JPS60172953A - Preparation of optical active beta-amino-alcohol - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an sympathomimetic agent in high selectivity from easily obtainable raw materials, by reacting a specific alpha- aminoketone with a hydrosilane in the presence of an acid. CONSTITUTION:In the presence of an extremely excess amount of an acid (e.g., HCl, H2SO4, trifluoroacetic acid, methanesulfonic acid, etc.), an alpha-aminoketone shown by the formula I (R<1> is aryl; R<2> is alkyl, or aralkyl; R<3> is alkoxycarbonyl, asyl, etc.) is reacted with a hydrosilane shown by the formula HSiR<4>R<5>R<6> (R<4> is aryl, alkyl, or aralkyl; R<5> and R<6> are aryl, aralkyl, H, etc.), to give an optically active beta-amino-alcohol shown by the formula II. Effectively the method is carried out in the absence of a solvent or in a solvent such as benzene, toluene, etc. preferably at -20-25 deg.C. Both the raw material compounds are easily obtainable.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (wherein 1 is an aryl group, le is an alkyl group or an aralkyl group, R3 is an alkoxycarbonyl group, an acyl group, an alkanesulfonyl group, and t& is an arenesulfonyl group). ) relates to a method for producing an optically active β-amino alcohol.

Induction into compounds useful as sympathomimetics or sympathomimetics such as the optically active β-amino alcohol tl-ephetomelin 41-methoxamine, which is obtained by the present invention and is represented by the general formula (1). (T, F, Buckley and H.

Rapoport, J., Am., Chem., Soc.
103, 6157 (1981)].

Conventionally, methods for producing (1) include a method in which α-7 minoketone represented by the general formula obtained from (S)-alanine in 2 to 3 steps is reduced with (i) sodium borohydride; A method of reducing with lithium triisobutylboron chloride and a method of hydrogenating in the presence of palladium on carbon (if
T., F., Buckley [[and H.

Rapport, J., Am., Chem.
, Soc., 1 R. 3.6157 (1981)].

However, in all of these methods, a considerable amount of the stereoisomer of (1) represented by the general formula is produced as a by-product, making it difficult to obtain only (I) with high selectivity.

As a result of research to overcome the drawbacks of such conventional methods, the present inventors found that the optically active β-
Discovered a method to produce amino alcohols with high selectivity,
The invention has been completed.

In the present invention, in the presence of an acid, the general formula (wherein R1 is an aryl group,
Alkyl group ns is an alkodicarbonyl group, an acyl group, an alkanesulfonyl group or an arenesulfonyl group)
A ketone represented by the general formula % (2) (where a4 is an aryl group, an alkyl group, or an aralkyl group, and R5 and t are an aryl group, an alkyl group, an aralkyl group, or a hydrogen atom) The optically active β-amino alcohol represented by the general formula (I) is produced with high selectivity.

α- represented by the general formula (]) which is the raw material of the present invention
Examples of the ami7ketone include (S)-2-(ethoxycarbonylamino)-1-phenyl-1-propanone, (
S)-2-(ethoxycarbonylamino)-03:
:f-1-phenyl-1-butanone, (8)-2-
(ethoxycarbonylamino)-1-(2-methoxyphenyl)-1-propanone, (S)-2-(ethoxycarbonylamino)-1-(4-methoxyphenyl)-1
-propanone, (S)-2-(ethoxycarbonylamino)-1-(3-methoxyphenyl)-1-propanone, (8)-2-(ethoxycarbonylamino"'3Y'
(2,5-dimethoxyphenyl)-1-propanone,
(Sl-2-(ethoxycarbonylamino)-1-naphthyl-1-propanone, (8)-2-(ethoxycarbonylamino)-1-(2-furyl)-1-propanone,
(S) -2-(benzyloxycarbonylamino)
-1-phenylpropanone, (S) -2-'(benzenesulfonylamino)-1-phenyl-1-propanone, (S)-2-(benzoylamino)-17phenyl-1-propanone, (S)-3- Benzyloxy-2-(
Ethocyccarbonylamino)-1-phenyl-1-propanone, etc., can be used, and these can be made from α-amino acids such as (S)-alanine and (S)-valine with 2 to 3
It can be easily produced in a process with good yield (see reference side).

One of the raw materials, hydrone 2, represented by the general formula (2) above, is also an easily available compound, such as trisubstituted hydron 2, such as triphenylsilane, diphenylmethyl silane, phenyldimethylsilane, and triethylsilane. , di-substituted hydrosilanes such as diphenylsilane and phenylmethylsilane, and monosubstituted hydrosilanes such as phenyldinine and octylsilane can be used. Hydrofucne 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 treatment.

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, tetrahydrofucne, dioxane, and other ethers, acetic acid, propionic acid, and other carboxylic acids, and the like can be used.

The reaction proceeds at a temperature of -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 u■e Under an argon atmosphere, 1.33 g (6,14 mmole) of 1,4-dimethoxy-2-pClmobenze y was dissolved in THFl.
Butyllithium (2,3M
.

hexane solution) 2.65+a/(6.10 mmole)
was added dropwise over 5 minutes. After stirring at -20°C for 30 minutes, 347 mg (1,99 m
A 5m solution of 'I'HF' of mo 1 e) was added dropwise over 5 minutes. After further stirring for 40 minutes at -15 to -20'O, 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. It was purified by thin layer Chromadog 2F (silica gel, methylene chloride: ethyl acetate = 9:1), and (81
-2-(methoxycarbonylamino)-1-(2,5-
White crystals of dimethoxyphenyl-1-propanone 53
I got 29. Yield 99.6%.

mp, +88.0-88.1°C.

[α] 20-33.08° (c = 1.07, CH
C1s)-'H-NMR (CDCI 3): δ
1,34 (d, J = 7.2Hz.

3H), 3.68 (s, 3H), 3.79 (s.

3H), 3.89(s, 31(), 5.40(q.

J=7.2Hz, LH), 5.77 (broad.

IH).

1 liter (KBr): 3380, 1709, 1680, 15
39°1500.1256,1230,1052°10
40 814aR.

+ Mass [m/z (%)): 267 (M, 9), 16
6(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 C13H17NO5: C
, 58,42; H, 6,41; N, 5.24% Actual value 2C, 5B, 30; H, 6,51; Nt 5.08% Reference example 2 0 e Under argon atmosphere, (8)- N,N-dimethyl-2XI
and l-(methoxycarbonylamino)pro-(amino)'
17411g (1,00mmole) 'I'HF 2
Phenylmagnesium bromide (0.93M, THF solution) 2.6au (2.4
Yuri <9 drops of mmol e) were added. 1.5 at -78℃
After stirring for 30 minutes at room temperature, a saturated ammonium chloride aqueous solution 2R1 was added, and the mixture was extracted with methylene chloride (5 m x 3 times). After drying the extract with anhydrous magnesium sulfate, filtration,
It was concentrated under reduced pressure to obtain a crude product. Thin layer chromatography (
By purifying with silica gel, ethyl acetate:hexane=2:3), (S)-2-(methoxycarbonylamino)-1-phenyl-1-propanone (colorless oil)
I got 34 da. Yield 64.7 inches.

[α brother'-15,2° (c=1.681CH2C12)
.

Literature I: [α): 3-14.2° (C=2.C1(2
C12).

'i(-NMR(CDCl,) : δ1.43 (d
, J = 6.9Hz.

3H), 3.70 (s, 3H), 5.31 (dq.

J-7, 2Hz, 6.9Hz, IH), 5
．． 77 (broad, IH), 7.3-7.7 (
m, 3H).

7.9-8.1 (m, 2H).

IR(neat): 3400.1735, 1701
, 1539.

1459.1266.1240,985°712c++
+'.

(T, F, Buckley l [and) (, Ra
port.

J, Am, Chem, Soc, Jj13.6157 (
1981)) Reference Example 3 e Under an argon atmosphere, 3.23 g (S)-2-(ethoxybonylamino)propionic acid (20, Ommole
), 0.1 WLt of dimethylformamide was dissolved in 60 ml of methylene chloride, and after cooling to 0°C, 1.1 WLt of dimethylformamide was dissolved.
83m/! Add (21, Ommole) and then 0
Stir overnight at °C. Methylene chloride 30d1 benzene 25
After adding 0 + t/w and cooling to -15°C, 5.61 g of aluminum chloride powder (42,π8) was added, and the mixture was further stirred at -15°C for 12 hours. and separated the organic layer and the aqueous layer.The organic layer was treated with 1M hydrochloric acid (60m7 x 2 times) and water (
60 tablespoons, and saturated aqueous sodium bicarbonate solution (soI
I7! x2@), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. 2-(Ethoxycarbonylamino)-1-phenyl-1-propanone was obtained as a colorless oil by distillation under reduced pressure.
I got g. Yield 86.9%. This product was crystallized by standing overnight.

bp: 130℃/3mm (Kugel)
.

mp: 64,0-64.3℃ (Reference 1t 2 62-3
℃).

(α formula' -5,12° (c=5.00, CH2Cl
2).

Literature A♂: [α); 5-5.9° (c=5, CH2
Cl2).

'n-]): 1p-zuLjF7-(CDCI 3) 2 δ 1.25 (t, J-7,11←) [2°3H),
1.42 (d, J, = 7.4Hz, 3H).

4.10 (q:F4T=7.IHz, 2H),
5.31 (d, q, J=7Hz, 7.4Hz, IH)
.

5.7 (broad, IH), 7.2-7.7
(m.

3H), 7.9-8.2 (m, 2H).

IR(KBr): 3400,1717.1689,1
526゜1 1250 704 Kushi.

CM T, F, Buckley [1 and H, Ra
port.

J,Am,Chem,Soc,,103.6157(1
981)) Example 1 e Under argon atmosphere, (8)-2-(methoxycarbonylamino)-1-phenyl-1-propanone 125In9
(0,604 mmole) was dissolved in 1 d of trifluoroacetic acid, and after cooling to 0°C, dimethylphenylsilane 0.1
A small amount of 11 mj (0,724 mmole) was added dropwise.

After stirring at 0°C for 4 hours, saturated aqueous sodium hydrogen carbonate solution 1
0m was added and extracted with methylene chloride (1 (W:X 3 times). The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Thin layer chromatography (
Purified with silica gel, ethyl acetate: 1:1), (1S)-2-(methoxycarbonylamino)-1-phenyl-1-7' lovanol (m color, j-yl ) Obtained 110 Da. Yield) ii. 1H-N
MB, then (IS.

No formation of 2S) bodies was observed.

bp: 130°C/1 mm (Kt+gel).

(Q):'-57,7° (c=0.970.CHC
l).

'n-NMa (cnct3): δ 0.99 (d, J
-7Hz.

3H), 2.6 (broad, IH), 3.6
7 (s, 3H), 4.00 (m, IH), 4.85 (d
, J-3Hz, IH), 4.9 (broad.

IH).

II too (neat): 3430, 1702, 1527
,1451°1250.1066.701cln.

Example 2 e Under argon atmosphere, (8)-2-(methoxycarbonyl 7/)-1-phenyl-1-propanone 2219(1
,00 tnmole) was dissolved in 1 ml of trifluoroacetic acid, and after cooling to 0°0, 0.1 tnmole of dimethylphenylsilane was dissolved.
A small amount of 84 m (1.20 mmole) was dropped into the solution.

After stirring at 0υ for 2.5 hours, the mixture was neutralized with saturated aqueous sodium bicarbonate solution 201, and extracted with methylene chloride (10a/X 3 times). The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.

By purification by thin layer chromatography (silica gel, ethyl acetate:hexane = 1:1) (IR, 28)
-(2-ditΦcarbonylamino)-1-phenyl-
194 da of white crystals of 1-propertool were obtained. Yield too. When observed with 1H-shintan, no formation of (18,28) body was observed.

mpnia 0.6-71.0°C.

[α) D-41 (c = 0.245, CHCl
3) -'H-NMR (CDCI, ): δ0.99 (
d, J-7Hz.

3H), 1.24(t, J -7Hz, 3H
).

2.83 (broad s, IH), 3.8-4.2 (
m, IH), 4.10 (q, J=7Hz, 2H).

4.84 (d, J-3Hz, IH), 4.9 (b
road, IH), 7.34 (s, 5H)
.

IR (KBr) 23350, 1694, 1552, 12
73°1043.1028.708.

+ 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), 1B(5).

Example 3 e Under argon atmosphere, (8)-2-(methoxycarbonyl 7/)-1-phenyl-1-propanone 43.6In
&(0,197 mmole) and 0.0% triethylsilane.
After cooling to 0° C., 0.2 m/trifluoroacetic acid was added at once. After stirring at 0°C for 2.5 hours, add 5 m of saturated aqueous sodium hydrogen carbonate solution.
1 was added to neutralize. Methylene chloride extraction (5m x 3 times)
Thereafter, by the same operation as in Example 2, the starting material ketone 87119 (18%) was recovered and the desired (
1 liter, 28)-(2-ethoxycarbonylamino)-1
-Phenyl-1-propertool 30 da was obtained. Yield 68
blood. (Conversion yield: 74 cm).No formation of the (18,28) isomer was observed when 'ii-width was observed.

Example 4 Under argon atmosphere, (S)-2-(methoxycarbonylamino)-1-(2,5-dimethoxy7enyl)-1
-Propano y 5644 (2,11 mmol e) was dissolved in trifluoroacetic acid 2-, and after cooling to 0 °C, dimethyl 7 x = 1k s y 0.39 m/(2,5
4 mmole) was slowly added dropwise. 15 at 0℃
After stirring for a minute, 50 m of a saturated aqueous sodium bicarbonate solution was added, and extraction with methylene chloride (30 m/×3 times) was performed.

The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. By purifying with column chromatography (silica gel, ethyl acetate:hexane = 1:1), (1 liter, 28)-2-(methoxycarbonylamino)-1-(2,5-dimethoxyphenyl)-1- White crystals of glopanol 479~ were obtained. Yield m. 1H
- In the Ikemas vector, the signal of the (Is, 28) body could not be used.

mp: 95.2-95.8°C.

(a) n' -31,67° (c-1,048, CH
Cl3) -'H-1%iB (CDCl2): δ
1,03 (d, J=7Hz.

3H), 3.13 (broad d, J=5Hz
.

IH), 3.63 (s, 3H), 3.77 (s.

3H), 3.80 (s, 3H), 4.1 (m.

IH), 5.03 (dd, J=4Hz, 5Hz.

IH), 5.1 (broad IH), 6-
77 (m.

2H), 6.97 (m, IH).

IR (KBr): 3455, 3370, 1700, 16
74°1558.150? , 1256, 1249°10
69cm.

+ Mass (m/z (96)): 269 (M
, 8), 237(6).

194(8), 16B(15), 167(100).

152(10), 139(35), 137(1B).

124(14), 109(5), 103(8), 102
(50), 88 (18), 77 (5), 59 (7), 5
B (21), 44 (6), 30 (9), 15 (10).

Elemental analysis value Calculated value for C1, Hl, N05: C
,57,98;H,7,11;N,5.20chi Actual measurement value:
C, 58,18; H, 7,25; N, 5.08% Example 5 Me Specific rotation 1K ((α)H'+54.81' (c=1.
08.

Cll2C12) (>89%ee).

Literature values: [α), -1-61,4° (T, F.

Buckley ill and H, Raporpor
t.

J, Am, Chem, Soc, □, 6157 (198
1) Tsukiwomotsu (S) -2-(benzenesulfonylamino)-
1-phenyl-1-propanone 57.0~(0,197
mrno 1 e ), + dimethyl fluoride x = leX/
Run 0.036+++/' (0,23 mmol e
) was added with 0.5 ml of trifluoroacetic acid and 0.5 rttl of methylene chloride at 0°C, and the mixture was stirred at 0°C for 20 hours. After neutralization with 10 ml of saturated aqueous sodium hydrogen carbonate solution, extraction with methylene chloride (10 dXa times) 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 obtain 38η of 2-benzenesulfonylamino-1-phenyl-1-propatol as a colorless oil. Yield 66%. (IR, 28) body: (
Is.

28) Body -98: 2° (Q ), ,' -7,93° (c -0,706, a
(2CI2).

'H-NMFL(■ci,): δ0.84(d, J=
8Hz.

3H), 2.87 (d, J=5Hz, IH).

3.53 (ctq, J=9) 1z, 8H2, IH
).

4.78 (dd, J=5Hz, 3Hz, IH).

5.20 (d, J-9Hz, IH), 7.28 (s.

5H), 7.4-7.7 (m, 3H), 7.7-8.1
(m, 2H)+ ■几(neat): 3520, 3280, 1443, 1
322°1158.1090,970,898,751
゜720.701,688,580cm.

Mass (m/z (%)): 186 (5), 185 (1
1), 184 (100, MeCHNkISO2Ph)
, 142(5).

141 (PhSO□, 60), 108(5), 1
07 (PhCHOH, 54), 79 (23), 78 (1
5), 77(Ph, 93), 51(17).

44 (35).

Reference example 4 Me (1 liter, 28)-2-(ethoxycarbonylamino)-
1-phenyl-1-propatool 336IR? (1,5
1 mmole) was dissolved in 3 m of THF, 125 da (3.29 mmole) of lithium aluminum hydride was added,
The mixture was stirred for 1.5 hours at 60"Q. A small amount of water was added for hydrolysis, followed by filtration through Celite. After concentrating the fighting liquid under reduced pressure, the resulting crude product was subjected to thin layer chromatography (silica gel, acetate ether). : Methanol-9: Purified with 1),
Colorless oil (IR, 28)-2-methylamino-1-phenyl-1-propatur (l-ephedrine) 198
I got ~. Yield: 80 cm.

'H-NM(CDCl2): δ 0.84 (d
, J76Hz.

3H), 2.45(s, 3H), 2.4-
2.9 (m, 3H), 4.74 (d, J=3
Hz, IH).

7.32 (s, 5H).

After converting the obtained l-ephedrine into a hydrochloride, the specific rotation was measured.

l-ephedrine hydrochloride mp: 212-216°C, literature value: 216-220°
0°(lD-33,51°(C=1.146, H2O
).

Literature value “[α] L0-34° (H2O).

(sMerck Index N1nth Editi
on, rp471) Reference Example 5 0Me Me (IR, 28)-2-Metho dicarbonylamino-1-
(2,5-dimethoxyphenyl)-1-propatool 2
69IRg (1,00mmole) in methanol 12d
Dissolved in water 4-1 potassium hydroxide 290 Ing (5,
18 mmole) was added thereto, and the mixture was heated under reflux for 24 hours.

After adding 51 liters of water and 1N phosphoric acid to make the pH acidic to below 1, the mixture was washed with methylene chloride (10 t/x twice). After adding excess potassium carbonate to the aqueous layer to make it alkaline (pH 14), sodium chloride was added until saturation, followed by ether extraction (101LIX 3 times). The extract was dried over anhydrous potassium carbonate, filtered, and concentrated under reduced pressure to obtain a crude product. Distilled under reduced pressure, colorless oil (IR, 28)-2
-Amino-1-(2,5-dimethoxyphenyl-1-propatol (l-methoxamine) 175~ was obtained. Yield: 83 cm.

bp2 120°C/1 mm (Kuge 1).

'a-(CDCl2): δ 0.97(d, J-7
Hz.

3H), 2.08 (broad, 3H), 3.22 (d
q, J-7Hz, 5Hz, IH), 3.
76 (s, 6H), 4.74 (d, J=5Hz.

IH), 6.76 (m, 2H), 6.99 (m.

IH).

IR(neat):3380,3300.3180,2
970°2950.1500,1220.1050 scratches
.

Got it! - After converting methoxamine into a hydrochloride, the specific rotation was measured. 'mp: 183-5℃, literature value'': 182-3℃.

(α): 5-27.91° (c = 3.088, H2
O).

Literature value': (a jH528-5"(c e4 v
H2O) -[-几、Ba1tzly and N、B
, Mehta, J., Med.

Chem, Dan, 833 (1968)) Patent Applicant Foundation Sumo Central Chemical Research Institute Proceedings Amendment (Spontaneous) December 18, 1980 Commissioner of the Japan Patent Office Shiga Gakudon 1, Indication of Case 1981 Patent Application No. 27213 2゜Name of the invention Process for producing optically active β-amino alcohol 3 Relationship with the case by the person making the amendment Patent applicant 5 Contents of the amendment 1) The following after propanone on page 6, line 12 of the specification of the present application ni r, (
S)-2-(methoxycarbonylamino)-1-(2,
5-dimethoxyphenyl)-1-propanone%(S)2
-(methoxycarbonylamino)-1-phenyl-1-
Propanone Jlf alone.

2) "Methoxy..." on page 17, line 4 and page 19, line 5
Correct it to "ethoxy...".

that's all

Claims (1)

[Claims] In the presence of an acid, α-aminoketone represented by the general formula and general formula 1 (SiR'
几5几6 A method for producing an optically active β-amino alcohol represented by the general formula, which comprises reacting with a hydrocycne represented by carbonyl group, acyl group, alkanesulfonyl group t7'crt, 7 lane sulfonyl group, B4 haaryl group, alkyl group or aralkyl group R5 and t are an aryl group, an alkyl group, an aralkyl group or a hydrogen atom).