process for preparing duloxetine hydrochloride according to claim 1, wherein the ethanol solution contains ethanol in a concentration of 31 to 34% by mass.
6. A preparation method of duloxetine hydrochloride according to claim 1, wherein in the preparation of the complex reducing agent, the weight ratio of sodium alginate aqueous solution with mass concentration of 0.4-0.6%, n-pentylamine aqueous solution with mass concentration of 2.5-2.8%, silver nitrate aqueous solution with mass concentration of 0.8-1%, sodium sulfite, ethanol is 350-380.
7. The method for preparing duloxetine hydrochloride according to claim 1, wherein the weight ratio of the carrier, sodium gluconate and sodium borohydride in the preparation of the composite reducing agent is 10-12.
8. A preparation method of duloxetine hydrochloride according to claim 1, wherein the weight ratio of (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine, dimethyl sulfoxide, 59-61% by mass of aqueous sodium hydride solution, 1-fluoronaphthalene in the alkylation reaction is 18-20.
9. A process for preparing duloxetine hydrochloride according to claim 1, wherein the weight ratio of (S) -N, N-dimethyl-3- (1-naphthyloxy) -2-thienylpropylamine, dichloromethane, 1-chloroethyl chloroformate to methanol in the demethylation reaction is from 38 to 40.
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