JPH0510333B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula (In the formula, R ¹ is an aryl group, R ² is an alkyl group or an aralkyl group, and R ³ is an alkoxycarbonyl group, an acyl group, an alkanesulfonyl group or an arenesulfonyl group.) Regarding the manufacturing method.

The optically active β-amino alcohol represented by the general formula () obtained by the present invention can be converted into compounds useful as sympathomimetic drugs or sympathostimulants such as l-ephedrine and l-methoxamine [TF Buckley and
H. Rapoport, J. Am. Chem. Soc., 103 , 6157
(1981)].

Conventionally, the method for producing () is the general formula obtained from (S)-alanine in 2 to 3 steps. The following methods are known: (i) reducing the α-aminoketone represented by sodium borohydride, (ii) reducing it with lithium triisobutylborohydride, and (iii) hydrogenating it in the presence of palladium-carbon. [TF Buckley and H.
Rapoport, J.Am.Chem.Soc., 103 , 6157 (1981)
reference〕.

However, all of these methods use the general formula A considerable amount of the stereoisomer of () represented by () was produced as a by-product, and it was difficult to obtain only () with high selectivity.

As a result of research to overcome the drawbacks of such conventional methods, the present inventors discovered a method for highly selectively producing the optically active β-amino alcohol represented by the general formula (), and completed the present invention. .

The present invention is based on the general formula (wherein, R ¹ is an aryl group, R ² is an alkyl group or an aralkyl group, and R ³ is an alkoxycarbonyl group, an acyl group, an alkanesulfonyl group, or an arenesulfonyl group) and a ketone with the general formula HSiR ⁴ R ⁵ R ^6- () (wherein, ^R4 is an aryl group, an alkyl group, or an aralkyl group, and ^R5 and ^R6 are an aryl group, an alkyl group, an aralkyl group, or a hydrogen atom) by reacting with a hydrosilane represented by the general formula ()
The optically active β-amino alcohol represented by the following formula is produced with high selectivity.

As the α-aminoketone represented by the general formula (), which is a raw material of the present invention, for example, (S)-2-
(ethoxycarbonylamino)-1-phenyl-1
-propanone, (S)-2-(ethoxycarbonylamino)-3-methyl-1-phenyl-1-butanone, (S)-2-(ethoxycarbonylamino)-1
-(2-methoxyphenyl)-1-propanone, (S)
-2-(ethoxycarbonylamino)-1-(4-
methoxyphenyl)-1-propanone, (S)-2-
(Ethoxycarbonylamino)-1-(3-methoxyphenyl)-1-propanone, (S)-2-(Ethoxycarbonylamino)-1-(2,5-dimethoxyphenyl)-1-propanone, (S) )-2-(ethoxycarbonylamino)-1-naphthyl-1-propanone, (S)-2-(ethoxycarbonylamino)-1
-(2-furyl)-1-propanone, (S)-2-(benzyloxycarbonylamino)-1-phenylpropanone, (S)-2-(benzenesulfonylamino)-1-phenyl-1-propanone , (S)-2-
(Benzoylamino)-1-phenyl-1-propanone, (S)-3-benzyloxy-2-(ethoxycarbonylamino)-1-phenyl-1-propanone, (S)-2-(methoxycarbonylamino)- 1
-(2,5-dimethoxyphenyl)-1-propanone, (S)-2-(methoxycarbonylamino)-1-
Phenyl-1-propanone, etc. can be used, and these are α-alanine, (S)-valine, etc.
It can be easily produced from amino acids in 2 to 3 steps with good yield (see Reference Examples).

The hydrosilane represented by the general formula (), which is one of the raw materials, is also an easily available compound, such as trisubstituted hydrosilanes such as triphenylsilane, diphenylmethylsilane, phenyldimethylsilane, and triethylsilane, diphenylsilane, and phenylmethylsilane. Disubstituted hydrosilanes such as silane, monosubstituted hydrosilanes such as phenylsilane and octylsilane can be used. The hydrosilane to be used can be used in an amount ranging from 0.3 equivalents to a large excess, but it is preferable to use an equimolar amount to 2 equivalents for efficient performance.

The present invention requires that it be carried out in the presence of an acid. Examples of acids that can be used include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid and methanesulfonic acid. The acid used can be used in an amount ranging from a catalytic amount to a large excess, but in order to carry out the reaction efficiently, it is preferable to use a large excess.
The reaction can be carried out without a solvent or in a solvent, and can be carried out using ordinary organic solvents such as aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, and diethyl ether. , diisopropyl ether, tetrahydrofuran, dioxane, and other ethers, acetic acid, propionic acid, and other carboxylic acids, and the like can be used.

The reaction proceeds at -80°C to 50°C, but preferably -20°C to 25°C to carry out efficiently and with high selectivity.

Hereinafter, the present invention will be explained in detail with reference to Examples and Reference Examples.

Reference example 1 1,4-dimethoxy-2- under argon atmosphere
Promobenzene 1.33g (6.14mmole) in THF10
ml, and 2.65 ml (6.10 mmole) of butyllithium (2.3 M, hexane solution) was added dropwise at -20°C over 5 minutes. After stirring at −20℃ for 30 minutes, at the same temperature (S)−
347 mg (1.99 mmole) of N,N-dimethyl-2-(methoxycarbonylamino)propanamide
5 ml of THF solution was added dropwise over 5 minutes. Furthermore -15~
After stirring at -20°C for 40 minutes, 10 ml of a saturated aqueous ammonium chloride solution was added, followed by extraction with methylene chloride (10 ml x 3). The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by thin layer chromatography (silica gel, methylene chloride: ethyl acetate = 9:1) yields (S)-2-(methoxycarbonylamino)-1-(2,5-dimethoxyphenyl)-1-propanone. White crystal 532mg
I got it. Yield 99.6%.

mp.：88.0−88.1℃． [α] ²⁰ _D −33.08° (c=1.07, CHCl ₃ ). 1H-NMR ( _CDCl3 ): δ 1.34 (d, J = 7.2Hz,
3H), 3.68 (s, 3H), 3.79 (s, 3H), 3.89
(s, 3H), 5.40 (q, J=7.2Hz, 1H), 5.77
(broad, 1H). IR (KBr): 3380, 1709, 1680, 1539, 1500,
1256, 1230, 1052, 1040, ^{814cm -1} ． Mass [m/z (%)]: 267 (M ⁺ , 9), 166 (11), 165
(100), 122(5), 107(9), 102(38), 77(8), 59
(5), 58(16), 30(7), 15(6). Elemental analysis value Calculated value for C ₁₃ H ₁₇ NO ₅ : C, 58.42; H, 6.41; N, 5.24% Actual value: C, 58.30; H, 6.51; N, 5.08% Reference example 2 (S)-N,N-dimethyl-2 under argon atmosphere
-(methoxycarbonylamino)propanamide
Dissolve 174 mg (1.00 mmole) in 2 ml of THF and cool at -78℃
After cooling to phenylmagnesium bromide (0.93M,
2.6 ml (2.4 mmole) of THF solution was slowly added dropwise. After stirring at -78°C for 1.5 hours and at room temperature for 30 minutes, 2 ml of a saturated ammonium chloride aqueous solution was added, and the mixture was extracted with methylene chloride (5 ml x 3). The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. By purifying with thin layer chromatography (silica gel, ethyl acetate:hexane = 2:3), 134 mg of (S)-2-(methoxycarbonylamino)-1-phenyl-1-propanone (colorless oil) was obtained. . Yield 64.7%.

[α] ²³ _D −15.2° (c=1.68, CH ₂ Cl ₂ ). Literature value ^* : [α] ²³ _D −14.2° (c=2, CH ₂ Cl ₂ ). 1H-NMR ( _CDCl3 ): δ 1.43 (d, J = 6.9Hz,
3H), 3.70 (s, 3H), 5.31 (dq, J=7.2Hz,
6.9Hz, 1H), 5.77 (broad, 1H), 7.3−7.7
(m, 3H), 7.9-8.1 (m, 2H). IR (neat): 3400, 1735, 1701, 1539, 1459,
1266, 1240, 985, 712cm ^-1 ． [＊TF Buckley and H. Rapoport, J.
Am.Chem.Soc., 103 , 6157 (1981)] Reference example 3 Under argon atmosphere, (S)-2-(ethoxycarbonylamino)propionic acid 3.23 g (20.0 mmole),
Dimethylformamide 0.1ml methylene chloride 60ml
After cooling to 0℃, add 1.83ml of oxalil chloride.
(21.0 mmole) was added, and the mixture was further stirred at 0°C overnight. Add 30ml of methylene chloride and 250ml of benzene.
After cooling to 15℃, aluminum chloride powder
Add 5.61g (42.0mmole) and further heat at -15℃ for 12
Stir for hours. 60 ml of 1M hydrochloric acid previously cooled to 0°C and 40 ml of ice water were added to separate the organic layer and the aqueous layer. The organic layer was mixed with 1M hydrochloric acid (60ml x 2), water (60ml),
and saturated sodium bicarbonate aqueous solution (60ml x 2
After washing with
Then, a crude product was obtained by filtration and concentration under reduced pressure. Distillation under reduced pressure yielded 3.84 g of 2-(ethoxycarbonylamino)-1-phenyl-1-propanone as a colorless oil. Yield 86.9%. This product crystallized by standing overnight.

bp: 130℃/3mm (Kugel). mp: 64.0-64.3℃ (Literature value ^* : 62-3℃). [α] ²⁰ _D −5.12° (c=5.00, CH ₂ Cl ₂ ). 1H-NMR (CDCl ₃ ): δ 1.25 (t, J = 7.1Hz,
3H), 1.42 (d, J = 7.4Hz, 3H), 4.10 (qJ =
7.1Hz, 2H), 5.31 (d, q, J = 7Hz, 7.4
Hz, 1H), 5.7 (broad, 1H), 7.2-7.7 (m,
3H), 7.9-8.2 (m, 2H). IR (KBr): 3400, 1717, 1689, 1526, 1250, 704
cm ^-1 ． [＊TF Buckley and H. Rapoport, J.
Am.Chem.Soc., 103 , 6157 (1981)] Example 1 Under argon atmosphere, (S)-2-(ethoxycarbonylamino)-1-phenyl-1-propanone 125
mg (0.604 mmole) was dissolved in 1 ml of trifluoroacetic acid, and after cooling to 0°C, dimethylphenylsilane was added.
0.111 ml (0.724 mmole) was slowly added dropwise. 0
After stirring at °C for 4 hours, 10 ml of saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride (10 ml x 3). The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. (1R,
2S)-2-(methoxycarbonylamino)-1-phenyl-1-propanol (colorless oil) 110mg
I got it. Yield 87%. In 1H−NMR, (1S, 2S)
No body formation was observed.

bp: 130℃/1mm (Kugel). [α] ²⁰ _D −57.7° (c=0.970, CHCl ₃ ). 1H-NMR ( _CDCl3 ): δ 0.99 (d, J=7Hz,
3H), 2.6 (broad, 1H), 3.67 (s, 3H),
4.00 (m, 1H), 4.85 (d, J=3Hz, 1H),
4.9 (broad, 1H). IR (neat): 3430, 1702, 1527, 1451, 1250,
1066,701cm ^-1 ． Example 2 Under argon atmosphere, (S)-2-(ethoxycarbonylamino)-1-phenyl-1-propanone 221
Dissolve mg (1.00 mmole) in 1 ml of trifluoroacetic acid, cool it to 0℃, and dimethylphenylsilane.
0.184 ml (1.20 mmole) was slowly added dropwise. 0
After stirring for 2.5 hours at
times). The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
(1R,2S)-(2-ethoxycarbonylamino)- was purified by thin layer chromatography (silica gel, ethyl acetate:hexane = 1:1).
White crystals of 1-phenyl-1-propanol 194
I got mg. The yield was 87%, and when observed by 1H-NMR, no formation of the (1S, 2S) form was observed.

mp: 70.6-71.0℃. [α] ²⁰ _D −41° (c=0.245, CHCl ₃ ). 1H-NMR ( _CDCl3 ): δ 0.99 (d, J=7Hz,
3H), 1.24 (t, J = 7Hz, 3H), 2.83 (broad
s, 1H), 3.8−4.2 (m, 1H), 4.10 (q, J
=7Hz, 2H) 4.84 (d, J = 3Hz, 1H), 4.9
(broad, 1H), 7.34 (s, 5H). IR (KBr): 3350, 1694, 1552, 1273, 1043,
1028,708cm ^-1 ． Mass [m/z (%)]: 223 (M ⁺ ), 117 (18), 116 (66
),
107(11), 88(21), 79(15), 77(14), 72(11), 51(5)
，
44(100), 29(23), 27(7), 18(5). Example 3 Under argon atmosphere, (S)-2-ethoxycarbonylamino)-1-phenyl-1-propanone 43.6
triethylsilane 0.035ml in mg (0.197mmole)
(0.22 mmole) was added, and after cooling to 0°C, 0.2 ml of trifluoroacetic acid was added at once. After stirring at 0°C for 2.5 hours, 5 ml of saturated aqueous sodium hydrogen carbonate solution was added to neutralize. Methylene chloride extraction (5 ml x 3 times)
Thereafter, by the same operation as in Example 2, 8 mg (18%) of the starting material ketone was recovered, and the desired (1R,2S)-(2-ethoxycarbonylamino) was recovered.
30 mg of -1-phenyl-1-propanol was obtained.
Yield 68%. (conversion yield 74%), and when observed by 1H-NMR, no formation of the (1S, 2S) form was observed.

Example 4 Under argon atmosphere, (S)-2-methoxycarbonylamino)-1-(2,5-dimethoxyphenyl)
564 mg (2.11 mmole) of -1-propanone was dissolved in 2 ml of trifluoroacetic acid, and after cooling to 0°C, 0.39 ml (2.54 mmole) of dimethylphenylsilane was slowly added dropwise. After stirring at 0°C for 15 minutes, 50 ml of saturated aqueous sodium hydrogen carbonate solution was added, and extraction with methylene chloride (30 ml x 3) was performed. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. (1R,2S)-2-(methoxycarbonylamino)-1-(2,5-dimethoxyphenyl) was purified by column chromatography (silica gel, ethyl acetate:hexane = 1:1).
479 mg of white crystals of -1-propanol were obtained. Yield 84%. In the 1H-NMR spectrum, (1S, 2S)
No body signals were detected.

mp.：95.2−95.8℃. [α] ²⁰ _D −31.67° (c=1.048, CHCl ₃ ). 1H-NMR ( _CDCl3 ): δ 1.03 (d, J=7Hz,
3H), 3.13 (broad d, J=5Hz, 1H), 3.63
(s, 3H), 3.77 (s, 3H), 3.80 (s, 3H),
4.1 (m, 1H), 5.03 (dd, J=4Hz, 5Hz,
1H), 5.1 (broad, 1H), 6.77 (m, 2H),
6.97 (m, 1H). IR (KBr): 3455, 3370, 1700, 1674, 1558,
1507, 1256, 1249, ^{1069cm -1} ． Mass [m/z (%)]: 269 (M ⁺ , 8), 237 (6), 194
(8), 168(15), 167(100), 152(10), 139(35), 137
(18), 124(14), 109(5), 103(8), 102(50), 88(18),
77(5), 103(8), 102(50), 88(18), 77(5), 59
(7), 58(21), 44(6), 30(9), 15(10). Elemental analysis value Calculated value for C ₁₃ H ₁₉ NO ₅ : C, 57.98; H, 7.11; N, 5.20% Actual value: C, 58.18; H, 7.25; N, 5.08% Example 5 Specific optical rotation {[α] ²³ _D +54.81° (c=1.08, CH ₂ Cl ₂ )
(＞89%ee), Literature value: [α] ²³ _D +61.4° (TF Buckley
and H.Rapoport, J.Am.Chem.Soc., 103 ,
6157 (1981))} (S)-2-(benzenesulfonylamino)
-1-phenyl-1-propanone 57.0mg
(0.197mmole), dimethylphenylsilane 0.036ml
(0.23 mmole) to 0.5 ml of trifluoroacetic acid at 0℃,
0.5 ml of methylene chloride was added and stirred at 0°C for 20 hours. After neutralization with 10 ml of a saturated aqueous sodium bicarbonate solution, extraction with methylene chloride (10 ml x 3) was performed. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The resulting reaction mixture was purified by thin layer chromatography (silica gel, methylene chloride) to yield 2-benzenesulfonylamino-1-phenyl-1-propanol as a colorless oil.
I got mg. Yield 66%. (1R, 2S) body: (1S, 2S)
Body = 98:2.

[α] ²³ _D −7.93° (c=0.706, CH ₂ Cl ₂ ). 1H-NMR ( _CDCl3 ): δ 0.84 (d, J=8Hz,
3H), 2.87 (d, J=5Hz, 1H), 3.53 (dq,
J=9Hz, 8Hz, 1H), 4.78(dd, J=5Hz,
3Hz, 1H), 5.20 (d, J=9Hz, 1H), 7.28
(s, 5H), 7.4-7.7 (m, 3H), 7.7-8.1 (m,
2H). IR (neat): 3520, 3280, 1443, 1322, 1158,
1090, 970, 898, 751, 720, 701, 688, 580
cm ^-1 ． Mass [m/z (%)]: 186(5), 185(11), 184(100,
Me ⁺ CHNHSO ₂ Ph), 142(5), 141(PhSO ⁺ ₂ , 60),
108(5), 107(Ph ⁺ CHOH, 54), 79(23), 78(15), 77
(Ph ⁺ , 93), 51(17), 44(35). Reference example 4 (1R,2S)-2-(ethoxycarbonylamino)
-1-phenyl-1-propanol 336 mg
(1.51 mmole) was dissolved in 3 ml of THF, and 125 mg (3.29 mmole) of lithium aluminum hydride was added.
The mixture was stirred at 60°C for 1.5 hours. After adding a small amount of water for hydrolysis, the mixture was filtered through Celite. After concentrating the filtrate under reduced pressure, the resulting crude product was subjected to thin layer chromatography (silica gel, ethyl acetate: methanol =
9:1) to produce (1R,2S)-2- as a colorless oil.
198 mg of methylamino-1-phenyl-1-propanol (-ephedrin) was obtained. Yield 80%.

1H-NMR ( _CDCl3 ): δ 0.84 (d, J=6Hz,
3H), 2.45 (s.3H), 2.4-2.9 (m, 3H), 4.74
(d, J=3Hz, 1H), 7.32 (s, 5H). After converting the obtained l-ephedrin into a hydrochloride, the specific rotation rate was measured.

l-ephedrin hydrochloride mp: 212-216℃. Literature value ^* : 216-220℃. [α] ²⁰ _D −33.51° (c=1.146, H ₂ O). Literature value ^* [α] ²⁰ _D −34° (H ₂ O). [＊Merck Index Ninth Edition, p471] Reference example 5 (1R,2S)-2-(ethoxycarbonylamino)
-1-(2,5-dimethoxyphenyl)-1-propanol 269 mg (1.00 mmole) in methanol 12 ml
Dissolved in 4 ml of water, 290 mg of potassium hydroxide
(5.18 mmole) was added and heated under reflux for 24 hours. After adding 5 ml of water and 1 ml of phosphoric acid to acidify the pH to below 1, the mixture was washed with methylene chloride (10 ml x 2). Add excess potassium carbonate to the aqueous layer to make it alkaline (>PH
14), sodium chloride was added until saturation, and ether extraction (10 ml x 3) was performed.
The extract was dried over anhydrous potassium carbonate, filtered, and concentrated under reduced pressure to obtain a crude product. By distillation under reduced pressure, a colorless oil (1R,2S)-2-amino-1-(2,5-
175 mg of dimethoxyphenyl-1-propanol (l-methoxamine) was obtained. Yield 83%.

bp: 120℃/1mm (Kugel). 1H-NMR ( _CDCl3 ): δ 0.97 (d, J=7Hz,
3H), 2.08 (broad, 3H), 3.22 (dq, J=7
Hz, 5Hz, 1H), 3.76 (s, 6H), 4.74 (d,
J = 5Hz, 1H), 6.76 (m, 2H), 6.99 (m,
1H). IR (neat): 3380, 3300, 3180, 2970, 2950,
1500, 1220, 1050cm ^-1 ． After converting the obtained l-methoxamine into hydrochloride,
Specific optical rotation was measured.

l-methoxamine hydrochloride mp: 183-5°C. Literature value ^* : 182-3℃. [α] ²⁵ _D −27.91° (c=3.088, H ₂ O). Literature value ^* [α] ²⁵ _D −28.5° (c=4, H ₂ O). [*R.Baltzly and NBMehta, J.Med.
Chem., 11 , 833 (1968)]

Claims (1)

[Claims] 1. In the presence of an acid, the general formula The general formula consists of reacting an α-aminoketone represented by the formula HSiR ⁴ R ⁵ R ⁶ with a hydrosilane represented by the general formula HSiR 4 R 5 R 6 A method for ^{producing an} optically active β ^- amino alcohol represented by ⁴ is an aryl group, an alkyl group, or an aralkyl group, and R ⁵ and R ⁶ are an aryl group, an alkyl group, an aralkyl group, or a hydrogen atom).