CN100432043C - Preparation method of 3-methylamino-1-phenylpropanol - Google Patents
Preparation method of 3-methylamino-1-phenylpropanol Download PDFInfo
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- CN100432043C CN100432043C CNB2006100520374A CN200610052037A CN100432043C CN 100432043 C CN100432043 C CN 100432043C CN B2006100520374 A CNB2006100520374 A CN B2006100520374A CN 200610052037 A CN200610052037 A CN 200610052037A CN 100432043 C CN100432043 C CN 100432043C
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- methylamino
- hydrochloride
- phenylpropyl alcohol
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- XXSDCGNHLFVSET-UHFFFAOYSA-N 3-(methylamino)-1-phenylpropan-1-ol Chemical compound CNCCC(O)C1=CC=CC=C1 XXSDCGNHLFVSET-UHFFFAOYSA-N 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 239000001257 hydrogen Substances 0.000 claims abstract description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 31
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 24
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 16
- 229930040373 Paraformaldehyde Natural products 0.000 claims abstract description 13
- 229920002866 paraformaldehyde Polymers 0.000 claims abstract description 13
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007788 liquid Substances 0.000 claims abstract description 10
- 230000003197 catalytic effect Effects 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 6
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 claims abstract description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 150000001298 alcohols Chemical class 0.000 claims abstract description 3
- -1 3-methylamino--1-phenylpropyl Chemical group 0.000 claims description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000012043 crude product Substances 0.000 claims description 15
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 9
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims 1
- 238000001816 cooling Methods 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000002699 waste material Substances 0.000 abstract description 3
- CEOSYRDTCHRIAY-UHFFFAOYSA-N 3-(methylamino)-1-phenylpropan-1-ol;hydrochloride Chemical compound Cl.CNCCC(O)C1=CC=CC=C1 CEOSYRDTCHRIAY-UHFFFAOYSA-N 0.000 abstract 3
- 239000007868 Raney catalyst Substances 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract 1
- 238000005984 hydrogenation reaction Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 238000003810 ethyl acetate extraction Methods 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- 238000005070 sampling Methods 0.000 description 7
- 239000010935 stainless steel Substances 0.000 description 7
- 229910001220 stainless steel Inorganic materials 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 5
- 229960002464 fluoxetine Drugs 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- GIYXAJPCNFJEHY-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine hydrochloride (1:1) Chemical compound Cl.C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 GIYXAJPCNFJEHY-UHFFFAOYSA-N 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960000389 fluoxetine hydrochloride Drugs 0.000 description 2
- 238000011946 reduction process Methods 0.000 description 2
- 238000001256 steam distillation Methods 0.000 description 2
- 238000006683 Mannich reaction Methods 0.000 description 1
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 description 1
- 229910000990 Ni alloy Inorganic materials 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940035613 prozac Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001519 thymoleptic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 3-methylamino-1-phenylpropanol, which comprises the steps of taking acetophenone, paraformaldehyde and monomethylamine hydrochloride as raw materials, heating to 60-100 ℃ by taking alcohols as solvents in a closed container for reaction, concentrating, cooling and crystallizing to obtain 3-methylamino-1-phenylpropanol hydrochloride; then reducing the mixture in a solvent under the catalytic condition to obtain a 3-methylamino-1-phenylpropanol hydrochloride solution; adjusting the pH value of the solution to 9-14 by liquid alkali, extracting, recovering the solvent, recrystallizing cyclohexane to obtain 3-methylamino-1-phenylpropanol, and carrying out hydrogenation reduction by adopting a Raney nickel catalyst in the process of obtaining the 3-methylamino-1-phenylpropanol hydrochloride solution by reduction under the catalytic condition, wherein the Raney nickel catalytic hydrogenation reduction condition is as follows: the hydrogen pressure is 0.3-1.5 MPa, and the temperature is 25-80 ℃. The scheme of the invention has the characteristics of high product yield, good quality, low production cost, less three-waste discharge and the like.
Description
Technical field
The invention belongs to the synthetic field of chemical intermediate, the preparation method of a kind of 3-methylamino--1-phenylpropyl alcohol of more specifically saying so.
Background technology
Fluoxetine is Lilly Co., Eli.'s exploitation, and in a kind of medicine for the treatment of dysthymia disorders of listing in 1987, the present commercially available Fluoxetine hydrochloride that mostly is.Product 3-methylamino--1-phenylpropyl alcohol is the key intermediate of synthetic antidepressant drug fluoxetine (Fluoxetine, trade(brand)name Prozac), and its structural formula is as follows:
3-methylamino--1-phenylpropyl alcohol fluoxetine Hydrochloride
Close as the yellow man of virtue and ability of volume the 1st phase 56-57 page or leaf in March, 1996 " Chinese pharmaceutical chemistry magazine " the 6th and to wait report " synthesizing of thymoleptic fluoxetine ", the preparation method of fluoxetine intermediate 3-methylamino--1-phenylpropyl alcohol that the document is introduced, with methyl phenyl ketone, Paraformaldehyde 96 and Monomethylamine hydrochloride is raw material, in dehydrated alcohol, carry out Mannich (Mannich) reaction and steam distillation, obtain 3-methylamino--1-Propiophenone hydrochloride; 3-methylamino--1-Propiophenone hydrochloride obtains 3-methylamino--1-phenylpropyl alcohol through potassium borohydride reduction behind ether, the chloroform extraction.The deficiency that this preparation method exists is employing potassium borohydride reduction agents useful for same costliness, the production cost height, and produce a large amount of high COD value waste water; Adopt big, the low-boiling solvent extraction target products of toxicity such as ether, chloroform, there is defectives such as reclaiming difficulty in solvent, has also influenced environment.
Summary of the invention
At the problems referred to above, we have invented the preparation method of a kind of yield height, production cost is low, the three wastes are few 3-methylamino--1-phenylpropyl alcohol.
For achieving the above object, the present invention has adopted following technical scheme: it is a raw material with methyl phenyl ketone, Paraformaldehyde 96 and Monomethylamine hydrochloride, in encloses container, be solvent with the alcohols material, be warmed to 60～100 ℃ and react, obtain 3-methylamino--1-Propiophenone hydrochloride behind the concentration of reaction solution crystallisation by cooling; In solvent, reduce under the catalytic condition again and obtain 3-methylamino--1-phenylpropyl alcohol hydrochloride solution; Solution is adjusted to pH value 9～14 through liquid caustic soda, obtain 3-methylamino--1-phenylpropyl alcohol through extraction, recovery solvent, hexanaphthene recrystallization, it is characterized in that described under catalytic condition reduction obtain adopting the Raney's nickel catalyst hydrogenating reduction in the process of 3-methylamino--1-phenylpropyl alcohol hydrochloride solution, described raney ni catalysis hydrogenating reduction condition: hydrogen pressure is that 0.3～1.5MPa, temperature are 25～80 ℃.
The mol ratio of described benzene feedstock ethyl ketone, Paraformaldehyde 96 and Monomethylamine hydrochloride is 1: 1～1.5: 1～1.5, and the weight of described hydrogenating reduction catalyzer Raney's nickel is 5～20% of 3-methylamino--1-Propiophenone hydrochloride weight
Described alcoholic solvent is methyl alcohol, ethanol or Virahol.
Reducing under the catalytic condition in the solvent and obtaining the solvent that the 3-methylamino--1-phenylpropyl alcohol solution is adopted is water.
The present invention program, 3-methylamino--1-Propiophenone hydrochloride reduces under the catalytic condition in solvent and obtains in 3-methylamino--1-phenylpropyl alcohol solution process, adopt the raney ni catalysis hydrogenating reduction, have the following advantages with the potassium borohydride reduction of bibliographical information: the product yield height, quality is good, characteristics such as production cost is low, and three wastes discharge amount is few.Experiment showed, under same condition, adopt Raney's nickel to substitute POTASSIUM BOROHYDRIDE, can improve yield 5%～10%, reduce production of by-products simultaneously, help environment protection as reductive agent.Particularly in reduction process, use water as solvent, reduced the generation of 3-methylamino--1-phenylpropyl alcohol dehydroxylation side reaction, reduced by product.Compare with traditional technology, the present invention has omitted in preparation 3-methylamino--1-Propiophenone hydrochloride process, and the technological process of this time-consuming power consumption of steam distillation helps save energy in the aftertreatment, has simplified preparation technology.
Embodiment
The present invention prepares 3-methylamino--1-phenylpropyl alcohol according to following synthetic route:
(I) Mannich reaction:
(II) reduction reaction:
(III) separation and Extraction of target product and refining:
Catalyzer in the hydrogenating reduction process of the present invention can adopt commercially available al-ni alloy powder self-control Raney's nickel or commercially available Raney's nickel.
Embodiment 1:
With 120.0g methyl phenyl ketone, 30.0g Paraformaldehyde 96,67.5g one first ammonia hydrochloric acid salt (mol ratio 1: 1: 1), join in the 100ml autoclave pressure, and adding ethanol 500ml, keep 60 ℃ of temperature of reaction, carry out Liquid Detection every sampling in 2 hours, 3-methylamino-in adjacent twice detected result-1-Propiophenone hydrochloride content difference is less than 5% o'clock, stopped reaction.Heating concentration of reaction solution volume is about 1/3 of an original volume, crystallisation by cooling, filter white crystal or yellow solid 3-methylamino--about 121g of 1-Propiophenone hydrochloride slightly.
The above-mentioned 3-methylamino-that obtains-1-Propiophenone hydrochloride is joined in the 1000mL stainless steel pressure still, adding water to solid dissolves fully, add Raney's nickel catalyst 6.1g, use nitrogen replacement 3 times earlier, then use 0.3MPa hydrogen exchange 3 times, control reaction temperature is 25 ℃ under stirring, and looks and inhales the continuous hydrogen make-up of hydrogen situation, does not inhale till the hydrogen to reacting.Reaction finishes, and obtains 3-methylamino--1-phenylpropyl alcohol hydrochloride aqueous solution.Being adjusted to PH through 30% aqueous sodium hydroxide solution is 9, adds ethyl acetate extraction, and underpressure distillation obtains 3-methylamino--1-phenylpropyl alcohol crude product after reclaiming ethyl acetate.Crude product obtains 3-methylamino--1-phenylpropyl alcohol 85.3 grams through the hexanaphthene recrystallization.
Embodiment 2:
With 120.0g methyl phenyl ketone, 30.0g Paraformaldehyde 96,101.3g one first ammonia hydrochloric acid salt (mol ratio 1: 1: 1.5), join in the 1000ml autoclave pressure, and adding Virahol 500ml, keep 90 ℃ of temperature of reaction, carry out Liquid Detection every sampling in 2 hours, 3-methylamino--1-Propiophenone hydrochloride content difference is less than 5% in adjacent twice detected result, heating concentration of reaction solution volume is about 1/3 of an original volume, crystallisation by cooling, filter white crystal or yellow solid 3-methylamino--about 162.7g of 1-Propiophenone hydrochloride slightly.
The above-mentioned 3-methylamino-that obtains-1-Propiophenone hydrochloride is joined in the 1000mL stainless steel pressure still, adding water to solid dissolves fully, add Raney's nickel catalyst 16.3g, use nitrogen replacement 3 times earlier, then use 1.5MPa hydrogen exchange 3 times, controlled temperature is 80 ℃ under stirring, and looks and inhales the continuous hydrogen make-up of hydrogen situation, does not inhale till the hydrogen to reacting.Reaction finishes, and obtains 3-methylamino--1-phenylpropyl alcohol hydrochloride aqueous solution, and being adjusted to PH through 30% potassium hydroxide aqueous solution is 10, adds ethyl acetate extraction, and underpressure distillation obtains 3-methylamino--1-phenylpropyl alcohol crude product after reclaiming ethyl acetate.Crude product obtains 3-methylamino--1-phenylpropyl alcohol 107.3 grams through the hexanaphthene recrystallization.
Embodiment 3:
With 120.0g methyl phenyl ketone, 45.0g Paraformaldehyde 96,67.5g one first ammonia hydrochloric acid salt (mol ratio 1: 1.5: 1), join in the 1000ml autoclave pressure, and adding ethanol 500ml, keep 90 ℃ of temperature of reaction, carry out Liquid Detection every sampling in 2 hours, 3-methylamino--1-Propiophenone hydrochloride content difference is cooled off reaction solution less than 5% in adjacent twice detected result.Heating concentration of reaction solution volume is about 1/3 of an original volume, crystallisation by cooling, filter white crystal or yellow solid 3-methylamino--about 170.2g of 1-Propiophenone hydrochloride slightly.
The above-mentioned 3-methylamino-that obtains-1-Propiophenone hydrochloride is joined in the 1000ml stainless steel pressure still, add water to solid and dissolve fully, add Raney's nickel catalyst 8.5g, use N earlier
2Replace 2 times, then use 1.0MPa hydrogen exchange 2 times, controlled temperature is 70 ℃ under stirring, and looks and inhales the continuous hydrogen make-up of hydrogen situation, does not inhale till the hydrogen to reacting, and reaction finishes, and obtains 3-methylamino--1-phenylpropyl alcohol hydrochloride aqueous solution.Being adjusted to PH through 30% potassium hydroxide aqueous solution is 11, adds ethyl acetate extraction, and underpressure distillation obtains 3-methylamino--1-phenylpropyl alcohol crude product after reclaiming ethyl acetate.Crude product obtains 3-methylamino--1-phenylpropyl alcohol 114.8 grams through the hexanaphthene recrystallization.
Embodiment 4:
With 120.0g methyl phenyl ketone, 45.0g Paraformaldehyde 96,101.3g one first ammonia hydrochloric acid salt (mol ratio 1: 1.5: 1.5), join in the 1000ml pressure reaction still, and adding methyl alcohol 500ml, keep 70 ℃ of temperature of reaction, carry out Liquid Detection every sampling in 2 hours, 3-methylamino--1-Propiophenone hydrochloride content difference is cooled off reaction solution less than 5% in adjacent twice detected result.Heating concentration of reaction solution volume is about 1/3 of an original volume, crystallisation by cooling, filter white crystal or yellow solid 3-methylamino--about 169.1g of 1-Propiophenone hydrochloride slightly.
The above-mentioned 3-methylamino-that obtains-1-Propiophenone hydrochloride is joined in the 1000ml stainless steel pressure still, adding water to solid dissolves fully, add Raney's nickel catalyst 10.2g, 0.8MPa hydrogen exchange 2 times are then used in elder generation's nitrogen replacement 2 times, and controlled temperature is 60 ℃ under stirring, look and inhale the continuous hydrogen make-up of hydrogen situation, do not inhale till the hydrogen to reaction, reaction finishes, and obtains 3-methylamino--1-phenylpropyl alcohol hydrochloride aqueous solution.Being adjusted to PH through 30% aqueous sodium hydroxide solution is 12, adds ethyl acetate extraction, and underpressure distillation obtains 3-methylamino--1-phenylpropyl alcohol crude product after reclaiming ethyl acetate.Crude product obtains 3-methylamino--1-phenylpropyl alcohol 111.5 grams through the hexanaphthene recrystallization.
Embodiment 5:
With 120.0g methyl phenyl ketone, 37.5g Paraformaldehyde 96,84.4g one first ammonia hydrochloric acid salt (mol ratio 1: 1.25: 1.25), join in the 1000ml autoclave pressure, and adding Virahol 500ml, keep 100 ℃ of temperature of reaction, carry out Liquid Detection every sampling in 2 hours, 3-methylamino--1-Propiophenone hydrochloride content difference is cooled off reaction solution less than 5% in adjacent twice detected result.Heating concentration of reaction solution volume is about 1/3 of an original volume, crystallisation by cooling, filter white crystal or yellow solid 3-methylamino--about 176.2g of 1-Propiophenone hydrochloride slightly.
The above-mentioned 3-methylamino-that obtains-1-Propiophenone hydrochloride is joined in the 1000ml stainless steel pressure still, adding water to solid dissolves fully, add Raney's nickel catalyst 35.2g, 0.6MPa hydrogen exchange 1 time is then used in elder generation's nitrogen replacement 2 times, and controlled temperature is 50 ℃ under stirring, look and inhale the continuous hydrogen make-up of hydrogen situation, do not inhale till the hydrogen to reaction, reaction finishes, and obtains 3-methylamino--1-phenylpropyl alcohol hydrochloride aqueous solution.Being adjusted to PH through 30% aqueous sodium hydroxide solution is 13, adds ethyl acetate extraction, and underpressure distillation obtains 3-methylamino--1-phenylpropyl alcohol crude product after reclaiming ethyl acetate.Crude product obtains 3-methylamino--1-phenylpropyl alcohol 90.2 grams through the hexanaphthene recrystallization.
Embodiment 6:
With 120.0g methyl phenyl ketone, 37.5g Paraformaldehyde 96,101.3g one first ammonia hydrochloric acid salt (mol ratio 1: 1.25: 1.5), join in the 1000ml autoclave pressure, and adding Virahol 500ml, keep 85 ℃ of temperature of reaction, carry out Liquid Detection every sampling in 2 hours, 3-methylamino--1-Propiophenone hydrochloride content difference is cooled off reaction solution less than 5% in adjacent twice detected result.Heating concentration of reaction solution volume is about 1/3 of an original volume, crystallisation by cooling, filter white crystal or yellow solid 3-methylamino--about 177.8g of 1-Propiophenone hydrochloride slightly.
The above-mentioned 3-methylamino-that obtains-1-Propiophenone hydrochloride is joined in the 1000mL stainless steel pressure still, adding water to solid dissolves fully, add Raney's nickel catalyst 3.6g, 0.5MPa hydrogen exchange 2 times are then used in elder generation's nitrogen replacement 2 times, and controlled temperature is 40 ℃ under stirring, look and inhale the continuous hydrogen make-up of hydrogen situation, do not inhale till the hydrogen to reaction, reaction finishes, and obtains 3-methylamino--1-phenylpropyl alcohol hydrochloride aqueous solution.Being adjusted to PH through 30% aqueous sodium hydroxide solution is 13, adds ethyl acetate extraction, and underpressure distillation obtains 3-methylamino--1-phenylpropyl alcohol crude product after reclaiming ethyl acetate.Crude product obtains 3-methylamino--1-phenylpropyl alcohol 78.7 grams through the hexanaphthene recrystallization.
Embodiment 7:
With 120.0g methyl phenyl ketone, 45.0g Paraformaldehyde 96,101.3g one first ammonia hydrochloric acid salt (mol ratio 1: 1.25: 1.5), join in the 1000ml autoclave pressure, and adding Virahol 500ml, keep 80 ℃ of temperature of reaction, carry out Liquid Detection every sampling in 2 hours, 3-methylamino--1-Propiophenone hydrochloride content difference is cooled off reaction solution less than 5% in adjacent twice detected result.Heating concentration of reaction solution volume is about 1/3 of an original volume, crystallisation by cooling, filter white crystal or yellow solid 3-methylamino--about 162.4g of 1-Propiophenone hydrochloride slightly.
The above-mentioned 3-methylamino-that obtains-1-Propiophenone hydrochloride is joined in the 1000mL stainless steel pressure still, add water to solid and dissolve fully, add Raney's nickel catalyst 6.5g, use N earlier
2Replace 2 times, then use 0.7MPa hydrogen exchange 2 times, controlled temperature is 30 ℃ under stirring, and looks and inhales the continuous hydrogen make-up of hydrogen situation, does not inhale till the hydrogen to reacting, and reaction finishes, and obtains 3-methylamino--1-phenylpropyl alcohol hydrochloride aqueous solution.Being adjusted to PH through 30% aqueous sodium hydroxide solution is 12, adds ethyl acetate extraction, and underpressure distillation obtains 3-methylamino--1-phenylpropyl alcohol crude product after reclaiming ethyl acetate.Crude product obtains 3-methylamino--1-phenylpropyl alcohol 82 grams through the hexanaphthene recrystallization.
Below be the yield of the foregoing description 1-7, the information slip of 3-methylamino--1-phenylpropyl alcohol purity:
| Embodiment | Yield (%) | Purity |
| 1 | 52 | 96 |
| 2 | 65 | 96 |
| 3 | 70 | 98 |
| 4 | 68 | 96 |
| 5 | 55 | 95 |
| 6 | 48 | 93 |
| 7 | 50 | 94 |
Claims (4)
1, the preparation method of a kind of 3-methylamino--1-phenylpropyl alcohol, it is a raw material with methyl phenyl ketone, Paraformaldehyde 96 and Monomethylamine hydrochloride, in autoclave pressure be that ℃ react solvent heating to 60～100 with the alcohols, the crystallization of concentration of reaction solution postcooling obtains 3-methylamino--1-Propiophenone hydrochloride; In solvent, reduce under the catalytic condition again and obtain 3-methylamino--1-phenylpropyl alcohol hydrochloride solution; Solution is adjusted to pH value 9～14 through liquid caustic soda, through extraction, reclaim solvent, crude product obtains 3-methylamino--1-phenylpropyl alcohol through the hexanaphthene recrystallization, it is characterized in that described under catalytic condition reduction obtain adopting the Raney's nickel catalyst hydrogenating reduction in the process of solution of 3-methylamino--1-phenylpropyl alcohol, described raney ni catalysis hydrogenating reduction condition: hydrogen pressure is that 0.3～1.5MPa, temperature are 25～80 ℃.
2, the preparation method of 3-methylamino-according to claim 1-1-phenylpropyl alcohol, the mol ratio that it is characterized in that described benzene feedstock ethyl ketone, Paraformaldehyde 96 and Monomethylamine hydrochloride is 1: 1～1.5: 1～1.5, and the weight of described hydrogenating reduction catalyzer Raney's nickel is 1～10% of 3-methylamino--1-Propiophenone hydrochloride weight.
3, the preparation method of 3-methylamino-according to claim 1 and 2-1-phenylpropyl alcohol is characterized in that described alcoholic solvent is methyl alcohol, ethanol or Virahol.
4, the preparation method of 3-methylamino-according to claim 1 and 2-1-phenylpropyl alcohol is characterized in that the following reduction of catalytic condition obtains 3-methylamino--1-phenylpropyl alcohol hydrochloride solution in the described solvent, and the solvent that is adopted is a water.
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| CN100432043C true CN100432043C (en) | 2008-11-12 |
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| CN115677512A (en) * | 2022-10-27 | 2023-02-03 | 大连万福制药有限公司 | Method for synthesizing lercanidipine intermediate N-methyl-3,3-diphenylpropylamine hydrochloride |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4313896A (en) * | 1974-01-10 | 1982-02-02 | Eli Lilly And Company | Aryloxyphenylpropylamines |
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2006
- 2006-06-19 CN CNB2006100520374A patent/CN100432043C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4313896A (en) * | 1974-01-10 | 1982-02-02 | Eli Lilly And Company | Aryloxyphenylpropylamines |
Non-Patent Citations (3)
| Title |
|---|
| Identification and comparison of impurities in fluoxetinehydrochloride synthesized by seven defferent routs. WIRTH DD,MILLER MS.Org process resdev,Vol.4 No.6. 2000 * |
| SYNTHESIS OF CARBON-14 AND TRITIUM LABELEDFLUOXETINE, A SELECTIVE SEROTONIN UPTAKEINHIBITOR. ROBERTSON DW,KRUSHINSKI JH.J LABELLED COMPD RADIOPHARM,Vol.24 No.11. 1987 * |
| 相转移催化法合成N-甲基-3-苯基-3-羟基丙胺. 艾菁，贺艳.三峡大学学报，第27卷第2期. 2005 * |
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| CN1865226A (en) | 2006-11-22 |
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