USRE30655E - Process for preparing 3-thienyl-acetate derivatives - Google Patents

Process for preparing 3-thienyl-acetate derivatives Download PDF

Info

Publication number
USRE30655E
USRE30655E US06/163,500 US16350080A USRE30655E US RE30655 E USRE30655 E US RE30655E US 16350080 A US16350080 A US 16350080A US RE30655 E USRE30655 E US RE30655E
Authority
US
United States
Prior art keywords
thienyl
acetate
formula
temperature
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US06/163,500
Other languages
English (en)
Inventor
Charles Pigerol
Marie-Madeleine Chandavoine
Michel Chignac
Paul DE Cointet de Fillain
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Labaz SA
Original Assignee
Labaz SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Labaz SA filed Critical Labaz SA
Application granted granted Critical
Publication of USRE30655E publication Critical patent/USRE30655E/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to a process for preparing thiophene derivatives.
  • the thiophene derivatives prepared by the process of the invention are the alkyl 3-thienyl-acetate derivatives corresponding to the general formula: ##STR3## wherein R 1 represents an alkyl radical preferably ethyl, a cycloalkyl radical, preferably cyclohexyl, or an aralkyl radical, preferably benzyl, R 2 represents an atom of hydrogen, or R 1 and R 2 , when they are taken together to form a cyclic group with the carbon atom to which they are attached, represent a polymethylene radical having from 2 to 5 carbon atoms, preferably tetramethylene or pentamethylene, and R 3 represents an alkyl radical preferably methyl or ethyl.
  • One of the best known compounds of this series is ⁇ -N-hexamethyleneiminoethyl ester of 2-cyclohexyl-3-thienyl-acetic acid of which the generic name is cetiedil.
  • Cetiedil has proved to be very useful as an anti-ischemia and peripheral vasoregulator agent and may be considered as being, presently, the most effective agent for the treatment of peripheral arterial diseases (Lille Medical. Actualites 3eme Serie, Tome XVIII, pp. 1303-1312--1973).
  • U.S. Pat. No. 2,685,589 discloses 3-thienyl-acetic esters bearing a cyclopolymethylene incorporating the ⁇ -carbon. These esters are described as possessing antispasmodic activity and more particularly an antispasmodic action on normal smooth muscle as well as against neurotropic and musculotropic spasms of smooth muscle. These compounds are also useful as antifungal agents.
  • the process of the invention does, in fact, provide a means of obtaining the esters of formula I which is very simple and consequently markedly superior to what is known up to present.
  • the alkylation in question may be effected by heating the appropriate acetic ester with a strong base such as sodium hydride and reacting the resultant alkali salt with an organic halide.
  • a strong base such as sodium hydride
  • organic halide can be used in this process including liquidammonia, alcohols, ethers and aromatic hydrocarbons.
  • the required 3-thienyl-acetic ester of formula I was prepared in accordance with this process by first heating an alkyl 3-thienyl-acetate with sodium hydride in dimethylformamide and then reacting the alkali metal salt so produced by heating it with the appropriate halide.
  • the operative conditions and specific temperatures employed were those described in U.S. Pat. No. 3,832,354 (Example 216).
  • the thiophene derivatives of formula I are prepared from a mixture constituted by a compound of the formula: ##STR4## wherein R 3 has the same meaning as in formula I and an organic halide of the formula:
  • X represents an atom of fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine and R 4 represents an alkyl radical, preferably ethyl, a cycloalkyl radical, preferably cyclohexyl, an aralkyl radical, preferably benzyl, or a --CH 2 (CH 2 ) n X radical in which n is an integer in the range of from 1 to 4 inclusive, preferably 3 or 4, and X has the meaning given above, which mixture is added to an alkali metal hydride, preferably sodium hydride, in dimethylformamide at a temperature between -20° C. and -5° C. and allowed to react in one step at a temperature between -20° C. and -5° C.
  • an alkali metal hydride preferably sodium hydride
  • cyclohexyl can be cited.
  • bromine is the preferred value for X.
  • methyl or ethyl ⁇ -(3-thienyl)- ⁇ -cyclohexyl-acetate is prepared by adding, at a temperature of -15° C., a mixture of methyl or ethyl 3-thienyl-acetate and cyclohexyl bromide to an alkali metal hydride, preferably sodium hydride, in dimethylformamide and allowing the reaction to occur, in one step, at a temperature between -15° C. and -10° C. to obtain methyl or ethyl ⁇ -(3-thienyl)- ⁇ -cyclohexyl-acetate.
  • an alkali metal hydride preferably sodium hydride
  • the alkyl 3-thienyl-acetate in question is treated so that at least two molar equivalents of the appropriate halide of formula III, preferably in excess, react with one molar equivalent of alkyl 3-thienyl-acetate.
  • esters of formula II may be prepared by known procedures and, in particular, by esterifying the corresponding 3-thienyl-acetic acids which are known compounds or one of their halides, such as the chloride, by means of an alcohol of the general formula R 3 OH in which R 3 has the same meaning as in formula I.
  • the halides of formula III are known compounds.
  • the starting compounds were the following:
  • the mixture was then heated for 30 minutes at 60° C. after which it was cooled to +2° C.
  • the temperature was allowed to increase and the mixture was stirred at room-temperature for 100 minutes and then heated to 60° C. for 20 minutes.
  • the mixture was cooled, poured into 300 ml of iced water and extracted with 4 fractions, each of 100 ml, of ethyl ether.
  • the ethereal fractions were washed with water, dried on magnesium sulphate and concentrated under vacuum.
  • the crude oil (40 g) so obtained was rectified by distillation first under 15 mm Hg and then under 0.7 mm Hg and 17 g of pure product were obtained.
  • the mixture was then heated for 30 minutes at 60° C. after which it was cooled to -15° C.
  • the method used was that of the present invention.
  • reaction medium When no more hydrogen was given off i.e. 2 to 4 hours later, the reaction medium was hydrolysed with 300 ml of iced water and extracted with 4 fractions, each of 100 ml, of ethyl ether.
  • the medium was cooled to +2° C. and cooling was suspended. After that, a solution of (I) and (II) in 20 ml of dimethylformamide was added. The operation lasted 15 minutes. The final temperature of the reaction medium was 30° C. with an intermediate increase to 58° C.
  • the process of the invention can be conducted in only one single step i.e. the addition of premixed alkyl 3-thienyl-acetate and halide of formula III to the reaction medium.
  • the process cited in U.S. Pat. Nos. 3,755,412 and 3,832,354 requires first that the alkyl 3-thienyl-acetate be added to and heated with the reaction medium and secondly that the halide of formula III be subsequently added to the resulting salt.
  • the thiophene derivatives of formula I when prepared in accordance with the process of the invention, constitute by virtue of the ease with which they are prepared, particularly useful intermediate products for obtaining the pharmacologically valuable thiophene derivatives mentioned above.
  • reaction medium was hydrolyzed with 500 ml of iced water.
  • the aqueous solution was extracted with 500 ml ether, the ethereal phase was washed with water and dried.
  • the solution was concentrated under reduced pressure and the residue so obtained was distilled under reduced pressure.
  • Example 2 In a 250 ml-flask equipped as in Example 1, hereabove, were introduced 2.4 g (0.1 mol) of sodium hydride and 70 ml of dimethylformamide.
  • the reaction medium was cooled to -20° C. and then a mixture of 17 g (0.1 mol) of ethyl 3-thienyl-acetate and 10 g (0.99 mol) of ethyl bromide were added, drop-by-drop, care being taken that the temperature did not exceed -10° C. This operation lasted 2 hours. The temperature was maintained at -10° C. for a further 2 hours and then the reaction mixture was allowed to return to room-temperature. Stirring was maintained for 12 hours after which the reaction medium was hydrolyzed with 100 ml of iced water. The aqueous phase was extracted twice with 100 ml of ether and the ethereal phase was washed with water, dried and concentrated. The residue so formed was finally distilled under reduced pressure.
  • Example 2 In a 250-ml-flask fitted as in Example 1, hereabove, were placed 2.4 g of a suspension of sodium hydride in 70 ml of dimethylformamide. The temperature of the flask was lowered to -15° C. and then a mixture of 8 g of ethyl 3-thienyl-acetate and 6.3 g of benzyl chloride was added, drop-by-drop, so that the temperature never rose above -10° C. This operation was effected in about 30 minutes during which time hydrogen was given off. If the escape of hydrogen was not terminated at the end of the operation of adding the mixture, the temperature of the reaction medium was maintained at -10° C. for a further hour. The mixture was then allowed to return to room-temperature and stirring was maintained for 12 hours. Drop-by-drop, 70 ml of water were then introduced and the mixture was extracted with ether. The ethereal phase was washed with water, dried and distilled.
  • Methyl- ⁇ -(3-thienyl)- ⁇ -benzylacetate can be produced by the procedure of Example 3, by substituting methyl 3-thienyl-acetate for ethyl 3-thienyl-acetate, all the other conditions being the same.
  • Example 2 In a one-liter-flask fitted as in Example 1, hereabove, were placed 300 ml of dimethylformamide and 9.8 g (0.41 mol) of sodium hydride. The temperature of the flask was lowered to -10° C. and then, under nitrogen atmosphere, a solution of 31.2 g (0.2 mol) of methyl 3-thienyl-acetate and 64.8 g (0.3 mol) of 1,4-dibromo-butane in 60 ml of dimethylformamide was added, care being taken to stir vigorously and maintain the temperature between -10° C. and -5° C. for the first 90 minutes. This operation of addition was effected in about 2 hours.
  • reaction medium was then poured into 500 ml of iced water and extracted with twice 200 ml of ethyl ether.
  • the ethereal phases were collected, washed with water, dried and concentrated under reduced pressure.
  • the crude product so obtained was then distilled under reduced pressure.
  • the fraction boiling at 100° C. under 0.3 mm Hg was collected, whereupon it solidified.
  • 32 g of methyl ⁇ -(3-thienyl)- ⁇ -cyclotetramethylene acetate were obtained which were recrystallized from pentane, representing a yield of 70%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US06/163,500 1973-08-30 1980-06-27 Process for preparing 3-thienyl-acetate derivatives Expired - Lifetime USRE30655E (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7331321 1973-08-30
FR7331321A FR2271225B1 (enrdf_load_stackoverflow) 1973-08-30 1973-08-30

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US05651174 Continuation-In-Part 1976-01-21
US05/778,498 Reissue US4186137A (en) 1975-02-14 1977-03-17 Process for preparing 3-thienyl-acetate derivatives

Publications (1)

Publication Number Publication Date
USRE30655E true USRE30655E (en) 1981-06-23

Family

ID=9124445

Family Applications (1)

Application Number Title Priority Date Filing Date
US06/163,500 Expired - Lifetime USRE30655E (en) 1973-08-30 1980-06-27 Process for preparing 3-thienyl-acetate derivatives

Country Status (15)

Country Link
US (1) USRE30655E (enrdf_load_stackoverflow)
JP (1) JPS5050359A (enrdf_load_stackoverflow)
BE (1) BE818305A (enrdf_load_stackoverflow)
CA (1) CA1028713A (enrdf_load_stackoverflow)
CH (1) CH592079A5 (enrdf_load_stackoverflow)
DE (1) DE2441441A1 (enrdf_load_stackoverflow)
DK (1) DK144914C (enrdf_load_stackoverflow)
ES (1) ES429678A1 (enrdf_load_stackoverflow)
FR (1) FR2271225B1 (enrdf_load_stackoverflow)
GB (1) GB1460536A (enrdf_load_stackoverflow)
IT (1) IT1020263B (enrdf_load_stackoverflow)
NL (1) NL7411146A (enrdf_load_stackoverflow)
NO (1) NO142398C (enrdf_load_stackoverflow)
SE (1) SE415257B (enrdf_load_stackoverflow)
SU (1) SU528876A3 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5314910A (en) * 1990-11-07 1994-05-24 Cortech Inc. Ester inhibitors

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES8204729A1 (es) * 1981-08-11 1982-05-16 Madaus Cerafarm Lab Procedimiento para la preparacion de acidos de 2-(3'-tienil)propionicos 5'-sustituidos
FR2751652B1 (fr) * 1996-07-24 1998-09-04 Expansia Sa Derives du thienylcyclohexane, des procedes pour leur preparation et leur utilisation en tant que produits industriels nouveaux pour la synthese de derives thienylcyclohexyles
EP3091406B1 (en) * 2015-05-08 2017-12-20 Sandvik Intellectual Property AB A method of determining pull-out of a cutting tool and a rotatable tool holder for a cutting tool

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3755412A (en) * 1969-07-07 1973-08-28 Exxon Research Engineering Co Alkylation of acetonitriles
US3832354A (en) * 1972-08-01 1974-08-27 Sandoz Ltd 4-hydroxy-5-phenyl-3-thiophene acetic acids and their derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3755412A (en) * 1969-07-07 1973-08-28 Exxon Research Engineering Co Alkylation of acetonitriles
US3832354A (en) * 1972-08-01 1974-08-27 Sandoz Ltd 4-hydroxy-5-phenyl-3-thiophene acetic acids and their derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5314910A (en) * 1990-11-07 1994-05-24 Cortech Inc. Ester inhibitors

Also Published As

Publication number Publication date
NO743096L (enrdf_load_stackoverflow) 1975-03-24
JPS5050359A (enrdf_load_stackoverflow) 1975-05-06
SE7410952L (enrdf_load_stackoverflow) 1975-03-03
CA1028713A (en) 1978-03-28
BE818305A (fr) 1975-01-31
NO142398C (no) 1980-08-13
GB1460536A (en) 1977-01-06
NL7411146A (nl) 1975-03-04
SE415257B (sv) 1980-09-22
FR2271225A1 (enrdf_load_stackoverflow) 1975-12-12
SU528876A3 (ru) 1976-09-15
NO142398B (no) 1980-05-05
ES429678A1 (es) 1976-10-01
FR2271225B1 (enrdf_load_stackoverflow) 1976-10-01
IT1020263B (it) 1977-12-20
CH592079A5 (enrdf_load_stackoverflow) 1977-10-14
DK144914C (da) 1982-11-29
DE2441441A1 (de) 1975-03-06
DK459874A (enrdf_load_stackoverflow) 1975-04-28
DK144914B (da) 1982-07-05

Similar Documents

Publication Publication Date Title
US6573404B2 (en) Method for producing ortho-alkylated benzoic acid derivatives
US4371699A (en) Process for preparation of optically active N-mercaptoalkanoylamino acids
USRE30655E (en) Process for preparing 3-thienyl-acetate derivatives
US4186137A (en) Process for preparing 3-thienyl-acetate derivatives
JPS62478A (ja) 分子複合体、その製造及び利用
US4673761A (en) Process for preparing anti-inflammatory cycloalkylidenemethylphenylacetic acid derivatives
US4982016A (en) Conversion of diethyl phenylmalonate to 2-phenyl-1,3-propanediol
US4108865A (en) Thiophene compounds and the production thereof
CA2233617A1 (en) Process for the preparation of 4-methylenepiperidine
JPH05238990A (ja) １，４，５，８−テトラキス（ヒドロキシメチル）ナフタレン誘導体およびその製造方法
KR900005681B1 (ko) 2-티오펜 아세트산 유도체의 제조방법
EP0169602B1 (en) Preparation of n-substituted azetidine 3-carboxylic acid derivatives
EP0101004B1 (en) Process for preparing 4-oxo-4, 5, 6, 7-tetrahydroindole derivative
US4886924A (en) Stereospecific synthesis of [E]-alkenes from enamines via hydroboration
JP3677786B2 (ja) アリールオキシプロピオン酸の製造法
JPH0558955A (ja) β−フルオロ−α−ケト酸等価体の製造方法
EP0423991B1 (en) Process for the preparation of 2-trifluoromethyl-4-hydroxybenzoic acid
CN115894594B (zh) 一种去氧胆酸中间体的制备方法
IE52326B1 (en) Process and intermediates for preparing pirbuterol
JPH0285233A (ja) ４―クロロ―３―アルコキシーブテン（２ｅ）酸アルキルエステルの製造方法
JPH0696564B2 (ja) α−（ω−ヒドロキシアルキル）フルフリルアルコ−ル及びその製造法
US4180510A (en) Method for preparing thienylacetic acids
CA1284153C (en) Preparation of alkyl trifluroacetoacetate
JPH02289539A (ja) Ｎ―メチル―３，４―ジメトキシフェニルエチルアミンの新規合成方法
JP3474009B2 (ja) チーグラーナッタ触媒の電子供与性化合物として有効なエステル化合物の製造方法