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(12) United States Patent (10) Patent No.: US 9,464,108 B2 Ostendorf (45) Date of Patent: Oct

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(12) United States Patent (10) Patent No.: US 9,464,108 B2 Ostendorf (45) Date of Patent: Oct USOO9464108B2 (12) United States Patent (10) Patent No.: US 9,464,108 B2 Ostendorf (45) Date of Patent: Oct. 11, 2016 (54) COMBINED SYNTHESIS ROUTE FOR 4th Edition, The Peterson Olefination Reaction, March J. Advanced DESOGESTREL AND ETONOGESTREL Organic Chemistry. pp. 952-953, Cairns, J. et al., Rapid, Efficient Regeneration of Steroidal Ketones (71) Applicant: MSD Oss B.V., Oss (NL) from Thioacetals by Periodic Acid, J. Chem. Soc., Chem. Commun, 1980, p. 886–887, vol. 18. (72) Inventor: Martin Ostendorf, Oss (NL) Dess, et al. Readily Accessible 12-I-5 Oxidant for the Conversion of Primary and Secondary Alcohols to Aldehydes and Ketones, J. Org. (73) Assignee: Merck Sharp & Dohme B.V., Haarlem Chem, 1983, pp. 4155-4156, vol. 48. (NL) Gao, H. et al., Synthesis of 13-Ethyl-11-Methylene-18, 19-DINOR 17a-PREGN-4-EN-20-YN-17-OL, OPPI Briefs, 1997, p. 572-576, (*) Notice: Subject to any disclaimer, the term of this vol. 29, No. 5. patent is extended or adjusted under 35 Greene, et al., Protection for the Carbonyl Group, Organic Synthe U.S.C. 154(b) by 116 days. sis, 1999, pp. 312-344. Krishnaveni, N. S. et al., Mild and Efficient Hydrolysis of Aromatic (21) Appl. No.: 14/383,709 Thioacetals/Thioketals using o-Iodoxybenzoic acid (IBX) in Pres ence of B-Cyclocextrin in Water, Synthesis, 2003, p. 2295. (22) PCT Fed: Mar. 13, 2013 Ley, S.V. et al., Tetrapropylammonium Perruthenate, Pr4N+RuO-4. TPAP: A Catalytic Oxidant for Organic Synthesis, Synthesis, 1994, (86) PCT No.: PCT/EP2013/055084 p. 639. S 371 (c)(1), Tebbe, et al., Olefin Homologation with Titanium Methylene Com (2) Date: Sep. 8, 2014 pounds, J. Am. Chem. Soc, 1978, p. 3611-3613, vol. 100. Van Den Heuvel, M. J., et al. A partial synthesis of 13-ethyl-11 (87) PCT Pub. No.: WO2013/135744 methylene-18, 19-dinor-17a-pregn-4-en-20-yn-17-ol (desogestrel) based upon intramolecular oxidation of an 11B-hydroxy-19 PCT Pub. Date: Sep. 19, 2013 norsteroid to the 18 11 B-lactone, Requeil des Travaux Chimiques des Pays-Bas, 1988, p. 331-334, vol. 107. (65) Prior Publication Data US 2015/OO31875 A1 Jan. 29, 2015 Primary Examiner — Barbara P Badio (74) Attorney, Agent, or Firm — Janet E. Fair; Anna L. (30) Foreign Application Priority Data CocuZZo Mar. 15, 2012 (EP) ..................................... 1215.9747 (57) ABSTRACT (51) Int. Cl. The present invention relates to a synthesis route and to C0731/00 (2006.01) steroid derivatives of general formula VI and VII useful in C07, 2L/00 (2006.01) the synthesis of desogestrel and etonogestrel. C0733/00 (2006.01) C07 L/100 (2006.01) C07, II/00 (2006.01) (I) (52) U.S. C. VI CPC ............. C07J 33/007 (2013.01); C07J I/0059 OR (2013.01); C07J I/0096 (2013.01); C07J OR4, II/00 (2013.01); C07J 21/008 (2013.01) (58) Field of Classification Search CPC ...................................................... CO7J 33/007 USPC ............................................... 552/524; 540/7 RS See application file for complete search history. (56) References Cited SR2 (II) U.S. PATENT DOCUMENTS VII OR3 3,927.046 A 12/1975 van den Broek OR4 4,031,074 A 6/1977 dejongh et al. 2005/0234251 A1 10/2005 Grisenti et al. FOREIGN PATENT DOCUMENTS CN 1865276 A 11 2006 RS CN 101857624 A 10, 2010 SR2 OTHER PUBLICATIONS 4th Edition, Oxidation or Dehydrogenation of Alcohols to Alde hydes and Ketones, Organic Chemisry, 1992, pp. 1167-1171. 11 Claims, No Drawings US 9,464,108 B2 1. 2 COMBINED SYNTHESIS ROUTE FOR -continued DESOGESTREL AND ETONOGESTREL O CROSS-REFERENCE TO RELATED APPLICATIONS Protection This application is a U.S. National Phase application Her under 35 U.S.C. S371 of PCT Application No. PCT/EP2013/ 055084, filed Mar. 13, 2013, which published as WO 2013/ 135744 A1 on Sep. 19, 2013, and claims priority under 35 10 U.S.C. S365(b) from European Application No. EP1215.9747.0, filed Mar. 15, 2012. The present invention relates to a process for the synthesis of desogestrel and etonogestrel. The present invention fur 15 ther relates to intermediates used in said process. Desogestrel (13 B-ethyl-17f8-hydroxy-11-methylene-18, 19-dinor-17C.-pregn-4-en-20-yn) is a molecule used in hor monal contraceptives. Etonogestrel (3-oxodesogestrel or 13 B-ethyl-17-hydroxy-11-methylene-18,19-dinor-17C.- pregn-4-en-20-yn-3-one) is the active metabolite of deso gestrel. It is a molecule used in hormonal contraceptives, most notably the subdermal implant IMPLANONR) As desogestrel and etonogestrel are used in hormonal (etonogestrel implant) and the contraceptive vaginal ring contraceptives, there remains a need for alternative synthesis NUVARING(R) (etonogestrel/ethinyl estradiol vaginal ring). 25 routes that are efficient and cost-effective. Etonogestrel is known, for example, from U.S. Pat. No. In a first aspect the present invention relates to a process 3,927.046 A. It can be synthesized according to methods for the manufacture of a steroid derivative according to described in U.S. Pat. No. 4,031,074. A or HEUVEL, M.J., formula IX et al. Requeil des Travaux Chimiques des Pays-Bas. 1988, 30 vol. 107, no. 4, p. 331-334. The key step in this synthesis is IX the oxidation of the 18 methyl group to give a lactone which is subsequently converted to a 13.f3-ethyl steroid by a Gri gnard reaction and a Wolff-Kishner reduction. This process, however, uses a long and therefore labour-intensive route. Desogestrel and etonogestrel are known, for example 35 from CN 1865276 A. They can, for example, be synthesised according to the method described in CN 1865276 A. This RS synthesis adopts 13,3-ethyl-1,3,5(10),8(9)-estratetraene-17 ol as raw material for the synthesis of desogestrel and SR etonogestrel. In this method, however, five steps are required 40 for the introduction of the 11-functionality. US 2005/0234251 A describes the synthesis of deso using a steroid derivative of general formula VI or VII gestrel from 18-methylnordione Hongwu Gao et al in OPPI BRIEFS, 1997, vol. 29, no. 5, 45 VI p. 572-576 describe the synthesis of desogestrel from 133 OR ethyl-11C.-hydroxy-gon-4-ene-3,17-dione (1). As part of this OR4 synthesis, an 11-ketone 2 was obtained by oxidation of 1 and O converted, by treatment with ethylene glycol/triethyl ortho formate/p-toluenesulfonic acid in methylene chloride at reflux temperature, into the 3,17-bisethylene acetal 3. This 50 process, however, is disadvantageous in that selective pro RS tection of two of the carbonyl groups of the triketone 2 is required. SR 55 VII OR Scheme 1 Synthesis method according to Gao et al. OR4 O HO, 60 RS Oxidation -e- SR 65 wherein in the steroid derivatives of general formula VI, VII and IX, R and Rare the same and are selected from Hand US 9,464,108 B2 3 (1-4C)alkyl; or R and R, together with the sulphur atoms -continued to which they are attached, form a 1,3-dithiolane or 1,3- O dithiane, said dithiolane or dithiane being optionally Substi tuted with one or more (1-4C)alkyl group; and R and Ra are the same and are selected from Hand (1-4C)alkyl: or R and 5 Step 6 Ra, together with the oxygen atoms to which they are He attached, form a 1,3-dioxolane or 1,3-dioxane, said dioxo RS ethynylation lane or dioxane being optionally Substituted with one or more (1-4C)alkyl group. 10 SR In another aspect, the present invention relates to a VIII process for the manufacture of a steroid derivative of general OH formula IX, comprising steps 1 through to 6 according to Scheme 2: 15 Scheme 2 O RS HO SR IX Step 1 Hip 3-protection In this process, in the steroid derivatives of general formula IV, V, VI, VII, VIII and IX, R and R are the same O 25 and are selected from H and (1-4C)alkyl; or R and R. 1 O together with the sulphur atoms to which they are attached, form a 1,3-dithiolane or 1,3-dithiane, said dithiolane or HO dithiane being optionally substituted with one or more 30 (1-4C)alkyl group and in the Steroid derivatives of general Step 2 formula V, VI and VII, R and R are the same and are -- selected from Hand (1-4C)alkyl; or R and R, together with RS 17-protection the oxygen atoms to which they are attached, form a 1,3-dioxolane or 1,3-dioxane, said dioxolane or dioxane SR 35 being optionally substituted with one or more (1-4C)alkyl IV group. OR3 In step 1.13 B-ethyl-11-hydroxygon-4-ene-3,17-dione, (1) HO OR4 is reacted with a thioalcohol into a 3-dithioacetal steroid derivative of general formula IV. Such dithioacetalisation 40 reactions are known in the art, for example, from Protective Step 3 groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. 3th -- 11-oxidation edition 1999, pages 333-344. RS In step 2, the 3-dithioacetal steroid derivative of general formula IV is reacted with an alcohol or a diol to protect the SR2 45 17-keto group to obtain a 17-acetal-3-dithioacetal steroid V derivative of general formula V. Acetalisation reactions are OR known, for example from Protective groups in Organic O OR4 Synthesis Greene, T. W.; Wuts, P. G.3th edition 1999, pages 312-322.
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