WO1996033984A1

WO1996033984A1 - N-sulfoxy anhydrides, a process for the preparation thereof and its use for the preparation of bioactive substances having ace inhibitory action

Info

Publication number: WO1996033984A1
Application number: PCT/SI1996/000009
Authority: WO
Inventors: Sonia Serra Mortes; Alberto Palomo Coll; Rok Zupet
Original assignee: Centro Genesis Para La Investigacion, S.L.
Priority date: 1995-04-24
Filing date: 1996-04-22
Publication date: 1996-10-31
Also published as: AU5294496A; CA2203435A1; SI9500140A

Abstract

Novel N-sulfoxy anhydrides, a process for the preparation thereof and its use for the preparation of bioactive substances having ACE inhibitory action. Novel compounds of formula (III), wherein R1 represents PhCH2-CH2- or CH3CH2-CH2- and R2 represents methyl or R3-NH-(CH2)3-CH2-, wherein R3 has the meaning of amino protective group, are disclosed. They are used as intermediates in the synthesis of ACE inhibitors, especially of enalapril and trandolapril.

Description

N-sulfoxy anhydrides, a process for the preparation thereof and its use for the preparation of bioactive substances having ACE inhibitory action

Technical Field

The present invention is from the field of chemical synthesis and relates to novel N-sulfoxy anhydrides, to a process for the preparation thereof as well as to the use thereof for a simple and cheap preparation of bioactive substances having ACE inhibitory action.

Technical Problem

There was a need for a simple and industrially suitable process for the synthesis of active derivative that would be apppropriate as starting material for the synthesis of ACE inhibitors disclosed e.g. in Drugs of the future 1992. 17(7), 551-558. and others.

Prior Art

For the preparation of ACE inhibitors two types of processes are most frequently used. The first one is a reductive amination, which is difficult to be carried out on industrial scale and is disclosed in US 4.374,829.

The second type uses e.g. N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N- carboxy-anhydride (NCA; see the formula (II) below) as reactant. In EP 0215335 A2 the reaction of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine of the formula (I)

with phosgene and polymers thereof is disclosed and there is obtained N-[ 1-(S)- ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-carboxy-anhydride (NCA) of the formula (II)

which is reacted with salts and esters of L-proline to enalapril.

The preparation of active NCA is also described in EP 0114067. wherein a reaction of phosgene with amino acid (I) is disclosed. In EP 0061768 Al the preparation of NCA (II) by a reaction of amino acid (I) and carbonyl diimidazole (CDI) is disclosed. The preparation of NCA is also disclosed in ES 2004804. The NCA (II) formed is then reacted with silylated L-proline (YU patent application 1355/88) and with non- silylated L-proline (SI patent 9200213) to enalapril and enalapril maleate, resp., which is an interesting ACE inhibitor.

In all disclosed cases of activation of amino acid (I) there are used toxic phosgene, phosgene polymers (diphosgene. triphosgene) or phosgene derivatives such as CDI, which may be prepared by only a few phosgene producers. The use of CDI for activating amino acid (I) is expensive and it is also necessary to regenerate the waste imidazole. which may be converted again into CDI only by a phosgene producer.

Also in the synthesis of trandolapril disclosed in EP 0088341 and in US 4,490,386, for activating the compound (I) expensive carbonyl diimidazole CDI is used, which is converted into the corresponding NCA (II).

Technical Solution

The first object of the invention are novel N-sulfoxy anhydrides of the formula (III) (NSA)

wherein R₁ represents PhCFH₂ -CH₂- or CH₃CH₂CH₂- and R₂ represents methyl or R₃-NH-(CH ₂) ₃-CH₂,-, R₃ being an amino protecting group, preferably CF₃CO-.

The second object of the invention is a process for the preparation of novel N-sulfoxy anhydrides of the formula (III), characterized in that a compound of the formula (IV)

wherein R₁ in R₂ have the above meanings,

is reacted with an N-(chlorosulfinyl)-heterocyclic compound of the general formula

(V)

wherein R₄ represents the rest of imidazole, of alkyl imidazole, of benzimidazole, of tetrazole and of similar other heterocyclic compounds.

Compounds of the general formulas (IV) and (V) are commercially available or may be prepared according to processes known from the literature.

The preparation of the compound of the general formula (V), wherein R₄ is an imidazole rest. i.e. chlorosulfinyl imidazole, is disclosed e.g. in Synthetic Communications. 10 ( 10), 733-742. 1980, Masaru Ogata and Hiroshi Matsumato. In the reaction in dry methylene chloride between SOCL, and imidazole in a 1:4 ratio there are obtained N.N'-thionyldiimidazole and imidazole hydrochloride, which is filtered off. An equimolar amount of thionylchloride is added to the filtrate with N.N'-thionyldiimidazole and two molar equivalents of N-chlorosulfinyl imidazole of the formula (V) are obtained. The preparation ot the compound of the general formula (V). wherein R₄ is a benzimidazole rest. i.e. N-chlorosulfinyl benzimidazole. is disclosed in Synthetic Communications. 10 (7). 559-567, 1980, Masaru Ogata and Hiroshi Matsumato.

The reaction between the compound of the formula (IV) and the compound ot the general formula (V) is carried out in dry organic solvents (humidity < 0.04% ). preferably in chlorinated organic solvents such as methylene chloride, or non- chlorinated organic solvents such as ethyl acetate, dimethyl carbonate, diethyl carbonate, acetonitrile etc.

The reaction between the compound of the formula (IV) and the compound ot the formula (V) is carried out at a temperature between -15°C and +25°C.

The formed hydrochloride of a heterocyclic compound, e.g. imidazole HCl . methyl- imidazole HCl , benzimidazole HCl , tetrazole HCl etc., is filtered off or sucked ott. Organic bases may be regenerated and recycled.

The pure novel compound of the formula (III) (NSA) remains in the organic solvent. The formation of the compound NSA is confirmed by

a) quantitative isolation of a heterocyclic compound corresponding to the rest R₄ in the form of hydrochloride, in two reaction steps;

b) iodometric titration of the amount of SO₂ formed after the hydrolysis of NSA; c) IR spectroscopy of the solution of a sample having characteristic absorption bands at 1820 cm^-1. 1750 cm^-1 in 1030 cm^-1;

d) NMR spectra which do not contain signals for protons of the heterocyclic compound (V) used;

e) a turther reaction of NSA with silylated amino acids under release of SO₂.

The third object of the invention is a process for the preparation of corresponding ACE inhibitors, wherein NSA (III) is reacted with corresponding derivatives ot amino acids defined below. More particularly, the object of the invention is a process for the preparation of ACE inhibitors of the formula

in racemate form as well as in the form of pure stereoisomers. and pharmaceutically acceptable salts thereof such as hydrochloride, maleinate. sulfate. wherein R₁ and R₂ are defined as above and R has the following meanings

characterized in that the compound NSA of the formula III is reacted with

a) mono- or disilvlated amino acids or with mixtures of mono- and disilvlated amino acids selected from the group consisting of

at a pH from 2 to 6, preferably 2 to 3, or

b) with inorganic or organic salts of amino acids defined as under a) at a pH over 7, or

c) with a free amino acid defined as under a), preferably with L-proline. and then the obtained compounds are converted in a conventional way into pharmaceutically acceptable salts thereof such as hydrochloride, maleinate, sulfate.

As inorganic salts e.g. potassium or sodium salts are used.

As organic salts preferably salts of DBU (1.8-diazabicyclo[5.4.0]undec-7-ene). DBN (1,5-diazabicyclo[4.3.0]non-5-ene). TEA (triethylamine). tetramethylguanidine. imidazole. methylimidazole etc. are used.

In the case of amino acid N-[ 1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine ( I ) after activation with N-chlorosulfinyl imidazole NSA N-[ 1-(S)-ethoxycarbonyl-3- phenylpropyl]-L-alanyl-N-sulfoxyanhydride is obtained, which is reacted with L-proline. siiylated L-proline or with an organic or inorganic salt ot L-proline to enalapril.

It the same NSA (III) is reacted with a mixture, a silylated mixture or w ith an organic or inorganic salt ot the mixture ot 2S,3aS,7aS- and 2R,3aR,7aR-octahydro- 1 H- indole-2-carboxylic acid, there is obtained a racemic mixture ot SSS and RRR ACE inhibitor having the chemical name 2S,3aS,7aS- or 2R.3aR,7aR-1-{2S-[( 1 R-ethoxy- carbonyl-3-phenylpropyl)amino]-1-oxopropyl }octa-hydro-1H-ιndole-2-carboxylic acid. It as octahydro-1H-indole-2-carboxylic acid a pure isomer is used such as 2S,3aS,7aS or 2S,3aR,7aS, SSS or SRS trandolapril is obtained (see J. Med. Chem. 1987, 30, 992-998).

For the preparation of enalapril the novel compound ot the formula (III) (R₁ means PhCH₂-CH₂-, R₂ means methyl), which remains in the organic solvent such as methylene chloride after sucking oft the hydrochloride ot heterocyclic compound such as imidazole hydrochloride and is very reactive, is reacted with siiylated L-proline (process variant a) or with inorganic or organic salt ot L-proline as defined above (process variant b), to N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L- prohne (known as enalapril) with a high yield. During the reaction a gaseous SO₂ is released, which also proves the existence ot the novel compound NSA ot formula (III). The reaction between NSA and silylated L-proline is carried out in the temperature range trom -20°C to +25°C. This process is shown in Scheme 1.

In the process variant b) besides the desired ACE inhibitors also novel deriv atives are formed, which in case ot the preparation ot trandolapril have the following formula VII

It may be identified with spectroscopic methods. In the mass spectrum the following signals m/z are present: 692 (M⁺. 18% ), 431 ( 100% ). 234 (78% ), 170 ( 13% ). 124 (29% ), 91 (35% ).

In the NMR spectrum of the compound VII the ratio between phenyl protons and the proton in position 2 in octahydroindole moiety is 10: 1 and thereby the suggested structure of the compound of the formula (VII) is confirmed.

The use of the compound of the formula (III) as a starting substance makes possible an economical, effective and simple industrial process for the preparation of enalapril. trandolapril and other ACE inhibitors, especially when the process variant a) is used.

The use of NSA is very convenient since the condensation reaction proceeds well already at lower temperatures in the range of from -15°C to + 25°C. Imidazole and other ambident compounds useful in the synthesis of NSA may be isolated quantitatively and recycled. The process is ecologically pure since a major part of reactants may be regenerated and recycled.

Synthetised ACE inhibitors are recrystallized from acetonitrile or are purified by reprecipitation in ethyl acetate thus achieving high yields at purification (about 94 %).

The invention is illustrated but in no way limited by the following Examples.

Example I

Synthesis of N-[ 1-(S)-ethoxycarbonyl-3-phenylprυpyl]-L-alanyl-N-sulfoxy anhydride (NSA. wherein R₁ means PhCH₂-CH₂- and R₂ means methyl)

SOCI₂ (0.18 ml: 0.0025 mole) was added to anhydrous methylene chloride (7 ml: water content according to Karl Fischer < 0.04%) and the mixture was cooled to -10°C and then imidazole (0.68 g: 0.01 mole) was added. During stirring for 60 minutes the temperature gradually increased to 15°C. The precipitate of imidazole hydrochloride was filtered off. washed with dry CH₂Cl₂ (5 ml) and a dry salt of imidazole hydrochloride (0.58 g) was obtained. The mother liquor was again cooled to -10°C and thionylchloride (0.18 ml: 0.0025 mole) was added. The solution was stirred for 60 minutes at a temperature between -10°C and +15°C. Then N-[1-(S)-ethoxy- carbonyl-3-phenylpropyl]-L-alanine (1.25 g; 0.0045 mole) and CH₂Cl₂ (16 ml) was added. After stirring for 65 minutes (the temperature increased from -15°C to +25°C). the precipitate was filtered off, washed with methylene chloride (5 ml) and a dry salt of imidazole hydrochloride (0.51 g) was obtained. After both filtrations imidazole hydrochloride could be regenerated and recycled. The mother liquor contained the novel compound N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N- sulfoxy- anhydride or NSA, which was analyzed. NSA is oily liquid, unstable in humidity and air. and has a molecular weight 325 determined by iodometric titration on the basis of the following Scheme:

2 H₂O + SO₂ + I₂→ 2I- + SO₄ ^2- + 4H⁺

Excessive I₂ was determined by titration with thiosulfate:

L₂ + 2 S₂O₃ ^2-→ 2I + S₄O₆ ^2- IR absorption cm^-1

NSA thus prepared may be used as starting material for the synthesis of ACE inhibitors.

Example 2

Synthesis of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proIine maleinate a) Preparation of siiylated L-proline

Trimethylchlorosilane (5.7 ml: 0.045 mole) was added to a mixture of L-proline (2.47 g; 0.0215 mole), anhydrous methylene chloride (90 ml) and triethylamine (2.5 ml: 0.018 mole) and the mixture was stirred for 2 hours. b) Thionylchloride (0.73 ml; 0.01 mole) was added to dry methylene chloride mixture (25 ml: H₂O < < 0.04 % ) and the mixture was cooled to AC. Then imidazole (2.72 g: 0.04 mole) was added. The mixture was stirred for 65 minutes at a temperature between -5°C and room temperature 20°C. Then the separated imidazole hydrochloride was filtered off and washed with methylene chloride (5 ml) (the yield of dry imidazole hydrochloride 2.09 g). Thionylchloride (0.73 ml: 0.01 mole) was added to the mother liquor and the mixture was stirred for 60 minutes between -5°C and + 20 °C. The reaction mixture was again cooled to -15°C and N-[ 1-(S)-ethoxy- carbonyl-3-phenylpropyl]-L-alanine (5 g; 0.0179 mole) in methylene chloride (65 ml) was added. The mixture was stirred for 65 minutes and during that time the temperature increased to 20-25°C.

Silylated L-proline was added to the reaction mixture containing only NSA. Acylation was controlled by IR spectroscopy - it was found that -C=O- vibration at 1820 cm^-1 disappeared. The reaction was completed in a few hours depending upon reaction temperature. Then the slightly yellowish solution was evaporated on rotavapor and the solvent was removed and water (36 ml). NaCl (12 g) and ethyl acetate ( 18 ml) were added to the residue. The pH 2.66 was changed to pH 4.22 with 33% NaOH. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate ( 10 ml). The combined ethyl acetate was dried with anhydrous sodium sulfate, sucked off and washed with ethyl acetate (2 x 10 ml) and then methyl acetate (14 ml) was poured thereto. Maleic acid (2.14 g; 0.01844 mole) was added. The mixture was stirred for 20 minutes at room temperature and then for 20 minutes at -25°C. The precipitate formed was filtered off, washed with ethyl acetate and there was obtained enalapril maleate (6.2 g) (yield 88%), m.p. 144-146°C (in the literature 143-144.5°C). [α]₂₀ ^D 1% MeOH -44.16 (in the literature -42.2).

Example 3

Synthesis of SSS trandolapril

Anhydrous methylene chloride (7 ml) and SOCl₂ (0.18 ml; 0.0025 mole) were blended. The solution was cooled to -5°C and imidazole (0.68 g: 0.01 mole ) was added (white suspension). The system was stirred for 1 hour and the temperature was allowed to increase from -5°C to room temperature. Then it was filtered off and solid was washed with CH₂Cl₂ (5 ml). The liquid was cooled to -5°C and additional SOCl₂ (0.18 ml) was added while stirring the system for 1 hour and allowing the temperature to increase from -5°C to room temperature. Then the system was cooled to - 15°C and N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine ( 1.25 g: 0.0045 mole) and anhydrous CH₂CI₂ (16 ml) were added. The system was stirred for 65 minutes and the temperature was allowed to increase from - 15°C to room temperature. Then it was filtered and the solid was washed with anhydrous CH₂Cl₂ (5 ml ). An opalescent solution A (the preparation thereof is disclosed below) of siiylated (2S.3aS.7aS)- octahydro- 1 H-indole-2-carboxylic acid was added to the filtrate and an opalescent yellow solution was obtained. This solution was stirred for 1 to 6 hours at room temperature (21°C). Then the solution of H₂O (10 ml) and NaCl (3 g) was added and 35% HCl was added to achieve pH 0.8. It was decanted and the organic phase was washed with water (5 ml). A solution of H₂O (10 ml) and NaCl (3 g) was added to the organic phase and 33% NaOH was added to achieve pH 4.33. Then it was decanted and the aqueous phase was washed with CH₂Cl₂ (5 ml). The organic phase was dried with anhydrous Na₂SO₄, filtered and evaporated on rotavapor. After the evaporation of CH₂ Cl₂ methyl-tert.-butylether (about 20 ml) was added and it was again evaporated on rotavapor. 2S,3aS,7aS-1 {2S-[(1R-ethoxycarbonyl-3-phenylpropyl)- amino]-1-oxopropyl}octahydro-1-H-indole-2-carboxylic acid (trandolapril base: 1.94 g) was obtained in a 100% yield, m.p. 60°C.

SSS trandolapril

IR: 1755, 1660, 1450, 1220 cm^-1

NMR: 7.14-7.32 (m, 5H); 4.46 (t. 1H); 3.95-4.22 (m. 6H): 2.25-2.4 (m. 3H): 2.05 (t.

1H): 1.4-1.85 (m, 5H); 1.31 (d, 3H): 1.23 (t. 3H); 0.9-1.35 (6H)

Mass spectrum: m/z 430 (M⁺, 2%): 429 (M⁺ - 1, 14% ): 368 (10): 357 (5): 339 (7):

308 (32); 262 (34); 234 (45); 206 (22); 160 (21): 147 (82): 117 (25); 91 (59); 73 (100); 57 (47).

Elemental analysis for C₂₄H₃₄N₂ O₅:

%H %C %N

calc: 7.96 66.95 6.51

found: 8.13 66.55 6.31

Preparation of the solution A

(2S.3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (0.90 g; 0.0053 mole ) was blended with anhydrous CH₂Cl₂ (25 ml), triethylamine (0.73 ml; 0.0053 mole) and (CH₃)₃ SiCl (0.67 ml: 0.0053 mole). The system was stirred for 1.5 to 2 hours at room temperature (21ºC).

Example 4

Synthesis of SRS trandolapril

It was proceeded in the same way as in Example 3 with the difference that instead of SSS octahydro-1H-indole-2-carboxylic acid, the 2S,3aR,7aS isomer was used. SRS trandolapril 2S,3aR,7aS-1{2S-[(1R-ethoxycarbonyl-3-phenylpropyl)amino]- 1 -oxo- propyl}octahydro-1-H-indole-2-carboxylic acid ( 1.72 g). m.p. 140-143°C. was obtained.

Spectroscopic data:

IR: 1735; 1670; 1450: 1415; 1280 cm^-1 mass spectrum (FAB) m/z: 431 (M⁺ + 1. 52%); 307 (41); 289 (22): 234 (23 ): 154

(100); 137 (89); 120 (18); 107 (27); 89 (25). 77 (21 )

Example 5

Synthesis of trandolapril sulfate

Trandolapril (0.5 g: 0.00116 mole) obtained in Example 3 and methyl-tert.-butyl ether (10 ml) were blended and a yellow solution was obtained. To this solution during 1 hour a sulfuric acid solution (0.5 ml; 0.00036 mole) (this solution was obtained in such a way that 1 ml of 96% sulfuric acid was diluted to 25 ml with methyl- tert.-butyl ether) was added at room temperature (22°C) and under good stirring. In 20 minutes another 0.3 ml (0.000216 mole) of the above sulfuric acid solution were added at - 15°C to -20°C. The system was filtered at -20°C and the solid was washed with methyl-tert.-butyl ether (5 ml) at -20ºC. A beige solid (0.41 g). which was trandolapril sulfate. was obtained with the yield 74.5%. m.p. 86 to 90 ºC. Example 6

Synthesis of trandolapril hydrochloride

Trandolapril (0.5 g; 0.001 16 mole) obtained in Example 3 and methyl-tert.-butyl ether ( 10 ml) were blended and a yellow solution was obtained. This solution was cooled at -15°C to -20°C and HCl gas was bubbled through it. The title product began to precipitate. Since the suspension was very thick, another 3 ml of methyl-tert.-butyl ether was added and HCl gas was bubbled through it (HCl gas was bubbled 5 to 10 minutes in total). The system was stirred at -15°C to -20°C for another 10 minutes and then filtered at this temperature. The solid was washed with methyl-tert.-butyl- ether (5 ml) at -20°C. A beige solid (0.43 g). which was trandolapril hydrochloride. was obtained with the yield 80%, m.p. 105 to 110°C.

Example 7

Synthesis of trandolapril (process variant b)

A racemic mixture (0.9 g; 0.0053 mole) of 2S,3aS,7aS and 2R,3aR,7aR octahydro- 1H-indole-2-carboxylic acid, anhydrous methylene chloride (22 ml) and tetramethyl- guanidine (TMG; 1.56 ml; 0.0124 mole) were blended. The mixture was stirred for 2 hours at 20°C.

To the mother liquor obtained in Example 1 and cooled to -5°C, some 4-N,N- dimethyl aminopyridine was added as a catalyst and the above solution was added drop by drop for 15 minutes at -5°C to 0°C. Then the system was stirred at -5°C to 0°C for 25 minutes and afterwards a solution of H₂ O (10 ml) and NaCl (3 g) was added. 1 N HCl was added to achieve pH 4.21 and it was decanted. The aqueous phase was washed with methylene chloride (5 ml) and finally the organic phase was dried with anhydrous sodium sulfate. filtered and evaporated on rotavapor. A yellow solid paste was obtained. Methyl-tert.-butyl ether (15 ml) was added and it was again evaporated on rotavapor. A mixture (2 g) of trandolapril and of the compound of the formula VII was obtained.

Claims

1. N-sulfoxy anhydrides of the formula (III) (NSA)

wherein R₁ represents PhCH₂-CH₂- or CH₃CH₂CH₂ - and R₂ represents methyl or R₃-NH-(CH₂)₃-CH₂-, R₃ being an amino protecting group, preferably CF₃CO-.

2. Process for preparing N-sulfoxy anhydrides of the formula (III) according to claim 1, characterized in that a compound of the formula (IV)

wherein R₁ in R₂ have the above meanings,

is reacted with a N-(chlorosultϊnyl)-heterocyclic compound of the general formula

(V)

wherein R₄ represents the rest of imidazole, of alkyl imidazole. of benzimidazole. of tetrazole and of similar other heterocyclic compounds, in dry organic solvents.

3. Process for preparing ACE inhibitors of the formula

in the racemate form as well as in the form of pure stereoisomers, and pharmaceutically acceptable salts thereof such as hydrochloride. maleinate. sulfate, wherein R₁ and R₂ are defined as in Claim 1 and R has the following meanings

characterized in that the compound NSA of the formula III is reacted with a) mono- or disilylated amino acids or with mixtures of mono- and disilylated amino acids selected from the group consisting of

at a pH from 2 to 6, preferably 2 to 3, or b) with inorganic or organic salts of amino acids defined as under a) at a pH over 7. or c) with a free amino acid defined as under a), preferably with L-proline, and then the obtained compounds are converted in a conventional way into pharmaceutically acceptable salts thereof such as hydrochloride, maleinate, sulfate.

4. Process according to claim 3. characterized in that enalapril and trandolapril are prepared.

5. Process according to claim 3 or 4. characterized in that the synthesized ACE inhibitor is purified by recrystallization from acetonitrile or by reprecipitation in ethyl acetate.