WO1994015904A1 - Nouveau procede et nouveaux intermediaires pour la preparation de precurseurs et medicaments - Google Patents

Nouveau procede et nouveaux intermediaires pour la preparation de precurseurs et medicaments Download PDF

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Publication number
WO1994015904A1
WO1994015904A1 PCT/SE1993/001115 SE9301115W WO9415904A1 WO 1994015904 A1 WO1994015904 A1 WO 1994015904A1 SE 9301115 W SE9301115 W SE 9301115W WO 9415904 A1 WO9415904 A1 WO 9415904A1
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WO
WIPO (PCT)
Prior art keywords
formula
substituted
tranexamic acid
salt
solution
Prior art date
Application number
PCT/SE1993/001115
Other languages
English (en)
Inventor
Nils Åke JÖNSSON
Original Assignee
Pharmacia Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia Ab filed Critical Pharmacia Ab
Priority to AU58452/94A priority Critical patent/AU5845294A/en
Publication of WO1994015904A1 publication Critical patent/WO1994015904A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton

Definitions

  • the present invention relates to a novel process and to novel chemical intermedi- ates for preparing derivatives, or prodrugs, of tranexamic acid which is a well known and effective antif ⁇ brinolytic drug. It is widely used clinically and is
  • Tranexamic acid i.e. trans-4-aminomethylcyclohexanecarboxylic acid, has the chemical structure I.
  • tranexamic acid The bio-availability of tranexamic acid is, however, fairly low. On oral adminis ⁇ tration only about 30-40% of the drug is absorbed and a considerable amount is excreted in the faeces. This may cause undesired gastrointestinal side effects in some patients.
  • EP-A- 0079872 discloses several ester derivatives (so-called prodrugs) of tranexamic acid. These ester derivatives have a high bioavailability and are rapidly metabolized to tranexamic acid in the human body.
  • ester derivatives disclosed inEP-A-0079872 l-(ethyloxy-carbonyloxy)ethyltrans-4-aminomethylcyclohexane- carboxylate-hydrochloride (formula II) has been selected for clinical studies and found to fulfill the expectations. See J.Med.Chem. 1986 29, 448-453, and Arz- neim.-Forsch. 1988 38, 735-738. l
  • EP-A-0079872 discloses the following methods for preparing the compound of formula II:
  • Z and Z are as defined above, or a functionally equivalent derivative thereof, with a compound HO-CO-OC Hg or a functionally equivalent derivative thereof, so as to form the above compound of Formula V.
  • the method d) gives rise to a mixture of cis- and trans-forms of the product, which has to be separated. Because of the delicate nature of the pro-drug II (the compound is sensitive to both high and low pH, and especially to high temperatures) this is an arduous task, especially on a commercial scale.
  • the method c) has the disadvantage that the starting materials are not available on a technical scale, especially not as pure trans-forms, so complicated procedures are required for preparing them.
  • the starting material is tranexamic acid which, as such or after proper protection of the amino group, is esterified to the pro-drug of Formula II or its protected derivative of Formula V, which then is deprotected.
  • the method b) is similar, but the esterification is carried out in two steps via the intermediate of Formula VI.
  • EP-A-0079872 does not disclose any example, wherein the unprotected tranexamic acid is used in the process, and experiments have shown that only marginal yields of a highly contaminated material can be obtained when using this starting material.
  • EP-A-0079872 generally states that the protecting groups Z- ⁇ and Z 2 preferably are groups which can be removed under neutral or acidic conditions or by hydrogenation, especially catalytic hydrogenation.
  • the protecting groups Z- ⁇ and Z 2 preferably are groups which can be removed under neutral or acidic conditions or by hydrogenation, especially catalytic hydrogenation.
  • Tert.-butyloxycarbonyl, benzyloxycarbonyl, dibenzyl, triphenylmethyl, alkylcarbonyl and arylcarbonyl are mentioned as examples of such groups, but only tert.-butyloxycarbonyl is used in the working examples.
  • the desired prodrug of Formula II as its hydrochloride can be prepared from tranexamic acid of Formula I in a simple and straight-forward reaction sequence using commer ⁇ cially readily available and inexpensive aldehydes, such as benzaldehyde, or similar aldehydes lacking an ⁇ -hydrogen atom, such as alkyl-, alkoxy- or halogen- substituted benzaldehydes or naphtaldehydes, for the protection of the amino group, and that the invented process can be carried out in one sequence without isolation of any intermediates.
  • the reaction sequence can, however, also be carried out such that novel chemical intermediates are isolated (for subsequent conversion to the prodrug of formula II). Such chemical intermediates are also comprised by the invention.
  • the prodrug of Formula II is a sensitive substance which in aqueous solution has satisfactory stability only in the pH range from about 1 to about 7 and at low temperatures.
  • the success of the process therefore depends on a delicate balance between the stability of the protecting group during the reactions in organic solvents and its ease of removal by acid hydrolysis in aqueous solution after the esterifi cation has taken place.
  • this balance is obtained by the use of the herein specified aldehydes lacking ⁇ -hydrogen atoms - which with tranexamic acid form Schiff s bases, that are stabile during the esterifi cation at elevated temperatures.
  • Other aldehydes, which undergo aldol condensation under the said conditions are not useful according to the invention.
  • the invention thus provides an improved process for preparing tranexamic acid prodrugs.
  • the process according to the invention thus involve the following steps, which can be carried out either in sequence without isolatio of any intermediate or with isolation of the novel ester intermediates accordin to the invention which are obtained in step 3 below.
  • M + is a salt forming ion such as an alkali metal ion, quaternar ammonium ion or possibly alkaline earth ion.
  • aldehyd Ar-CHO being an aromatic aldehyde, e.g. a benzaldehyde or naphtaldehyd lacking ⁇ -hydrogen atom and preferably being substituted by alkyl or alkox groups or halogen atoms, and removal of water from the resulting solution of N substituted tranexamic acid (preferably N-benzylidenetranexamic acid) b azeotropic distillation, preferably with a solvent which is not miscible with wate but is capable of forming azeotropes with water boiling in the range between 40 150°C to form a salt of the Formula
  • Ar-CH N-CH 2 - ⁇ )-COO " M + .
  • potassium hydroxide instead of potassium hydroxide other water soluble bases such as sodium hydrox ⁇ ide, lithium hydroxide or calcium hydroxide, or a quaternary ammonium hydrox ⁇ ide can be used.
  • the invention also provides novel chemical intermediates useful for preparing the prodrug of formula II.
  • novel chemical intermediates useful for preparing the prodrug of formula II.
  • a preferred group of such intermediates are protected esters which can be represented by the following formula:
  • R-CH N-CH 2 -T -COO-CH(CH 3 )-O-COOC 2 H 5
  • R signifies phenyl or naphtyl which may be substituted with lower alkyl or lower alkoxy groups or halogen atoms, said lower alkyl and lower alkoxy groups comprising 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms.
  • Schiff s bases with unsubstituted aldehydes like benzal- dehydes are, however, generally considered to be too unstable to be of more general value and aromatic aldehydes containing an ortho hydroxy group, which stabilizes the Schiffs base by hydrogen bond formation, or a J-discarbonyl compound such as ethyl acetoacetate, which form hydrogen bond stabilized enamines, are generally preferred.
  • Potassium hydroxide (88%, 12% water) 638 g (10.0 mol) is dissolved in 500 ml o water. Tranexamic acid (1572 g; 10.0 mol) is added with stirring. The clea solution formed is chilled to about 50°C and benzaldehyde (1114 g; 10.5 mol) is added with stirring. A precipitate forms which rapidly goes into solution. Toluene (10 1) is added and the mixture is stirred and boiled with continous separation o water by azeotropic distillation. A sticky, jellied mass is formed which, as the water is removed, is converted into a suspension of fine needle-like, coulorless crystals of potassium trans-4-benzylideneiminomethyl-cyclohexane-carboxylate.
  • the mixture is chilled to 40-60°C, tetrabutylammonium bromide (323 g; 1.0 mol) is added followed by 1-chlorethyl ethyl carbonate (1602 g; 10.5 mol) and the mixture is stirred for 4-5 hours at 55-65°C.
  • the solid salt gradually passes into solution and is replaced by a jellylike precipitate of potassium chloride.
  • the mixture is chilled to below 10°C and rapidly washed with three 7 1 portions o ice cold water.
  • the toluene phase containing the l-(ethyloxycarbonyloxy)ethyl trans-4-benzylideneiminomethyl cyclohexane carboxylate is separated, mixed with 5 1 of ice cold water, and treated with rapid stirring below 10°C with a 1 molar solution of hydrochloric acid added at such a rate that the pH of the mixture is kept at about 1.2 to 1.8 (a total amount of about 10 1 is required).
  • the aqueous phase is separated and repeatedly washed with cold toluene to remove benzalde ⁇ hyde and traces of neutral impurities yielding an aqueous solution of l-(ethyloxy- carbonyloxy)ethyl trans-4-aminomethyl cyclohexane carboxylate hydrochloride containing a small amount of unreacted tranexamic acid, usually less than 2%.
  • the product is isolated from this solution by rapid evaporation of the water at below 30°C in a vacuum, which gives an oil that sets into a crystalline mass, by spray drying.
  • the yield of product of about 99% purity is about 84%. If desire the product can be purified by dissolution in hot 2-propanol and precipitation wit petrol.
  • the melting point of the recrystallized product is 142°C.
  • a suspension of potassium trans-4-benzylidene iminomethyl cyclohexane carbox late in trichloroethene is prepared following the directions of Example 1 but usin 10 1 of trichloroethene instead of toluene.
  • the salt is esterified by stirring ove night with 1-bromoethyl ethyl carbonate (2068 g; 10.5 mol) at 30-40°C. Th reaction mixture is worked up and the product is isolated as described in Exampl 1. The yield of product of 98% purity is 85%.
  • Tetrabutylammonium bromide (3.2 g; 0.010 mol) and chloroethyl ethyl carbonate (32.0 g; 0.21 mol) are added and the mixture is stirre and heated at 50-60°C for 5 hours. It is poured into iced water and repeatedl washed with cold water, dried over anhydrous sodium sulphate, and evaporate in vacuum below 30°C. An oil, 77 g, is obtained that according to gas chrom tography is 92% pure. Yield 98%. The identity of the compound was confirmed b gas chromatography-mass spectroscopy. b) l-(Ethyloxycarbonyloxy)ethyl trans-4-(4-chlorobenzylideneimino)methy cyclohexanecarboxylate
  • This compound is analogously prepared from4-chlorobenzaldehyde.
  • the compoun is obtained in 88% purity and 83% yield.
  • This compound is analogously prepared from 4-methylbenzaldehyde. Purity 76 yield 68%.
  • This compound is analogously prepared from2-methoxybenzaldehyde. Purity 83 yield 70%.
  • This compound was analogously prepared from 1-naphtaldehyde. Purity 65 yield 57%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Un précurseur de l'acide tranexamique de la formule générale (II) est préparé par la conversion de l'acide tranexamique en un sel, en solution aqueuse. Un adhéhyde aromatique de la formule Ar-CHO n'ayant pas d'hydrogène en position α est ajouté à la solution et l'eau est éliminée de manière à former un sel de la formule (a). La suspension obtenue du sel anhydre de l'acide tranexamique N-substitué est estérifiée avec un 1-halogénoéthyle éthyle carbonate, où l'halogène est le chlore ou le brome. L'halogénure formé et le catalyseur éventuellement présent sont enlevés. Les esters protégés de la formule (b) où R est un phényle ou un naphtyle qui peuvent être substitués avec des groupes alkyle inférieurs, des groupes alcoxy inférieurs ou des atomes d'halogène, sont de nouveaux intermédiaires qui peuvent être utilisés pour la préparation du précurseur du médicament (II).
PCT/SE1993/001115 1992-12-30 1993-12-30 Nouveau procede et nouveaux intermediaires pour la preparation de precurseurs et medicaments WO1994015904A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58452/94A AU5845294A (en) 1992-12-30 1993-12-30 Novel process and intermediates for the preparation of prodrugs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9300013A SE9300013L (sv) 1992-12-30 1992-12-30 Nytt förfarande och mellanprodukter för framställning av pro- läkemedel
SE9300013-1 1992-12-30

Publications (1)

Publication Number Publication Date
WO1994015904A1 true WO1994015904A1 (fr) 1994-07-21

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007002013A2 (fr) * 2005-06-20 2007-01-04 Xenoport, Inc. Prodrogues de carbamate d'acyloxyalkyle d'acide tranexamique, leurs procedes de synthese et leur utilisation
US7511158B2 (en) 2003-12-30 2009-03-31 Xenoport, Inc. Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof
WO2011028234A1 (fr) 2009-09-04 2011-03-10 Xenoport, Inc. Utilisations de promédicaments acyloxyalkyl carbamates de l'acide tranexamique
US7947739B2 (en) 2004-03-04 2011-05-24 Ferring B.V. Tranexamic acid formulations
WO2011091164A1 (fr) 2010-01-22 2011-07-28 Xenoport, Inc. Formes galéniques orales ayant une charge élevée d'un promédicament d'acide tranexamique
US8022106B2 (en) 2004-03-04 2011-09-20 Ferring B.V. Tranexamic acid formulations
US8273795B2 (en) 2004-03-04 2012-09-25 Ferring B.V. Tranexamic acid formulations
US8957113B2 (en) 2004-03-04 2015-02-17 Ferring B.V. Tranexamic acid formulations
US8968777B2 (en) 2003-07-31 2015-03-03 Ferring B.V. Tranexamic acid formulations with reduced adverse effects
US9944592B2 (en) 2003-08-20 2018-04-17 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
CN116284814A (zh) * 2023-01-17 2023-06-23 杭州三式化妆品有限公司 超分子传明酸甘醇酸离子盐及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0041826A2 (fr) * 1980-06-04 1981-12-16 Kureha Kagaku Kogyo Kabushiki Kaisha Acides 4-(N-(benzylidène substitué)aminométhyl)cyclohexane-1-carboxylique
EP0079872A1 (fr) * 1981-11-17 1983-05-25 KabiVitrum AB Composés à activité antifibrinolytique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0041826A2 (fr) * 1980-06-04 1981-12-16 Kureha Kagaku Kogyo Kabushiki Kaisha Acides 4-(N-(benzylidène substitué)aminométhyl)cyclohexane-1-carboxylique
EP0079872A1 (fr) * 1981-11-17 1983-05-25 KabiVitrum AB Composés à activité antifibrinolytique

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8968777B2 (en) 2003-07-31 2015-03-03 Ferring B.V. Tranexamic acid formulations with reduced adverse effects
US9944592B2 (en) 2003-08-20 2018-04-17 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
US8003809B2 (en) 2003-12-30 2011-08-23 Xenoport, Inc. Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof
US9353057B2 (en) 2003-12-30 2016-05-31 Xenoport, Inc. Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof
US7511158B2 (en) 2003-12-30 2009-03-31 Xenoport, Inc. Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof
US8378137B2 (en) 2003-12-30 2013-02-19 Xenoport, Inc. Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof
US8809394B2 (en) 2004-03-04 2014-08-19 Ferring B.V. Tranexamic acid formulations
US8957113B2 (en) 2004-03-04 2015-02-17 Ferring B.V. Tranexamic acid formulations
US7947739B2 (en) 2004-03-04 2011-05-24 Ferring B.V. Tranexamic acid formulations
US9060939B2 (en) 2004-03-04 2015-06-23 Ferring B.V. Tranexamic acid formulations
US8791160B2 (en) 2004-03-04 2014-07-29 Ferring B.V. Tranexamic acid formulations
US8022106B2 (en) 2004-03-04 2011-09-20 Ferring B.V. Tranexamic acid formulations
US8273795B2 (en) 2004-03-04 2012-09-25 Ferring B.V. Tranexamic acid formulations
US8487005B2 (en) 2004-03-04 2013-07-16 Ferring B.V. Tranexamic acid formulations
US8372881B2 (en) 2005-06-20 2013-02-12 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of tranexamic acid, methods of synthesis and use
US7592369B2 (en) 2005-06-20 2009-09-22 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of tranexamic acid, methods of synthesis and use
CN101253148B (zh) * 2005-06-20 2013-01-02 克塞诺波特公司 凝血酸的酰氧基烷基氨基甲酸酯前药，合成和使用的方法
US7777070B2 (en) 2005-06-20 2010-08-17 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of tranexamic acid, methods of synthesis and use
WO2007002013A2 (fr) * 2005-06-20 2007-01-04 Xenoport, Inc. Prodrogues de carbamate d'acyloxyalkyle d'acide tranexamique, leurs procedes de synthese et leur utilisation
JP2008546717A (ja) * 2005-06-20 2008-12-25 ゼノポート，インコーポレーテッド トラネキサム酸のカルバミン酸アシルオキシアルキルプロドラッグ、合成法、および使用
US7351740B2 (en) 2005-06-20 2008-04-01 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of tranexamic acid, methods of synthesis and use
WO2007002013A3 (fr) * 2005-06-20 2007-03-22 Xenoport Inc Prodrogues de carbamate d'acyloxyalkyle d'acide tranexamique, leurs procedes de synthese et leur utilisation
WO2011028234A1 (fr) 2009-09-04 2011-03-10 Xenoport, Inc. Utilisations de promédicaments acyloxyalkyl carbamates de l'acide tranexamique
WO2011091164A1 (fr) 2010-01-22 2011-07-28 Xenoport, Inc. Formes galéniques orales ayant une charge élevée d'un promédicament d'acide tranexamique
CN116284814A (zh) * 2023-01-17 2023-06-23 杭州三式化妆品有限公司 超分子传明酸甘醇酸离子盐及其制备方法和应用

Also Published As

Publication number Publication date
SE9300013D0 (sv) 1992-12-30
AU5845294A (en) 1994-08-15
SE9300013L (sv) 1994-07-01

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