WO2000061574A2

WO2000061574A2 - Method for producing thiophenyl-amidines

Info

Publication number: WO2000061574A2
Application number: PCT/EP2000/003018
Authority: WO
Inventors: Thomas Zierke; Helmut Mack
Original assignee: Basf Aktiengesellschaft
Priority date: 1999-04-09
Filing date: 2000-04-05
Publication date: 2000-10-19
Also published as: EP1169315A2; JP2002541252A; AU3559000A; CA2369267A1; WO2000061574A3

Abstract

The invention relates to a method for producing amidines that are not substituted on the nitrogen atom and salts thereof with inorganic or organic acids. According to said method, the corresponding carboxylic acid amidoximes are reacted with Zn in the presence of carboxylic acids.

Description

Process for the preparation of amidines

description

The present invention describes a new process for the preparation of amidines which are not substituted on nitrogen and their salts with inorganic or organic acids, characterized in that corresponding carboxamide amides are reacted with Zn in the presence of carboxylic acids such as formic acid, acetic acid, propionic acid.

For the production of amidines, which are important structural elements in a number of biologically active molecules such as fibrinogen antagonists (L. Alig et al., J. Med. Chem. 1992, 32, 4407), thrombin inhibitors (H. Vieweg et al. ^' , Pharmazie 1982, 37, 178) or factor Xa inhibitors (T. Nagahara et al., J. Med. Chem. 1993, 36, 1811) already exist, a large number of synthetic methods already exist.

One of the most proven methods is the two-stage transformation of nitriles via imino esters into amidines, known as the Pinner reaction (A. Pinner, Chem. Ber. 1885, 18, 2845). As a rule, large excesses of hydrogen chloride in alcohols are used to form the imino esters. The reaction times are often very long (J. B. Medwid, J. Med. Chem. 1990, 33, 1237). Due to the accompanying elimination of acid-labile protective groups or transesterification reactions, the method is not suitable for the production of more complex molecules. The alternative base-catalyzed preparation of imino esters (F.C. Schaefer et al., J. Org. Chem., 26, 412, 1961) remains limited to electron-poor nitriles.

A variant of the Pinner reaction is the conversion of nitriles via thioamides and S-alkylthioimino esters to amidines (H. Bredereck, Chem. Ber. 1957, 90, 1837). This method is widely used when it comes to building up the amidine functionality in complex compounds such as synthetic thrombin inhibitors (B. Voigt, Pharmazie, 1983, 38, 835). However, the method can only be used for the production of small laboratory quantities. The chemicals used, hydrogen sulfide (malodorous and highly toxic), methyl iodide or dirnethyl sulfate (carcinogenic alkylating agents) and the accompanying methyl mercaptan (malodorous and highly toxic) require extensive safety measures and disposal options that can only be guaranteed in special systems. In addition, the products usually have to be cleaned chromatographically. Another possibility for the production of amidines consists in the hydrogenolytic cleavage of the NO bond of carboxylic acid amidoximes (H.Jendralla et al., Tetrahedron 1995, 51, 12047; BD Judkins, Synth. Commun. 1996, 26, 4351) with hydrogen and 5 palladium / carbon catalysts. This method cannot be used for the synthesis of amidines, which may contain functionalities which can be hydrogenated, such as CC double bonds, benzyl-substituted 0 or N atoms, etc.

Recently, a number of synthetic drugs, such as integrin receptor antagonists, there in particular fibrinogen receptor antagonists, or serine protease inhibitors, there in particular thrombin inhibitors, factor Xa inhibitors, factor villa inhibitors, factor IXa inhibitors , 5 urokinase inhibitors, tryplase inhibitors, complement inhibitors (for example Ci _s and Cι _r ), which contain substituted thienylamidines as structural elements: Factor Xa inhibitors: RPR 120844 (Thromb. Haemostasis 81, No 1, 157-160, (1999)); Urokinase inhibitors: (Fujisawa, WO 9811089); Thrombin inhibitors: 0 Eli Lilly WO95 / 23609 (Ex. 65), BASF, WO 98/06741 (Ex. 1-9 etc), Boehringer Ingelheim DE 19754490 (Ex. 98-103 etc)). The unsubstituted 2- or 3-thiophenecarboxamidines could be prepared in good yields by the Pinner reaction described above (S. Gronowitz, Acta Chem. Scand B 31, 1977, 771).

25

The through the above Complex substituted thienylamidines disclosed in patent applications have generally been made available in small amounts via the thioamide route described above. A satisfactory access to the production of larger quantities

30 of these compounds has not yet been described in view of the disadvantages of this method mentioned. The catalytic hydrogenation of corresponding carboxamide oximes is also out of the question because of the generally known property of sulfur-containing compounds of poisoning hydrogenation catalysts

35 (see R. Schröter, Houben-Weyl 11/1, p. 350 and W.D. Rudolf Houben-Weyl E6a, p.492).

The simple addition of ammonia under pressure in the presence of ammonium salts (F.C. Schaefer et al., J. Org. Chem., 27, 1255, 40 1962) only leads to poor conversions in thiophene carbonitriles.

One of the objects of the invention was to find a method which also enables the preparation of substituted amidines in a simple manner, with good yields and on an industrial scale. Aryl and He arylamidine syntheses are of particular interest, in particular those of thienylamidines. The invention relates to a new generally applicable process for the preparation of amidines which are not substituted on nitrogen and their salts with inorganic or organic acids, characterized in that a corresponding carboxamide amide oxime with Zn in the presence of carboxylic acids such as formic acid, acetic acid, propionic acid, preferably acetic acid, implements.

The new process can also be used to prepare substituted thienylamidines, preferably those in which the amidine function is either in the 2-position or 3-position and another substituent in one of the three other positions with respect to sulfur, the substituent in turn via a C, N or O atom is bonded to the thiophene radical.

In particular, amidines of the formula I can be prepared by the process according to the invention

where n = 1-3 and R can have the following meanings

Ci-C _ß- alkyl-CO, with alkyl meaning straight-chain or branched alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl,

C ₁ -C ₆ -alkoxy-CO, with alkoxy in the meaning methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,

Benzyloxy,

Aryl such as phenyl, naphthyl, or heteroaryl such as pyridyl, thienyl, furyl, benzothiazolyl, benzimidazolyl, where these aromatics can optionally be substituted one or more times. Examples of substituents are Ci-C _δ- alkyl, Ci-Cg-alkoxy, halogen, amino, mono- or di-Ci-C _δ- alkylamino.

an α-amino acid fragment in the R or S configuration, the N atom of which is protected or unprotected in the usual manner as tert-butoxycarbonyl or benzyloxycarbony derivative, preferably the amino acid fragments 3, 4-dehydroproline, 4,5-dehydro - pipecolic acid, azetidine, proline, pipecolic acid, a dipeptide fragment, optionally substituted one or more times at the N-terminus, consisting of the natural amino acids, the corresponding D-amino acids or the very similar amino acids in the L or D form, preferably combinations of the amino acids 3, 4-dehydroproline , 4,5-dehydropipecolic acid, azetidine, proline, pipecolic acid, phenylalanine, phenylglycine, cyclohexylalanine, cyclohexylglycine, alanine, valine, glycine, particularly preferably combinations of the amino acids azetidine, proline, 3, 4-dehydroproline, cyclohexylalanine, glycinohexyl , Phenylglycine and phenylalanine,

further residues for R are specified in the published integrin receptor antagonists and serine protease inhibitors, where R corresponds in each case to the molecular fragment which is attached to the heterocyclic alkylamino-substituted amidine residue,

produce.

Carboxylic acid amidoximes of the formula II are used for this

in which n and R have the same meaning as in formula I, with Zn in the presence of carboxylic acids such as formic acid, acetic acid, propionic acid, preferably acetic acid, to give the corresponding amidines of the formula I.

Compounds of formula I can contain one or more centers of asymmetry. Both pure enantiomers or diastereomers and a mixture of the enantiomers or diastereomers can be prepared by the process according to the invention. The

Configuration of the asymmetry centers is retained during the reaction according to the method according to the invention.

The process for the preparation of compounds of the formula I thus provides easy access to thrombin inhibitors of WO 98/06741, represented there by the general formula III

with D in meaning

The structural elements A, B, E in the meanings of WO 98/06741 correspond to particularly preferred compounds of the formula I in which the unit A-B-E is represented by the radical R.

The carboxylic acid amidoximes required to carry out the process according to the invention are prepared by known methods (F. Eloy et al., Chem. Rev. 1962, 62, 155) by reacting the corresponding nitriles with hydroxylamine or preferably its salts, particularly preferably hydroxylamine. Hydrochloride. The corresponding hydroxylamine derivative is preferably used in a 1 to 3-fold excess. The reaction is carried out in an inert solvent. Preferred solvents are alcohols such as methanol, ethanol, n-propanol, iso-propanol or n-butanol, possibly in a mixture with methylene chloride, toluene or water. If salts of hydroxylamine are used, at least one equivalent of a stronger base than hydroxylamine itself must be added to release the hydroxylamine. The base can also be used in excess, based on the hydroxylamine salt. Both inorganic bases such as sodium carbonate (F. Tiemann, Chem. Ber. 17, 1884, 126), metal alcoholates such as sodium methylate or potassium tert-butoxide (BD Judkins, Synth. Commun. 1996, 26, 4351) are particularly suitable as bases but preferably also tert. Amines such as triethylamine (H. Jendralla et al., Tetrahedron 1995, 51, 12047) or diisopropylethylamine in

Consideration. The reaction takes place at room temperature, but to accelerate it can also be heated to the boiling point of the reaction solution, but usually not higher than 80 ° C.

The isolation of the carboxamide oximes is different. In the case of crystallization from the reaction solution, the products are isolated by filtration. In other cases, it is concentrated, taken up with a water-immiscible solvent in which the products are readily soluble. This solution is washed with water, which may be acidified to pH 2 with mineral acid, and concentrated. The residues can be brought to crystallization in a suitable solvent in the usual way. However, it is usually also possible to continue to implement the products without further cleaning. Some of the compounds of the formula II prepared in this way are new compounds and are therefore also an object of the present invention. The following compounds are particularly preferred:

2-N-Boc-aminomethyl- (4-amidoximo) -thiophene 2-N-Cbz-aminomethyl- (4-amidoximo) -thiophene N-Boc-Pro-2- (4-amidoximo) -thienylmethylamide N-Cbz-Pro -2- (4-amidoximo) thienylmethylamide N-Boc-Aze-2- (4-amidoximo) thienylmethylamide N-Boc-Dhp-2- (4-amidoximo) thienylmethylamide N-Boc-Dep-2- (4th -amidoximo) -thienylmethylamide Pro-2- (4-amidoximo) -thienylmethylamide Aze-2- (4-amidoximo) -thienylmethylamide Dhp-2- (4-amidoximo) -thienylmethylamide Dep-2- (4-amidoximo) -thienylmethylamide

N- (t-BuOOC-CH) -N-Boc-D-Chg-Dhp-2- (4-amidoximo) -t ienylmethylamide N- (t-BuOOC-CH ₂ ) -N-Boc-D-Cha-Dhp -2- (4-amidoximo) thienylmethylamide N- (t-BuOOC-CH ₂ ) -N-Boc-D-Phe-Dhp-2- (4-amidoximo) thienylmethylamide N- (t-BuOOC-CH ₂ ) -N-Boc-D-Phg-Dhp-2- (4-amidoximo) -thienylmethylamide N- (t-BuOOC-CH ₂ ) -NH-D-Chg-Dhp-2- (4-amidoximo) -thienylmethylamide N- (t-BuOOC-CH ₂ ) -NH-D-Cha-Dhp-2- (4-amidoximo) thienylmethylamide N- (t-BuOOC-CH) -NH-D-Phe-Dhp-2- (4-amidoximo ) -thienylmethylamide N- (t-BuOOC-CH ₂ ) -NH-D-Phg-Dhp-2- (4-amidoximo) -thienylmethylamide

List of abbreviations: Aze: Azetidincarbonsäure Boc: tert. -Butoxycarbonyl t-Bu: tert-butyl Cbz benzyloxycarbonyl

Cha cyclohexylalanine Chg cyclohexylglycine Dep 4, 5-dehydropipecolic acid Dhp 3, 4 dehydroproline Phe phenylalanine Phg phenylglycine pro proline

The amidines are preferably synthesized by the process according to the invention by converting the carboxamide oximes into an acetic acid solution, where they are reacted by adding metallic zinc, which is usually used as a fine powder. The reaction is usually carried out in a pure acetic acid solution. However, it is also possible to carry out the reaction in, for example, propionic acid solution or in a solvent mixture. For example, alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol are suitable. The zinc is used in excess of up to 10 equivalents. The reaction can be carried out in a temperature range from -10 ° C to 70 ° C, a temperature range between 20 and 50 ° C is preferred. The conversion can be checked by means of thin layer chromatography. A reaction time of 2 to 5 hours is usual. But it is also possible to stir at 20 ° C for a long time.

Refurbishing is easy. Excess zinc and the resulting zinc salts are filtered off and concentrated. The reaction products can either be isolated and characterized at this stage or can be directly implemented further. In particular, the elimination of any protective groups such as tert-butyl ester or N-tert. -Butoxycarbonyl groups can advantageously be carried out after the solid Zn residues have been separated off without intermediate isolation.

Reductions of carboxamide amides with Zn to amidines have not yet been described. Compared to the known reduction of carbaldoximes with Zn to aminomethylene compounds (GD Pandey et al. Indian J. Chem. Sect. B 1980, 19, 160; E. Testa et al. Chimia 1957, 11, 310; S. Negi et al. Synthesis , 1996, 991) it is surprising that the N, O bond can be cleaved by the process according to the invention without reducing a C, N double bond present in the same structural element.

The following examples serve to illustrate the method according to the invention.

example 1

Synthesis of 2-N-Boc-aminomethyl- (4-amidino) thiophene

a) 2-N-Boc-aminomethyl- (4-amidoximo) -thiophene

70 g (294 mmol) of 2-N-Boc-aminomethyl- (4-cyano) thiophene were initially charged together with 51.1 g ((735 mmol) of hydroxylammonium chloride in 700 ml of ethanol. The mixture was then between 20 ° C. and 30 ° C. 113.8 g (882 mmol) of diisopropylethylamine were added and the mixture was subsequently stirred at 20 ° C. to 30 ° C. For working up, the ethanol was distilled off in vacuo, and the residue was taken up in 1000 ml of methylene chloride (CH ₂ C1 ₂ ) The organic phase was washed once with 500 ml and a second time with 250 ml of water After the organic phase had been concentrated, the product was precipitated by adding methyl tert-butyl ether (MTBE). Weight: 78 g

"C-NMR (DMSO; ppm): 148.3 (amidoxime) CnHι ₇ N ₃ 0 ₃ S (271.34); calculated: (M + H) ⁺ = 272; found: (M + H) ⁺ = 272

b) 2-N-Boc-aminomethyl- (4-amidino) -thiophene

5 g (18.4 mmol) of the carboxamide produced according to a) were dissolved at 20 ° C. in a mixture of 25 ml of acetic acid and 25 ml of methanol. Subsequently, 2.4 g (36.9 mmol) of zinc powder were added in portions while the internal temperature rose to 30-35 ° C. After stirring for a further 12 h at 25 to 40 ° C, no more starting product was detectable by TLC (CH ₂ C1 ₂ / methanol 9: 1). After filtering off the solids, the filter residue was washed with methanol. The collected filtrates were concentrated at about 50 ° C. in vacuo. The residue was dissolved in CH ₂ C1. The CHC1 ₂ phase was washed with water, which was adjusted to pH 12 with sodium hydroxide solution. After the phase separation, the water phase was re-extracted with CH ₂ C1 ₂ . The combined CH ₂ C1 ₂ phases were washed neutral and concentrated. Weight: 2.4 g solidified foam I3c-NMR (DMSO; ppm): 158.8 (broadened, amidine)

CnHιN ₃ 0 ₂ S (255.34); calculated: (M) ⁺ = 255; found: (M) ⁺ = 255 Example 2

Synthesis of N-Boc-3, 4-dehydroprolyl-2- (4-amidino) thienylmethylamide

a) N-Boc-3, 4-dehydroprolyl-2- (4-amidoximo) thienylmethylamide

50 g (177 mmol) of N-Boc-3, 4-dehydroprolyl-2- (4-cyano) thienylmethylamide were placed in 590 ml of ethanol together with 30.8 g ((442.5 mmol) of hydroxylammonium chloride 113.8 g (882 mmol) of diisopropylethylamine were added between 20 ° C. and 30 ° C. and the mixture was subsequently stirred at 20 ° C. to 30 ° C. for 12 hours, after which the conversion was 9: 1 according to TLC (CH ₂ C1 / methanol) For working up, the ethanol was largely distilled off in vacuo. The residue was taken up in 120 ml of CH ₂ C1 _2. The organic phase was washed with 180 ml of water. The water phase was extracted once with 60 ml of CHC1 _2. The combined CH ₂ C1 phases were washed again with 30 ml of water, filtered and concentrated. Weighed out: 66.3 g of solidified foam. ¹³ C-NMR (DMSO; ppm): 147.9 (amidoxime)

Cι ₆ H ₂₂ N ₄ 0 ₄ S (366.44); calculated: (M + H) ⁺ = 367; found: (M + H) ⁺ = 367

b) N-Boc-3,4-dehydroprolyl-2- (4-amidino) thienylmethylamide

41.4 g (113 mmol) of the carboxylic acid amidoxime prepared according to a) were dissolved in 400 ml of acetic acid at 40 ° C. Subsequently, an internal temperature of max. 50.1 ° C in portions 41.1 g (630 mmol) of zinc powder. After 2.5 h of stirring at 25 to 40 ° C was after TLC

(CHC1 / methanol 9: 1) no longer recognizable as a starting product. After filtering off the solids, the filter residue was washed with acetic acid. The collected filtrates were concentrated in vacuo at about 50 ° C. and distributed between 180 ml of MTBE and 370 ml of water. The water phase was with

Sodium hydroxide solution adjusted to pH 7. After the MTBE phase had been separated off, 180 ml of CHC1 _{2 were} added and the water phase was adjusted to pH 12 using sodium hydroxide solution. After the CH ₂ C1 ₂ phase had been separated off, it was extracted twice with 150 ml of CHC1. The combined CH ₂ C1 phases were washed once with water and concentrated. Weight: 34.6 g of solidified foam. 13 C-NMR (DMSO; ppm): 159.9 (amidine) -C ₆ H ₂₂ N ₄ θ ₃ S (350.44); calculated: (M + H) ⁺ = 351; found: (M + H) ⁺ = 351 Example 3

Synthesis of N- (t-butoxycarbonylmethylene) -N-Boc-D-Chg-3,4

Dehydroprolyl-2- (4-amidino) thienylmethylamide

a) N- (t-Butoxycarbonylmethylene) -N-Boc-D-Chg-3,4-dehydroprolyl- 2- (4-amidoximo) thienylmethylamide

365.8 g (0.623 mol) of N- (t-butoxycarbonylmethylene) -N-Boc-D-Chg-3,4-dehydroprolyl-2- (4-cyano) thienylmethylamide were combined with 108.3 g (( 1.559 mol) of hydroxylammonium chloride are introduced in 1.83 1 of ethanol, then 241.3 g (1.870 mol) of diisopropylethylamine were added between 20 ° C. and 30 ° C. and the mixture was subsequently stirred at 20 ° C. to 30 ° C. for 12 h according to TLC (CH ₂ C1 ₂ / methanol 9: 1) completely. For working up, the ethanol was largely distilled off in vacuo. The residue was taken up in 730 ml of MTBE. The MTBE phase was washed once with 1.1 l of water, the The combined MTBE phases were washed again with 180 ml of water and then dried at 0.5 bar by azeotropic distillation and concentrated to a residual volume of 730 ml 2.2 l of petroleum ether (60/40) precipitated and dried in a drying cabinet at 50 ° C. for 12 hours, weighed out: 371.5 g of leic ht yellow to colorless powder ¹³ C-NMR (DMSO; ppm): 147.9 (amidoxime)

C ₃ O ₄₅ N ₅ 0 ₇ S (619.79); calculated: (M + H) ⁺ = 620; found: (M + H) + = 620

b) N- (t-Butoxycarbonylmethylene) -N-Boc-D-Chg-3, 4-dehydroprolyl- 2- (4-amidino) -thienylmethylamide, acetic acid salt

5 g (8.1 mmol) of the carboxamide amideoxime prepared according to a) were dissolved in 50 ml of acetic acid at 30 ° C. Subsequently, 2.9 g (44.4 mmol) of zinc powder were added in portions at an internal temperature of 50 to 55 ° C. After a subsequent stirring time of 2 h at approx. 50 ° C, no more starting product was detectable by TLC (CH ₂ C1 ₂ / methanol 9: 1). After filtering off the solids, the filter residue was washed with acetic acid. The collected filtrates were concentrated at about 50 ° C in a vacuum.

Weight: 4.3 g light yellow to colorless powder ¹³ C-NMR (DMSO; ppm): 159 (broadened, amidine), 1H-NMR (DMSO; ppm): 1.87 (CH ₃ C0 ₂ -) C ₃₀ H ₄₅ N ₅ O ₆ S (603.79); calculated: (M + H) ⁺ = 604; found: (M + H) ⁺ = 604 N- (-Butoxycarbony1-methylene) -N-Boc-D-Chg-3, 4-dehydroprolyl- 2- (4-amidino) thienylmethylamide, base

62 g (100 mmol) of the carboxylic acid amidoxime prepared according to a) were dissolved in 620 ml of acetic acid at 35 ° C. 36 g (550 mmol) of zinc powder were then added in portions at an internal temperature of 35 to 40 ° C. After a subsequent stirring time of 4 h at approx. 40 ° C, no more starting product was detectable by TLC (CHCl ₂ / methanol 9: 1). After filtering off the solids, the filter residue was washed with acetic acid. The collected filtrates were concentrated at about 50 ° C. in vacuo and distributed between 200 ml MTBE and 410 ml water. The water phase was adjusted to pH 7 with sodium hydroxide solution. After the water phase had been separated off, the MTBE phase was extracted twice with 200 ml of water and discarded. The combined water phases were then adjusted to pH 12 with sodium hydroxide solution and extracted twice with 330 ml of MTBE each. The combined MTBE phases were dried at approx. 0.7 bar by azeotropic distillation and concentrated to a residual volume of approx. 270 ml. The product is precipitated by dropping the MTBE solution in 740 ml of n-heptane and dried in a drying cabinet at 50 ° C. for 12 hours. Weight: 57.2 g light yellow to colorless powder C ₃ oH ₄₅ N ₅ 0 ₆ S (603.79); calculated: (M + H) + = 604; found: (M + H) ⁺ = 604

Claims

claims

1. Process for the preparation of amidines and their salts not substituted on nitrogen with inorganic or organic acids, corresponding carboxamide amide oximes being reacted with Zn in the presence of carboxylic acids.

2. The method according to claim 1 for the preparation of substituted aryl or heteroarylamidines, in particular thienyl amidines.

3. The method according to claim 1 for the preparation of substituted thienylamidines, wherein the thienylamide group is a structural fragment of a medicament.

4. The method according to claim 1 for the preparation of substituted thienylamidines of the formula I.

where n = 1-3 and

R can have the following meanings

C ₁ -C ₆ alkyl CO,

-C ₆ alkoxy-CO,

Benzyloxy,

Aryl or heteroaryl, where these aromatics can optionally be further substituted one or more times,

an oc-amino acid fragment in the R or S configuration, the N atom of which is protected or unprotected in the usual manner, a dipeptide fragment, optionally substituted one or more times at the N-terminus, consisting of the natural amino acids, the corresponding D-amino acids or the very similar amino acids in the L or D form,

produce,

characterized in that carboxamide of formula II

in which n and R have the same meaning as in formula I, reacted with Zn in the presence of a carboxylic acid.

5. The method according to any one of claims 1 to 4, wherein the carboxylic acid is acetic acid.

6. Compounds of formula II according to claim 4.