CN101914032B - Synthetic method of (s)-N-trifluoroacetyl-2-(4-Methoxyphenyl)ethylamine - Google Patents
Synthetic method of (s)-N-trifluoroacetyl-2-(4-Methoxyphenyl)ethylamine Download PDFInfo
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- CN101914032B CN101914032B CN 201010227031 CN201010227031A CN101914032B CN 101914032 B CN101914032 B CN 101914032B CN 201010227031 CN201010227031 CN 201010227031 CN 201010227031 A CN201010227031 A CN 201010227031A CN 101914032 B CN101914032 B CN 101914032B
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000005893 bromination reaction Methods 0.000 claims abstract description 5
- 238000006198 methoxylation reaction Methods 0.000 claims abstract description 5
- 230000031709 bromination Effects 0.000 claims abstract description 4
- 239000007787 solid Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 11
- 125000003368 amide group Chemical group 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 8
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 7
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- 239000012267 brine Substances 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 206010013786 Dry skin Diseases 0.000 claims description 3
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical class CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 125000001246 bromo group Chemical class Br* 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 150000001805 chlorine compounds Chemical class 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 235000011837 pasties Nutrition 0.000 claims description 2
- 239000012266 salt solution Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000010265 sodium sulphite Nutrition 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 238000003828 vacuum filtration Methods 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 150000003842 bromide salts Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 abstract description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000003287 optical effect Effects 0.000 abstract description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- 238000002425 crystallisation Methods 0.000 abstract description 2
- 230000008025 crystallization Effects 0.000 abstract description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method of (s)-N-trifluoroacetyl-2-(4-Methoxyphenyl)ethylamine, which comprises the following steps of obtaining an amino protection matter by protecting amino of S-phenylethy lamine through ethyl trifuoroacetate; obtaining bromide by carrying out para-position bromination on the amino protection matter in methylene dichloride with bromine; and carrying out methoxylation on the bromide in a sodium methoxide solution to obtain the product. In the invention, the used raw material is optical antimer pure and a chiral center is not changed during the reaction so that the optical purity of products is 99.5%. In the method of the invention, an intermediate is a solid easy to be purified through crystallization. The method of the invention has the advantages of common industrial raw materials, low cost and simple industrialization operation.
Description
Technical field:
The present invention relates to a kind of (S)-N-TFA base-to the synthetic method of anisole ethamine.
Background technology:
The chirality phenylethylamine is the reagent that well splits and build new chirality in medicine industry production.Because it is combined with the form of covalent linkage with reaction substrate, need the pressure method for hydrogenation more than medium to limit its industrial applications in the time of will dissociating before obtaining final product.And chirality can remove by the method with ceric ammonium nitrate or DDQ oxidation anisole ethamine, and reaction conditions is gentle, does not need special equipment, is that the ideal of chirality phenylethylamine substitutes.
Existing (S)-N-TFA base-complicated, not easy to operate to the synthetic method of anisole ethamine.
Summary of the invention:
The object of the present invention is to provide a kind of simple to operate, (S)-N-TFA base that cost is low-to the synthetic method of anisole ethamine
Technical solution of the present invention is:
A kind of (S)-N-TFA base-to the synthetic method of anisole ethamine, it is characterized in that: comprise the following steps: successively
(1) amido protecting: the amino with Trifluoroacetic Acid Ethyl Ester protection S-phenylethylamine obtains the amido protecting thing;
(2) bromination: above-mentioned amido protecting thing is used bromine para-bromination in methylene dichloride, obtain bromide;
(3) methoxylation: bromide methoxylation in sodium methoxide solution is obtained product.
The reaction of step (1) amido protecting is take anhydrous methanol as solvent.
The present invention is because the raw material that uses is the variation that the pure and reaction of optics mapping end relates to chiral centre, product optical purity 99.5%.In method of the present invention, intermediate is the solid that is easy to by crystallization purifying.In the inventive method, use is the Industrial raw material of commonly using, and cost is low, industrialization is simple to operate.
The invention will be further described below in conjunction with embodiment.
Embodiment:
1) amido protecting: 600 kilograms of anhydrous methanols of vacuum difference suction, 180 kilograms of S-phenylethylamines in 1000 liters of reactors of drying.Control reaction solution and drip 250 kilograms of Trifluoroacetic Acid Ethyl Esters at 45 ℃.Drip and finish, keep 30 ℃ and stirred 24 hours.Decompression was steamed most methyl alcohol approximately 5 hours.Naturally cool to 0 ℃, centrifuge dripping.50 ℃ of vacuum-dryings got 280 kilograms of purity of amido protecting product (HPLC) in 16 hours: 99.5% fusing point: 92-94 ℃.
2) bromination: 600 kilograms of methylene dichloride of vacuum suction in 1000 liters of reactors of drying, emptying; Add 280 kilograms of amido protecting things of upper step under stirring from manhole; Reacting liquid temperature is controlled at 10 ℃ and drips 218 kilograms of bromines.Drip to finish and keep 25 ℃ of stirrings 18 hours.Drip 20% 100 kilograms of sodium sulfite solutions (exothermic heat of reaction has gas to emit, and drives waste gas air inducing absorption unit).In the unlatching chuck, salt solution is cooled to 5 ℃, centrifuge dripping, and centrifugal solids washes with water to neutrality, dries to get wet product.With 300 kilograms of re-crystallizing in ethyl acetate.80 ℃ of oven dry, the 300 kilograms of purity of dry product (HPLC) of spending the night to get: 99% fusing point: 158-160 ℃.
3) methoxylation: vacuum 600 kilograms of sodium methylates of suction, 100 kilograms of DMF emptying respectively in 1000 liters of reactors of drying; Add respectively 300 kilograms of step bromides, 5 kilograms of cuprous chlorides under stirring from hand hole; Build hand hole plate, be warming up to 80 ℃ and keep 18 hours after, the lower 80 ℃ of reclaim under reduced pressure of vacuum are reaction solvent to the greatest extent, is cooled to 500 kilograms of ethyl acetate of 30 ℃ of vacuum suction, stirs lower chuck and passes into chilled brine and be cooled to 10 ℃.400 kilogram of 10% aqueous ammonium chloride solution of vacuum suction stirs layering in 30 minutes. the ethyl acetate bed of material, with 200 kilograms of saturated sodium-chloride water washings once.Add 25 kilograms of anhydrous magnesium sulfate dryings to spend the night, vacuum filtration removes sal epsom, and filtrate decompression is concentrated into pasty state, and chilled brine is cooled to 0 ℃.Centrifuge dripping gets wet product.80 ℃ of dryings got 200 kilograms of dry products in 16 hours.Purity (HPLC): 99.2% fusing point: 131-133 ℃.
Reaction formula of the present invention is expressed as:
Claims (1)
1. (S)-N-TFA base-to the synthetic method of anisole ethamine, it is characterized in that: comprise the following steps: successively
1) amido protecting: 600 kilograms of anhydrous methanols of vacuum difference suction, 180 kilograms of S-phenylethylamines in 1000 liters of reactors of drying, control reaction solution and drip 250 kilograms of Trifluoroacetic Acid Ethyl Esters at 45 ℃, drip and finish, keeping 30 ℃ stirred 24 hours, methyl alcohol is to the greatest extent steamed in decompression, naturally cool to 0 ℃, centrifuge dripping, 50 ℃ of vacuum-dryings got the amido protecting thing in 16 hours;
2) bromination: 600 kilograms of methylene dichloride of vacuum suction in 1000 liters of reactors of drying, emptying; Add 280 kilograms of amido protecting things of upper step under stirring from manhole; Reacting liquid temperature is controlled at 10 ℃, drip 218 kilograms of bromines, drip to finish and keep 25 ℃ of stirrings 18 hours, 100 kilograms of the sodium sulfite solutions of dropping 20%, in the unlatching chuck, salt solution is cooled to 5 ℃, centrifuge dripping, centrifugal solids washes with water to neutrality, dry to get wet product, with 300 kilograms of re-crystallizing in ethyl acetate, spend the night to get 300 kilograms of dry products of 80 degree oven dry;
3) methoxylation: 600 kilograms of sodium methylates of vacuum difference suction, 100 kilograms of DMFs in 1000 liters of reactors of drying, emptying; Add respectively 300 kilograms of step bromides, 5 kilograms of cuprous chlorides under stirring from hand hole; Build hand hole plate, be warming up to 80 ℃ and keep 18 hours after, the lower 80 ℃ of reclaim under reduced pressure of vacuum are reaction solvent to the greatest extent, be cooled to 500 kilograms of ethyl acetate of 30 ℃ of vacuum suction, under stirring, chuck passes into chilled brine and is cooled to 10 ℃, 400 kilogram of 10% aqueous ammonium chloride solution of vacuum suction stirs layering in 30 minutes, the ethyl acetate bed of material, with 200 kilograms of saturated sodium-chloride water washings once, add 25 kilograms of anhydrous magnesium sulfate dryings to spend the night, vacuum filtration removes sal epsom, and filtrate decompression is concentrated into pasty state, chilled brine is cooled to 0 ℃, and centrifuge dripping gets wet product; 80 dry 16 hours of degree get dry product.
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|---|---|---|---|
| CN 201010227031 CN101914032B (en) | 2010-07-15 | 2010-07-15 | Synthetic method of (s)-N-trifluoroacetyl-2-(4-Methoxyphenyl)ethylamine |
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| CN 201010227031 CN101914032B (en) | 2010-07-15 | 2010-07-15 | Synthetic method of (s)-N-trifluoroacetyl-2-(4-Methoxyphenyl)ethylamine |
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| CN101914032B true CN101914032B (en) | 2013-06-05 |
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| EP2673265B1 (en) | 2011-02-10 | 2016-10-19 | MannKind Corporation | Formation of n-protected bis-3,6-(4-aminoalkyl) -2,5,diketopiperazine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101462970A (en) * | 2007-12-18 | 2009-06-24 | 上海百灵医药科技有限公司 | Process for synthesizing chiral methoxybenzylamine |
| CN101704762A (en) * | 2009-11-13 | 2010-05-12 | 六安市捷通达化工有限责任公司 | Production technology of beta-hydroxyalkylamide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101462970A (en) * | 2007-12-18 | 2009-06-24 | 上海百灵医药科技有限公司 | Process for synthesizing chiral methoxybenzylamine |
| CN101704762A (en) * | 2009-11-13 | 2010-05-12 | 六安市捷通达化工有限责任公司 | Production technology of beta-hydroxyalkylamide |
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Denomination of invention: Synthesis method of (S) -N- three fluoro acetyl - methoxy ethylamine Effective date of registration: 20141215 Granted publication date: 20130605 Pledgee: Jiangsu Qidong Pearl River Village bank Limited by Share Ltd. Pledgor: QIDONG HUDONG CHEMICAL Co.,Ltd. Registration number: 2014320000017 |
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