Long-acting contraceptive agents: Esters of norethisterone with alkoxy- and halogeno-substituted carboxylic acids

285

2934

LONG-ACTING CONTRACEPTIVE AGENTS: ESTERS OF NORETHISTERONE WITH ALKOXY- AND HALOGENO-SUBSTITUTED

CARBOXYLIC ACIDS

A. SHAFIEE AND M. VOSSOGHI Department of Chemistry, College of Pharmacy, Tehran University, Tehran, Iran C.G. FRANCISCO, R. FREIRE, R. HERNANDEZ, J.A. SALAZAR, AND E. SUAREZ* Institute de Productos Naturales Organicos de1 CSIC, Carretera La Esperanza, 2, La Caguna, Tenerife, Canary Islands, Spain S. SOTHEESWARAN* Department of Chemistry, University of Sri Lanka, Peradeniya Campus, Peradeniya, Sri Lanka

ABSTRACT The chemical synthesis and physical data of several new esters of norethisterone (17a-ethynyl-17S-hydroxyestr-4-en-X-one) are reported, which contain either a chloro- or an alkoxy-group as a substituent in the acid side-chain.

INTRODUCTION There is a great demand for long-acting, injectable steroid contraceptives. Since depot-medroxyprogesterone preg-4-ene-3,20-dione

acetate (17a-hydroxy-6n-methyl-

acetate) and norethisteroneenanthatesuffer

from a

number of disadvantages

(11, several alkoxylated and cz-substituted

Volume

S

41, Number

3

%??BROID=

March 1983

S

TIIROIDS

aliphatic acids were synthesized and were esterified with norethisterone at the 17B-OH function, as part of the World Health Organization's programme on the synthesis of long-acting injectable contraceptives. syntheses of these esters are reported in this paper.

The

An accompanying

paper in this Journal by Bialy and co-workers describes the biological activities of these compounds in an estrus suppression assay in rats.

CHEMICAL SYNTHESIS Commonly available a-substituted aliphatic acids were purchased.

4-

Butoxybutanoic acid was synthesized by conversion of 2-butoxyethanol to the corresponding bromide and chain extension with diethyl sodiomalonate. 5-Propoxypentanoic acid and 7-methoxyheptanoic acid were synthesized from l-iodo-4-chlorobutane and 1-iodo-6-chlorohexane respectively, by displacement of iodide with the appropriate alkoxide and then displacement of the chloride with cyanide, followed by hydrolysis.

Menthyloxyacetic

acid was synthesized by condensing sodium menthoxide with chloroacetic acid. The norethisterone esters with a-chloro- and a-methoxyacetic acids were prepared by the thallous ethoxide method of Herz -et al (Z), with slight modification: 1:l.l:l.Z.

the ratio of steroid, TlOEt and acid chloride was

The esters with 3-pentoxypropionic, 5-propoxypentanoic and

7-methoxyheptanoic acids were also prepared by the TlOEt method.

As an

alternative to the thallium method for esterification using the acid chloride, the benzenesulphonyl

chloride method developed by one of us in

a related study (3) was used to prepare norethisterone esters with 4butoxybutanoic acid and menthyloxyacetic acid.

The latter method was

S

287

TIIROXDS

found to be suitable for esterifying carboxylic acids of the type R1CH2C02H and R1R2CHC02H with norethisterone. Seven esters of norethisterone

(I) to (VII) were synthesized for

evaluation of their potential as long-acting contraceptive agents.

OCOR

I

11

III

R

=

CH2C1

R

=

'H20CH3

R

=

CH20 -Q

IV

R

=

~H*CH2O(C~2)4~H3

V

R

=

CH2(CH2)20(CH2)3CH3

VI

R

=

CH2(CHZ)30(CH2)2CH3

VII

R

=

CH~(CH2)~OC~3

EXPERIMENTAL Chloroacetic acid and methoxyacetic acid were purchased from Aldrich Ltd. 3-Pentoxypropanoic acid was supplied by Maybridge Ltd., England, through the World Health Organization. Menthoxyacetic acid was synthesized using the procedure of Frankland and O'Sullivan (4). All ru1, values were obtained in CHCl 3 solution. 4-Butoxybutanoic acid: To a solution of 2-butoxyethanol (167 ml) in ether (192 ml&, pyridine (25.6 ml) and PBr (48 ml) were added during 0.5 h. at -15 C. The en allowed to warm to room temperature and was reaction mixture was tF1

288

S

TIlROXDS

refluxed for 2 h. After this period, ice was added and the mixture was extracted with ether, and pure 2-butoxy-l-bromoethane (157 g) was obtained. N_MR: 3.6 (6H, m), 1.5 (4H, m), 0.92 (3H, t) 6. A solution of 2-butoxy-l-bromoethane (157 g) and diethyl malonate (157 ml) was heated to 85-90°C and then an ethanolic solution of EtONa (prepared from 436 ml ethanol and 20.4 g sodium) was added dropwise SO as to maintain a steady reflux (approx. 45 min.). The reaction mixture was refluxed for a further 4 h. and then the ethanol distilled off, KOH (188 g) in water (700 ml) added and the heating continued for 4 h. The reaction mixture was poured into ice water, washed with ether, acidified and extracted with diethyl ether/ethyl acetate (l/l), to yield 140 g of the diacid. The diacid underwent decarboxylation by heating at 120-13O'C for 4 h. undoer argon. The resulting acid was purified by vacuum distillation (102-103 C, 1 mm Hg) giving 91 g of 4-butoxybutanoic acid. NMR: 11.31 (lH, s), 3.45 (2H, t), 3.41 (2l&, t), 2.42 (2H, t), 1.94 (2H, q), 1.45 C NMR: 179.5, 70.8, 69.6, 31.8, 31.0, (4H, m), and 0.89 (3H, t) 6. 24.8, 19.3, and 13.9 ppm. 5-Propoxypentanoic acid: To a sclution of 1-iodo-4-chlorobutane (250 g) in dry propanol (600 ml) was added n-PrOga/n-PrOH (prepared from 26.3 g of sodium agd 658 ml of propanol) at 0 C and the mixture was then heated to 50-60 for 1.5 h. Usual work-up and vacuum distillation (66'C, 11 mm Hg) gave lchloro-4-propoxybutane (71 g). NMR: 3.56 (2H, t), 3.42 (2H, t), 3.36 (2H, t), 1.6 (6H, m), and 0.90 (3H, t) 6. A mixture of 1-chloro-4-propoxybutane (68 g), ethanol (474 ml), NaCN (66 g) and NaI (68 g) was refluxed for 8 h. The reaction mixture was filtered, the filtrate treated with excess KOH solution and the mixture refluxed for 12 h. Usual work-up and vacuum distillation (95'C, 0.4-0.5 mm Hg) yielded 5-propoxypentanoic acid (71 g). NMR: 8.96 (lH, s), 3.47 (ZH, t),+3.40 (ZH, t), 2.40 (2H, t), 1.6 (6H, m), and 0.92 (3H, t)6. MS: m/e 142(M ), 131, 117, 101, 99. 7-Methoxyheptanoic acid: A solution of NaI (450 g) and 1,6-dichlorohexane (500 g) in dry acetone (2.5 1) was refluxed for 3 h. The reaction was followed by GLC and worked up when 25% of 1,6-dichlorohexane, 25% of 1,6-diiodohexane and 50% of 1-chloro-6-iodohexane were present. The mixture was resolved by fractional distillation giving 200 g of 1-chloro-6-iodohexane, b.p lOO-llO°C, 5-8 mm Hg. To a solution of 1-chloro-6-iodohexane (112 g) in dry methanol (300 ml) was added dropwise, at room temperature, NaOMe/MeOH (prepared from 10.5 g of sodium and 140 ml of methanol). The reaction mixture was refluxed for 2.5 h. and checked by GLC. After the usual work-up, 1-chloro -6-methoxyhexane (75 g) was obtained. NMR: 3.51 (2H, t), 3.36 (2H, t), 3.30 (3H, s), and 1.5 (8H, m) f.

S

TDROIDS

289

A mixture of 1-chloro-6-methoxyhexane (61 g) in ethanol (370 ml), NaCN (59 g) and NaI (61 g) was refluxed for 8 h., the reaction being followed by GLC. The mixture was filtered and the filtrate treated with KOH (66 g) and refluxed for 12 h. The reaction was followed By GLC. After the usual work-up, purification by distillation (95-102 C, 0.01 mm Hg) gave 7-methoxyheptanoic acid (19 g). NMR: 10.5 (lH, s), 3.38+(211, t), 3.32 (3H, s), 2.33 (2H, t), and 1.4 (8H, m) 6. MS: m/e 160(M ), 128. General procedure for the preparation of norethisterone esters: Thallous ethoxide method: The published procedure of Herz -et al (2) was followed. Benzenesulphonyl chloride method: The experimental procedure has been published earlier (3). The data on the new norethisterone Norethisterone IR: NMR: Anal:

chloroacetate

compounds are given below:

(I):

m.p. 171-2'C, [cl& - 32'; -1 1660, 1760, 2118, 3215 cm 5.9 (lH, s, -C=CH), 4.07 (2H, s, -CH2C1), 2.65(18, s, -C-CH), 0.93 (3H, s, 6. C22H27C103 requires -CH3) C: 70.49 H: 7.21 Found c: 70.65 H: 7.42

Norethisterone methoxyacetate IR: NMR: Anal:

(II): m.p. 171-4'C, cell, -25O; -1 1665, 1750, 3295 cm 5.80(1H, s), 4.00 (2H, s), 3.48 (3H, s), 2.67 (lH, s), 0.93 (3H, s) 6. C23113004 requires C: 74.59 H: 8.11 Found c: 74.36 H: 8.35

Norethisterone menthyloxyacetate IR: NMR:

MS:

Norethisterone IR: NMR: MS: Anal:

Norethisterone IR:

(III):-1 oil , [“ID

-48’;

1615, 1660, 1730, 1755 cm 5.7 (lH, s, -C=CH), 3.95 (2H, s, 0CH2C=O), 2.5 (lH, s, -CXH), 1.0 - 0.7 (CH3 signals), 2.4 - C.8 (methylene envelope) 6. m[e 357, 326, 298, 281, 270, 265, 242, 230, 138 (lOOZ), M not observed (5). 3-pentoxypropionate

(IV): oil, [cI& -15O; -1 1620, 1670, 1740, 3260 cm 5.82 (lH, s), 3.68 (2H, t), 3.41 (2H, t), 2.60 (lH, s), 2.58 (2H,+t), 0.92 (3H, s), 0.90 (3H, t) 6. m/e 440(M ), 408, 337, 352 C28H4004 requires C: 76.33 H: 9.15 Found c: 76.50 H: 9.13 4-butoxybutanoate

(V): oil -1,

1625, 1675, 1740, 3260 cm

S

290

NMR: MS : Anal:

TDROXDS

5.85 (111,s), 3.42 (4H, m), 2.59 (lH, s), 0.90 (3H, s and 3H, t) 6. m/e 440(M+), 425, 298, 272. %28H4004 requires C: 76.33 H: 9.15 Found c: 76.08 H: 9.14

Norethisterone 5-propoxypentanoate IR: NMR: MS: Anal:

Norethisteronc IR: NMR: MS: Anal:

(VI): oil, ["ID -12O; -1 1620, 1670, 1740, 3260 cm 5.82 (lH, s), 3.36 (4H, m), 2.59 (lH, s), 0.8i (3H, t), 0.90 (3H,+s) 6. m/e 440(M f, 424, 326 C28H4Q04 requires C: 76.33 H: 9.15 Found c: 76.41 H: 9.21 7-methoxyheptanoate

(VII): m.p. 55-S'C, [aID -12O -1 1625, 1670, 1740, 3260 cm 5.83 (lH,+s), 3.32 (3H, s), 2.58 (lH, s), 0.81 (3H, s) 6. m/e 44O(M >, 425, 412, 298, 280 C2gH4C04 requires C: 76.33 H: 9.15 c: 76.21 H: 9.28

ACKNOWLEDGEMENT The authors thank the World Health Organization for financial support of this research work.

1.

2. 3. 4. 5.

WORLD HEALTH ORGANIZATION SPECIAL PROGRAMME OF RESEARCH, DEVELOPMENT AND RESEARCH TRAINING IN HUMAN REPRODUCTION, SIXTH ANNUAL REPORT p. 29 (1977). Herz J.E., Cruz S., Torres J.V. and Murillo A., SYNTHETIC COMMUN. 7, 383 (1977). zunatilaka A.A.L. and Sotheeswaran S., CHEM. COMMUN. 980 (1978). Frankland P.F. and Sullivan H.H.O., J. CHEM SOC. 99, 2329 (1911). Elemental analysis data for this compound was slightly outside normal limits. The compound was subsequently purified by the Quality Control Laboratory.