NO139438B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE SECO PROSTAGLANDINS - Google Patents

Description

The present invention relates to an analogue method for the production of therapeutically active 8-aza-9-dioxo-thia-11,12-seco-

prostaglandins. These compounds have prostaglandin-like biological activity and are particularly useful as renal vasodilators,

to prevent thrombus formation, to induce growth hormone-free

making and for the treatment of certain autoimmune diseases.

The new 8_aza-9-dioxo-thia-11,12-seco-prostaglandins which

is produced according to the invention, has the following structural formula:

including optically active derivatives thereof,

where A is ethylene, α-methylethylene or oxymethylene,

R is methyl, ethyl or propyl, and

5 6 6

R is -(CH ) -R where R is hydrogen or lower alkyl, or

R can be attached to the carbon atom carrying the hydroxy group

during the formation of a carbocyclic ring with 5-8 members.

A is ethylene (-CH2CH2-), a-methylethylene (-CH2-CH(CH^)-)

or oxymethylene (-0-CH2-).

It will be seen that the carbon atom bearing the hydroxyl group i

formula I, is asymmetric. The invention also includes making

none of the stereoisomers where the asymmetric center is exclusively in one or the other of the two possible configurations, R and S.

The compounds of formula I are designated 8-aza-9-dioxo-thia-11,12-secoprostaglandins because of their structural relationship to the naturally occurring prostaglandins.

The prostaglandins constitute a biologically prominent group of naturally occurring, highly functionalized C2Q fatty acids that are readily anabolized in a heterogeneous group of mammalian tissues from three essential fatty acids, namely 8,11,14-eicosatrienoic acid, 5,8,11,14-eicosatetraenoic acid and 5,8,8 11,14,17-eicosapentaenoic acid. Each known prostaglandin is a formal derivative of the parent compound, called "prostanic acid", which is a C2Q fatty acid covalently bridged between the 8-12 carbon atoms to form a trans, neighboring atom-substituted cyclopentane in which the carboxy-bearing side chain is in the "alpha" position or below the plane of the ring, and the other side chain is in the "beta" position or above the plane of the ring as shown in formula II:

The six known main prostaglandins, PGE-^, PGE2 / PGE^, PGF1, PGF2a and PGF3a' SOm are obtained directly from anabolism of the above-mentioned essential fatty acids by the action of prostaglandin synthetase, as well as the three prostaglandins obtained from in vivo dehydration of The PGEs, i.e. PGA-^, PGA2 and PGA3, are divided into three groups namely the PGE, PGF and PGA series on the basis of three distinct cyclopentane core substitution patterns illustrated as follows:

It should be noted that the Arabic indices denote the number of carbon-carbon double bonds in the indicated compound, and that the Greek indices used in the PGF series indicate the stereochemistry of the hydroxyl group in the 9-position.

Although the prostaglandins were discovered independently in the mid-1930s by Goldblatt (J. Chem. Soc. Chem. Ind. Lond., 52, 1056 (1933)) in England and Von Euler (Arch. Exp. Path. Pharmark., 175 , 78 (1934)) in Sweden, these complex natural products attracted little attention in the scientific world until the early 1960s which coincides with the advent of modern instrumentation, e.g. mass spectrometry, which again was necessary for their successful isolation and structural investigation by Bergstrom et al. (see Angew. Chem. Int. Ed., £, 410 (1965) and references cited therein for an account of this work). During the last 10 years, a great international scientific effort has been made to develop both biosynthetic and chemical routes to., production of the prostaglandins, and then to investigate their biological activity; During this time it has been recognized that prostaglandins occur extensively in low concentrations in a number of mammalian tissues where they are both rapidly anabolized and catabolized and exhibit an enormous spectrum of pharmacological activities including prominent roles in (a) functional hyperemia, ( b) the inflammatory response, (c) the central nervous system, (d) transport of water and electrolytes, and (e) regulation of cyclic AMP. Further details regarding the prostaglandins can be found in recently published reviews of their chemistry (J.E. Pike, Fortschr. Chem. Org. Naturst., 2jJ, (1970) and G.F. Bundy, A.Rep. in Med. Chem., 1_, 157 (1972 )), biochemistry >(j.W. Hinman, A.Rev. Biochem., 41, 161 (1972)), physiological significance (e.W. Horton, Physiol. Rev., 49, 122 (1969)) and general clinical application

(j. W. Hinman, Postgrad. Med. J., 4j5 , 562 (1970)).

The potential application of natural prostaglandins as medically useful therapeutic agents in various mammalian disease states is obvious, but suffers from three major drawbacks, namely (a) prostaglandins are known to be rapidly metabolized in vivo in various mammalian tissues to a variety of metabolites free of the desired original biological activities, (b) the natural prostaglandins have an inherent lack of biological specificity necessary for a successful drug, and (c) although limited quantities of prostaglandins are now produced by both chemical and biochemical methods, the cost of production is very high,

and therefore their availability is rather limited.

The aim of the present invention has therefore been to synthesize new compounds which are structurally related to the natural prostaglandins, but with the following major advantages: (a) simplicity of the synthesis which leads to low production costs, (b) specificity of biological activity which can be either of a prostaglandin-mimicking or prostaglandin-antagonizing type, (c) increased metabolic stability. The combination of these advantages serves to provide effective, orally and parenterally active therapeutic agents for the treatment of a variety of human and animal diseases. These include applications in the renal, cardiovascular, gastrointestinal, respiratory, immune and reproductive systems, and in combating lipid metabolism, inflammation, blood clotting, skin diseases and certain cancers.

More specifically, in the clinic, prostaglandin agonists can act as agents to improve renal function (e.g. renal vasodilation), anti-ulcer agents, agents for fertility regulation, anti-thrombotics, anti-asthmatics, anti-lipblytics, anti-neoplastic agents, agents for the treatment of certain skin diseases, dwarfism (by causing growth hormone release) and certain autoimmune diseases.

Prostaglandin antagonists can act as anti-inflammatory agents, anti-diarrheal agents, antipyretics, agents to prevent premature labor and agents to treat headaches.

The process compounds have the unexpected and valuable property of acting as renal vasodilators (they increase renal blood flow in dogs when administered orally). The process compounds also have the unexpected and valuable activity of inhibiting platelet aggregation in the blood of guinea pigs after oral administration of one of the process compounds.

The procedure connections can be managed either

locally or systemically, i.e. intravenously, subcutaneously, intramuscularly, orally, rectally or by aerosolization in the form of sterile long-acting implants. They can be processed into a number of pharmaceutical preparations and non-toxic carriers for this purpose.

The pharmaceutical preparations may be sterile injectable suspensions or solutions, or solid orally administrable pharmaceutically acceptable tablets or capsules. The preparations can also be intended for sub-lingual administration, local application or for suppository use. It is particularly advantageous to produce the preparations in unit dose forms for easy and economical administration of regular doses.

It is preferred to prepare preparations, whether aqueous or oily, in a concentration in the range from 2 to 50 mg/ml. Lower concentrations require unnecessary amounts of liquid. Higher concentrations than 50 mg/ml are difficult to maintain, and are preferably avoided.

A fixed dosage unit is usually prepared containing

from 0.5 mg to 25 mg of active ingredient.

Regardless of the method of administration, doses in the range from approx. 0.10 to 20 mg/kg body weight administered one to four times per day. The exact dose depends on the age, weight and condition of the patient, and the frequency and method of administration.

The new chemical compounds with formula I are prepared according to the invention by

a) a compound with the formula:

1 8 where R and A are as stated above, and R is lower alkyl with 1-5 carbon atoms, is reacted with approx. an equivalently strong base, and then with approx. one equivalent of a compound with the formula:

where X is halogen, R 5 is as indicated above, and R ^ is lower alkanoyl with 1-4 carbon atoms, the compound formed being recovered and subjected to mild hydrolysis to remove the blocking groups R Q and R Q, after which the desired product is recovered, or

b) a compound of the formula:

where R"*" and R^ are as above, and R"*"*"* is tet rahydropyranyl, is reacted with about one equivalent of a strong base and then with about one equivalent of a compound of the formula: where X is halogen, A and R 8 are as indicated above, and that the resulting intermediate is recovered and subjected to mild hydrolysis to remove the blocking groups R° 8 and R 10, whereupon the desired product is recovered. In the first method, the reaction can be is carried out by preparing the alkali metal salt of the compound of formula III by reacting compound III with sodium hydride in a solvent, such as a 1:1 mixture of benzene and dimethylformamide, adding compound IV at room temperature, and then heating the reaction mixture at 50 - 100°C in from 1 to 20 hours This reaction scheme gives intermediates with the formula:

■1 Q C R

where A, R , R and R are as above, indicated , and R is alkyl of 1-5 carbon atoms. Mild basic hydrolysis (NaOH in aqueous methanol or ethanol) of the ester functions in compound V gives compounds of formula I.

In the second method, the reaction can be carried out by preparing the alkali metal salt of compound VII (where R^ is

6 6

-(CH2)2~R where R is hydrogen or lower alkyl with 1-4 carbon atoms) by reacting compound VII with sodium hydride in a solvent such as a 1:1 mixture of benzene and dimethylformamide, adding compound VIII at room temperature and then heating the reaction mixture at 50 - 100°C for 1 - 20 hours. This reaction scheme gives intermediate products with formula:

Mild acid hydrolysis (aqueous HCl in methanol or ethanol) removes the protecting tetrahydropyranyl group, and then mild basic hydrolysis (NaOH in aqueous methanol or ethanol) of the ester function gives compounds of formula I. It is often advantageous-

like from a therapeutic point of view to produce pre-

bonds of formula I where the asymmetric carbon atom bearing OH is only in the R or S configuration. As is known, the corresponding center in the natural prostaglandins is in S-configuration, and inversion of this center may possibly cause a reduction in biological activity, although a marked increase in biological specificity is often obtained.

In the present series of .. 8-aza-9-dioxo-thia-11,12-secoprostaglandins, compounds that are exclusively R or S at this center can be prepared by using pre//cleaved compounds IV or VII, and performing the steps in methods 1 or 2. An example of the use of such a pre-cleaved compound IV is given under the description of the preparation of intermediate products (examples J and K).

Manufacture of derivatives of products

The directly obtained products by the present methods described above can be transferred to derivatives thereof to form the other products with formula I.

Production of starting materials

1. The reagent III having the general formula:

18

where A, R and R are as indicated above, is prepared in the following way. The sodium salt of the corresponding alkanesulfonamide is treated with the appropriate halogen compound (ie X-(CH2)^-A-COOR°Q) whereby the reagent of formula III is obtained.

2. The reagent IV with the general formula:

where X is halogen and RJ and R are as indicated above, is prepared in the following way. A Grignard reagent R^-Mgl or R^-MgBr is reacted, in ether, with a nitrile X(CH ) CN-. The formed imine is hydrolysed in aqueous acidic solution to obtain ketones with the formula:

The ketones (XI) are reduced to the corresponding alcohols X(CH-j)gCH(OH)-R with sodium or potassium borohydride in a suitable solvent such as methanol, ethanol or diglyme. Acetylation of these alcohols, preferably with acetic anhydride, gives the reagents IV.

3. The reagent VII with the formula:

is produced by treating the alcohol produced under point 2 above with the formula with dihydropyran and a catalytic amount of acid, whereby treatment of this halogen compound with the sodium salt of phthalimide in dimethylformamide gives the corresponding phthalimido compound. Cleavage of this compound with hydrazine in ethanol yields the amine

as in treatment with the appropriate

alkanesulfonyl chloride • ■ J in pyridine gives reagent-: set VII. ' • f

4. Preparation of reagents of formula VIII:

has been described in the scientific and patent literature in cases where A is ethylene, trimethylene, α-methylethylene, B-methylethylene, α,α-dimethylethylene, 6,8-dimethylethylene. To prepare reagents where A is oxymethylene,. an ester of glycolic acid, HOCH2COOR, is treated with a strong base, preferably sodium hydride, in a non-protic solvent (dimethylformamide, glyme and the like) and the anion formed is reacted with a 1,4-dihalo-butane, preferably 1,4-dibromobutane. The glycol acid ester and the base are used in approximately equimolar amounts, with a 1.5 - 2 molar excess of the dihalobutane being used with advantage. 5. Methods for obtaining optical antipodes of some compounds produced according to the invention are described whereby one of the compounds of the molecule is cleaved before it is placed in the entire molecule. Other methods can also be used, e.g. mixtures.of racemates can. are separated by taking advantage of physiochemical differences between the components using chromatography and/or fractional crystallization. The racemic products and intermediates of this invention may be resolved into their optically active components by any of a number of resolution methods well described in the chemical literature.

The compounds which are carboxylic acids can be converted to the diastereoisomeric salts by treatment with an optically active base such as + or - ct-methylbenzylamine, or - ct-(1-naphthyl)-ethyl-amine, brucine, cinchonine, cinchonidine or quinine. These diastereoisomeric salts can be separated by fractional crystallization.

The carboxylic acids produced according to the invention can also be converted to esters using an optically active alcohol, such as estradiol-3-acetate or d- or 1-methol, and the diastereoisomeric esters can be separated by crystallization or by chromatography.

Racemic carboxylic acids can also be resolved by reverse phase and absorption chromatography using an optically active carrier and absorbent.

Compounds produced according to the invention, which contain free hydroxyl groups, can be esterified with acid chlorides or anhydrides derived from optically active acids, such as (=)-10-camphor-sulfonic acid, ( = )-α-bromocamphor-ir-sulfonic acid, or d- or 1-6,6'-dinitrodiphenic acid with the formation of esters which can be separated by crystallization.

Another method of obtaining pure optical isomers involves incubating the racemic mixture with certain microorganisms such as fungi, by well-known methods, and recovering the product formed by the enzymatic conversion.

The methods described above are particularly effective

if the method is applied to a compound where an asymmetric center is separated by the methods already described.

The invention will be described further in the following examples.

Production of intermediate products

A. Preparation of l-chloro-4-acetoxynonane

Step 1. Preparation of l-chloro-4-nonanone

To 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 1000 ml of ether are added dropwise over the course of 1 hour to 155.34 g (1.5 mol) of 4-chlorobutyronitrile. Stirring is continued for a further 1 hour. The reaction mixture is poured into a mixture of 1000 g of finely crushed ice and 750 ml of concentrated hydrochloric acid. The ether layer is quickly separated and discarded. The aqueous layer is heated on a steam bath for 1 hour to hydrolyze the imine intermediate and cause the ketone to separate as an oil. After cooling, the oil is extracted with ether and the combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed under vacuum and

the residual oil is distilled, whereby 69.0 g (26%) of colorless oil is obtained, b.p. 115 - 117°C/14 mm, pmr (CDCl 3 ) <5 0.90 (3H,t), 3.56 (2H,t,CH 2 Cl).

Step 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 treated dropwise over 1 hour with 61.40 g (0.349 mol) of -1-chloro-4-nonanone while maintaining the temperature at 45 - 50° C. Stirring is continued for a further 1 hour without external cooling.

The reaction mixture is acidified with concentrated hydrochloric acid to the Congo red end point and then the ethanol is removed under reduced pressure. The residue is treated with 200 ml of water and the oil formed is extracted with ether. The combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed under vacuum whereby the title compound is obtained as a light yellow residual oil, yield 58.85 g, .ir (pure) 3400 cm<-1>.

Step 3. Preparation of l-chloro-4-acetoxynonane

A mixture of 111.99 g (0.627 mol) of 1-chloro-4-nonanol and 128.0 g (1.254 mol) of acetic anhydride is heated on a steam bath for 1.5 hours.

The volatile substances are removed under reduced pressure and the residual oil is distilled, whereby 88.6 g (64%) of colorless oil is obtained,

k.p. 130 - 133°C/14 mm, pmr (CQCl-j) a 0.89 (3H,t), 2.02 (3H,s CH3~ COO), 3.53 (2H,t CH2Cl), 4.89 (lH,m). Analysis: Calculated for <C>ll<H>21Clo2: C 59'85> H 9'59-

Found: C 59 .87., H 9.67.

B. Preparation of 1-chloro-4-acetoxy-8-methylnonane

Step 1. Preparation of l-chloro-8-methyl-4-nonanone

To the Grignard reagent prepared from a mixture of 200.00 g (1.21 mol) l-bromo-4-methylpentane and 29.43 g (1.21 mol) magnesium in 800 ml ether is added dropwise over the course of 1 hour 125 .30 g (1.21 mol) of 4-chlorobutyronitrile. Stirring is continued for a further 1 hour.

Reaction mixtures are poured into a mixture of 800 g of finely crushed ice and 600 ml of concentrated hydrochloric acid. The ether layer is quickly separated and discarded. The aqueous layer is heated on a steam bath for 1 hour to hydrolyse the imine intermediate and cause separation of the ketone as an oil. After cooling, the oil is extracted with ether and the combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed under vacuum and the residual oil is distilled, yielding 23.3 g (10%) colorless oil, b.p. 121 - 122°C/15 mm, pmr (CDCl 3 ) a 0.89 (6H,d), 3.57 (2H,t CH 2 Cl ).

Analysis: Calculated for C^H^gCl/:

C 62.98, H 10.04

Found: C 62.86, H 10.20

Step 2. Preparation of l-chloro-8-methyl-4-nonanol

A suspension of 2.3 g (0.061 mol) of sodium borohydride and 0.5 g of sodium hydroxide in 110 ml of ethanol is treated dropwise over the course of 1 hour with 23.0 g (0.121 mol) of 1-chloro-8-methyl-4-nonanone while the temperature is kept at 45 - 50° C. The stirring is continued for a further 1 hour without external cooling.

The reaction mixture is acidified with concentrated hydrochloric acid to the congo red end point and then the ethanol is removed under reduced pressure. The residue is treated with 70 ml of water and the oil formed is extracted with ether. The combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed under vacuum whereby the title compound is obtained as a pale yellow residual oil, yield 22.73 g, ir (pure) 3400 cm<-1>..

Step 3. Preparation of l-chloro-4-acetoxy-8-methylnonane

A mixture of 22.73 g (0.118 mol) of 1-chloro-8-methyl-4-nonanol and 24.07 g (0.236 mol) of acetic anhydride is heated on a steam bath for 1.5 hours.

The volatile substances are removed under reduced pressure and the residual oil is distilled, whereby 14.58 g (58%) of colorless oil is obtained,

kp. 138 - 139°C/15 mm, pmr (CDCl 3 ) a 0.85 (6H,d), 2.02 (3H,s CH 3 COO), 3.53 (2H,tCH 2 Cl), 4.92 (1H,m) .

C. Preparation of l-chloro-4-acetoxyundecane

Step 1. Preparation of l-chloro-4-undecanone

This compound is prepared essentially by the same procedure as described for 1-chloro-4-nonanone (Example A, step 1) using the following reagents:

The title compound is obtained as a colorless oil, yield 60.4 g (15%), b.p. 135 - 14 0°C/15 mm,, pmr (CDCl 3 ) a 0.93, (3Hjt) , 3.57 (2H,t CH 2 Cl ).

Step 2. Preparation of l-chloro-4-undecanol

This compound is prepared essentially by the same procedure as described for 1-chloro-4-nonanol (Example A, step 2) using the following reagents:

The title compound is obtained as a yellow residual oil in a yield of 60.02 g.

Step 3. Preparation of l-chloro-4-acetoxy-undecane

This compound is prepared essentially by the same procedure as described for 1-chloro-4-acetoxynonane (Example A, step 3), using the following reagents:

The title compound is obtained as a colorless oil, yield 44.6 g (62%), b.p. 155 - 158°C/15 mm, pmr (CDCl3) a 0.88 (3H,t), 2.02 (3H,s CH3COO), 3.53 (2H,t CH2Cl), 4.92 (1H,m ).

Analysis: Calculated for C^H^CIO,^:

C 62.76, H 10.13

Found: C 63.03, H 10.40

D. Preparation of 1-chloro-4-acetoxy-8,8-dimethyl-nonane

By following the procedure described for 1-chloro-4-acetoxynonane (Example A), but using 1-brpm-4,4-dimethylpentane instead of amyl bromide, one obtains successively: 1-chloro-8,8- dimethyl-4-nonanone,,- 1-chloro-8,8-dimethyl-4-nonanol and 1-chloro-4-acetoxy-8,8-. dimethyl nonane.

L. Preparation of T- kTor- 4- acetoxv- 9, 9, 9- trifluoro- nonane

By following the procedure described for l-chloro-4-acetoxynonane (Example A), but using l-bromo-5,5,5-trifluoropentane instead of amyl bromide, one obtains one after the other: l-chloro-9,9 ,9-trifluoro-4-nonanone, 1-chloro-9,9,9-trifluoro-4-nonanol and 1-chloro-4-acetoxy-9,9,9-trifluorononane.

F. Preparation of l-chloro-4-acetoxy-8-nonene

By following the procedure described for l-chloro-4-acetoxynonane (example A), but by using l-bromo-4-pentene instead of amyl bromide, l-chloro-8-nonen-4-one, l- chloro-8-nonen-4-ol and 1-chloro-4-acetoxy-8-nonene.

G. Preparation of l-chloro-4-acetoxy-5,5-dimethyl-4-nonane Step 1. Preparation of l-chloro-5,5-dimethyl-4-nonanone

400 ml of a solution in ether of 1,1-dimethylpentylmagnesium chloride prepared from 24.3 g (1.0 mol) magnesium and 134.5 g (1.0 mol) 1-chloro-1,1-dimethylpentane according to to the method of Whitmore and Badertscher (J.Am. Chem. Soc, 5-5, 1559 (1933)) is added dropwise with stirring to 197 g (1.4 mol) of 4-chlorobutyryl chloride in 400 ml of ether over the course of 6 hours. The reaction mixture is stirred for a further 12 hours. It is then poured into a mixture of ice and dilute hydrochloric acid. The ether layer is separated, washed with water and brine, and dried over sodium sulfate. The ether is evaporated and the residue is distilled by water jet vacuum through a Vigreaux column, whereby the product is obtained as a colorless oil.

Step 2. Preparation of l-chloro-5,5-dimethyl-4-nonanol

By following the procedure described for l-chloro-4-nonanol (Example A, step 2), but using l-chloro-5,5-dimethyl-4-nonanone instead of l-chloro-4-nonanone and continuing the stirring and the heating at 50° C. for 6 hours, 1-chloro-5,5-dimethyl-4-nonanol is obtained.

Step 3. Preparation of l-chloro-4-acetoxy-5,5-dimethylnonane

By following the procedure described for l-chloro-4-acetoxynonane (Example A, step 3), but using l-chloro-5,5-dimethyl-4-nonanol instead of l-chloro-4-nonanol, and proceeding heating on a steam bath for 4 hours, 1-chloro-4-acetoxy-5,5-dimethylnonane is obtained.

H. Preparation of l-bromo-4-acetoxy-2-nonene

A mixture of 73.5 g (0.4 mol) of 4-acetoxy-2-nonene, 80.0 g (9.45 mol) of N-bromosuccinimide and 500 ml of carbon tetrachloride is refluxed for 3 hours. The mixture is then cooled and the suspended succinimide is removed by filtration. Carbon tetrachloride solution is washed with dilute sodium bicarbonate solution and water, and dried over sodium sulfate. The carbon tetrachloride is evaporated in vacuo and the residual oil is distilled, whereby 62 g (59%) of l-bromo-4-acetoxy-2-nonene is obtained as a light yellow oil, b.p. 110 - 112°C/0.1 mm.

I. Preparation of l-bromo-4-acetoxy-2-nonyne

Step 1 Preparation of 3-acetoxy-l-octyne

100 g (0.794 mol) of 1-octyn-3-ol are dissolved in 79 g (1.0 mol) of pyridine and 81.6 g (0.80 mol) of acetic anhydride are added dropwise with stirring over the course of 1 hour. The temperature rises to 45° C. The solution is heated at 55° C for 1 hour and then cooled and poured

in 200 ml of ice-cold 5% hydrochloric acid. The oily product is taken up in ether, washed with water and brine, and dried over sodium sulfate. The ether is evaporated and the residual oil is distilled, whereby 106.4 g (80%) of 3-acetoxy-1-octyne, b.p. 91 - 92°C/15 mm.

Step 2 Preparation of 1-diethylamino-4-acetoxy-2-nonyne

A mixture of 58.8 g (9.35 mol) 3-acetoxy-l-octyne, 28.5 g (0.39 mol) diethylamine, 13.8 g (0.46 mol) paraformaldehyde and 60 ml p-dioxane heated on a steam bath under reflux for 17 hours. The solution obtained is cooled and diluted with 250 ml of ether. The solution is extracted with 300 ml of 5% hydrochloric acid. The acidic aqueous extract is made alkaline with 10% sodium hydroxide solution.

The liberated amine is taken up in ether, washed with water and brine, and dried over sodium sulphate. The ether is evaporated and the residual oil is distilled, thereby obtaining 73.1 g (89%) of 1-diethylamino-4-acetoxy-2-nonyne, b.p. 103 - 109°C/0.3 mm.

Analysis: Calculated for ci5H27N02:

C 71.10, H 10.74, N 5.33

Found: C 70.73, H 11.03, N 5.55

Step 3 Preparation of l-bromo-4-acetoxy-2-nonyne

A solution of 50.6 g (0.20 mol) 1-diethylamino-4-acetoxy-2-nonyne and 21.2 g (0.20 mol) cyanogen bromide in 250 ml ether is allowed to stand at 25 - -27° C for 18 hours. The ether solution is washed with 5% hydrochloric acid solution, water and brine, and dried over sodium sulphate. The ether is evaporated and the residual oil is distilled. After a course of diethylcyanamide, 34.1 g (65%) of 1-bromo-4-acetoxy-2-nonyne, b.p. 97 - 105°C/0.2 mm.

Analysis: Calculated for C-^H^BrC^:

C 50.59, H 6.56 Found: C 50.54, H 6.49.

— Preparation of l-bromo-4(R)-acetoxy-2-nonyne

Following the procedure described in Example H, but using (R)-l-octyn-3-ol, (ct)D + 6.1° (c 3.1, CHCl3) instead of the racemic l-octyn-3 -ol, are obtained one after the other: 3(R)-acetoxy-1-octyne, (a)D + 70° 3.1, CHCl3), 1-diethylamino-4(R)-acetoxy-2-nonyne, ia-} ^+ 74° (c 3>2' CHCl 3 ), and l-bromo-4(R)-acetoxy-2-nonyne, (ct)^6 + 75° (C 3.2, CHCl 3 ).'

K. Preparation of l-bromo-4(S)-acetoxy-2-nonyne

By following the procedure described in example H, except by using (S)-l-octyn-3-ol, (a)^ - 6.4° (c 3.3, CHCl3), instead of the racemic l-octyn- 3-ol, is obtained successively: 3 (S)-acetoxy-1-octyne, (a)n - 79° (c 3.0, CHC1,}, 1-diethylamino-4(S)-acetoxy-2-nonyne , (a)Q - 80° (C 3.3, CHCl 3 ), and 1-bromo-4(S)-acetoxy-2-nonyne, (a)£<6> 83° (3.7, CHCl 3 ).

L. Preparation of methyl-7-bromo-2-methylheptanoate

Step 1 Preparation of 5-acetoxypentyl chloride

102 g g (1 mol) acetic anhydride is added dropwise with stirring to 90 g (0.74 mol) pentamethylene chlorohydrin. The resulting solution is heated on a steam bath for 1 hour and allowed to stand overnight at room temperature. The reaction mixture is distilled, whereby 83.6 g (69%) of 5-acetoxypentyl chloride, b.p. 101 - 104°C/20 mm.

Step 2 Preparation of diethyl-(5-aceoxypentyl)-methylmalonate

4.8 g (0.2 mol) of sodium hydride as a 50% suspension in mineral oil is washed with petroleum ether under nitrogen to remove the mineral oil, suspended in 150 ml of dry benzene and the suspension cooled in an ice bath. 34.8 g (0.2 mol) diethylmethylmalonate dissolved in 150 ml sieve-dried dimethylformamide is added dropwise to the suspension a<y> sodium hydride. The mixture is left overnight at room temperature. 0.4 g potassium iodide and 32.9 g (0.2 mol) 5-acetoxy-

phenyl chloride is then added and the mixture is heated for 24 hours at 125° C. in an oil bath. The reaction mixture is evaporated in vacuo, diluted with 200 ml of ether and filtered to remove sodium chloride. The filtrate is washed with brine, dried over anhydrous magnesium sulfate and evaporated to obtain 39.6 g (66%) of oily product.

Step 3 Preparation of 7-bromo-2-roethyT^heptanoic acid."

A mixture of 68 g (0.23 mol) of the crude diethyl-(5-acetoxypentyl)-methyl malonate and 100 ml of 48% aqueous hydrogen bromide is boiled under reflux for 20 hours. The mixture is then concentrated by distillation until the internal temperature rises to 120° C, as 96 ml of distillate (2 layers) is collected. The remaining liquid is cooled, dissolved in ether, washed with brine, dried over magnesium sulfate, and the solution is evaporated in vacuo to obtain 54 g of crude 7-bromo-2-methylheptanoic acid as a dark viscous liquid.

Step 4 Preparation of methyl-7-bromo-2-methylheptanoate

A solution of 54 g (0.24 mol) of crude 7-bromo-2-methylheptanoic acid and 2 drops of concentrated sulfuric acid in 300 ml of absolute methanol is refluxed for 5 hours. , After standing overnight at room temperature, the solution is evaporated in a vacuum and diluted with water. The mixture is made alkaline by adding saturated sodium carbonate solution and the product is taken up in ether. The ether extract is washed with water, dried over anhydrous magnesium sulfate and distilled, whereby 11.8 g (16%) of methyl-7-bromo-2-methylheptanoate, b.p. 67 - 70°C/0.05 mm, pmr (CDCl3) a 1.13 (3H,d 2-CH3), 2.42 (1H,m CHCOOCH3), 3.38 (2H,t-CR^Br) , 3.65 (3H,s CH 3 O).

M. Preparation of ethyl-4-bromobutoxyacetate

9.0 g (0.375 mol) of sodium hydride is suspended in 1,2-dimethoxyethane. The mixture is stirred and cooled in an ice bath while 39.0 g (0.375 mol) of ethyl glycolate is added dropwise over the course of 1 hour. 108 g (0.5 mol) of 1,4-dibromobutane is added once to the thick suspension formed. The mixture is heated gently to initiate a strong exothermic reaction, then the mixture is heated for 3 hours on a steam bath. The mixture is poured into cold water. The heavy oil layer is taken up in ether, washed with three portions of water and dried over sodium sulphate.

Evaporation of the ether and distillation of the remaining oil gives 21.3 g (24%) of ethyl-4-bromobutoxyacetate, a colorless oil with a boiling point of 99 - 103°C/0.2 mm.

N. Preparation of N-(4-(2-tetrahydropyranyloxy)-nonyl)-methanesulfonamide

Step 1 Preparation of l-chloro-4-(2-tetrahydropyranyloxy)-nonane

To a stirred solution of 11.0 g (0.062 mol) of 1-chloro-4-hydroxynonane (Example A, step 2) and 5.2 g (0.062 mol) of hydropyran cooled in an ice bath, 5 drops of concentrated hydrochloric acid are added. A weak exothermic reaction is observed and when this has ended, the reaction mixture is allowed to reach room temperature and then stands for 2 hours. At the end of this period, several pellets of sodium hydroxide are added and the reaction mixture is distilled in a vacuum. The yield of 1-chloro-4-(2-tetrahydropyranyloxy)-nonane is 12.5 g (77%), boiling point 96 - 102°C/0.1 mm. Redistillation gives a boiling point of 90 - 92<2>C/0.1 mm.

Step 2 Preparation of N-(4-(2-tetrahydropyranyloxy)-nonyl)-phthalimide

1.5 g excess of 53% sodium hydride is washed with benzene three times by decantation, then 100 ml of dimethylformamide is added. To this stirred suspension is added a solution of 4.3 g (0.03 mol) of phthalimide in 50 ml of dimethylformamide at such a rate that the temperature is kept below 35° C. A clear solution is obtained and to this is added 7.8 g (0. 03 mol) 1-chloro-4-(2-tetrahydropyranyloxy)-nonane, and the resulting solution is stirred and heated at 95° C. for 20 hours. The reaction mixture is then evaporated to half the volume in a vacuum, poured into 200 ml of ice water and extracted with 2 x 150 ml of ether. The ether is washed with 2 x 50 ml of 5% sodium hydroxide, 2 x 50 ml of saturated sodium chloride solution, and then dried over sodium sulphate. Evaporation of the ether gives 4.5 g (45% yield) of N-(4-(2-tetrahydropyranyloxy)-nonyl)-phthalimide which melts at 59 - 61° C. After crystallization from cyclohexane the product melts at 62 - 63° C .

Analysis: Calculated for C22<H>31<N>04:

C 70.75, H 8.36, N 3.75

Found: C 71.03, H 8.28, N 3.81

Step 3 Preparation of 4-(2-tetrahydropyranyloxy)-nonylamine

To a solution of 33.0 g (0.88 mol) N-(4-(2-tetrahydro-pyranyloxy)-nonyl)-phthalimide in 300 ml absolute ethanol, 10 ml excess of 64% hydrazine is added and the reaction mixture is heated under reflux for 1.5 hours. A further 5 ml of 64% hydrazine is added and the reflux is continued for 1.5 hours. The reaction mixture is cooled to room temperature and the solid white substance present is removed by filtration. The filtrate is evaporated in vacuo to 75 ml, and then poured into 200 ml of water. The solution is made alkaline with 5% sodium hydroxide and then extracted with 3 x 100 ml of ether. The ether layer is washed with saturated sodium chloride solution, and then dried over sodium sulfate. The ether is removed in vacuo and the oil obtained is distilled. The yield of 4-(2-tetrahydropyranyloxy)-nonylamine is 16.0 g (75%), b.p. 100 - 102°C/0.1 mm.

Analysis: Calculated for ci4H<2>9N<0>2<:>

C 69.08, H 12.01, N 5.75

Found: C 68.58, H 12.42, N 5.66

Step 4 Preparation of N-(4-(2-tetrahydropyranyloxy)-nonyl)-methanesulfonamide

To a stirred, ice-cold solution of 7.29 g (0.03 mol) 4-(2-tetrahydropyraryloxy)-nonylamine in 40 ml pyridine is added 3.42 g (0.03 mol) methanesulfonyl chloride at such a rate that the reaction temperature kept at 5 - 10° C. The reaction mixture is then allowed to stand at room temperature for 6 hours, poured into 200 ml of ice water and extracted with 2 x 100 ml of ether. The ether is washed with 2 x 20 ml ice-cold 5% hydrochloric acid, 2 x 25 ml brine and dried over sodium sulphate. Evaporation in vacuo gives N-(4-(2-tetrahydropyranyloxy)-nonyl)-methanesulfonamide as a pale yellow liquid.

O. Preparation of ethyl 7-(methanesulfonamido)heptanoate

A stirred suspension of 2.33 g (0.055 mol) of 57% strength sodium hydride in a solvent mixture of 50 ml of benzene and 50 ml of dimethylformamide is treated over 30 minutes with 4.75 g (0.055 mol) of methanesulfonamide. This mixture is heated on a steam bath for 1.5 hours and then cooled to room temperature. At this temperature, 13 g (0.055 mol) of ethyl 7-bromoheptanoate are added and the reaction mixture is heated at 90° C. for 20 hours. The reaction mixture is then poured into 200 ml of water, neutralized with hydrochloric acid and extracted with 2 x 100 ml of ethyl acetate. The ethyl acetate layer is washed with brine, dried over sodium sulfate and then evaporated in vacuo. The yield of ethyl 7-(methanesulfonamido)heptanoate is 7.1 g (51%), b.p. 165 - 168°C/0.1 mm.

Analysis: Calculated for ClQH21<N>O^S:

C 47.78, H 8.42, N 5.57

Found: C 47.05, H 8.51, N 5.41

P. Preparation of ethyl 7-(ethanesulfonamido)heptanoate

The synthesis of this compound is carried out as described in example 0, except that the methanesulfonamide is replaced by an equimolar amount of ethanesulfonamide. Ethyl 7-(ethanesulfonamido)heptanoate is obtained as a pale yellow oil by evaporation of the ethyl acetate extracts.

Q. Preparation of ethyl 7-(propanesulfonamido)heptanoate

By following the procedure described in example 0, but using propanesulfonamide instead of methanesulfonamide, ethyl 7-(propanesulfonamido)heptanoate is obtained.

R. Preparation of ethyl 7-((1-methylethane)-sulfonamido)-heptanoate

By following the procedure described in example 0, but by using 1-methylethanesulfonamide instead of methanesulfonamide, ethyl 7-((1-methylethane)-sulfonamido)-heptanoate is obtained.

S. Preparation of l-chloro-4-acetoxy-4-methylnonane

The Grignard reagent prepared from 14.2 g (0.1 mol) iodomethane and 2.4 g (0.1 mol) magnesium in ether solution is added dropwise to an ether solution of 17.6 g (0.1 mol) l-chloro- 4-Nonanone (Example A, Step 1). The reaction mixture is carefully refluxed for 3 hours, then cooled and carefully poured into 300 ml of ice water. The ether layer is separated, washed with brine and dried over sodium sulphate. Removal of the ether in vacuo gives 1-klbr-4-hydroxy-4-methylnonane as an oil. The tertiary alcohol is dissolved in pyridine and treated with one molar equivalent of acetic anhydride at 60 - 80°C

for 8 - 16 hours to obtain l-chloro-4-acetoxy-4-methylnonane as a colorless oil.

T. Preparation of l-brom-4-acetoxy-4-propyl-2-heptyne

Step 1 Preparation of 3-acetoxy-3-propyl-l-hexyne

98.0 g (0.7 mol) of 3-propyl-1-hexyn-3-ol is added dropwise with stirring to a mixture of 79.5 g (0.78 mol) of acetic anhydride and 0.25 ml of sulfuric acid over 50 minutes as the temperature rises to 50° C. The mixture is allowed to stand for 18 hours and then poured into 300 ml of ice water. The oily product is taken up in ether, washed with water, dilute sodium bicarbonate solution and brine, and dried over sodium sulfate. Distillation gives 108.5 g (86%) of 3-acetoxy-3-propyl-1-hexyne, b.p. 93 - 95°G/17mm.

Step 2 Preparation of 1-diethylamino-4-acetoxy-4-propyl-2-heptyne

A mixture of 115.2 g (0.634 mol) 3-acetoxy-3-propyl-1-hexyne, 51 g (0.7 mol) diethylamine, 24.9 g (0.83 mol) paraformaldehyde and 120 ml dioxane is stirred and heated on a steam bath for 2 hours. The reaction mixture is cooled, treated with ether and the product is extracted into ice-cold 5% hydrochloric acid. The cold acidic solution is then made alkaline with ice-cold 10% sodium hydroxide. The oily amine is taken up in ether, washed with water and brine, and dried over sodium sulfate. Distillation gives 99.5 g (59%) of the amine product, b.p. 101 - 110°C/0.1 mm.

Step 3 Preparation of l-bromo-4-acetoxy-4-propyl-2-heptyne

46.6 g (0.44 mol) of cyanogen bromide are added to a solution of 99.0 g (0.371 mol) of 1-diethylamino-4-acetoxy-4-propyl-2-heptyne in 400 ml of ether and the resulting solution leave at 25 - 27° C for 16 hours. The ether solution is washed with 5% hydrochloric acid solution, water and brine, and dried over sodium sulfate. The ether is evaporated and the residual oil is distilled. 70.0 g (69%) of 1-bromo-4-acetoxy-4-propyl-2-heptyne is obtained, a colorless oil with a boiling point of 106 - 107°C/0.1 mm.

Analysis: Calculated for C12HigBr02:

C 52.88, H 6.96

Found: C 52.00, H 6.91

Example 1

Preparation of 7-(n-(4-hydroxynonyl)-methanesulfonamido)-heptanoic acid

Step A: Preparation of ethyl 7-(n-(4-acetoxynonyl)-methanesulfonamido]-heptanoate

°.715 g (0.0298 mol) of sodium hydride is suspended in 30 ml

benzene and 30 ml of dimethylformamide. 6.8 g (0.0271 mol) of ethyl 7-(methanesulfonamido)-heptanoate (Example 0, step 1) is added and the suspension is heated on a steam bath for 15 minutes. After cooling to room temperature, 6.55 g (0.0298 mol) of 1-chloro-4-acetoxynonane (Example A, step 3) are added within 15 minutes and the resulting solution is heated on a steam bath for 20 hours. The reaction mixture is then poured into 300 ml of water and extracted with 3 x 100 ml of ethyl acetate. The organic layer is washed with 2 x 50 ml of brine, dried over sodium sulphate and then evaporated in vacuo to an oil which is purified by chromatography on silica gel. The silica gel is eluted with 3% methanol in chloroform and evaporation of the appropriate fraction gives ethyl 7-(n-(4-acetoxynonyl)-methanesulfonamido)-heptanoate. The yield is 6.0 g (51%). Rf 0.8 (ether).

Analysis: Calculated for C2-^H^^NOgS:

C 57.90, H 9.49, N 3.22

Found: C 58.08, H 9.99, N 2.99

Step B: Preparation of 7-(n-(4-hydroxynonyl)-methanesulfonamido)-heptanoic acid

A solution consisting of 6.0 g (0.0134 mol) ethyl 7-(n-(4-acetoxynonyl)-methanesulfonamido)-heptanoate, 1.66 g (0.0414 mol) sodium hydroxide, 9 ml water and 81 ml ethanol is kept at room temperature for 20 hours. Most of the solvent is removed in vacuo, 150 ml of water is added and the solution is extracted with 100

ml of ethyl acetate. The aqueous layer is then acidified with hydrochloric acid and extracted again with 2 x 75 ml of ethyl acetate. The organic layer is dried over sodium sulfate and then evaporated in vacuo, whereby 7-(n-(4-hydroxynonyl)-methanesulfonamido)-heptanoic acid is obtained. The yield is 4.3 g (88%). Rf o.64 (5% methanol in ether).

Analysis: Calculated for C17H35N05S:

C 55.86, H 9.65, N 3.83

Found: C 56.07, H 9.77, N 3.65

Example 2

Preparation of 7-(n-(4-hydroxy-2-nonynyl)-methanesulfonamido)-heptanoic acid

The synthesis of this compound is carried out as described in example 1 except that in step A the l-chloro-4-acetoxynonane is replaced by an equimolar amount of l-bromo-4-acetoxy-2-nonyne (example I, step 3). The product from step A is thus ethyl 7-(n-(4-acetoxy-2-nonynyl)-methanesulfonamido}heptanoate. Rf 0.9 (ether).

Analysis: Calculated for C^H-^NOgS:

C 58.44, H 8.64, H 3.25

Found: C 57.92, H 9.15, N 3.20

The subsequent step gives 7-{n-(4-hydroxy-2-nonynyl)-methanesulfonamido)-heptanoic acid (B). Rf 0.73 (5% methanol in ether).

Analysis calculated for Cl7H31N05S:

C 56.48, H 8.64, N 3.88

Found: C 56.42, H 9.03, N 3.68

Example 3

Preparation of 7-(N-(4(R)-hydroxynonyl)-methanesulfonamido)-heptanoic acid

The synthesis of this compound is carried out as described in example 1, except that in step A the l-chloro-4-acetoxynone is replaced by an equimolar amount of l-bromo-4(R)-acetoxy-2-nonyne (example J). The product from step A is thus ethyl 7-N-(4(R)-acetoxy-2-nonynyl-methanesulfonamido-heptanoate, (a)^<6> + 46°. (C 2.95, CHCl-j) .

Analysis calculated for C2^H37NOgS:

C 58.44, H 8.64, N 3.25

Found: C 58.77, H 8.98, N 3.13

The subsequent step gives 7-{(N-(4(R)-hydroxy-2-nonyl)-methanesulfonamido)-heptanoic acid (B) , (ct)^<6> + 0.93° (C- 3,3, CHC13).

Analysis calculated for C-^7H31N05S:

C 56.48, H 8.64, N 3.88 Found: C 55.96, H 9.13, N 3.85

The product from step B is hydrogenated over a platinum-on-charcoal catalyst to give 7-(n-(4(R)-hydroxynonyl)-methanesulfonamido}-heptanoic acid, (a) ^6 - 3.0° (C 3 , 72, CHC13).

Analysis calculated for Cl7H3gN0gS:

C 55.86, H 9.65, N 3.83

Found: C 55.62, H 9.76, N 3.70

Example 4

Preparation of 7-(n-(4(S)-hydroxynonyl)-methanesulfonamido)-heptanoic acid

The synthesis of this compound is carried out as described in example 1 except that in step A the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4 (S)-acetoxy-2-nonyne (Example K)'. The product from step A is thus ethyl 7-(n-(4(S)-acetoxy-2-nonynyl)-methanesulfonamido)heptanoate, (et)D - 48.8° (C 2.865, CHCl 3 ).

Analysis calculated for C^H^NOgS:

C 58.44, H 8.64, N 3.25

Found: C 58.72, H 9.15, N 3.13

The subsequent step gives 7-{n-(4(S)-hydroxy-2-nonynyl)-methanesulfonamido}-heptanoic acid (B) , (a)-^6 0.53° (C 3.015, CHCl 3 )

Analysis calculated for C^7H3^NO,-S:

C 56.48, H 8.64, N 3.88

Found: C 56.30, H 8.61, N 3.79

The product from step B is hydrogenated over a platinum-on-charcoal catalyst to give 7-(n-(4(S)-hydroxynonyl)-methanesulfonamido}-heptanoic acid, (°0p6 + 3.92° (C 2.44, CHC13).

Analysis calculated for C^H^NO^S:

W 55.86, H 9.65, N 3.83

Found: C 55.45, H 9.40, N 3.74

Example

Preparation of 7-(n-(4-hydroxynonyl)-methanesulfonamido)-2-methylheptanoic acid

Step A: Preparation of ethyl 7-fN-(4-(2-tetrahydropyranyloxy)-nonyl)-methanesulfonamido}-2- methylheptanoate A stirred suspension of 5.0 g (excess) 57% sodium hydride in a solvent mixture of 75 ml of benzene and 75 ml of dimethylformamide are treated during 30 minutes with 32.1 g (0.1 mol) of N-(4-(2-tetrahydropyranyloxy)-nonyl)-methanesulfonamide (Example N, step 4) dissolved in 20 ml of benzene . The stirring is continued for 1 hour. 25.3 g (0.1 mol) of ethyl 7-bromo-2-methylheptanoate (Example L, step 4) are then added dropwise, and the reaction mixture is heated on a steam bath for 6 hours. The cooled reaction mixture is poured into 400 ml of water and extracted with 2 x 200 ml of ethyl acetate. The organic fractions are combined, washed with brine and dried over sodium sulfate. The solvent is removed in vacuo to give 7-{N-(4-(2-tetrahydropyranyloxy)-nonyl)-methanesulfonamido}-2-methylheptanoate as a pale yellow liquid.

Step B: Preparation of 7-(n-(4-hydroxynonyl)-methanesulfonamido)-2-methylheptanoic acid

A solution is prepared from 4.9 g (0.01 mol) ethyl 7-{N-(4-(2-tetrahydropyranyloxy)-nonyl)-methanesulfonamido}-2-methylheptanoate, 50 ml of ethanol and 4 drops of concentrated hydrochloric acid, and kept at room temperature for 4.5 hours. A solution of 0.72 g (0.081 mol) of sodium hydroxide in 10 ml of water is added to this reaction mixture and the reaction mixture is kept at room temperature for a further 20 hours. Most of the ethanol is removed in vacuo and the residue is dissolved in 100 ml of water. The solution is extracted once with 75 ml of ether and then acidified with dilute hydrochloric acid. The oil that separates is extracted into ether, the ether is washed with brine, dried over sodium sulfate and then removed under vacuum, whereby 7-(n-(4-hydroxynonyl)-methanesulfonamido)-2-methylheptanoic acid is obtained as a yellow liquid.

Example 6 <*>

Preparation of 4-(N-(4-hydroxynonyl)-methanesulfonamido)-butoxyacetic acid

The synthesis of this compound is carried out as described in example 5, except in step A, the ethyl 7-bromo-2-methyl-heptanoate is replaced by an equimolar amount of ethyl-4-bromobutoxyacetate (example -M). The product from step A is thus ethyl 4-{N-(4-(2-tetrahydropyranyloxy)-nonyl)-methanesulfonamido}-butoxyacetate. The following step gives 4-(n-(4-hydroxynonyl)-methanesulfonamido)-butoxyacetic acid (B).

Analysis calculated for C^<H>^NOgS:

C 52.29, H 9.05, N 3.81

Found: C 52.04, H 8.90, N 3.81

Example 7

Preparation of 7-{N-(3-(1-hydroxycyclohexyl)-propylj-methane-sulfonamido}-heptanoic acid

The synthesis of this compound is carried out as described in example 3 except that in step A 1-bromo-4(R)-acetoxy-2-nonyne is replaced by an equimolar amount of 1-acetoxy-1-(3-bromo-1-propynyl)- cyclohexane (Example U). The product from step A is thus ethyl 7-{N-(3-(1-acetoxycyclohexyl)-2-propynyl)-methanesulfonamido}heptanoate. Rf 0.6 (ether).

Analysis calculated for C2iH35N06S:

C 58.72, H 8.21, N 3.26

Found: C 59.05, H 8.39, N 3.05

The subsequent step gives 7-{N-(3-(1-hydroxycyclohexyl)-2-propynyl)-methanesulfonamido}heptanoic acid (B). Rf 0.74 (5% methanol in ether).

Analysis calculated for C17<H>29<N>05S:

C 56.80, H 8.13, N 3.90

Found: C 56.24, H 8.52, N 3.51

The hydrogenation step (c) gives 7-{N-(3-(1-hydroxycyclohexyl)-propyl)-methanesulfonamido}-heptanoic acid (C). Rf 0.60 (5% methanol in ether).

Analysis calculated for C17H33NOgS:

C 56.17, H 9.15, N 3.85

Found: C 56.01, H 9.48, N 3.73

Example 8

Preparation of methyl-7-(n-(4-hydroxynonyl)-methanesulfonamido)-heptanoic acid

A resolution of approx. 2.5 g (0.06 mol) of diazomethane in 100 ml of ether are mixed with a solution of 10.8 g (0.03 mol) of 7-(n-(4-hydr-oxynonyl)-methanesulfonamido)-heptanoic acid (example. 1, step B) in 50 ml of ether. The obtained solution is left at room temperature for 4 hours. Acetic acid is then added to destroy excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water, and dried over sodium sulfate. Evaporation of volatiles under reduced pressure gives methyl 7-(n-(4-hydroxy-nonyl)-methanesulfonamido)-heptanoate as a viscous oil.

Claims (1)

Analogous procedure for the preparation of therapeutically active compounds with the formula: including optically active' derivatives thereof, where A is ethylene, α-methylethylene or oxymethylene, R1 is methyl, ethyl or propyl, and 5 is -(CH ) -R^ where R^ is hydrogen or lower alkyl, or R may be bound to the carbon atom carrying the hydroxy group forming a carbocyclic ring with 5 - 8 members. characterized in that a) a compound with the formula: 1 8 where R and A are as stated above, and R is lower alkyl with 1-5 carbon atoms, is reacted with approx. an equivalent. strong base, and then with approx. an equivalent of a compound with the formula: where X is halogen, R 5 is as indicated above, and R-? ' is lower alkanoyl with 1-4 carbon atoms, the compound formed being recovered and subjected to mild hydrolysis to remove the blocking groups R and R , after which the desired product is recovered, or b) a compound of the formula: where R<1> and R^ are as indicated above, and R<10> is tetrahydrobpyranyl, is traded with approx. one equivalent strong base and then with approx. one equivalent of a compound with the formula: where X is halogen, A and R Q are as indicated above, and that the resulting intermediate is recovered and subjected to mild hydrolysis to o remove the blocking groups R R and R 10 , whereupon o the desired product is recovered.