CA1044701A - Seco-prostaglandins - Google Patents

Abstract

TITLE OF THE INVENTION:
NEW COMPOUNDS AND PROCESSES.
ABSTRACT OF THE INVENTION:
This invention relates to 8-aza-9-oxo(and dioxo)-thia-11,12-secoprostaglandins and processes for their manufacture. These compounds have prostaglandin-like biological activity and are particularly useful as renal vasodilators, for the prevention of thrombus forma-tion, to induce growth hormone release and for the treatment of certain autoimmune diseases.

Description

11 SUMMARY OF THE INV~NTION:
12 This invention relates to novel 8-aza-9-oxo(and 13 dioxo)thia-11,12-secoprostaglandins. These compounds can 14 be represented by the following s-tructural formula:

~SOy Rl l - (CH2) 4-A-R
CH Z C~R4 ) CH CH R5 R OR : .
wherein R is selected from the group consisting of carboxy 16 and a carboxy salt which incorporates a pharmaceutically 17 acceptable cation, such as metal cation derived from 18 alkali metals, alkaline earth metals and amines such as 19 ammonia, primary and secondary amines and quaternary ammonium hydroxides. Especially preferred metal cations 21 are those derived from alkali metals, e.g., sodium, 22 potassium, lithium, and the like and alkaline earth me-tals, , . ...,,~

:
-1- ' . . .. . . . . . .

:. -- , - . . . .,.. , . : :
: .. .... . - . :
: ~:. . - . . -: . . . , . :
: .:
,.
, ' ,' , ~ '' .. ' ; ' ' : . ' ., -. .

1 e.g., calcium, magnesium, and the like and other metals,

2 i.e., aluminum, iron and zinc.

3 Pharmaceutically acceptable cations derived ~ from primary, secondary, or tertiary amines, or quaternary ammonium hydroxides are methylamine, dimethylamine, 6 trimethylamine, ethylamine, N-methylhexylamine, benzyl-7 amine, a-phenethylamine, ethylenediamine, piperidine, 8 morpholine, pyrrolidine, 1,4-dimethylpiperazine, ethanol-9 amine, diethanolamine, triethanolamine, tris(hydroxymethyl)-aminomethane, N-methylglucamine, N-methylglucosamine, 11 ephedrine, procaine, tetramethylammonium hydroxide, tetra-12 ethylammonium hydroxide, benzyltrimethylammonium and the 13 like.
1~ R is also selected from alkoxycarbonyl (-COOY) wherein Y is alkyl having 1-10 carbon atoms, l--succinimido-16 ethyl, l-pivaloyloxyethyl, 2-acetamidoethyl or diloweralkyl-17 aminoloweralkyl; carbamoyl (-CONH2); substituted carbamoyl 18 (-CONR R ) wherein R and R7 are selected from the group 19 consisting of hydrogen, lower alkyl having 1-4 carbon atoms and diloweralkylaminoalkyl having 4-7 carbon atoms; and 21 carbazoyl (-CONH NH2~.
22 A is selected from the group consisting of 23 ethylene (-CII2CH2-), trimethylene (-CH2CH2CEI2-), a-methyl-24 ethylene (-CH2 CH(CH3)-), ~-methylethylene (-CEI(CH3)CH2-), a,a-dimethylethylene (-CH2-C(CH3)2-), ~,~-dimethylethylene 26 (-C(CH3)2CH2-) and oxymethylene (-O-CH2-). (Note that when 27 A consists of a two carbon bridge, the term "a" refers to 28 the carbon adjacent to R, while ~" refers to the other carbon 29 atom.) Rl is selected from the group consisting of 31 methyl, ethyl, propyl and isopropyl.

f~

1 Z is selected from the group consistlng of 2 ethylene (-CH2-CEl2-), vinylene (-CH=CH-) and ethynylene 3 (-C~C-). R2 is independently selected from the group con-

4 sisting of hydrogen, methyl, eth~l or propyl.
R3 is selected from the group consisting of 6 hydrogen and lower alkanoyl of 1-5 carbon atoms, e.g., 7 formyl, acetyl, propionyl, but~ryl, isobutyryl, valeryl, 8 pivaloyl, and the like.
9 R4 is selected from the group consisting of hydrogen and methyl.
11 R5 is selected from the group consisting of 12 hydrogen, lower alkyl of 1-4 carbon atoms either straight 13 or branched chain (e.g., methyl, ethyl, propyl, isopropyl, 14 butyl, tert-butyl), vinyl and 2,2,2-trifluoroethyl.
In addition, when R5 is lower alkyl and R2 is 16 methyl, they can be joined togekher (with abstraction of 17 hydrogen) to form a carbocyclic ring with from 6 to 9 -18 members.
19 Also, wh0n R5 is lower alkyl and R2 is hydrogen, ;
R5 can be joined to the carbon atom bearing R2 and oR3 21 to form a carbocyclic ring with from 5 to 8 members.
22 y is 1 or 2.
23 A preferred embodiment of this invention relates 24 to the 8-aza-9-oxo(and dioxo)tllia-11,12-secoprostaglandins having the following general formula:
26 R -SO2-N-(CH2~-A-COOH II
(CH2) ~ C-C(R )2-(CH2) R
H OH
27 wherein Rl, A, and R4 are as defined in formula I and R9 28 is lower alkyl of 1-4 carbon atoms. An even more preferred 29 embodiment encompasses compounds of formula II, wherein Rl ... ~ . . ,. ~ .

~f~ Q~
1 is methyl or ethyl; A i~ ethylene or oxymethylene; and R9 2 is ethyl, isopropyl, or butyl. In addition, another pre-3 ferred embodiment includes compounds of formula II, wherein 4 R9 is joined to the carbon bearing H,OH to form ~ carbocyclic ring with from 6 to 9 members.
6 It is to be noted that the carbon atom bearing .
7 the oR3 group in formula I and the one bearing one hydroxyl 8 group in formula II is asymmetric. This :invention also~ -9 covers stersoisomers in which the asymmetric center is 10 exclusively in either one or the other of the two possible :
11 configurations, R and S. :~
12 BACKGROUND OF THE INVENTION:
13 The compounds of formula I are described as 8-aza-14 9-oxo(and dioxo)thia-11,12-secoprostaglandins because of their structural relationship to the naturally OCGUrring 16 prostaglandins.
17 The prostaglandins constitute a biologically 18 prominent class of naturally occuring, highly functionalized 19 C20 fatty acids which are anabolized readily in a diverse array of mammalian tissues from three essential fatty acids;
21 namely, 8,11,14-eicosatrienoic acid, 5,8,11,14-eicosatetrae-22 noic acid and 5,8,11,14,17-e.icosapentaenoic acid. Each 23 known prostaglandin is a formal derivative of the parent 24 compound, termed "prostanoic acid"; the latter is a C20 fatty acid covalently bridged between carbons 8 and 12 such 26 as to form a trans, vicinally-substituted cyclopentane in 27 which the carboxy-bearing side chain is "alpha" or below 28 the plane of the ring and the other side chain is "beta" or ~ -29 above the plane of the ring as depicted in formula III:

. . .

. .

.

` ~' ~\ ~ Co2H
~ 8 III

11 12Y~4~4 ~_~6 ~_~18 ~' 20 2 The six known primary prostaglandins, PGEl, 2 3' la' PGF2a, and PGF3a, resulting directly 4 from anabolism of the above cited essential fatty acids via the action of prostaglandin synthetase, as well as 6 the tree prostaglandins resulting from ln vivo dehydration 7 of the PGE's, i.e., PGAl, PGA2, and PGA3, are divided 8 into three groups; namely, the PGE, PGF, and PGA series 9 on the basis of three distinct cyclopentane nuclear sub-10 stitution patterns as illustrated as follows: ;
O 0~1 0 1' ''' :' ~ a ~ Ra ~ r 11 PGE nucleus PGFa nucleusPGA nucleus ::
PG Ra b 12 El, Fl, Al ~ CO2H ¦

13 E2, F2, A2 "~ ~ ~ CO~

OH
14 E3~ F3~ A3 ' ~ CO2H
OH
Eol Fo, Ao ., ~ CO2H
OH

.. . . . . . ` . . ` . - ;
- . . : . . : ~ ~ . .

1495'1Y

-~13~

It should be noted that the Arabic subscripts designate the number o~ carbon-carbon double bonds in the side chain of the designated compound and that the ~reek subscript used in the PGF series designates the stereochemistry of the C-9 hydroxyl group.
Although the prostaglandins were discovered inde-pendently in the mid-1930's by Goldblatt ~. Chem. Soc. Chem.
Ind. Lond., 52, 10$6 (1933 ~ in England and Von Euler ~rch.
Exp. Path. Pharmark., 175, 78 (1934 ~ in Sweden, these complex natural products received little attention from the scientific community until the early 1960's which coincides with the advent of modern instrumentation (e.g., mass spectrometry) which, ln turn, was requisite for their successful 1solation and structural elucidation by Bergstr~m and colleagues ~ee Angew. Chem. Int. Ed., 4, 410 (1965) and references cited therein for an account of this wor ~. Within the last decade, a massive international scientific effort has been expended in developing both biosynthetic and chemical routes to the prostaglandins and, subsequently, in investigating of their biological activities. During this period, prostaglandins have been shown to occur extensively in low concentrations in a myriad of mammalian tissues where they are both rapidly anabolized and catabolized and to exhibit a vast 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 concerning the prostaglandins can be found . ~ .
- ~ ~. . - . .

'70~
1 in recent reviews of their chemistry [J.E. Pike, Fortschr.
2 Chem. Org. Naturst., 28, (1970) and G.F. Bundy, A. Rep~
3 in Med. Chem., 7, 157 (1972)], biochemistry [J.W. Hinman, 4 A. Rev. Biochem., 41, 161 (1972)], physiological signficance ;~
S [E.W. Horton, Physiol. Rev., 49, 122 (1969)] and general 6 clinical application lJ.W. Hinman, Postgrad. Med. J., 7 46, 562 (1970)].
8 The potential application of natural prostaglan- ;
9 dins as medicinally useful therapeutic agents in various mammalian disease states is obvious but suffers from three 11 formidable major disadvantages; nam~ly, (a~ prostaglandins 12 are known to be rapidly metabolized ln vivo in various 13 mammalian tissues to a variety of metabolites which are 14 devoid of the desired orig~nal biological activities, (b) lS the natural prostaglandins are inherently devoid o bio-16 logical specificity which is requisite for a successful 17 drug, and (c) although limited qua~tities of prostaglandins 18 are presently produced by both chemical and biochemical 19 processes, their production cost is extremely high; and, ~ ~
20 consequently, their availability is quite restricted. ~ ;
21 Our interest has, therefore, been to synthesize 22 novel compounds structurally related to the natural 23 prostaglandins but with the following unique advantages~
24 (a) simplicity of synthesis :Leading to low cost of pro-duction, ~b) specificity of biological activity which may 26 be either of a prostaglandin-mimicking or prostaglandin-27 antagonizing type; (c) enhanced metabolic stability The 28 combination of these advantages serves to provide effective, 29 orally and parenterally ac~ive therapeutic agents for the , . .

1 treatment of a variety of human and animal diseases. Inclu-2 ded are appllcations in renal, cardiovascular, gastrointes-3 tinal, respiratory, immune, and reproductive systems, and 4 in the control of lipid metabolism, inflammation, blood .r clotting, skin diseases, and certain cancers.
6 More specifically, in -the clinic, prostaglandin 7 agonists can function as agents for improving renal function 8 (e.~., renal vasodilation), anti-ulcer agents, agents for 9 fertility control, antithrombotics, antiasthmatics, anti-lipolytics, antineoplastic agents, agents for the txeatment 11 of certain skin diseases, dwarfism (by inducing growth 12 hormone release) and certain autoimmune diseases.
13 Prostaglandin antagonists can function as anti-14 inflammatory agents, anti-diarrheal agents, antipyretics, agenks for prevenkion of premature labor, and agents for 16 the treatment of headache.
17 The compounds of this invention are particularly 18 useful for improving renal function, for the treatment of 19 ulcers, and prevention of thrombus formation. It is emphasized that not all of these compounds possess each 21 utility; however, each compound has been tested in a 22 variety of assays and has shown activity in at least one 23 area of activity.
24 The compounds of this invention can be adminis-tered either topically or systemically, i.e., intravenously, 26 subcutaneously, intramuscularly, orally, rectally, or by 27 aerosolization in the form of sterile implants for long 28 action. They can be formulated in any of a number of 29 pharmaceutical compositions and non-toxic carriers to this end.

.. .

f~ ~

1 The pharmaceu~ical compositions can be sterile 2 injectable suspensions or solutions, or solid orally 3 administrable pharmaceutically acceptable tablets or ~ capsules; the compositions can also be intended for sub-lingual administration, topical application, or for 6 suppository use. It is especially advantageous to formu-7 late compositions in dosage unit forms for ease and economy 8 of administration uniformity of dosage. "Dosage unit 9 form" as a term used herein refers to physically discrete units suitable as unitary dosages for animal and human 11 subjects, each unit containing a predetermined quantity of 12 active material calculated to produce the desired biological 13 effect in association with the required pharmaceutical means.
14 Illustratively, a sterile injectable composition can be in the form of aqueous or oleagenous suspensions or 16 solutions.
17 The sterile injectable composition can be 18 aqueous or oleagenous suspension or solution. Suspensions 19 dispersing and wetting agents and suspending agents. Solu-tions are similarly prepared from the salt form of the 21 compound. For the laboratory animals, we prefer to use 22 incomplete Freund's adjuvant or sterile saline (9%) as 23 carrier. For human parenteral use, such as intramuscularly, 24 intravenously, or by regional perfusion, the diluent can be a sterile aqueous vehicle containing a preservative; for 26 example, methylparaben, propylparaben, phenol, and chloro-27 butanol. The aqueous vehicle can also contain sodium chlo-28 ride, preferably in an amount to be isotonic; as well as a ~
29 suspending agent, for example, gum arabic, polyvinylpyrroli- ~-done, methylcellulose, acetylated monglyceride (available _ g _ . .- .

` l495lY

1 commercially as ~yvace~ from Distillation Products Industry, ;
2 a division of Eastman Kodak Company), monomethyl glyceride, 3 dimethyl glyceride, Emulphor~(available from sadische 4 Anilin Sodafabrik) or a moderately high molecular weight polysorbitan (commercially available under the tradenames 6 Tween or Span from Atlas Powder Company, Wilmington, 7 Delaware). Other materials employed in the preparation 8 of chemotherapeutic compositions containing the compound 9 may include glutathione, 1,2-propanediol, glycerol and glucose. Additionally, the pH of the composition is 11 adjusted by use of an aqueous solution such as tris(hydroxy-12 methyl)aminomethane (tris buffer).
13 Oily pharmaceutical carriers can also be used, 14 since they dissolve the compound and permit high doses.
Many oily carriers are commonly employed in pharmaceutical 16 use, such as, for e~ample, mineral oil, lard, cottonseed 17 oil, peanut oil, sesame oil, or the like.
18 It is preferred to prepare the compositions, l9 whether aqueous or oils, in a concentration in the range of from 2-50 mg./ml. Lower concentrations require need-21 less qualities of liquid. Higher concentrations than 50 22 mg./mg. are difficult to maintain and are preferably 23 avoided.
24 Oral administration forms of the drug can also be prepared for laboratory animals or human patients 26 provided that they are encapsulated for delivery in the 27 gut. The drug is subject to enzymatic breakdown in the ~-28 acid environment of the stomach. The same dosage levels 29 can be used as for înjectable forms; however, even higher ~Y~q -10-.

~0 ~'J'Q ~

1 levels can be used to compensate for biodeyradation in ~-2 the transport. Generally, a solid unit dosage form can 3 be prepared containiny from 0.5 mg. to 25 mg. active ingre-4 dient.
Whatever the mode of administration, doses in 6 the range of about 0.10 to 20 mg./kg. of body weight 7 administered one to four times per day are used. The 8 exact dose depending on the age, weight, and condition 9 of the patient, and the frequency and route of administra-tion.
11 The low cost and ready accessibility of the 12 compounds of this invention make them particularly promis-13 ing for applications in veterinary medicine in which Eield 14 their utilities are comparable to those in human medicine.
PROCESSES TO PREPARE THE COMPOUNDS OF THIS INVENTION:
; _ 16 The new chemiaRl compounds with which this 17 invention is concerned are prepared by the following two 18 processes. The first process involves the reaction of a 1~ compound such as III with a compound such as IV, wherein A, ~0 y, Z, Rl, R2, R4 and R5 are as defined~

21 Rl-SOy~NH~(CH2)4-A-COOR III

22 X~CH2-Z/c ~ R )2CH2cH2R IV

23 as in formula I above and R8 is loweralkyl having 1-5 24 carbon atoms, preferably ethyl; and X is halogen, e.g., chloro, bromo, or iodo. The reaction is carried out by 26 preparing the alkali metal salt of III by reaction of III

27 with sodium hydride in a solvent, such as a 1:1 mixture of `, ' .

:

.'~ ' ~"

~ . .

:' r~

1~)44 1 benzene and dimethylformamide, adding compound IV at ambient 2 temperature, then heating the reaction mixture at 50-100C.
3 for from one to twenty hours. This reaction scheme affords 4 intermediates represented by formula V:
Rl-SOy~N~(CH2)4-A-COOR V
CH2-Z/C\ ~R )2-CH2CH2R

6 Mild basic hydrolysis (NaOH in aqueous methanol or ethanol~
7 of the ester functions of compound V affords compounds of 8 formula I, e.g., VI:
9 R -SOy~N~(CH2)4-A-COOH VI
CH2-Z-~C \ (R )2CH2CH2 R OH
In the second process a compound such as VII
11 is caused to react with a compound of formula VIII, wherein 12 A, X, y, Z, Rl, R4, and R~ are as defined as in formulas 13 III and IV above, and THP is the 2-tetrahydropyranyl 14 group. The reaction is carried 15 R -soy-NH-cH2-z-cH-c(R )2CH2CH2R VII
~THP
16 X-(CH2)4-A-COOR VIII
9 ' ~ . .
17 out by preparing the alkali metal salt of VII (wherein R
18 is hydrogen, loweralkyl of 1-4 carbon atoms, or 2,2,2-19 trifluoroethyl) by reaction of VII with sodium hydride in a solvent such as 1:1 mixture of benzene and dimethylforma-21 mide, adding compound VIII at ambient temperature then 22 heating the reaction at 50-100C. for from 1-20 hours.

~ . ~ . .
, 4~

1 This reaction scheme affords intermediates represented by 2 formula IX:
3 R -SOy~N~(C112)~~A~COOR IX
C}l2-Z-CII(R )2CH2~H2R
OTEIP
4 Mild acid hydrolysis (aqueous HCl in methanol or ethanol) removes the tetrahydropyranyl protecting group, then mild 6 basic hydrolysis (NaOH in aqueous methanol or ethanol) of 7 the ester function affords compounds of formula I, e.g., 8 X~
9 Rl-SOy~N~(CH2)~~A~COOH X
CEI2 Z-CII-C(R )2CEI2C~2R
OH
It is frequently advantageous from a therapeutic standpoint 11 to prepare compounds of -this invention (formula I) in which 12 the asymmetric carbon atom which bears oR3 is exclusively 13 in the R or S configuration. It will be recalled that the 14 corresponding center in the natural prostaglandins is in the S configuration; inversion of this center may or may not 16 produce a reduction in biological activity, although a -17 marked increase in biological specificity is often realized.
18 In our series of 8-aza-9-oxo(and dioxo)thia-11,12-19 secoprostaglandins, compounds which are exclusively R or S
at this center can be produced by employing preresolved com-21 pounds IV or VII and carrying out the steps of process 1 or i 22 2. An example of the use of such a preresolved compound IV
23 is given under the section "Preparation of Intermediates 24 (Example~ J and K)".

', ' ~,' .

f~ r ~ 4~7~ ~

DERIVRTIZATION OF P~ODUCT~
2 The directly obtained products oE the processes 3 described supra can be derivatized to yield the other 4 products of formula I.
1. The fundamental processes yield compounds 6 where R is carboxy. To obtain carboxy salts the acid 7 products are clissolved in a solvent such as ethanol, 8 methanol, glyme and the like and the solution treated with 9 an appropriate alkali or alkaline earth hydroxide or alkoxide to yield the metal salt, or with an equivalent 11 quantity o~ ammonia, amine or quaternary c~mmonium hydroxide 12 to yield the amine salt. In each instance, the salt either 13 separates from the solution and may be separated by Eiltra-14 tion or, when the salt is soluble it may be recovered by evaporation of the solvent. Aqueous solutions of the 16 carboxylic acid salts can be prepared by treating an a~ueous 17 suspension of the carboxylic acid with an equivalent amount 18 of an alkaline earth hydroxide or oxide, alkali metal 19 hydroxide, carbonate or bicarbonate, ammonia, an amine or a quaternary ammonium hydroxide.
21 To obtain carboxy esters ~i.e., compo~mds where R
22 is alkoxycarbonyl) the acid products are treated in ether 23 with an ethereal solution of the appropriate diazoal]cane.
24 For example, methyl esters are ~roduced by reaction of the acid products with diazomethane. To obtain products where 26 R is carbamoyl or substituted carbamoyl, the acid product 27 is first converted to an active Woodward ester. For example, 28 the acid product can be made to react with N-tert-butyl-5-29 methylisoxazolium perchlorate in acetonitrile in the presence .. . ..
.

~ ~ 14951 I2 l of a base such as triethylamine to yield an active ester in 2 which R is 3 -C-O-C(CH3)=CH-NEI-C-(CH3)3. Active esters of this type 4 can be reac-ted with ammonia to yield products of formula I
where R is carbamoyl, with primary or secondary amines or 6 di-lower-alkylaminoalkylamines to yield products where 7 R is substituted carbamoyl, i.e., -CoNR6R7, and with 8 hydrazine to yield products wherein R is carbazoyl.
9 2. The fundamental process yields products where R3 is hydrogen. In compounds of formulas VI and X, 11 reaction with formic acid, acetic anhydride, propionic 12 anhydride, butyric anhydride, isobutyric anhydride, valeric 13 anhydride, pivalic anhydride, and the like, without solvent 14 and at temperatures ~rom 25 to 60C., gives compounds wherein R3 is formyl, acetyl, propionyl, butyryl, isobutyryl, 16 valeryl, and pivaloyl, respectively.
17 PREPARATION OF STARTING MATERIALS:
18 l. The reagent III which has the general formula l9 shown, wherein A, Y, Rl, and R8 are as defined previously, is prepared in the following manner. The sodium salt of the 21 corresponding alkanesulfonamide or alkanesulfinamide is 22 treated with the appropriate halo compound (i.e., 23 X-(CH2)4-A-COOR ) to give reagent III:

R -SOy~NH~(C~I2)4-A-24 The reagent IV A which has the following general formula wherein X is halogen and R5 and R4 are as previously ... - . : . - ~ . . . ............................ ..
: .. ~. . : -. , . ~ . . , ."

r~ i~-- 14g51 I~
r7~L

1 X-(C~E2) ~C-C(R )2CH2C~I2R5 IV A
H ~ COCH3 2 defined as prepared in -the following man:ner. A Grignard 3 reagent R CH2CH2(R )2C-MgI or R5CH2CH2(R )2C-MgBr is 4 allowed to react, in ether, with a nitrile X(CH2)3CN. The S resulting imine is hydrolyzed in aqueous acidic solution 6 to give ketones of the formula XI:
7 X(CH2)3C(=O)C(R )2CH2CIl2R XI
8 The ketones (XI) are reduced to the corresponding alcohols 9 X(cH2)3cH~oH)-c(R )2CH2CH2R with sodium or potassium ; 10 borohydride in a suitable solvent such as methanol, ethanol, 11 or diglyme. Acetylation of these alcohols, preferably 12 with acetic anhydride, yiel.ds the reagents IV A.
13 By treatment of ketone XI with Grignard reagents 14 R2MgBr(or I) where R2 is methyl, ethyl or propyl, compounds of formula X(CH2)3C(R )(OH)C(R )2CH2CH2R5 are obtained 16 which upon acetylation with acetic anhydride in pyridine ~ :
17 give compounds of formula IV B:
18 X-~cH2)~c-c(R4)2cH2cH2R5 IV B
. R OCOCH3 19 The reagents IV C which have the following general formula 21 X-CH2C ~-C-C(R )2CH2CH2R IV C

22 wherein X, R and R4 are as defined previously and R9 is 4'70~
1 hydrogen, loweralkyl of 1-4 carbon atoms or 2,2,2-trifluoro-2 ethyl are prepared in the following manne:r. Acetylenic 3 alcohols HC-C-C(R )(OH)CtR )2CH2CE~2R are treated with 4 acetic anhs~dride to give the acetylated alcohols HC-.C-C(R )(OCOCH3)C(R )2CH2CH2R . Those compounds are 6 treated with paraformaldehyde and diethylamine to afford the 7 tertiary amines (C2H5) 2N-CH2C-C-C(R )(OCOCH3)C(R )2CH~CH2R -8 which when treated with cyanogen halide, e.g, bromide yield 9 the reagents IV C. The acetylenic alcohols HC.C-C(R2)-(OH)-C~R )2CH2CH2R intermediates for compounds of formula 11 IV C are prepared by reaction of ethynylmagnesium bromide -12 or lithium acetylide with aldehydes or ketones of the 13 formula R9CH2CH2C(R4)2C(R2)=o.
14 By using the resolved R and S orms o the HC-.C-CH(OlI)CtR4)2CH2CH2R9 in the above scheme, the corres-16 ponding R and S forms of the reagent IV C can be obtained.
17 It should be noted here that the use of the 18 R or S enantiomers of reagent IV C produce the R and S
19 enantiomers, respectively, of compounds of formula VI A
20 wherein Rl, R2, R4, R9, and Y are as defined previously and ~, 21 Zl is -C-C-.
;: ,,.. :,`
22 R -SOy~7~tCH2)4~A~COOH VI A

CH2-Z ~C-CtR ) 2OEI2CH2R

23 These optically active products VI A can be hydrogenated 24 over a platinum catalyst to give the R and S enantiomers of compounds of formula VI A where Z is ethylene -CH2~CH2-.

f~ r~`~

,"~V~lL4~

1 The rea~ent Iv D which has the following gener~l 2 formula:
3 X-CH2-CH=CH-CH-C(R )2CH2CH2R IV D

4 wherein X, R4 and R9 are as defined above and are prepared in the following manner. A Grignard reagent R9CH2CH2C~R )2-6 MgBr or R CH2CH2C(R )2MgI is allowed to react with 7 crotonaldehyde to give, after hydrolysis, the alcohol 8 CH3CH=CH-CH(OH)-C(R )2CH2CH2R . This alcohol is acetyl-9 ated, preferably with acetic anhydride without solvent at 30-100C. for 2-12 hours, to give the intermediate 11 CH3CH=CH-CH(OCOCN3)-C(R )2CH2CH2R9. This intermediate is 12 allowed to react with N-bromosuccinimide in carbontetrachloride 13 at 50-70C. for 2.5 to 5 hours to efEect allylic bromination 14 and give the reagent of formula IV D.
3. The reagent VII which has the formula shown 16 is prepared by the following reactions. The alcohol 17 prepared 18 R _soy-NH-(cH2)3-cH-c(R )2CH2CH2R VII
OTHP
19 in Section 2 above with the formula X(CH2)3CH-C(R4)2CH2CH2R5 OH
is treated with dihydropyran and a catalytic amount of 21 acid to give X(CH2)3-CH-C(R4)2CH2CH2R5. Treatment of this OTHP
22 halo compound with the sodium salt of phthalimide in -23 dimethylformamide affords the corresponding phthalimido 24 compound. Cleavage of this compound with hydrazine in , ~. . . , :
: ~ ' ,~ ,, ' : - . . . .

'71~

1 ethanol yields the amine NH2-(CEl2)3-CfI-C~R )2CH2C]-l2R5 OTHP
2 which u~on treatment with the appropriate alkanesulfonyl 3 chloride or alkanesulfinyl chloride in pyridine affords 4 the reagent VII. 7

5 4. The preparation of reagents of formula VIII ~-

6 has been described in the scientific and patent literature

7 in instances

8 X-(CH2)4-A-cOoR VIII

9 where A is ethylene, trimethylene, a-methylethylene, ~
methylethylene, a,a-dimethylethylene, ~ dimethylethylene.
11 To prepare reagents where A is oxymethylene, an ester of 12 glycolic acid, HOCH2COOR is treated with a strong base, 13 preferably sodium hydride, in a non-protic solvent 14 (dimethylformamide, glyme, and the like) and the resulting ~.
anion caused to react with a 1,4-dihalobutane, preferably 16 1,4-dibromobutane. The glycolic ester and base are 17 employed in approximately equimolar quantities; a 1.5 to 18 2 molar excess of the dihalobutane is advantageously used.
19 5. Methods for obtaining optical antipodes of some compounds of this invention have been described supra 21 whereby one o~ the compounds o~ the molecule is preresolved 22 prior to its assembly into the whole molecule. Other 23 methods also can be employed; for example, mixtures of 24 racemates may be separated by taking advantage of the physiochemical difference between the components using 26 chromatography and/or fractional crystallization. The 27 racemic products and intermediates of this invention can 28 be resolved into their optically active components by any .~ .

, ~

. --19--: , . . . ~ .. :

;~ ~

1 one of a number of methods of reso~ution which are well described in the chemical literature.
3 Those compounds which are carboxylic acids can 4 be converted to the diastereoisomeric salts by tr~atment with an optically active base such as ~ or - a-methylbenzyl-6 amine, + or - a-~1-naphthyl)-ethylamine, brucine, cincho-7 nine, cinchonidine, or quinine. These diastereoisomeric 8 salts can be separated by fractional crystallization. ;
9 The carboxylic acids of this invention also can be converted to esters using an optically active 11 alcohol, such as, estradiol-3-acetate, or d- or l-menthol 12 and the diastereoisomeric esters resolved by crystallization 13 or by chromatographic separation.
14 Racemic carboxylic acids also may be resolved by reverse phase and absorption chromatography using an 16 optically active suppart and absorbent.
17 Compounds of this invention which contain free 18 hydroxyl groups can be esterified with acid chlorides or 19 anhydrides derived from optically active acids, such as, (Y) -10-camphorsulfonic acid, (=)-a-bromocamphor-~/-21 sulfonic acid, or d- or 1-6,6'-dinitrodiphenic acid to 22 form esters which can be resolved by crystallization.
23 Another method of obtaining pure optical isomers 24 involves incubation of the racemic mixture with certain microorganisms such as fungi, by processes well estab-26 lished in the art, and recovering the product formed by 27 the enzymatic transformation.
28 The methods described supra are especially 29 effective if one applies the process to a compound where ..
., :

4~7o~L .

1 one asymmetric center has been preresolved by the techniques -2 already described.
3 This invention is further described in the follow-4 ing examples.
5 PREPARATION OF INTERME:DIATES :.
~ A. Preparation of l-Chloro-4-acetoxynonane 7 Step 1. Preparation of l-Chloro-4-nonanone 8 To ~he Grignard reagent prepared from a mixture 9 of amyl bromide (226.59 g.; 1.5 moles) and magnesium (36.48 g.; 1.5 moles) in èther (1000 ml.) is added, 11 dropwise, during one hour, 4-chlorobutyronitrile .
12 (155.34 g.; 1.5 moles). Stirring is continued for an .: : ..
13 additional one hour. The reaction mixture is poured into 14 a mixture of finely crushed ice (1000 g.) and concentrated hydrochloric acid ~750 ml.). The ether layer is separated 16 quickly and discarded. The aqueous layer is heated on a 17 steam bath for one hour to hydrolyze the intermediate imine ~ `

18 and cause the separation of the ketone as an oil. After 19 cooling, the oil is extracted with ether and the combined extracts are washed with saturated sodium chloride solution 21 and dried over anhydrous sodium sulfate. The solvent is 22 removed under vacuum and the residual oil is distilled to 23 give 69.0 g. (26%) of colorless oil, b.p. 115-117/14 mm.;

24 pmr (CDC13) ~ 0.90 (3H,t), 3.56 (2~l,t,CH2Cl).

Step 2. Preparation of l-Chloro-4-nonanol ~ -2S A suspension of sodium borohydride (6.62 g.;

27 0.175 mole) and sodium hydroxide (1.3 g.) in ethanol 28 (310 ml.) is treated, dropwise, over 1 hour with l-chloro-29 4-nonanone (61.40 g.; 0.349 mole) while the temperature is maintained at 45-50C. Stirring is continued for one hour, 31 longer without external cooling.

..... .. ........ . .. . . .. . . . . . .

~)44'70~L

1 The reaction mlxture is acidif:led with con-2 centrated hydrochloric acid to the Congo red endpoint and 3 then the ethanol is removed under reduced pressure. The 4 residue is treated with water (200 ml.) and the resulting oil is extracted with ether. The comblned extracts are 6 washed with saturated sodium chloride solution and dried 7 over anhydrous sodium sulfate. The solvent is removed 8 under vacuum to give the title compound as a light yellow 9 residual oil, yield 58.85 g.; ir (neat) 3400 cm 1 Step 3. Preparation of l-Chloro-4-acetoxy-11 nonane 12 A mixture of l-chloro-LI-nonanol (111.99 g.;
13 0.627 mole) and acetic anhydride (128.0 g.; 1.254 moles) 14 ls heated on a steam bath for 1-1/2 hours.
The volatile materlals are removed under 16 reduced pressure and the residual oil is distilled to 17 give 88.6 g. (64%) of colorless oil, b.p. 130-133/14 mm.;
18 pmr (CDC13) ~ 0.89 (3H,t), 2.02 (3H,s CH3C00), 3.53 19 (2H,t CH2Cl), l1.89 (lH,m). Anal. Calcd. for CllH21C102:
C, 59.85; H, 9.59 21 Found: C, 59.87; H, 9.67.
22 B. Preparation of l-Chloro-4-acetoxy-8-methylnonane 23 Step 1. Preparatlon of l-Chloro-8-methyl-4-24 nonanone To the Grignard reagent prepared from a mixture 26 of 1-bromo-4-methylpentane (200.00 g.; 1.21 mole) and 27 magnesium (29.43 g.; 1.21 mole) in ether (800 ml.~ is 28 added, dropwise during one hour, 4-chlorobutyronitrile -~ ~' 14951I~
,,,, :

1 (125.30 g.; 1.21 mole). Stirring is continued for an ~;
2 additional one hour.
3 The reaction mixture is poured into a mixture 4 of finely crushed ice (800 g.) and concentrated hydro-chloric acid (600 ml.). The ether layer is separated 6 quickly and discarded. The aqueous layer i5 heated on 7 a steam bath for one hour to hydrolyze the intermediate ~-8 imine and cause the separation o~ the ketone as an oil.
9 After cooling, the o~1 is extracted with ether and the combined extracts are washed with saturated sodium 11 chloride solution and dried over anhydrous sodium 12 sulfate. The solvent is removed under vacuum and l;he 13 residual oll is distilled to glve 23.3 g. (10%) Or 14 colorless oll, b.p. 121-122/15 mm.; pmr (CDC13) ~ o.89 (6H,d), 3.57 (2H,t CH2Cl).
16 Anal. Calcd. for CloHlgC10:
17 C, 62.98; H, lO.OLI
18 Found:
19 C, 62.86; H, 10.20 Step 2. Preparation of l-Chloro-8-methyl-4-21 nonanol 22 A suspenslon o~ sodlum borohydrlde (2.3 g., 23 0.061 mole) and sodium hydroxide (0.5 g.) in ethanol 24 (110 ml.) is treated dropwise during one hour with 25 1-chloro-8-methyl-4-nonanone (23.0 g., 0.121 mole) ;`~
26 while the temperature is maintained at 45-50C. Stirring 27 is continued for one hour longer without external cooling.
28 The reaction mixture is acidified with con-29 centrated hydrochloric acid to the Congo Red endpoint and then the ethanol is removed under reduced pressure.

~ J 9 5 l ~

-1~344~

1 The residue is treated with water (70 ml.) and the 2 resultlng oil is extracted with ether. The combined 3 extracts are washed with saturated sodium chloride 4 solution and dried over anhydrous sodium sulfate. The solvent is removed under vacuum to give the title 6 compound as a light yellow residual oil, yield 22.73 g.;
7 ir (neat) 3400 cm 1. --8 Step 3. Preparation of l-Chloro-4-acetoxy-8-9 methylnonane _ _ _ _ A mixture of l-chloro-8-methyl-4-nonanol 11 (22.73 g.; 0.118 mole) and acetic anhydride (24.07 g.;
12 0.236 mole) is heated on a steam bath for 1-1/2 hours.
13 The volati~e materials are removed under reduced 14 pressure and the residual oil is distilled to give 14.58 g. (58%) of colorless oil, b.p. 138-139/15 mm.;
16 pmr (CDC13) ~ 0.85 (6H,d), 2.02 (3H,s CH3CO0), 3.53 17 (2H,t CH2Cl), 4.92 (lH,m).
18 C. Preparation of l-Chloro-4-acetoxyundecane 19 Step 1. Preparation of l-Chloro-4-undecanone This compound is prepared essentially by the 21 same procedure as descrlbed for 1-chloro-4-nonanone 22 (Example A, Step 1) using the following reagents: ;
23 l-Bromoheptane . . . . . . . 214.91l g. tl-2 mole?
24 Magnesium . . . . . . . . . 29.18 g. (1.2 mole) Ether . . . . . . . . . . . 800 ml.
26 4-Chlorobutyronitrile . . . 124.27 g. (1.2 mole) 27 The title compound is obtalned as a colorless 28 oil, yield 60.4 g. (15%), b.p. 135-140/15 mm.; pmr 29 (CDC13 ~ 0.93, (3H,t), 3.57 (2H,t CH2Cl).

, ~ 14951 1 ' t^~ "~

1 Step 2 Preparation of l-Chloro-4-undecanol 2 This compound is prepared essentially by the 3 same procedure as described for 1-chloro-4-nonanol 4 (Example A, Step 2) using the following reagents:
5 Sodium borohydride . . . . . 5.56 g. (0.147 mole) ' 6 Sodium hydroxide . . . . . . 1.12 g.
7 Ethanol . . . . . . . . . . 265 ml.
8 1-Chloro-4-undecanone . . . 60.00 g. (0.294 mole~
9 The title compound is obtained as a yellow residual oil, yield 60.02 g.
11 SteP 3. Preparation of l-Chloro-4-acetoxy-12 undecane _ _ 13 This compound ls prepared essentially by the 14 same procedure as described for 1-chloro-4-acetoxy-norlane (Example A, Step 3), using the following reagents:
16 1-Chloro-4-undecanol . . . . 60.02 g. (0.29 mole) 17 Acetic anhydride . . . . . . 59.16 g. (o.58 mole) 18 The title compound is obtained as a colorless 19 oil, yield 44.6 g. (62%), b.p. 155-158/15 mm.; pmr (CDC13) ~ 0.88 (3H~t), 2.02 (3H,s CH3C00)~ 3.53 (2H,t 21 CH2Cl), 4.92 (lH,m).
22 Anal. Calcd- for C13H25C12 23 C, 62.76; H, 10.13 24 Found:
C, 63.o3, H, 10.40 26 D. Preparation of l-Chloro-4-acetoxy-8,8-dimethyl-nonane 27 By following the procedure described for 28 1-chloro-4-acetoxynonane (Example A) but substituting , ,. . . ~ , . . .

,, ,i~ 1 11 9 5 1 ~,o44t7~

1 1-bromo-4,4-dimethylpentane for amyl bromide, there is 2 obtained in succession: 1-chloro-8,8-dimethyl-4-nonanone~
3 1-chloro-8,8-dimethyl-4-nonanol, and 1-chloro-4-acetoxy-4 8,8-dimethylnonane.
E. Preparation of l-Chloro-4-acetoxy-9,9,9-trifluoro-6 nonane 7 By followlng the procedure described for 8 1-chloro-4-acetoxynonane (Example A) but substituting 9 1-bromo-5,5,5-trifluoropentane for amyl bromide, there is obtained in succession: l-chloro-9~9~9-trifluor 11 nonanone, l-chloro-959,9-trifluoro-4-nonanol, and 1-12 chloro-4-acetoxy-9,9,9-trifluoronane.
13 F. Preparation of l-Chloro-4-acetoxy-8-nonene 14 By followlng the procedure described for 1-chloro-4-acetoxynonane (Example A) but substituting 16 1-bromo-4-pentene for amyl bromide, there is obtained ~;
17 in succession: 1-chloro-8-nonen-4-one, 1-chloro-8- ;
18 nonen-4-ol, and 1-chloro-4-acetoxy-8-nonene.
19 G. Preparation of l-Chloro-4-acetoxy-5,5-dimethyl-nonane 21 Step 1. Preparation of l-Chloro-5,5-dimethyl-22 4-nonanone 23 Four hundred ml. of a solution in ether of 1,1-24 dimethylpentylmagnesium chloride prepared from mag-25 nesium (24.3 g., 1.0 mole) and l-chloro-l,l-dimethyl- -26 pentane (134.5 g., 1.0 mole) according to the procedure 27 of Whitmore and Badertscher [J. Am. Chem. Soc., 55, 1559 28 (1933)] is added dropwise with stirring to 4-chloro-29 butyryl chloride (197 g.3 1.4 moles) in ether (400 ml.) during 6 hours. The reaction mixture is stirred for an 14951 I~
. ;

~044~7~
1 additional 12 hours. It is then poured into a mixture 2 of ice and dilute hydrochlorlc acid. The ether layer 3 is separated, washed with water and brine and dried over 4 sodium sul~ate. The ether is evaporated and the residue distilled at aspirator vacuum through a Vigreaux column 6 to yield the product as a colorless oil.
7 Step 2. Preparation of l-Chloro-5,5-dimethyl-8 4-nonanol _ 9 By following the procedure described ~or 1-chloro-4-nonanol ~Example A, Step B) but substituting 11 1-chloro-5~5-dimethyl-4-nonanone for 1-chloro-4-nonanone 12 and continuing stirring and heating at 50 ~or 6 hours, 13 there is obtained 1-chloro-5,5-dimethyl-4-nonanol.
1ll Step 3. Pr-eparation of l-Chloro-4-acetoxy-5,5-dimethylnonane 16 By following the procedure described for 17 1-chloro-4-acetoxynonane (Example A, Step 3) but substitut-18 ing 1-chloro-5,5-dimethyl-4-nonanol for 1-chloro-4- ;
19 nonanol and continulng the steam bath heating for 4 hours, there is obtained 1-chloro-4-acetoxy-5,5-dimethylnonane.
21 H. Preparation of l-Bromo-4-acetoxy-2-nonene ;
:: .
22 A mixture of 4-acetoxy-2-nonene (73.5 g., 23 0.4 mole), N-bromosuccinimide (80~0 g., 0.45 mole), 24 and carbon tetrachloride (500 ml.~ is boiled under ~ -reflux for 3 hours. The mixture is then cooled and the 26 suspended succinimide, removed by filtration. The carbon 27 tetrachloride solution is washed w1th dilute sodium 28 bicarbonate solution and water, and is dried over 29 sodium sulfate. The carbon tetrachloride is evaporated in vacuo and the residual oil is distilled to yield 62 g.

,. . . ... , . , . . .. , - . ~

14951Ii 1 (59%) of 1-bromo-Ll-acetoxy~2-nonene as a light yellow oil, 2 b.p. 110-112/0.1 mm.
3 I. Preparation of 1-Bromo-4-acetoxy-2-nonyne 4 Step 1. Preparation of 3-Acetoxy-l~octyne 1-Octyn-3-ol (100 g., 0.79ll mo:Le) is dissolved 6 in pyrldine (79 g., 1.0 mole) and acetic anhydride (81.6 g., 7 0.80 mole) is added dropwise with stirring during one hour.
8 The temperature rises to 45. The solut:lon is heated at 9 55 for one hour and is then cooled and poured into 200 ml., ice-cold 5% hydrochloric acid. The oily product is taken 11 up in ether, washed with water and brine and dried over 12 sodium sulfate. The ether is evaporated and the resldual 13 oil distilled to yield 106.4 g. (80%) of 3-acetoxy-1-14 octyne, b.p. 91-92/15 mm.
Step 2. Preparation of l-Diethylamino-ll-acetoxy-16 2~nonyne ~7 A mixture of 3-acetoxy-1-octyne (58.8 g., 0.35 18 mole), diethylamine (28.5 g., 0.39 mole), paraformal-19 dehyde (13.8 g., o.46 mole) and p-dioxane (60 ml.) is heated on the steam bath under a reflux condenser for 21 17 hours. The resulting solution is cooled and diluted 22 with 250 ml. of ether. The solution is extracted with 23 300 ml. of 5% hydrochloric acid. The acidic aqueous 24 extract is made basic with 10% sodium hydroxide solution.
The liberated amine is taken up in ether, washed with 26 water and brine and dried over sodium sulfate. The ether 27 is evaporated and the residual oil distilled to yield 28 73.1 g. (89%) of 1-diethylamino-4-acetoxy-2-nonyne, b.p.
29 103-109/0.3 mm.

~ 14951 I
/

7~
1 Anal. calcd. ~or C15H27NO2:
2 C~ 71.10; H, 10.74; N, 5.33 3 Found:
4 C, 70.73; H~ 11.03; N, 5.55 Step 3. Preparation of l-Bromo-4-acetoxy-2- ;~
6 nonyne 7 A solution of l-diethylamino-4-acetoxy-2-nonyne 8 (50.6 g., 0.20 mole) and cyanogen bromide (21.2 g., 9 0.20 mole) in ether (250 ml.) is allowed to stand at ~ -25-27 for 18 hours. The ether solution is washed 11 with 5~ hydrochloric acid solution, water, and brine and 12 dried over sodium sulfate. The ether is evaporated and 13 the residual oil distilled. After a forerun of diethyl-14 cyanamide, there is collected 3ll.1 g. (65%) of 1-bromo-4-acetoxy-2-nonyne, b.p. 97-105/0.2 mm.
16 Anal. calcd. for CllH17BrO2:
17 C, 50.59; H, 6.56 18 Found:
19 C, 50.54; H~ 6.49 J. Preparation of l-Bromo-4(R)-acetoxy-2-nonyne 21 By following the procedure described in Example H
22 but substituting (R)-l-octyn-3-ol [a]26 + 6.1 [C 3.1, ;
23 CHC13] for the racemic 1-octyn-3-ol, there is obtained 24 successively: 3(R)-acetoxy-l-octyne, [a]D6 + 7oo [C 3.1, CHC13], 1-diethylamino-4(R)-acetoxy-2-nonyne, [a]26 + 74 26 [C 3.2, CHC13], and 1-bromo-4(R)-acetoxy-2-nonyne, 27 [a]D6 + 75 [C 3.2, CHC13].
28 K. Preparation of l-Bromo-4(S)-acetoxy-2-nony_e 29 By following the procedure described in Example H
but substituting (S)-l-octyn-3-ol, [a]26 - 6.4 [C 3.3,CHC13], -2 ~

,.- . , ~.... .. - .......... ~ , ~ ., , . ;. .

~ ~ 14951I~

~ 4~

1 for the racemic l-octyn-~, there are obtained succes-2 sively: 3(S)-acetoxy-l-octyne~ C~]26 _ 79 [C 3.0, CHC13], 3 1-diethylamino-4(S)-acetoxy-2~nonyne, [a326 _ 80 tC 3.3, 4 CHC13], and 1-bromo-4(S)-acetoxy-2-nonyne, [a]D6 - 83 [3.7, CHC13].
6 L. Preparation of Methyl 7-bromo-2-methylheptanoate 7 Step_l. Preparation of_5-Acetoxypentyl chloride 8 Acetic anhydride (102 g., 1 mole) is added 9 dropwise with stirring to pentamethylene chlorohydrin (90 g., 0.74 mole). The resulting solution is heated 11 on the steam bath for one hour and allowed to stand 12 overnight at room temperature. The reaction mixture is 13 distilled to yield 83.6 g. (69%) of 5-acetoxypentyl 14 chloride, b.p. 101-104/20 mm.
Step 2. Preparation of Diethyl (5-Acetoxy-16 ~entyl)methylmalonate 17 Sodium hydride (4.8 g., 0.2 mole) as a 50%
18 suspension in mineral oil is washed with petroleum 19 ether under nitrogen to remove the mineral oil, suspended in dry benzene (150 ml.), and the suspension 21 cooled in an ice bath. Diethyl methylmalonate (34.8 g., 22 0.2 mole) dissolved in sieve drled DMF (150 ml.) is 23 added to the suspension of sodium hydride dropwise.
24 The mixture is allowed to stand overnight at room tem-perature. Potassium iodide (0.4 g.) and 5-acetoxyphenyl 26 chloride (32.9 g., 0.2 mole) are then added, and the 27 mixture is heated for 24 hours at 125 in an oil bath.
28 The reaction mixture is concentrated in vacuo, diluted 29 with ether (200 ml.), and filtered to remove sodium chloride. The filtrate is washed with brine, dried lL~951 r~ ~

1 over anhydrous magnesium sulfate and concentrated to 2 yleld 39.6 g. (66%) of olly product.
3 Step 3. Preparation of 7-Bromo~2~methyl-4 he~tanoic acid A mixture of the crude dlethyl (5-acetoxy-6 pentyl)methylmalonate (68 g., 0.23 mole) and 48% aqueous 7 hydrobromic acid (lOO ml.) is refluxed for 20 hours.
8 The mixture is then concentrated by dist:Lllation until 9 the internal temperature rises to 120; 96 ml. of distillate (2 layers) is collected. The residual liquid 11 is cooled, dissolved in ether, washed with brine, dried -12 over magnesium sulfate, and the solution concentrated 13 in vacuo to yield 54 g. oP crude 7-bromo-2-methyl-14 heptanoic acid as a dark viscous liquid.
Step Ll Preparation of Methyl 7-Bromo-2-16 methylheptanoate 17 A solution of crude 7-bromo-2-methylheptanoic ;~-18 acid (54 g., 0.24 mole) and concentrated sulfuric acid 19 (2 drops) in absolute methanol (300 ml.) is refluxed for 5 hours. After standing overnight at room temperature, 21 the solution is concentrated in vacuo and diluted with 22 water. The mixture is made basic by the addition of 23 saturated sodlum carbonate solution and the product 24 taken up in ether. The ether extract is washed with water, dried over anhydrous magnesium sulfate and 26 distilled to yield 11.8 g. (16%) of methyl 7-bromo-2- ;~
27 methylheptanoate, b.p. 67-70/0.05mm.; pmr (CDC13) 28 1.13 (3H,d 2-CH3), 2.42 (lH,m C_COOCH3), 3.38 (2H,t 29 CH2Br), 3.65 (3H,s CH30).

: .. ,, : : : . - . , , -lL~951 r~
:~.

1044'~
1 M. Preparation of Ethyl 4-Bromobutoxyacetate 2 Sodium hydride (9.0 g., 0.375 mo:le) is sus-3 pended in 1,2-dimethoxyethane. The mixture is stirred Ll and cooled in an ice bath while ethyl glycollate (39.0 g., 0.375 mole) is added dropwise during one hour.
6 1,4-Dibromobutane (108 g., 0.5 mole) is added all at 7 once to the resulting thick suspension. The mixture is 8 warmed gently to initiate a strongly exothermic reaction;
9 then the mixture is heated 3 hours on the steam bath.
The mixture is poured into cold water. The heavy oil 11 layer is taken up in ether, washed with three portions 12 of water, and dried over sodium sulfate.
13 Evaporation of the ether and distillation of 14 the residual oil yields 21.3 g. (24%) of ethyl ll-bromobutoxyacetate, a colorless oil, b.p. 99-103/0.2 mm.
16 N. Preparation of N-[4-(2-Tetrahydropyranyloxy)nonyl]-17 methanesulfonamide 18 Step 1. Preparation of l-Chloro-4-(2-tetra~
19 hydropyranyloxy)nonane _ _ To a stlrred solution of l-chloro-4-hydroxy-21 nonane (Example A, Step 2) (11.0 g., 0.062 mole) and di-22 hydropyrane (5.2 g., 0.062 mole) cooled in an ice bath is 23 added 5 drops of hydrochloric acid (conc.). A slight 24 exothermic reaction is noted and when this is complete the reaction is allowed to come to room temperature~ then 26 stand for 2 hours. At the end of this period several ~ -27 pellets of sodium hydroxide are added and the reaction is 28 distilled in vacuo. The yield of l-chloro-4-(2-tetra-29 hydropyranyloxy)nonane is 12.5 g. (77%), boiling :, :: : .. . .

.

~4'71 196-102/0.1 mm. Upon redistilla~ion a boiling point of ` ~-2 90-92/0.1 mm. is obtained.
3Ste~ ?~ Preparation of N-[4-(2-Tetrahydro- ~ ~
4pyranyloxy)nonyl3phthalimide ~ -5Sodium hydride (53%) (1.5 g. excess) is washed 6 with benzene three times ~y decantation, then dimethyl ~-7 formamide (100 ml.) is added. To this stirred suspension 8 is added a solution of phthalimide (4.3 g., 0.03 mole) in 9 dimethyl formamide (50 ml.) at such a rate as to keep the temperature below 35C. A clear solution is obtained and 11 to it is added 1-chloro-4-(2-tetrahydropyranyloxy)nonane 12 (7.8 g. 0.03 mole) and the resulting solution is stirred 13 and heated at 95C. for 20 hours. The reaction ls then 14 concentrated to one-half lts volume in vacuo, poured into ice water (200 ml.) and extracted with ether (2 x 150 ml.).
16 The ether is washed with 5% sodium hydroxide (2 x 50 ml.), 17 saturated sodium chloride solution (2 x 50 ml.), then 18 dried over sodlum sulfate. Evaporation of the ether 19 affords 4.5 g. (45% yield)of N-[4-(2-tetrahydropyranyl-oxy)nonyl]phthalimide melting 59-61C. After crystalli-21 zation from cyclohexane the product melts at 62-63C.
22 Anal. Calcd. for C22H31N04: .
23 C, 70.75; H, 8.36; N, 3.75 24 Found:
C, 71.03; H, 8.28; N, 3.81 -26 Step 3. Preparation of 4-(2-tetrahydropyranyl-27 oxy)nonylam_ne _ _ 28 To a soIution of N-[4-(2-tetrahydropyranyloxy) , 1~1951 1 nonyl]-phthalimide (33.0 g., o.88 mole) in absolute 2 ethanol (300 ml.), is added hydrazine (64%) (10 ml.
3 excess) and the reaction is heated at reflux for 1.5 4 hours. An addltional 5 ml. of hydrazine (64%) is added and reflux continued for 1.5 hours. The reaction is 6 cooled to room temperature and the white solid that is 7 present is removed by filtration. The filtrate is con-8 centrated in vacuo to 75 ml., then pourecl into water 9 (200 ml.). The solution is made basic with 5% sodium hydroxide and then extracted with ether (3 x 100 ml.~.
11 The ether layer is washed with saturated sodium chloride 12 solution, then dried over sodium sulfate. The ether is 13 removed in vacuo and the resulting oil is distilled.
14 The yleld of ll-(2-tetr-ahydropyrarlyloxy)nonylamine is 16.0 g. (75%), boilin~ 100-102/0.1 mm.
16 Anal. Calcd. for C14H29NO2:
17 C, 69.08, H, 12.01; N, 5.75 18 Found:
19 C, 68.58; H, 12.42, N, 5.66 Step 4. Preparation of N-[4-(2-Tetrahydro-21 pyranyloxy)nonyl]methanesulfonamide 22 To a stirred, ice cold solution of 4-(2-tetra-23 hydropyranyloxy)nonylamine (7.29 g., 0.03 mole) in 24 pyridine (40 ml.) is added methanesulfonylchloride -(3.l12 g., 0.03 mole) at such a rate as to maintain the 26 reaction temperature at 5-10C. The reaction is then 27 allowed to stand at room temperature for six hours, poured 28 into ice water (200 ml.) and extracted with ether 29 (2 x 100 ml.). The ether is washed with ice cold 5%
hydrochloric acid (2 x 20 ml.), with brine (2 x 25 ml.), and .
.

~ 951 :

'70~
1 then dried over sodium sulfate. Evaporation in vacuo 2 affords N-[4-(2-tetrahydropyranyloxy)nonyl]methanesul~on-3 amide as a pale yellow liquid.
4 _ Preparation of Ethyl 7-(methanesulfonamido)heptanoate A stirred suspenslon of sodium hydride (57%) 6 (2.33 g., 0.055 mole) in a solvent mixture of benzene 7 (50 ml.) and dimethylformamide (50 ml.) is treated, over 8 30 minutes with methanesulfonamide (4.75 g., 0.055 mole).
9 This mixture is heated on the steam bath for 1.5 hours, then cooled to room temperature. At this temperature is 11 added ethyl 7-bromoheptanoate (13 g., 0.055 mole) and the 12 reaction is heated at 90C. for twenty hours. The reaction 13 is poured into water (200 ml.), neutrallzed with hydro-1~l chloric acid and extracted with ethyl acetate (2 x 100 ml.).
The ethyl acetate layer is washed with brine, dried over 16 sodium sul~ate, then concentrated in vacuo. The yield of 17 ethyl 7-(methanesulfonamido)heptanoate is 7.1 g. (51%) ~-18 boiling 165-168/0.1 mm.
19 Anal. Calcd. for CloH21NO4S:
C, 47.78; H, 8.42; N, 5.57 21 Found:
22 C, 47.05; H, 8.51; N, 5.41 23 P. Preparation of Et yl 7-(ethanesulfonam do)heptanoate 24 The synthesis of this compound is carried out 25 as described in Example O except that the methanesulfon- -26 amide is replaced by an equimolar amount of ethanesulfon-27 amide. Ethyl 7-(ethanesulfonamido)heptanoate is obtained 28 as a pale yellow oll upon evaporation of the ethyl acetate 29 extracts.

~. Preparation of Ethyl 7~Propanesulfonamido)heptano-31 ate _ _ . _ _ 32 By following the procedure described in -~ f~ 1~1951 :1~)4470~
1 Example O but substituting propanesulfonamide for 2 methanesulfonamide there is obtained ethyl 7-(propane-3 sulfonamido)heptanoate.
4 R. Preparation of Ethyl 7-[(1-methylethane)sulfon-amido]heptanoate , 6 By following the procedure described in 7 Example 0 but substituting l-methylethanesulfonamide 8 for methanesulfonamide there is obtained ethyl 9 7-[(1-methylethane)sulfonamido}heptanoate.

10 S. Preparation of l-Chloro-4-acetoxy-4-methylnonane ~

11 The Grignard reagent prepared from iodo- -~ ;

12 methane (14.2 g., 0.1 mole) and magnesium (2.LI g,,

13 0.1 mole) in ether solution is added, dropwise to an

14 ether solution Or l-chloro-4-nonanorle (Example A, Step 1) (17.6 g., 0.1 mole~. The reaction is refluxed 16 gently for three hours then cooled and poured carefully 17 into ice water (300 ml.). The ether layer is separated~
18 washed with brine, and dried over sodium sulfate. Re- ;
19 moval of the ether in vacuo gives 1-chloro-4-hydroxy-4-20 methylnonane as an oil. The tertiary alcohol is dis- ' 21 solved in pyridine and treated with one molar equivalent 22 of aoetic anhydride at 60-80 ~or 8-16 hours to give 23 1-chloro-4-acetoxy-4-methylnonane as a colorless oil.
24 T. Preparation of Ethyl 7-(methanesulfinamido~heptano-ate _ 26 The synthesis of this compound is carried out 27 as described in Example O except that the methanesulfon-28 amide is replaced by an equimolar amount of methane-29 sulfinamide. The ethyl 7-(methanesulfinamido~heptanoate is obtained as a yellow liquid upon evaporation of the 31 ethyl acetate extracts.

. .. : . . ~ , : . . - ., . ~ .

~t~

1 U. Preparation of l-Acetoxy-1-(3-bromo-1-propynyl)-2 cyclohexane 3 Step 1. Prepaxation of l-Acetoxy-l-ethynylcyclo-~ hexane ... . . .
l-Ethynylcyclohexan-l-ol (100 g., 0.8 mole) is 6 added dropwise with stirring to a mixture of acetic 7 anhydride (86.7 g., 0.85 mole) and sulfuric acid ~0.25 ml.).
8 The temperature of the reaction~mixture is kept at 10-12C.
g during the addition by means of an ice bath. The ~ixture is then stirred without cooling for 1.5 hours. It is then 11 poured into 300 ml. of ice water. The oily product is 12 taken up in ether, washed with water, dilute sodium 13 bicarbonate solution and brine and dried over sodium 14 sulfate. Distillation affords 107 g. (80%) of l-acetoxy-l-e-thynylcycloh~xane, b.p. 95-97C./15 mm.
16 Step 2. Preparation o~ l-Acetoxy-1-(3-diethyl-17 amino-l-propynyl)cyclohexane 18 A mixture of l-acetoxy-1-ethynylcyclohexane 19 (64.00 g., 0.385 mole), diethylamine (30.95 g., 0.424 mole), paraformaldehyde, (15.00 g.; 0.500 mole), cuprous chloride 21 (1.5 g.) and dioxane (60 ml.) is stirred well. An exo-22 thermic reaction gradually results which may require 23 extexnal cooling to prevent spillage. After this initial 24 reaction, the mixture is heated on a steam bath for 1-1/2 hours.
26 The cooled reaction mixture is treated with ether 27 and the product is extracted into ice-cold 5~ hydrochloric 28 acid. This cold aqueous acidic solution is then basified 29 with ice-cold 10% sodium hydroxide. The oily amine is ;
extracted with ether and the combined extracts are washed 31 with saturated sodium chloride solution and then dried over 7~
1 anhydrous sodium sulfate. The solvent is removed under 2 vacuum and the residual oil is distilled to give 72.7 g.
3 (75~) of light yellow oil, b.p. 113-115C./0.15 mm.;
4 pmr (CDC13) 1.07 (6H,t), 2.02 (3H,s CH3COO), 2.60 (4H,q CH3C~12N), 3.52 (2H,s CH2C~).
6 Step 3. Prepara-tion of l~Acetoxy-1-(3-bromo-7 ~ ~ rloh~xane ...... ...
8 Cyanogen bromide (31.8 g., 0.3 mole) is added 9 to a solution of 1-acetoxy-1-(3-diethylamino-1-propynyl)-10 cyclohexane (61 g., 0.24 mole) in ether (250 ml.) and the ;~
11 resulting solution is allowed to stand at 25-27C. for -12 18 hours. The ether solution is washed with 5% hydro- ;
13 chloric acid solution, water and brine and dried over sodium 14 sulfate. The ether is evaporated and the residual oil distilled. There is obtained 34.8 g. (55%) of l-acetoxy-16 1-(3-bromo-1-propynyl)cyclohexaner a slightly yellowish oil, 17 b.p. 114-120C./0.2 mm.
18 V. Preparation of l-Acetoxy-1-(3-bromo-1-propynyl)cyclo-19 ~ octane By the following the procedure described in 21 Example U but substituting in Step 1 l-ethynylcyclooctan-l-22 ol for l-ethynylcyclohexan-l-ol there are obtained success-23 ively 1-acetoxy-1-(3-diethylamino-1-propynyl)cyclooctane 24 (Step 2), and 1-acetoxy-1-(3-bromo-1-propynyl)cyclooctane (Step 3).
26 W. Preparation of l-Bromo-4-acetoxy ~4-propyl-2-heptyne - ~
27 Step 1. Preparation of 3-Acetoxy-3-propyl-1-hexyne ; -28 3-Propyl-l-hexyn-3-ol (98.0 g., 0.7 mole~ is 29 added dropwise with stirring to a mixture of acetic anhydride (79.5 g., 0.78 mole) and sulfuric acid (0.25 ml.) during 31 50 min~ the temperature rises to 50C. The mixture is 1 allowed to stand 18 hours and i5 then poured into 300 ml.
2 of ice water. The oily product is -taken up in ether, 3 washed with water, dilute sodium bicarbonate solution 4 and brine and dried over sodium sulfate. Distillation yields 108.5 g. (86%) of 3-acetoxy-3-propyl-1-hexyne, 6 b.p. 93-95C./17 mm.
7 Step 2. Preparation of l-Diethylamino-4-acetoxy-8 4-propyl-2-heptyne 9 A mixture of 3-acetoxy-3-propyl-1-hexyne .. . ................................. .. .
(115.2 g., 0.634 mole), diethylamine (51 g., 0.7 mole), 11 paraformaldehyde (24.9 g., O.B3 mole) and dioxane (120 ml.) 12 is stirred and heated on the steam ba-th for 2 hours. The 13 reaction mixture is cooled, treated with ether and the 14 product extracted into ice-cold 5~ hydrochloric acid. The lS cold acidic sol-ltion is then basiEied with ice-cold 10 16 sodium hydroxide. The oily amine is taken up in ether, 17 washed with water and brine and dried over sodium sulfate.
18 Distillation yields 99.5 g. (59%) o~ the amine product, 19 b.p. 101-110C./0.1 mm.
Step 3. Preparation of l-Bromo-4-acetoxy-4-21 propyl-2-heptyne 22 Cyanogen bromide (46.6 g.; 0.44 mole) is added 23 to a solution o 1-diethylamino-4-acetoxy-4-propyl-2-24 heptyne (99.0 g., 0.371 mole) in ether (400 ml.) and the resulting solution is allowed to stand at 25-27C. for 26 16 hours. The ether solution is washed with 5% hydrochloric 27 acid solution, water and brine and dried over sodium sulfate.
28 The ether is evaporated and the residual oil distilled.
29 There is obtalned 70.0 g. ~69%) of 1-bromo-4-acetoxy-4-propyl-2-heptyne, a colorless oil, b.p. 106-107C./0.1 mm.

Anal. Calcd. for C12HlgBrO2: C, 52-88; H, 6-96;
Found: C, 52.00; H, 6.91.

~ ~ I4951 ~
' L~
' 1 EX~MPLh 1 2 Preparation of 7- ~-(4-Hydroxynonyl)methanesulfonamido]-3 heptanoic Acid 4 STEP A: Preparation of Ethyl 7-[N-~4-Acetoxynonyl)-5 methanesulfonamido]heptanoate _ ~ `
6 Sodium hydride (0.715 g., 0.0298 mole) is sus-7 pended in benzene ~30 ml.) and dimethylformamide (30 m].).
8 Ethyl 7-(methanesulfonamido)heptanoate ~6.8 g., 0.0271 g mole) (Example O, Step l? is added and the suspension 10 heated on the steam bath for 15 minutes. After cooling -11 to room temperature, 1-chloro-4-acetoxynonane ~6.55 g., 12 0.0298 mole) (Example A, Step 3) is added over 15 minutes -13 and the resulting solution heated on the steam bath for 14 20 hours. Then the reaction is poured into water (300 ml.) and extracted with ethyl acetate ~3 x 100 ml.). The 16 organic layer is washed with brine (2 x 50 ml.), dried over 17 sodium sulfate then concentrated ln vacuo to an oil which ~
18 is purified by chromatography on silica gel. The silica ~ -19 gel is eluted with 3~ methanol in chloroform and evapora- -tion of the appropriate fraction affords ethyl 7-[N-(4-21 acetoxynonyl)methanesulfonamido]heptanoate. The yield is 22 6,0 g. (51~).
23 Analysis calculated for C21H4~NO6S:
24 C, 57.90; H, 9.49; N, 3.22 Found:
26 C, 58.08; H, 9.99; N, 2.99 -27 STEP B: Preparation of 7-[N-(4-Hydroxynonyl)methane-28 sulfonamido]heptanoic Acid 29 A solution composed of ethyl 7-[N-(4-acetoxy-nonyl~methanesulfonamido]heptanoate (6.0 g., 0.0134 mole), 31 sodium hydroxide (1.66 g., 0.0414 mole), water (9 ml.), 32 and ethanol (81 ml.) is kept at room tamperature for 20 ~ ,r~ 149511 , 1 hours. Most of the solvent is removed ln vacuo, water 2 tl50 ml.) is added and the solution extracted with ethyl 3 acetate (100 ml.). Then the aqueous layer is acidified 4 (hydrochloric acid) and extracted again with ethyl acetate (2 x 75 ml.). The organic layer is dried over sodium 6 sulfate then concentrated ln vacuo to yield 7-[N-(4-7 hydroxynonyl)methanesulfonamido]heptanoic acid. The 8 yield is 4.3 g. (88%).
9 Analysis calculated or C17H35NO5S:
C, 55.86; H, 9.65; N, 3.83 11 Found:
12 C, 56.07; H, 9.77; N, 3.65 14 Preparation of 7-tN-t4-Hydroxy-2-nonynyl)methanesul-~onamido]heptanoic Acid 16 The synthesis of this compound is carried out 17 as described in Example 1 except that, in Step A, the 18 1-chloro-4-acetoxynonane is replaced by an equimolar amount ~ -19 of 1-bromo-4-acetoxy-2-nonyne tExample I, Step 3).
The product of Step A is thus ethyl 7-~N-t4-acetoxy-2-21 nonynyl)methanesulfonamido]heptanoate.
22 Analysis calaulated for C21H37NO6S:
23 C, 58.44; H, 8.64; N, 3.25 24 Found:
C, 57.92; H, 9.15; N, 3.20 26 The subsequent step yields 7-[N-~4-hydroxy-2-27 nonynyl)methanesulfonamido]heptanoic acid tB).
28 Analysis calculated for C17H31NO5S:
29 C, 56.48; H, 8.64; N, 3.88 Found:
31 C, 56.42; H, 9.03; N, 3.68 r~ r~ 14951 r 1 EXAMPLE_ ;
2 Preparation of 7-[N-~4(R)-Hydroxynonyl)methanesulfonamido]-3 hepkanoic Acid _ 4 The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 6 1-chloro-4-acetoxynonane is replaced by an equimolar 7 amount of 1-bromo-4~R)-acetoxy-2-nonyne (Example J).
8 The product of Step A is thus ethyl 7-[N-~4~R)-acetoxy-2-g nonynyl)methanesulfonamido]heptanoatP, [a]36 ~ 46 ;-[C 2.95, CHC13].
11 Analysis calculated for C21H37N06S:
12 C, 58.44; H, 8.64; N, 3.25 13 Found:
14 C, 58.77; H, 8.98; N, 3.13 The subsequent step yields 7-1N- (4(R)-hydroxy-2-16 nonynyl)methanesulfonamido]heptanoic acid (B), [aJ26 ~ 0 930 17 [C 3.3, CHC13].
18 Analysis calculated for C17H31N05S:
19 C, 56.48; H, 8.64; N, 3.88 Found:
21 C, 55.96; H, 9.13; N, 3.85 22 The product of Step B is hydrogenated over a platinum on 23 charcoal catalyst to afford 7-[N-(4~R)-hydroxynonyl)-24 methanesulfonamido]heptanoic acid, [a]26 - 3.0 [C 3.72, CHC13].
26 Analysis calculated for C17H35N05S:
27 C, 55.86; H, 9.65; N. 3.83 28 Found:
29 C, 55.62; H, 9.76; N, 3.70 . , ,, . , . . . , , . - . . .

'~ ~` 149511 , ~(~4~7~1 1 ~XAMPLE 4 2 Preparation of 7-[N-(4(S)-IIydroxynonyl)methanesulfonamido]~
3 heptanoic Acid .~
; 4 The synthesis of this compound is carried out as : 5 described in Example 1 except that, in Step A, the 1-6 chloro-4-acetoxynonane is replaced by an equimolar amount 7 of 1-bromo-4~S)-acetoxy-2-nonyne ~Example K). The product 8 of Step A is thus ethyl 7-[N-~4~S)-acetoxy-2-nonynyl)-9 methanesulfonamido]heptanoate, [a]D6 - 48.8 [C 2.865, ;~
10 CHC13]. :
11 Analysis calculated for C21H37NO6S:
12 C, 58.44; II, 8.64; N, 3.25 13 Found: . .
14 C, 58.72; H, 9.15; N, 3.13 : ; .
The subsequent step ~elds 7-[N-~4~S)-hydroxy- : -16 2-nonynyl)methanesulfonamido]heptanoic acid (B), [a]D ~ Q53 17 [C 3.015, CHC13~. :
:~:
18 Analysis calculated for C17H31N05S: ' :
19 C, 56.48; H, 8.64; N, 3.88 ~:
Found:
21 C, 56.30; H, 8.61; N, 3.79 22 The product o Step B is hydrogenated over a platinum on 23 charcoal catalyst to afford 7-[N-t4(S)-hydroxynonyl)-24 methanesulfonamido]heptanoic acid, [a~26 + 3.92 IC 2.44, ;
CHC13].
26 Analysis calculated for C17H35NO5S~
27 C, 55.86; H, 9.65; N, 3.83 ;.
28 Found:
29 C, 55.45; H, 9.40; N, 3.74 _4~

r~ ~ 14951 :
.~

`t7~1 , , 2 Preparation of 7-[N-(4-Hydroxynonyl)ethanesul~onamido3-3 heptanoic Acid .. . . . _ . . .
4 The synthes.is of this compound is carried out as described in Example 1 except that, in Step A, the 6 ethyl 7-(methanesulfonamido)heptanoate is replaced by an 7 equimolar amount of ethyl 7-ethanesulfonamidoheptanoate 8 (Example P). The product of Step A is thus ethyl 7-[N-9 (4-acetoxynonyl)ethanesulfonamldo]heptanoate. The 1~ subsequent step yields 7-[N-~4-hydroxynonyl)ethanesul- .
11 onamido}heptanoic acid (B).

13 Preparation oF 7-[N-(4-Hydroxynonyl)propanesulfonamido]-14 heptanoic Acid The synkhesis of -this compound is carried out 16 as described in Example 1 except that, in Step A, the .
17 ethyl 7-(methanesulfonamido)heptanoate is replaced by an 18 equimolar amount of ethyl 7-~propanesulfonamido)heptanoate 19 (Example Q). The product of Step A is thus ethyl 7-[N- ..
~4-acetoxynonyl)propanesulfonamido]heptanoate. The 21 subsequent hydrolysis step yields 7~[N-(4-hydroxynonyl)-22 propanesulfonamido]heptanoic acid (B).

24 Preparation of 7-[N-(4-Hydroxynonyl)-l-methylethanesul-fonamido3heptanoic Acid - ~ ~
26 The synthesis of this compound is carried out ~ :~
27 as described in Example 1 except that, in Step ~, the 28 ethyl 7-(methanesulfonamido)heptanoate is replaced by an 29 equimolar amount of ethyl 7-[(1-methylethane)sulfonamido]-heptanoate (Example R). The product of Step A is thus 31 ethyl 7-[N-(4-acetoxynonyl)-1-methylethanesulfonamido]-32 heptanoate. The subsequent step yields 7-[N-(4-hydro~y-33 nonyl)-l-methylethanesulfonamido]heptanoic acid (B).

14g51 ]

47~

2 Preparation of 7-[N-(4-Hydroxynonyl)methanesulfollamido]-3 2-methylhep~anoic Acid 4 STEP A: Preparation of Ethyl 7-{N-[4-(2-Tetrahydro-pyranyloxy)nonyl]methanesulforlamido~-2-methyl-6 heptanoate 7 A stirred suspension of sodium hydride (57~) ;
8 (5.0 g., excess) in a solvent mixture of benzene (75 ml.) g and dimethylformamide ~75 ml.) is treated, over 30 minutes, with N-~4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamide 11 (Example N, Step 4) (32.1 g., 0.1 mole) dissolved in 12 benzene (20 ml.). Stirring is continued for one hour.
13 Then ethyl 7-bromo-2-methylheptanoate ~Example L, Step 4) 14 (25.3 g., 0.1 mole) is added dropwise, and the reaction is heated on the steam bath ~or 6 hours. The cooled 16 reaation mixture is poured into water (400 ml.) and ~;
17 extracted with ethyl acetate (2 x 200 ml.). The organic ~ ;~
18 fractions are combined, washed with brine, then dried -~
19 over sodium sulfate. The solvents are removed in vacuo to give 7-tN-[4-~2-tetrahydropyranyloxy)nonyl]methane-21 sulfonamido}-2-methylheptanoate as a pale yellow liquid.
22 STEP B: Preparation o 7-[N-~4-Hydroxynonyl)methanesul- ; ~
23 fonamido]-2-methylheptanoic Acid - -24 A solution is prepared from ethyl 7-{N-~4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamido~-2-methyl-26 heptanoate (4.9 g., 0.01 mole), ethanol (50 ml.), and 4 27 drops of hydrochloric acid (conc.~, and kept at ambient 28 temperature for 4.5 hours. Then to the reaction is adde~
29 a solution of sodium hydroxide ~0.72 g., 0.018 mole) in water (10 ml.) and the reaction is ~ept at ambient 31 temperature for an additional 20 hours. Most of the _45~

.... .
. . .

f 14951 ]
' '7 1 ethanol is removed in vacuo and the residue dissolved in 2 water (100 ml.). 'rhe solution is extracted once with 3 ether(75 ml.) then acidified wlth hydrochloric acid 4 (dil~). The oil that scparates is extracted into ether, 5 the ether is washed with brine, dried over sodium sulfate, 6 then removed under vacuum to give 7-[N-t4-hydroxynonyl)-7 methanesulfonamido]-2-methylheptanoic ac:id as a yellow 8 liquid.
g EXAMPLE 9 10 Preparation of 7-[N-(4-Hydroxynonyl)methanesulfonamido]-11 2,2-dimethylheptanoic Acid 12 The synthesis of this compound is carried out 13 as described in ~xample 8 except that, in Step A, the 1~ ethyl 7-bromo-2-methylheptanoate is replaced by an

15 equimolar amount of methyl 2,2-dimethyl-7-iodoheptanoate.

16 The product of Step A is thus methyl 7-{N-[4-~2-tetra- ,

17 hydropyranyloxy)nonyl]methanesulfonamido}-2,2-dimethyl-

18 heptanoate. The subsequent step yields 7-~N-~4-hydroxy

19 nonyl)methanesulfonamido]-2~2-dimethylheptanoic acid ~B).

20 EXAMPLE 10

21 Preparation of 7-~N-~4-Hydroxynonyl)methanesulfonamido]-

22 3-methvlhe~tanoic Acid

23 The synthesis of this compound is carried out

24 as described in Example 8 except that, in Step ~, the 51 ethyl 7-bromo-2-methylheptanoate is replaced by an 26 equimolar amount of methyl 3-methyl-7-iodoheptanoate.
27 The product of Step A is thus methyl 7-~N-~4-(2-tetra-28 hydropyranyloxy)nonyl]methanesulfonamido~-3-methyl-29 heptanoate. The subsequent hydrolysis step yields 7-~N-~4-hydroxynonyl)methanesulfonamido]-3-methylheptanoic 31 acid (B).

.. , . , , , '~, 2 Preparation of 7-[N-(4-Eiydroxynonyl)~ethanesulfonamido]-3 3,3-dimethylheptanoic Acid 4 The synthesis of this compound i.s carried out as described in Example 8 except -that, in Step A, the ethyl ; .
6 7-bromo-2-methylheptanoate is replaced by an equimolar 7 amount of methyl 3,3-dimethyl-7-iodoheptanoate. The product 8 of Step A is thus methyl 7- N-[4-(2-tetrahydropyranyloxy)-9 nonyl]methanesulfonamido -3,3-dimethylheptanoate. The ;
. : :
subsequent step yields 7-[N-(4-hydroxynonyl)methanesulfona-11 mido]-3,3-dimethylheptanoanoic acid (B).

13 Preparation of 4-[N-(4-Hydroxynonyl)methanesulfonamido]-14 butoxyacetic Acid The synthesis of this compound is carried out as 16 described in Example 8 except that, in Step A, the ethyl 17 7-bromo-2-methylheptanoate is replaced by an equimolar 18 amount of ethyl 4-bromobutoxyacetate (Example M). The 19 product of Step A is thus ethyl 4-~N-[4-(2-tetrahydropyranyl-oxy)nonyl]methanesulfonamido~butoxyacetate. The subsequent 21 step yields 4-[N-(4-hydroxynonyl)methanesulfonamido]butoxy-22 acetic acid (B). -23 Anal. Calcd. for C16H33NO6S:
24 C, 52.29; H, 9.05; N, 3.81;
Found:
26 C, 52.04; H, 8.90; N, 3.81 28 Preparation of 7-[N-(4-Hydroxy-8-methylnonyl)methane- -~
29 sulfonamido~he~tanoic Acid .
The synthesis of this compound is carried out as 31 described in Example 1 except that, in Step A, the l-chloro-.

14951 Ii 1 4-acetoxy-8-methylnonane (Example B, Step 3). The product 2 of Step A is thus ethyl 7-[N-(4-acetoxy-8-methylnonyl)-3 methanesulfonamido]heptanoate. ~he subsequent step yields 4 7-[N-(4-hydroxy-8-methylnonyl)methanesulfonamido]heptanoic S acid (B).

7 Preparation of 7-~N-(4-Hydroxyundecyl)methanesulfonamido]-8 heptanoic Acid . .. _ 9 The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the l-chloro-11 4-acetoxynonane is replaced by an equimolar ~ ount of 1-12 chloro-4-acetoxyundecane (Example C, Step 3). The product 13 of Step A is thus ethyl 7-[N-(4-acetoxyundecanyl)methane-14 sulfonamido]heptanoate. The subsequent step yields 7-[N-~4-hydroxyundecanyl)methanesulfonamido]heptanoic acicl ~B).

17 Preparation of 7-[N-(4-Hydroxy 8,8-dimethylnonyl)methane-18 sulfonamidoJhePtanoic Acid 19 The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the l-chloro-21 4-acetoxynonane is replaced by an equimolar amount of 22 1-chloro-4-acetoxy-8,8-dimethylnonane (Example D). The 23 product o Step A is thus ethyl 7-[N-(4-acetoxy-8,8-dimethyl-24 nonyl)methanesulfonamido~heptanoate. The subsequent step yields 7-[N-(4-hydroxy-8,8-dimethylnonyl)methanesulfonamido]-26 heptanoic acid (B).

28 Preparation of 7-[N-(4-Hydroxy-9,9,9-trifluorononyl)methane-29 sulfonamido]heptanoic Acid The synthesis of this compound is carried out as 31 described in Example 1, except that, in Step A, the l-chloro-.

.~ r~ ,.

1 4-acetoxy-9,9,9-trifluorononane (Example E). The product 2 of Step A is thus ethyl 7-[N-(4-acetoxy-9,9,9--tri~luoro-3 nonyl)methanesulfonamido]heptanoate. The subsequent step 4 yields 7-[N-(4-hydroxy-9,9,9-trifluorononyl)methanesulfo-namido]heptanoic acid (B).

, 7 Preparation of 7-[N-(4-Hydroxy-8-nonenyl)methanesulfo-8 namido]hevtanoic Acid 9 The synthesis of this compound is carxied out as described in Example 1 except that, in Step A, the l-chloro-11 4-acetoxynonane is replaced by an equimolar amount of 1- ~ i 12 chloro-4-acetoxy-8-nonene. The product of Step A is thus 13 ethyl 7-[N-(4-acetoxy-8-nonenyl)methanesulfonamido]heptano-14 ate. The subsequent step yields 7-[N-(4-hydroxy-8-nonenyl)-methanesulfonamido]heptanoic acid (B).

17 Preparation of 7-[N-(4-Hydroxy-5,5-dimethylnonyl)methane-18 sulfonamido]he~tanoic Acid 19 The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the l-chloro-21 4-acetoxynonane is replaced by an equimolar amount of 1-22 chloro-4-acetoxy-5,5-dimethylnonane (Example G). The 23 product of Step A is thus ethyl 7-[N-(4-acetoxy-5,5-dimethyl-24 nonyl)methanesulfonamido]heptanoate. The subsequent step yields 7-[N-t4-hydroxy-5,5-dimethylnonyl)methanesulfonamidoJ-26 heptanoic acid (B).

28 Preparation of 7-[N-(4-Hydroxy-(E~-2-nonenyl)methanesulfo-29 namido]he~tanoic Acid ~
The synthesis of this compound is carried out as 31 described in Example 1 except that, in Step A, the l-chloro--49- ~

,r~

1 4-acetoxynonane is replaced ~y an equimol~r amount of 1-2 bromo-4-acetoxy-2-nonene (~xc~mple H). The product of 3 Step A is thus ethyl 7-[N-(4-acetoxy-(E)-2-nonenyl)-4 methanesulfonamido]heptanoic acid ~B).

6 Preparation of 7-~N-(4-Hydroxy-4-methylnonyl)methanesulfo-7 namido]heptanoic_Acid _ _ 8 The synthesis of this compound is carried out as 9 described in Example 1 except that, in Step A, the l-chloro-4-acetoxynonane is replaced by an equimolar amount of l-11 chloro-4-acetoxy-4-methylnonane (Example S). The product 12 of Step A is thus ethyl 7-[N-(4-acetoxy-4-methylnonyl)-13 methanesulfonamido]heptanoate. The subsequent step yields 14 7-[N-(4-hydroxy-4-methylnonyl)methanesulfonamido]heptanoic acid (B).
16 EXAMPLE ~1 17 Preparation of 7-[N-(4-Hydroxynonyl)methanesulfinamido]-18 heptanoic Acid 19 The syn-thesis of this compound is carried out as described in Example l except that, in Step A, the ethyl 21 7-(methanesulfon~mido heptanOat6 is replaced by an equimolar 22 amount of ethyl 7-(methanesulfinamido)heptanoate (Example 23 T). The product of Step A is thus ethyl 7-[N-(4-acetoxy-24 nonyl)methanesulfinamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxynonyl)methanesulfinamido]heptanoic 26 acid (B).

28 Preparation of Methyl 7-[N-(4-Hydroxynonyl)methanesul-29 fonamido]heptanoic Acid ~ solution of diazomethane (approx. 2.5 g., 31 0.06 mole) in ether (100 ml.) is mixed with a solution of - : . .
, ., . ~:

~ 14951I-.
3l~4~703L

1 7-[N-(4-hydroxynonyl)methanesulfonamido]heptanoic acid 2 (10.8 g., 0.03 mole) (Example 1, Step B) in ether (50 ml.3.

3 The resulting solution is allowed to stand at room tem-4 perature for 4 hours. Acetic acid is -then added to destroy the excess diazomethane and -the solution is 6 washed with dilute sodium bicarbonate solution and water `

7 and dried over sodium sulfate. Evaporation of volatile 8 materials at reduced pressure yields methyl 7-[N~(4- ~ `

9 hydroxynonyl)methanesulfonamido]heptanoate as a viscous oil.

12 Preparation of Decyl 7-~N-t4-Hydroxynonyl)methanesulEona-13 mido]heptanoate 14 Using the method of E'xample 22 but substituting an ether solution o~ l-diazodecane or the ether solution 16 of diazomethane, there is obtained decyl 7-[N-(4-hydroxy-17 nonyl)methanesulfonamido]heptanoate, as a viscous oil. .~ ~ `

19 Preparation of N-~(2-Dimethylamino)ethyl]-7-~N-~4-hydroxy-nonvl)methanesulfonamido]he~tanamide , 21 A solution of 7-[N-(4-hydroxynonyl)methanesul-Z2 fonamido]hep~anoic acid t3.65 g., 10 millimoles)(Example 1, 23 Step B~, triethylamine (1.74 ml., 12.5 millimoles) and :~
24 distilled water tl8 ml.) in a~etonitrile (100 ml.) is treated with N-t-butyl-5-methyl-isoxazolium perchlorate 26 (3.0 g., 12.5 millimoles). The resulting solution is 27 evaporated in vacuo at 20-25C. over 4 hours providing a 28 tacky residue which is triturated with water ~150 ml.) 29 at 0-5C. ~or 15 minutes. After decanting the aqueous phase, the oily residue is dissolved in benzene-ether - 51- ;
,~

r~ - 149511 7~
1 [(1:1), 200 ml.]. The organic extract is dried over 2 sodium sulfate, then evaporated ln vacuo providing the 3 desired "active ester".
4 A solution of 2-dimethylaminoethylamine (0.88 g., 10 millimoles) in acetonitrile (25 ml.) is added to a 6 solution of the "active ester" in acetonitrile (25 ml.) 7 and the solution is stirred at 25C. for 17 hours. The 8 solvent is removed ln vacuo, the residual oil is partitioned 9 between ether (200 ml.) and water (200 ml.). The ether layer is extracted with 5~ hydrochloric acid (2 x 50 ml.).
11 The aqueous acid phase is made basic with aqueous sodium 12 carbonate then extracted with ether. The ether extract 13 is washed with brine solution ~100 ml.), dried over sodium 14 sulfate, evaporated in vacuo leaviny the N-E~2-dimcthyl-amino)ethyl]-7-~N-(4~hydroxynonyl)methanesulfonamido~-16 heptanamide as a viscous oil. ~ -18 Preparation of 7- [N- (4-Hydroxynonyl)methanesul~onamido]-19 heptanamide Using the method of Example 24 bu-t substituting 21 an acetonitrile solution of ammonia for the acetonitrile 22 solution of 2-dimethylaminoethylamine, there is obtained 23 7- EN- (4-hydroxynonyl)methanesulfonamido]heptanamide.

Preparation of 7-[N-(4-Acetoxynonyl)methanesulfonamido]-26 heptanoic Acid 27 A mixture of 7-[N-t4-hydxoxynonyl)methanesul-28 ~onamido]heptanoic acid (10.9 g., 0.03 mole) (Example 1, 29 Step B) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60C. for 18 hours. The mixture is cooled and /

... . ~ ~ .

~ 951 1 and ta~en up in 80 ml. of ethyl ether. The solu-tion is 2 extracted with an ice-cold solution of 8 g. of sodium 3 hydroxide in 150 ml. of water. The basic solution is 4 separated and acidified with concentrated hydrochloric acid. The crude product tha-t separates :is extracted into 6 ether, washed with water and dried over sodium sulfate.
7 The ether is evaporated and the residual oil is purified 8 by chromatography on silica gel using 2~ methanol in 9 chloroform as the eluting solvent. There is obtained 7-[N-(4-acetoxynonyl)methanesulfonamido]heptanoic acid 11 as a viscous oil.
12 By substituting for the acetic anhydride used 13 in Example 26, an equivalent amount oE acetic formic 14 anhydride, propionic anyhydride, butyric anyhydride, isobutyric anhydride, valeric anhydride, or pivalic 16 anhydride and conducting the reaction as described in 17 Example 21, there is obtained 7-~N-(4-formyloxynonyl)- ;
18 sulfonamido]heptanoic acid, 7-[N-~4-propionyloxynonyl)-19 sulfonamido]heptanoic acid, 7-[N-(4-butyryloxynonyl)-sulfonamido]heptanoic acid, 7-~N-(4-isobutyryloxynonyl)-21 sulfonamido]heptanoic acid, 7-EN-~4-valeryloxynonyl)-22 sulfonamido]heptanoic acid, and 7-~N-(4-pivaloyloxynonyl)-23 sulfonamido]heptanoic acid, respectively.

_53_ L~Lt7~
1 -~XAMPLEI_27 2 Preparation of 7-~N-[3-(1-Hydroxycyclohexyl)propyl]methane-3 5ulfonamido~heptanoic Acid 4 The synthesis of this compound is carried out as described in Example 3 except that, in Step A, the l-bromo-6 4(R)-acetoxy-2-nonyne is replaced by an equimolar amount 7 of 1-acetoxy-1-(3-bromo-1-propynyl)cyclohexane (Example U).
8 The product of Step A is thus ethyl 7-~N-[3-(1-acetoxy-9 cyclohexyl)-2-propynyl]methanesulfonamido~heptanoate.
Anal. Calcd- for C21H35NO6S:
11 C, 58.72; H, 8u21; N, 3.26;
12 Found:
13 C, 59.05; H, 8.39; N, 3.05.
14 The subsequent step yields 7-~N-[3-(1-hydroxycyclohexyl)-2-propynyl]methanesulfonamido~heptanoic acid tB).
16 Anal. Calcd. for C17H29NO5S:
17 C, 56.80; H, 8.13; N, 3.90;
18 Found:
19 C, 56.24; H, 8.52; N, 3.51.
The hydrogenation step(c) yields 7-~N-[3-(1-hydroxycyclo-21 hexyl)propyl]methanesulfonamido~heptanoic acid (C).
22 Anal. Calc- for X17H33NO5S:
23 C, 56.17; H, 9.15; N, 3.85; :
24 Found:
C, 56.01; H, 9.48; N, 3.73. ~ -26 EXAMPLE 28 ~ ~
~, 27 Preparation of 7-~N-[3-(1-Hydroxycyclooctyl)propyl]methane-28 sulfonamido3heptanoic Acid 29 The synthesis of this compound is carried out as described in Example 3, except that, in S-tep A, the l-bromo-31 4(4)-acetoxy-2-nonyne is replaced by an equimolar amount of ;~
, ,~ ., , . . ~ , .

~ (~44';'~3~
l-acetoxy-1-(3-bromo-1-propynyl)cyclooctane (Example V~. The product of Step A is thus ethyl 7-{ ~-(1-acetoxycyclooctyl)-2-propyny ~methanesulfonamido}heptanoate. The subsequent steps yield 7-{N- ~-(l-hydroxycyclooctyl)-2-prop~yny~7methanesulfon- ~' amido}heptanoic acid (B) and 7-{N-~-(l-hydroxycyclooctyl)-propy ~methanesulfonamido}heptanoic acid (C).

Preparation of 7- ~-(4-Hydroxy-4-propylheptyl)methanesulfon-amid~7heptanoic Acid The synthesis of this compound is carried out as described in Example 3, except that, in Step A, the l-bromo-4(R)-acetoxy-2-nonyne is replaced by an equimolar amount of l-bromo-4-acetoxy-4-propyl-2-heptyne (Example W). The product of Step A is thus ethyl 7- ~-(4-acetoxy-4-propyl-2-heptynyl)-methanesulfonamid ~heptanoate. The subsequent steps yield 7-~-(4-hydroxy-4-propyl-2-heptynyl)methanesulfonamid ~heptanoic acid (B) and 7- ~-(4-hydroxy-4-propylhexyl)methanesulfonamid ~-heptanoic acid (C).
EXAMPLE 30 ` , Capsule Formulation .
7- ~-(4-hydroxynonyl)methanesulfonamid ~-heptanoic acid . . . . . . . . . . . . . . . . . . . . 50 gm.
Stearic Acid (U.S.P. triple pressure) . . . . . . . . . 125 gm.
Pluronic~ F-68 a polyoxyalkylene derivative of propylene glycol . . . . . . . . . . . . . . . . . 7.5 gm.
Corn Starch . . . . . . . . . . . . . . . . . . . . . . 125 gm.
The stearic acid and pluronic are united in a vessel ,;
and melted using water bath at 60-65C. The sulfonamido heptanoic acid is dispersed into the mixture and the corn starch is added with stirring which is continued until the mixture cools to ambient temperature. The mixture is reduced .
to granules by screening and placed in a number O.hard ~elatin . - . , ; , .
. . : -, - . ... .

containing 307.5 mg. of total solids and 50 mg. of 7- ~-(4-hydroxynonyl)methanesulfonamid ~heptanoic acid per capsule.

Parenteral Formulation of a Multidose Solution of Intramuscular and intravenous Use -7-{N- ~-(l-hydroxycyclohexyl)propy ~methanesulfonamido}-heptanoic acid . . . . . . . . . . . 1 gm.
Tris(hydroxymethyl)aminomethane (Reagent Grade Tham) . . . . . . . . q.s. to adjust solution to pH 7.4 Sodium chloride (U.S.P.) . . . . . . . q.s. to yield isotonic solution Methylester of p-hydroxybenzoic acid .............................. 10 mg.
Propylester of p-hydroxybenzoic acid ............................... 1 mg.
Distilled water (pyrogen-free) . . . . q.s. to 10 ml.
The 7-{N- ~-(l-hydroxycyclohexyl)propy ~methane-sulfonamido}heptanoic acid suspended in about 6 ml. of the water is treated with tris(hydroxymethyl)aminomethane with stirring until the pH reaches 7.4. The methylester and propyl-ester are added with stirring and sufficient sodium chloride added to produce an isotonic solùtion. After water is added to bring the final volume to 10 ml., the solution is sterilized by membrane filtration and placed in a vial by an aseptic tech-nique. The solution contains the Tham salt of 7-{N- ~-(1-hydroxycyclohexyl)propy ~methanesulfonamido}heptanoic acid equivalent to 100 mg./ml. of the free acid.

30 Preparation of Suppositories 7- ~-(4(S)-hydroxynonyl)methanesulfonamid ~heptanoic acid ................................................ 200 gm.

, . ' ` ' ' ~4'70~L
1 Butylated hydroxyanisole ~ . . . . . . . . . . . . 82 my.
2 Butylated hydroxytoluene . . . . . . . . . . . . . 82 mg.
3 Ethylenediamine tetraacetic acid . . . . . . . . . 163 mg.
4 Glycerine, U.S.P. . . . . . . . . . . . . . . . . 128 gm.
Sodium chloride, microfine . . . . . . . . . . . 52.5 gm.
6 Polyethylene glycol 6000 . . . . . . . . . . . . . 128 gm.
7 Polyethylene glycol 4000 . . ~ . . . . . . . . . 1269 gm.
8 The polyethylene ylycol 4000 and polyethylene 9 glycol 6000 were placed in a vessel surrounded by a water bath at such a temperature required to maintain the melted 11 contents at 60-65C. To themelt is added the butylated 12 hydroxyanisole and butylated hydroxytoluene with stirring.
13 Then the ethylenediamine tetraacetic acid and microfine 14 sodium chloxide are added to and dispersed in the mixture.
The 7-[N-4~S)-hydroxynonyl)methanesulfonyl]heptanoic acid 16 is then added and dispersed into -the mixture. Finally~
17 the temperature is lowered to 55-60C. and the glycerine 18 added and dispersed.
19 While maintaining the temperature of 55-60C.
and continuous mixing, the melt is dispersed into plastic 21 suppository cavities o a conventional suppository cold-22 molding device. The suppositories thus prepared contain 23 a total of 1.7778 gm. of contents of which 200 mg. are 24 7-[N-(4-hydroxy-8,8-dimethylnonyl)methanesulfonamido]-.. ~.
heptanoic acid.

.., ~ . .:

-57- ;
- ... ,. . . , ~.

Claims (15)

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

1. The process of preparing the compound having the formula:

wherein:
A is ethylene, trimethylene, .alpha.-methylethylene, .beta.-methylethylene, .alpha.,.alpha.-dimethylethylene, .beta.,.beta.-dimethylethylene, or oxymethylene;
R1 is methyl, ethyl, propyl, or isopropyl;
R2 is hydrogen, methyl, ethyl, or propyl;
Z is ethylene, vinylene, or ethynylene;
R4 is independently hydrogen or methyl;
R5 is hydrogen, loweralkyl, vinyl, or 2,2,2-trifluoroethyl; and y is 1 or 2;
in addition, when R5 is loweralkyl and R2 is methyl, they can be joined together (with abstraction of hydrogen) to form a carbocyclic ring with from 6 to 9 members;
also, when R5 is loweralkyl and R2 is hydrogen, R5 can be joined to the carbon atom bearing R2 and OH to form a carbocyclic ring with from 5 to 8 members;
which comprises;
(a) reacting a compound of the formula:
R1-SOy-NH-(CH2)4-A-COOR8 wherein R1 and A are as defined above, and R8 is a loweralkyl of 1-5 carbon atoms;
with about an equivalent of a strong base, and then y with approximately about an equivalent of the compound:

wherein X is halogen, Z, R2, R4 and R5 are as defined above, and R3 is loweralkanoyl of 1-4 carbon atoms;
recovering the intermediate product thereby produced, subject-ing it to mild hydrolysis to remove R8 and R3 blocking group, and recovering the desired product; or (b) when R2 is hydrogen and R5 is other than vinyl: reacting a compound of the formula:

wherein R1, y, Z, R4 is as defined above and R5 is as defined above but not vinyl, and R10 is tetrahydropyranyl;
with about an equivalent of strong base and then with approxi-mately an equivalent of the compound:
X-(CH2)4-A-COOR3 wherein X is halogen, A is as defined above, and R8 is a loweralkyl of 1-5 carbon atoms;
recovering the intermediate product thereby produced, subject-ing the latter to mild hydrolysis to remove the R8 and R10 blocking groups, and recovering the desired product.

2. The process of preparing the compound having the formula:

wherein A is ethylene, trimethylene, .alpha.-methylethylene, .beta.-methylethylene, .alpha.,.alpha.-dimethylethylene, .beta.,.beta.-dimethylethylene, or oxymethylene;

R1 is methyl, ethyl, propyl or isopropyl;
R2 is hydrogen, methyl, ethyl or propyl;
Z is ethylene, vinylene or ethynylene;
R4 is independently hydrogen or methyl;
R5 is hydrogen, loweralkyl, vinyl, or 2,2,2-trifluoroethyl, and y is 1 or 2;
in addition, when R5 is loweralkyl and R2 is methyl, they can be joined together (with abstraction of hydrogen) to form a carbocyclic ring with from 6 to 9 members, also, when R5 is loweralkyl and R2 is hydrogen, R5 can be joined to the carbon atom bearing R2 and OH to form a carbocyclic ring with from 5 to 8 members;
which comprises reacting a compound of the formula:
R1-SOy-NH-(CH2)4-A-COOR8 wherein R1 and A are as defined, and R8 is loweralkyl of 1-5 carbon atoms;
with about an equivalent of strong base, and then with approximately about an equivalent of the compound:

wherein X is halogen, Z, R2, R4 and R5 are as defined, and R3 is loweralkanoyl of 1-4 carbon atoms;
recovering the intermediate product thereby produced, subject-ing it to mild hydrolysis to remove the R8 and R3 blocking groups, and recovering the desired product.

3. The process of Claim 2, wherein A is ethylene.

4. The process of Claim 3, wherein R8 is ethyl, and R2 is acetyl.

5. The process of preparing the compound of the formula:

wherein A is ethylene, trimethylene, .alpha.-methylethylene, .beta.-methylethylene, .alpha.,.alpha.-dimethylethylene, .beta.,.beta.-dimethylethylene, or oxymethylene;
R1 is methyl, ethyl, propyl, or isopropyl;
Z is ethylene, vinylene or ethynylene;
R4 is hydrogen or methylene; and R9 is hydrogen, loweralkyl, or 2,2,2-trifluoroethyl;
which comprises reactiny a compound of the formula:

wherein R1 is methyl, ethyl, isopropyl or propyl;
y is 1 or 2;
Z is ethylene, vinylene or ethynylene;
R is hydrogen or methyl;
R9 is hydrogen, loweralkyl, or 2,2,2-trifluoroethyl;
and R10 is tetrahydropyranyl;
with about an equivalent of strong base and then with approximately about an equivalent of the compound:

X-(CH2)4-A-COOR8 wherein X is halogen, A is as defined, and R8 is loweralkyl of 1-5 carbon atoms:
recovering the intermediate product thereby produced, subjecting the latter to mild hydrolysis to remove the R8 and R10 blocking groups, and recovering the desired product.

6. The process of Claim 2, wherein ethyl 7-(methane-sulfonamido)heptanoate is reacted with 1-chloro-4-acetoxynonane to form the ethyl 7-[N-(4-acetoxynonyl)methanesulfonamido]-heptanoate and subjecting the latter to mild hydrolysis to form the 7-[N-(4-hydroxynonyl)methanesulfonamido]heptanoic acid.

7. The process of Claim 2, wherein ethyl 7-(methane-sulfonamido)heptanoate is reacted with 1-bromo-4-acetoxy-2-nonyne and the resulting intermediate is subjected to mild hydrolysis to form the 7-[N-(4-hydroxy-2-nonynyl)methanesulfon-amido]heptanoic acid.

8. The process of Claim 2, wherein ethyl 7-(methane-sulfonamido)heptanoate is reacted with 1-bromo-4(R)-acetoxy-2-nonyne to form the ethyl 7-[N-(4(R)-acetoxy-2-nonynyl)methane-sulfonamido]heptanoate and subjecting the latter to mild hydrolysis to form the 7-[N-(4(R)-hydroxy-2-nonynyl)methane-sulfonamido]heptanoic acid.

9. The compound having the formula:

wherein A is ethylene, trimethylene, .alpha.-methylethylene, .beta.-methylethylene, .alpha.,.alpha.-dimethylethylene, .beta.,.beta.-dimethylethylene, or oxymethylene;
R1 is methyl, ethyl, propyl or isopropyl;
R2 is hydrogen, methyl, ethyl or propyl;
Z is ethylene, vinylene or ethynylene;
R4 is independently hydrogen or methyl;
R5 is hydrogen, loweralkyl, vinyl, or 2,2,2-trifluoroethyl, and y is 1 or 2;

in addition, when R5 is loweralkyl and R2 is methyl, they can be joined together (with abstraction of hydrogen) to form a carbocyclic ring with from 6 to 9 members;
also, when R5 is loweralkyl and R2 is hydrogen, R5 can be joined to the carbon atom bearing R2 and OH to form a carbocyclic ring with from 5 to 8 members, when prepared by the process defined in Claim 1 or by an obvious chemical equiva-lent.

10. The compound of Claim 9, wherein A is ethylene, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.

11. The compound of Claim 9, wherein R8 is ethyl, and R2 is acetyl, when prepared by the process defined in Claim or by an obvious chemical equivalent.

12. The compound of the formula:

wherein A is ethylene, trimethylene, .alpha.-methylethylene, .beta.-methylethylene, .alpha.,.alpha.-dimethylethylene, .beta.,.beta.-dimethylethylene, or oxymethylene;
R1 is methyl, ethyl, propyl, or isopropyl;
Z is ethylene, vinylene or ethynylene;
R4 is hydrogen or methylene; and R9 is hydrogen, loweralkyl, or 2,2,2-trifluoroethyl, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.

13. The 7-[N-(4-hydroxynonyl)methanesulfonamido]-heptanoic acid, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.

14. The 7-[N-(4-hydroxy-2-nonynyl)methanesulfon-amido]heptanoic acid, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.

15. The 7-[N-(4(R)-hydroxy-2-nonynyl)methanesulfon-amido]heptanoic acid, when prepared by the process defined in Claim 8 or by an obvious chemical equivalent.