WO1994015904A1

WO1994015904A1 - Novel process and intermediates for the preparation of prodrugs

Info

Publication number: WO1994015904A1
Application number: PCT/SE1993/001115
Authority: WO
Inventors: Nils Åke JÖNSSON
Original assignee: Pharmacia Ab
Priority date: 1992-12-30
Filing date: 1993-12-30
Publication date: 1994-07-21
Also published as: SE9300013L; AU5845294A; SE9300013D0

Abstract

A tranexamic acid prodrug of general formula (II), is prepared by conversion of tranexamic acid in aqueous solution into a salt. An aromatic aldehyde of the formula Ar-CHO, lacking α-hydrogen atom is added to the solution and water is removed so as to form a salt of formula (a). The obtained suspension of anhydrous N-substituted tranexamic acid salt is esterified with 1-halogenethyl ethyl carbonate, wherein the halogen is chloro or bromo, and the halogenide formed and possibly present catalyst are removed. Protected esters of formula (b) wherein R signifies phenyl or naphthyl which may be substituted with lower alkyl or lower alkoxy groups or halogen atoms, are novel intermediates which can be used for the preparation of the prodrug (II).

Description

Novel process and intermediates for the preparation of prodrugs.

Field of the invention. 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 antifϊbrinolytic drug. It is widely used clinically and is

® available from e.g. Kabi Pharmacia AB under the trademark Cyklokapron .

Background of the invention Tranexamic acid, i.e. trans-4-aminomethylcyclohexanecarboxylic acid, has the chemical structure I.

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.

Attempts have been made to overcome these disadvantages. For example, 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. Of the specific 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

H₂NCH₂ -Q- COO-CH(CH₃)-0-CO-0-C₂H₅, HC1 II

EP-A-0079872 discloses the following methods for preparing the compound of formula II:

a) Reacting a compound of Formula III

Z₁Z₂N-CH₂-^ -COOH III wherein Z 1 and Z 2 are hydrogen or protecting groups, or a functional equivalent derivative thereof such as a salt, with a compound of Formula IV

HO-CH(CH₃)-O-CO-OC₂H₅ IV

or a functionally equivalent derivative thereof, to form a compound of Formula V,

Z₁Z₂N-CH₂- ^)-COO-CH(CH3)-0-CO-OC₂H₅ V

wherein Z 1 and Z 2 are as defined above.

If necessary, the protecting groups Z 1 and Z 2 are removed so as to form the com- pound of Formula II,

b) Reacting a compound of Formula VI

wherein 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.

c) Reducing a compound of the Formula VII

X_r(^OOCH(CH₃)-O-CO-C₂H₅ VII

wherein X¹ is -CN, -CH₂N0₂, -CH₂N₃, -CONH₂, or -CH = NOH, so as to form the compound of Formula II.

d) Reducing a compound of the Formula VIII

in the presence of ammonia and subsequent treatment with hydrogen chloride so as to form the compound of Formula II.

All of the above described, previously known methods have certain disadvantages. For example, 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.

In the method a) 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.

On page 9 EP-A-0079872 generally states that the protecting groups Z-^ and Z₂ 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.

All of the protecting groups mentioned in EP-A-0.079.872 require a separate reaction step for the preparation and isolation of the protected tranexamic acid (Formula III above). With the exception of alkylcarbonyl and arylcarbonyl, the raw materials used for the protecting groups are also rather expensive. Simple representatives of alkylcarbonyl and arylcarbonyl protecting groups such as acetyl or benzoyl are, however, much too resistent to hydrolysis to allow their removal from the protected ester of Formula V without extensive destruction of the intermediate of formula VI and the desired product of Formula II. Use of protect¬ ing groups, which are removed by catalytic hydrogenation, is also disadvanta¬ geous since it requires special equipment and precautions for handling of hydro- gen.

It is obvious from the above that an improved method, which permits conversion of tranexamic acid to the prodrug of Formula II without requiring isolation of any intermediate(s) and which makes use of inexpensive, commercially available starting materials for the protecting group, would be highly desirable.

Summary of the invention

According to the invention, it has surprisingly been found, that 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 α-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. According to the invention this balance is obtained by the use of the herein specified aldehydes lacking α-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.

In one aspect 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.

1. Conversion of tranexamic acid of formula I

into a salt H₂NCH₂- ^ - COO^"M ⁺

wherein M⁺ is a salt forming ion such as an alkali metal ion, quaternar ammonium ion or possibly alkaline earth ion.

It is preferred to convert the tranexamic acid to a potassium salt, e.g. as illustrat ed by the following equation:

H₂NCH₂ .Q-^C00H + KOH-> H2NCH₂-0-COOK + H₂0

2. Addition of an aldehyde of the formula Ar-CHO to the solution, said aldehyd Ar-CHO being an aromatic aldehyde, e.g. a benzaldehyde or naphtaldehyd lacking α-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-CH₂-<^)-COO^"M⁺.

This reaction can be illustrated as follows for the preferred benzaldehyde:

θ -CHO + → - g)-CH_S:NCH₂- )-COOK + H₂0

3. Esterifi cation of the suspension of anhydrous N-substituted tranexamic aci salt thus obtained with 1-halogenethyl ethyl carbonate, wherein the halogen i chloro or bromo, preferably in the presence of a catalytic amount of a quaternar ammonium salt such as tetrabutyl ammonium bromide, especially when th halogen is chloro, at an elevated temperature, preferably between 30 and 110°C. This esterification can be illustrated as follows for the preferred N-benzyliden tranexamic acid:

@-CH=NCH₂- >-COOK ⁺ Cl-CHCIty-O-CO-O-CgHg →

^θ -CH=NCH₂- COO-CH(CH3)-O-CO-O-C₂H₅ + KC1

4. Removal of the halogenide formed and the catalyst, e.g. by washing with wate after cooling, preferably below room temperature and especially below 10°C.

5. Optional treatment of the solution of the N-substitutued tranexamic ester thus obtained with a slight excess of dilute aqueous hydrochloric acid, preferably 0.1-1 molar and preferably below 10°C in order to hydrolytically remove the protecting group. This step can be illustrated as follows:

(o CHsN-CHg-^-COO-CHCHg^O-CO-O-C^g- + HC1 + H₂0

— H₂NCH₂H^COO-CH(CH₃)-0-CO-O-C2H5-, HC1 + o -CHO

6. Optional washing of the resulting aqueous solution of prodrug II with a solvent, preferably the same as used in steps 2 to 5 in order to remove dissolved benzalde¬ hyde, and isolation of the product in crystalline form by cautious evaporation, e.g. by thin film evaporation, spray-drying or freeze drying or combinations thereof, or by extraction with an organic solvent such as dichloromethan.

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.

Instead of benzaldehyde other aldehydes as defined above can be used. Instead o toluene or trichloroethylene other solvents not miscible with water but forming azeotropes with water boiling in the range between 40-150°C can be used, toluene and trichloroethylene being, however, the preferred solvents. The end product obtained is of satisfactory purity to be processed into tablets without further purification, but it may, if desired, be further purified by recrys- tallisation, e.g. from a mixture of 2-propanol and light petrol.

In another aspect the invention also provides 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-CH₂-T -COO-CH(CH₃)-O-COOC₂H₅

wherein 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.

As mentioned above these intermediates can be isolated by interruping the reaction sequence after the esterifϊcation step. The novel intermediates are usually oils which are rather stable if stored at a temperature below room temperature, preferably below 10°C. Characterizing data for some intermediates are shown in the enclosed Figures 1-4.

The use of Schiff s bases from aldehydes as protecting groups for amines in organic synthesis, is well known. (See e.g. T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York 1981, 275-279, Houben-Weyl Methoden der organischen Chemie, Band 15:1 pp. 277-285, 295-297. GeorgThieme Verlag, Stuttgart 1974.) 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.

The initial experiments leading to the present invention were therefore carried out with such hydrogen bond forming protective groups. These derivative of II were, however, found to be too stabile in the hydrolysis step to allow the isolation of the desired compound II in high yield and purity. The use of /?-discarbonyl compounds like ethyl acetoacetate was also hampered by the fact that the protected I was too unstable thermally to function satisfactorily in the esterifica tion step, again resulting in low yields and impure products.

It was therefore entirely unexpected that the simple aldehydes which are use according to the invention, especially unsubstituted benzaldehyde, an inexpensiv and readily available commercial product, proved to be ideal for the purposes o the invention.

Example 1

1 -(Ethyl oxycarbonyloxy)ethyl trans-4-aminomethyl cyclohexane carboxylate hydrochloride

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.

Example 2

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%.

Example 3 Preparation of N-substituted 1 -(ethyl oxycarbonyloxy) ethyl trans-4-iminomethyl cyclohexane carboxylates

a) l-(Ethyloxycarbonyloxy)ethyltrans-4-benzylideneiminomethyl cyclohexan carboxylate

A mixture of potassium hydroxide (88%; 12.8 g; 0.20 mol), tranexamic acid (31.4 0.20 mol), and water (50 ml) is stirred until a clear solution is obtained. Benzald hyde (21.2 g; 0.20 mol) is added and the mixture is stirred until a clear solutio is again obtained. The solution is evaporated to dryness in vacuum on a wat bath. Toluene (500 ml) is added and the last traces of water are removed b azeotropic distillation. 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.

c) l-(Ethyloxycarbonyloxy)ethyl trans-4-(4-methylbenzylideneimino)methyl-cv lohexanecarboxylate

This compound is analogously prepared from 4-methylbenzaldehyde. Purity 76 yield 68%.

d) l-(Ethyloxycarbonyloxy)ethyl trans-4-(2-methoxybenzylideneimino)methy cycl ohexanecarboxyl ate

This compound is analogously prepared from2-methoxybenzaldehyde. Purity 83 yield 70%.

e) l-(Ethyloxycarbonyloxy)ethyl trans-4-(l-naphtylmethyleneimino)methy cycl ohexanecarb oxy 1 ate

This compound was analogously prepared from 1-naphtaldehyde. Purity 65 yield 57%.

Claims

1. An improved process for preparing a tranexamic acid prodrug of t general formula II,

H₂NCH₂- H COO-CH(CH₃)-0-CO-0-C₂H₅, HCl π

characterized in that it comprises the following steps:

a) conversion of tranexamic acid of formula I in aqueous solution

H₂NCH₂ - )-COOH

into a salt H₂NCH₂ -/^""V COO'M⁴"

wherein M ⁺ is a salt forming ion,

b) addition of an aromatic aldehyde of the formula Ar-CHO to the solution, sa aldehyde lacking α-hydrogen atom, and removal of water from the resulti solution of N-substituted tranexamic acid to form a salt of the Formula

Ar-CH=N-CH₂- ^COO^_M⁺.

c) esterifi cation of the suspension of anhydrous N-substituted tranexamic acid sa thus obtained with 1-halogenethyl ethyl carbonate, wherein the halogen is chlo or bromo, preferably in the presence of a catalytic amount of a quaterna ammonium salt,

d) removal of the halogenide formed and possibly present catalyst, and

e) treatment of the solution of the N-substituted tranexamic ester thus obtain with a sligh excess of dilute aqueous hydrochloric acid.

2. The process of claim 1, characterized in that the aldehyde Ar-CHO is benzaldehyde or naphtaldehyde, which may be substituted by alkyl or alko groups or halogen atoms, that the salt forming ion M⁺ is an alkali metal ion a quaternary ammonium ion and that water is removed by azeotropic distillatio

3. The process of claim 1 or 2, characterized in that the protected este obtained is isolated before removal of the protecting group.

4. Novel chemical intermediates useful for preparing the prodrug of formul II, characterized in that they are protected esters which can be represented b the following formula:

R-CH=N-CH₂- OO-CH(CH₃)-0-COOC₂H₅

wherein R signifies phenyl of naphtyl which may be substituted with lower alkyl or lower alkoxy groups or halogen atoms.