CA1064961A - 9-thia- or oxothia and dioxothia-11,12-seco-prostaglandins - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to 9-thia- and oxothia- and 9-dioxothia-11,12-seco-prostaglandins and processes for their manufacture. These compounds have prostaglandin-like biological activity and are particularly useful for the treatment of skin diseases such as psoriasis, for the prevention of thrombus formation, and in stimulating the production of growth hormone in intact animals.

Description

--` 15663Y
. .

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SUMMARY OF THE INVENTION
This invention relates to novel 9-thia-(including 9-oxothia- and 9-dioxothia)-11,12~seco-prostaglandins of the following formula:

( )n I 2 2 2 CH2-Z/C\C(R4)2-R5 (I) R2 oR3 wherein R is selected from the group consisting of carboxy and a carboxy salt, said salt being formed from a pharmaceutically acceptable cation, such as metal cations derived Erom alkali metals, alkaline earth metals and amines such as ammonia, primary and secondary amines such as methyl amine or dimethyl amine, and quaternary ammonillm hydroxides such as tetramethyl or tetraethyl ammonium hydroxide.
R is also selected from carbalkoxy (-COOR6) wherein R6 is Cl 10 alkyl, carbamoyl ( CONH2~; substituted carbamoyl (-CoNR7R8) wherein R7 and R8 may be hydrogen, Cl 4 alkyl, diloweralkylaminoalkyl having 4-7 carbon atoms, or carbazoyl (--CONHNH2) .
A is methylene (-CH2-) or oxygen (-O-).

~~ ~ 15663IA

1~64~6~l ' M H
1 Y is ethylene (-CH2-CH2-), cis-vinylene (-C=C-) or

2 ethynylene (-C-C-).

3 n is 0, 1, or 2.

4 Rl is methylj ethyl, 2-hydroxyethyl, 2-(loweralkyl-oxy)ethyl, or vinyl.
6 Z is ethylene, vinylene, or ethynylene.
7 R2 is hydrogen or methyl.
8 R3 is hydrogen or Cl 5 alkanoyl 9 R4 is hydrogen or methyl.
R5 is C3 6 alkyl or branched alkyl.
11 Further:
12 In addition, when R5 is straight chain alkyl and R2 13 i9 methyl, the terminal carbon atom of R5 can be joined to R2 14 (with abstraction of hydrogen) to form a carbocyclic ring of from 6-9 carbon atoms, or when R5 is straiyht chain alkyl and 16 R2 is hydrogen, the terminal carbon atom of R5 can be joined 17 to the carbon bearing oR3 to form a carbocyclic ring of from 18 5-8 carbon atoms.
19 Further, R5 can be OR a wher~ ~5a is alkyl, C2_5 branched alkyl, substituted alkyl including 3,3,3-tri~luoro-21 propyl, 5- or 6-membered heterocyclic ring containing nitro-22 gen or oxygen including pyridyl, ~uryl or ur~uryl, or phenyl 23 in which the phenyl ring can be substituted with one or two 24 substituents selected from halogen, methyl, methoxy, and tri-fluoromethyl.
26 A preferred embodiment o$ this invention relates to 27 the 11,12-seco-prostaglandins having the following general 28 formula:
/ 2\ / 2\ / CH2 / COOH

29 H3C CH Y- CH2 ~ H2 (II) CH2 Z ~ ~- C(R )2 R5 R OH

~6496~

1 wherein Z is ethylene, vinylene, or ethynylene; R2 and R4 are 2 as defined above7 Y is ethylene, cls-vinylene, or ethynylene;
3 and P~5 is alkyl, branched C3_6 chain alkyl, vinyl, 4,4,4-tri-4 fluorobutyl, or OR5a wherein RSa is as defined above.
It is to be notea that the carbon bearing R2 and 6 oR3 is asymme~ric. This invention includes stereo-isomers in 7 which this asymmetric center is exclusively in eith~r one or 8 the other of the two possible configurations, R and S.

_ . .
The compounds of Formula I are described as 11,12-11 seco-prostaglandins because of their structural relationship 12 to the naturally-occurring prostaglandins.
13 The compounds of the present invention are useful 14 as pharmaceutically active compounds. Thus, these compounds lS are orally active in the kreatment of conditions which are 16 responsive to the actions of the natural prostaglandins.
17 These compounds are indicated as useful in the treatment of a 18 variety of skin diseases including psoriasis, atopic de~mati-19 tis, non-specific dermatitis, forms of dermatitis due to irritation, allergic extrinsic dermatitis, scaly skin~cell 21 carcinoma, lamella, ichthyosis, epidermolytic hyperkeratosis, 22 pre-malignant keratosiq induced by sun, non-malignant kerato-23 sis, acne, and seborrheic dermatitis in humans, as well as 24 atopic dermatitis and mange in domestic animals.
2S Certain of the compounds of this invention are 26 particularly effective in inhibiting the aggregation in 27 platelets in blood stimul~ted with collagen to cause platelet 28 aggregation; and khus, in inhibiting platelet aggregation, 29 they are useful in preventing thrombus formation.

In addition, certain of the compounds of this in-31 vention are particularly effective in causing the release of ~6~961 growth hormone ~rom pituitary glands in both in vivo and in vitro assays. Compounds ~ound to be active in these assays are useful in stimulating growth hormone in poorly-functioning pituitary glands.
The compounds of this invention can be administered either topically or systemically i.e., intravenously, sub-cutaneously, intramuscularly~ orally, rectally, or by aero-solization in the form of sterile implants for long action.
The pharmaceutical compositions can be sterile, injectable suspensions or solutions, or solid, orally-administrable, pharmaceutically-acceptable tablets or capsules: the compositions can also be intended for sublingual administration, or for suppository use. It is especially advantageous to formulate compositions in dosage unit forms ~or ease and economy of administration and uniformity of dosage. 'Dosage unit form' as a term used herein refers to physically-discrete units suitable as unitary dosages for animal and human subjects, each unit containing a prede-termined quantity of active material calculated to produce the desired biolo~ical efect in association with required pharmaceutical means.
It is pr~err~d to prepar~ the compo~ition~.r wh~ther aqueous or oils, in a concentration in the. range. of from 2~5Q
mg./ml. Lower concentrations require needless quantities of liquid. Higher concentrations than 50 mg./ml. are difficult to maintain and are preferably avoided.
The low cost and ready accessibility of the compounds of this invention make them particularly promising for applications in ve-terinary medicine in which field their utilities are comparable to those in human medicine.

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PROCESSES FOR THE SYNTHESIS OF COMPOI~NDS OF THIS INVENTION
2 One of the preferred groups o~ compounds of the 3 present invention is represented by the formula Rl--S (O) --CE--CH2--Y-CH --A--CH CO H

/2 \ ( I ) :R OH
wherein Rl, n, Y, A, Z, R , R , and R are as previously 6 defined. Three principal methods are employed in the synthe-7 sis of compounds of this general type.
8 The first method of synthesis is useful in the 9 preparation of a preferred sub-group of compounds of the formula ( )n f 2 2CH2CH2 ~ CH2 CO2H
11 CH~-CH2-CH2-fH-C(R4)2-R10 (II) OH
12 whexein ~, P~4, and n are as previously defined; R9 is meth~
13 ethyl, 2-hydroxyethyl, 2-methoxyethyl; and R10 is C3 6 alkyl 14 or branched alkyl, or 4,4,4-trifluorobutyl. This method essentially involves successivel~ alkylating in any order 16 di-tert.-butyl malonate, in the presenae o~ sodium hydroxide, 17 with halo~suhstituted esters of the ~ormula 18 X CH2-CH2-C~I2-c~l2-A-c~I2~co2~
19 wherein X is halogen, and Rll is ethyl or methyl; and 20 X-CH2-CH2-CH2-fH-C(R4) -R10 (V~

21 and heating the resulting appropriately-substituted malonic 22 ester of Formula VI
(CH2)4-ACH2CO2R
23 (t C4H9O2C)2 ~C~ CH2cH2cH-c(R4)2R (VI)

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1 in the presence of a strong acid (P-toluene sulfonic or H2SO4 2 in an inert solvent) to eliminate isobutylene and carbon di-3 oxide with production of the key intermediate VII of the 4 ~ormula 2 IH ~CH2) 4 A-CH2--C02-Rll f (VI I )

6 This carboxy diester VII is then treated with red mercuric

7 oxide and bromide to effect replacement of the carboxy func-

8 tion with bromine. The resulting bromo compound is then

9 treated with a lower alkyl mercaptan in methanol or ethanol to displace the bromo substituent and produce a derivative of 11 compound II which has the hydroxyl and carboxy functions pro-12 tected as esters. This alkylthio compound is then subjected 13 to basic hydrolysis (dilute NaOH or KOH in methanol, ethanol, 14 or tetrahydrofuran) to produce one of the preferred sub-groups of compounds of this invention of formula II wherein 16 n = 0. This thia compound II is then converted by oxidation 17 with sodium metaperioda;te in dilute NaHCO3 solution to the 18 corresponding oxothia compound II of this invention wherein 19 n = 1 or with hydrogen peroxide ~30~ ~l2O2 in water) in a sol-vent such a9 ethanol, iso PrOH, and acetic acid to give the 21 dioxothia compound II wherein n = 2.
22 The second method is especially use~ul for the 23 preparation o another preferred sub-group of compounds 24 (formula XIII~
R -SO2-fH- (C~2~ 6C2H 5 CH2-Z~C-C(R4)2 R5 (XIII) R OH
26 wherein Z, R~, R4, and R5 are as defined above, and R12 is 27 methyl or ethyl.

. 15663IA

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1 In this method, an alkyl sulfonyl derivative of an azelaic 2 acid diester iS alkylated under basic conditions With a Sub-3 stituted halo ester or ether and the alkylated product heated 4 to effect decarbalkoxylation of the intermediate and resul-tant production of a derivative of compound XIII in which the 6 hydroxyl substituent is protected by an alkanoyl or benzyl 7 group and the carboxy function by esterif1cation. Mild basic 8 hydrolysis and/or hydrogenolysis of the benzyl group, if 9 present, produces the compounds of sub-group XIII. This syn-thesis can be summarized as follows:
11 R9SH in alcohol ~ R9SNa 12 CH3o2c-lcEI~-(cH2)6co2cH3 ~ R9 S C~ CO2CH3 (XIV) 13 (XIV) H O R12SO~CH 2 3 NaH anion 2 2,~ (CH ) CO CH
(optional catalyst 2 6 2 3 1n (NH4)M.. oO4) (XV) aprotic X-CH2-Z-C-C-~R )2-R
14 ~ \ (XVIa) R 0-Loweralkanoyl 15 ~ or X-CH2-Z~C-C(R4)2-R5 16 ~ \ (XVIb) P~ OCH2C6H5 17 ~X is halogen) fO2CH3 18 R SO2-f-~CH2)6CO2CH3 ~XVII) CH2Z~\-c(~ )2 R O-Loweralkanoyl or benzyl / 1~
3-10 hours / R sO2-fH-~C~I2)6CO2C 3 19 + ~ ~ CH2Z-C-C~R ) 2-R
NaCl in ~ \
D~SO R OCOCH3(or OCH2C6H5) 130-160~C (XVIII) 1~)64~36~

1 ~hen XVIII is acetoxy, XVIII NaOH, H20R So2fH-(cH2)6co2H

2 alcohol C~2Z-C-C(R )2-R
or THF ~ OH
( XI I I ) 3 When XVIII is benzyl/
XVIII NaOH, H20 RS02CH-(CH2)6co2H
4 CH2Z-C-C(R4)2-R
~\

~XIX) XIX H2 (Pd)Rl S02fH- (CH2) 6C02H
CH 2 Z -C-C ( R4 ) 2-R5 R 0~1 ( XI I I ) 6 The hydrogenolysis of the benzyl will at the same time result 7 in reduction of any unsaturated bonds in Z or R5.
8 The third method of s~nthesis o~ thls invention is 9 especially useful ~or the preparation of still another pre-~rred sub-~roup of compounds of ~oxmula XX:
Rl ~-so2-cH-c~l2-~-c~I2-~ CH2C2 11 c~2-z/c\-c(R )2 R (XX) R OH
12 wherein all symbols are as previously defined. In this 13 method, an alkyl sulfon~l derivative of ethyl acetate is 14 successively alkylated ln the presence of a strong base with two selected bromo esters and the resulting product decarb-16 alkoxylated by heating in a solvent. Mild basic hydrolysis 17 gives the compounds of the present invention.

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1 R12-SO2-CH2-COOC2H5 _NaH ~ anion aprotic solvent 2 X-CH2-Y-CH2-A-C~2C~ORll > R -SO -CH ~ 5 ~CH2_y_cEI2_A_ (XXI) tXXII) R OAcetyl 3 NaH ~ anion X-CH2-Z-C-C(R4)2-R5 in aprotic solvent 12 ~ NaCl 4R SO2-f-CH2-Y CH2-A-CH2-CO2R 130-160C
/ \ 3-5 hours (XXIII) R12SO -CH-CH2-Y-CH2-A-CH2-CO2R WaOH or KOH
2 1 4 5 in alcohol 5CH2-Z-C-C(R )2-R 25-65C
R2 OCOCH3 24-64 hour 5 (XXIV) s~2 f~' C~l2 Y-CH2-~ cH2 co2H
6CH2-Z~C\-C(R~)2-~5 R OH
( XX) _g_ --~ 15663Y
.
~06496~
It is ~requently advantageous Erom a therapeutic standpoint to prepare compounds of this invention (formula I) in which the asymmetric carbon atom bearing R2 and oR3 is exclusively in the R or S configuration. It will be recalled that the corresponding center in the natural prostaglandins is in the S configuration; inversion of this center usually produces a reduction in biological activity, although some-times a marked increase in biological specificity results.
In our series of 9-thia-,9-oxothia-, and 9-dioxo-thia-11,12-seco-prostaglandins, compounds exclusively R or S
at this center can be produced by employing, in any of the three fundamental methods, intermediates V, XVIa or XVIb, which are optically active, i.e., resolved into their R and S
stereoisomeric forms.
We have found it particularly advantageous to employ an optically active reagent XVIac, *

BrCH2C_C~C\C(R4)2-R

XVIac in which R2, R4 clnd R5 are as previou~ly deEined, and the carbon atom mArked with an asterisk is exclusively in either the R or S configuration.
For example, the use of XVIac in method III gives intermediates XXIIIa - lQ -!~\
15663I~
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CO C H
, 2 2 5 R12S02-C-CIl2-Y*C~l2 A C~l2C02R
CE~2C_C-f~-C ~R ) 2R

XXIIIa 2 which are decarbalkoxylated and subsequently hydrolyzed 3 in base to yield the optically active products of the 4 invention XXa in which the carbon marked R12S02CI~-CH2-Y-CH -A-CH CO H
* 2( 4 2 5 2 R OH
XXa 6 with an asterisk is exclusively in eitT~er the ~ or S

7 configuration.

8 Catalytic hydrogenati~n of products Y.Xa gives 9 further compounds of the inventio~, XXb, with the asterisked carbon exclusively in either the R or S config~lration:

R S02CH-(C~l2)~-~-co2H

11 CI`l2CH2Cll2/c C(R )2 ~2 \0~l XXb 12 DERIVATIZATION OF PRODUCTS FROM THE M~JOR PROCESSES
13 The directly--obtained products of Methods I, II, 14 and III described supra can be derivatized in a variety of ways to yield other products of Formula I in a manner known 16 to one skilled in the art.

. ~ O 6 4~ ~ 1 15663 1 EX~MPLE l 2 Pre~aration of 8-methylthio-12-hydroxyheptadecanoic acid 3 Step A: Preparation of di-tert.-butyl ~6-ethoxycarbonylhexyl)-4 malon te A suspension of 57~ sodium hydride in mineral oil 6 (5.05 g. net weight, 0.21 mole) in a solvent mixture of 7 benzene (95 ml.) and dimethylformamide (95 ml.) is treated, 8 dropwise, over 30 minutes with di-tert.-butyl malonate 9 (41.09 g., 0.19 mole). Stirring is continued for an additional 30 minutes. Then ethyl-7-bromoheptanoate 11 (49.80 g., 0.21 mole) is added, dropwise, over 30 minutes, 12 and the mixture is heated at 100C. for 4-1/2 hours.
13 The cooled reaction mixture is treated with water 14 (380 ml.) and the organic layer is separated. The aqueous layer is extracted with ether. The combined organic 16 solutions are washed with ~aturated sodium chloride 17 solution and then dried over anhydrous sodium sulfate.
18 The solvents ara removed under vacuum to give the title 19 compound as a re~idual oil, yield 70.78 g.
Step B.: Prepaxation of l-chloro-4-acetoxynonane 21 Step B-l. Preparation of l-chloro-4-nonanone 22 To the Grignard reagent prepared erom a mixture 23 of amyl bromide (226.59 g., 1.5 moles) and magnesium 2~ ~36~48 g., 1.5 moles) in ether (100 ml.) is added, dropwlse, during one hour, 4-chlorobutyronitrile ~lS5.34 g., 1.5 26 moles). Stirring is continued for an additional one hour.
27 The reaction mixture i9 poured into a mixture of finely 28 crushed ice (1000 g.) and concentrated hydrochloric acid 29 (750 ml.). The ether layer is separated quickly and discarded.
The aqueous layer is heated o~ a steam bath for one hour to 31 hydrolyze the intermediate imine and cause the separation of 32 the ketone as an oil. After cooling, the oil is extracted ~1~64916~

1 with ether and the combined extracts are washed with 2 saturated sodium chloride solution and dried over anhydrous 3 sodium sulfate. The solvent is removed under vacuum and 4 the residual oil is distilled to give 69.0 g. (Z6%) of colorless oil, b.p. 115-117/14 mm.; pmr tCDC13) Of 0.90 6 (3H,t~, 3.56 ~2H,t,CH2Cl).
7 Step B-2. Pr~p ration of l-chloro~4-nonanol 8 A suspension of sodium borohydride (6.62 g., 9 0.175 mole) and soaium hydroxide (1.3 g.) in ethanol (310 ml.) is treated, dropwise, over 1 hour with l-chloro-11 4-nonanone (61.40 y., 0.349 mole) while the temperature is 12 maintained at 45-50C. Stirring is continued ~or one 13 hour, longer without external cooling.
14 The reaction mixture iq acidified with concentrated hydrochloric acid to the Congo red endpoint and then the 16 ethanol is removed under reduced pressure. The residue is 17 treated with water (200 ml.) and the resulting oil is 18 extracted with ether. The combinecl extracts are washed 19 with satuxated ~odium chloride solution and dried over anhydxou~ ~odium sulfate. The 901vent iS removed under 21 vacuum to give the title compound as a light yellow residual 22 oil, yield 58.85 g., ir (neat) 3400 cm Step 3-3, Preparation o~ l-chloro-4 acetoxynonane 24 A mixture of l-chloro-4-nonanol (111.99 g., 0.627 mole) and acetic anhydride (128.0 y., 1.254 moles) 26 is heated on a steam bath for 1-1/2 hours.
27 The volatile materials are removed under -13~

15663]
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1 reduced pressure and the residual oil is distilled to 2 give 88.6 g. (64%) of colorless oil, b.p. 130-133C./14 mm., 3 pmr (CDC13) ~0.89 (3H,t), 2.02 (3H, s C~3COO), 3.53 4 (2H,t CH2Cl), 4.89 (lH,m).

Step C. Preparation of di-tert.-butyl 2-(4-acetoxynonyl)-6 2-(6-ethoxYcarbonYlhexYl)malonate 7 A suspension of 57% sodium hydride in mineral 8 oil (5.05 g. net weight, 0.21 mole) in a solvent mixture 9 of benzene ~95 ml.) and dimethylformamide (95 ml.) is treated, dropwise~ over 30 minutes, with di-tert.-butyl-(6-11 ethoxycarbonylhexyl)~malonate (69.70 g., 0.187 mole).
12 Stirring is continued for an additional 2 hours. Then 13 1-chloro-4-acetoxynonane (46.35 g., 0.21 mole) is added, 14 dropwise, over 30 minute3, and the mixture is heated at lOO~C. for 42 hours.
16 The cooled reaction mixture is treated with 17 water (380 ml.) and the organic layer is separated. The 18 aqueous layer is extracted wlkh ether. The combined organic 19 solution~ are washed with saturated sodium chloride solution and then dried over anhydrous sodiurn sulEate. The solvents 21 are removed under vacuum to give the title compound as a 22 residual oil, yield 104.12 g.; p.m.r. (CDC13) Of 0.88 (3H,t), 23 1.45 (18H,s), 2.00 (3H, s CH3COO), 4.12 (2H, q).
24 Step D. Preparation of ethyl 8-carboxy-12-acetoxy-he~tadecanoate . . ,~ ,_ _ .
26 A mixture of di-tert.-butyl 2-(4-acetoxynonyl)-27 2-(6-ethoxycarbonylhexyl~malonate (104.12 g., 0.187 mole), 28 p-toluenesulfonic acid monohydrate (3.30 g.) and toluene 29 (330 ml.) is heated under reflux for 9-1/2 hours.

~14~

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1 The cooled reaction mixture iæ washed well with 2 saturated sodium chloride solution and then dried over 3 anhydrous sodium sulfate~ The solvent is removed under 4 vacuum to give the title compound as a residual oil, yield 74.9 y. The oil is purified by column chromatography 6 on silica gel with 2~ methanol in chloroform as an eluent;
7 pmr (CDCL3) J 0.88 (3H,t), 2.0Z (3H, s CH3COO), 4.12 (2H, q), 8 10.97 (lH, s COOH).

9 Ste~ E. Prepaxation of_ethyl 8-bromo-12-acetoxyheptadecanoate A mixture of ethyl 8-caxboxy-12-acetoxy-11 heptadecanoate (31.5 g., 0.079 mole), red mercuric oxide 12 (12.8 g., 0.059 mole), and carbon tetrachloride (200 ml.) 13 is stirred at room temperature while bromine (12.6 g., 14 0.079 mole) is added dropwise during one hour. The resulting mixture is heated at reflux for one hour. The 16 mixture is then cooled, ~iltered, washed with dilute 17 hydrochloric acid, water and brine and dried over sodium 18 sulate. The solution is evaporated in vacuo to leave 19 the product as a yellow residual oil weighing 24.5 g.
r~he product is purified by chromatography on a column 21 containing 250 g. of silica gel using chloroform as 22 eluting solvent. There is obtained 14.4 g. o~ purified 23 ethyl 8-bromo-12-acetoxyheptadecanoate, a yellow oil with 24 Rf 0.49 on silica gel thin layer chromatography with chloroform elution. pmr (CDC13) Or0.90 (3H,t); 2.03 (3H, 26 s CH3CO); 4.07 (lH, m HCBr); 4.13 (2H, q); 4.92 (lH, m HCO).

~6~

1 Step P. Preparation of 8-methylthio-l2-hydroxyhepta 2 decanoic acid . _ _ _ . . . _ .
3 Gaseous methyl mercaptan is bubbled into a 4 solution of sodium (3.7 gO, 0.16 mole) in methanol (150 ml.) until 7.7 g. (0.16 mole) of the gas is absorbed.
6 Ethyl 8-bromo-12-acetoxyheptadecanoate (17.8 g., 0.041 mole) 7 is added and the resulting solution is heated at reflux 8 for 4 hours. Then, a solution of 5.0 g. of sodium 9 hydroxide in 50 ml. of water is added and reflux is continued for an additional hour. The solution is cooled, 11 diluted with 500 ml. of water and extracted with ether.
12 The aqueous solution is acidified with concentrated hydro-13 chloric acid. The oily acid which separates is taken up 14 in ether, washed with water and dried over sodium sulfate.
The ether is evaporated to leave 12O5 g. of the crude 16 product as a yellow viscous~oil. Purification is effected 17 by chromatography on a column containing 250 g. of silica 18 gel using 2% methanol in chloroform as eluant. There is 19 obtained 7.0 g. (51%~ of 8-methylthio-12-hydroxy-~0 heptadecanoic acid as a light ~ellow viscou~ oil; pmr 21 (CDC13) ~ 0.90 (3H,t); 2.07 ~3H, s CH3S); 3.64 ~lEl, m ~ICO).
22 Step F i5 repeated using ethyl mer~aptan in place 23 of methyl mercaptan with production of 8-ethylthio-12-24 hydroxyheptadecanoic acid.
Step F is again repeated using 2-mercaptoethanol 26 in place of methyl meraaptan with production of 8-(2-hydroxy-27 ethylthio)-12-hydroxyheptadecanoic acid.

29 Prepara*ion of 8-methx~ ulfonyl-12-hydroxyhe~tAdecanoic acid A mixture of 8-methylthio-12-hydroxyheptadecanoic 31 acid (Ex. 1) (3.0 g., 0.009 mole) and ammonium molybdate ~-~ 15663Y

96~
(0.10 g.) in isopropyl alcohol (10 ml.) is stirred and cooled in an ice bath while 30~ aqueous hydrogen peroxide (5 ml., 0.044 mole) is added dropwise at such a rate to keep the temperature below 20C. The mixture is then stirred 16 hours at 25C. It is diluted with water (75 ml.) and the product extracted into chloroform, washed with brine and dried over sodium sulfate. The chloroform is evaporated in vacuo and the crude product purified by chromatography on silica gel with benzene-dioxane-acetic acid, 90:30:1, elution. The title compound is obtained as a yellowish viscous oil weighing 1.85 g. (56% yield).

Preparation of 8-methylsulfonyl-12-h~drox~vhe~tadecanoic acid Step A. Preparation of dimethyl 2-methylthioazelate Methyl mercapt:an (excess) is passed into a rapidly-stirred solution of sodium methoxide (13.5 g., 0.25 mole) in dry methanol (200 ml.) at 0C. to generate sodium methyl-mercaptide. The resultin~ solution is treated with dimeth~l 2-bromoazelate (55.0 g., 0.186 mole), then stirred and heated at reflux under nitrogen Eor 5 hours. The reaction solution is concentrated ~n vaczLo~ diluted with ether and Eiltered.
The filtrate is washed with water (until the washin~s are neutral), dried over sodium sulfate and distilled providing the title compound as a colorless liquid (28.4 g., 58~), bp 0.2 m~l 128-138C.; pmr ~CDC13) ~ 2.10 (s, 3H), 2.31 (t, 2H), 3,20 (t, H), 3.63 (s, 3H) and 3.71 (s, 3H).

3 ~6~
1 Step B-l. Preparation of dimethyl 2-methylsulfonylazelate 2 30~ Hydroyen peroxide (28 g.,~ 0.25 mole) is 3 added dropwise to a cooled (--10C.), ~tirred mixture of 4 dimethyl 2-mercaptoazelate (26.2 g., 0.01 mole) and ammonium molybdate (0.3 g., catalyst) in methanol (20 ml.) at such 6 a rate as to maintain an internal temperature less than 7 30~C. The resulting reaction mixture is stirred at 8 ambient temperature for 16 hours, then diluted with water 9 (150 ml.) and filterea to yield the title compound as a white, crystalline solid (26.2 g., 89%), m.p. 47-8C.
11 Recrystallization from ether at -10C. provides an analytical 12 sample as colorless needles, m.p. 50-50.5C.; pmr 13 (CDC13) ~ 3.0 (s, 3H), 3.63 (s, 3H), 3.72 (t, H) and 14 3.82 (s, 3H).

Step B-2._ Preparation of l-iodo-4-acetoxynonane 16 A mixture of 1-chloro-4-acetoxynonane (Ex. 1, 17 Step B-3) (35.3 g., 0.16 mole) and sodium iodide (120 g., 18 0.8 mole) in acetone (350 ml.) is stirred and heated at 19 re~lux with exclusion of light for 10 hours. The resulting suspen~ion ls ~iltered and the collected sodium chloride 21 washed with acetone. The combined Eiltrate ancl washings 22 are evaporated in vacuo leaving a residual mass which is 23 partitioned between ether and water. The organic extract 24 ig washed with dilute ac~ueous sodium thiosulfate and water, dried over sodium sulate and evaporated ~ ~3~Q
26 providing the title compound as a colorless liquid 6~

(48.7 g., 98%), pmr ~CDC13) of 2.0 (s, 3H), 3.18 (t, 2H) 2 and 4. 98 (m, H) .
3 Step C. Preparation of methyl 8-methoxycarbonyl-8-4 methylsulfonyl 12-ace~oxyhe~tadecanoate A suspension of 57% sodium hydride/mineral oil 6 (3. 84 g., 0. 091 mole) is washed by decantation with 7 petroleum ether to remove the mineral oil. The residual 8 solid is suspended in dry dimethylformamide (100 ml~ ) and 9 treated with a solution o~ dimethyl-2-methylsulfonyl-azelate (23.5 g., 0 . 08 mole~ in dry dimethylformamide 11 ~60 ml.) added dropwise at ambient temperature under a 12 nitrogen atmosphere. The resulting solution is stirred 13 for 1 hour at room temperature, cooled tor'10C., and 14 treated with 1-iodo-4~acetoxynonane (30 g., 0.096 mole) added at such a rate as to maintain an lnternal temperature 16 less than 35C. Ater 19 hours at ambient temperature, 17 the reaction mixture is filtered. Collected sodium 18 iodide (17.1 g.) is washed with ether. The combined 19 filtrate and washings are concentrated ln vacuo at r- 100C.
yielding a residual oil which is partitioned between ether 21 and dilute hydrochloric acid. The organic extract is 22 washed with water and saturated brine, dried over magnesium 23 sul~ate and evaporated in vacuo leaving the title compound 24 as a viscous oil (37.7 g., 98%), pmr (CDC13) ~2.0 (~, 3H), 3.0 (s, 3H), 3.65 (s, 3H), 3.81 (s, 3H) and 4.9 (b, H).
26 Step D. Preparation of methyl 8-methylsulfonyl-12-27 acetoxYheptadecanoate _ _ 28 A mixture of methyl 8-methoxycarbonyl-8-methyl-29 sulfonyl-12-acetoxyheptadecanoate (36.7 g., 0.077 mola), 1566~
~64961 1 sodium chloride (4.68 g., 0.08 mole), water (1 ml.) and 2 dimethylsul~oxide (60 ml.) is heated in a bath maintained 3 at ]85C. under nitrogen for 5 hours. The resulting 4 reaction mixture is concentrated in vacuo at 100C.
providing an oily residue which is diluted with water.
6 The aqueous mixture is acidified to Congo Red with 6N
7 hydrochloric acid and extracted with ether. The organic 8 extract is washed with water, dried over magnesium 9 sulfate, filtered and evaporated in vacuo leaving the title compound as a viscous oil (31 g., 95~), pmr (CDC13) 11 ~ 2.0 (s, 3H), 2.82 (s, 3H), 3.63 (s, 3H) and 4.9 (b, H).
12 Step E. Preparation of 8-methylsulfonyl-12-hydroxy-13 __ heptadecanoic acid _ _ 14 A solution o~ methyl 8-methylsulfonyl-12-acetoxyheptadecanoate ~29~4 g., 0.07 mole) and 20%
16 aqueous sodium hydroxide (70 ml~) in methanol (70 ml.) 17 is stirred at room temperature for 17 hours. The 18 resulting solution is evaporated in vacuo at ~ 100C. to 19 an oily residue which is dissolved in water. The a~ueous solution is extracted with ether and the organic extract 21 discarded. Then, the aqueou9 phase ls acidi~ied to 22 Congo Red with 6N hydrochloria acid and extracted with 23 ether. The organic extract is washed with water, dried 24 over magnesium sul~ate, filtered and concentrated in vacuo at ~ 100C. providing crude title compound as a viscous 26 oil (23.6 g., 93%).
27 The viscous oil is applied to a silica gel 28 column (700 g., 0.063-0.2 mm., E. Merck, ~armstadt) with 29 benzene-dioxane-acetic acid (90:15:1; v:v:v). Elution with ~69~96~
1 the same mixture provides the pure title compound as a 2 colorless, viscous oil (16.5, 65%), pmr (CDC13) ~ 2.82 3 (s, 3H), 2.82 (b, H), 3.63 (b, H) and 7.2 ts, 2H, 4 exchangeable); PKa 5.20 twater).
s ~XAMPLE 4 6 Preparation of 8-methylsulfinyl-12-hydrox ~ eptadecanoic acid 7 8-Methylthio-12~hydroxyheptadecanoic acid tEXo 1) 8 t6.7 y., 0.0202 mole) is dissolved in a solution of sodium 9 hydroxide tl.0 g., 0.025 mole~ in water t80 ml.). Sodium metaperiodate t4.7 g., 0.022 mole) is added and the resulting 11 mixture is stirred at room temperature overnight tl7 hours).
12 The solids present are then filtered off and the Eil-trate 13 is acidified with dilute hydrochloric acid to liberate the 14 oily acid product. The oil is taken up in ether, washed with water and dried over sodium sulfate. The ether is 16 evaporated ln vacuo to leav~ the crude 8-methylsulfinyl-12-17 hydroxy-heptadecanoic acid as a viscous yellowish oil 18 weighing 5.8 g. Purification is effected by chron~atography 19 on a column containing 125 g~ of silica gel using ~
methanol in chloro~orm as elwant. There is obtained 2.2 g.
21 o~ pur~ 8-methylsul~inyl-12-hydroxyheptadecanola acid, 22 a colorless vi~cous oil with R~ 0.14 on silica gel thin 23 layer chromatograms with chloroform-methanol-acetic acid 24 96-3:1 as eluant; pmr ~CDC13) d~ O.9Q ~3H, t); 2.50 2S (3H, s CH3S0); 3.64 ~lH, m HCO).
26 EX~MPLE 5 27 Preparation of 8-(2-hydroxyethylsulfonyl~-12-hydroxy-28 heptadecanoic acid _ -. . .
29 A solution consisting of 8-(2-hydroxyethylthio)-12-hydroxyheptadecanoic acid (6.0 g., 0.0165 mole), 30~ aqueous 31 hydrogen peroxide (8 ml.) and isopropyl alcohol (40 ml.) is 32 allowed to stand 18 hours at 25C. The solution is then ~21-1~D69L96~

1 diluted with 140 ml. of water. The oily product is taken up 2 in ether, washed with water and dried over sodium sulfate.
3 The ether is evaporated to leave 6.8 g. of crude product as a 4 viscous yellow oil. The product is purified by chromatQgra-phy on a column containing 125 g. of silica gel using 3~
6 methanol in chloroform as eluant. There is obtained 2.4 gO
7 o~ 8-(2-hydroxyethylsulfonyl)-12~hydroxyheptadecanoic acid, a 8 colorless viscous oil with Rf 0.18 on the silica gel thin 9 layer chromatogram with chloroform-methanol-acetic acid 95:4:1 as eluant; pmr (CDC13) 0-090 t3H, t); 2.37 (2H, t 11 CH2CO2H); 3.21 (2H, t CH2SO2); 3.66 (lH, m HCO); 4.14(2H, t 12 CH2OH); 5.52 (3H, s COOH and OH).

14 ~35~5~ ~ =a~ sy~ lfonyl-12-hydroxyheptadecanoic acid Step ~. Preparation of ethyl 8-(2-hydroxyethylthio)-12-16 acetoxvhe~tadecanoate ~ ,. .. . . ~ _ .. .
17 2-~ercaptoethanol (31.2 g., 0.4 mole) is dissolved 18 in a solution of sodium (9.2 g., 0.4 mole) in methanol (300 19 ml.). Ethyl 8-bromo-12-acetoxy-heptadecanoate (Ex. l,~Step F) (43.5 g., 0.1 mole) is added and the resulting solu-tion is 21 heated at reflux ~or 5 hours. r.~Os-t o~ the methanol is then 22 r~mov~d by evaporation ln vacuo. Water (350 ml.) is adcled -to 23 the residue and the oily product taken up in ether, washed 24 with water and brine and dried over sodium sulfate. Evapora-tion o~ the ether leav~s the title compound as a yellow re-26 sidual oil which is used in the next step without further 27 purification.
28 Step B. Preparation of ethyl 8-(2-chloroethylthio)-12-29 acetox~he~tadecanoate .. . . . . . .
Thionyl chloride (13.1 g., 0.11 mole) is added 31 dropwise with stirring to a solution of ethyl 8-(2-hydroxy-32 ethylthio)-12-acetoxyheptadecanoate (43.2 g., 0.10 mole~ in ~al6~

1 benzene (150 ml.). The solution is heated at reflux for 2 2 hours. Then, the solvent and excess thionyl chloride are 3 removed by evaporation in vacuo to leave the title compound 4 as an orange yellow residual oil.
Step C. Preparation of ethyl 8-(2-chloroethylsulfonyl)-6 _ 12-acetoxyheptadecanoate 7 A solution of ethyl 8-(2-chloroethylthio)-12-8 acetoxyheptadecanoate (45.1 g., 0.1 mole) and 30~ aqueous 9 hydrogen peroxide (50 ml.) in acetic acid (225 ml.) is allowed to stand 20 hours at 25C. The solution is diluted 11 with 600 ml. of water. The oily product is taken up in 12 ether, washed with dilute sodium bicarbonate solution and 13 ~our portions of water and dried over sodium sulate.
14 Evaporation of the ether in vacuo leaves the title compound as a light yellow viscous oil.
16 Step D. Preparation of 8-vinylsulfonyl-12-hydroxy-17 heptadecanoic acid 18 A mixture of ethyl 8-(2-chloroethylsulfonyl)-19 12-acetoxyheptadecanoate (43.S g., 0.09 mole), sodium hydroxide (14.4 g., 0.36 mole), water (150 ml.) and tetra-21 hydro~uran (600 ml.) i9 stirred at 25C. Eor 24 hours.
22 Most of the tetrahvdro~uran i9 removed by evapQration in 23 vacuo keeplng the temperature o~ thë evaporatin~ solution 24 at 30C. or below. The residue is diluted with water (300 ml.) and extracted with ether. The aqueous solution 26 i~ acidi~ied with dilute hydrochloric acid. The oily 27 product is taken up in elher, washed with water and dried 28 over sodium sulfate. The. ether is evaporated to leave the 29 product as a yellowish, very viscous oil. Purification is effec~ed by column chromatography on silica gel with 31 benzene-dioxane as eluting solvent mixture. The title 32 compound is obtained as a colorless viscous oil.

1~6~6~

2 Preparation of 5-methylsulfonyl-9 hydroxytetradecyloxy-3 acetic acid 4 Step A. Ethyl 4-bromobutoxyacetate Sodium hydride t9.0 g., 0.375 mole) is suspended 6 in 1,2-dimethoxyethane. The mixture is stirred and cooled 7 in an ice bath while ethyl glycollate (39.0 g., 0.375 mole) 8 is added dropwise during one hour. 1,4-Dibromobutane 9 (108 g., 0.5 mole) is added all at once to the resulting thick suspension. The mixture is warmed gently to 11 initiate a strongly exothermic reaction; then the mixture 12 is heated 3 hours on the steam bath. The mixture is poured 13 into cold water. The heavy oil layer is taken up in 14 ether, washed with three portions of water, and dried over sodium sul~ate.
16 Evaporation of the ether and distillation of the 17 residual oil yields 21.3 g. (24%) of ethyl 4-bromobutoxy-18 acetate, a colorless oil, b.p. 99-103C./0.2 mm.
19 Step B. Preparation of di-tert.-butyl E4-tethoxycarbonyl-methoxy)-butyl]malonate .. . . _ . ~ _ .
21 Method of Example 1, Step A is repeated exaept 22 that the ethyl 7-bromoheptanoate of the example is replaced 23 by ethyl 4-bromobutoxyacetate. The title compound is ob-24 tained as a residual oil.
Steps Cj D, E, Preparation of 5-methylsulfonyl-9-hydroxy-26 F, and G tetradec~loxyacetic acid _ _ _ _ 27 This compound is prepared essentially by the me-thod 28 described in Example 1, Steps C, D, E, F, and Example 2, 29 except that t.he starting material of Example 1, Step C, di-tert.-butyl(6-ethoxycarbonylhexyl)-malonate is replaced by 31 di-tert.-butyl[4-ethoxycarbonylmethoxy)-butyl]malonate with 32 intermediate production of di-tert.-butyl 2-t4-acetoxynonyl)-33 2-[4-(ethoxycarbonylmethoxy)butyl]malonate; ethyl 5-carboxy--2~-1al649&i 1 9-acetoxytetradecyloxyacetate; ethyl 5-bromo-9-acetoxy-2 tetradecyloxyacetate; and 5-methylthio-9-hydroxytetra-3 decyloxyacetic acid. The product is purified by chroma-4 tography on silica gel and is obtained as a very viscous, yellowish oil.

~25 156~3:

~64961 1 EX~MPLE 8 2 Preparation o~ 8-methylsulfonyl-12-hydroxy-5-hepta-3 decynoic acid 4 Step A. Ethyl 2-(6-methoxycarbonyl-2-hexyn-1-yl)-2-(methYlsulfonYl)acetate . _ .r . _____ -- . ._. ___ -6 A suspension of 57% sodium hydride in mineral 7 oil (5.05 g. net weisht, 0.21 mole) in a solvent mixture 8 of benzene (95 ml.) and dimethylformamide (95 ml. ) i5 9 treated, dropwise over 30 minutes, with ethyl methylsulfonyl-acetate (33.2 g., 0.20 mole). Stirring is continued for 11 an additional 30 minutes. Then methyl 7-bromo-5-heptynoate 12 (43.8 g., 0.20 mole) is added dropwise during 30 minutes 13 and the mixture is heated at 80C. for 1.5 hours.
14 The cooled mixture is treated with water and the organic layer separated, wa~hed with water and brine and 16 dried over sodium sul~ate. ~he solvent is evaporated 17 in vacuo to leave the title compound as a yellow residual .
18 oil.
19 Step B. Preparation of ethyl 2-(6-methoxycarbonyl-2-hexyn-1-yl)-2-(4-acetoxynonyl)-2-(methylsulfonyl)-21 acetate 22 This compound is prepared essentially by the 23 method described in Example 1, Step C, exaept that the 24 di-tert.-butyl (6-ethoxycarbonylhexylhmalana~e o~ the example is replaced by ethyl 2-~6~methoxycarbonyl-2-26 hexyn-1-yl)-2-(methylsul~onyl)acetate.
27 Step C. Preparation of methyl 8-methylsulfonyl-12-acetoxy-28 5~heptadeaynoa~e 29 A solution of ethyl 2-~6-methoxycarbonyl-2-hexyn-1-yl)-2-(4-acetoxyr~onyl)-2-(methylsulfonyl)-acetate 31 (48.8 g., 0.1 mole), water ~3.6 g., 0.2 mole), and sodium 32 chloride (6.5 g., 0.11 mole) in 120 ml. of dime~hyl sulfoxide 33 is heated at 130-150C. for 6 hours until evolution of carbon 34 dioxide is co~pleted. ~he mixture is cooled, treated with ~11 06~96~

1 400 ml. of water and the oily product taken up in ~ther, ~ washed with water and dried over sodium sulfate. Evapora-3 tion of the ether in vacuo leaves the title compound as a 4 yellow viscous oil .
Step D. Preparation of B-methylsulfonyl-12-hydroxy-5-6 heptaaecy~oic acid ~
7 Methyl 8-methylsulfonyl-12-acetoxy-5-hepta-8 decynoate (41.6 g., 0.10 mole) is added to a solution of 9 soaium hydroxide (12.0 g., 0.3 mole) in water (120 ml.) and methanol (600 ml.). The resulting solution is heated 11 at 55-60C. for 24 hours. Most of the methanol is 12 removed by evaporation in vacuo. The residue is diluted 13 with water and extracted with ether. The aqueous solution 14 is acidified with concentrated hydrochloric acid. The product which separates is taken up in ether, washed with 16 water and dried over sodium sulfate. Evaporation o~ the 17 ether ln vacuo leaves the title compound as a viscous yellow 18 oil. Purification is effected by column chromatography on 19 silica gel with 2% methanol in chloroform as eluant.
The title compound is obtained as a nearly colorless 21 viscous oil.
22 BX~MPLE 9 23 Prepara~ion of 8-methy.l~ulfonyl-12-hydroxy-5-cis-24 he~tadecenoic ac.id ~_ . . . ... .
8-Methylsul~onyl-12-hydroxy-5-hep~adecynoic 26 acld (Example 10) (3.6 g., 0.01 mole) is dissolved in 27 ethyl acetate (50 ml.). Lindlar catalyst (1.0 g.) is 28 added and the mixture is hydrogenated at 1 atmosphere and 29 25C. When 0.01 mole o hydrogen is ab~orbed, the catalyst is removed by filtration and the solvent evaporated in vacuo.

~27-1 ~ 6 ~

1 The oil residue consisting of the crude product is purified 2 by column chromato~raphy on silica gel with 2% methanol in 3 chloroform as eluant. 8-Methylsulfonyl-12-hydroxy-5-cis-4 heptadecenoic acid is obtained as a colorless viscous oil.

6 Preparation of 8 methylsulfonyl-12-hydroxy-10-hepta-7 decenoic acid 8 Step A. Preparation of l-bromo-4~acetoxy-2-nonene 9 A mixture of 4-acetoxy-2-nonene (73.5 g., 0.4 mole), N-bromosuCcinimide (80.0 g., 0.45 mole), and 11 carbon tetrachloride (500 ml.) is boiled under reflux for 12 3 liours. The mixture is then cooled and the suspended 13 succinimide removed by filtration. The aarbon tetxa~
14 chloride solution is washed with dilute sodium bicarbonate solution and water, and is dried over sodium sulfate.
16 The carbon tetrachloride i5 evaporated ln vacuo and the 17 residual oil is distilled to yield 62 g. (59%) of l-bromo-18 4-acetoxy-2-nonene as a light ye~low oil, b.p. 110-112C./
19 0.1 mm.
Step B, C, Preparation of 8-methylsulfonyl-12-hydroxy~10-21 ard~ 3s~ enoic_acid 22 Method of Example 3, Steps C, D, and E, except -that 23 the starting l~iodo-4-acetoxy-nonane is replaa~d by an equiv-24 alent quantity of 1-bromo-4-acetoxynonane with intermediate production of methyl 8-methoxycarbonyl-8-methyl-sul~onyl-12-26 acetoxy-10 heptadecenoate and methyl 8-methylsulfonyl-12-27 acetoxy-10-heptadecenoate.

29 Preparation of 8-methylsulfonyl-12(S)-hydroxy-10-hepta-decynoic acid . . _ _ . . _ . . .
31 Step A 1 Pre~aration of 3(S)-acetoxy-l-octyne 32 (S)-l-Octyn-3~ol (100 g~, 0.794 moIe) is dissolved 33 in pyridine (79 g., 1.0 mole) and acetic anhydride (81.6 g., ~8-96~

1 0.80 mole) is added dropwise with st~rring during one hour.
2 The temperature rises to 45C. The solution is heated at 3 55C. for 1 hour and is then cooled and poured into 200 ml.
4 ice-cold 5% hydrochloric acid. The oily product is taken up in ether, washed with water and brine and dried over sodium 6 sulfate. The ether is evaporated and the residual oil dis-7 tilled to yield 106.4 g. ~80%) of 3(S)-acetoxy-l-octyne, b.p.
8 91-92C./15 mm~; [a]26_790 (C 3.0, CHC13).
9 Step A-2. Preparation of l-diethylamino-4~S)-acetoxy-2-nonYne 11 A mixture of 3(S)-acetoxy-l-octyne (58.5 g., 0.35 12 mole), diethylamine (28.5 g., 0.39 mole), paraformaldehyde 13 (13.8 g., 0.46 mole) and p-dioxane (60 ml.) is heated on the 14 steam bath under a reflux condenser for 17 hours. The re-sulting solution is cooled and diluted with 250 ml. of ether.
16 The solution is extracted with 300 ml. of 5% hydrochloric 17 acid. The acidic aqueous extract is made basic with 10%
18 sodium hydroxide solution. The liberated amine is taken up 19 in ether, washed with water and brine and dried over sodium sulfate. The ether is evaporat.ed and the residual oil dis-21 tilled to yield 73.1 g. ~89~) o~ 1-diethylamino-4(S)-acetoxy-22 2-nonyne, b.p. 103-109/0.3 mm.; [a]D6-80 (C 3.3~ CHC13).
23 Step ~ 3. Preparation of _-bromo-4(S)-acetoxy-2~nonyne 24 A solution of l-diethylamino-4(S)-acetoxy-2-nonyne (50.6 g., 0.20 mole) and cyanogen bromide (21.2 ~., 0.20mol~
26 in ether (250 ml.) is allowed to stand at 25-27C. for 18 27 ~hours. The ether solution is washed with 5% hydrochloric 28 acid solution, water, and brine and dried over sodium sulfab~
29 The ether is evaporated and the residual oil distilled.
After a forerun of diethylcyanamide, there is collected 34.1 31 g. (65%) of 1-bromo-4(S)-acetoxy-2-nonyne, b.p. 97-105/0.2 1~6~96~L

1 mm.; [a] D -83 (C 3.7, CHC13).
2 Steps ~, C, Preparation of 8-methylsulfonyl-12(S)-hydroxy-3 and D 10-he~tadecvnoic acid 4 Method of Example 3, Steps C, D, and E, except that 1-iodo-4-acetoxynonane is replaced by an equivalent quantity 6 of 1-bromo-4~S)-acetoxy-nonyne with successive intermediate 7 production of methyl 8-methoxycarbonyl-8~methylsulfonyl 12~S)-8 acetoxy-10-h~ptadecynoate and methyl 8-methylsulfonyl-12(S)-9 acetoxy-10-heptadecynoate.
EX~MPLE_12`
11 Utilizing one or more of the procedures outlined in 12 the preceding specification and examples or variations there-13 of apparent to one skilled in the art, the following product~
14 are produced Erom the indicated starting materials and inter-mediates:
16,,1. 8-methylsulfonyl-12~R)-hydroxy~10-heptadecynoic acid ,, 17 using R-l-octyn-3-ol as starting material and the interme--18 diates in order:
19 a. ~(R)-acetoxy-l-octyne []D6~700 (C 3.1, CIIC13) b. 1-diethylamino-4(R)-acetoxy-2-nonyne [a]26~740 2.1 (C 3.2, CHC13) 22 c. 1 bromo-4(R) acetoxy-2-nonyne ~a~26,~750 tC 3~2, C~IC13) 23 d. m~thyl 8-methoxycarhonyl-8-methylsulfonyl-12 24 acetoxy-10-heptadecynoate e. methyl 8-methylsulfonyl-12(R)-acetoxy-10-hepta~
26 decynoate;
,",27 2. 8-methylsulfonyl-12(S)-hydroxyheptadecanoic acid using 8 --28 methylsulfonyl-12(S)-hydroxy-10-heptadecynoic acid as 29 starting material;
" 30-- 3. 8-methylsulfonyl-12(R)-hydroxyheptadecanoic acid using 8-31 methylsulfonyl-12(R)-hydroxy-10-heptadecynoic acid as 32 starting material;

6~
1 4. 8-methylsulfonyl 12-hydroxy-12~methyl-heptadecanoic acid 2 using 8-methylsulfonyl-12~hydroxyheptadecanoic acid as 3 starting material and the following intermediates in order:
4 a. 8-methylsulfonyl-12-oxoheptadecanoic acid b. 8-methylsulfonyl-12-hydroxy-12-methylheptadecanoic 6 acid;
7 5. 8-methylsulfonyl-12 hydroxy-i3,13-dimethylheptadecanoic 8 acid using lithium acetylide ethylene diamine complex as 9 starting material and the following intermediates in order.
a. 3-acetoxy-4,4-dimethyl-1-octyne 11 b. 1-diethylamino-4-acetoxy-5,5-dimethyl-2-nonyne 12 c. 1-bromo-4-acetoxy~5,5-dimethyl-2 nonyne 13 d. methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxy-14 13,13-dimethyl-10-heptadecynoate e. methyl 8-methylsulfonyl-12-acetoxy-13,13-dimethyl-16 10-heptadecynoate 17 f. 8-methylsulfonyl-12-hydroxy-13,13-dimethyl-10-hepta-18 decynoic acid;
19 6. 8-methylsulfonyl~ (1-hydroxycyclohexyl)-10-undecynoic acid using l-ethynylcyclohexan-l-ol as starting material and 21 the following intermediates in order:
22 a. l-acetoxy-l-ethynylcyalohexane 23 b. 1-acetoxy-1-(3-diethylamino-1-propynyl)-cyalohexane 24 c. 1-acetoxy-1-(3-bromo-1-propynyl)-cyclohexane d. methyl 8-methoxycarbonyl-8-methylsulfonyl-11-(1~
26 acetoxycyclohexyl)-10-undecynoate 27 e. methyl 8-methylsulfonyl-11-(1-acetoxycyclohexyl)-10-28 undecynoate;
29 7. 8-methylsulfonyl-11-tl-hydroxycyclohexyl)undecanoic acid using 8-methylsulfonyl-11-(1-hydroxycyclohexyl)-10-undecynoic 31 acid as starting material;

~31-64~96i 1 8. 8-methylsulfonyl-12-hydroxy-16-heptadecenoic acid using 2 5-bromo-1-pentene as starting material and the following 3 intermediates in order:
4 a. 1-chloro-8-nonen-4-one b. 1-chloro-8-nonen-4-ol 6 c. 1-chloro-4-acetoxy-8-nonene 7 a. 1-iodo-4-acetoxy-8-nonene 8 e. methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxy-9 16-heptadecenoate f. methyl 8-methylsulfonyl-12-acetoxy-16-heptadecenoate;
11 9. 8-methylsulfonyl-12-hydroxy-17,17/17-tri~luorohepta- .
12 decanoic acid using 1,1,1-trifluoro-5-bromopentane as 13 starting material and the following intermediates in order:
14 a. di-tert-butyl-(6-ethoxycarbonylhexyl)-malonate b. 1-chloro-9,9,9-trifluoro-4-nonanone 16 c. 1-chloro-9,9,9-trifluoro-4-nonanol 17 d. 1-chloro-9,9,9-trifluoro-4-acetoxynonane 18 e. di~tert.-butyl-2-(4-acetoxy-9,9,9-trifluorononyl)-2-19 (6-ethoxycarbonylhexyl)-malonate f. ethyl 8-carboxy-12-acetoxy-17,17,17-trifluoxohepta-21 decanoa~e 22 g. ethyl 8-bromo-12-acetoxy-17,17,17-trifluorohepta-23 decanoate 24 h. 8-methylthio-12-hydroxy-17,17,17-trifluorohepta-decanoic acid;
26 10. 8-methylsulfonyl-12t-hydroxy-16,16-dimethylheptadecanoic 27 acid using 1-bxomo-4,4-d.~.methylpentane as starting material 28 and the following interm~ldiates in order:
29 a. 1-chloro-8,8-dimet~yl-4-nonanone b. 1-chloro-8,8-dimet~yl-4-nonanol 31 c. 1-chloro-8,8-dimetl~yl-4-acetoxynonane -~32-1al 64961 1 d. di-tert.-butyl 2~(4-acetoxy-8,8-dimethylnonyl)-2-(6-2 ethoxycarbonylhexyl)-malonate 3 e. ethyl 8-carboxy-12~acetoxy-16,16-dimethylhepta-4 decanoate f. ethyl 8-bromo-12-acetoxy-16,16-dimethylheptadecanoate 6 g. 8-methylthio-12-hydroxy-16,16-dimethylheptadecanoic 7 acid;
8 11. 8-meth~lsulfonyl-12-hydroXy-13-(4-flUOrOphenOXy)tri-9 decanoic acid using p-fluorophenol as starting material and the following intermediates in order:
11 a. 4-fluorophenoxyacetaldehyde diethylacetal 12 b. 4-fluorophenoxyacetaldehyde 13 c. 5-(4-fluorophenoxy)-1-penten-4-ol 14 d. 4-benzyloxy-5-(4-fluorophenoxy)-1-pentene e. 4-benzyloxy-5-(4-fluorophenox~)-1-pentanol 16 f. 4-benzyloxy-5-(4-~luorophenoxy)-1-pentanol tosylate 17 g. 4-benzyloxy-5-(4-fluorophenoxy)-1-iodopentane 18 h. methyl 8-methylsulfonyl-8-methoxycarbonyl-12-19 benzyloxy-13-(4-fluorophenoxy)tridecanoate i. methyl 8-methylsul~onyl-12-benzyloxy-13~(4-~luoro-21 phenoxy)tridecanoate 22 ~. 8~methyl~ul~onyl-12-benzyloxy-13-(4-fluoxophenoxy)tri-23 decanoic acid;
24 12. 8-methylsulfonyl-12-hydroxy-13-(4-methylphenoxy)tri-decanoic acid using p-cresol as starting material and the -~
26 following intermediates in order:
27 a. 4-methylphenoxyacetaldehyde diethyl acetal 28 b. 4-methylphenoxyacetaldehyde 29 c. 5-(4-methylphenoxy)-1-penten-4-ol d. 4-benzyloxy-5-(4-methylphenoxy)-1-pentene 31 e. 4-benzyloxy-5-(4~methylphenoxy~-1-pentanol .

~ 15663IA

106491Eii3L

1 . 4-benzyloxy-5-~4-methylphenoxy)-1-pentanol tosylate 2 g. 4-benzyloxy-5-(4-methylphenoxy)-1-iodopentane 3 h. methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyl-4 oxy-13-(4-methylphenoxy~tridecanoate i. methyl 8-methylsulfonyl-12-benzyloxy-13-t4-methyl-6 phenoxy)-tridecanoate 7 j. 8-methylsulfonyl-12-benzyloxy-13-~4-methylphenoxy)-8 tridecanoic acid;
9 13. 8-methylsulfonyl-12-hydroxy-13-(3-trifluoromethyl-phenoxy)~ridecanoic acid using 3-trifluoromethylphenol as 11 starting material and the following intermediates in order:
12 a. 3-trifluoromethylphenoxyacetaldehyde diethyl acetal 13 b. 3-trifluoromethylphenoxyacetaldehyde 14 c. 1-(2-tetrahydropyranyloxy)-4-acetoxy-5-~3-trifluoro methylphenoxy)-2-pentyne 16 d. 1-(2-tetrahydropyranyloxy)-4-acetoxy-5-(3-trifluoro 17 methylphenoxy)pentane 18 e. 4-acetoxy-5-(3-trifluoromethylphenoxy)-1-pentanol 19 f. 1-(p-Toluenesulfonyloxy)-4-acetoxy-5-(3-trifluoro-methylphenoxy)pentane 21 g. 1-iodo-4-ac~toxy-5-(3-trlfluoromethylphenox,y~pentane 22 h. methyl 8-methylsulfonyl-8-methoxycarbonyl-12-acetoxy-23 13-(3-trifluoromethylphenox,y)-tridecanoate 24 i. methyl 8-methylsulfonyl-12-acetoxy-13-(3-trifluoro-methylphenoxy)tridecanoate;
26 14. 8-methylsulfonyl-12-hydroxy-13-phenoxytridecanoic acid 27 using phenol as starting material with intermediate prepara- ~--28 tion in oxder o~:
29 a. phenoxyacetaldehyde diethyl acetal b. phenoxyacetaldehyde 31 c. 5-phenoxy-1-penten-4-ol -3~-~64961 1 d. 4-benzyloxy-5-phenoxy-1-pentene 2 e. 4-benzyloxy-5-phenoxy-1-pentanol 3 f. 4-benzyloxy-5-phenoxy-1-pentanol tosylate 4 g. 4-benzyloxy-5-phenoxy-1-iodopentane h. methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyl-6 oxy-13-phenoxytridecanoate 7 i. methyl 8-methylsulfonyl-12-benzyloxy-13-phenoxytri-8 decanoate g j. 8-methylsulfonyl-12-benzyloxy-13-phenoxytridecanoic acid 11 k. 8-methylsulfonyl-12-hydroxy-13-phenoxytridecanoic acid;
12 15. 8-methylsulfonyl-12-hydroxy-13-(2,4-dichlorophenoxy)tri-13 decanoic acid using 2,4-dichlorophenol as starting material 14 and the ~ollowing intermediates in o.rder:
a. 2,4-dichlorophenoxyacetaldehyde diethyl acetal 16 b. 2,4-dichlorophenoxyacetaldehyde 17 c.~ 5-(2,4-dichlorophenoxy)-1-penten-4-ol 18 d. 4-benzyloxy-5-(2,4-dichlorophenoxy~-1-pentene 19 e. 4-benzylox~r-5-~2,4-dichlorophenoxy)-1-~pentanol f. 4-benzyloxy-5-~2,4-dichlorophenoxy)-1-pentanol 21 tosylate 22 g. 4-benzyloxy-5-t2,4-diahlorophenoxy-1-iodopentane 23 h. methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyl-24 oxy-13-~2,4-dichlorophenoxy)tridecanoate i. methyl 8-methylsulfonyl-12-benzyloxy-13-~2,4-dichloro-26 phenoxy)tridecanoate 27 j. 8-methylsulfonyl-12-benzyloxy-13-(2/4-dichloro-28 phenoxy)-tridecanoic acid 29 k. 8-methylsulfonyl-12-hydroxy-13-(2,4-dichlorophenoxy)-tridecanoic acid;

1~D64~
1 16. 8-methylsulfonyl-12~hydroxy-13-(4-methylphenoxy)tri-2 decanoic acid usi.ng 4-methoxyphenol as starting material and 3 the following intermediates in order:
4 a. 4-methoxyphenoxyacetaldehyde diethyl acetal b. 4-methoxyphenoxyacetaldehyde 6 c. 5-(4-methoxyphenoxy)-1-penten-4-ol 7 d. 4~benzyloxy-5-(4-methoxyphenoxy)-1-pentene 8 e. 4-benzyloxy-5-~4-methoxyphenoxy)-1-pentanol 9 f. 4-benzyloxy-5-(4-methoxyphenoxy)-l~pentanol tosylate g. 4-benæyloxy-5-(4-methoxyphenoxy)-1-iodopentane 11 h. methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyl-12 oxy-13-(4-methoxyphenoxy)tridecanoate 13 i. methyl 8-methylsulfonyl-12-benzyloxy-13-(4-methoxy-14 phenoxy)-tridecanoate j. 8-methyLsulfonyl-12-benzyloxy-13-~4-methoxyphenoxy)-16 tridecanoic acid 17 k. 8-methylsulfonyl-12-hydroxy-13-(4-methoxyphenoxy)tri-18 decanoic acid;
19 17. 8-methylsulfonyl-12-hydroxy-13-(3-pyridyloxy)-tri-decanoic acid starting with 3-hydroxypyridine, and the fol-21 lowing intermediates in order:
22 a. 3-pyridyloxyacetaldehyde diethyl acetal 23 b. 3-pyridyloxyacetaldehyde 24 c. 5-(3-pyridyloxy)-1-penten-4-ol d. 4~benzyloxy-5-(3-pyridyloxy)-1-pentene 26 e. 4-benzyloxy-5-~3-pyridyloxy)-1-pentanol 27 f. 4-benzyloxy-5-(3-pyridyloxy)-1-pentanol tosylate 28 g. 4-benzyloxy-5-~3-pyridyloxy)~l-iodopentane 29 h. methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyl-oxy-13-(3-pyridyloxy)-tridecanoate :~6496~

1 i. methyl 8-methylsulfonyl-12-benzyloxy-13-(3-pyridyl-2 oxy)-tride~anoate 3 j. 8-methylsulonyl-12-benzyloxy 13-(3-pyridyloxy)tri-4 decanoic acid k. 8-methylsulfonyl-12-hydroxy-13-~3-pyridyloxy)tri-6 decanoic acid;
7 18. 8-methylsulfonyl-12-hydroxy-13-propoxytridecanoic acid 8 using l-propanol as startîng material and the followin~
9 intermediates in order:
a. propoxyacetaldehyde diethyl acetal 11 b. propoxyacetaldehyde 12 c. 5-propoxy-1-penten-4-ol 13 d. 4~benzyloxy-5-propoxy-1-pentene 14 e. 4-benzyloxy-5-propoxy-1-pentanol f. 4-benzyloxy-5-propoxy-1-pentanol tosylate 16 g. 4-benzyloxy 5-propoxy-1-iodopentane 17 h. methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyl-18 oxy-13-propoxytridecanoate 19 ~ i. methyl 8-methylsulfonyl-12-benzyloxy-13-propoxytri-decanoate 21 j. 3-methylsulfonyl~12-benzyloxy-13-propoxytridecanoic 22 a~id 23 k. 8-methylsulfonyl-12-hydroxy-13-propoxytridecanoic acid;
24 19. methyl 8-methylsulfonyl-12-hydroxyheptadecanoate.

~ ~a~4s6~

2 8-Methylsulfon~1-12-acetoxy eptadecanoic acid 3 A mixture of 8-methylsulfonyl-12-hydroxyhepta-4 decanoic acid (9.1 g., 0.025 mole) and acetic anhydride (0.1 g., 0.06 mole) is heated at 60C. for 18 hours. The 6 mixture is then cooled and dissolved in 80 ml. ethyl 7 ether. The solution is extracted with an ice-cold 8 solution of 8 g. sodium hydroxide in 150 ml. water. The 9 basic solution is separated and acidi~ied with concentrated hydrochloric acid. The oily acid which separates is taken 11 up in ether, washed with water and dried over sodium 12 su1fate. The ether is evaporated to leave 9.0 g. of the 13 oily crude product.
14 The product is purified by chromatography on a column containiny 150 g. oE silica gel ancl with 1%
16 methanol in chloro~orm as the elutincJ solvent. ~her~ is 17 obtained 8-methylsul~onyl~12-acetoxyheptadecanoic acid 18 as a colorless viscous oil.
19 By substituting the acetic anhydride used in 20 Example 32 with an equivalent amount of propionic 21 anhydride, butyric anhydride, isobutyric anhydride, 22 ~aleric anhydride, or pivalic anhydride and conducting 23 the reaction as described in Example 32, there is obtained ~6~96~
1 8-methylsulfonyl-12-propionyloxyheptadecanoic acid, 2 8-methylsulfonyl-12-butyrylox~heptadecanoic acid, 3 8-methylsulfonyl-12-isobutyryloxyheptadecanoic acid, 4 8-methylsulfonyl-12-valeryloxyheptadecanoic acid, and 8-methylsulfonyl-12-pivaloyloxyheptadecanoic acid, 6 respectively.

8 Preparation of N-(2-dimethylaminoethyl)-~-methylsulfonyl-9 12-hydroxyheptadecanamide A solution of 8-methylsulfonyl-12-hydroxyhepta-11 decanoic acid (3.6 g., 10 millimole), Example 2, 12 triethylamine (1.74 ml., 12.5 millimole) and distilled 13 water (18 ml., 1.0 mole) in acetonitrile (100 ml.) is 14 treated with N-t-butyl-S-methylisoxazolium perchlorate (3.0 g., 12.5 millimole). The resulting solution is 16 evaporated in vacuo (water aspirator) at 20-23C. for 17 4 hours providing a tacky residue which is triturated 18 with water (150 ml.) at 0-5C. for 15 minutes. After 18 decanting the aqueous phase, the oily residue is dissolved 19 in benzene-ether ~ 1), 200 ml.] The organic extract is dried over sodium sul~ate, ~iltered and evaporated in vacuo 21 at 35-40C. providing the desixed ' active e~ter ', 22 N-t-butyl-3-~8-methyl~ulonyl-12-hydroxyheptadecanoyloxy)~
23 crotonamide, as a pale yellow oil.
24 A solution of 2~dimethylaminoethylamine ~0.88 g.,

10 millimole) in acetonitrile ~25 ml.) is added to a 26 solution of the ' active ester ' in acetonitrile ~25 ml.) 27 providing a clear solution which is stirred at 25C. for 28 17 hours. The solvent is removed in vacuo at 40--50C.
29 leaving a residual oil which is partitioned between ether 1566:
1~4~

1 (200 ml.) and water (2 x 100 ml.~. The organic 2 extract is washed with saturated brine (2 x 100 ml.), 3 dried over sodium sulfate,,filtered and evaporated 4 in vacuo at 40-50Co providing a tan, crude oil.
S The oil is partitioned between 5% hydrochloric 6 acid (100 ml.) and ether (2 x 100 ml.). The aqueous acid 7 phase is slowly basified with ,sodium bicarbonate (16.8 g., 8 0.2 mole), then with 40~ aqueous sodium hydroxide (10 ml.
9 providing a heterogeneous mixture which is extracted Wit3.1 ether (100 ml.). The ether extract is washed with water

11 and brine and dried over sodium sulfate. The ether is

12 then evaporated in vacuo to leave the title compound as ,

13 a pale yellow viscous oil.
, :, . ,

Claims (4)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. A process for the preparation of compounds of the formula:

wherein:
A is selected from the group consisting of methylene and oxygen;
R4 is hydrogen;
n is 0, 1 or 2;
R9 is methyl, ethyl, or 2-hydroxyethyl, and R10 is alkyl or branched alkyl of 3-6 carbon atoms, or 4,4,4-trifluorobutyl, which comprises successively alkylating di-tertiary-butyl malonate in either order with a halo ester of the formula:

wherein A is as previously defined, X is halogen, and R11 is straight chain lower alkyl of 1 to 2 carbon atoms, and a halo ester of the formula:

wherein X, R4 and R10 are as defined above, to produce a disubstituted malonic ester of the formula:

wherein R4, R10 and A are as previously defined, and R11 is straight chain lower alkyl of 1 or 2 carbon atoms, heating said disubstituted malonic ester in the presence of a strong acid to produce a substituted decarboxylated malonic acid compound of the formula:

wherein R4, R10, R11 and A are as previously defined, contact-ing the said decarboxylated malonic acid compound with bromine in the presence of mercuric oxide to effect replacement of carboxy with bromo with resultant production of a substituted bromo ester of the formula:

wherein R4, R10, R11 and A are as previously defined, contact-ing said substituted bromo ester with an alkali metal salt of a mercaptan and then hydrolyzing the ester functions in dilute aqueous alkali, to form a thia-11,12-seco-prostaglandin compound of the formula:

wherein R4, R9, R10 and A are as previously defined, and oxidizing said thia-11,12-seco-prostaglandin compound to form an oxo or dioxo thia-11,12-seco-prostaglandin compound selected from the group consisting of compounds of the formula:

and wherein R4, R9, R10 and A are as previously defined.

2. The process of Claim 1, wherein di-tert.-butyl malonate is reacted with ethyl 7-brornoheptanoate to form the di-tert.-butyl-(6-ethoxycarbonylhexyl)-malonate and reacting the latter with 1-chloro-4-acetoxynonane to form the di-tert.-butyl-2-(4-acetoxynonyl)-2-(6-ethoxycarbonylhexyl))-malonate, heating the latter in the presence of a strong acid to form the ethyl 8-carboxy-12-acetoxyheptadecanoate, contacting the latter with bromine in the presence of mercuric oxide to form the ethyl 8-bromo-12-acetoxyheptadecanoate, contacting the latter with an alkali metal salt of mercaptan and hydrolyzing the resulting compound to form the 8-methylthio-12-hydroxy-heptadecanoic acid.

3. The compound of the formula:

wherein:
A is selected from the group consisting of methylene and oxygen;
R4 is hydrogen;
n is 0, 1 or 2;

R9 is selected from the group consisting of methyl, ethyl, 2-hydroxyethyl;
R10 is alkyl, branched chain alkyl of 3-6 carbon atoms, or 4,4,4-trifluorobutyl, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

4. The 8-methylthio-12-hydroxyheptadecanoic acid, when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.