DE2810262A1 - PROCESS FOR THE PRODUCTION OF THIOPHENE DERIVATIVES AND ALPHA-SUBSTITUTED 2-THIOPHENACIC ACID COMPOUNDS AND 2- (2,2-DIHALOGENVINYL) -THIOPHENE - Google Patents

Description

uZ: M 625
Case: FS / 1-14

SAGAMI CHEMICAL RESEARCH CEHTER
Tokyo, Japan

"Process for the preparation of thiophene derivatives and also Cl -substituted 2 -'-Qiiophenacetic acid compounds and 2- (2,2-dihalovinyl) -thiophenes"

The invention relates to processes for the preparation of thiophene derivatives and οί-substituted 2-thiophenacetic acid compounds and 2- (2,2-dihalovinyl) thiophenes. The invention specifically relates to processes for the preparation of a number of 2-thiophene derivatives from which 2-thiophene acetic acid derivatives are readily formed in high yield and selectivity from substituted or unsubstituted thiophenes or 2-acetylthiophenes can be produced, which in turn can easily be prepared from the aforementioned thiophenes.

It is also described, for example, by H. D. Hartough, "The Chemistry of Heterocyclic Compounds", Thiophenes and its Derivatives, Interscience Publishers, Inc., Few York, 1952, S. 189 known, compounds of the general formula I.

"1

R *

CHCX,

(I)

OH
35

1 2

/ ass only off- R and RV or H _a lied atoms or lower

809839/075 $

Represent alkyl radicals and X represents a chlorine or bromine atom, convert them into valuable insecticides, for example through condensation with other aromatic compounds, which are analogous to DDT. The carboxylic acid esters derived from the compounds of the general formula I also show insecticidal activity; see R.C. Blinn et al., J. Am. Chem. Soc, 76, 37 (1954).

The known process for the preparation of (γ-'Irihalogenraethyl-2-thiophenmethanolen consists in the preparation of the Grignard compound from a 2-bromothiophene and magnesium and the subsequent reaction of this compound with a Trihalogenaeetaldehyd; cf. J. Am. Chem, Soc, Vol. 71 (1949), p. 2859. However, the process is unsuitable for industrial purposes because it is difficult to selectively produce the 2-bromothiophene and because the process for producing the Grignard compound is cumbersome because it is carried out under anhydrous conditions and must be carried out using flammable ethers.
20th

There are also processes for the production of tf-substituted ones 2-Thiophenacetic acid compounds of the general formula II

CHCOOH

l

(II)

1 2

known in which R and R are hydrogen or halogen atoms or

'represent lower alkyl radicals and R is a hydroxyl or amino group or represents an alkoxy radical. One method is to condense a 2-thiophene aldehyde with bromoform in the presence of a base (cf. J. Am. Chem. Soc., Vol. 83 (1961), p. 2755), another method consists in the 0xi ~ dation of a 2-acetylthiophenes with selenium dioxide and then Reaction of the compound obtained with a base

809839/0756

(Arkiv Kemi, Vol. 11 (1957), 3. 519), nocA another method consists in the hydrolysis of 2-2hiophenaldehydcyanhydrin (JA-AS 8775/73) and a fourth process is condensation of glyoxylic acid with i'hiophen (cf. JA-AS 49 954/74).

The former method requires the use of expensive bronioform and 2 -Ihi ophen al de hy d, and the yield is low. The second method requires the use of expensive yon selenium dioxide, and it is difficult to carry out in industrial scale. The drixte method requires the use of what is technically difficult to access two-Thiophenaldehyds and hydrogen cyanide. The fourth process is distinguished by fewer reaction stages, but the yield is low and the process is difficult to carry out on an industrial scale.

There is also known a process for the preparation of 2-thiophene glycolic acid by reducing 2-thiophene glyoxylic acid in an alcohol with sodium amalgam; see S ¹ . Ernst, Reports of the German Chemical Society, Vol. 19 (1886), p. 3278. However, the process is difficult to carry out on an industrial scale, since the 2-thiophene glyoxylic acid used according to the process cannot be produced in high yield by any known process.

It is known that o ^ -substituted 2-Ihiophenacetic acid compounds can be used for the production of penicillins with antibiotic shear effect; see e.g. NL-OS 65.06584. 2-Thiophene acetic acids are valuable chemical modifiers for penicillins and cephalosporins; see J.Am.

Chea. S ₀ C., Vol. 84 (1962), 3. 3401. Various processes for the preparation of 2-thiophenacetic acids are known; See Senda Yuki Gosei Kagaku Kyokai-shi (J-Synth. Org. ^ hem «Japan), Vol. 34 (1976), p. 779. The known process for the preparation of 2-2hiophenacetic acid by reducing a 2-thiophene glycolic acid consists in Heating of 2- ^{i; L>} hiophene glycolic acid with hydrogen iodide and phosphorus (see S ^1. Ernst, Ber.

809833/0756 .., ^, ^ j

of the German Chemical Society, Vol. 19 (1886),

P. 3278. However, there is no yield in this publication specified. Experimentally, "when repeating the Experiment found that practically no 2-thiophenacetic acid is formed. The procedure is therefore for technical purposes unusable.

The main known processes for the production of 2-Ihiophenacetic acid can be divided into 3 groups, depending on the starting compounds used:

1) The reaction of 2-chloromethylthiophene with an alkali metal cyanide to 2-cyanomethylthiophene and then

Hydrolysis; see GB-PS 1 122 658; 15th

2) Reaction of 2-acetylthiophene with ammonium polysulphide in a V / illgerodt reaction to 2-thiophenacetamide and subsequent Hydrolysis; see DE-PS 832 755;

3) (a) Implementation of potassium cyanide and an oleoformic acid ester with 2 -'-ethiophenaldehyde to tf-alkoxycarbonyloxy-2-thiophenacetonitrile, subsequent catalytic ^ hydrogenation to 2-cyanomethylthiophene and its hydrolysis; see"

GB-PS 1 122 658; 25th

(b) reaction of the condensation product of 2- 'ε-hiophenaldehyde and methylthiomethylsulfoxide with hydrogen chloride in alcohol to form an ester of 2-'l ¹ hiophenacetic acid and subsequent hydrolysis; see JA-AS 46 063/77. Process (1) has the disadvantage that 2-chloromethylthiophene is difficult to handle because of its instability, explosiveness and tear-irritating properties, and the poisonous bis (chloromethyl) ether is obtained as a by-product in the production of this compound. The method (2) has the

Disadvantage that there are high temperatures and high pressures when carrying out the V / Illgerodt- ^ action as well as energetic conditions

^r a

belts required for hydrolysis. The method (3) (a) has the Ifach'ceil that worked with poisonous gyanide compounds must be, and that it requires numerous .Reaktionsstufe. The method (3) (b) has the disadvantage that sulfur compounds handled and produced with an obtrusive unpleasant smell need to be adorned.

O ^/ -Acyloxy ~ 2-thiophene acetic acid compounds are also known as chemical modifiers for penicillins and cephalosporins; see JA-AS 10 095/73. To prepare the acyloxy derivatives of glycolic acids, acyl halides were generally used with advantage, but the thiophene ring was cleaved when the acyl halides were reacted with 2-thiophene glycol acids. Therefore, this process for the preparation of c (- acyloxy-2-thiopheneacetic acids could not be considered.

The invention is based on the task of producing methods to create a series of thiophene derivatives from which 2-thiopheneacetic acid derivatives can be easily and in high quantities Yield using substituted or unsubstituted thiophenes or 2-acetylthiophenes can be produced which are easily obtained from the aforementioned thiophenes. Another object of the invention is to provide new thiophene derivatives to provide.

The processes according to the invention and the products of the process are illustrated by the following reaction scheme.

809839/075 $

co ο

ro

cn

Q CO OO 8a>

(A)

R ^

Trihaloacetaldehyde + Acid

R R

R-R

Acetylation

I - CCH,

I! J

Halogenation

(E)

(B)

r:

reduction

OH

-CCHXp

Il

+ Alkali or

Alkaline earth hydroxide

R R

f— \

Alkali or

Alkaline earth hydroxide reduction

CH COOR
R ³

Acylation
(G)

(H)

R ⁵

I — CH = CX,

+ Base

R-

CH ₂ COOR

reduction

OCOR-CHCOOR ^

30th

In this reaction scheme, R and R denote hydrogen or halogen atoms, alkyl, aroyl or acyl radicals. R ^ means a hydroxyl or amino group, an alkoxy, alkylthio or arylthio group. R represents a hydrogen atom or a Alkylx'est, R is an aryl group and X ^Ä lkyl- or a halogen atom, preferably a chlorine, bromine or iodine atom ·

Compounds of general formula (C) are new if R represents an arylthio radical. The "connections are valuable Intermediate products for the production of the end products of general formula (F), i.e. the 2-'ihiophenacetic acid derivatives. The compounds of the general formula (H) are also new. They can be according to the inventive method easily converted into the end products of the general formula (F), ^ he compounds of the general formula (E) are not only valuable intermediates for the preparation of the end products of the general formula (F), but also intermediates for the production of l'hioprofenic acid, a well-known anti-inflammatory drug.

The compounds of the general formula (C)

CHCOOR ⁴ (C)

can be selected from the compounds of the general formula (A)

via the intermediates of the general formula (B) 35

(B)

809839/0756

-j can be prepared in good yield and selectivity by reacting an optionally substituted thiophene with a trihaloacetaldehyde in the presence of an acid in the first stage. The starting compounds are known technical products. A Lewis acid is preferably used as the acid. The intermediate product of the general formula (B) obtained is then reacted further with a compound of the general formula RH in the presence of an alkali metal or alkaline earth metal hydroxide. The reaction product obtained is optionally esterified in a customary manner, for example by reaction with an alcohol of the general formula R OH. To
ren referred to as method (I).

of the general formula R OH. In the following this procedure is carried out according to the invention can use the 2-thiophene glycolic acid derivatives of general formula (C)

R ^

-CHCOOR ⁴

° ^H (C)

^tG;

in good yield and selectively by reacting the 2-acetylthiophene derivatives of the general formula (D)

^R

R ^? -

J CCH,

Il *

with a halogenating agent to give the 2-dihaloacetylthiophene derivatives of the general formula (E)

_s ^ -CCHX ₂ (E)

0

and then reacting these compounds with an alkali or alkaline earth metal hydroxide. Possibly the reaction product is ver-L in the usual manner

S09839 / 07SS

^Γ -y - 28102S2

esters, for example by reaction with an alcohol of the general form
(II).

general formula H OH. This procedure is called Procedure

The compounds of the general formula (C) obtainable by process (I) or (II) can be obtained by reduction easily into the end products of the process according to the invention, namely the 2-thiophene acetic acids of the general formula (F) convict. The compounds of the general formula (C) can also be acylated. The acylated compounds of general formula (G-) can also be used in high yield and selectivity to the compounds of the general formula

(F) can be reduced. They can also be used as chemical modifiers be used for cephalosporins.

The invention thus aims as a third object a process for reducing the compounds of the general formula (C) to Preparation of compounds of general formula (F) and a process for acylating the compounds of general Formula (C) for the compounds of the general formula

(G) and finally a process for reducing the compounds of the general formula (G-) to the compounds of general formula (F).

A fourth object of the invention is to provide a method for Preparation of the compounds of the general formula (F) from compounds of the general formula (A) via compounds of the general formula (B) and new compounds of the general formula (H).

In this process for the preparation of the compounds of general formula (F)

R R '

CH ₀ COOR

an optionally substituted thiophene of the general

^L ~ 309839/0755

my formula (A)

Λ- _Λ Ii r

(A)

with a trihaloacetaldehyde of the general formula

GX ₅ CHO

in the presence of an acid to a # ~ £ rihalogenmethyl-2-thio phenmethanol of the general formula (B)

(B)

OH

implemented. Then this compound is combined with a reducing agent to a 2- (2,2-dihalovinyl) thiophene of the general formula (H)

on R.

² (H)

implemented. This compound is then hydrolysed with a compound of the general formula R OH in the manner of a base or subjected to alcoholysis. If necessary, then 1 ? / L

acidified the reaction mixture. R, R, R and X have the above meaning. This method is referred to as method (III). It differs from the procedure (I) and (II), since here the preparation of compounds of the general Formula (C) is not required.

Another object of the invention is to provide new compounds of the general formula (C) in which R is restricted to arylthio radicals is, as well as to create new compounds of the general formula (H).

809839 / 075S

The method according to the invention is explained in more detail below. Examples of the thiophenes of the general formula (A) used in process (I)

rL

1 2

in which R and R have the above meaning, are thiophene, 2-chlorothiophene, 2-bromothiophene, 2,3- ^ chlorothiophene, 2-methylthiophene, 2-ethylthiophene, 2-methyl-3-chlorothiophene and 2-chloro-3-meth.ylthioph.en. Specific examples of the trihaloacetaldehydes according to the process are trichloroacetaldehyde and tribromoacetaldehyde.

In process (I), the reaction is carried out in the presence of an acid. Examples of acids that can be used are inorganic Acids, such as sulfuric acid and phosphoric acid, cation resin exchangers in the acid form or Lewis acids,

such as titanium tetrachloride, tin tetrachloride, boron trifluoride,

Iron (IH) chloride and aluminum trichloride. Will be common

the acidic catalyst is used in an equimolar amount. In In some cases, 1,1-dithienylethanes are formed as by-products. The reaction is preferably carried out in the presence

of titanium tetrachloride and / or a titanium alkoxide

leads to minimize the formation of these by-products. The implementation is preferably also in a common solvent for Friedel-Crafts seactions carried out, for example an aliphatic hydrocarbon such as hexane or heptane, a halogenated

Hydrocarbon, v / ie methylene chloride or trichloroethane,

or carbon disulfide. If appropriate, ethers can also be used as solvents. Usually the order The reaction is carried out at room temperature, but the rate of reaction can vary can be increased by heating. 35

809839/075

As already mentioned, in some cases they form as a side products 1,1-dithienylethane. To avoid the formation of the Like by-products, the reaction can be carried out in a solvent, or the process will be so carried out that only the starting compounds are circulated and brought into contact with the catalyst, by taking advantage of the different boiling points of the starting compounds and the end products.

Under the conditions described above, the o (-Trihalomethyl-2-thiophenemethanols of the general formula (B) can be produced in high yield. These compounds can optionally be passed into the next without isolation Level are used.

The second stage consists in the implementation of the cy-trihalomethyl-2-thiophenemethanols of the general formula (B) with

a compound of the general formula RH. Specific examples for the compounds of the general formula IrH

Water, alcohols such as methanol, ethanol, isopropanol and butanol, mercaptans such as methyl mercaptan, ethyl mercaptan, Isopropyl mercaptan, thiophenol and tolyl mercaptan, as well Amines, such as ammonia, methylamine, sthylamine, isopropylamine,

Dimethylamine and diethylamine. 25th

In the second stage, an alkali or Alkaline earth metal hydroxide is used. Sodium hydroxide and potassium hydroxide are preferred. Preferably at least three molar equivalents of the hydroxide based on the

Compound of the general formula (B) used. The connections the general formula (C) can generally be selectively using 3 to 4 colequivalents of the base getting produced. The reaction is preferably carried out in the presence of a solvent. Unless the connection of the general formula SH is an alcohol, can Excess alcohol can be used as a solvent.

809839/0 ^ 56 ^J.

/ S 28 Ί 0262

■ 5

If the compound of the general formula RH is a mercaptan or an amine can be used as a solvent an alcohol can be used. This reacts in this pail Mercaptan or amine preferred due to the different reaction rates. The second stage is also in progress at room temperature, but it is preferably carried out at the reflux temperature of the solvent used, to speed up the reaction speed.

10 In process (II), the starting compounds are the

2-Acetylthiophenes of the general formula (D) are used, the easily derived from the thiophene compounds of the general Have formula (A) produced. The compounds of the general formula (E) can be prepared in process (II).

These compounds are not only valuable intermediates for the production of 2-thiopheneacetic acids, but also Intermediate products for the production of thioprofenic acid.

In the method (II), a 2-acetylthiophene becomes the general Formula (D) reacted with a halogenating agent to give a compound of the general formula (E).

Specific examples of 2-acetylthiophenes of the general formula (D) used according to the process are 2-acetylthiophene and 2-acetylthiophenes substituted by lower alkyl radicals. Specific examples of the alkyl radicals are the methyl, ethyl, h-propyl, isopropyl, η-butyl, isobutyl, sec-butyl and tert-butyl groups. These radicals can be in the 3-, 4- or 5-position. Further examples are 2-acetylthiophenes which are substituted by chlorine, bromine or iodine atoms in the 4- or 5-position, 2-acetylthiophenes which are substituted by a halogen atom and a lower alkyl radical * "in the 3r4-, 3, 5- or 4, 5-position, and 5-aroyl-2-acetylthiophenes, such as S-benzoyl ^ -acetylthiophene. These 2-acetylthiophenes can be easily and in high yield from the corresponding thiophenes by Aeety-

809839 / 07SS

Production in the 2-position with acetyl chloride or acetic anhydride in the presence of a Lewis acid or a protic acid. If appropriate, they can be prepared by introducing alkyl radicals, halogen atoms or aroyl radicals into 2-acetylthiophene. Examples of halogenating agents which can be used are chlorine; Bromine, sulfuryl chloride, suIfuryl bromide, tert-butyl hypochlorite, selenoxy chloride, N-chlorosuccinimide and N-bromosuccinimide. Chlorine and bromine are preferred.
10

The reaction is also preferably carried out in the presence of a solvent carried out. Examples of solvents that can be used are halogenated hydrocarbons, such as carbon tetrachloride, Methylene chloride and chloroform, or polar solvents such as aliphatic ^ carboxylic acids, for example Acetic acid, propionic acid and butyric acid, the use of an aliphatic carboxylic acid is particularly preferred to the formation of by-products, for example the formation of compounds halogenated in the thiophene ring, monohaloacetylated Keep compounds and trihaloacetylated compounds to a minimum.

The reaction can take place at temperatures from 0 ° C. to the boiling point of the solvent used.

Temperatures from 0 to 50 C are preferred for the formation of by-products of the type described above to a minimum. In the method according to the invention the 2- (dihaloacetyl) thiophenes are formed in high yield.

The 2- (dihaloacetyl) thiophenes of the general formula (E) are then treated with an alkali metal or alkaline earth metal hydroxide implemented. Sodium or potassium hydroxide is preferably used. 4 molar equivalents are preferred Hydroxide based on the compound (E) is used. In general the compounds of the general formula (C) can be

S09839 / O75S

^r Il -ι

Selectively produced using 3 to 6 hol equivalents of hydroxide. The reaction with heating is expedient performed to get the reaction going, a Heating to around 50 C is sufficient. The reaction then proceeds with evolution of heat. The connections of the general Formula (C) are obtained in high yield and in practically pure form.

According to the method (i) or (II) described above produced Ot'-substituted 2-thiopheneacetic acid derivatives of the general formula (C) can be converted into the 2-thiophenacetic acid compounds of the general formula by reduction (F) transferred v / earth.

The type of reduction depends on the type of radical R in the Compounds of the general formula (C). If the rest of R represents an alkoxy radical, a Mckel catalyst, for example Raney-lTickel, a palladium catalyst, for example Palladium-on-carbon, or a platinum catalyst be used. These catalysts are usually used for the catalytic hydrogenation of benzyl ethers. The hydrogenation can be carried out in a solvent. Examples of solvents that can be used are V / water, Acetone, hydrocarbons or ethers. The hydrogenation can

²⁵ carried out at room temperature and at atmospheric pressure

will. To improve the selectivity of the reaction, a mineral acid, such as hydrochloric acid or sulfuric acid, or an inorganic or organic base such as sodium or potassium hydroxide, sodium or potassium acetate, triethylamine

³⁰ or pyridine, can be added. Except the catalytic one

Hydrogenation can also reduce with a hydrogen halide, in particular hydrogen iodide, red phosphorus and hydrogen iodide (or iodine) or red phosphorus and hydrogen chloride, be performed. The reaction is carried out in a mixture of Water and acetic acid, but other solvents can also be used, such as acetone, hydrochloric

809839/0756 ORIGINAL INSPECTED

Substances and ethers that do not subsequently influence the implementation » The reaction is generally carried out by refluxing carried out.

■ "• o ¹ -

If the radical R represents a hydroxyl group, the Reduction in general with the tin (II) chloride system and hydrochloric acid or by catalytic ^ hydrogenation with a copper odorous oxide or molybdenum sulfide catalyst will. Furthermore, the above in connection

3
with the radical R = alkoxy radical] hydrogenation processes can be used.

with the radical R = alkoxy radical explained reduction "resp.

The use of metal catalysts is particularly preferred the platinum group or the red phosphorus and iodine system. This is explained in more detail below.

If the radical R represents an alkylthio or arylthio radical, can reductive desulphurisation be used, as is customary with ^ -thiocarboxylic acids. To this Purpose can be the combination of zinc with an acid such as acetic acid, hydrochloric acid or sulfuric acid, or aluminum amalgam or zinc amalgam or a nickel catalyst such as Raney-Hickel can be used.

If the radical R represents an amino group, the reduction is "for example with a nickel catalyst, such as Raney-lTickel, or a palladium catalyst, such as palladium-on-carbon, carried out.

Some of the typical reduction processes are explained below.

One of the "preferred reduction processes" is catalytic Hydrogenation of oi -substituted 2-thiophene acetic acids the general formula

809839 / 075S

28V0262 '

OR ^
CHCOOR ⁴

12 4 V

in which R, S and R have the above meaning and Br represents a hydrogen atom, an alkyl, aryl, aroyl or acyl radical. The hydrogenation is carried out in the presence of a platinum group metal or a platinum group metal supported on a carrier as a catalyst.

It is known that the double bond and the carbon-sulfur bond of the thiophene ring sensitive to reduction is. Various products are formed during the reduction and thiophenes poison the catalyst. It was found that ketal catalysts, which are a metal of the Platinum group containing, or catalysts containing a platinum group metal on a carrier, give good results deliver. Palladium black and palladium applied to a carrier are particularly active and therefore preferred. Examples carriers that can be used are carbon, calcium carbonate, barium sulfate, barium bicarbonate and asbestos.

The hydrogenation is preferably carried out in a hydrogen atmosphere. The catalyst is added to (^ -substituted 2- ^ hiophenacetic acid or its solution. Examples of solvents that can be used are alcohols, such as methanol and ethanol. The hydrogenation can be carried out at temperatures from room temperature to 150 ° C. With regard to the reaction rate and selectivity are Temperatures in the range from 50 to 80 ° C. The reaction can be carried out under higher pressure. However, it is preferably carried out at atmospheric pressure. The use of 0.1 to 10 percent by weight of a palladium catalyst, based on that to be hydrogenated, is usually sufficient

809833 / 075S "*""'"

28-0262

Acid. Preferably 1 "to 3 weight percent catalyst is used used.

The selective cleavage of the oxygen-carbon bond in the o-position of the o-substituted 2-thiophene acetic acids of the general formula (C) without cleavage of the ihiophene ring can surprisingly also when using red. Phosphorus and iodine can be achieved. For this purpose, the ctf-substituted 2-thiophene acetic acid is used in one. Solvent dissolved and mixed with a mixture of red phosphorus and iodine, which has been mixed in a solvent beforehand. Acetone, methanol and organic acids can be used as solvents, which dissolve the "^ -substituted 2 - ^ 'hiophenacetic acid used and do not interfere with the reduction. The use of organic acids is preferred in terms of solubility, reaction rate and yield. Acetic acid as a solvent is particularly preferred. The reaction can be carried out by adding a strong acid such as phosphoric acid or sulfuric acid to the reaction system. In this reaction, phosphorus is used in the Oi-substituted 2-'i hiophenessigsäure ^1, in an amount of 0.1 molar equivalent to a slight excess. Iodine is only used in catalytic amounts. The process can be carried out at temperatures from room temperature to 150.degree. The reaction is preferably carried out with heating in order to accelerate the rate of the reaction.

The 2-thiophene glycolic acids obtained by process (I) or (II) can be acylated with a carboxylic acid anhydride to prepare the compounds of the general formula (G) will. For this purpose, the reactants are mixed with one another. When using a liquid carboxylic acid anhydride a separate solvent is not required. In this case, the carboxylic anhydride is im Used excess and serves as a solvent at the same time.

809839/0756 _mspECTED

^Γ "". 2810252

When using 70η solid carboxylic acid anhydride is preferred a solvent used - Examples of solvents that can be used are saturated hydrocarbons such as hexane and pentane, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as carbon tetrachloride, Chloroform and methylene chloride, as well as cyclic ones or acyclic ethers such as tetrahydrofuran and diethyl ether, as well as other aprotic solvents that do not interfere with the reaction. The procedure can be carried out at OK temperatures in the range from room temperature to 150 ° C. Preferably the reaction is carried out with heating to increase the reaction rate to accelerate.

The acylated compounds are easily converted into the compounds by reduction in the manner described above the general formula (F) convert. The acylated compounds are also valuable chemical modifiers for Cephalosporins.

Las process (III) starts from the intermediate products of the general Formula (B), i.e. the c ^ -trihalomethyl-2-thiophenemethanol derivatives. This process produces the new compounds of the general formula (H). With this one

Process is a tf- ■ Irihalomethyl-2-thiophenemethanol-25

Derivative of the general formula

OR

³⁰ 1 2

in which R, R and X have the above meaning and R

represents a hydrogen atom, an alkyl, acyl, arylsulfonyl or alkanesulfonyl radical, treated with a reducing agent. The compounds of the general formula (B ¹ ) used according to the process can be obtained by condensation of a Srihalogenacetaldehyde, such as chloral, with shiophene and given

809839/075 ". ORIGINAL INSPECTED

^r j £ 2810282

if necessary, subsequent reaction with an acylating agent, an alkylating agent or a sulfonylating agent produce.

Examples of those which can be used in the process according to the invention ! Reducing agents are zinc or a zinc-copper alloy and acetic acid, hydrochloric acid or acetic acid-hydrochloric acid, a metal such as sodium, magnesium or aluminum or its amalgam, a metal salt in its lower oxidation state, such as an ear om (H) salt, the zinc (II) chloride system, Phosphorus oxychloride and pyridine, an alkali metal salt, such as Sodium iodide or potassium iodide, as well as an organometallic one Compound, such as butyllithium or phenyllithium, the usual reducing agent for the production of olefins from halohydrins represent. The system zinc and acetic acid is preferred.

In practice, the process can be carried out in the absence of a solvent be performed. Preferably, however, a solvent is used, for example an ether such as Diethyl ether or tetrahydrofuran, a hydrocarbon such as benzene, toluene or hexane, an alcohol such as methanol or Ethanol, or acetic acid. The reaction proceeds smoothly at temperatures from room temperature to reflux temperature

^{25 of} the solvent used.

To prepare the 2-thiophenacetic acids of the general formula (F), it is necessary to undergo hydrolysis or alcoholysis the 2- (2,2-dihalovinyl) thiophenes of the general formula (H) to be carried out in the presence of a base. examples for Usable bases are basic alkali metal salts, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, Alkali metal alkoxides, such as sodium methoxide, Sodium ethoxide and potassium methoxide, in water or an alcohol. The reaction proceeds smoothly at temperatures from room temperature to the boiling point of the water or alcohol

809 8 39 / Q 7SS ORIGINAL INSPECTED

r Zs π

- * - 281Ü2Ö2

1 at this stage a compound of the general formula is formed

" _{V η} ^ ^τ and / or 2JL J

K SA-CB = C ^ _0R

in the R ¹ a hydrogen atom or the reads of an alcohol

1 2

represents, and R, R and X are as defined above.

At least one of the halogen atoms of the dihalovinyl group is subject to hydrolysis or alcoholysis. The reaction mixture is then preferably acidified. This level can can be accelerated by directly adding an acidic compound to the reaction system. Examples of usable Acids are inorganic acids such as hydrochloric acid, sulfuric acid or ammonium chloride, and organic acids, such as acetic acid, benzoic acid and p-toluenesulfonic acid. These Stage also proceeds smoothly at temperatures from room temperature to boiling point. The connections of the 20th

general formula (F) obtained in high yield.

The following examples illustrate the invention. The abbreviations "sh" and "br" mean "shoulder" and "broad". Tetramethylsilane is used as an internal standard for the MR spectra. The <f values are given in ppm.

Example 1 A solution of 4.2 g (50 mmol) of thiophene and 7.35 g (50 mmol)

Chloral in 25 ml of n-heptane is refluxed for 3 1/2 hours

heated, the condensate getting into a Soxhlet, which with 4.2 g of a cation resin exchanger in the acid fora (Amberlyst 15) is filled. After cooling, the reaction mixture becomes evaporated and the residue purified by distillation. There are 2.32 g of oi-trichloromethyl-2-thiophenemethanol obtained from b.p. 98 to 100 C / 1 Torr.

809839/0756 original inspected.

2810232 *

1 example 2

30 ml of a 1 molar solution of titanium tetrachloride in methylene chloride are under argon as protective gas with stirring and with water cooling with 4.26 g (15 mmol) of titanium tetraisopropoxide offset. After 10 minutes, 2.52 g (30 mmol) of thiophene and then within 10 meows with stirring and under Cooling with sis water, 8.82 g (60 mmol) of chloral were added dropwise. After the addition has ended, the mixture is stirred for a further 10 minutes. Water and then methylene chloride are then added to the reaction mixture. The organic phase will separated off, washed with water and dried over magnesium sulfate. The solution is then filtered and the solvent evaporated under reduced pressure. The residue is distilled. Chloral isopropyl alcoholate is used as the forerunner above. Then 5.0 g (72 $ d. Th., Based on thiophene) 0i-'irichloromethyl-2-thiophenemethanol of bp 95 M-s 97 ° C / 0.7 torr obtained.

IR (cm " ¹ ): 3425, 1065, 1044, 822 and 7t0. HMR (CDCl ₅ ): 3.48 (d, J = 5 Hz, 1H), 5.40 (d, J = 5 Hz, 1H)

20 and 6.88 - 7.50 (m, 3H).

Example3

A solution of 2.13 g (7.5 mmol) of titanium tetraisopropoxide in 10 ml of methylene chloride is mixed with 30 ml of a 1 molar solution of titanium tetrachloride in methylene chloride. The mixture is cooled to -70 ° C. and then initially treated with 8.8 g (59.7 mmol) of chloral and then with a solution of 3.56 g (30 mmol) of 2-chlorothiophene in 10 ml of methylene chloride. The mixture is stirred at the same temperature for 1 hour. The temperature is then slowly increased to -10 ° C. The reaction mixture is then poured into ice water. The organic phase is separated, washed with aqueous "brine and dried over magnesium sulfate. After evaporation of the solvent, the product is distilled under reduced pressure. There are 3 _S 52 g (44 5SD. Th.) Of 2,2,2-trichloro- 1- (5-chlorothiophene-2) ethanol with a boiling point of 94 to 100 ° C / 0.15 ° C obtained

L- J

809839 / 075B

ORIGINAL ISMSPECTED

^{Γ n} 30 28102S2

BIiR (CCl ₄ ): 3.20 (d, J = 4 Hz, 1H), 5.20 (d, J = 4 Hz, 1H),

6.72 (d, J = 4 Hz, 1H) and 6.97 (d, J = 4 Hz, 1H).

5 Example4

Under argon as a protective gas, 1.12 g (20 ml-lol) potassium hydroxide are released dissolved in 10 ml of methanol. Then a solution of 1.16 g (5 mmol) is added while stirring and while cooling with water tf-Trichiormethy 1-2-thiophenmethanol in 3 ml of methanol are added. After 10 minutes the mixture is gradually warmed and finally refluxed for 1 hour while doing so vigorously stirred,! times cooling to room temperature most of the solvent under reduced pressure distilled off. After adding diethyl ether, the reaction mixture is decomposed with dilute hydrochloric acid. The ether solution is separated off and the aqueous solution extracted with stylacetate. The organic solutions are combined with washed aqueous sodium chloride solution and dried over sodium sulfate. After filtering, the piltrate is reduced

²⁰ evaporated under the pressure. 620 mg (73 i> d. 5? H.) Of methoxy-2-thiophenacetic acid are obtained,

IR (cm ^-1 ): 3loo, 2925, 1730, 1180, 1100, 880, 845 and 707. NMR (CDCl ₅ ): 3.38 (s, 3H), 5.00 (s, 1H), 6.81 - 7.40

(m, 3H) and 10.58 (s, 1H). 25th

Example 5

1.12 g (20 mKol) potassium hydroxide are grounded under argon as a protective gas dissolved in 10 ml of methanol. The solution is stirring and while cooling with water with 0.6 g (5.45 mmol) of thiophenol

³⁰ staggered. After 10 minutes a solution of 1.16 g

(5 mKol) tf, -trichloromethyl-2-thiophene-methanol in 3 ml of methanol registered. After 10 minutes the mixture is gradually warmed and finally refluxed for 2 hours and vigorously stirred. After cooling to room temperature, the largest rope becomes the solvent under reduced pressure distilled off. Diethyl ether is added to the residue

809839/0756

^r j ^ _ 28Ί0232

and decompose the mixture with dilute hydrochloric acid. The ether solution is separated off, washed with water, dried over magnesium sulfate and filtered. The piltrate is evaporated under reduced pressure and the residue is purified by chromatography on silica gel. A mixture of ethyl acetate and n-hexane (1: 4) is used as the mobile phase. The eluate is evaporated. 940 mg (76% of theory) of o ^ -phenylthio-2-thiophenacetic acid are obtained as a viscous oil. IR (cnT ¹ ): 3060, 1715, 1587, 1485, 1440, 1416, 1253, 750, 705 and 694.

CLOCK (CDCl ₅ ): 5.03 (a, 1H), 6.62-7.60 (m, 8H) and 11.47 (s, 1H).

Example 6

A solution of 2.32 g (10 mmol) of c / trichloromethyl-2-thiophenemethanol in 20 ml of ethanol is mixed with 10 g (29 mmol) of sodium methyl mercaptide in the form of a 20 percent aqueous solution. A solution of 2.4 g (36 mmol) of potassium hydroxide in 20 ml of ethanol is then added dropwise to the solution. After the addition has ended, the mixture is stirred for 30 minutes at room temperature. The temperature is then increased to 50 ° C. and the mixture is stirred at this temperature for a further 5 hours. The solvent is then distilled off under reduced pressure. The residue is dissolved in water, washed with methylene chloride, acidified with hydrochloric acid and extracted with methylene chloride, after drying the methylene chloride extract over magnesium sulfate, the extract is evaporated. 1.75 g (93 ί * d. Th ₃ ) of crude ot-methylthio-2-thiophene acetic acid are obtained. After chromatographic purification on silica gel, 1.66 g (88 % of th.) Of pure compound are obtained.

HMR (CCl ₄ ): 1.98 (s, 3H), 4.67 (s, 1H), 6 _? 75-6.97 (m, 1H), 7.00-7.28 (m, 2H) and 11.95 (s, 1H).

INSPECTED 809839 / 075S

^Γ j ^ 2810232

¹ example 7

A solution of 0.67 g (12 mmol) of potassium hydroxide and 0.254 g (6 mmol) of lithium chloride in 2.4 ml of water is mixed with a solution of 0.693 g (3 mmol) of trichloromethyl-2-thiophenemethanol in 2.4 ml of dioxane added and stirred for 12 hours at room temperature and a further 3 hours at 80.degree. Then 20 ml of water and diethyl ether are added to the mixture. The ether solution is separated off and the aqueous phase is acidified with hydrochloric acid and extracted with diethyl ether. The ether extract is dried over magnesium sulfate, treated with activated charcoal and filtered. The filtrate is then evaporated. 0.246 g (52% of theory) of crude crystalline 2-thiophene glycolic acid are obtained. NMR (CDCl ₃ ): 5.47 (s, 1H), 6.80-7.35 (m, 3H) and 8.52

¹⁵ (br. S, 2H).

Example 8

Chlorine gas is passed into a solution of 6.31 g (50.0 mmol) of 2-acetylthiophene in 25 ml of glacial acetic acid, while cooling with water. The amount of cooling water is adjusted so that the temperature of the reaction system remains below 28 C. After introducing chlorine gas for about 2 hours, the reaction is complete and the reaction solution is light yellow in color. At this point in time, the introduction of chlorine gas is stopped and the reaction mixture is poured into 150 ml of crushed ice and extracted with diethyl ether. The ether extract is washed with cold water and dried over sodium sulfate. Mach distilling off the ether under reduced pressure behind remain 9.8 g (100 fo d. Th.) Of 2- (dichloroacetyl) -thiophene as an oil. The compound boils at 79 to 82 ° C / 0.15 torr. NMR (CCl ₄ ): 6.24 (s, 1H), 7.13 (dd, J = 5.2 Hz,

J = 3.9 Hz, 1H), 7.73 (dd, J = 5.2 Hz, J = 1.0 Hz, 1H) and 7.97 (dd, J = 3.9 Hz, J = 1, 0 Hz, 1H).
³⁵ IR (liquid PiIm, KBr plate): 3090, 1692, 1682 (sh),

1675 (sh), 1515, 1413, 805, 727 and 716 (cm ~ ¹ ).

809839/0758 ORiGfNAL inspected

2810252

MS (70 eV) (m / e): 196 (<1 $), 194 (<1 #) 111 (100 §δ)

and 83 ($ 10).

Example9
Example 8 is repeated, but the reaction is carried out at rtauurb temperature and with carbon tetrachloride as solvent. 3.7 g (39 % of theory ) of 2- (dichloroacetyl) thiophene are obtained.

10 Example 10

Example 8 is repeated, but the reaction is carried out at 4-7 G in carbon tetrachloride as solvent. 4.0 g (41 ^c ß> d. 'I'h. ) 2- (dichloroacetyl) thiophene are obtained «

Example 11

9.8 g (50 mmol) of 2- (dichloroacetyl) thiophene are added dropwise and with vigorous stirring to a 50 ° C. aqueous solution of 10.0 g (2 §0 nmol) of hatriura hydroxide. As a result of the exothermic reaction, the temperature of the reaction mixture rises to 55.degree. The rate of addition is adjusted so that the temperature does not rise above this value. ^ i _e addition of the 2 - (- ^Li ichloracetyl) -thiophens requires about 2 hours. After the addition has ended, the mixture is stirred for a further hour at the same temperature.

The reaction mixture is then cooled to room temperature, freed from neutral substances with diethyl ether and then adjusted to a pH of 1 with 12 η hydrochloric acid while cooling with ice. The aqueous acidic solution is extracted three times with 100 ml of diethyl ether each time. The ether extracts are combined, washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The ether is then distilled off under reduced pressure. There remain 7.9 g (100 ^c / o d. Th.) 2-thiophene glycolic acid, which after the conversion

³⁵ crystallize from benzene at 75 ° C melts.

■ - _. . "Ti% i-" t-OTISn -1

80983 9/075 B ORIGINAL INSPECT!

r 3 <t "i

¹ MMR (CDCl ₅ ): 5.42 (s, 1H), 6.7-7.4 (πι, 3H) and 8.17

(br. s, 2H).
IR (KBr disk): 33BO, 3500 - 2500 (wide), 1725, 152ö,

1430, 127ö, 1Q5Q and 703 (cm " ¹ ).

MS (7OeT) (m / e): 158 (4.1 #) (M ⁺ ), 156 (4.6 $ S), 113 (37.3? O,

111 (100 fo) and 97 (77.9 #).

Example 12

Example 11 is repeated, but a solution of 8.0 g (200 mmol) of sodium hydroxide in 90 ml of water is used. 14.2 g (50 mmol) of 2- (dibromoacetyl) thiophene are also used. 5.6 g (77 i> d. Tn.) Of 2-thiophene glycolic acid are obtained.

¹⁵ Example13

In a solution of 6.31 g (50 mmol) of 2-acetylthiophene in Chlorine gas is introduced into 25 ml of glacial acetic acid. There is a exothermic reaction, and the mixture is mixed with water in such a way cooled so that the temperature remains below 28 C. As soon as the

If the reaction solution is colored pale yellow by excess chlorine, the reaction is terminated. The acetic acid is then distilled off at room temperature under reduced pressure. What remains is crude 2- (dichloroacetyl) thiophene. The crude product is added dropwise with vigorous stirring to a 50 ° C. solution of 10.0 g (250 mmol) sodium hydroxide in 90 ml v / water. The temperature of the reaction solution rises to about 55 ° C. The addition is complete after about 2 hours. The mixture is then stirred for an additional hour at the same temperature. After cooling to room temperature, the reaction mixture is washed with diethyl ether and then acidified to pH 1 with 12 η hydrochloric acid while cooling with ice. The aqueous acidic solution is then extracted with diethyl ether. The ether extract is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. 7.9 g (100 % of theory ) of 2-thiophene glycolic acid are obtained.

809839/0756

1 example 14

A solution of 6.30 g (50 mmol) of 2-acetylthiophene in 4-0 ml of carbon disulfide is treated dropwise with 16.0 g (100 mmol) of bromine while cooling with -isis. The carbon disulfide is then distilled off under reduced pressure at room temperature. What remains is crude 2- (dibromoacetyl) thiophene. The crude product is reacted according to Example 13 with sodium hydroxide solution. After working up, 5.0 g (63 ° d “^ h.) 2-thiophene glycolic acid are obtained.

Example. 15th

A mixture of 421 mg of 2-thiophene glycolic acid and 40 mg of a 30 percent palladium-on-asbestos catalyst in 2.7 ml of methanol is refluxed and stirred in a hydrogen atmosphere at normal pressure. The will be awake for 15 hours. The catalyst is filtered off and the methanol is distilled off under reduced pressure. There are obtained 127 mg of 2- ⁱ 'hiophenessigsäure and 283 mg unreacted 2-Thiophenylglycolsäure. The conversion of 2-thiophene glycolic acid is 33 io and the selectivity for the formation of 2-thiophene acetic acid is 100 $.
IMR (CDCl ₃ ): 3.91 (s, 2H), 7.30 (d, J = 3 Hz, 2H),

7.31 (t, J = 3 Hz, 1H), and 11.12 (s, 1H).

25 Example 16

A solution of 2.06 g (13 mmol) of 2-Thiophenglykolsäure in 2.65 g (26 mmol) of acetic anhydride is heated for 15 hours 50 ⁰ C. Thereafter, acetic anhydride and acetic acid are distilled off under reduced pressure. 2.27 g (87% of theory) of c ^ -acetoxy-2-thiopheneacetic acid remain as residue.
MKR (CDCl ₅ ): 2.17 (s, 3H), 6.22 (s, 1H), 7.03 (t,

J = 4 Hz, 1H), 7.23 (d, J = 4 Hz, 1H), 7.37 (d, J = 4 Hz, 1H) and 11.68 (s, 1H).

8 09839/0758

r 30? ι

¹ example 17

A mixture of 1.51 g of cy-acetoxy-2-thiophenacetic acid and 0.40 g of a 30 percent palladium-on-asbestos catalyst in 0 ml of methanol is heated under reflux at normal pressure and in V / a touched. After 75 hours, the catalyst is filtered off and the methanol is distilled off under reduced pressure. 1.165 g of 2-thiophene acetic acid are obtained. The conversion is 66 γ>, the selectivity 83 #.
10

Example 1b

5.0 ml of acetic acid are mixed with 372 mg of red phosphorus and 141 mg of iodine. The mixture is 20 minutes at room temperature touched. A solution of 1565 mg of 2-thiophene glycolic acid in 1.0 ml of acetic acid is then added to the mixture and refluxed for 2 hours. After cooling to room temperature, the insoluble precipitate is filtered off and the acetic acid is distilled off under reduced pressure. The residue is taken up in diethyl ether. ^ ie Ether solution is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The ether is then distilled off. There are 1258 mg (89 # d. Lh.) 2-thiopheneacetic acid obtain.

25 Example19

2.85 ml of acetic acid are mixed with 180 mg of red phosphorus and 60 mg Iodine added. The mixture is stirred for 30 minutes. Then the mixture is treated with a solution of 60 mg v / water and 860 mg (5 mmol) of o (methoxy-2-thiopheneacetic acid in 1.5 ml of acetic acid offset. The resulting mixture is refluxed for 2 hours and stirred vigorously. After cooling to room temperature V / water and ethyl acetate are added to the mixture. The precipitate is filtered off with kieselguhr and the organic Phase separated, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After this The solution is filtered under reduced pressure.

809839 / G75S

steams. The crystalline residue is recrystallized from a mixture of - ^ thylacetate and η-hexane. 610 mg (86 io of theory ) of 2-thiophene acetic acid with a melting point of 62 ° C. are obtained.
5

Example 20

1.5 ml of acetic acid are mixed with 100 mg of red phosphorus and 40 mg Iodine added. The mixture is stirred for 20 minutes at room temperature and then with a solution of 564 mg of o ^ -acetoxy-2-thiopheneacetic acid added in 1.5 ml of acetic acid.

The mixture obtained is then refluxed for 2 hours, after cooling to room temperature the insoluble one becomes Precipitation is filtered off and the acetic acid is distilled off under reduced pressure. The residue is dissolved in diethyl ether recorded. The ether solution is washed with saturated aqueous sodium chloride solution and dried over sodium sulfate and evaporated. There are 400 mg (100 ^ d. '%.) 2- '-Thiophene s ig acid obtained.

20 Comparative Example A.

4.0 ml of hydriodic acid (density 1.7) are mixed with 186 mg of red phosphorus and 632 mg of 2-hiophene glycolic acid. The mixture is refluxed for 2 hours. After cooling to room temperature, insoluble substances are filtered off. The insoluble substances are washed with diethyl ether. The ether solutions become aqueous The filtrate is added and the mixture is extracted by further addition of diethyl ether. The ether solution is sequentially washed with saturated aqueous sodium chloride solution containing a small amount of sodium thiosulfate. Then the ether solution is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. 283 mg of an oil remain. The NMR spectrum of the product shows strong absorption between 1 to 3 ppm and practically no absorption that can be assigned to an ihiophene ring.

809839/075 $ ^Λ

1 Example 21

A solution of 890 mg (3.5o mmol) of o (-I ^> henylthio-2-thiopheneacetic acid in 6 ml of acetic acid is mixed with 350 mg (5.4 mmol) of zinc dust, heated under reflux and vigorously stirred, and again after 30 minutes 350 mg of zinc dust are introduced and the mixture is refluxed and stirred for a further 4 hours, the reaction mixture is then cooled to room temperature, most of the solvent is distilled off and the residue is mixed with water

10 and ethyl acetate are added and the resulting precipitate with

Kieselguhr filtered off. The layers of the filtrate are separated. The organic phase is washed with an aqueous common salt solution and dried over magnesium sulfate, and the solution is evaporated under reduced pressure after filtering. The crystalline residue obtained is recrystallized from a mixture of ethyl acetate and n-hexane. 430 mg (85 '/ 0 of theory ) of 2-thiophenacetic acid with a melting point of 62 ° C. are obtained.

20th Example 22

A mixture of 15.5 g (67.1 mmol) of oi-'J-'riehlomethyl-2-thiophene-methanol and 15.5 ml of acetyl chloride is refluxed and stirred for 15 hours; see VW Floutz, J. Am. Qhem. Soc, Vol. 71 (1949) '3. 2859. then the acetyl chloride is distilled off under reduced pressure and the residue is extracted with diethyl ether. The ether extract is washed with aqueous sodium bicarbonate solution and water / water, dried over magnesium sulfate, filtered and evaporated. There are 18.0 g (97.8 ft of theory ) of white crystalline 2,2,2-trichloro

^{30 obtained} 1- (2-thiophene) ethyl acetate.

Example 23

A solution of 18 g of 2,2,2-trichloro-1- (2-thiophene) ethyl acetate 3 g of zinc dust are added to 108 ml of acetic acid, the mixture is heated under reflux and stirred vigorously. At a distance of 3 g of zinc dust are injected twice for 1 hour each

809839/0756

wear. After 5 hours, the reaction mixture is cooled to room temperature. The acetic acid is distilled off under reduced pressure and the residue is extracted with diethyl ether. The ether extract is washed with saturated sodium chloride solution and dried over magnesium sulfate. After treatment with activated charcoal, the solution is evaporated
What remains is 10.8 g (91.5% of theory) of crude 2- (2,2-dichlorovinyl) thiophene. The crude product is distilled under reduced pressure. Today 9.23 g of pure compound of bp 103

up to 108 ° C / 20 Torr. The product crystallizes on standing. The yield is 78.2 $ d. Th. M.p. 38 to 39 ° C
IR (NUjOl): 1605, 1510, 1420, 1350, 1310, 1282, 1245,

1215, 1120, IO75, 1050 and 910 (cm " ¹ ).
NMR (CDCl ₅ ): 6.88 - 7.30 (m, 3H, Ring H) and 6.93 (s, 1H,

¹⁵ CH = CCl ₂ ).

Example 24

A solution of 300 mg (1.3 mmol) of or-trichlorine thyl-2-thio ~ phenmethanol in 3 ml of acetic acid is mixed with 170 mg (2.6 mmol) of zinc dust and refluxed for 3 hours and stirred vigorously. After cooling, water and ethyl acetate are added to the mixture and the organic phase is separated off. The organic phase is washed successively with water, aqueous sodium bicarbonate solution and again water and dried over magnesium sulfate. The solution is then filtered and evaporated. 200 mg of an oil are obtained. The gas chromatographic analysis (2 i <> EGA, 1 m, 120 ⁰ C) shows the formation of 2- (2,2-dichlorovinyl) thiophene in

77 percent yield. 30th

Example 25

A solution of 300 mg (1.3 mmol) of o (- 'frichloromethyl-2-thiophenemethanol in 3 ml of acetic acid is mixed with 170 mg (2.6 mmol) of zinc dust and 11 mg (0.13 mmol) of sodium acetate
and heated to reflux and stirred vigorously. After 4 hours, another 100 mg (1.5 mmol) of zinc dust are added,

8 0 9 8 3 9/0 7 5 %

and the mixture is refluxed for an additional 3 hours. After cooling, the reaction mixture is according to Example 24 worked up and analyzed gas-omatographically. It is 2- (2,2 ~ dichlorovinyl) thiophene in 68 percent

^{Get 5} loot.

Example 26

A solution of 300 mg (1.3 mmol) of 0 '- ^£ riehlormethyl-2-thiophene methanol in 500 mg of pyridine is added under stirring and cooling with ice water with 400 mg of acetic anhydride. The temperature of the mixture is gradually increased to room temperature. iTach 2 hours are 3 ml of acetic acid as well

170 mg (2.6 mmol) of zinc dust added. The mixture is under Heated to reflux and stirred vigorously. Each 2 hours a further 80 mg of zinc dust are entered and after 30 minutes another 80 mg (1.2 mmol) of target entered deaf. After total After refluxing for 3 hours, the reaction mixture is cooled and worked up as in Example 24. The gas chromatographic Analysis shows the formation of 2- (2,2-diehlor-

²⁰ vinyl) -thiophene in a tal yield of 74 i> of the theory.

Example 27 A solution of 1.53 g of sodium in 85 ml of methanol is mixed with

3 »0 g (16.8 mmol) of 2- (2,2-dichlorovinyl) thiophene were added. The mixture is refluxed for 15 to 10 hours. As soon as it is established by thin-layer chromatographic analysis that the starting material has disappeared, the reaction solution is acidified by introducing hydrogen chloride gas while cooling with ice water. The mixture is then refluxed for 15 to 18 hours. Thereafter, the methanol under reduced pressure, ¹ a, bdestilliert and the residue extracted with diethyl ether. The ether extract is washed with water / water, dried over magnesium sulfate, filtered and evaporated. The residue is distilled under reduced pressure. There are 2.10 g (80.2 ? O d.

L _J

809839 / 075S

ty -I

1 2-Thiophenessigsäuremethylester from bp 1C9 to 111 G /

23 I received ¹ Orr.

NKR (COl ₄ ): 3.65 (s, 3H), 3.70 (s, 2H) and 6.75-7.20

(m, 3H). 5

809839/0756

Claims (1)

VOSSIUS · VOSSIUS · HILTL · TAUCHNER · HEUNEMANN PATENT LAWYERS SIEBERTSTRASSE 4 8000 MÖNCHEN 86. PHONE: (O89) 47 4O75 CABLE: B ENZOLPATENT MÖNCHEN TELEX 5-29 453 VOPAT D 5 ET: M 625 (Vo / kä) Case; PS / 1-14 SJMSAMI CHEMICAI. RESEARCH CENTER Tokyo, Japan
10 ¹¹ Process for the preparation of thiophene derivatives and CY-substituted 2-thiopheneacetic acid compounds and 2- (2,2-dihalovinyl) -thiophenes » 15 Claims 1y 'Process for the preparation of o / -Trihalomethyl-2 - "" thiophenemethanols the general formula _π 1 25 OH 1 2 in the R and R Y / water or halogen atony, alkyl, Represent aroyl or acyl radicals and X is chlorine, bromine or Iodine atom means, characterized in that that one is a thiophene derivative of the general formula Rl S ' with a trihaloacetaldehyde of the general formula CX ₃ CHO 809839/0758 1 2 in which X, R and R are as defined above, reacts in the presence of an acid. 2. The method according to claim 1, characterized in that a Lewis acid is used as the acid. 3. The method according to claim 1 and 2, characterized in that the acid used is titanium tetrachloride and / or a titanium alkoxide used. 10 4. Process for the preparation of or-substituted thiophene acetic acid compounds the general formula ¹⁵ R 1 -C 3 _{-CHCO 9} R ⁴ 1 2 in which R and R are hydrogen or halogen atoms, alkyl, 3
Represent aroyl or acyl radicals, R a hydroxyl or amino group, an alkoxy, alkylthio or arylthio radical and R ^ represents a hydrogen atom or an alkyl group, thereby characterized in that one A'-trihalomethyl-2-thiophenemethanol the general formula 25 ΊΓ " OH 1 2 in which R and R have the above meaning and X represents a chlorine, bromine or iodine atom, in the presence of an alkali or alkaline earth metal hydroxide with a compound of the general formula RH and optionally the obtained Esterified compound with an aliphatic alcohol. 809839/0756 5. Process for the preparation of 2-thiophene glycolic acid compounds the general formula "1 CH-CO ₉ R OH 1 2 in which R and R represent hydrogen or halogen atoms, alkyl, aroyl or acyl radicals and R represents a hydrogen atom or denotes an alkyl radical, characterized in that a 2-acetylthiophene of the general formula R ' C-CH * - »' _8th ⁵ first with a halogenating agent to form a 2- (dihaloacetyl) thiophene de :: general formula R ¹ J— C- CHX ₉ it ^ 1 2 in which R and R have the above meaning and X represents a chlorine, bromine or iodine atom, and this compound is reacted treated with an alkali or alkaline earth metal hydroxide and optionally the compound obtained with a esterified aliphatic alcohol. 6. The method according to claim 5, characterized in that the halogenation is carried out in an aliphatic carboxylic acid as solvent. 7. Process for the preparation of o (-Acyloxy-2-thiophenacetic acid compounds the general formula 809839 / 075S - ■ S ' OCOR ^ 'CHCO ₀ R ⁴ " 1 in which R and R are hydrogen or halogen atoms, alkyl, Aroyl or acyl radicals represent, R an ^ hydrogen atom or an alkyl radical and R denotes an alkyl or aryl radical ", characterized in that there is a 2-thiophene glycol acid compound of the general formula OH CHCO ₀ R ⁴ in which R, ■ R and R have the above meaning, with a carboxylic acid anhydride of the general formula in which R has the above meaning, for implementation brings. 8. Process for the preparation of 2-thiophenacetic acid compounds the general formula "1 CH ₂ CO ₂ R ^ 1 in which R and R represent hydrogen or halogen atoms, alkyl, aroyl or acyl radicals and R represents a hydrogen atom or denotes an alkyl radical, characterized in that one is an o ^ -substituted 2-thiophenacetic acid compound the general formula - CHCO ₂ R ⁴ 809839 / 075S ι 1 2 4 3 ' in which R, R and R have the above meaning and R a hydroxyl or amino group, an alkoxy, acyloxy, Represents aroyloxy, alkylthio or arylthio radical, hydrogenated. 9. The method according to claim 8, characterized in that there is an o-substituted 2-thiophenacetic acid compound 3 · uses, in which R represents a hydroxyl group, an alkoxy, aryloxy, acyloxy or aroyloxy radical, and the Carries out hydrogenation in the presence of a platinum group catalyst optionally applied to a support. 10. The method according to claim 9, characterized in that the catalyst is optionally applied to a support Palladium black used. 11. The method according to claim 8, characterized in that one is an δ-substituted 2-thiophene acetic acid compound 3 ¹ uses, in which R represents a hydroxyl group, an alkoxy, aryloxy, acyloxy or aroyloxy radical and the hydrogen tion with red phosphorus and iodine. 12. The method according to claim 8, characterized in that one is a {^ -substituted 2-thiophene acetic acid compound 31
uses, in which R is an alkylthio or arylthio radical and performs the hydrogenation with zinc and an acid. 13. Process for the production of 2- (2,2-i> Lhalogenvinyl) - thiophenes of the general lOrmel 30th -GH = C 1 2 in which R and R represent hydrogen or halogen atoms, alkyl, aroyl or acyl radicals and X is a Qxior-, bromine- 809839/075 $ 2810252 or iodine atom, characterized in that an i-trihalomethyl-2-thiophenemethanol of the general formula "1 CHCX OR 1 2 in which R and R have the above meaning, R is a hydrogen atom, an alkyl, acyl, arylsulfonyl or alkanesulfonyl radical and X is a chlorine, bromine or iodine atom, treated with a reducing agent. 14- · Process for the preparation of 2-Thiophenessigsäure-Ver bonds of the general formula 1 2 in. the R and R hydrogen or halogen atoms, alkyl, Aroyl or acyl radicals represent and R is a hydrogen atom or denotes an alkyl radical, characterized in that a 2- (2,2-dihalo vinyl) thiophene of the general formula -CH = CX. 1 2 in which R and R have the above meanings and X is a Represents chlorine, bromine or iodine atom, subjected to hydrolysis or alcoholysis in the presence of a base and optionally acidifies the reaction mixture. 15 · o <-substituted-2- ^ hiophenacetic acid compounds of the general formula 809839/0758 - 7 ~
■ _Η 1 z \ _s JL CHGO ₂ R ⁴ 1 2 in which R and R are hydrogen or halogen atoms, Alley l-, 3 represent aroyl or acyl radicals, R an arylthio radical and A.
R. denotes a hydrogen atom or an alkyl radical. 16. 2- (2,2- ^ ihalovinyl) -thiophenes of the general formula R "15 J- CH = CX, 1 2 in which R and R are hydrogen or halogen atoms, Al & yl, Represent aroyl or acyl radicals and X represents a chlorine, bromine or iodine atom ".
20th ^L 8Q9839 / Q7SS