JPH02311442A - Production of 2-phenylpropionic acid derivative - Google Patents

Abstract

PURPOSE:To easily obtain the subject optical isomer compound in high stereoselectivity and yield by carrying out Friedel-Crafts reaction of a cyclic carbonic acid ester and a specific compound and subjecting the resultant acyl derivative successively to reduction, hydrolysis and oxidation. CONSTITUTION:A cyclic carbonic acid ester of formula I or formula II and a compound of formula III (R is alkyl or aryl) such as isobutyl chloride are subjected to Friedel-Crafts reaction in a solvent (e.g. CS2) in the presence of a catalyst (e.g. anhydrous AlCl3). The resultant acyl derivative of formula IV or formula V is reduced with a reducing agent such as hydrazine hydrate in a solvent (e.g. diethylene glycol) to obtain a compound of formula VI or formula VII, which is hydrolyzed with HCl, etc., in a mixture of water and diethylene glycol, etc., and then oxidized with an oxidizing agent (e.g. NaIO3) in a mixture of CH3CN-CCl4-H2O, etc., to obtain the objective optical isomer compound of formula VIII or formula IX having excellent anti-inflammatory activity.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a stereoselective method for producing optically active 2-phenylpropionic acid derivatives.

2-phenylpropionic acid derivatives, typified by ibuprofen, are known to have excellent anti-inflammatory effects. These derivatives have an asymmetric carbon at the 2-position, and one optical isomer is often more active than the other, so it is desired to selectively produce a specific isomer. There is.

[Conventional technology]

Optically active 2-phenylpropionic acid derivatives are generally produced by a method in which a dR-integrated 2-phenylpropionic acid derivative is optically resolved to separate necessary optical isomers. And in this prior art method, first dR
Since the 2-phenylpropionic acid derivative is obtained by chemical synthesis, and the resulting dR is optically resolved by selecting an optical resolving agent that is compatible with the desired optically active form, the procedure is as follows: However, when looking at the overall yield of the desired optically active substance, d
Since it is the product of the U-integrated yield and the split yield, it is always 50%.
It will be slightly less than .

[Problem to be solved by the invention]

As mentioned above, in order to eliminate the complexity of the conventional method for obtaining optically active 2-phenylpropionic acid derivatives by optical resolution of dR-integrated and to improve the yield of the desired optically active substance, dg-integrated There is a need for a method for obtaining an optically active substance without relying on optical resolution, and the present invention attempts to achieve this objective by stereoselectively producing a desired optically active substance.

[Means to solve the problem]

As a result of intensive research into methods for selectively producing a desired optical isomer, the present inventors discovered that a desired optical isomer could be stereoselectively produced by the method described below, and completed the present invention. Ta.

According to the invention, formula (Ta) or (I b) :(I
a) A cyclic carbonate ester represented by the formula (■): R-C(I
I) A compound of the formula (H
a) or (IIIb): (wherein R is as described above) An acyl derivative represented by the formula (Ha) or (
DIb) is reduced to a compound of formula (IVa) or (IVb): (IVa) in which R is the above-mentioned group, and then reduced to a compound of formula (IVa) or (rt
/b) is hydrolyzed to form a compound of formula (Va) or (Vb
): (Va) (vb) (wherein R is as described above), and then a compound represented by the formula (V a) or (Vb
) by oxidizing a compound of formula (Via) or (
Vlb): (Via) (vtb) (wherein R is as described above) A 2-phenylpropionic acid derivative represented by the following formula can be used.

In the Friedelkraff reaction of the first step, the compound of formula (II) is generally added at 1% to the compound of formula (I).
．． It is used in an amount of 0 to 3.0 times the mole, preferably 2 times the mole. Chloroform, methylene chloride, carbon disulfide, etc. can be used as a reaction solvent, and carbon disulfide is preferred. The reaction temperature is generally -10°C to 50°C, preferably 0°C to 1°C.
The temperature is 5°C.

The reaction time varies depending on the reaction temperature, but is generally 5 hours to 4 hours.
It is 0 hours. As a catalyst, p, D Cl33°F e
CRa can be used.

The reduction step of the second step (νolff K15hner
In reaction), conventional reducing agents can be used, but hydrazine hittride is preferred. High boiling alcohols such as diethylene glycol can be used as reaction solvents. The reaction temperature is generally 100°C to 250°C.
℃, preferably 160℃ to 200℃. The reaction time varies depending on the reaction temperature, but is generally 2 to 10 hours,
At 180°C, the reaction is completed in about 3 hours.

In the hydrolysis reaction of the third step, HCΩ, HSo HCNO3゜24゜A c OH, (COOH) 2, etc. can be used as a reaction reagent. As a reaction solvent, a mixture of alcohols, THF, dioxane, etc. and water can be used.

The reaction temperature is generally 0-50°C. The reaction time is generally 1 to 24 hours.

In the oxidation reaction of the fourth step, N a I Oa
Generally, 3 to 5 equivalents of an oxidizing agent such as the like can be used. As a reaction solvent, for example, a halogen compound (CH(JI
CHCΩ, CN CH2CH2CR3'22, etc.)-acetonitrile-H20 system, etc. can be used. The reaction temperature is generally -10°C to 50°C, preferably 10°C to 20°C. The reaction time is generally 1 to 24 hours, 3 to 6 hours. As a catalyst, for example, RuCΩ
About 2 to 5 mol % 3' of Os 04 or the like can be used.

Specific examples of compounds of formula (n) that can be used in the method of the invention include acetyl chloride, propanoyl chloride, n-butyryl chloride, isobutyryl chloride,
Aliphatic carboxylic acid chloride and benzoic acid chloride such as caproyl chloride, C1-e on the phenyl nucleus
Examples include aromatic carboxylic acid chlorides such as substituted benzoic acid chlorides having an alkyl group of .

The compound of formula (1) above can be produced according to the following reaction formula.

(Left below) -A↑↑↑↑↑↑Senko Add a catalytic amount of trans-cinnamic alcohol of the above formula (■) to (L
) or (D) Sharpless oxidation is performed using tartaric acid diisopropyl ester to obtain the epoxy compound (■a) or (■b). (■a) or (■b)
was treated with organocopper obtained from methyllithium and CuCN to form 3-phenylglycidol (IXa) or (I
obtain Xb). (IXa) or (IXb) is then treated with diethyl carbonate in the presence of potassium carbonate in benzene to give formula (Ia) or formula (Ib).

The present invention will be explained in more detail with reference to the following production examples and examples. These production examples and examples do not limit the present invention in any way.

Production Example 1 6.27 g (7 buttons 1 1 ol) of 1.0 (IX a ) Cu CN was added to 200 ml of anhydrous ethyl ether at -68°C under an argon stream.
Methyllithium (1,4M in ethyl ether solution)
Add 100ml (1401Il11o1), -50
Stir at ℃. Compound *1) (■a) at the same temperature after 1 hour
4.2 g (28 nmol) of anhydrous ethyl ether 50
The m1 solution was added dropwise and stirred at the same temperature. After 30 minutes, a saturated aqueous ammonium chloride solution was added, followed by washing with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution,
Dry with magnesium sulfate. The solvent was distilled off under reduced pressure,
A colorless oily residue was obtained. This was subjected to column chromatography using 300 g of silica gel, and the compound, (2
9,31? 3.58f (77%) of -3-phenyl-1,2-butanediol 2) (IXa) was obtained.

Formula (IXa): [α)23+17.24' (c-2,006,CH
CJll)IRν(neat)cm-':3370
18X NMR (CDCΩ3) δ2 1.27 (d, 3H, J-7,08), 2.11 (
br, s, 2H.

exchange cable), 2.69 to 3.01 (
+n, LH), 3.40-3.86(m, 3H
), 7.27 (4n, 5H).

*l) Y, Gas, R, M, Hans
on, J.M., Klunder.

S, Y, 'So, H, Masamune and
K.B.

5harpress, J., Am., Chem., S.
oc, +109°*2) S, Takano,
M., Yanase and K.

Ogasavara, Heterocycles, in
press.

Example I e (2S, 31?) -3-phenyl- of formula (IXa)
1,2-butanediol 1.04g (6,26gMm
7.58 ml (62,58 nu
2Co31.73g (12,5211
mol) was added, heated to 80°C, and stirred. After 25 hours, the mixture was returned to room temperature, diluted with ethyl ether, and then filtered through Celite. The solvent of the filtrate was distilled off under reduced pressure, and the resulting colorless oily residue was subjected to column chromatography using 20 g of silica gel, and ethyl ether-hexane (2:
1 v/v) Flow % Formula %) Leu 1.3-dioxolan-2-one 1.182 g (
A yield of 98.3%) was obtained.

Formula (I a): mp, :H ~ 67°C ((E) -7,74" (cm1.11.C
HCΩ3)IR, (nuj o 1) am-1:
L780ax NMR (CDCΩ3) δ: 1.385 (d, 3H, J-7, 08H2), 2.94
~3.25 (m, .

IH), 4.06-4.51 (a+, 2H), 4.7
4-4.97 (1°LH), 7.18-7.42 (l
W, 5H).

MS m/e: 192 (M”) 105 (1
00%) Elemental analysis・C1□H1203 Calculated value: C1g,73, H6,29 Theoretical value: C
88,74,H8,23 Example 2 (Ia) O(Ha)' Anhydrous aluminum chloride 1.777 g (13,33s
1.40 g of isobutyryl chloride (13.33 mmol) was added to 10 ml of anhydrous carbon disulfide solution under water cooling.
1) was slowly added dropwise and stirred at the same temperature. 15 minutes later,
1.28 g of compound of formula (Ia) (8,87111 mo
3 ml of anhydrous carbon disulfide solution of 1) was added, and the mixture was stirred at room temperature. After 35 hours, a 10% aqueous hydrochloric acid solution was added, the mixture was vigorously stirred, and then extracted with ethyl ether. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained yellow oily residue was subjected to column chromatography using silica gel 50. From the ethyl ether:hexane (2:1 v/v) stream, the formula % formula % (solan-2-one 1.OLr (62%).

Formula (Ha)' IRν (neat) cm-1: m a, x 1800, 1680.1605 NMR (CDCj! 3) δ: 1.218 (d, 8H, J-8, 83Hz), 1.40
5 (d, 3H, J-7,08Hz), 3.07-34
6 (+n, IH), 349-3.69 (m, IH)
, 4.07-4.58 (m, 2H), 4.75-4.9
9 (m, 3H), 7.35 (dd, 2H, J-1, 59
,8,06),7.95(dd,2H,J-1,95,
8,55).

MS m/e: 2G2(M”) 219(1
00%) Elemental analysis: Calculated value: C88,68, H6,92 Theoretical value: C88,73; H7,00 Example 3 (Va)' Compound of formula (Ha)' 6hg (0,2311n+ol
) in 1 ml diethylene glycol solution of potassium hydroxide 38a+g (0,69ml Ilol) and 90% hydrazine monohydrate 3'ruQ (0,69IIi
ol) was added, heated to 120°C, and stirred. After 30 minutes, the mixture was heated to 180°C and stirred. After 3 hours, the mixture was returned to room temperature, diluted with ethyl ether, washed successively with a 5% aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, and dried over magnesium sulfate.

The solvent was distilled off under reduced pressure, and the resulting residue was diluted with ethyl ether.
It was subjected to preparative thin layer chromatography using hexane (4:1 v/v) as a developing solvent to obtain a colorless oily compound [formula (
Va)' ), (2S, 3R) -3-(4-isobutylphenyl)-1,2-butanediol in 37a+g
(72.3%) was obtained.

Formula (Va)': [α) 26+ 16.22° (c −0,912,
CHCN)1, Rν(neat)am-1:340
0Iax NMR (CDCN 3) δ: 0.896 (d, 8H, J-8,35), 1.24 (d
, 3H, J-7,08Hz), 1.82~2.07(
m, LH), 2.39 (d, 2H, J=1.98H
z), 2.45 (br, d, 2H), 2.66-2.
89 (a+, lH), 3.45-3.83 (m, 3H)
, 7.10 (o+, 4H).

MS m/e: 222 (M) Elemental analysis:
C14H2゜o2 Calculated value: C75,63; H9,97 Theoretical value: C7
5,15; H9,84 Example 4 (Via)' Compound of formula (va)' 38 mg (0,17 mmol
) of CHs CN -CCi' 4- H20 (2:2
: 3 v/v) N a I O414 in 1 ml solution
Gmg (0,68 mmol) and Ru C() a
φ3 H200-4510-45H11%IIol)
was added and stirred at room temperature for 3 hours. After diluting with ethyl ether, the mixture was extracted with a saturated aqueous sodium bicarbonate solution, acidified with concentrated hydrochloric acid, and then extracted with ethyl ether. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a yellow oily residue. This was subjected to column chromatography using 2 g of silica gel, and 27 mg (76.6%) of the compound of formula (VIa)' was obtained from the ethyl ether-hexane (2:2 v/v) fraction.

Formula (VIa)’: ip, near 5-78°C (literature value = 75-7B'C).

C, Giordano, G, Ca5tald1. P
, Casagrandeand^, Be1li, J.
Chew, Soc, PerkinTrans,
I, 1982.2575) [α) -58,
71” (c = 1.836, 95% EtOH) (Literature value: +
60" (c-2,95,95%EtOH), 0,
PIccolo, P, 5preaf'1co, G,
Visentlnand Ejaloti, J.O.
rg, Chem, 52.10IRν(n u j
o l) am-1: 3000.1700flaX NMR (CDCff 3) δ: 0.887 (d, 6H, J-6, 59H2), 1.49
2(d,3)1. J-7, 33Hz), 1.533~
1.914 (+n, LH), 2.441 (d,
2)1. J-7, 33H2), 3.703 (q, IH,
J-7, 33, 14, 29Hz).

Claims (1)

[Claims] Formula (I a) or (I b): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I b) Cyclic carbonic acid represented by An ester and a compound of formula (II): ▲Mathematical formula, chemical formula, table, etc.▼(II) (in the formula, R represents an alkyl group or an aryl group) are subjected to a Friedel-Crafts reaction to form the formula ( III
a) or (IIIb): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IIIa) or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IIIb) (In the formula, R is as above) Acyl represented by derivative, and then reduce the compound of formula (IIIa) or (IIIb) to obtain formula (IVa) or (IVb): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IVa) ▲There are mathematical formulas, chemical formulas, tables, etc. ▼(IVb) (wherein R is as described above) A compound represented by formula (IVa) or (IVb)
By hydrolyzing the compound of formula (Va) or (Vb): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Va) or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Vb) (In the formula, R is as described above), and then the formula (Va) or (Vb)
Formula (VIa) or (
VIb): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VIa) or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VIb) 2-phenylpropionic acid represented by (in the formula, R is as above) Method for producing derivatives.