Note: Descriptions are shown in the official language in which they were submitted.
--` 15663Y
. .
1~6~
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-).
- 1 -
~~ ~ 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
15663IA
~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.
9 BACKGROUND OF THE INVENTION
_ . .
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
-3-
15663Y
~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.
15663IA
~6~6~9eE;~
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~
OCOCEI3
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)
COCH3
-5-
15663IA
1~64~6~
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 )
OCOCH3
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~ 6C2H5 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.
--6--
. 15663IA
~6496~
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)
15663IA
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
~\
2C6H5
~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.
--8--
15663IA
~64~6~
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
CO2C2H5 2 H2O
12 ~ NaCl
4R SO2-f-CH2-Y CH2-A-CH2-CO2R 130-160C
/ \ 3-5 hours
R OCOCH3
(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
R OCOCH3
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~
i~6q~96~
CO C H
, 2 2 5
R12S02-C-CIl2-Y*C~l2 A C~l2C02R
CE~2C_C-f~-C ~R ) 2R
R OCOCH 3
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
15663
~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]
~(~6~
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~
1566
;496~
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).
-15-
15663
~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.
28 EXAMPLE 2
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
-16-
~-~ 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).
EXAMPLE 3
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).
- 17 -
15663I
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
-18-
1566
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),
--19--
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
-20-
15663
~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-
15663IA
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).
13 EXAMPLE 6
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
-22-
1566
~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.
-23-
1566
1~6~6~
1 EXAMPLE 7
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~-
15663IA
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
-26-
1566
~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-
1566
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.
EXAMPLE 1 0
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.
28 EXAMPLE 11
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-
15663IA
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
-29-
15663IA
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;
-30-
15663IA
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-
15663IA
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-
15663IA
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
-33-
.
~ 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~-
15663IA
~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;
-35-
15663IA
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
-36-
15663IA
:~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.
-37-
15 6 63IA
~ ~a~4s6~
1 EXAMPLE 13
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
-38-
1566
~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.
7 EXAMPLE 14
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
-39-
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.
,
-40-
:, . ,
