JPH0262548B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 2-(10,11-
Dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid () K0273 is a very useful 5-
The present invention relates to a method for producing (1-carboxyethyl)-2-phenylthiophenyl acetic acid (). At present, a method using a nitrile compound is cited as a useful method for producing () (Japanese Patent Application No. 56,028/1982). K0274 However, KCN (or
NaCN) is extremely toxic and is a reagent that should be avoided if possible in large-scale production.
In addition, this nitrification reaction produces styrene-type byproducts due to dehydrohalogenation,
Many by-products are produced and the yield of nitrile is unfavorable. As a method that does not involve nitrification, there is a method using Dalzens condensation reaction K0275 or a method using addition reaction of CHBr ₃ (JP-A-16437-1983) K0276 etc., but the reaction selectivity is poor and the formula () This is not suitable as a method for industrially producing the compound represented by. The inventors of the present invention have conducted intensive studies on new manufacturing methods that can solve these drawbacks, and as a result, have found a safe and economical manufacturing method, and have completed the present invention. The production method of the present invention is illustrated by the following reaction steps. _K0277 (In the formula, X; Cl, BrR: C _{1 to} C ₅ alkyl group or _H

[Formula]) That is, after hydroxyacetalizing the α-halgenopropiophenone derivative of the general formula () with an alcoholate (if the alkyl groups of R and the alcoholate-alcohol are different, transesterification proceeds simultaneously), R″ 5-(1-carboxyethyl) represented by the formula () is obtained by converting R _″ SO ₂ with SO 2 Cl and further rearrangement reaction with an alkali.
-2-phenylthiophenyl acetic acid is obtained. Since the present invention handles substances that are much less toxic than the above-mentioned known production methods, there is no need to take special precautions in terms of equipment, and equipment costs can be reduced. Furthermore, each step has a high yield due to high reaction selectivity, so it is an industrially and economically advantageous manufacturing method. For example, in the practice of the present invention, the reaction from α-bromopropiophenone derivative () to hydroxyacetal () is carried out by dropping a sodium methoxide-methanol solution in a methanol solvent under water cooling, followed by stirring (preferably for 5 hours). ) The reaction proceeds almost quantitatively with the conversion of the substituent R into a methyl group, and the yield is 97.6%. Additionally, a small amount of base (e.g. pyridine, triethylamine, sodium methoxide, etc.)
Systems added as HCl trapping agents (e.g. methylene chloride, ethyl acetate, toluene, etc. as solvents)
When the compound () is dissolved in the solution and methanesulfonyl chloride is added dropwise under ice cooling, the methanesulfonyl group immediately proceeds to quantitatively obtain the compound (). Next, the compound () is dissolved in water-organic solvent-alkaline solvent and heated under reflux to obtain the target compound () with a yield of 80.4%. Examples of organic solvents include methanol, ethanol, dimethylformamide, and the like.
Further, its content is 10 to 90%, preferably 30 to 80%. Furthermore, as an alkali, for example, NaOH,
KOH, K ₂ CO ₃ , Na ₂ CO ₃ , NaHCO ₃ , Ca
(OH) ₂ , CaCO ₃ , triethylamine, morpholine, piperidine, piperazine, etc. can be mentioned, and the content thereof is 1 to 20%, preferably 1 to 10%. The reaction mechanism of this step is that the phenyl group has 1,
It is thought that two rearrangements occur and then a hydrolysis reaction occurs. The post-reaction treatment in each step is simply to distill off and reduce the organic solvent in the reactant, pour the reactant into water, extract with an organic solvent, and then distill off the solvent. If necessary, it can be easily purified by recrystallization. Benzene and toluene-n-hexane, acetone-n-hexane, ethyl acetate-n- as recrystallization solvents
Examples include a mixed solvent of hexane. In other words, the production method of the present invention has a total yield of 78% or more, and its reaction and processing equipment does not require special equipment, and its operation is very simple and safe, and it can be used in a variety of ways, including the nitrification method. This method is significantly superior to known techniques. The present invention will be explained below with reference to Examples. Example (1) (A) 75 g of 3-ethoxycarbonylmethyl-4-phenylthio-α-bromopropiophenone and 150 ml of ethanol were placed in a 300 ml three-necked flask and thoroughly stirred in a water bath. Then, 42.1 g of a 28% methanol solution of sodium methoxide was added dropwise over about 20 minutes. Stirring was continued in a water bath for about 5 hours after the dropwise addition. After the reaction, pour into water (100ml), extract with dichloromethane, wash with 5% saline,
The mixture was then dehydrated using Glauber's salt to obtain a dichloromethane solution of the target product (R=CH ₃ , R'=CH ₃ in the general formula). (Target component amount: 67.5 g) (B) The liquid obtained in (A) was placed in a 500 ml three-necked flask and thoroughly stirred in an ice bath. Next, 25.6 g of methanesulfonyl chloride was added at a reaction temperature of 30°C.
The addition was carried out while adjusting the dropping rate as follows. After the addition, the reaction was continued for an additional hour, and then water (60 ml) was added to decompose excess methanesulfonyl chloride. After separation, washing with 5% saline and removing the solvent under reduced pressure yielded 84.6 g of the target product (R=CH ₃ , R′, R″=CH ₃ in the general formula)
was gotten. (C) The compound obtained in (3) (in the general formula, R=CH ₃ , R′, R″=CH ₃ ) in the three-necked flask of 2.
86.6g, methanol 860ml, 8% sodium bicarbonate water - 860ml
was collected and refluxed for 19 hours. After the reaction, methanol was distilled off under reduced pressure, and then dichloromethane
120 ml was added and unreacted substances were transferred to the organic layer and removed. When 52 ml of concentrated hydrochloric acid was added dropwise to the aqueous solution, the desired product () precipitated out. This was mixed with ethyl acetate (200
After extraction, washing with water, and dehydration of Glauber's sulfate (ml), the mixture was concentrated under reduced pressure until the liquid volume was reduced to one-fourth, and n-hexane (100 ml) was added to obtain white crystals (49.0 g). mp 140°C The overall yield from (A) to (C) was 84.1%. Example (2) Place 72 g of 3-methoxycarbonyl-4-phenylthio-α-bromopropiofenone and 150 ml of methanol in a 300 ml three-necked flask and prepare Example (1).
When reacting in the same manner as
Obtained 47.0g. The overall yield was 78.4%.
(Each NMR signal is the same as in Example (1)) NMR spectrum [δ value] of each compound in Example (solvent acetone d ₆ ) K0279 K0280 K0281

Claims (1)

[Claims] 1. An α-halgenopropiophenone derivative represented by the general formula () K0268 (X represents Cl or Br, R represents a C ₁ to _{C 5} alkyl group or H) is converted into a hydroxyacetal using an alcoholate. K0269 (R is the same as above, R' represents a C ₁ to C ₅ alkyl group) The compound of general formula () is converted to R″SO ₂ Cl (R″ is − CH ₃
or [Formula]) to form a compound with the general _formula () K0271 (R and R″ are the same as above) Then, the compound of the general formula () is converted to 5-(1-carboxyethyl) represented by formula () characterized by causing a rearrangement reaction
- A method for producing 2-phenylthiophenyl acetic acid. K0272