CH615659A5 - Process for the preparation of novel 11,12-secoprostaglandins - Google Patents

Description

The present invention relates to a process for the preparation of new 11,12-secoprostaglandins. The compounds mentioned have a biological activity similar to

Prostaglandin and are particularly suitable as renal vasodilators, antihypertensives and antithrombotics.

The 11,12-prostaglandins which can be prepared according to the invention have the following formula q

r, (i)

ch3co-c- (ch2) 4-a- ^

(ch2) 3 - ^ - C (R3) 2- (CH2) 2-R4

R oh

A represents an ethylene, trimethylene, a-methylethylene, / 3-methylethylene, a, a-dimethylethylene, / 3, / 3-dimethylethylene or oxymethylene group,

R is the carboxy group or an alkoxycarbonyl radical with 1-6 C atoms,

R1 represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom or a methyl group, R4 represents a hydrogen atom, a lower alkyl radical or a 2,2,2-trifluoroethyl group, or

R4 and R1 may be linked to form a 5- to 9-membered carbocyclic ring, and Q represents a halogen atom.

If they are present as free acid, the compounds mentioned can be converted into pharmacologically acceptable salts. The cations of these salts are, for example, metal cations, such as alkali or alkaline earth metal ions, or ammonium ions or cations derived from primary and secondary amines and quaternary ammonium hydroxides. Particularly preferred metal cations are the alkali ions, such as sodium, potassium or lithium ions, the alkaline earth ions, such as calcium or magnesium ions, and of other metals, i. H. Aluminum, iron and zinc, derived cations.

Specific examples of primary, secondary or tertiary amines or quaternary ammonium hydroxides, from which pharmacologically acceptable cations are derived, are methylamine, dimethylamine, trimethylamine, ethylamine, N-methylhexylamine, benzylamine, a-phenethylamine, ethylenediamine, piperidine, morpholine, pyrrolidine, 1,4-dimethylpiperazine, ethanolamine, diethanolamine, triethanolamine, tris (hydroxymethyl) aminomethane, N-methylglucamine, N-methylglucosamine, ephedrine, procain, tetramethylammonium hydroxide, tetraethylammonium hydroxide and benzyltrimethylammonium hydroxide.

A is an ethylene group (—CH2CH2—), a trimethylene group (-CH2CH2CH2—), an a-methylethylene group (-CH2-CH (CH3) -), a / 3-methylethylene group (-CH (CH3) CH2—), an a, a-dimethylethylene group (-CH2-C (CH3) 2-), a / 3, / 3-dimethylethylene group (-C (CH3) 2CH2-) or an oxymethylene group (-0-CH2-). It should be noted that if A consists of a bridge having two carbon atoms, “” refers to the carbon atom adjacent to the radical R and “ß” to the other carbon atom.

Q is halogen, preferably a chlorine or bromine atom. The 11,12-secoprostaglandins of tornei p (II) are preferred

CH, CO-C- (CH,). -A • -COOH

i I £ 4 rj

(CHp) ^ -C ~ (CHo) ^ ~ R

2 3 / \ 23

in the H ° H

A 'is an ethylene or oxymethylene group,

R1 and Q have the meaning given above and

R7 represents an ethyl, isopropyl or butyl group.

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It should be noted that the carbon atom bearing R1 and OH is asymmetric. The stereoisomers in which this asymmetry center occurs exclusively in one of the two possible configurations (R or S configuration) are therefore also included. It is also within the framework that the asymmetric carbon atom bearing the Q substituent occur in any of its possible configurations.

The compounds of general formula I are referred to as 11,12-secoprostaglandins because of their structural relationship to the naturally occurring prostaglandins.

Prostaglandins are a biologically significant class of naturally occurring, highly functionalized ones

C20 fatty acids, which are easily found in numerous types of warm-blooded tissues by building metabolism (anabolism) from three essential fatty acids, i.e. H. 8,11,14-eicos trienoic acid, 5,8,11,14-eicosatetraenoic acid and 5,8,11,14,17-5 eicosapentaenoic acid arise. Every known prostaglandin is formally derived from the parent compound called "prostanoic acid". This acid is a C20 fatty acid which has a covalent bridge bond between the carbon atoms 8 and 12 io, so that a trans, vicinally substituted cyclopentane forms, in which, according to formula III below, the one carrying the carboxyl group Side chain has the designation «a» or is located below the ring level and the other side chain has the designation «ß» or is 15 above the ring level:

(III)

13 15 17 19

The six known primary prostaglandins PGE15, PGE2, PGE3, PGFto, PGFj, and PGF ^, which result directly from the anabolism of the aforementioned essential fatty acids due to the action of prostaglandin synthetase, as well as through in vivo dehydration of the PGE-Pro

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Three prostaglandins (i.e., PGA ^ PGA2 and PGA3) resulting from staglandins are divided into three groups, namely the PGE-PGF and PGA series, based on the three different cyclopentane core substitution schemes illustrated below:

Oh

PGE core

PGA core pg ra rb

E "F" A,

oh e2, f2, a2

'co2h oh e3, f3, a3

Eq, FQ, AQ

The subscript Arabic numerals indicate the number of carbon-carbon double bonds in the compound in question, while the subscript Greek letters used in the PGF series indicate the stereochemistry of the C-9 hydroxyl group.

02h oh oh

Although prostaglandins in the mid-1930s-65s were the result of independent research by Goldblatt [J. Chem. Soc. Chem. Ind. Lond., 52, 1056 (1933)] in England and by von Euler [Arch. Exp. Path. Pharmark., 175, 78 (1934)] in Sweden found them

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Complicated natural products received little attention in the professional world until the early 1960s. In the latter period, the introduction of modern technical aids (e.g. mass spectrometry), with the help of which the successful isolation and structure elucidation of these compounds by Bergström et al. was made possible [cf. Appl. Chem. Int. Ed., 4, 410 (1965) and the references cited there with regard to this work]. During the past decade, extensive international scientific efforts have been devoted to developing both biosynthetic and chemical prostaglandin production methods and then studying the biological activities of these compounds. It was shown that prostaglandins are largely present in low concentrations in a variety of warm-blooded tissues, where they are rapidly subject to both anabilism and catabilism (metabolism), and that they have an extensive range of pharmacological activities. You play e.g. B. an important role (a) in functional hyperemia, (b) in the inflammatory response, (c) in the central nervous system, (d) in the transport of water and electrolytes and (e) in the regulation of cyclic AMP (adenosine monophosphoric acid). Further details concerning prostaglandins can be found in the more recent literature, the chemistry of which [J. E. Pike, progress. Chem. Org. Naturst., 28, 313 (1970) and G. F. Bundy,

A. Rep. In Med. Chem., 7, 157 (1972)], biochemistry [J. W. Hinman, A. Rev. Biochem., 41, 161 (1972)], pharmacology [J. R. Weeks, A. Rev. Pharm., 12, 317 (1972)], physiological significance [E. W. Horton, Physiol. Rev., 49, 122 (1969)] and general clinical use [J. W. Hinman, Postgraduate. Med. J., 46, 562 (1970)].

The potential use of naturally occurring prostaglandins as medically valuable therapeutic agents for various diseases of warm-blooded animals is obvious. There are three major drawbacks to using it, however:

(a) the prostaglandins are known to be rapidly converted in vivo in a variety of warm-blooded tissues to a variety of metabolites which do not have the desired original biological activities;

(b) the natural prostaglandins as such do not have the biological specificity that is necessary for a successful drug; and

(c) although limited amounts of prostaglandins are currently produced by both chemical and biochemical processes, their manufacturing costs are extremely high; they are therefore only available to a very limited extent.

In the present invention, the interest was in the synthesis of new compounds which are structurally related to the natural prostaglandins, but on the other hand have the following outstanding advantages:

(a) simplicity of synthesis, which requires low manufacturing costs;

(b) specificity of biological activity, which may be either the same or opposite to that of prostaglandin; and

(c) increased resistance to metabolism (metabolic stability).

The combination of these advantages helps to create effective, orally and parenterally active therapeutic agents for the treatment of a variety of human and animal diseases. The possible uses of these agents extend to the kidney, cardiovascular, gastrointestinal, respiratory and reproductive systems and to the control of lipid metabolism, inflammatory symptoms, blood clotting, skin diseases and certain types of cancer.

The prostaglandin agonists are clinically particularly suitable as agents for improving kidney function (for example, renal vasodilation), antihypertensives, anti-ulcer agents, anti-fertility agents, antithrombotic agents, anti-asthmatics, anti-lipolytic agents, anti-tumor formation agents (anti-neoplastic agents) and agents for the treatment of certain skin diseases .

The prostaglandin antagonists are suitable as anti-inflammatory agents, antidiarrheals, antipyretics, agents for preventing premature birth or premature labor and headache medications.

The compounds which can be prepared according to the invention are particularly suitable as agents for improving kidney function, as antihypertensives, as well as for the treatment of dwarfism and for the prevention of thrombus formation. It should be emphasized that not all of these connections are useful in every respect; however, each individual compound was tested on the basis of numerous experiments and showed efficacy in at least one activity area.

The compounds that can be produced according to the invention can either be topical or in the interior of the body, ie. H. intravenously, subcutaneously, intramuscularly, orally, rectally, by aerosol therapy or in the form of sterile implants intended for long-term effects. The compounds can be incorporated into a variety of medicinal products and non-toxic carriers for this purpose.

The medicaments can be in the form of sterile injectable suspensions or solutions or as solid, orally administrable, pharmacologically acceptable tablets or capsules. The preparations can also be formulated for sublingual administration or as suppositories. In view of the simplicity and economy of administration and the uniformity of the dosage, it is particularly advantageous to provide the pharmaceuticals in the form of unit doses. “Unit doses” are to be understood here as physically separate units which are suitable as uniform administration forms for humans and animals. Each unit contains a predetermined amount of active ingredient, which is dimensioned so that it produces the desired biological effect in connection with the required pharmaceutical method.

A sterile injection preparation can be in the form of an aqueous or oily suspension or solution, for example.

The sterile injection preparation can be an aqueous or oily suspension or solution. Suspensions can be prepared in a known manner using suitable dispersing and wetting agents and suspending agents. Solutions are generated analogously from the salt form of the compound. Incomplete Freund's adjuvant or sterile saline (9%) is preferred as the medium for the experimental animals. In human medicine, parenteral use, e.g. B. by intramuscular or intravenous administration or by regional perfusion, serve as a diluent, a sterile aqueous medium containing a preservative such as methyl paraben (methyl p-hydroxybenzoate), propyl paraben (propyl p-hydroxybenzoate), phenol or chlorobutanol. The aqueous medium may also contain sodium chloride, preferably in an isotonic amount, and a suspending agent, e.g. B. gum arabic, polyvinylpyrrolidone, methyl cellulose, acylated monoglyceride (commercial product "Myvacet" from the Distillation Products Industry, division of the Eastman Kodak Company), monomethylglyceride, dimethylglyceride or polysorbitan with moderately high molecular weight (commercial product "Tween" or "Span" from Atlas Powder Company, Wilmington, Delaware). Examples of other substances

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Zen that are used to prepare chemotherapeutic agents containing the respective compound are glutathione, 1,2-propanediol, glycerol and glucose. The pH of the preparation is further adjusted using an aqueous solution such as tris (hydroxymethyl) aminomethane (Tris buffer).

Oily pharmaceutical carriers can also be used, since these loosen the connection and allow high doses. It is common practice to use numerous oily carriers for pharmaceutical purposes, such as mineral oil, lard, cottonseed oil, peanut oil and sesame oil.

The liquid (aqueous or oily) preparations are preferably produced in concentrations in the range from 2 to 50 mg / ml. Concentrations higher than 50 mg / ml are difficult to maintain and are better avoided.

Oral forms of administration of the drug suitable for experimental animals or human patients can also be prepared, provided that these preparations are placed in capsules from which they are released in the gastrointestinal tract. The drug is subject to enzymatic breakdown in the acidic environment of the stomach. The same doses can be used for injectables; however, even higher proportions can be used to compensate for the biodegradation during transport. You can generally make a fixed unit dose containing 0.5-25 mg of active ingredient.

Regardless of the method of administration, doses are used e.g. B. in the range of about 0.1-20 mg / kg body weight, which are administered 1 to 4 times a day. The exact dose depends on the age, weight and condition of the patient, as well as the frequency and route of administration.

Because of their low cost and easy accessibility, the new compounds are particularly promising in veterinary medicine; Their applicability in this area is comparable to that in human medicine.

The process according to the invention is characterized in that a compound of the formula ch3co-ck- (ch2) 4-a-.r (iv)

(CH2) 3 ^ 3-C (R3) 2- (CH2) 2-R4 R OH

in which R, R1, A, R3 and R4 have the meaning given above, are reacted with a halogenating agent and any compounds obtained are converted into their salts.

The compounds of the formula I obtained according to the invention, in which Q is bromine and R is an alkoxycarbonyl group having 1-6 C atoms, can be used to prepare compounds of the following formula

YH3

CH3CO-C- (CH2) 4-A-COOH

(CH2) 3- <J-C (R3) 2 (CH2) 2R4

R1 ^ OH

can be used, wherein A, R1, R3 and R4 are defined above. To prepare these compounds, the compound of the formula I mentioned, in which the free hydroxyl group is temporarily protected by a lower alkanoyl radical, is reacted with lithium dimethyl copper, and the ester group is converted into the carboxy group by alkaline hydrolysis.

The starting compounds of formula IV are described in DE-OS 2 354 085.

The starting compounds of formula IV, in which R represents a carboxyl group, z. B. with copper (II) chloride and lithium chloride to compounds of formula I in which Q is a chlorine atom; the reaction with copper (II) bromide and lithium bromide gives z. B. corresponding compounds in which Q represents a bromine atom.

From a therapeutic point of view, it can be advantageous to prepare compounds of the formula I in which the various asymmetric carbon atoms occur exclusively in a specific configuration. The asymmetric carbon atom carrying the residues R1 and OH is, for example, in the S configuration in the naturally occurring prostaglandins; inversion of this center usually leads to a decrease in biological effectiveness, although sometimes there is a considerable increase in biological specificity. Only the compounds having the R or S configuration can be obtained by the methods described above using optically active, ie. H. starting compounds or intermediates split into the isomeric R or S form.

From the products obtained by the processes described above, derivatives, i.e. H. other compounds of formula I can be prepared.

1. The basic processes provide in particular compounds in which R is a carboxyl group. For the production of carboxy salts, z. B. the acids in a solvent such as ethanol, methanol or ethylene glycol dimethyl ether (Glyme). A suitable alkali or alkaline earth metal hydroxide or alkoxide is added to the solution to produce the corresponding metal salt, or the equivalent amount of ammonia of an amine or quaternary ammonium hydroxide to produce the corresponding amine salt. In any case, the salt either separates from the solution and can be filtered off, or it can be

if it is soluble, recover by evaporating the solvent. Aqueous solutions of the carboxylic acid salts can be prepared by treating an aqueous suspension of the carboxylic acid with the equivalent amount of an alkaline earth metal hydroxide or oxide, alkali metal hydroxide, carbonate or bicarbonate, ammonia of an amine or quaternary ammonium hydroxide.

For the production of carboxyesters, i.e. H. Compounds in which R is an alkoxycarbonyl radical having 1-6 carbon atoms are preferably treated with the acids in ether with an ethereal solution of the appropriate diazoalkane. Methyl esters are prepared, for example, by reacting the acids with diazomethane.

Methods for producing optical antipodes of some new compounds are described above, in which one of the components of the molecule is subjected to antipode separation before it is integrated into the overall molecule. You can also work with other methods; for example, mixtures of racemates can be separated chromatographically and / or by fractional crystallization, taking advantage of the different physicochemical properties of the components. The racemic products and intermediates of the invention can be separated into their optically active components by any of the numerous antipode disruption methods described in the chemical literature.

Those compounds which are carboxylic acids can be reacted with an optically active base, such as (+) - or (-) - a-methylbenzylamine, (+) - or (-) - a- (l-naphth-

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thyl) ethylamine, brucine, cinchonine, cinchonidine or quinine, are converted into the diastereomeric salts. These salts can be separated by fractional crystallization.

The carboxylic acids obtained according to the invention can also be converted into esters with the aid of an optically active alcohol, such as estradiol-3-acetate or d- or 1-menthol, and the diastereomeric esters can be split into the optical antipodes by crystallization or by chromatography.

Racemic carboxylic acids can also be resolved into the optical antipodes by reverse phase chromatography and adsorption chromatography using an optically active carrier and adsorbent.

Another preferred method for producing pure optical isomers is e.g. B. by incubating the racemic mixture with certain microorganisms, such as fungi (fungi), according to conventional methods and recovering the product formed by the enzymatic conversion.

The methods described above give particularly good results if they are applied to a compound in which an antipode splitting has already been carried out on an asymmetry center according to the methods described.

example 1

Preparation of 8-acetyl-8-chloro-12-hydroxyheptadecanoic acid

Level A:

Preparation of ethyl 8-tert-butoxycarbonyl-9-oxodecanoate

A suspension of 57 percent sodium hydride in mineral oil (37.05 g net weight; 0.88 mol) in a solvent mixture of 400 ml benzene and 400 ml dimethylformamide is tert-dropwise mixed with 126.56 g (0.8 mol) within 30 minutes .-Butylacetoacetate added. The stirring is then continued for a further 30 minutes. 208.5 g (0.88 mol) of ethyl 7-bromheptanoate are then added dropwise in the course of 30 minutes, and the mixture is heated at 100 ° C. for 21/2 hours.

The cooled reaction mixture is mixed with 1600 ml of water and the organic layer is separated. The aqueous layer is extracted with ether. The combined organic solutions are washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvents are evaporated off in vacuo and the oil remaining as a residue is distilled; 158.6 g (63%) of ethyl 8-tert-butoxycarbonyl-9-oxodecanoate are obtained in the form of a yellow oil with a boiling point of 175 to 177 ° C./0.5 mm.

Level B:

Production of l-chloro-4-nonanone

The Grignard reagent, prepared from a mixture of 226.59 g (1.5 mol) of amyl bromide and 36.48 g (1.5 mol) of magnesium in 1 liter of ether, is added dropwise with 155.34 g (1 , 5 mol) of 4-chlorobutyronitrile. Stirring is continued for another hour. The reaction mixture is then poured into a mixture of finely crushed ice (1000 g) and 750 ml of concentrated hydrochloric acid. The ether layer is quickly separated and discarded. The aqueous layer is heated for 1 hour on a steam bath, the imine formed as an intermediate being hydrolyzed and the ketone being separated off in the form of an oil. After cooling, the oil is extracted with ether and the combined extracts are washed with saturated sodium chloride solution. Then it is dried over anhydrous sodium sulfate, the solvent is evaporated off in vacuo and the remaining oil is distilled. This gives 69 g (26%) of l-chloro-4-nona-non as a colorless oil with a boiling point of 115-117 ° C./14 mm; Proton resonance (pmr) (CDC13) ò 0.90 (3H, t). 3.56 (2H, t, CH2C1).

Level B (2):

Preparation of l-chloro-4-nonanol A suspension of 6.62 g (0.175 mol) of sodium borohydride and 1.3 g of sodium hydroxide in 310 ml of ethanol is added dropwise with 61.4 g (0.349 mol) of l-chloro- 4-nonanon offset. The temperature is kept at 45-50 ° C. Stirring is continued for another hour without external cooling.

The reaction mixture is acidified against Congo red with concentrated hydrochloric acid. The ethanol is then evaporated off under reduced pressure. The residue is mixed with 200 ml of water and the resulting oil extracted with ether. The combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After evaporation of the solvent in vacuo, 1-chloro-4-nonanol is obtained in the form of a light yellow oil residue (58.85 g); IR (pure) 3400 cm "1.

Level B (3):

Preparation of l-chloro-4-acetoxynonane A mixture of 111.99 g (0.627 mol) of l-chloro-4-nonanol and 128 g (1.254 mol) of acetic anhydride is heated for 1 2 hours on a steam bath.

The volatiles are then evaporated off under reduced pressure and the residual oil is distilled. This gives 88.6 g (64%) of 1-chloro-4-acetoxynonan as a colorless oil with a boiling point of 130-133 ° C./14 mm; pmr (CDCI3) ó 0.89 (3H, t), 2.02 (3H, s CH3COÖ), 3.53 (2H, t CH2C1), 4.89 (1H, m).

CnH21C102:

calc .: C 59.85 H 9.59 found: C 59.87 H 9.67

Level B (4):

Production of ethyl-8-acetyl-8-tert-butoxy-carbonyl-

12-acetoxyheptadecanoate A suspension of 57 percent sodium hydride in mineral oil (3.03 g net weight, 0.072 mol) in a solvent mixture of 40 ml benzene and 40 ml dimethylformamide is added dropwise with 20.41 g (0.065 mol) ethyl-8 within 30 minutes -tert.-butoxycarbonyl-9-oxo-decanoate. Stirring is continued for a further 30 minutes. 15.8 g (0.072 mol) of 1-chloro-4-acetoxy-nonane are then added dropwise over the course of 30 minutes. Then 50 mg of potassium iodide are added and the mixture is heated at 100 ° C. for 66 hours.

The reaction mixture is then cooled and 160 ml of water are added. The organic layer is separated. The aqueous layer is extracted with ether and the combined organic extracts are washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvents are evaporated off in vacuo. An oil-like residue of ethyl 8-acetyl-8-tert-butoxycarbonyl-12-acetoxyheptadecanoate remains. The yield is 32.04 g; pmr (CDC13) ö 0.90 (3H, t), 1.45 (9H, s), 2.02 (3H, s CH3CÖO), 2.12 (3H, s CH3CO), 4.13 (2H, q ).

Level C:

Preparation of ethyl 8-acetyl-12-acetoxyheptadecanoate A mixture of 32.04 g (0.0643 mol) of ethyl 8-acetyl-8-tert-butoxycarbonyl-12-acetoxyheptadecanoate, 1.1 g of p -Toluenesulfonic acid monohydrate and 110 ml of toluene under reflux for 18 to 22 hours. The developed CO 2 is indicated by introducing the gas into aqueous Ba (OH) 2.

The cooled reaction mixture is washed with 25 ml of saturated sodium bicarbonate solution and twice with 25 ml of saturated sodium chloride solution and then

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dried over anhydrous sodium sulfate. After evaporation of the solvent in vacuo, 26.69 g (theoretical value 25.63 g) of an oily residue are obtained. The oil is purified by column chromatography on silica gel with chloroform as the eluent. This gives 9.6 g (38%) of ethyl 8-acetyl-12-acetoxyheptadecanoate; pmr (CDC13) ó 0.90 (3H, t), 2.02 (3H, s CH3COO), 2.12 (3H, s CHjCO), 4.13 (2H, q), 4.84 (1H, m HCOCOCH3). C23H42Os:

ber.? C 69.31 H 10.62 Found: C 69.47 H 10.83

Level D:

Preparation of 8-acetyl-12-hydroxyheptadecanoic acid A solution of 12.21 g (0.0306 mol) of ethyl 8-acetyl-12-acetoxy-heptadecanoate is dissolved in a solution of 3.67 g (0.0918 mol) of sodium hydroxide 17 ml of water and 153 ml of methanol entered. The solution obtained is left to stand at 25 ° C. for 72 hours. The majority of the methanol is then evaporated off in vacuo. The remaining solution is diluted with 150 ml of water. The mixture is then extracted with ether and the aqueous layer is acidified against Congo red paper.

The ether extract is washed with water, then dried over anhydrous sodium sulfate and then evaporated in vacuo. This gives 9.65 g (95%) of 8-acetyl-12-hydroxyheptadecanoic acid in the form of a viscous yellow liquid. This is purified by column chromatography on silica gel with 2% methanol in chloroform as the eluent. 6.9 g (69%) of pure 8-acetyl-12-hydroxy-heptadecanoic acid are obtained in the form of a colorless liquid; pmr (cdci3) Ó 0.88 (3H, t), 2.12 (3H, s CH3CO), 3.64 (1H, m HCOH), 6.65 (2H, s OH and COOH).

Ci9H3604:

calc .: C 69.47 H 11.05 found: C 69.55 H 11.22

Level E:

Preparation of 8-acetyl-8-chloro-12-hydroxyheptadecanoic acid A mixture of 16.4 g (0.05 mol) of 8-acetyl-12-hydroxy-heptadecanoic acid, 20.5 g (0.12 mol) of copper (II) Chloride di-hydrate, 2.5 g (0.06 mol) of lithium chloride and 30 ml of dimethylformamide are heated for 16 hours with stirring on a steam bath. The reaction mixture is then cooled and water is added. The oil that separates is taken up in ether. It is washed with water and sodium chloride solution and dried over sodium sulfate. When the ether is distilled off, an orange oil (19.3 g) remains. The product is purified chromatographically on silica gel using 2% methanol in chloroform as the eluent. 3.5 g (19%) of 8-acetyl-8-chloro-12-hydroxy-heptadecanoic acid are obtained in the form of a light yellow oil; pmr (proton resonance) (CDC13) ó 0.88 (3H, t), 2.34 (3H, s ch3co), 3.65 (IH, m HCOH).

C19H35CIO4:

calc .: C 62.88 H 9.72 found: C 62.48 H 9.65

Following the same procedure, but using 8-acetyl-12 (R) -hydroxyheptadecanoic acid or 8-acetyl-12 (S) -hydroxyheptadecanoic acid, 8-acetyl-8-chloro-12 (R) -hydroxyheptadecanoic acid or 8-Acetyl-8-chloro-12 (S) -hydroxyheptadecanoic acid.

Example 2

Preparation of 8-acetyl-8-bromo-12-hydroxy-heptadecanoic acid According to Example 1, stage E, but using copper (II) bromide and lithium bromide instead of copper (II) chloride

If dihydrate and lithium chloride are used, 8-acetyl-8-bromo-12-hydroxyheptadecanoic acid is obtained in the form of a viscous, yellow oil, which is purified chromatographically on silica gel using 2% methanol in chloroform as the eluent.

Example 3

8-acetyl-8-methyl-12-hydroxyheptadecanoic acid

Level A:

Preparation of ethyl 8-acetyl-8-bromo-12-acetoxy heptadecanoate

A solution of 16.7 g (0.104 mol) of bromine in 100 ml of carbon tetrachloride is stirred within 1 hour in a solution of 37.4 g (0.094 mol) of ethyl 8-acetyI-12-acetoxyheptadecanoate (Example 1, step C ) dropped into 200 ml carbon tetrachloride. The oil remaining as a residue in the vacuum evaporation of the solvent is dissolved in ether. The solution is washed with dilute sodium bicarbonate solution, water and sodium chloride solution and dried over sodium sulfate. When the ether evaporates, the crude bromester remains in the form of a yellow oil (43 g). The oil is purified by column chromatography on silica gel using benzene as the eluent. In this way, the desired bromo ester is derived from a small amount of a by-product, i.e. H. Ethyl 8-bromoacetyl-8-bromo-12-acetoxyheptadecanoate, separated. 12.7 g (28%) of ethyl 8-acetyl-8-bromo-12-acetoxyheptade kanoate are obtained in the form of a light yellow oil.

Level B:

Preparation of ethyl 8-acetyl-8-methyl-12-acetoxy heptadecanoate

A suspension of 7.1 g (0.037 mol) of copper (I) iodide in 150 ml of ether is added dropwise within 30 minutes with a 1.66 m solution of methyl lithium in ether (45 ml; 0.075 mol). 11.9 g (0.025 mol) of ethyl 8-acetyl-8-bromo-12-acetoxyheptadecanoate are then added dropwise within 30 minutes. During these measures, the temperature is kept at -4 to -2e C with the aid of a salt bath. Stirring is continued at this temperature for a further 30 minutes; the mixture is then stirred for 2 hours without cooling. The reaction mixture is then mixed with 200 ml of saturated ammonium chloride solution. The organic layer is separated, washed with sodium chloride solution and dried over sodium sulfate. When the solvent is distilled off in vacuo, the crude product remains in the form of an orange oil (9.2 g). The product is purified by column chromatography on 250 g of silica gel using chloroform as the eluent. Ethyl 8-acetyl-8-methyl-12-acetoxy heptadecanoate is obtained in the form of a yellow, viscous oil.

Level C:

Preparation of 8-acetyl-8-methyl-12-hydroxyhepta-decanoic acid

According to the hydrolysis method described in Example 1, stage D, but using instead of ethyl 8-acetyl-12-acetoxyheptadecanoate the equimolar amount of ethyl 8-acetyl-8-methyl-12-acetoxyheptadecanoate gives 8-acetyl 8-methyl-l 2-hydroxyheptadecanoic acid in the form of a colorless, viscous oil.

The following compounds can be prepared in an analogous manner:

Example 4

Preparation of 8-acetyl-8-chloro-12-hydroxy-16-methyl-heptadecanoic acid

According to Example 1, stage E, but using 8-acetyl-12-hydroxy-16-methylheptadecanoic acid instead of 8-acetyl-

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If 12-hydroxyheptadecanoic acid is used, 8-acetyl-8-chloro-12-hydroxy-16-methylheptadecanoic acid is obtained.

Example 5

Preparation of 8-acetyl-8-chloro-12-hydroxy-16,16-dimethylheptadecanoic acid According to Example 1, Step E, but using 8-acetyl-12-hydroxy-16,16-dimethylheptadecanoic acid instead of 8-acetyl-12- If hydroxyheptadecanoic acid is used, 8-acetyl-8-chloro-12-hydroxy-16,16-dimethylheptadecanoic acid is obtained.

Example 6

Preparation of 8-acetyl-8-chloro-12-hydroxy-17,17,17-trifluoroheptadecanoic acid According to Example 1, Step E, but using 8-acetyl-12-hydroxy-17,17,17-trifluoroheptadecanoic acid instead of 8- If acetyl-1 2-hydroxyheptadecanoic acid is used, 8-acetyl-8-chloro-12-hydroxy-17,17,17-trifluoroheptadecanoic acid is obtained.

Example 7

Preparation of 8-acetyl-8-chloro-12-methyl-12-hydroxyheptadecanoic acid According to Example 1, Step E, but using 8-acetyl-12-methyl-1,2-hydroxyheptadecanoic acid instead of 8-acetyl-12-hydroxyheptadecanoic acid, 8-acetyl-8-chloro-12-methyl-12-hydroxyheptadecanoic acid is obtained.

Example 8

Preparation of 8-acetyl-8-chloro-12-hydroxy-13,13-dimethylheptadecanoic acid According to Example 1, Step E, but using 8-acetyl-12-hydroxy-13,13-dimethylheptadecanoic acid instead of 8-acetyl-12 -hydroxyheptadecanoic acid is used to obtain

8-acetyl-8-chloro-12-hydroxy-13,13-dimethylheptadecanoic acid.

Example 9

Preparation of (5-acetyl-5-chloro-9-hydroxy-tetradecyloxy) acetic acid According to Example 1, Step E, but using (5-acetyl-

9-hydroxytetradecyloxy) acetic acid instead of 8-acetyl

If 12-hydroxyheptadecanoic acid is used, (5-acetyl-5-chloro-9-hydroxytetradecyloxy) acetic acid is obtained.

Example 10

Preparation of 8-acetyl-8-chloro-ll- (l-hydroxy-cyclohexyl) -undecanoic acid According to Example 1, stage E, but using 8-acetyl-1 l- (l-hydroxycyclohexyl) -undecanoic acid instead of 8-acetyl If 1-l 2-hydroxyheptadecanoic acid is used, 8-acetyl 8-chloro-11 - (1-hydroxycyclohexyl) -undecanoic acid is obtained.

Example 11

Preparation of 2-methyl-8-acetyl-8-bromo-12-hydroxyheptadecanoic acid According to Example 2, but using 2-methyl-8-acetyl-12-hydroxyheptadecanoic acid instead of 8-acetyl-12-hydroxy-heptadecanoic acid, is obtained 2-methyl-8-acetyl 8-bromo-12-hydroxyheptadecanoic acid.

Example 12 Preparation of 3-methyl-8-acetyl-8-bromo-12-hydroxyheptadecanoic acid According to Example 2, but using 3-methyl-8-acetyl-12-hydroxyheptadecanoic acid instead of 8-acetyl-1 2-hydroxyheptadecanoic acid man 3-methyl-8-acetyl 8-bromo-12-hydroxyheptadecanoic acid.

Example 13

Preparation of 2,2-dimethyl-8-acetyl-8-bromo-12-hydroxyheptadecanoic acid According to Example 2, but using 2,2-dimethyl-8-acetyl-12-hydroxyheptadecanoic acid instead of 8-acetyl-1,2-hydroxyheptadecanoic acid used, 2,2-dimethyl-8-acetyI-8-bromo-12-hydroxyheptadecanoic acid is obtained.

Example 14

Preparation of 3,3-dimethyl-8-acetyl-8-chloro-12-hydroxyheptadecanoic acid According to Example 1, step E, but using 3,3-dimethyl-8-acetyl-1,2-hydroxyheptadecanoic acid instead of 8-ace -tyl-12-hydroxyheptadecanoic acid is used to obtain 3,3-dimethyl-8-acetyl-8-chloro-12-hydroxyheptadecanoic acid.

Example 15 Preparation of methyl 8-acetyl-8-chloro-12-hydroxyheptadecanoate A solution of about 2.5 g (0.06 mol) of diazomethane in 100 ml of ether is mixed with a solution of 10.9 g (0.03 mol ) 8-Acetyl-8-chloro-l2-hydroxyheptadecanoic acid mixed in 50 ml ether. The solution obtained is left to stand for 4 hours at room temperature. The excess diazomethane is then destroyed by adding acetic acid and the solution is washed with dilute sodium bicarbonate solution and water. After drying over sodium sulfate and evaporation of the volatile components under reduced pressure, methyl 8-acetyl-8-chloro-l 2-hydroxyheptadecanoate is obtained in the form of a colorless, viscous oil.

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Claims (7)

615 659 1. Process for the preparation of new compounds of the formula ? (I) CH3CO-C- (CH2) 4-A-K (CH2) 3 - ^ - C (R3) 2- (CK2) 2-R4 R OH in the A represents an ethylene, trimethylene, a-methylethylene, β-methylethylene, a, a-dimethylethylene, / 3, / 3-dimethylethylene or oxymethylene group, R is the carboxy group or an alkoxycarbonyl radical with 1-6 C atoms, R1 represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom or a methyl group, R4 represents a hydrogen atom, a lower alkyl radical or a 2,2,2-trifluoroethyl group, or R4 and R1 can be linked to form a 5- to 9-membered carbocyclic ring, and Q represents a halogen atom, or of salts thereof, characterized in that a compound of the formula CH3CO ~ CH- (CH2) /, - A-R (IV) (CH2) 3- <3-C (R3) 2- (CH2) 2-R4 R OK in which R, R1, A, R3 and R4 have the meaning given above, reacted with a halogenating agent and any compounds obtained are converted into their salts. 2. The method according to claim 1, characterized in that Q is a chlorine atom. 2nd PATENT CLAIMS 3. The method according to claim 2, characterized in that the halogenating agent is copper (II) chloride. 4. The method according to claim 1, characterized in that Q is a bromine atom. 5. The method according to claim 4, characterized in that the halogenating agent is copper (II) bromide. 6. The method according to claim 1, characterized in that obtained compounds which are present as free acid are converted into their lower alkyl ester by esterification. 7. Use of the compounds of the formula I obtained by the process according to claim 1, in which 0 is bromine and R is an alkoxycarbonyl group having 1 to 6 carbon atoms, for the preparation of compounds of the formula ? H3 CH3CO-C- (CH2) 4-A-COOH (CH2) 3- ^ C-C (R3) 2 (CH2) 2R4 R1 ^ OH wherein A, R1, R3 and R4 are defined in claim 1, characterized in that the compounds of formula I, in which the free hydroxy group is temporarily protected by a lower alkanoyl radical, are reacted with lithium dimethyl copper and the ester group is saponified by alkaline hydrolysis .