CN1136186C - Method for preparing intermediate of methylsalfonamido phenethylamine derivative - Google Patents
Method for preparing intermediate of methylsalfonamido phenethylamine derivative Download PDFInfo
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- CN1136186C CN1136186C CNB991145690A CN99114569A CN1136186C CN 1136186 C CN1136186 C CN 1136186C CN B991145690 A CNB991145690 A CN B991145690A CN 99114569 A CN99114569 A CN 99114569A CN 1136186 C CN1136186 C CN 1136186C
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Abstract
The present invention relates to a new preparation process of a general formula (I) of O2n-y-*-alk-x-* (V). In the general formula (I), R6 is CH3, phenyl and acetyl; X is O, S or a single bond; Y is 1, 2-ethylidene arbitrarily substituted by methyl; alk is 1, 2-ethylidene, 1, 3-propylidene or tetramethylene and is arbitrarily substituted by the methyl; R2 is H, halogen or C1-C4 alkyl; R3 is a group of NO2 or CONR4 R5, wherein R<4> and R<5> are respectively H or C1-C4 alkyl or nitrogen atoms connected with the C1-C4 alkyl independently, which denotes morpholinyl together. The present invention provides a new synthetic route using beta-phenylethylamine as a raw material, which is convenient and applicable.
Description
The present invention relates to a kind of key intermediate with methylsulfonyl amine of cardiac vascular activity.
The patent No. is 87103300 patent, and with N-methyl-4-oil of mirbane ethamine and the substitution reaction of halo virtue oxidative ethane generation nitrogen, through reduction, the alkane sulfonylation obtains title compound
At first, the preparation of N-methyl-4-oil of mirbane ethamine-[J.O.C. (1956), 21,45] be to be raw material with p-nitrophenyl ethene, with methylamine generation addition reaction gained, this goes on foot yield very low (25%), and the preparation of p-nitrophenyl ethene, then needing with the bata-phenethyl alcohol is raw material, obtains through bromination (86%), nitrated (54%) and dehydrogenation bromic acid (80%) [J.A.C.S.62 1435 and 69,2141] three-step reaction.
Secondly, owing to use n-methyl-4-oil of mirbane ethamine to be raw material, that is, the methyl on the N is the R in the general formula (I), and (R is C thereby limited the scope of general formula (I)
1-C
4Alkyl), if wish to obtain the compound that R is an aralkyl, then can not use this method.
The objective of the invention is to avoid above-mentioned weak point of the prior art and providing a kind of is the novel method that starting raw material prepares key intermediate N-methyl-4-oil of mirbane ethamine with β-phenylethylamine.
Purpose of the present invention can reach by following measure:
1. the new preparation process of general formula (I):
In the formula, R is CH
3R
1Be C
1-C
4Alkyl;
X is O, a S or a singly-bound;
Y is the ethylene that is replaced arbitrarily by methyl;
" alk " is ethylene, trimethylene or tetramethylene, and " alk is replaced arbitrarily by methyl;
R
2Be H, halogen or C
1-C
4Alkyl;
R
3Be formula-NHSO
2(C
1-C
4Alkyl) or CONR
4R
5Group, R wherein
4And R
5Be H or C independently of one another
1-C
4Alkyl or represent morpholinyl with the nitrogen-atoms that it connected.The preparation method of general formula (I) comprising:
(A) compound of general formula (II) under acidic conditions with the alkylated reaction of formaldehyde/formic acid system,
In the formula, R
1, R
2, R
3, X, Y, " alk " be identical with general formula (I).
2. the preparation method of general formula (II): (B) general formula (III) R
6For the compound of benzyl at acid solvent, particularly in the Glacial acetic acid, under the Pt/c catalysis, a 0-100 ℃ of logical hydrogen 1-30 normal atmosphere reacted 1-10 hour, and debenzylation takes place.(C) general formula (III) R
6For the compound of ethanoyl in acidic aqueous solution, particularly among the 48%HBr, back flow reaction 2-8 hour, the deacetylation reaction takes place,
In the formula, R
6Be benzyl and ethanoyl, R
1, R
2, R
3, X, Y, " alk " be identical with general formula (I).
3. the preparation method of general formula (III): (D) compound of general formula (IV) is under alkyl sulfonyl chloride, alkyl sulfonyl bromine, the effect of alkylsulphonic acid acid anhydride, and (alkyl is C to the acylation reaction of generation
1-C
4):
In the formula, R
6Identical with the compound of general formula (III), R
2, X, Y, " alk " be identical with the compound of general formula (I), R
3For-NH
2Or CONR
4R
5Group, R wherein
4And R
5Be H or C independently of one another
1-C
4Alkyl or coupled nitrogen-atoms are represented morpholinyl together.
4. the preparation method of general formula (IV): (E) reduction reaction particularly in iron powder/hydrochloric acid system, takes place in iron powder/acid in the compound of logical formula V; (F) compound of logical formula V is at Raney nickel/H
2In the system, reduction reaction takes place; (G) reduction reaction takes place in the compound of logical formula V in Raney nickel/hydrazine hydrate system;
In the formula, R
6For benzyl, ethanoyl ,-CH
3, R
2, X, Y, " alk " be identical with the compound of general formula (I), R
3For-NO
2Or CONR
4R
5Group, radicals R
4And R
5Be H or C independently of one another
1-C
4Alkyl or coupled nitrogen-atoms are represented morpholinyl together.
5. the preparation method of logical formula V: (H) compound of general formula (VI) under acidic conditions with formaldehyde/formic acid system generation alkylated reaction; (I) compound of general formula (VI) is under the effect of aceticanhydride; acylation reaction takes place; (J) compound of general formula (VI) is under the effect of benzyl chloride; base catalysis, particularly K
2CO
3, substitution reaction takes place,
In the formula, R
2, X, Y, " alk " be identical with the compound of general formula (I), R3 is identical with the compound of logical formula V.
6. the preparation method of general formula (VI): (K) compound of the compound or its salt of general formula (VII) and general formula (VIII) is at alkalescence K particularly
2CO
3Condensation reaction under the condition,
In the formula, R
2, R
3, X, Y, " alk " all the compound with general formula (VI) is identical.
7. the preparation method of general formula (VII): (L) the deacetylation reaction takes place in the compound of general formula (X) in 48%HBr,
In the formula, Y is identical with the compound of general formula (VI).
8. the preparation method of general formula (X): (M) compound of general formula (IX) is at nitrating agent, particularly HNO
3/ H
2SO
4Nitration reaction in the system,
In the formula, Y is identical with the compound of general formula (VI).
The preparation of following embodiment formula (I) compound, all temperature all are ℃.
Embodiment 1: to nitro acetyl β-phenylethylamine
In 1000 milliliters of β-phenylethylamines, in the ice-water bath, drip 76 milliliters of aceticanhydrides, reacted 2 hours, standby,
In the mixed solution of 1500 milliliters of vitriol oils and 1500 milliliters of nitric acid, the above-mentioned reserve liquid of dropping below 0 ℃ drips and finishes, and continues reaction 2 hours, pours in the frozen water, uses ethyl acetate extraction three times, merges the ester layer, washing, anhydrous Na
2SO
4Drying is concentrated into driedly, uses the acetone-water recrystallization, title compound 600 grams, fusing point 138-141 ℃.
Embodiment 2: to nitro β-phenylethylamine hydrobromate
In to nitro β-phenylethylamine (600 gram), add 47%HBr (1000 milliliters), reflux 6 hours, cooling is separated out title compound (650 gram), fusing point 218-220 ℃.
Embodiment 3:1-(4-nitrophenoxy)-2-[N-(4-oil of mirbane ethyl) amido] ethane
Salt of wormwood (66 gram) is added to nitro β-phenylethylamine hydrobromate (80 gram) and 2-(p-nitrophenyl oxygen base) monobromoethane (100 gram) in the solution of acetonitrile (800 milliliters), this suspension stirred 7 hours under refluxing, be evaporated to do after, resistates distributes between ethyl acetate and water.After using the ethyl acetate extraction secondary again, merge organic phase, be evaporated to dried, light yellow title compound (105 gram), fusing point: 58-60 ℃.
Embodiment 4:(A) 1-(4-nitrophenoxy)-2-[N-(4-oil of mirbane ethyl)-N-benzyl amido] ethane
With 1-(4-nitrophenoxy)-2-[N-(4-oil of mirbane ethyl) amido] ethane (10 gram) and the mixture of salt of wormwood (6.0 gram) in acetonitrile (60 milliliters), drip the benzyl chloride (3.54 gram) of acetonitrile (40 milliliters) dilution, reflux and stirred 3.5 hours, filter, filtrate is concentrated into dried, logical HCl salify crystallization, and crystallization is free with alkali, get title compound (3.6 gram), fusing point 94-96 ℃.
Nucleus magnetic resonance (CDCl
3) ppm, δ=2.912 (unimodal, 4H) 2.98 (triplet, 2H) 3.76 (unimodal, 2H) 4.03 (triplet, 2H) 6.885 (multiplet, 2H) 7.261-7.30 (multiplet, 7H) 8.1-8.2 (multiplet, 4H)
Mass spectrum (M/Z): 422 (MH
+) (B) 1-(4-nitrophenoxy)-2-[N-(4-oil of mirbane ethyl)-N-acetamido of 285 (base peaks)] ethane 1-(4-nitrophenoxy)-2-[N-(4-oil of mirbane ethyl)-N-acetamido] stir in ethane (2 gram) ice bath, add aceticanhydride (2 milliliters), stirring at room 2 hours, add ether, there is solid to separate out, get title compound, fusing point 112-113 ℃.
Nucleus magnetic resonance (CDCl
3) ppm, δ=2.04,2.21 (doublet, 3H) 3.04 (triplet, 2H) 3.72 (multiplet, 4H) 4.03-4.30 (multiplet, 2H) 6.88-6.98 (multiplet, 2H) 7.30-7.48 (multiplet, 2H) 8.01-8.29 (multiplet, 4H)
Mass spectrum (M/Z): 374 (MH
+) 235 (base peak) 140 89 (C) 1-(4-nitrophenoxy)-2-[N-methyl-N-(4-oil of mirbane ethyl)] ethylamine
36%HCHO (70 milliliters) is splashed into 1-(4-nitrophenoxy)-2-[N-(4-oil of mirbane ethyl) amido] ethane (105 gram) is in the solution of 88% formic acid (50 milliliters), to under refluxing, stir 4 hours than solution, underpressure distillation is to doing, gained solid recrystallization from ethyl acetate/petroleum ether, get title compound (80 gram), fusing point 72-74 ℃.
Embodiment 5:(A) 1-(4-amino-benzene oxygen)-2-[N-(4-amino-benzene ethyl)-N-benzamido group] ethane (A
1) in the presence of room temperature and normal pressure and Raney nickel, with 1-(4-nitrophenoxy)-2-[N-(4-oil of mirbane ethyl)-N-benzamido group] ethane (3.0 gram), the solution in acetone (20 milliliters) leads to H
2Stirred 48 hours, reaction mixture filtered, be concentrated into dried, title compound (1.4 gram).
Nucleus magnetic resonance (CDCl
3) ppm, δ=2.8 (unimodal, 4H) 3.0 (triplet, 2H) 3.73 (unimodal, 2H) 3.87 (triplet, 2H) 6.9-7.0 (multiplet, 8H) 7.27 (unimodal, 5H) (A
2) hydrazine hydrate (5 milliliters) is slowly splashed into 1-(4-nitrophenoxy)-2-[N-(4-oil of mirbane ethyl)-N-benzamido group] ethane (5 gram) and Raney nickel (2 milliliters) be in the suspension of acetone (100 milliliters), stir down and refluxed 30 minutes, filter, filtrate is concentrated into dried, use ether dissolution, filter, after concentrating, use recrystallization from ethyl acetate/petroleum ether, get title compound.(A
3) in 10 milliliters of hydrochloric acid and 40 ml methanol, add iron powder (6.72 gram) and a small amount of ammonium chloride, heat-activated iron powder, 1-(4-nitrophenoxy)-2-[N-(4-oil of mirbane the ethyl)-N-benzamido group of dropping dissolve with methanol] ethane, back flow reaction 3 hours, cold slightly, alkali is neutralized to PH=10, while hot suction filtration, ethyl acetate extraction, concentrated extracting solution, recrystallization from ethyl acetate/petroleum ether gets title compound.(B) 1-(4-amino-benzene oxygen)-2-[N-(4-amino-benzene ethyl)-N-acetamido] ethane
Title compound is pressed embodiment 5 (A
3) operation preparation,
Nucleus magnetic resonance (CDCl
3) ppm, δ=1.92 2.15 (doublet, 3H) 2.75 (triplet, 2H) 3.41-3.62 (quartet, 4H) 4.03 (triplet, 2H) 6.57-6.68 (multiplet, 6H) 6.89-7.01 (multiplet, 2H)
Mass spectrum (M/E): 314 (MH
+) 205 (base peaks) 120 86
Embodiment 6:(A) 1-(4-Toluidrin phenoxyl)-2-[N-(4-methylsulfonyl amido styroyl)-N-benzamido group] the ethane sodium salt
With 1-(4-amino-benzene oxygen)-2-[N-(4-amino-benzene ethyl)-N-benzamido group] ethane (1.4 gram) and methylsulfonyl chloride (1.3 gram) and the solution room temperature reaction of pyridine (0.6 restrains) in anhydrous methylene chloride (30 milliliters) 2 hours, refluxed 4 hours, the buck dissolving, concentrate with dichloromethane extraction is dry, splash into dense NaOH and an amount of anhydrous propanone, cooling is solidified, and gets title compound (2 gram).
Nucleus magnetic resonance (CDCl
3) ppm, δ=2.53 (unimodal, 6H) 2.61 (unimodal, 4H) 2.82 (triplet, 2H) 3.71 (unimodal, 2H) 3.90 (triplet, 2H) 6.60-6.80 (multiplet, 8H) 7.28 (unimodal, 5H)
Mass spectrum (M/Z) 518 (MH
+, base peak) and 440 333 271 209 190 86.(B) 1-(4-Toluidrin phenoxyl)-2-[N-(4-methylsulfonyl amido styroyl)-N-acetamido] the ethane sodium salt
Title compound is pressed embodiment 6 (A) operation preparation
Nucleus magnetic resonance (DMSO-d
6) ppm, δ=1.858 2.054 (doublet, 3H) 2.852 (unimodal, 3H) 2.871 (unimodal, 3H) 3.626 (multiplet, 6H) 4.046 (triplet, 2H) 6.828 6.931 (doublet, and 2H) 7.122 7.193 (doublet, 6H)
Mass spectrum (M/Z): 470 (MH
+) 350 283 109 78 (base peaks)
Embodiment 7:1-(4-Toluidrin phenoxyl)-2-[N-(4-methylsulfonyl amido styroyl)] ethane
Method one: in the presence of 30 ℃ and 15 kilograms of normal atmosphere and palladium carbon, with 1-(4-Toluidrin phenoxyl)-2-[N-(4-methylsulfonyl amido styroyl)-N-benzamido group] solution stirring of ethane (1.5 gram) in acetate (40 milliliters) 8 hours, reaction mixture is filtered, be neutralized to neutrality with alkali, use ethyl acetate extraction, concentrate, get title compound (0.5 gram), fusing point 149-151 ℃.
Nucleus magnetic resonance (CD
3COCD
3) ppm, δ=2.81077 (triplet, 2H) 2.90368 (multiplet, 5H) 2.95003 (unimodal, 3H) 2.99738 (triplet, 2H) 4.09113 (triplet, 2H) 6.92117 (doublet, and 2H) 7.27722 (multiplet, 6H)
Method two: 1-(4-Toluidrin phenoxyl)-2-[N-(4-methylsulfonyl amido styroyl)] ethane
In 1-(4-Toluidrin phenoxyl)-2-[N-(4-methylsulfonyl amido styroyl)-N-acetamido] added 47%HBr 20ml reflux in the ethane sodium salt 6 hours, cooling is neutralized to neutrality with alkali, ethyl acetate extraction, concentrate, get title compound, fusing point 148-150 ℃.
Nucleus magnetic resonance (CD
3COCD
3) ppm, δ=2.81 (triplet, 2H) 2.90 (multiplet, 5H) 2.95 (unimodal, 3H) 2.997 (triplet, 2H) 4.091 (triplet, 2H) 6.921 (triple, and 2H) 7.277 (multiplet, 6H)
Embodiment 8:1-(4-Toluidrin phenoxyl)-2-[N-(4-methylsulfonyl amido styroyl)-N-methyl] ethane
36%HCHO (7ml) is splashed into 1-(4-Toluidrin phenoxyl)-2-[N-(4-methylsulfonyl amido styroyl)] ethane is in the solution of 88% formic acid (5ml), this solution was stirred 4 hours under refluxing, underpressure distillation is to doing, recrystallization from ethyl acetate/petroleum ether, get title compound, fusing point 147-149 ℃.
Nucleus magnetic resonance (DMSO-d
6) ppm, and δ=2.293 (unimodal, 3H) 2.62 (doublets, 2H) 2.666 (doublet, 2H) 2.752 (triplet, 2H) 2.752 (triplets, 2H) 2.876 (unimodal, and 3H) 2.926 (unimodal, 3H) 4.000 (triplets, 2H) 6.910 (doublets, 2H) 7.114 (doublet, 2H) 7.144 (doublet, 2H) 7.189 (doublets, 2H) 9.471 (broad peak, 2H)
The present invention has following advantage compared to existing technology:
1. raw material β-phenyl ethylamine is cheap and easy to get.
2. prior art is take sodium iodide as catalyst, expensive in condensation reaction. Be unsuitable for mass production, the present invention By preparation to nitro β-phenyl ethylamine hydrobromate, with general formula be the compound of VII when carrying out condensation reaction, only need use carbon Acid potassium is as catalyst, and yield is higher.
3. the invention provides a new synthetic route, more convenient, simpler and more direct, more suitable.
Claims (1)
1. the preparation method of leading to formula V:
In the formula, R
6Be ethanoyl;
X is O, a S or a singly-bound;
Y is the ethylene that is replaced arbitrarily by methyl;
" alk " is ethylene, trimethylene or tetramethylene, and " alk " replaced arbitrarily by methyl;
R
2Be H, halogen or C
1-C
4Alkyl;
R
3Be NO
2Or CONR
4R
5Group, R wherein
4And R
5Be H or C independently of one another
1-C
4Alkyl or represent morpholinyl with the nitrogen-atoms that it connected;
The preparation method of logical formula V comprises:
Acylation reaction takes place in the compound of general formula (VI) under the effect of aceticanhydride,
In the formula, R
2, X, Y, " alk ", R
3Identical with the compound of logical formula V.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB991145690A CN1136186C (en) | 1999-11-24 | 1999-11-24 | Method for preparing intermediate of methylsalfonamido phenethylamine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB991145690A CN1136186C (en) | 1999-11-24 | 1999-11-24 | Method for preparing intermediate of methylsalfonamido phenethylamine derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95112798A Division CN1055682C (en) | 1995-12-06 | 1995-12-06 | Process for preparing mesylamido-phenethylamine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1287999A CN1287999A (en) | 2001-03-21 |
| CN1136186C true CN1136186C (en) | 2004-01-28 |
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ID=5277636
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|---|---|---|---|---|
| CN104557566A (en) * | 2014-12-23 | 2015-04-29 | 安徽德信佳生物医药有限公司 | Preparation method for 4-nitrobenzene ethylamine hydrobromide |
| CN107759477A (en) * | 2017-11-20 | 2018-03-06 | 阿里化学(常州)有限公司 | A kind of preparation method of p-nitrophenyl ethylamine hydrochloride |
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