JPS5857359A - Keto ester derivative and its prepration - Google Patents

Abstract

NEW MATERIAL:A 2-oxo-3-(4-substituted or unsubstituted phenyl)-3-(2-nitrophenylthio)-propionic ester derivative expressed by formulaI(X1 and X2 are H, halogen, trifluoromethyl, lower alkyl or lower alkoxyl; R is H, alkyl, aryl or aralkyl). EXAMPLE:Methyl 2-oxo-3-(4-methoxyphenyl)-3-(2-nitrophenylthio)-propionate. USE:Useful as a synthetic intermediate for benzazepine derivatives useful as coronary vasodilators, tranquilizers, etc. PROCESS:A halopyruvic acid derivative expressed by formula II (X is halogen) is reacted with an alkali metallic salt of a 2-nitrothiophenol derivative expressed by formula III in a solvent, e.g. tetrahydrofuran or dioxane, to give the compound expressed by formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to an excellent conductor of unsubstituted phenyl)-3-(2-ditrophenylthio)monoglopionic acid ester (hereinafter abbreviated as a ketoester derivative) and a method for producing the same. Sara Ki
# In detail, (in the formula, x1 and x2 are each independently a hydrogen atom, a haldan atom, a trifluoromethyl group, and a lower alkyl group is a lower alkoxy group, and R is a hydrogen atom, a straight chain or branched alkyl group) , alicyclic alkyl group, aryl group, or aralkyl group) and a method for producing the same.

The above ketoester derivatives [! ] is treated with Kg base material to form cohydroxy-3-(ff-substituted phenyl)-3-[
2-ditrophenylthio) monoglopionic acid ester derivative (hereinafter abbreviated as ester derivative).

One of the above ester derivatives [''], ethyl hydroxy-3-(xyphenyl)-3-(ditrophenylthio)-ropionic acid, is a coronary vasodilator or tranquilizer. It is an important medicine as a drug (
4'-methoxyphenyl)-3-acetoxy-s-(1
-dimethylaminoethyl)-23-dihydrols-penzazebin (see Cog. Datar No. 36.227 and Cog. 4t Day'II; No. 305).

Therefore, an object of the present invention is to provide a novel intermediate useful for producing the above-mentioned benzazepine derivatives that can be used as pharmaceuticals, and a method for producing the same.

That is, the present invention provides a co-oxo-3-(+-substituted or unsubstituted phenyl)-3-<2-nitrophenylthio) monoglopion represented by the formula (wherein x1, x2 and R are as defined above) Acid esthetics, derivatives, and KX (
II) Halopyruvic acid ester derivative K represented by the general formula (wherein X, x2 and RFi are the same as above), 1-1-2 trothiophenol derivatives shown by the general formula (wherein X1 1d is the same as above) The present invention relates to a method for producing the above-mentioned ketoester derivative (1), which comprises reacting the following.

Halopyruvate derivative used in the present invention Ki (
1), for example -monoxo-3-7" rom-3-
Methyl (+-methoxyphenyl)-propionate, ethyl-3-bromo-3-phenylglopionate, ethyl-3-(II-methoxyphenyl)-globionate
Ethyl 3-7 enyl pionate and the like are used. Furthermore, in the general formula (1), x2 is a heron atom such as fluorine or chlorine, a lower alkyl group such as a methyl group, an ethyl group, or a globyl group, a lower alkoxy group such as a methoxy group or an ethoxy group, or a triple oxymethyl group. halopyruvic acid ester derivatives, which are groups such as R, methyl group, ethyl group, n
- Straight chain alkyl groups such as globyl group, n-butyl group, n--e methyl group, n-hexyl group; isobutyl group, isobutyl group, co-butyl group, tertiary butyl group, impentyl group,
Branched alkyl groups such as isohexyl group; cyclopentyl group, cyclohexyl group, menthyl group, gernyl group, etc. iv group, +7+kts'4 aryl group recruiting benzyl group,
Halopyruvate ester derivatives which are aralkyl groups such as phenethyl group and -1(-17thyl)ethyl group may also be used.

The halopyruvate derivative (If) is a pyruvate derivative (^nn, ch1m, (Prev. 1s) 1
．． 1ItI2 (1952) can be produced according to the method described in K) with a halogenating agent.

Examples of the above-mentioned pyruvate ester derivatives include methyl nioxo-3-(+-methoxyphenyl)glypionate, methyl nioxo-3-phenylnotetrapionate,
Methyl nioxo-3-(gumethoxyl)propionate, ethyl nioxo-3-phenylpropionate, and the like can be used.

As the above-mentioned 8a), N-bromoimide, N-bromoacetamide, N-chlorosuccinimide, bromine, chlorine, etc. can be used.

The reaction between the above-mentioned pyruvate ester derivative and the herodanizing agent is usually carried out in a solvent such as carbon tetrachloride or chloroform (see Reference Example 1).

Examples of the ninitrothiophenol derivatives used in the present invention include ninitrothiophenol,
Turquoroonitrothiophenol, gouethyl-co-nitrothiophenol, q-methoxy-co-nitrothiophenol, di-trifluoromethylnitrothiophenol, and the like are used. Furthermore, in the general formula [iris], x1 is a group such as a halodane atom such as fluorine or chlorine, a lower alkyl group such as a methyl group, an ethyl group, or a globyl group, a lower alkoxy group such as a methoxy group or an ethoxy group, or a trifluoromethyl group. Ni-nitrothiophenol derivatives may be used.

Is 112 trothiophenol a literature organ synthesis, collective,? Rhum ■, Ko 20 pages (/9s4
) and Farmaco (Pavla), King d.

scl, /2.201sC/DeS7). Other ni=)rothiophenol derivatives can also be produced according to the production method in the above-mentioned document.

Ketoester derivatives of the present invention [! ] can be produced by reacting the above halopyruvate derivative [...] with the alkali metal salt of the above 2-nitrothiophenol derivative [Otori] in a reaction solvent. The reaction is usually carried out at room temperature or as necessary. It is heated or cooled for 7 to 7 hours.

The alkali metal salts of the above-mentioned ninitrothiophenol derivatives can be obtained by reacting the derivatives with IJium (usually hydrogenated), lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.

The amount of the herovirpine ester derivative [Nezumi] to be used is usually equimolar to the amount of the ko-nitrothiophenol derivative [厘K].

As the reaction solvent, tetrahydro-7rane, l-dimethoxyethane, dioxane, N,N-dimethylformamide, etc. are usually used. The amount of the reaction solvent to be used is not particularly limited, but it is usually used in an amount of 5 to 75 times the volume of the 112 trothiophenol derivative.

The thus obtained +) ester derivative (1) of the present invention can be reduced in an organic solvent using a monomer usually used for reducing car & nyl groups, thereby converting it into a benzazepine derivative useful as a pharmaceutical. An ester derivative (IV) which can be used as a starting material is provided.

(depending on the type of reducing agent) or the type of ester residue R in the ketoester derivative represented by formula (1), the threo type and B2H6, LI of the ester derivative of formula (ff)
BH(CH(CH5)CH2CH5)5, LL4/H(
t-8uo)5, Na, U H2(OCH2CH20C
H5) 2, will be done.

Reaction solvents include methanol, ethanol, and inglo.
Organic solvents such as f-nor, tetrahydro7ran, 12-dimethoxyethane, dioxane, silene, and benzene are used.

Reaction conditions vary depending on the nature of the reducing agent, but are usually -70C-
It is carried out for 7 to 7 hours at room temperature (see Reference Example U, II).

The present invention will be explained in more detail by showing Examples and Reference Examples below.

Example 1 After washing 17119 hydrogenated F 17119 with n-hexane IO- twice, THF 100- was added and cooled. 212) Rochio 7/-ruq, 1Isq, T
A solution of 20 db of HF was added dropwise over 30 minutes.
-Methyl bromo-3-(gumethoxyphenyl)propionate/750, THFllO- solution at 5 C for 10
After the mixture was added dropwise, the mixture was further stirred at 2 sC for 1 hour. Subsequently, 78F was distilled off under reduced pressure, and after death, the ether extract was extracted with ether. The ether extract was washed with water, dried over MgSO4, and the residue obtained by distilling off the ether was subjected to column chromatography (silica, ethyl acetate: n- Developed with hexane-387) to purify nioxo-3-(Gume F xyphenyl).
-3-(2-nitrophenylthio)-methyl propionate (hereinafter abbreviated as ketoester) was obtained /1.30Q NMR (COC(3-TMS)J +Nia7(AH,S
), mu03(/H,S)mugO-g,/7(gH,m
) MS a/@ + JA/(M+), 3/2.2
7 Da, Koda/, Ko07 Reference Example/11 Methyl oxo 3-('I-methoxyphenyl)propionate lII'll,g,N-promfusuccinimide 12'109 by adding carbon tetrachloride/DO- The mixture was heated under reflux for 7 hours. After cooling, insoluble matter was separated from P and the mother liquor was concentrated to give twooxo-3-bromo-3-(4'-methoxyphenyl)! 00 g of methyl lopionate was obtained.

NMR(C(Xj!, -TMS)δ: 3.gO,
3,gl,(3Hx2.s)mu23(lH9S)u,7
-7.5OCIIH, m) Reference example: A solution of NaBH402'IQ, diglyme 20-
5 ether complex salt 15-, the 82 H6 gas generated by dropping it into the solution of diglyme 5d is
5; After decomposing and decomposing the excess B2H6 that was blown into the solution of Q, rHFlo- at -5C by adding ethanol,
The residue obtained by distilling off the solvent was recrystallized from ethanol S- to give threo-type α-coco-hydroxy-3-C'1-methoxyphenyl-3-(conitoc17enylthio)-gropionic acid. Methyl 03029 was obtained.

mp/AJ'-/Otsu SC I RV', :1. ” cIIL-1: 3 jθ
0. /73ON MR(C1)ff3:DMSO-d
4 = / : / -TMS) δ:ls7゜37S(
3HXYU,S)'433-'A90(2H,m).

/2 (/H, d D20 processing disappeared) 1, . 7777
-110(, m> Reference example 3 'r t x 7. f ru 0./g 39, THF, 2 m,
Iso! Solution of Lonoyanol 10-K Na8H4&g
and stirred at room temperature for several hours. The residue obtained by distilling the solvent under reduced pressure was recrystallized from ethanol to give α-coco-
Methyl hydroxy-3-1'-methoxyphenyl 13(conitrophenylthio)-propionate S/T was obtained.

mp /ls3 /AjC* Reference example JP-A-58-57359
(5) A solution of 993 g of ketoester θ and THFlo was cooled to -70C, and 3.3 - of selectride solution (manufactured by Aldrich, /M solution) was added dropwise over 70 minutes. -70
After reacting at C for 3 hours, the reaction solution was poured into water and extracted with chloroform. The chloroform extract was washed with water, dried, concentrated, and the resulting residue was recrystallized from ethanol to obtain erythro-type β-21)"o-+CJ-(4-methoxyphenyl)-3- 0 g of C2-nitrophenylthio)-propionic methyl θ colo was obtained.

mp /37-/39c IR')"n'a'x" cm-1! 3500. /
73! NMR(C[XJ3: DMSO-d6=/
: /-TMS) δ+ 3. b O-275 (J H
XJ*S) -4450'Ag 7 (-28m
) to 0 (/H, d, D2o processing disappears).

7.3-g/l (ZH, m)

Claims (1)

[Claims] /) General formula (in the formula, x1 and x2 each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group, or a lower alkoxy group, and RFi hydrogen atom, straight chain or co-oxo-3-(gu-substituted [1-substituted phenyl)-3-(2-2)07
(Elthio)-propionic acid ester derivative. (In the formula, xVi is a halogen atom, x2 is a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group, or a lower alkoxy group, and R is a hydrogen atom, a linear or branched alkyl group, an alicyclic atom, and Alkyl group, aryl group,
or an aralkyl group). (In the formula, x1 is a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group, or a lower alkoxy group.) , x2 and R are as described above).
)-,3-<1-nitrophenylthio)-globionic acid ester derivative manufacturing method.