CH628341A5 - Process for the preparation of thienylpolyenes - Google Patents

Description

The invention relates to a process for the preparation of thienyl polyenes.

The polyenes obtainable according to the invention correspond to the following general formula in which one of the groups R 1 or R 2

III

55

Is 60 and the other of the groups R 1 or R 2 and R 3 and R 4 are hydrogen, lower alkoxy lower alkyl, hydroxymethyl, halogen, lower alkyl, lower alkoxy, lower alkylthio, carboxyl, amino, mono (lower alkyl) amino, di (lower alkyl) amino, mono (never-the-alkyl) amino-lower alkyl, di (lower-alkyl) amino-lower-65 alkyl, hydroxy, lower-alkenyl, lower-alkenoxy, lower-alkanoyl , lower alkanoyloxy, nitro, lower alkoxycarbonyl, never-the-alkanoylamido or a nitrogen-containing heterocycle, and Rs formyl, lower alkoxy-methyl, lower alkanoyloxy-

3rd

628341

methyl, carboxyl, lower alkoxycarbonyl, lower alkenoxycar- wherein one of the groups R 1 or R 2 is bonyl, lower alkynoxy carbonyl, di (lower alkyl) carbamoyl or N-heterocyclyl carbonyl, and their pharmaceutically acceptable salts. 1 3 3

Here, “lower alkyl” means alkyl groups which have up to 6 5 Jk. / Rc-

Contain carbon atoms, e.g. B. methyl, ethyl, propyl, Isopro P

pyl or 2-methyl-propyl, “lower alkoxy” means alkoxy

groups containing up to 6 carbon atoms, e.g. B. Meth- and the other of the groups Ri or R2 and R3 and R4 Was- • oxy, ethoxy or isopropoxy, "halogen" includes fluorine, chlorine, serstoff, lower alkyl or halogen and Rs lower alkoxycar bromine and iodine , with bromine and chlorine being preferred, “lower-10-bonyl, carboxyl or mono (lower-alkyl) -carbamoyl, and alkenyl” means alkenyl groups which contain up to 6 carbon-salts thereof.

contain atoms, e.g. Vinyl, allyl and butenyl, lower alkene. Examples of polyenes obtainable according to the invention are

noxy »means alkenoxy groups which have up to 6 carbon genes:

contain atoms, e.g. B. vinyloxy and allyloxy, «lower alkanoy-3,7-dimethyl-9- (3-thienyl) -2,4,6,8-nonatetraenoic acid-ethyl-

loxy »means alkanoyloxy groups containing up to 6 carbon 15 esters;

contain atoms, e.g. B. acetoxy, propionyloxy, butyryloxy and 3,7-dimethyl-9- (3-methyl-2-thienyl) -2,4,6,8-nonatetraen

the like. acid ethyl ester;

The alkanoyl part of the lower alkanoylamido and lower 3,7-dimethyl-9- (5-methyl-2-thienyl) -2,4,6,8-nonatetraen

Alkanoyl groups derive from lower alkane carboxylic acids - ethyl ester;

with up to 6 carbon atoms, e.g. B. acetic acid, propion-20 3,7-dimethyl-9- (3-methyl-5-methoxy-2-thienyl) -2,4,6,8-nona acid, pivalic acid and the like. The expression «ethyl aroyloxetetraenoate;

methyl »means aroyloxymethyl groups in which the aroyl-3,7-dimethyl-9- (3-methyl-5-nitro-2-thienyl) -2,4,6,8-nonatetra part of an aromatic carboxylic acid residue with 7 to 11 carbonic acid ethyl ester;

lenstoffatomen is derived, for. B. benzoic acid, tolyl-, xylyl-3,7-dimethyl-9- (2,5-dimethyl-3-thienyl) -2,4,6,8-nonatetraen

carboxylic acid and the like, preferred are ethyl benzoyloxyme;

thyl and tolyloxymethyl. 3,7-dimethyl-9- (2,4-dimethyl-3-thienyl) -2,4,6,8-nonatetraen

The terms "alkoxymethyl" and "alkoxycarbonyl" acid ethyl ester;

include straight or branched chain alkoxy groups 3,7-dimethyl-9- {2,4-dimethyl-5-methoxy-3-thienyl) -2,4,6,8-

with up to 20 carbon atoms, e.g. B. methoxy, ethoxy, isononatetraenoic acid ethyl ester;

propoxy or cetyloxy. However, alkoxy 30 3,7-dimethyl-9- (2,4-dimethyl-5-methoxymethyl-3-thienyl) groups which contain up to 6 carbon atoms are preferred. This Alko-2,4,6,8-nonatetraenoic acid ethyl ester;

xy groups can be unsubstituted or by functional 3,7-dimethyl-9- {2,4-dimethyl-5- (l-methoxyethyl) -3-thienyl) -

Groups, e.g. B. by nitrogen-containing groups, substituted 2,4,6,8-nonatetraenoic acid ethyl ester;

be, e.g. B. by substituted or alkyl-substituted amino-3,7-dimethyl-9- (2,4-dimethyl-5- (methylthio) -3-thienyl) -2,4,6,8-

or morpholino groups, or by an ethyl piperidyl or pyrin 35 nonatetraenate;

dyl group. The terms «alkenoxycarbonyl» and «alkino-3,7-dimethyl-9- {2,4-dimethyl-5-acetyl-3-thienyl) -2,4,6,8-nona-

xycarbonyl »include alkenoxy and alkynoxy groups with bis-tetraenoic acid ethyl ester;

to 6 carbon atoms, e.g. B. allyloxy or propargyloxy. The 3,7-dimethyl-9- {2,4-dimethyI-5-dimethylamino-3-thienyI) alkanoyloxy groups in the alkanoyloxymethyl groups conduct ethyl 2,4,6,8-nonatetraenoate;

from alkane carboxylic acids with 1 to 20 carbon atoms 40 3,7-dimethyl-9- (2,4-dimethyl-5-chloro-3-thienyl) -2,4,6,8-nona-ab, e.g. B. acetic acid, propionic acid, pivalic acid, palmitic acid tetraenoic acid ethyl ester;

or stearic acid, the preferred group of alkane carbon-3,7-dimethyl-9- (2,4-diethyl-5-methyl-3-thienyl) -2,4,6,8-nona-

Acids, however, is that of the lower alkane carboxylic acids, the 1 to ethyl tetraenoate;

Contain 6 carbon atoms. The carbamoyl group in Rah-3,7-dimethyl-9- (2,4-diethoxycarbonyl-5-acetylamino-3-thie

The invention may be monosubstituted or disubstituted 45 nyl) -2,4,6,8-nonatetraenoic acid ethyl ester;

by straight-chain or branched-chain never-3,7-dimethyl-9- (3,4,5-trimethyl-2-thienyl) -2,4,6,8-nonatetra-

their alkyl groups, e.g. As methyl, ethyl or isopropyl. Ethyl benzenate;

Examples of such substituted carbamoyl groups are the Me- 3,7-dimethyl-9- (2,4,5-trimethyl-3-thienyl) -2,4,6,8-nonatetra-

ethyl carbamoyl, dimethyl carbamoyl and diethyl carbamoylenic acid ester;

groups. The terms "N-heterocyclyl" and "nitrogen-containing 50 3,7-dimethyl-9- (2,4,5-trimethyl-3-thienyl) -2,4,6,8-nonatetrager heterocycle" include 5-membered and 6-membered heteroensic acid;

cyclic groups, in addition to nitrogen, a second stick- 3,7-dimethyl-9- (2,4,5-trimethyl-3-thienyl) -l-methoxy-2,4,6,8-atom, oxygen or sulfur can contain. Under nonatetraen;

the heterocyclic rings are those of piperidine, morpho-3,7-dimethyl-9- (2,4,5-trimethyl-3-thienyl) -2,4,6,8-nonate-

Lins, Thiomorpholins and Pyrrolidins preferred. 55 traen-l-al;

Polyene compounds with anti-tumor effects are 3,7-dimethyl-9- (2,5-dichloro-3-thienyl) -2,4,6,8-nonatetraen

known from German Offenlegungsschrift 24 14 619. This acid ethyl ester;

known polyene compounds differ from the 3,7-dimethyl-9- (2l5-dichloro-4-methyl-3-thienyl) -2,4,6,8-nona-

Compounds obtainable according to the invention structurally tetraenoic acid ethyl ester;

in that they contain a phenyl radical instead of the thienyl radical. 60 3,7-Dimethyl-9- {2,4-dichloro-5-methyl-3-thienyl) -2,4,6,8-nona. ethyl tetraenoate;

Compounds preferred in the context of the formula I are the 3,7-dimethyl-9- (5-bromo-2-thienyl) -2,4,6,8-nonatetraenoic acid of the formula ethyl ester;

p £ n 3,7-dimethyl-9- (3,4-dibromo-2-thienyl) -2,4,6,8-nonatetraen

v '65 acid ethyl ester;

3,7-dimethyl-9- (3,4-dibromo-5-methyl-2-thienyl) -2,4,6,8-nona-o // a Ia ethyl tetraenoate;

^ 3,7-Dimethyl-9- (3,4,5-tribromo-2-thienyl) -2,4,6,8-nonatetraen-0 acid ethyl ester.

628341

4th

The polyenes of formula 1 obtainable according to the invention are non-toxic and pharmaceutically valuable pharmacodynamically. They are effective when acceptable.

Decrease in tumor growth, e.g. B. in papillomas. For local administration, the inventive

The toxicity of the compounds according to the invention is expediently low in the form of sal compounds. For example, all-trans-3,7-dimethyl-9- (2,4,5-trisben, tinctures, creams, solutions, lotions, sprays and methyl-3-thienyl) -2,4,6,8 -Nonatetraensäure-ethyl ester mice suspensions and the like. Ointments, creams and with 30 g weight in a daily dose of 100 mg / kg intraperi solutions are preferred. These pharmaceutical preparations, administered tonally, show no signs of hyper- for topical use can be mixed by mixing an invented vitamin-A after 14 days (total 10 days of the active compound as an active ingredient with pharmaceutical

chung). io pharmaceutically acceptable, non-toxic, inert, solid or

The first signs of hypervitaminosis A in mice liquid carriers, which are customary for such preparations and are suitable for local application at a daily dose of 200 mg / kg after 14 days on administration, are produced (total of 10 days administration). This is shown in a recipe for topical application for the

Weight loss and moderate hair loss and use contain the following amounts of active compounds

a slight skin flaking. Weight-based manure: About 0.01 to about 0.3%, preferred

The tumor inhibitory activity of the compounds of about 0.02 to about 0.1%, in solutions and about 0.05 to about 5%, Formula I is considerable. The papilloma test preferably forms about 0.1 to about 2% in ointments or creams. Dimethylbenzanthracene and croton oil-induced tumors A conventional pharmaceutically acceptable antioxidant

back. The diameter of the papilloma increases within dans, e.g. B. tocopherol, N-methyl-y-tocopheramine, butylated two weeks after the intraperitoneal administration of 20 hydroxyanisole or butylated hydroxytoluene can also in all-trans-3,7-dimethyl-9- (2,4,5-trimethyl-3 -thienyl) -2,4,6,8-nonate- the ethyl phartraenate containing the compounds according to the invention are incorporated into pharmaceutical preparations at a dose of 400 mg / kg / week.

79% and at a dose of 100 mg / kg / week by 60%. The compounds of formula I can be used as salts with pharmaceutical

The compounds of formula 1 can be used as pharmaceuticals in pharmaceutically acceptable acids and bases or in the form of pharmaceutical preparations which they can be used in 25 den. The salts can be obtained by reacting a carboxylic acid of the compound with a compatible carrier material. Formula I in a conventional manner with a base, e.g. B. Alkali

Pharmaceutical preparations for systemic use metal hydroxides, such as. As sodium or potassium hydroxide, z. B. be prepared in that a compound or an amine of formula I with an organic or of formula 1 as an active ingredient pharmaceutically acceptable inorganic acid, for. B. hydrohalic acid, such as. B. ren, non-toxic, inert, solid or liquid carriers, the 30 hydrochloric or hydrobromic acid, or benzoic acid, are common for such preparations, is added. The pharmaceutical acetic acid, citric acid or lactic acid can be produced, generic preparations can be administered locally, enterally or parenterally. According to the method according to the invention, they will be administered. Suitable preparations for enteral administration- polyenes of the formula I by reacting a compound of the chung are, for. B. tablets, capsules, dragees, syrups, suspensions- general formulas, solutions and suppositories. Suitable pharmaceutical preparations for parenteral administration are infusion solutions.

The dosages at which the compounds are administered can be varied according to the route and route of administration and depending on the requirements of the patient. For example, the compounds can be administered in amounts of 5 to 200 mg daily in one or more doses. Capsules containing from about 10 to about 100 mg of the active compound are a preferred form of administration. 45

In addition to the active compounds according to the invention, the pharmaceutical preparations can contain pharmaceutically wherein one of the groups Rs or R7 contains acceptable inert or pharmacodynamically active additives. Tablets or granules e.g. For example, a number of pharmaceutically acceptable binders, fillers, carriers, or thinners may be included. Liquid preparations can e.g. B. have the form of sterile, water-miscible solutions. Capsules can contain a pharmaceutically acceptable filler or thickener. Further, pharmaceutically acceptable flavor-enhancing additives 55 and pharmaceutically acceptable substances commonly used as preservatives, stabilizers, and the other of the groups Rs or R? and R3 and R4 water-moisturizing agents or emulsifiers, salts to the substance, lower alkoxy-lower alkyl, hydroxymethyl, halogen, never changing the osmotic pressure, buffers and other phar-alkyl, lower alkoxy -Alkylthio, carboxyl, amino, pharmaceutically acceptable additives also in the pharmaceutical- 60 mono (lower alkyl) amino, di (lower alkyl) amino, mono (lower preparations. Alkyl) amino lower alkyl, di (lower -alkyl) amino-lower-alkyl,

The aforementioned pharmaceutically acceptable hydroxy, lower alkenyl, lower alkenoxy, lower alkanoyl,

Carrier materials and diluents are well known in the art - lower alkanoyloxy, nitro, lower alkoxycarbonyl, lower and can be organic or inorganic alkanoylamido or a nitrogen-containing heterocycle; m 0 be substances, such as. B. water, gelatin, lactose, starch, 65 or 1, A oxo, -P (X> 3 + Y ~ or -P — 0 (Z> 2, X aryl, Z low-magnesium stearate, talc, gum arabic, polyalkylene glycol, Alkoxy and Y is an anion of an organic acid or a kole, etc. It is of course a prerequisite that inorganic acid is with a compound of the general formula used in the manufacture of pharmaceutical preparations

II

5

628341

Aryl and Y is an anion of an organic or inorganic acid, and the formula

III

wherein B is oxo when A of the compound of formula II is -P (X> 3 + y "or -P-0 (Z) î, or when A is oxo, B is -P (X) 3 + y ~ or- P is 0 (Z) 2, n is 0 or 1 and X, Y and Z are as in Formula 11, and when B is -P (X) 3 + y_ or -P- ~ 0 (Z) 2, Rs' Formyl, carboxyl, lower alkoxycarbonyl, lower alkenoxycarbonyl, lower alkyneoxycarbonyl is di (lower alkyl) carbamoyl or 15N-heterocyclylcarbonyl and when B is oxo, Rs' carboxyl, lower alkoxymethyl, lower alkanoyloxymethyl, lower alkoxycarbonyl, is lower alkenyloxycarbonyl, lower alkynyloxycarbonyl or N-heterocyclylcarbonyl.

In formulas II and III the sum of m and n is always 1.20

The “aryl” group denoted by X includes all generally known aryl groups; mononuclear aryl groups, such as B. phenyl, lower alkyl-substituted phenyl or lower alkoxy-substituted phenyl, e.g. B. xylyl, mesityl and p-methoxyphenyl. The inorganic acid anions denoted by Y are preferably chloride, bromide, iodide and hydrogen sulfate. The preferred organic acid anion labeled Y is tosyloxy.

The reaction products of the compounds of the formula II and III which contain carboxyl on Rs' can be esterified or amidated on the carboxyl group. If Rs' is an ester group, the reaction product can be saponified or amidated on the ester group. If Rs' is a carboxyl or an ester group, the reaction product can be reduced to a hydroxymethyl group at this point. The 35 R5'-hydroxymethyl group can be esterified or etherified. The alcohol ester obtained can, if desired, be saponified. In the cases where Rs 'is a free hydroxymethyl group or its ester, such groups can be oxidized to the corresponding compound in which Rs' is formyl or carboxyl.

The compounds of formula II are partly new.

Certain new compounds that fall under Formula II

are those of the formula

IIb in which one of the groups R "ó or R"?

CH-

CKp-P (Z) p 0

and the other of the groups R "6 or R" 7 and R3 and R4 is hydrogen, lower alkoxy-lower alkyl, hydroxymethyl, halogen, lower alkyl, lower alkoxy, lower alkylthio, carboxyl, amino, mono (lower -alkyl) amino, di (lower alkyl) amino, mono (lower alkyl) amino lower alkyl, di (lower alkyl) amino lower alkyl, hydroxy, lower alkenyl, lower alkenoxy, lower alkanoyl, lower Alkanoyloxy, nitro, lower alkoxycarbonyl, lower alkanoylamido or a nitrogen-containing heterocycle and Z is lower alkoxy.

In addition, some of the compounds in which one of the groups R '6 or R' 7 -CH2-P (X) 3 + y ~ or one of the groups R "6 or R" 7 -CH2-P-0 (Z> 2 is new.

The compounds of formula II in which Rs or R7 is -CH2-P (X) + 3y ~ or -CH2-P ^ O (Z) 2 can be treated by treating the appropriately substituted thiophene with formaldehyde in the presence of a hydrohalic acid, e.g. B. concentrated hydrochloric acid, in a solvent such as. B. glacial acetic acid, if desired, to form the halide. The halide is then treated in a conventional manner with a triarylphosphine in a solvent, preferably triphenylphosphine in toluene or benzene, or with a trialkylphosphite, e.g. B. T riäthylphosphit implemented.

The compounds of formula II in which Rs or R7

IIa in which one of the groups R '<, or R' -,

CH2 -? (X) ^ Y

50

or is and the other groups R'e or R'7 and R'3 and R'4 are hydrogen, lower alkoxy-lower alkyl, hydroymethyl, halogen, lower alkyl, lower alkoxy, lower alkylthio, carboxyl, amino , Mono (lower alkyl) amino, di (lower alkyl) amino, mono (never alkyl) amino lower alkyl, di (lower alkyl) amino lower alkyl, hydroxy, lower alkenyl, lower alkenoxy, lower alkanoyl, lower alkanoyloxy, nitro, lower alkoxycarbonyl, lower alkanoylamido or a nitrogen-containing heterocycle, X

+, r ch2 -p (x) 3 Y

CH2 -PCZ) 2 0

is can be prepared by first formylating the corresponding thiophene, e.g. B. in the presence of a Lewis acid. An orthoformic acid ester, formyl chloride, dimethylformamide and N-methyl-60 formanilide can be used as the formylating agent. Particularly suitable Lewis acids are the halides of zinc, aluminum, titanium, tin and iron, e.g. B. zinc chloride, aluminum trichloride, titanium tetrachloride, tin tetrachloride and iron trichloride and the halides of inorganic and organic acids, such as. B. phosphorus-65 oxychloride and methanesulfonyl chloride.

If the formylating agent is in excess, the formylation can be carried out without the addition of another solvent. In general, however, the form

h28 541

preparation in an inert solvent, /. B. in nitrobenzene or chlorinated hydrocarbons, such as. B. methylene chloride. The formylation can be carried out at a temperature between 0 ° C. and the boiling point of the mixture.

A obtained substituted thiophene carboxaldehyde can then be extended in a conventional manner by condensation with acetone in the cold, i. H. about 0 ° C to 30 ° C, in the presence of alkali, e.g. B. dilute aqueous sodium hydroxide solution to lead to a substituted thienyl-but-3-en-2-one, which in the correspondingly substituted thienyl-3-methyl-3-hydroxy-penta-4-en-l-in in conventional Way can be transferred, e.g. B. using a Grignard reaction by adding acetylene. The resulting acetylenic carbinol can then be processed in a conventional manner using a partially deactivated noble metal catalyst, e.g. B. a Lindlar catalyst, are partially hydrogenated. The tertiary ethylenic carbinol obtained can alternatively be synthesized by adding a vinyl magnesium halide to a substituted thienyl-but-3-en-2-one.

The resulting tertiary ethylenic carbinol can then be converted into the desired phosphonium salt with allyl rearrangement.

The compounds of formula II in which Rs or R-

CH

—-C «2

-P (X) 3 + y ~, can by treating the tertiary ethylenic carbinol with a triarylphosphine, preferably triphenylphosphine, in the presence of a hydrogen halide, such as. B. hydrogen chloride or hydrogen bromide, in a solvent, e.g. B. benzene. The tertiary ethylenic carbinol can also be halogenated to the compound of formula II, in which m 1 and A is a halide. This halide can be treated with a trialkyl phosphite, e.g. B.Triäthylpho-sphit, to be converted into a corresponding phosphonate of the formula II in which Rs or R-

2 V 2

0

is.

Compounds of formula II in which m is 0 and A is oxo can, for. B. by formylating a substituted thiophene, as described above, to the corresponding thiophene-carboxalde-hyd.

Compounds of formula II, in which m is 1 and A is oxo, z. Example, be prepared by subjecting a substituted thienyl-but-3-en-2-one, as described above, to a Wittig reaction with ethoxycarbonylmethylene triphenylphosphorane or with diethyl ethyl phosphonoacetic acid. The resulting substituted thienyl-3-methyl-penta-2,4-diene-1-carboxylic acid ethyl ester is then cold with a mixed metal hydride, e.g. B. lithium aluminum hydride, in an organic solvent, such as. As diethyl ether or tetrahydrofuran, reduced to a substituted thienyl-3-methyl-penta-2,4-dien-l-ol. The dienol is then treated with an oxidizing agent, such as. B. manganese dioxide, in an organic solvent, e.g. As acetone or methylene chloride, oxidized at a temperature between 0 ° C and the boiling point of the mixture to the correspondingly substituted thienyl-3-methyl-penta-2,4-diene-l-al.

The compounds of formula III are prepared as follows:

The compounds of the formula III, in which n is zero and B is a triarylphosphonium group or a dialkoxyphosphinyl group, can easily be reacted with an optionally esterified 3-halomethylcrotonic acid or an etherified 3-halomethylcrotyl alcohol with a triarylphosphine in a solvent, preferably with triphenylphosphine in toluene or benzene, or with a trialkylphosphite, such as. B. triethyl phosphite. .

Compounds of formula III, in which 1 and B is a triarylphosphonium group or a dialkoxyphosphinyl group, z. B. by reducing the formyl group of the corresponding aldehyde, wherein n is 1, to the hydroxymethyl group with a metal hydride, such as. B. sodium boranate, in an alkanol, e.g. B. ethanol or isopropanol.

The alcohol obtained can be prepared using a conventional halogenating agent, e.g. As phosphorus oxychloride, are halogenated, and the resulting 8-halogen-3,7-dimethyl-octa-2,4,6-triene-l-carboxylic acid ester, a halide of the formula III, in which n 1 and B is halogen, or a derivative thereof can either be reacted with a triarylphosphine in a solvent, preferably triphenylphosphine in toluene or benzene, to give a phosphonium salt or with a trialkylphosphite, preferably triethylphosphite, to give the corresponding phosphonate.

Compounds of formula III, in which n is zero and B is an oxo group, z. B. by oxidative cleavage of an optionally esterified tartaric acid, for example using lead tetraacetate at room temperature in an organic solvent, such as. B. benzene. The glyoxalic acid derivative obtained is then processed in a conventional manner, e.g. B. conveniently in the presence of an amine, with propionaldehyde at elevated temperature, e.g. B. condensed at a temperature between 60 ° C and 110 ° C with elimination of water to the corresponding 3-FormyI-crotonic acid derivative.

Compounds of formula III, in which n 1 and B is an oxo group, z. B. by reacting 4,4-dimethoxy-3-methyl-but-l-en-3-ol with phosgene in the cold, preferably at minus 10 ° C to minus 20 ° C, in the presence of a tertiary amine, such as . B. pyridine and condensing the resulting 2-formyl-4-chloro-but-2-ene, a halide of the formula III, in which B is halogen and n is 0, under the conditions of a Wittig reaction with an optionally esterified 3-formyl Cro-Tonic acid or an optionally esterified or etherified 3-formyl-crotyl alcohol to produce the corresponding aldehyde of the formula III.

The reaction of aldehydes of the formula II with phosphonium salts or phosphoranes of the formula III or of aldehydes of the formula III with phosphonium salts or phosphorans of the formula II to give compounds of the formula I can, for. B. either according to the Wittig or Horner technique.

After the Wittig reaction, the reaction components in the presence of an acid-binding agent, for. B. in the presence of an alkali metal alcoholate, such as. B. sodium methylate, or in the presence of an optionally alkyl-substituted alkylene oxide, preferably in the presence of ethylene oxide or 1,2-butylene oxide. If desired,

can be a solvent, e.g. B. a chlorinated hydrocarbon, such as. As methylene chloride or dimethylformamide can be used. The reaction takes place at a temperature between room temperature and the boiling point of the reaction mixture.

According to the Horner process, the reaction components with the aid of a base and preferably in the presence of an inert organic solvent, for. B. with the help of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofo-ran, dioxane or 1,2-dimethoxyethane, or with the help of a

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

628341

Alkali metal alcoholate in an alkanol, e.g. B. sodium methylate in methanol, at a temperature between 0 ° C and the boiling point of the reaction mixture.

In some cases, the reactions described above can conveniently be carried out without isolating the phosphonium salt or the phosphonate from the reaction medium.

A carboxylic acid of formula I can be prepared in a conventional manner e.g. B. by treatment with thionyl chloride, preferably in pyridine, can be converted into an acid chloride, which can be converted into an amide by treating with ammonia or with an amine and by reaction with an alkanol into an ester.

A carboxylic acid ester of formula I can be hydrolyzed in a conventional manner, e.g. B. by treatment with alkali, is preferably aqueous-alcoholic sodium hydroxide or potassium hydroxide, at a temperature between room temperature and the boiling point of the mixture, and then either amidated via an acid halide or, as described below. 20th

A carboxylic acid ester of formula I can directly in the corresponding amide, for. B. be transferred by treatment with lithium amide. The lithium amide is preferably treated with the ester at room temperature.

A carboxylic acid or a carboxylic acid ester of the formula I 25 can be reduced to the corresponding alcohol of the formula I in a conventional manner. The reduction is preferably carried out using a metal hydride or an alkyl metal hydride in an inert solvent. The preferred hydrides are the mixed metal hydrides, such as 30 z. B. lithium aluminum hydride or bis (methoxyethyleneoxy) sodium aluminum hydride. Suitable solvents include a. Ether, tetrahydrofuran or dioxane if lithium aluminum hydride is used, and ether, hexane, benzene or toluene if diisobutyl aluminum hydride or bis (methoxyethy- 35 lenoxy) sodium aluminum hydride is used.

An alcohol of formula I can with an alkyl halide, e.g. B. ethyl iodide, in the presence of a base, preferably sodium hydride, in an organic solvent, e.g. B. dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethylformamide, at a temperature between 0 ° C and room temperature.

An alcohol of formula I can also be treated by treatment with an alkanoyl halide or an anhydride, advantageously in the presence of a base, e.g. As pyridine or triethyl amine, at a temperature between room temperature and the boiling point of the mixture, are esterified.

An alcohol ester can be prepared in a conventional manner, e.g. B. after the method previously described in connection with the hydrolysis of a carboxylic acid ester. 50

An alcohol of formula I or its ester can be oxidized in a conventional manner to the corresponding acid of formula I. The oxidation is advantageously carried out with silver (I) oxide and alkali in water or in an organic, water-miscible solvent at a temperature 55 between room temperature and the boiling point of the mixture.

An amine of formula I forms addition salts with inorganic and organic acids. Examples of such salts are those which are combined with hydrohalic acids, preferably hydrochloric acid or hydrobromic acid, with other mineral acids, e.g. B. sulfuric acid, and with organic carboxylic acids, e.g. As benzoic acid, acetic acid, citric acid or lactic acid arise.

A carboxylic acid of formula I forms salts with bases, 65 preferably with alkali metal hydroxides, e.g. As sodium hydroxide or potassium hydroxide.

The compounds of the formula I can occur as cis / trans mixtures which, if desired, can be separated into the ice and trans components or can be isomerized to the all-trans compounds in a conventional manner.

The following examples illustrate the invention. In the examples, the ether used was diethyl ether. Concentrated hydrochloric acid also refers to an aqueous solution containing about 37% by weight of hydrochloric acid. The term 35% formaldehyde that occurs in the examples refers to an aqueous solution containing 35% formaldehyde.

The sodium hydride used in the examples (50 to 60%) relates to a mineral oil suspension which contains 30 to 60 percent by weight sodium hydride.

example 1

All-trans-3,7-dimethyl-9- (2,4,5-trimethyl-3-thienyl) -2,4,6,8-nona-tetraenoic acid ethyl ester

10 g (2,4,5-trimethyl-3-thenyl) triphenylphosphonium chloride were suspended in 200 ml of butylene oxide, then 5.2 g of ethyl 3-methyl-7-formyl-octa-2,4,6-trienate were added. The resulting mixture was refluxed with argon and stirring until a clear solution was formed. After heating for a further 15 min, the solvent was evaporated. The oily residue was diluted with about 300 ml of a methanol / water mixture (ratio 6: 4) and extracted four times with hexane. The combined hexane solutions were washed once with methanol / water (6: 4) and twice with pure water, dried with sodium sulfate, filtered and concentrated. The crude product obtained was purified by column chromatography (hexane / ether 95: 5) and from hexane / ether (4: 1> to all-trans-3,7-dimethyl-9- (2,4,5-trimethyl-3-thienyl) -2,4,6,8-nonatetra-enoic acid ethyl ester, mp. 88-89 ° C, recrystallized.

The starting material used in Example 1 (2,4,5-tri-methyl-3-thenyl) triphenylphosphonium chloride can, for. B. can be produced as follows:

a) Production of

2,4,5-trimethyl-3-chloromethylthiophene

24.6 g of 2,3,5-trimethyl-thiophene, 14.8 g of freshly distilled chloromethyl methyl ether and 52 g of glacial acetic acid were brought together in a glass pressure bottle and stirred at room temperature for 4.5 hours. The reaction mixture obtained was poured into ice water, stirred for 10 min and extracted with benzene. The combined benzene extracts were washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The 2,4,5-trimethyl-3-chloromethyl-thiophene obtained was used for the next step without further purification.

b) production of

(2,4,5-Trimethyl-3-thenyl) triphenylphosphonium chloride

33.2 g of 2,4,5-trimethyl-3-chloromethyl-thiophene and 55.0 g of triphenylphosphine were dissolved in 200 ml of benzene. The resulting mixture was refluxed under argon overnight and then cooled to room temperature. The deposited white phosphonium salt that had formed was collected by filtration, washed several times with cold benzene and dried at 80 ° C. under high vacuum and gave (2,4,5-trimethyl-3-thenyl) triphenylphosphonium chloride with a mp of 236 up to 237 ° C.

Example 2

3,7-Dimethyl-9- (2,4,5-trimethyl-3-thienyl) -2,4,6,8-nonatetraenic acid ethyl ester

1.9 g of 2,4,5-trimethyl-3-thiophenecarboxaldehyde and 6.75 g (7-ethoxycarbonyl-2,6-dimethyl-2,4,6-heptatrienyl) triphenyl-phosphonium bromide are dissolved in 50 ml of dry dimethyl -

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formamide dissolved. The solution is treated dropwise at 10 ° C. with a solution of 0.29 g sodium in 8 ml ethanol. The mixture is then stirred for 4 hours at room temperature, then in 100 ml of methanol / water (60:40 parts by volume)

brought and extracted thoroughly with hexane. The Hexanex 5 tract is washed with methanol / water (60:40 parts by volume), then with water, dried over sodium sulfate and concentrated. 3.7-Dimethyl-9- (2,4,5-trimethyl-3-thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester is obtained, which melts at 88 to 89 ° C. after recrystallization from hexane . 10th

The (7-ethoxycarbonyl-2,6-dimethyl-2,4,6-heptatrienyl) triphenylphosphonium bromide used as the reacting compound in Example 2 can be prepared, for example, as follows:

15

a) Production of

8-Hydroxy-3,7-dimethyl-octa-2,4,6-triene-l-acidic acid ethyl ester

36 g of 7-formyl-3-methyl-octa-2,4,6-triene-l-acidic acid ethyl ester are dissolved in 600 ml of absolute ethanol. The solution is treated in portions with 1.8 g of sodium atrium boranate. The 20th

The mixture is stirred at 10 ° C. for 2 h, then poured onto ice water and 3 N aqueous hydrochloric acid and extracted with ether. The ether extract is washed successively with water, a saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate and concentrated. 8-Hydroxy-3,7-dimethyl-octa-2,4,6-triene-l-acidic acid ethyl ester is obtained.

b) production of

8-bromo-3,7-dimethyl-octa-2,4,6-triene-l-acidic acid ethyl ester 30

36.5 g of ethyl 8-hydroxy-3,7-dimethyl-octa-2,4,6-triene-1-acid are dissolved in 380 ml of ether. The solution is cooled to 0 = C and, after adding 3 drops of pyridine, treated dropwise with 28.6 g of phosphorus tribromide in 120 ml of hexane. The mixture is stirred at 0 ° C. for 20 min, then poured onto ice water 35 and extracted with ether. The ether extract is washed successively with water, a saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate and concentrated. 8-Bromo-3,7-dimethyl-octa-2,4,6-triene-l-acidic acid ethyl ester is obtained. 40

e) Preparation of l-ethoxy-carbonyl-2,6-dimethyl-hepta-l, 3,5-trien-7-yl-triphenyl-phosphonium bromide

43.7 g of ethyl 8-bromo-3,7-dimethyl-octa-2,4,6-triene-l-45 are dissolved in 500 ml of benzene and treated with 42.0 g of triphenylphosphine. The mixture is stirred at room temperature for 12 h, then cooled to 0 ° C. The precipitated 1-ethoxy-carbonyl-2,6-dimethyl-hepta-l, 3,5-trien-7-yl-triphenylphosphonium bromide melts at 193 to 194 ° C. 50

Example 3

3,7-Dimethyl-9- (2,4,5-trimethyl-3-thienyl) -2,4,6,8-nonatetraenoic acid, ethyl ester

1.7 g8- (diethoxyphosphinyl) -3,7-dimethyl-octa-2,4,6-triene-55 acid ethyl ester are introduced into 8.0 ml of tetrahydrofuran. After adding 0.27 g of sodium hydride (50 to 60%), the solution is cooled to 0 ° C., then stirred at 0 ° C. for 30 minutes, and a solution of 1.0 g of 2,4,5-trimethyl- 3-thiophenecarboxaledehyde in 5 ml of tetrahydrofuran was added dropwise over 15 min. The to reaction mixture is stirred at room temperature for 7 h, then poured onto ice water and, after adding 2N hydrochloric acid, extracted with diethyl ether. The ether extract is washed neutral with water, dried over sodium sulfate and concentrated under reduced pressure. The remaining 3,7-dimethyl65-9- (2,4,5-trimethyl-3-thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester is recrystallized from hexane, mp. 88 to 89 ° C. Instead of the sodium hydride used above (0.27 g), an alkali metal alcoholate, e.g. B. sodium ethylate (0.125 g of sodium in 5 ml of ethanol) can be used.

The 8- (diethoxyphosphinyl) -3,7-dimethyl-octa-2,4,6-trienoic acid ethyl ester used as the reaction component in Example 3 can e.g. B. can be produced as follows:

A) Preparation of 3-formyl-crotonic acid butyl ester

Aa) Preparation of butyl glyoxalate

1775 g of lead tetraacetate (90%) are gradually within 30 min. at 25 to 30 ° C in a solution of 1000 g of L (+) tartaric acid dibutyl ester in 3850 ml of benzene. The reaction mixture is then stirred at room temperature for 1 h. The sediment is filtered off and extracted with 500 ml of benzene. The benzene extract is concentrated under reduced pressure. The remaining butyl glyoxalate boils after rectification at 50 to 65 ° C / 12 mm Hg.

Ab) Preparation of 3-formyl-crotonic acid butyl ester 836 g of the glyoxalic acid butyl ester obtained are introduced into 376 g of propionaldehyde. The mixture is treated dropwise at 60 ° C with 40.8 g of di-n-butylamine. The reaction temperature should not exceed 105 ° C. The reaction mixture is then stirred at 116 to 111 ° C. for 2 h, cooled and taken up in ether. The diethyl ether extract is washed successively with 500 ml of 1N sulfuric acid, 700 ml of water, 1000 ml of a 5% by weight sodium bicarbonate solution and then with 1000 ml of water, dried over sodium sulfate and concentrated under reduced pressure. The remaining 3-formyl-crotonic acid butyl ester boils after rectification at 93 to 105 ° C / 14 mm Hg.

B) Preparation of 2-formyl-but-2-en-4-yl-triphenylphospho-

nium chloride

Ba) Production of

4,4-dimethoxy-3-methyl-but-1-yn-3-ol

After adding a small amount of iron (III) nitrate, 2700 ml of liquid ammonia were treated with 169.5 g of potassium in portions while stirring and cooling. As soon as the initially blue color has disappeared, i. H. after about 30 to 45 min, an acetylene gas flow of 31 / min is introduced until the dark color of the reaction mixture becomes lighter. Then the gas flow is reduced to 21 / min and the mixture is treated dropwise with a solution of 500 g of methylglyoxal dimethylacetal in 425 ml of absolute diethyl ether. Acetylene is introduced with stirring for an additional hour. The reaction mixture is then treated in portions with 425 g of ammonium chloride, gradually warmed to 30 ° C. in the course of 12 h with evaporation of the ammonia and extracted with 1600 ml of diethyl ether. The ether extract is dried over sodium sulfate and concentrated under reduced pressure. The remaining 4,4-dimethoxy-3-methyl-but-1-yn-3-ol boils after rectification at 33 ° C / 0.03 mm Hg; nD25 = 1.4480.

Bb) Preparation of 4,4-dimethoxy-3-methyl-but-l-en-3-ol

198 g of 4,4-dimethoxy-3-methyl-but-l-in-3-ol are dissolved in 960 ml of high-boiling petroleum ether and, after addition of 19.3 g of 5% palladium catalyst and 19.3 g of quinoline, under normal conditions hydrated. After 33.51 of hydrogen have been taken up, the hydrogenation is ended. The catalyst is filtered off. The filtrate is concentrated under reduced pressure. The remaining 4,4-dimethoxy-3-methyl-but-l-en-3-ol boils after rectification at 70 to 72 ° C / 18 mm Hg.

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Bc) production of

2-formyl-4-chloro-but-2-ene

195 ml of phosgene are introduced into 1570 ml of carbon tetrachloride at minus 10 ° C. After adding 213 g of pyridine, the solution is added dropwise with 327 g of 4,4-dimethoxy-3-methyl-but-l-ene at a temperature of minus 10 to minus 20 ° C.

3-ol treated. The reaction mixture is slowly warmed to 25 ° C. with stirring, stirred for a further 3 h at room temperature, cooled to 15 ° C. and treated with 895 ml of water. The aqueous phase is separated off and discarded. After standing in the cold for 12 hours, the organic phase is treated with 448 ml of 5% by weight aqueous sulfuric acid, stirred for 5 h, then washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residual 2-formyl-4-chloro-but-2-ene boils after rectification at 37 to 40 ° C / l, 8 mm Hg; nD25 = 1.4895.

Bd) Production of

2-formyl-but-2-en-4-yl-triphenylphosphonium chloride

165.7 g of 2-formyl-4-chloro-but-2-ene are dissolved in 840 ml of benzene and treated with 367 g of triphenylphosphine. The reaction mixture is heated to boiling under reflux conditions in a nitrogen atmosphere for 12 h, then cooled to 20 ° C. The precipitated 2-formyl-but-2-en-4-yl-triphenylphosphonium chloride melts after washing with benzene and drying at 250 to 252 ° C.

C) Preparation of ethyl 8- (diethoxyphosphinyl) -3,7-dimethyl-octa-2,4,6-triene-l-acid Ca) Preparation of

7-formyl-3-methyl-octa-2,4,6-triene-l-acidic acid butyl ester

212.6 g of 2-formyl-but-2-en-4-yl-triphenylphosphonium chloride and 95 g of 3-formyl-crotonic acid butyl ester are introduced into 1100 ml of butanol and at 5 ° C. with a solution of 57 g of tri- Treated ethylamine in 60 ml of butanol. The reaction mixture is then stirred at 25 ° C. for 6 h, then cooled and introduced into water and extracted thoroughly with hexane. The hexane phase is first repeated with methanol / water (6: 4 parts by volume), then washed with water, dried over sodium sulfate and filtered. The filtrate is isomerized for 12 hours by shaking with iodine. The iodine is removed by adding sodium thiosulphate. The filtrate is washed again with water, dried and concentrated under reduced pressure. The remaining 7-formyl-3-methyl-octa-2,4,6-triene-l-acidic acid butyl ester boils after rectification at 102 to 105 ° C / 0.09 mm Hg.

Cb) Manufacture of

8- (Diethoxyphosphinyl) -3,7-dimethyl-octa-2,4,6-triene-l-acidic acid ethyl ester

3.03 g of ethyl 8-bromo-3,7-dimethyl-octa-2,4,6-triene-1-acid are slowly heated to 125 ° C. with 1.66 g of triethyl phosphite. The excess bromester is distilled off. The residue is cooled, poured into ice and extracted with diethyl ether and an aqueous solution of sodium hydrogen carbonate, dried and concentrated under reduced pressure. The remaining 8- (diethoxyphosphinyl) -3,7-dimethyl-octa-2,4,6-triene-l-acidic acid ethyl ester is immediately, as described in Example 3, with 2,4,5-trimethyl-3-thiophene -carboxaldehyde treated.

Example 4

All-trans-3,7-dimethyl-9- (3,4,5-trimethyl-2-thienyl) -2,4,6,8-nona-tetraenoic acid ethyl ester

3.2 g (3,4,5-trimethyl-2-thenyl) triphenylphosphonium-bro-mid were suspended in 80 ml of butylene oxide and 1.5 g of 3-methyl-7-formyl-octa-2,4. 6-trienoic acid ethyl ester was added. The resulting mixture was refluxed under argon for 1 h after which the solvent was evaporated. The resulting residue was diluted with a mixture of methanol / water (6: 4) and extracted four times with hexane. The combined hexane solutions were washed once with methanol / water (6: 4) and twice with pure water, dried with sodium sulfate, filtered and concentrated. The resulting crude product was purified by column chromatography on silica gel and by elution with hexane / ether (95: 5). Recrystallization of the all-trans-3,7-dimethyl-9- (3,4,5-trimethyl-2-thienyl) -2,4,6,8-nonatetraenoic acid thus obtained from hexane / ethyl acetate (99: 1) ethyl ester gave yellow crystals, mp. 96 to 98 ° C.

The (3,4,5-trimethyl-2-thienyl) triphenylphosphonium bromide used as the starting material in Example 4 can e.g. B. can be produced as follows:

a) Production of

2-hydroxymethyl-3,4,5-trimethylthiophene

1.9 g of 3,4,5-trimethyl-2-thiophenecarboxaldehyde was dissolved in 20 ml of ethanol. The resulting solution was cooled to 0 to 5 ° C and 125 mg sodium boranate was added in small portions. The reaction mixture obtained was stirred at room temperature for 3 h, poured into ice water, extracted with ethyl acetate, dried with sodium sulfate, filtered and concentrated. The crystalline 2-hydroxymethyl-3,4,5-tri-methyl-thiophene obtained melts at 45 to 48 ° C.

b) production of

(3,4,5-trimethyl-2-thenyl) triphenylphosphonium bromide

2.2 g of 2-hydroxymethyl-3,4,5-trimethylthiophene was dissolved in 25 ml of acetonitrile and 4.6 g of triphenylphosphonium bromide were added. The reaction mixture obtained was heated to 50 ° C. for 3 h. After the solvent had been evaporated off, the residue thus formed was diluted with ethyl acetate, heated briefly and filtered. The crystalline (3,4,5-trimethyl-2-thenyl) triphenylphosphonium bromide obtained was dried at 50 ° C. under high vacuum and melted at 208 to 215 ° C.

Example 5

All-trans-3,7-dimethyl-9- (3-methyl-2-thienyl) -2,4,6,8-nonatetra-enoic acid ethyl ester

Sodium hydride (1.16 g of a 50% suspension in mineral oil) was washed three times with pentane, dried and suspended in 50 ml of dimethylformamide. A suspension of 7.5 g (3-methyl-2-thenyl) triphenylphosphonium umbromide in 25 ml of dimethylformamide was added dropwise at 0 ° C. After stirring for 15 minutes, a solution of 3.74 g of 3-methyl-7-formylocta-2,4,6-trienoic acid ethyl ester in 40 ml of dimethylformamide was added dropwise. After stirring for 2.5 hours at room temperature, the reaction mixture was poured into a methanol / water mixture (ratio 6: 4) and extracted several times with hexane. The combined organic phases were washed once with methanol / water (6: 4), dried over sodium sulfate, filtered and concentrated. The crude product was purified by recrystallization from hexane and gave all-trans-3,7-dimethyl-9- (3-methyl-2-thienyl) -2,4,6,8-nonatetraenoic acid, ethyl ester, mp. 86 bis 87 ° C.

The (3-methyl-2-thenyl) triphenylphosphonium bromide used as starting material in Example 5 can, for. B. can be produced as follows:

a) Production of

(3-methyl-2-thenyl) triphenylphosphonium bromide

4.5 g of 2-hydroxymethyl-3-methylthiophene was dissolved in 90 ml of acetonitrile and 12.3 g of triphenylphosphonium bromide was added. The reaction mixture was heated to 70 ° C for 3 h. After cooling, the precipitate obtained was filtered off, washed with benzene and at 80 ° C. under Hochva5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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vacuum dried. The (3-methyl-2-thenyl) triphenylphosphonium bromide obtained melts at 266 to 269 ° C.

Example 6

All-trans-3,7-dimethyl-9- (5-methyl-2-thienyl) -2,4,6,8-nonatetra- senoic acid ethyl ester

I, 45 g of a 50% suspension of sodium hydride in mineral oil were washed three times with pentane, dried and suspended in 75 ml of dimethylformamide. At 0 ° C a suspension of 10.3 g (5-methyl-2-thienyl) triphenylphos-10 phonium bromide in 50 ml of dimethylformamide was added dropwise. After stirring for 15 minutes, a solution of 6.25 g of 3-methyl-7-formyl-octa-2,4,6-trienoic acid ethyl ester in 50 ml of dimethylformamide was added dropwise. After stirring for 1 hour at room temperature, the reaction mixture was poured into a methanol / water mixture (ratio 6: 4) and extracted several times with hexane. The combined organic phases were washed once with methanol / water (6: 4), dried over sodium sulfate, filtered and concentrated. The crude product was purified by recrystallization from hexane and gave all-20 trans-3,7-dimethyl-9- (5-methyl-2-thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester, mp 92 up to 93 ° C.

The (5-methyl-2-thenyl) triphenylphosphonium bromide used as the starting material in Example 6 can e.g. B. can be produced as follows: 25

a) Production of

(5-methyl-2-thenyl) triphenylphosphonium bromide

4.6 g of 2-hydroxymethyl-5-methylthiophene was dissolved in 100 ml of alcotonitrile, and 12.2 g of triphenylphosphonium bromide 30 were added. The reaction mixture was heated to 75 ° C for 2.5 h. After cooling, the precipitate obtained was filtered off, washed with benzene and dried at 80 ° C. under high vacuum. The (5-methyl-2-thenyl) triphenylphosphonium bromide obtained melts at 262 to 266 ° C. 35

Example 7

All-trans-3,7-dimethyl-9- (2,5-dimethyl-3-thienyl) -2,4,6,8-nonate-traenic acid, ethyl ester

7.0 g (2,5-dimethyl-3-thenyl) triphenylphosphonium chloride 40 were suspended in 200 ml of butylene oxide, and 3.4 g of 3-methyl-7-formyl-octa-2,4,6-trienoic acid ethyl ester were added. The mixture was refluxed under argon for 5.5 hours. The solution obtained was poured into 500 ml of a methanol / water mixture (ratio 6: 4), extracted four times with hexane, washed with 45 methanol / water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by recrystallization from hexane and gave all-trans-3,7-dimethyl-9- (2,5-dimethyl-3-thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester, Mp 119 to 121 ° C. 50

The (2,5-dimethyl-3-thenyl) triphenylphosphonium chloride used as starting material in Example 7 can, for. B. can be produced as follows:

a) Production of ss

(2,5-dimethyl-3-thenyl) triphenylphosphonium chloride

II, 8 g triphenylphosphine and 7.0 g 2,5-dimethyl-3-chloromethyl-thiophene were dissolved in 100 ml toluene. The mixture was refluxed under argon overnight, cooled to room temperature, and the white precipitate of the phosphonium salt was collected by filtration, washed several times with cold benzene and dried at 80 ° C. under high vacuum. The resulting (2,5-dimethyl-3-thenyl) triphenyl phosphonium chloride melts at 246 to 250 ° C.

65

Example 8

All-trans-3,7-dimethyl-9- (2,4-dimethyl-5-chloro-3-thienyl) -2,4,6,8-nonatetraenecarboxylic acid ethyl ester

According to the procedure of Example 9, (2,4-dimethyl-5-chloro-3-thenyl) triphenylphosphonium chloride with 7-formyl-3-methyl-octa-2,4,6-trienoic acid ethyl ester becomes alltrans-3, Condensed ethyl 7-dimethyl-9- (2,4-dimethyl-5-chloro-3-thienyl) -2,4,6,8-nonatetraenoate, which is recrystallized from hexane, mp. 109 to 110 ° C.

The (2,4-dimethyl-5-chloro-3-thenyl) triphenylphosphonium chloride used as the starting material in Example 8 can, for. B. can be produced as follows:

a) Preparation of 2,4-dimethyl-5-chloro-thiophene

2.5 g of 2,4-dimethyl-thiophene are dissolved in 45 ml of methylene chloride and 3.3 g of sulfuryl chloride are added dropwise. The mixture is kept at room temperature for Vi h and then refluxed for 2 h. The reaction mixture is poured into water, extracted with hexane, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Distillation gave 2,4-dimethyl-5-chlorothiophen, b.p. 73 to 75 ° C / 18 mm Hg.

b) production of

2,4-dimethyl-3-chloromethyl-5-chlorothiophene

3.04 g of 2,4-dimethyl-5-chlorothiophene are dissolved in 60 ml of acetic acid, and 2.1 g of formalin and 32 ml of concentrated hydrochloric acid are added. The mixture is stirred at room temperature for 2 h, then poured into ice water and extracted with hexane. The organic solution is washed with 5% sodium bicarbonate solution, dried, filtered and concentrated to give 2,4-dimethyl-3-chloromethyl-5-chlorothiophene.

c) Manufacture of

(2,4-dimethyl-5-chloro-3-thenyl) triphenylphosphonium chloride

2,4-Dimethyl-5-chloro-3-thenyl) triphenylphosphonium chloride can be prepared in a manner analogous to that described in Example 13 by reacting 2,4-dimethyl-3-chloromethyl-5-chlorothiophene with triphenylphosphine, mp .246 to 251 ° C.

Example 9

3,7-Dimethyl-9- (2,5-dichloro-3-thienyl) nona-2,4,6,8-tetraenoic acid ethyl ester

To a (minus 10 ° C) cold suspension of 1.02 g (2 mmol) of crude (2,5-dichloro-3-thenyl) triphenylphosphonium bromide in 20 ml of dry ether was added 0.82 ml (2 mmol) of one 2.45 molar solution of n-butyllithium in hexane slowly added via syringe. After the addition was complete, the mixture was stirred at minus 10 ° C for 10 min. Then a solution of 416 mg (2 mmol) of 3,7-dimethyl-7-formyl-2,4,6-octatrienic acid ethyl ester was added at 0 to 2 ° C. The mixture was allowed to warm slowly to room temperature for 1.5 h and was poured into 25 ml of sodium chloride solution. Some brown solid was filtered off and the organic layer of the filtrate was separated and washed with two 50 ml portions of sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave a yellow solid which was extracted with several 25 ml portions of hexane. The hexane extracts were combined and concentrated to give a yellow solid which was purified chromatographically on 45 g silica gel in hexane with 2% ether. Elution with this solvent mixture gave ethyl 3,7-dimethyl-9- (2,5-dichloro-3-thienyl) -nona-2,4,6,8-tetraenoate.

The (2,5-dichloro-3-thenyl) triphenylphosphonium bromide used as starting material in Example 9 can, for. B. can be produced as follows:

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a) Production of

(2,5-dichloro-3-thenyl) triphenylphosphonium bromide

22 g (90 mmol) of 2,5-dichloro-3-bromomethylthiophene were mixed with 26 g (99 mmol) of triphenylphosphine and 150 ml of benzene. The mixture was refluxed for 2.5 h, cooled and filtered to give (2,5-dichloro-3-thenyl) triphenylphosphonium bromide, mp. 208 to 215 ° C.

Example 10

All-trans-3,7-dimethyl-9- (3,4-dibromo-5-methyl-2-thienyl) -2,4,6,8-io-ethyl nonatetraenoate

According to the procedure of Example 7, (3,4-dibromo-5-methyl-2-thenyl) triphenylphosphonium chloride with 7-formyl-3-methylocta-2,4,6-trienoic acid ethyl ester becomes all-trans-3, 7-DimethyI-9- (3,4-dibromo-5-methyl-2-thienyl) -2,4,6,8- 15 condensed ethyl nonatetraenate, which is recrystallized from hexane / ethyl acetate (1: 1) , Mp 150 to 153 ° C.

The (3,4-dibromo-5-methyl-2-thenyl) triphenylphosphonium bromide used as starting material in Example 10 can, for. B. can be produced as follows: 20

a) Production of

2-chloromethyl-3,4-dibromo-5-methylthiophene

A solution of 11.7 g of 2-methyl-3,4-dibromothiophene in 30 ml of acetic acid was added to 60 ml of concentrated hydrochloric acid. After the dropwise addition of 4.1 g of a 37% strength aqueous solution of formaldehyde, the mixture was heated to 70 ° C. for 1 hour. The reaction mixture was cooled, diluted with water and extracted with ether. The combined organic phases were washed with water, sodium bicarbonate and water, dried over sodium sulfate, filtered and concentrated to 2-chloromethyl-3,4-dibromo-5-methyl-thiophene.

b) production of

3,4-dibromo-5-methyl-2-thenyl) triphenylphosphonium chloride 35

(3,4-Dibromo-5-methyl-2-thenyl) triphenylphosphonium chloride can be prepared analogously to Example 7a) by reacting 2-chloromethyl-3,4-dibromo-5-methylthiophene with triphenylphosphine, mp. 215 to 216 ° C.

40

Example 11

All-trans-3,7-dimethyl-9- (3,4,5-tribromo-2-thienyl> 2,4,6,8-nonate-traenic acid, ethyl ester

Following the procedure of Example 5, (3,4,5-tribromo-2-thenyl) triphenylphosphonium chloride with 7-formyl-3-methyl-45 octa-2,4,6-trienoic acid ethyl ester becomes all-trans-3 , 7-Dimethyl-9- (3,4,5-tribromo-2-thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester, which is recrystallized from hexane / ethyl acetate (95: 5), mp. 84 up to 86 ° C.

The (3,4,5-50 tribromo-2-thenyl) triphenylphosphonium chloride used as starting material in Example 11 can, for. B. can be produced as follows:

a) Production of

(3,4,5-Tribromo-2-thenyl) triphenylphosphonium chloride 55

9.0 g of triphenylphosphine and 10.4 g of 3,4,5-tribromo-2-chloro-methyl-thiophene were dissolved in 200 ml of toluene. The mixture was refluxed overnight under argon, cooled to room temperature, and the excreted phosphonium salt was collected by filtration, washed several times with cold benzene and dried at 80 ° C. under high vacuum. The (3,4,5-tribromo-2-thenyl) triphenylphosphonium chloride obtained melts at 248 to 249 ° C.

Example 12

All-trans-3,7-dimethyl-9- (2,4-dichloro-5-methyl-3-thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester

A suspension of 10.83 g (22.6 mmol) (2,4-dichloro-5-me-

ethyl 3-thenyl) triphenylphosphonium chloride and 5.15 g (24.8 mmol) of 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester in 350 ml of butylene oxide was at 70 ° for 4.5 h C warmed. The resulting clear solution was cooled, poured into 500 ml of a methanol / water mixture (6: 4) and extracted with hexane. The combined hexane extracts were washed with methanol / water (6: 4), dried and concentrated. The raw material obtained was purified by chromatography (silica gel, hexane / ethyl acetate = 4: 1) in order, after recrystallization from hexane, to give all-trans-3,7-dimethyl-9- (2,4-dichloro-5-methyl-3-thienyl) ) -2,4,6,8-nonatetraenoic acid ethyl ester, mp. 99 to 100 ° C, to give.

The (2,4-dichloro-5-methyl-3-thenyl) triphenylphosphonium chloride used as starting material in Example 12 can, for. B. can be produced as follows:

a) Production of

3-chloromethyl-2,4-dichloro-5-methylthiophene

8.6 g (0.107 mol) of formalin and 90 ml of concentrated hydrochloric acid were added to a solution of 10.87 g (0.065 mol)

2-Methyl-3,5-dichlorothiophene in 45 ml acetic acid added. The resulting mixture was heated to 70 ° C for 18 h, cooled, poured into ice water and extracted with ether. The organic solution was washed with water, sodium bicarbonate and water, dried and concentrated to

To give 3-chloromethyl-2,4-dichloro-5-methylthiophene as crude oil.

b) production of

(2,4-dichloro-5-methyl-3-thenyl) triphenylphosphonium chloride

A mixture of 13.1 g (~ 0.061 mol) of crude 3-chloromethyl-2,4-dichloro-5-methylthiophene, 26.2 g (0.10 mol) of triphenylphosphine and 200 ml of toluene were at 100 ° C. for 20 h heated, then cooled to room temperature. The resulting precipitate was collected by filtration, washed with cold benzene and dried at 80 ° C under high vacuum to give (2,4-dichloro-5-methyl-3-thenyi) triphenylphosphonium chloride, mp. 211 to 214 ° C surrender.

Example 13

All-trans-3,7-dimethyl-9- (2,4-diethoxycarbonyl-5-acetylamino-3-thienyl-2,4,6,8-nonatetraenoic acid, ethyl ester

A suspension of 30.0 g (47 mmol) with 11% succinimide) (2,4-diethoxycarbonyl-5-acetylamino-3-thenyi) triphenylphos-phononium bromide and 9.75 g (47 mmol) 7-formyl Ethyl 3-methyl-2,4,6-octatrienate in a mixture of 500 ml of toluene and 100 ml of butylene oxide was refluxed until the solution was clear (3 h). The resulting solution was cooled and the solvent evaporated. The residue obtained was suspended in 600 ml of a methanol / water mixture (ratio 6: 4) and one liter of hexane and stirred for 6 hours. The insoluble material was filtered and heated to boiling with three liters of hexane. The insoluble material was filtered from the cold solution, washed with hexane and purified by chromatography (silica gel, ethyl acetate). Recrystallization of the purer fractions from hexane / 40% ethyl acetate gave all-trans-3,7-dimethyl-9- (2,4-diethoxycarbonyl-5-acetylamino-3-thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester , Mp 159 to 161 ° C.

The (2,4-diethoxycarbonyl-5-acetylamino-3-thenyl) triphenylphosphonium umbromide used as the starting material in Example 13 can e.g. B. can be produced as follows:

a) Production of

2,4-diethoxycarbonyl-3-methyl-5-acetylamino-thiophene

A solution of 23.0 g (0.09 mol) of 2,4-diethoxycarbonyl-3-methyl-5-aminothiophene in 250 ml of acetic anhydride was heated to 100 ° C. for 1.5 hours. The resulting mixture was cooled in an ice bath and the separated crystals were filtered to give 2,4-diethoxycarbonyl

62834t

12

3-methyl-5-acetylamino-thiophene, mp. 130 to 131 ° C, to give.

b) production of

2,4-diethoxycarbonyl-3-bromomethyl-5-acetylamino-thiophene s

10.5 g (59 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added to a solution of 17.5 g (59 mmol) of 2,4-dieth-oxycarbonyl-3-methyl-5-acetylamino-thiophene in 250 ml of carbon tetrachloride added. The resulting mixture was refluxed for 24 hours until all of the solid material floated on the surface. After 1 or 7 hours, 20 mg of benzoyl peroxide were added. Since it proved to be very difficult to separate the product 2,4-dietho-xycarbonyl-3-bromomethyl-5-acetylamino-thiophene and succinimide, the solvent was evaporated off and the crystalline residue was used without further purification.

c) production of

(2,4-diethoxycarbonyl-5-acetylamino-3-thenyl) triphenylphos-20 phonium bromide

22.2 g of crude 2,4-diethoxycarbonyl-3-bromomethyl-5-acetylamino-thiophene, 19.7 g (75 mmol) of triphenylphosphine and 700 ml of toluene were refluxed for 3 hours. The precipitate obtained was filtered off from the hot solution and washed well with toluene to give (2,4-diethoxycarbonyl-5-acetylamino-3-thenyl) triphenylphosphonium bromide, mp. 186 to 195 ° C. The NMR spectrum showed that the material contained 11% succinimide.

30th

Example 14

All-trans-3,7-dimethyl-9- (3-methyl-5-methoxy-2-thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester

A suspension of 5.9 g (13.5 mmol) (3-methyl-5-methoxy-2-thenyl) triphenylphosphonium chloride and 2.81 g 35 (13.5 mmol) 7-formyl-3-methyl Ethyl 2,4,6-octatrienate in 70 ml of butylene oxide and 200 ml of toluene were heated to 100 ° C. for 14 h. The clear solution obtained was cooled, poured into 500 ml of a methanol / water mixture (6: 4) and extracted with hexane. The combined hexane extracts were washed with 10 methanol / water (6: 4), dried and concentrated. The crude, oily material obtained was purified by chromatography (silica gel, hexane / ether, ratio 7: 3) in order, after recrystallization from hexane, to give all-trans-3,7-dimethyl-9- (3-methyl-5-methoxy-2 -thienyl> 2,4,6,8-nonatetraenoic acid ethyl ester, 45 mp. 66 to 72 ° C, to give.

The (3-methyl-5-methoxy-2-thenyl) triphenylphosphonium chloride used as starting material in Example 14 can e.g. B. can be produced as follows:

50

a) Production of

2-hydroxymethyl-3-methyl-5-iodothiophene

6.58 (33 mmoles) of mercury (H) oxide and 7.62 g (30 mmoles) of iodine were alternately added in small amounts to a vigorously stirred solution of 3.84 g (30 mmoles) of 2-hydroxymethyl-3-55 methylthiophene in Given 30 ml of benzene. The reaction was kept at room temperature with cooling in an ice bath. The orange mercury iodide that precipitated was filtered and washed well with benzene. The combined organic solutions were washed with sodium thiosulfate and saturated sodium chloride solution, dried and concentrated to give crude 2-hydroxymethyl-3-methyl-5-iodothiophene as a colorless oil.

b) production of

2-hydroxymethyl-3-methyl-5-methoxythiophene

10.0 g (0.125 mol) copper (II) oxide and 11.0 g (0.0433 mol) 2-hydroxymethyl-3-methyl-5-iodothiophene were added to a solution

65

of 10.0 g (0.435 mol) sodium in 90 ml methanol was added. The reaction mixture obtained was heated to 80 ° C. for 18 h with vigorous stirring. The cold solution was filtered, the filtrate poured into ice water and extracted with ether / hexane (ratio 4: 1). The organic extracts were washed with 10% sodium thiosulfate solution and saturated sodium chloride solution, dried and concentrated to give 2-hydroxymethyl-3-methyl-5-methoxythiophene as a colorless oil.

c) Manufacture of

(3-methyl-5-methoxy-2-thenyl) triphenylphosphonium chloride

21.0 g (80.2 mmol) of triphenylphosphine were added to a solution of 5.8 g (36.7 mmol) of 2-hydroxymethyl-3-methyl-5-methoxy-thiophenin, 60 ml of dry carbon tetrachloride and 80 ml of toluene. The temperature of the reaction mixture was slowly raised to 80 ° C and further heated overnight. The resulting precipitate was filtered off from the cold solution, washed well with cold benzene and dried under high vacuum to give (3-methyl-5-methoxy-2-thenyl) triphenylphosphonium chloride, mp. 180 to 185 ° C.

Example 15

All-trans-3,7-dimethyl-9- (2,4-dimethyl-5-methoxy-3-thienyl-2,4,6,8-nonatetraenoic acid, ethyl ester

A suspension of 11.0 g (22.1 mmol) (2,4-dimethyl-5-methoxy-3-thenyl) triphenylphosphonium bromide and 5.1 g (24.5 mmol) 7-formyl-3-methyl Ethyl 2,4,6-octatrienoate in 450 ml of butylene oxide was heated to 70 ° C. until a clear solution was obtained (about 12 h). The resulting clear solution was cooled, poured into 500 ml of methanol / water (6: 4) and extracted with hexane. The combined hexane extracts were washed with methanol / water (6: 4), dried and concentrated. The resulting raw material was purified by column chromatography (silica gel, hexane / ether = 10: 3) in order, after recrystallization from hexane, to give all-trans-3,7-dimethyl-9- (2,4-dimethyl-5-methoxy-3 -thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester, mp. 81 to 83 ° C, to give.

The (2,4-dimethyl-5-methoxy-3-thenyI> triphenylphosphonium bromide used as starting material in Example 15 can be prepared, for example, as follows:

a) Production of

2,4-dimethylthiophene-3-carboxaldehyde

A solution of 15 g (79.0 mmol) of 2,4-dimethyl-3-bromothiophene in 120 ml of dry ether was cooled to minus 70 ° C., and 36 ml of a hexane solution of n-butyllithium (2.4 molar , 86.4 mmol) were added dropwise. The reaction mixture was then heated to minus 20 ° C. for 10 minutes, whereupon it was cooled again to minus 70 ° C. and then “quenched” by the dropwise addition of 15 g (0.205 mol) of dimethylformamide. The mixture was stirred at room temperature overnight, poured into ice water, stirred for 15 min and extracted four times with ether. The ether phase was washed with saturated sodium chloride solution, dried and concentrated. The resulting oily residue was distilled and gave 2,4-dimethylthiophene-3-carboxaldehyde, b.p. 50 to 55 "CI 0.1 mm Hg.

b) production of

2,4-dimethyl-3-hydroxymethylthiophene

0.68 g (18 mmol) of sodium boranate was added in 3 portions of a solution of 10.08 g (72 mmol) of 2,4-dimethylthiophene-3-carboxaldehyde in 120 ml of ethanol. After 15 min the reaction mixture was poured into water, extracted with ether, dried and the solvent evaporated. The resulting residue was recrystallized from hexane to give 2,4-dimethyl-3-hydroxymethylthiophene, mp. 80 to 81 ° C.

13

628341

c) Manufacture of

2,4-dimethyl-3-hydroxymethyl-5-iodothiophene

10.0 g (46 mmol) of mercury (II) oxide and 14.7 g (58 mmol) of iodine were alternately over a period of 1.25 h to a vigorously stirred solution of 8.2 g (57.7 mmol) 2, 4-Dime-5 thyl-3-hydroxymethylthiophene in 300 ml of benzene. The reaction mixture was kept at room temperature by cooling with an ice bath and stirred for an additional hour. The precipitated mercury iodide was filtered and washed well with warm ethyl ether. The combined organic solutions were washed with 10% sodium thiosulfate and saturated sodium chloride solution, dried and concentrated. The resulting residue was dissolved in a minimal amount of hot ether, an equal amount of hexane was added, and the solution was cooled to minus 50 ° C. The 15 deposited crystals were filtered and washed with cold hexane to give, after drying, 2,4-dimethyl-3-hydroxymethyl-5-iodothiophene with a mp of 118.5 to 120.5 ° C.

20th

d) production of

2,4-dimethyl-3-hydroxymethyl-5-methoxythiophene

12.0 g (0.151 mol) of copper (III) oxide and 12.5 g (0.0466 mol) of 2,4-dimethyl-3-hydroxymethyl-5-iodothiophene were added to a solution of 12.5 g (0.543 mol) of sodium in 100 ml of dry methanol. The reaction mixture was heated to 80 to 82 ° C (internal temperature) with vigorous stirring for 20 h, then cooled. The cold solution was diluted with 150 ml of methanol, filtered, poured into ice water and extracted with ether / hexane (4: 1 ratio). The organic layers were washed with 5% sodium carbonate solution, dried and concentrated. The residue obtained was recrystallized from hexane to give 2,4-dimethyl-3-hydroxymethyl-5-methoxythiophene, melting point 55 to 60 ° C. This product contained about 10% 2,4-dimethyl-3-hydroxymethylthiophene, which is formed in this reaction by reducing the iodide. Fractional recrystallization of a sample from hexane gave pure 2,4-dimethyl-3-hydroxymethyl-5-methoxythiophene, mp. 64 to 65 ° C.

40

e) production of

(2,4-dimethyl-5-methoxy-3-thenyl) triphenylphosphonium bro-mid

6.1 g (35.5 mmol) of 2,4-dimethyl-3-hydroxymethyl-5-methoxythiophene were at 35 ° C. with vigorous stirring to a suspension of 13.4 g (39.0 mmol) of triphenylphosphonium bro-mid in 250 ml of acetonitrile. The deep purple color that forms immediately disappeared after a few minutes. The reaction mixture was stirred for 3 hours. The solvent was concentrated to a volume of about 25 ml and an excess of cold ether was added. The solvent was then decanted from the resulting oily precipitate, which was dissolved in warm acetone and precipitated again by adding cold ether. The solvent was decanted and the resulting oily residue was dried under high vacuum to give 55 µm (2,4-dimethyl-5-methoxy-3-thenyl) triphenylphosphonium bromide.

Example 16

3,7-Dimethyl-9- (2,4-dimethyl-5-methoxymethyl-3-thienyl) -2,4,6,8-eo nonatetraenoic acid ethyl ester

3.6 g of a 50% suspension of sodium hydride in mineral oil were washed once with pentane and suspended in 200 ml of dimethylformamide at 5 ° C. 40.2 g of a solution of triphenyl (7-ethoxycarbonyl-2,6-dimethyl-2,4,6-heptatrien-65 nyl> phosphonium bromide in 75 ml of dimethylformamide were slowly added and stirred for 30 minutes. 12.6 g a solution of 2,4-dimethyl-5-methoxymethyl-thiophene-3-carboxaldehyde in

50 ml of dimethylformamide was then slowly added. The reaction mixture obtained was stirred at 5 ° C. for 10 h, poured into ice water and extracted with hexane. The hexane extracts were combined and washed twice with a methanol / water mixture (ratio 6: 4) and once with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. The raw material was purified by column chromatography on silica gel and eluted with ethyl ether / hexane (1: 3) to give cis-and-trans-3,7-dimethyl-9- (2,4-dimethyl-5-methoxymethyl-3-thienyl) ) To give -2,4,6,8-nonatetraenoic acid ethyl ester.

The 2,4-dimethyl-5-methoxymethyl-thiophene-3-carboxaldehyde used as the starting material in Example 16 can e.g. can be produced as follows:

a) Production of

4-bromo-3,5-dimethylthiophene-2-carboxaldehyde

15.0 g of 2,4-dibromo-3,5-dimethylthiophene were dissolved in 250 ml of anhydrous ether and cooled to minus 70 ° C. with stirring under argon. 24 ml of a 2.4 molar solution of n-butyllithium was slowly added to the solution and the mixture was warmed to minus 35 ° C for 10 minutes and then cooled back to minus 70 ° C. 7.3 g of dimethylformamide was slowly added to the mixture and the reaction mixture was warmed to room temperature for 14 h. The solution obtained was poured into ice water, stirred for 20 min and extracted with ethyl ether. The ether extracts were combined, washed with a 5% aqueous sodium carbonate solution, a saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated to give 4-bromo-3,5-dimethyIthio-phen-2-carboxaldehyde, mp. 44 to 45 ° C. to surrender.

b) production of

4-bromo-3,5-dimethyl-2-hydroxymethylthiophene

11.8 g of 4-bromo-3,5-dimethylthiophene-2-carboxaldehyde were dissolved in 250 ml of dry ethanol and stirred at 20 ° C. 0.52 g of sodium boranate was added and the resulting solution was stirred for 30 minutes, then poured into ice water and extracted with ethyl ether. The combined ether extracts were washed with a 5% sodium carbonate solution and a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Crystallization from cold hexane gave 4-bromo-3,5-dimethyl-2-hydroxymethylthiophene, mp. 85 to 90 ° C.

c) production of

4-bromo-3,5-dimethyl-2-methoxymethylthiophene

2.9 g of a 50% suspension of sodium hydride in a mineral oil were washed once with pentane and suspended in 100 ml of dimethylformamide at 5 ° C. 10.5 g of a solution of 4-bromo-3,5-dimethyl-2-hydroxymethylthiophene in 40 ml of dimethylformamide were slowly added to the suspension and stirred for 30 minutes. 10 g of methyl iodide was added and the resulting mixture was stirred at 20 ° C for 14 h. The reaction mixture was then poured into water and extracted with hexane. The hexane extracts were washed with a 5% sodium carbonate solution and a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to give 4-bromo-3,5-dimethyl-2-methoxymethylthiophene.

d) production of

2,4-DimethyI-5-methoxymethyI-thiophene-3-carboxaldehyde

15.5 g of 4-'bromo-3,5-dimethyl-2-methoxymethylthiophene were dissolved in 200 ml of anhydrous ethyl ether under argon. The resulting solution was cooled to minus 70 ° C and 22 ml of a 2.4 molar solution of n-butyllithium was slowly added. The reaction mixture was at minus 30 ° C for 10 min

628 341 14

warmed and then cooled to minus 70 ° C. 7.3 g of dimethyl [2,4-

Formamide was slowly added and the reaction mixture of dimethyl-5- (methylthio) -3-thenyl] -triphenylphosphonium was warmed to room temperature for 14 h. The mid obtained can e.g. B. can be produced as follows:

The reaction mixture was poured into ice water. Stirred for 15 min and extracted with ethyl ether. The combined ether-) Extracts were washed with a 5% sodium carbonate solution and 3-bromo-2,4-dimethyl-5- (methyithio) thiophene, a saturated sodium chloride solution, over Na-tri-20.0 g of 2,4- Dibromo-3,5-dimethyIthiophene were dried in 300 ml of sulfate, filtered and concentrated to give 2,4-dimethyl-5-anhydrous ethyl ether. The resulting solution was methoxymethyl-thiophene-3-carboxaldehyde to give. cooled to minus 70 ° C while stirring under argon. 32 ml of a 2.4

10 molar solution of n-butyllithium was slowly added and the solution was warmed to minus 32 ° C for 10 min and then Example 17 cooled again to minus 70 ° C. 7.5 g dimethyl disulfide

All-trans-3,7-dimethyl-9- (2,4-dimethyl-3-thienyl) -2,4,6.8-nonate- was added slowly while the temperature was kept at 70 ° C minus ethyl trenate. The solution obtained was

1.35 g of a 50 ° o suspension of sodium hydride heated to u temperature and stirred for 2 h, then poured into ice water - a mineral oil was washed once with hexane and stirred in Sen for 15 min and extracted with ethyl ether. The unified 120 ml of dimethylformamide suspended. At 0 ° C., 12.0 g of ether extracts were washed with water, 5% strength sodium carbonate suspension of (2,4-dimethyl-3-thenyl) triphenylphosphonate and saturated sodium chloride solution, added dropwise over nium bromide in 20 ml of dimethylformamide and sodium sulfate was dried , filtered and concentrated to give 3-bromo

Stirred for 30 min: 5.8 g of a solution of 3-methyl-7-formyl-octa-20 to give 2,4-dimethyl-5- (methylthio) thiophene. Ethyl 2,4,6-trienate in 30 ml of dimethylformamide was then added dropwise. After stirring for 2 hours at 0 ° C., the b) preparation of

Poured reaction mixture in ice water and extracted several times with 2,4-dimethyr-5- (methylthio) thiophene-3-carboxaldehyde hexane. The combined hexane extracts were two - 18.5 g of 3-bromo-2,4-dimethyl-5- (methylthio) thiophene were mixed with a methanol / water mixture (ratio 6: 4), one in 250 ml of anhydrous ethyl ether dissolved and washed to minus 70 ° C times with a saturated sodium chloride solution, cooled with stirring under argon. 34 ml of a 2.4 molar dried over sodium sulfate, filtered and concentrated. The solution of n-butyllithium was slowly added, and the resulting crude product was column chromatographed on solution and heated to minus 25 ° C. for 10 min. The reaction silica gel and mixed by elution with ethyl ether / hexane (1: 4) was cooled again to minus 70 ° C. and 7.3 g was inclined. Recrystallization from hexane gave all-trans-3,7-dimethyl-30 dimethylformamide was slowly added. The reaction 9- (2,4-dimethyl-3-thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester. mixture was stirred at room temperature for 2 h, in ice water mp 69 to 71 ° C. poured, stirred for 15 min and finally extra with ethyl ether

The (2,4-) used as starting material in Example 17. The combined ether extracts were prepared with water, a dimethyl-3-thenyl-triphenylphosphonium bromide can be prepared, for example, like 5% sodium carbonate solution and saturated sodium chloride. 35 washed rid solution, dried over sodium sulfate, filtered and concentrated to give 2,4-dimethyl-5- (methylthio) thiophene-3-car-a) production of boxaldehyde.

(2,4-dimethyl-3-thenyl) triphenylphosphonium bromide

4.4 g of 2,4-dimethyl-3-hydroxymethylthiophene and 10.7 g of tri- c) Preparation of phenylphosphonium bromide were dissolved in 40 ml of acetonitrile 10 2,4-dimethyl-3-hydroxymethyl-5- (methylthio) thiophene and stirred at 40 ° C for 1 h. The solution obtained was cooled, 15.0 g of 2,4-dimethyl-5- (methylthio) thiophene-3-carboxalde and 150 ml of ethyl ether were added. The white precipitate, hyd were stirred in 150 ml of dry ethanol, which was formed, was filtered and washed with cold acetone at 20 ° C. 0.8 g of sodium boranate was added and this to see to give (2,4-dimethyl-3-thenyl) triphenylphosphonium-bro mixture was stirred for 30 min, then poured into ice water, mp 262-265 ° C . 45 and extracted with ethyl ether. The combined ether extracts were washed with a 5% sodium carbonate solution and a saturated sodium chloride solution, dried over sodium example 18 sulfate, filtered and concentrated to give 2,4-dimethyl-3-

All-trans-3,7-dimethyl-9- [2,4-dimethyl-5- (methylthio) -3-thienyl] hydroxymethyl-5- (methylthio) thiophene. 2,4,6,8-nonatetraenoic acid ethyl ester 50

1.40 g of a 50% suspension of sodium hydride in d) production of

Mineral oils were washed once with pentane and suspended in 120 ml of [2,4-dimethyl-5- (methylthio) -3-thenyl] triphenylphosphonium dimethylformamide. At 0 ° C 14.5 g of a bromide

Suspension of [2,4-dimethyl-5- (methylthio) -3-thenyl] triphenyl- 14.0 g of 2,4-dimethyl-3-hydroxymethyl-5- (methylthio) thio-phosphonium bromide in 30 ml of dimethylformamide was added dropwise 55 phen and 26.0 g triphenylphosphonium bromide were stirred in and 30 min. 6.5 g of a solution of 3-methyl-7-formyl-75 ml of acetonitrile dissolved and stirred at 40 ° C for 1 h. The ethyl halo-octa-2,4,6-trienate in 30 ml of dimethylformamide was cooled and poured into 150 ml of ethyl acetate, which was then added dropwise. After stirring for two hours at 0 ° C Sen and then treated with ethyl ether / hexane (5: 1). The reaction mixture obtained was poured into ice water and several solutions were extracted from a rubbery residue of corn with hexane. The combined hexane extracts were decanted. The residue was treated with hot acetone twice with methanol / water (6: 4), once with one, and the white crystals obtained were filtered, washed with saturated sodium chloride solution, washed with cold acetone over sodium sulfate and under high vacuum at 80 ° C dried, filtered and concentrated. The resulting crude product was dried to give [2,4-dimethyl-5- (methylthio> 3-thenyl] triphenyl) by column chromatography on silica gel while eluting phosphonium bromide, mp. 245 to 248 ° C., with ethyl ether / hexane ( 1: 4), recrystallization from 65 ethyl ether / hexane (1: 9) gave all-trans-3,7-dimethyl-9 [2,4- Example 19

dimethyl-5- (methylthio> 3-thienyl> 2,4,6,8-nonatetraenoic acid-3,7-dimethyl-9- (3-methyl-5-nitro-2-thienyl) -2,4,6,8 -Nonatetraen-ethyl ester, mp 76 to 78 ° C

15

628341

3.7 g of a 50% suspension of sodium hydride in mineral oil were washed once with pentane and suspended in 450 ml of dimethylformamide. At 0 ° C., 42.8 g of a solution of triphenyl- (7-älhoxycarbonyl-2,6-dimethyl-2,4,6-heptatrienyD-phosphonium bromide in 200 ml of dimethylformamide was slowly added and the mixture was stirred for 45 min. This reaction mixture was slowly added to a (0 ° C) cold solution of 3-methyl-5-nitrothiophene-2-carboxaldehyde in 350 ml of dimethylformamide under argon, and the reaction mixture was stirred at 5 ° C for 2 h, poured into ice water and extracted with ethyl ether> °. The ether extracts were combined, washed twice with water, dried over sodium sulfate, filtered and concentrated. The crude solid obtained was dissolved in 600 ml of ethyl acetate and diluted with 41 hexane. Methanol (4: 6 ratio) and the washes were extracted twice with hexane All organic extracts were combined, washed once with a water / methanol mixture (4: 6 ratio) and once with a solution of saturated sodium chloride over sodium sulfa t dried, filtered and concentrated to give ethyl cis-and-20 trans-3,7-dimethyl-9- (3-methyl-5-nitro-2-thienyl) -2,4,6,8-nonate-traenate to surrender.

b) production of

2,4-diethyl-5-methyl-3-chloromethylthiophene

15.0 g of 2,4-diethyl-5-methylthiophene, 65 ml of acetic acid, 130 ml of 12N hydrochloric acid and 8.9 g of formaldehyde (37% solution) were heated to 70 ° C. for 2.5 hours. The reaction mixture obtained was cooled, poured into 600 ml of water and extracted several times with diethyl ether. The combined organic phases were washed with water, sodium bicarbonate solution and water, dried over sodium sulfate, filtered and concentrated to give 2,4-diethyl-5-methyl-3-chloromethylthiophene.

c) production of

(2,4-diethyl-5-methyl-3-thenyl) triphenylphosphonium chloride

19.7 g of 2,4-diethyl-5-methyl-3-chloromethylthiophene and 39.5 g of triphenylphosphine were dissolved in 400 ml of toluene. The resulting solution was heated to 115 ° C overnight under nitrogen and then cooled to room temperature. The precipitated white phosphonium salt was collected by filtration, washed with toluene and dried at 100 ° C. under high vacuum to give (2,4-diethyl-5-methyl-3-thenyl) triphenylphosphonium chloride, mp. 192 to 194 ° C. to surrender.

25th

Example 20

All-trans-3,7-dimethyl-9- (2,4-diethyl-5-methyl-3-thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester

27.0 g (2,4-diethyl-5-methyl-3-thenyl) triphenylphosphonium chloride were suspended in 400 ml of butylene oxide and 13.3 g of 3-methyl-7-formyl-octa-2,4,6 -trienic acid ethyl ester was added. The resulting mixture was refluxed under argon for 3 hours after which the solvent was evaporated. The residue obtained was diluted with a methanol / water mixture (6: 4) and extracted several times with hexane. The combined organic phases were washed once with methanol / water (6: 4), dried over sodium sulfate, filtered and concentrated. The crude product obtained was purified by column chromatography (hexane / 5% ethyl acetate). Two 40 recrystallizations from hexane gave ethyl all-trans-3,7-dimethyl-9- (2,4-diethyl-5-methyl-3-thienyl) -2,4,6,8-nonatetraenoate, mp. 79 bis 80 ° C.

The (2,4-diethyl-5-methyl-3-thenyl) triphenylphosphonium chloride used as starting material in Example 20 can 45 z. B. can be produced as follows:

a) Preparation of 2,4-diethyl-5-methyl-thiophene

18.2 g of 2,4-diacetyl-5-methylthiophene and 40 ml of hydrazine (95%) were dissolved in 160 ml of diethylene glycol. The resulting solution was refluxed for 1 hour during which 4.0 ml of distillate was collected. Then 50 ml of diethylene glycol was added and after another hour of refluxing another 4.0 ml of distillate was collected. The reaction mixture was then refluxed at 160 ° C for 2.5 hours and cooled below 80 ° C. 50 g of potassium hydroxide were then added with stirring and the resulting mixture was carefully heated to 120 ° C, refluxed for 20 minutes and finally distilled until no further distillate was collected at 210 ° C. The distillate obtained was cooled and poured into 500 ml of ice-cold 2N hydrochloric acid. The product obtained was extracted several times with diethyl ether. The combined organic phases were washed with water, sodium bicarbonate solution and water, dried over sodium sulfate, filtered and concentrated. The crude product obtained was purified by distillation and gave 2,4-diethyi-5-methylthiophene, mp. 85 to 87 ° C / 20 mm Hg.

Example 21A

2,4,6-trans-8-cis-3,7-dimethyl-9- (3-thienyl) -2,4,6,8-nonatetraenic acid, ethyl ester

22.5 g (3-ThenyI) triphenyIphosphonium bromide were suspended in 200 ml of dimethylformamide and cooled to 0 to 5 ° C. 2.4 g of a 50% suspension of sodium hydride in mineral oil was added in portions. After stirring for 30 minutes, a solution of 11.4 g of 3-methyl-7-formyl-octa-2,4,6-trienoic acid ether in 45 ml of dimethylformamide was added dropwise. After stirring for 3 hours at 0 to 5 ° C, the reaction mixture was poured into 1000 ml of water and extracted several times with ethyl acetate. The combined organic phases were washed twice with water, dried over sodium sulfate, filtered and concentrated. The crude product obtained was purified by column chromatography (hexane / 10% ethyl acetate). Recrystallization from hexane / 15% ethyl acetate and hexane gave 2,4,6-trans-8-cis-3,7-dimethyl-9- (3-thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester, mp. 59.5 to 60 ° C.

Example 21B

All-trans-3,7-dimethyl-9- (3-thienyl) -2,4,6,8-nonatetraenoic acid ethyl ester

26.6 g (3-thenyl) triphenylphosphonium bromide was suspended in 200 ml of dimethylformamide and the mixture was cooled to 0 to 5 ° C. 2.90 g of a 50% suspension of sodium hydride in mineral oil were added in portions. After stirring for one hour, a solution of 13.7 g of ethyl 3-methyl-7-formyl-octa-2,4,6-trienate was added dropwise. After stirring for two hours at 0 to 5 ° C, the reaction mixture was poured into 1000 ml of water and extracted several times with ethyl acetate. The combined organic phases were washed twice with water, dried over sodium sulfate, filtered and concentrated. The crude product obtained was purified by column chromatography (hexane / 25% ethyl acetate). Single recrystallization from hexane / 25% ethyl acetate and repeated from hexane / ether gave all-trans-3,7-dimethyl-9- (3-thienyl> 2,4,6,8-nonatetraenoic acid ethyl ester, mp. 99 to 101 ° C.

The (3-thenyl) -4-triphenylphosphonium bromide used as the starting material in Examples 21A and 21B can, for. B. can be produced as follows:

a) Production of

(3-Thenyl) triphenylphosphonium bromide

628341

34.3 g of 3-bromomethylthiophene and 61.0 g of triphenylphosphine were dissolved in 500 ml of benzene. The resulting mixture was refluxed under argon overnight and then cooled to room temperature. The precipitated tan phosphonium salt was collected by filtration, washed several times with toluene and dried at 100 ° C under high vacuum to give (3-thenyl) triphenylphosphonium bromide, mp> 270 ° C.

Example 22

All-trans-3,7-dimethyl-9- (2,5-dichloro-4-methyl-3-thienyl) nona-2,4,6,8-tetraenoic acid ethyl ester

12.3 ml of n-butyllithium (2.45 molar in hexane) were added to a (minus 10 ° C.) cold suspension of 14.6 g (30.1 mmol) (2,5-dichloro-4-methyl-3-thenyl) ) -Triphenylphosphonium chloride slowly added in 250 ml ether. The reaction mixture obtained was stirred for 10 min. A solution of 6.27 g (30.1 mmol) of 3-methyl-7-formyl-octa-2,4,6-trienoic acid ethyl ester in 100 ml of ether was then added at minus 10 ° C. The reaction mixture was then slowly warmed to room temperature over 2 h, after which it was poured into ice water and extracted with ether. The ether extracts were washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated to give a yellow oil, which was triturated with hexane several times, and filtered. The hexane extracts were concentrated and the residue obtained was purified by chromatography on silica gel. Elution with hexane containing 1% ether gave a yellow oil which crystallized. Repeated crystallization from pentane gave all-trans-3,7-dimethyl-9- (2,5-dichlo'r-4-

16

methyl-3-thienyl) -nona-2,4,6,8-tetraenoic acid ethyl ester as yellow crystals, mp. 77 to 83 ° C.

The (2,5-dichloro-4-methyl) -3-thenyl) triphenylphosphonium chloride 5 used as the starting material in Example 22 can, for. B. can be produced as follows:

a) Production of

3-Chloromethyl-2,5-dichloro-4-methylthiophene i A mixture of 61.59 g (0.368 mol) of 2,5-dichloro-3-methyl-io thiophene, 13.1 g of paraformaldehyde and 3.1 zinc chloride was added Heated to 55 ° C. Hydrogen chloride gas was bubbled through the mixture for 7.25 hours. The resulting mixture was cooled and poured into a mixture of ether and ice water. The organic phase was separated and washed with sodium chloride solution, i5 sodium bicarbonate solution and again sodium chloride solution. Concentration of the dried solvent gave a dark brown oil which was distilled under reduced pressure to yield 3-chloromethyl-2,5-dichloro-4-methylthiophene as a pale yellow liquid, bp 87-92 ° C / 0.75 mm Hg -20 ben.

b) production of

(2,5-dichloro-4-methyl-3-thenyl) triphenylphosphonium chloride A mixture of 25.4 g (0.12 mol) of 3-chloromethyl-2,5-di-25 chloro-4-methylthiophene, 34.6 g (0.132 mol) triphenylphosphine and 200 ml of benzene were heated to reflux overnight. The beige solid obtained was filtered to give (2,5-dichloro-4-methyl-3-thenyl) triphenylphosphonium chloride, mp. 238 to 240 ° C.

Claims (6)

628341 1. A process for the preparation of a compound of the general formula in which one of the groups Ri or R: and the other of the groups R 1 or R 2 and R 3 and R 4 are hydrogen, lower alkoxy lower alkyl, hydroxymethyl, halogen, lower alkyl, lower alkoxy, lower alkylthio, carboxyl, amino, mono (lower alkyI) amino , Di (lower alkyl) amino, mono (lower alkyl) amino lower alkyl, di (lower alkyl) amino lower alkyl, hydroxy, lower alkenyl, lower alkenoxy, lower alkanoyl, lower alkanoyloxy , Nitro, lower alkoxycarbonyl, lower alkanoylamido or a nitrogen-containing heterocycle and Rs formyl, lower alkoxymethyl, lower alkanoyloxy-methyl, carboxyl, lower alkoxycarbonyl, lower alkenoxycarbonyl, lower alkynoxycarbonyl, di (lower alkyl) is carbamoyl or heterocyclylcarbonyl, and their pharmaceutically acceptable salts, characterized in that a compound of the general formula wherein one of the groups R6 or R- CH- R ' n wherein B is oxo when A of the compound of formula II is -P (X) 3 + Y ~ or -P-0 (Z) 2, or when A is oxo, B is -P (X) + Y ~ or - P — 0 (Z> 2; n is 0 or 1 and X, Y and Z are as in Formula II; when B is -P (X) j + Y ~ or -P — 0 (Z) 2, R's formyl, Carbo- 5 xyl, lower-alkoxycarbonyl, lower-alkenyloxy-carbonyl, never-the-alkynyloxycarbonyl, di (lower-alkyl) carbamoyl or N-heterocyclylcarbonyl, if B is oxo, R's carboxyl, lower-alkoxymethyl, lower-alkanoyloxymethyl, lower- Alkoxycarbonyl, lower alkenoxycarbonyl, lower alkyneoxycarbonyl 10 or N-heterocyclylcarbonyl and where in formulas II and III the sum of m and n is always one, is implemented. 2. The method according to claim 1, characterized in that that the reaction in the presence of an alkali metal alcoholate, e.g. As sodium methylate, or in the presence of sodium hydride 15 or an alkylene oxide, optionally alkyl-substituted, is carried out. 3. The method according to claim 2, characterized in that the reaction in an inert organic solvent, preferably in a chlorinated hydrocarbon, or in 20 dimethylformamide is carried out. 4. The method according to claim 1, characterized in that the reaction with a base in the presence of an inert organic solvent, preferably with sodium hydride in 1,2-dimethoxyethane, or with an alkali metal alcoholate in 25 an alkanol is carried out. 5. The method according to any one of claims 1 to 4, characterized in that 3-methyl-7-formyl-octa-2,4,6-trienoic acid ethyl ester with a (2,4,5-trimethyl-3-thenyl) triphenylpho -sphonium halide or with a dialkyl (2,4,5-trimethyl-3- 30 thenyl) phosphonate is implemented. 5. The method according to any one of claims 1 to 4, characterized in that 2,4,5-trimethyl-3-thiophenecarboxaldehyde with a (7-ethoxycarbonyl-2,6-dimethyl-2,4,6-heptatrie-nyOtriphenylphosphonium halide or with a dialkyl (7- 35 ethoxycarbonyl-2,6-dimethyl-2,4,6-heptatrienyl) phosphonate is reacted. II and the other of the groups Rs or R? and Rj and R4 are hydrogen, lower alkoxy lower alkyl, hydroxymethyl, halogen, lower alkyl, lower alkoxy, lower alkylthio, carboxyl, amino, mono (lower alkyl) amino, di (lower alkyl) amino, mono ( lower alkyl) amino lower alkyl, di (lower alkyl) amino lower alkyl, hydroxy, lower alkenyl, lower alkenoxy, lower alkanoyl, lower alkanoyloxy, nitro, lower alkoxycarbonyl, lower alkanoylamido or a nitrogen-containing heterocycle, m 0 or 1, A oxo, -P (X) 3+ Y ~ or -P-0 (Z) 2, X aryl, Z lower alkoxy and Y is an anion of an organic or an inorganic acid, with a compound of the general formula 40