WO2007048361A1 - A method of removing the triphenylmethane protecting group from precursors of antihypertensive drugs - Google Patents

A method of removing the triphenylmethane protecting group from precursors of antihypertensive drugs Download PDF

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Publication number
WO2007048361A1
WO2007048361A1 PCT/CZ2006/000073 CZ2006000073W WO2007048361A1 WO 2007048361 A1 WO2007048361 A1 WO 2007048361A1 CZ 2006000073 W CZ2006000073 W CZ 2006000073W WO 2007048361 A1 WO2007048361 A1 WO 2007048361A1
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formula
mixture
solvent
solvents
crystallization
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PCT/CZ2006/000073
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English (en)
French (fr)
Inventor
Stanislav Radl
Jan Stach
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Zentiva, A.S.
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Publication of WO2007048361A1 publication Critical patent/WO2007048361A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention concerns an improved method of removing the triphenyhnethane protecting group from precursors of antihypertensive drugs of general formula I
  • angiotensin II antagonists which are used therapeutically as cardiovascular system drugs, mainly for the control of high blood pressure.
  • This group includes important drugs, such as losartan (Cozaar R ), irbesartan (Avapro R ), or valsartan (Diovan R ).
  • the substances according to the invention are biologically inactive; the active substance is formed first by the metabolic degradation of group R.
  • These precursors have better bioavailability and are used therapeutically instead of the active substance itself.
  • B represents a heterocyclic unit with one or two 5- or 6-membered rings at least one of which contains two nitrogen heteroatoms, and R is a metabolically degradable group.
  • the method consists in the reaction of the substance of formula I with water in the presence of an organic solvent which is completely, or at least partially, miscible with water, leading to the formation of the substance of formula II.
  • R usually such substituents are selected that contain in their structures acetals of C 2 to C 8 aliphatic or aromatic aldehydes, ketals of C 3 to C 10 aliphatic or aromatic ketones, esters of carbonic acid with Ci to Cio aliphatic alcohols, or cyclic 5-, 6-, or 7-membered esters of carbonic acid.
  • tritylated precursors of antihypertensive drugs include for example 5 -methyl-2-oxo- 1 , 3 -dioxol-4-ylmethyl-4-( 1 -hydroxy- 1 -methylethyl)-2-propyl- 1 - [2 ' - (iV-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]imidazole-5-carboxylate (trityl olmesartan medoxomil) of formula III
  • triphenylmethane protecting group from substituted tetrazoles is usually carried out by the action of a mineral acid in a suitable solvent, for example dioxane (US patent 5,399,578).
  • a suitable solvent for example dioxane
  • this method is suitable only for substances not containing in their molecules other groups sensitive to acids, which is the case of the above-mentioned compounds.
  • Another method is based on the methano lysis of the triphenylmethane protecting group, where methyltriphenyl ether and free tetrazole are formed during the boil (WO 2005/021535).
  • the starting trityl candesartan cilexetil of formula IV whose synthesis is described in the original patent (US patent 5,196,444) and which is currently already commercially available, is, in methanol using hydrochloric acid, converted into candesartan cilexetil of formula VI.
  • the method described in the original patent (US patent 5,196,444) has a very low yield and the product has to be purified chromato graphically.
  • the Takeda company has improved this key step by using anhydrous hydrogen chloride in methanol (US patent 5,763,619), wherein the amount of decomposition products is lower and the yield is higher.
  • Disadvantages of the aforementioned methods include a high content of impurities associated with the decomposition of the ester function, the use of strongly corrosive acids, and also the need to process the reaction mixture using complicated extractions. Such a production is then not economical.
  • the subject-matter of the invention consists in an improved method of removing the triphenylmethane protecting group from precursors of antihypertensive drugs having a labile, metabolically degradable group.
  • the essence of the invention consists in the surprising finding that the removal of the triphenylmethane protecting group from the aforementioned substances can be carried out using only water in a suitable solvent without using acids, which results in a significantly lower decomposition of the ester functions of these substances.
  • R is a metabolically degradable group
  • B is a heterocyclic moiety with one or two 5- or 6-membered rings at least one of which contains two nitrogen heteroatoms
  • the reaction is advantageously carried out at a temperature of 30 to 100 °C for 1 to 48 hours, preferably 5 to 20 hours.
  • the reaction can be carried out using water in solvents which are miscible with water.
  • the reaction proceeds faster in dipolar aprotic solvents such as dimethylsulfoxide, dimethylformamide, acetonitrile, or acetone. It proceeds very slowly for example in tetrahydrofuran and dioxane.
  • the reaction is carried out preferably at the boil of the mixture of solvents. The amount of water is usually one to five fold with respect to the weight of the starting substance.
  • the solvent is advantageously selected from a group of polar aprotic solvents or a mixture of polar and nonpolar aprotic solvents.
  • Polar aprotic solvents are advantageously selected from a group comprising C 3 to C 5 ketones, preferably acetone or ethyl methyl ketone, acetonitrile, and C 1 to C 4 acetates, preferably ethyl or isopropyl acetate.
  • Nonpolar aprotic solvents that can advantageously be used include C 5 to C 8 aromatic or cyclic compounds, both carbocyclic and heterocyclic, preferably toluene, cyclohexane or tetrahydrofuran.
  • the resulting trityl alcohol of formula IX is removed by crystallization from a solvent, or a mixture of solvents, in which candesartan cilexetil of formula IV is insoluble, whereas the trityl alcohol soluble.
  • trityl alcohol of formula IX is removed by stirring with solvents or their mixtures in which candesartan cilexetil of formula IV is insoluble, whereas the trityl alcohol soluble, at a temperature of 5 to 50 0 C, preferably at 15 to 30 0 C.
  • Suitable mixed solvents are mixtures of solvents in which candesartan cilexetil dissolves easily with solvents in which this substance dissolves only partially.
  • Suitable solvents in which candesartan cilexetil dissolves easily include C 1 -C 4 alcohols, preferably methanol, ethanol or 2-propanol, C 1 -C 2 halogenated solvents, preferably dichloromethane or chloroform, C 1 -C 4 aliphatic ketones, preferably acetone or 2-butanone, dialkyl ethers with Ci- C 4 alkyls, preferably diisopropyl ether and methyl t-butyl ether, and esters OfCi-C 5 carboxylic acids with Ci-C 4 aliphatic alcohols, preferably methyl acetate, ethyl acetate, isopropyl acetate or ethyl propionate.
  • Suitable solvents in which candesartan cilexetil dissolves only partially include cycloalkanes, for example cyclohexane, C 5 -C 8 aliphatic hydrocarbons, for example pentane, hexane, heptane or isooctane.
  • cycloalkanes for example cyclohexane, C 5 -C 8 aliphatic hydrocarbons, for example pentane, hexane, heptane or isooctane.
  • Trityl alcohol of formula IX can advantageously be removed from the crude product by crystallization or stirring out of cyclohexane or toluene.
  • Ethyl ester 3 (20 g) was dissolved in THF (80 ml) at 50 0 C (60 minutes). After cooling to 25 0 C, a 40% solution of KOH (10 ml) was added, and the mixture was stirred vigorously for 24 h. After adding ethyl acetate (10 ml), the solution cleared up (neutralization). After concentrating to ca. 40 ml in vacuo, the mixture was diluted with ethyl acetate (100 ml), and solid NaCl (20 g) was added. After separating the phases, the organic layer was filtered and concentrated to ca. 30 ml in vacuo. Methyl ethyl ketone (50 ml) was added to this solution, the mixture was concentrated to 30 ml in vacuo for the subsequent reaction.
  • a solution of potassium salt 4 in methyl ethyl ketone from the preceding experiment (ca. 20 g of the salt) was diluted with methyl ethyl ketone (290 ml), and, after adding potassium iodide (2 g) and 4-chloromethyl-5-methyl-l,3-dioxol-2-one (7 g), the mixture was stirred at 50 0 C for 7.5 h. After the reaction was completed, the mixture was filtered, and the filtrate was washed with methyl ethyl ketone (3 x 50 ml). After concentrating to ca. 160 ml in vacuo, ethanol (250 ml) was added, and the reaction mixture was again concentrated to ca. 300 ml in vacuo.
  • the starting substance (III; 10 g) was dissolved in acetone (50 ml), and, after adding water (25 g), the mixture was heated to a mild boil for 14 h. After evaporating acetone and adding ethyl acetate (50 ml), water was separated, and the organic layer was again washed with water (10 ml). The extract was concentrated and evaporated with toluene (50 ml) once more, the residue was dissolved in ethyl acetate (20 ml) and toluene (20 ml).
  • Example 16 The crystals obtained by the method described in Example 14 were stirred with acetonitrile (15 ml) at room temperature for 4 hours. A product having HPLC purity of 99.3 % was obtained.
  • Example 16 The crystals obtained by the method described in Example 14 were stirred with acetonitrile (15 ml) at room temperature for 4 hours. A product having HPLC purity of 99.3 % was obtained.
  • Example 14 The crystals obtained by the method described in Example 14 were purified by crystallization from acetonitrile (15 ml) and then by stirring at room temperature for 4 hours. A product having HPLC purity of 99.7 % was obtained.
  • Example 14 The crystals obtained by the method described in Example 14 were purified by crystallization from the mixture toluene/2-methoxyethane and then by stirring at 10 0 C for 6 hours. A product having HPLC purity of 99.4 % was obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/CZ2006/000073 2005-10-27 2006-10-25 A method of removing the triphenylmethane protecting group from precursors of antihypertensive drugs WO2007048361A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2005-679 2005-10-27
CZ20050679A CZ299902B6 (cs) 2005-10-27 2005-10-27 Zpusob odstranování trifenylmethanové chránicí skupiny u prekurzoru antihypertenzních léciv

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010026255A1 (en) * 2008-09-05 2010-03-11 Krka, Tovarna Zdravil, D.D., Novo Mesto Process for preparing olmesartan medoxomil intermediate
WO2010134052A1 (en) 2009-05-20 2010-11-25 Ranbaxy Laboratories Limited Process for the preparation of olmesartan medoxomil
WO2011007368A2 (en) 2009-07-14 2011-01-20 Cadila Healthcare Limited An improved process for preparation of olmesartan
KR20110109638A (ko) * 2010-03-31 2011-10-06 주식회사 씨티씨바이오 올메사탄 실렉세틸의 제조 방법
WO2011155291A1 (ja) * 2010-06-09 2011-12-15 株式会社トクヤマ カンデサルタンシレキセチルの製造方法
WO2012055994A1 (en) 2010-10-29 2012-05-03 Interquim, S.A. Process for preparing olmesartan medoxomil
WO2012055380A1 (en) * 2010-10-29 2012-05-03 Zentiva, K. S. A method of obtaining olmesartan medoxomil
WO2013021312A1 (en) * 2011-08-05 2013-02-14 Lupin Limited Process for the preparation of olmesartan medoxomil
CN103012382A (zh) * 2012-12-05 2013-04-03 威海迪之雅医药化工开发有限公司 一种奥美沙坦酯的制备方法
CN103304550A (zh) * 2012-03-16 2013-09-18 湖南欧亚生物有限公司 一种奥美沙坦酯的制备方法
US8735598B2 (en) 2008-06-09 2014-05-27 Daiichi Sankyo Company, Limited Method for producing 1-biphenylmethylimidazole compound
US8859600B2 (en) 2009-04-28 2014-10-14 Daiichi Sankyo Company, Limited Acetone solvate crystals of trityl olmesartan medoxomil
US8933241B2 (en) 2009-04-28 2015-01-13 Daiichi Sankyo Company, Limited Method for producing olmesartan medoxomil
CN107311990B (zh) * 2017-07-25 2021-09-03 浙江华海致诚药业有限公司 一种奥美沙坦酯的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0503785A1 (en) * 1991-02-21 1992-09-16 Sankyo Company Limited 1-Biphenylimidazole derivatives, their preparation and their therapeutic use
WO2005021535A2 (en) * 2003-08-27 2005-03-10 Zentiva, A.S. A method of removing the triphenylmethane protecting group
WO2005111021A1 (en) * 2004-05-05 2005-11-24 Teva Pharmaceutical Industries Ltd. Preparation of candesartan cilexetil in high purity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0503785A1 (en) * 1991-02-21 1992-09-16 Sankyo Company Limited 1-Biphenylimidazole derivatives, their preparation and their therapeutic use
WO2005021535A2 (en) * 2003-08-27 2005-03-10 Zentiva, A.S. A method of removing the triphenylmethane protecting group
WO2005111021A1 (en) * 2004-05-05 2005-11-24 Teva Pharmaceutical Industries Ltd. Preparation of candesartan cilexetil in high purity

Non-Patent Citations (1)

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Title
USIFOH C O: "Anticonvulsant activity of reaction products of 5,5-diphenylhydantoin with substituted methylene bromides", ARCHIV DER PHARMAZIE, VCH VERLAGSGESELLSCHAFT MBH, WEINHEIM, DE, vol. 334, no. 11, 2001, pages 366 - 368, XP002319792, ISSN: 0365-6233 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8735598B2 (en) 2008-06-09 2014-05-27 Daiichi Sankyo Company, Limited Method for producing 1-biphenylmethylimidazole compound
WO2010026255A1 (en) * 2008-09-05 2010-03-11 Krka, Tovarna Zdravil, D.D., Novo Mesto Process for preparing olmesartan medoxomil intermediate
US8933241B2 (en) 2009-04-28 2015-01-13 Daiichi Sankyo Company, Limited Method for producing olmesartan medoxomil
US8859600B2 (en) 2009-04-28 2014-10-14 Daiichi Sankyo Company, Limited Acetone solvate crystals of trityl olmesartan medoxomil
WO2010134052A1 (en) 2009-05-20 2010-11-25 Ranbaxy Laboratories Limited Process for the preparation of olmesartan medoxomil
WO2011007368A2 (en) 2009-07-14 2011-01-20 Cadila Healthcare Limited An improved process for preparation of olmesartan
KR20110109638A (ko) * 2010-03-31 2011-10-06 주식회사 씨티씨바이오 올메사탄 실렉세틸의 제조 방법
KR101628758B1 (ko) 2010-03-31 2016-06-09 주식회사 씨티씨바이오 올메사탄 실렉세틸의 제조 방법
WO2011155291A1 (ja) * 2010-06-09 2011-12-15 株式会社トクヤマ カンデサルタンシレキセチルの製造方法
JP5738288B2 (ja) * 2010-06-09 2015-06-24 株式会社トクヤマ カンデサルタンシレキセチルの製造方法
WO2012055380A1 (en) * 2010-10-29 2012-05-03 Zentiva, K. S. A method of obtaining olmesartan medoxomil
WO2012055994A1 (en) 2010-10-29 2012-05-03 Interquim, S.A. Process for preparing olmesartan medoxomil
WO2013021312A1 (en) * 2011-08-05 2013-02-14 Lupin Limited Process for the preparation of olmesartan medoxomil
US8981110B2 (en) 2011-08-05 2015-03-17 Lupin Limited Process for the preparation of olmesartan medoxomil
CN103304550A (zh) * 2012-03-16 2013-09-18 湖南欧亚生物有限公司 一种奥美沙坦酯的制备方法
CN103304550B (zh) * 2012-03-16 2016-01-27 湖南欧亚生物有限公司 一种奥美沙坦酯的制备方法
CN103012382A (zh) * 2012-12-05 2013-04-03 威海迪之雅医药化工开发有限公司 一种奥美沙坦酯的制备方法
CN103012382B (zh) * 2012-12-05 2016-10-05 迪沙药业集团有限公司 一种奥美沙坦酯的制备方法
CN107311990B (zh) * 2017-07-25 2021-09-03 浙江华海致诚药业有限公司 一种奥美沙坦酯的制备方法

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CZ2005679A3 (cs) 2007-05-09

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