SI9500140A - Novel n-sulfoxy anhydrides, process for the preparation thereof and its use for the preparation of bioactive substances having ace inhibitory action - Google Patents

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

CENTRO GENESIS PARA LA INVESTIGACION, S.L.

New N-sulfoxy anhydrides, a process for their preparation and their use for the preparation of bioactive agents with ACE inhibitory activity

FIELD OF THE INVENTION

The invention is in the field of chemical synthesis and relates to novel N-sulfoxy anhydrides, to a process for their preparation and to their use for the simple and inexpensive preparation of bioactive substances with ACE inhibitory action.

A technical problem

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

The state of the art

Two types of process are most commonly used to prepare ACE inhibitors. The first is reductive amination, which, however, is difficult on an industrial scale and is described in US 4,374,829.

For the second type, however, it is used as a reactant, e.g. N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl-N-carboxy-anhydride (NCA; see formula (II) below). EP 0 215 335 A2 describes the reaction of N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine of formula (I)

with phosgene and its polymers to form N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl-N-carboxy-anhydride (NCA) of formula (II)

II (NCA) which reacts with the salts and esters of L-proline in enalapril.

The preparation of active NCA is also described in EP 114 067, which describes the reaction of phosgene with an amino acid (I). EP 61768 A1 describes the preparation of NCA (II) by the reaction between amino acid (I) and carbonyl diimidazole (CDI). The preparation of NCA has also been described in EC 2004804. The resulting NCA (II) is reacted with silylated L-proline (YU patent application 1355/88) and unsilylated L-proline (SI patent 9200213) in enalapril or. enalapril maleate, which is an interesting ACE inhibitor.

In all the described cases of amino acid (I) activation, they use toxic phosgene, phosgene polymers (diphosgene, triphosgene) or phosgene derivatives, such as CDI, which can only be produced by rare phosgene producers. The use of CDI for the activation of amino acid (I) is expensive, and it is also necessary to regenerate the waste imidazole, which can only be converted back to CDI by the phosgene manufacturer.

Also, for the synthesis of trandolapril described in EP 0 088 341 and US 4,490,386, expensive carbonyl diimidazole CDI is used to activate compound (I), which is converted to the corresponding NCA (II).

Description of solution to a technical problem

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

COOEt H

R 1 - CH-NCR ₂ • II ² sc // \ / \\ ooo (III) where PhCH ^ CH ^ or CHjCt ^ CH ^ and R ₂ represents methyl or

R _{3 is} -NH- (CH ₂ ) ₃ -CH ₂ -, wherein R _{3 is an} amino protecting group, preferably CF ₃ CO-.

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

COOEt I *

Ri-CH-NH-CH— r ₂ (iv)

COOH wherein R ₁ and R _{2 have} the above meaning, is reacted with an N- (chlorosulfinyl) -heterocyclic compound of general formula (V)

O a — i ¹ - r ₄ v

wherein R _{4 represents the} residue of imidazole, alkylimidazole, benzimidazole, tetrazole and the like other heterocyclic compounds.

The compounds of general formula (IV) and (V) are commercially available or can be prepared by methods known in the literature.

The preparation of a compound of general formula (V) wherein R _{4 is a} residue of imidazole, i.e. chlorosulfinyl imidazole, e.g. described in Synthetic Communications, 10 (10), 733 742, 1980, Masaru Ogata and Hiroshi Matsumato. The reaction in dry methylene chloride between SOCl ₂ and imidazole in a ratio of 1: 4 yields N, N'-thionyldiimidazole and imidazole hydrochloride, which is filtered off. An equimole amount of thionyl chloride is added to the filtrate with Ν, tion-thionyldiimidazole to give two mole equivalents of N-chlorosulfinyl imidazole of formula (V).

The preparation of a compound of general formula (V) in which R ₄ is a benzimidazole moiety, i.e. N-chlorosulfinyl benzimidazole, is described in Synthetic Communications, 10 (7), 559 567,1980, Masaru Ogata and Hiroshi Matsumato.

The reaction between a compound of formula (IV) and a compound of general formula (V) takes place in dry organic solvents (moisture <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 a compound of formula (IV) and a compound of formula (V) is carried out at a temperature between -15 ° C and +25 ° C.

The resulting hydrochloride of a heterocyclic compound, e.g. imidazole HCl, methylimidazole HCl, benzimidazole HCl, tetrazole HCl, etc., are filtered off or filtered off. we suck. Organic bases can be regenerated and recycled.

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

a) quantitative isolation of the heterocyclic compound corresponding to the R ₄ residue, in the form of hydrochloride, in two reaction steps;

b) iodometric titration of the amount of SO ₂ formed after hydrolysis of NSA;

c) IR spectroscopy of a sample solution having characteristic absorption bands at 1820 cm ^-1 , 1750 cm ^-1 and 1030 cm ^-1 ;

d) NMR spectra containing no signals for the protons of the heterocyclic compound (V) used;

e) further reaction of NSA with silylated amino acids, thus releasing SO ₂ .

A third object of the invention is a process for the preparation of suitable ACE inhibitors, wherein the NSA (III) reacts with the corresponding derivatives of the amino acids defined below.

More specifically, the present invention is a process for the preparation of ACE inhibitors of the formula

COOEt R

I I

R, - CH - N - CH - CO - R H both in the form of racemates as well as pure stereoisomers, and their pharmaceutically acceptable salts, such as hydrochloride, maleate, sulfate, where defined as above and R having the following meanings

H

H, at \ C00H

characterized in that the compound NSA of formula III is metabolised

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

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

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

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

As inorganic salts, e.g. potassium but sodium salt.

DBU (1,8diazabicyclo [5.4.0] undec-7-ene), DBN (1,5-diazabicyclo [4.3.0] non-5-ene), TEA (triethylamine), tetramethylguanidine are preferably used as organic salts. , imidazole, methylimidazole, etc.

In the case of N- [1- (S) -ethoxycarbonol-3-phenylpropyl] L-alanine (I) amino acid, NSA- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L is obtained after activation with N-chlorosulfinimidazole. -alanyl-N-sulfoxyanhydride, which reacts with L-proline, silylated L-proline or an organic or inorganic salt of L-proline in enalapril.

If the same NSA (III) reacts with a mixture, a silylated mixture or an organic or inorganic salt of a mixture of 2S, 3aS, 7aS- and 2R, 3aR, 7aR-octahydro-1H-indole-2-carboxylic acids, a racemic mixture of SSS and RRR ACE is obtained inhibitors of the chemical name 2S, 3aS, 7aS- or 2R, 3aR, 7aR-1- {2S - [(1R-ethoxycarbonyl-3-phenylpropyl) amino] -loxopropyl} octa-hydro-1H-indole-2-carboxylic acid. If a pure isomer such as 2S, 3aS, 7aS or 2S, 3aR, 7aS is used as octahydro-1H-indole-2carboxylic acid, SSS or SRS of trandolapril is obtained (see Article J.Med.Chem. 1987,30,992-998).

For the preparation of enalapril, a novel compound of formula (III) (R _t is PhCH ₂ -CH ₂ -, R ₂ is methyl) which remains in an organic solvent such as methylene chloride after suction of the hydrochloride compound of the heterocyclic compound, such as imidazole hydrochloride, and is highly reactive , is reacted with silylated L-proline (variant a) of the process), or with an inorganic or organic salt of L-proline, as defined above (variant b) of the process), in N- [1 (Setoxycarbonyl-3-phenylpropyl] -L- high-yield alanyl-L-proline (known as enalapril) Gaseous SO ₂ is released during the reaction, which also proves the existence of a novel NSA compound of formula (III) The reaction between NSA and silylated L-proline takes place in a temperature range of -20 to + 25 ° C. This procedure is shown in Scheme 1.

In the variant b) of the process, in addition to the desired ACE inhibitors, new derivatives are formed which have the following formula VII when preparing trandolapril

COOEt CH ₃ H- «HII ³ : h ₂ -ch ₂ -CH - N — CH— CO (VII)

O = C R COOH

CH ₃ -

COOEt

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

In the NMR spectrum of compound VII, the ratio of phenyl protons to protons at site 2 in the octahydroindole moiety is 10: 1, which also confirms the assumed structure of the compound of formula (VII).

Using the compound of formula (III) as the starting material provides an economical, efficient and easy industrial process for the production of enalapril, trandolapril and other ACE inhibitors, especially if the variant a) method is used.

The use of NSA is very suitable because the condensation reaction is well under way at lower temperatures in the range of -15 ° C to +25 ° C. Imidazole and other ambivalent compounds used for NSA synthesis can be quantitatively isolated and recycled. The process is eco-friendly as most of the reactants can be regenerated and recycled.

The synthesized ACE inhibitors were recrystallized from acetonitrile or purified by conversion to ethyl acetate, yielding high purification yields (about 94%).

Scheme 1

ch ₂ q ₂ ailylated L-proline (SO2)

Scheme 2 (Case Procedure 4)

III

Silylated SRS octahydro-1H-indole-2carboxylic acid ^

CSOi)

SRS TRANDOLAPRIL

The invention is explained, but by no means limited to the following embodiments.

Example 1

Synthesis of N- [1 (S-ethoxycarbonyl-3-phenylpropyl] -L-alanyl-N-sulfoxy anhydride (NSA where R is PhCH ₂ -CH ₂ -, R ₂ is methyl)

To 7 ml of anhydrous methylene chloride (Karl Fischer water content <0.04%), 0.18 ml of SOCl ₂ (0.0025 mol) was added and the mixture cooled to -10 ° C, then 0.68 g (0.01 mol) was added. ) of imidazole. With stirring for 60 minutes, the temperature gradually rises to 15 ° C. The precipitated precipitate of imidazole hydrochloride was filtered off and washed with 5 ml of dry CH ₂ Cl ₂ to give 0.58 g of the dry salt of imidazole hydrochloride. The mother liquor was cooled again to -10 ° C and 0.18 ml (0.0025 mol) of thionyl chloride was added. The solution was stirred for 60 minutes at -10 ° C to +15 ° C. Then 1.25 g (0.0045 mol) of N- [1 (S-ethoxycarbonyl-3-phenylpropyl] -L-alanine and 16 ml of CH ₂ Cl _{2 were added} . After stirring for 65 minutes (temperature increased from -15 ° C to + 25 ° C) filter the precipitate and wash with 5 ml of methylene chloride to give 0.51 g of dry salts of imidazole hydrochloride Imidazole hydrochloride can be regenerated and recycled after both filtrations The mother liquor contains the new compound N- [1 (Setoxycarbonyl-3 -Phenylpropyl] -L-alanyl-N-sulfoxy-anhydride or NSA to be analyzed NSA is an oily, moisture and air insoluble oily liquid with a molecular weight of 325, determined by an iodometric titration according to the following scheme:

2H ₂ O + SO ₂ + I ₂ - * 21- + SO ₄ ² '+ 4H ⁺

I ₂ in excess is determined by titration with thiosulphate:

And ₂ + 2S, O? - 21- + s ₄ o; 11

IR absorption cm ' ¹

1820 cm -1

1750 cm ¹

1030 cm - ¹

The NSA thus prepared can be used as a starting material for the synthesis of ACE inhibitors.

Example 2

Synthesis of N- [1 (S-Ethoxycarbonyl-3-phenylpropyl] -L-alanyl-L-proline maleinate

a) Preparation of silylated L-proline

A mixture of 2.47 g (0.0215 mol) of L-proline, 90 ml of anhydrous methylene chloride and 2.5 ml of triethylamine (0.018 mol) was added 5.7 ml (0.045 mol) of trimethylchlorosilane and the mixture was stirred for 2 hours.

b) To the mixture of 25 ml of dry methylene chloride (H ₂ O <<0.04%, 0.73 ml (0.01 mol) of thionyl chloride is added and the mixture is cooled to -5 ° C. Then 2.72 g (0.04 mol) is added. It is stirred for 65 minutes at a temperature between -5 ° C and room temperature 20 ° C. Then the filtered imidazole hydrochloride is filtered off and washed with 5 ml of methylene chloride (yield 2.09 g of dry imidazole hydrochloride). 73 ml (0.01 mol) of thionyl chloride and the mixture was stirred for 60 minutes between -5 ° C and +20 ° C. The reaction mixture was again cooled to -15 ° C and 5 g (0.0179 mol) of N- [1 (S -ethoxycarbonyl-3-phenylpropyl] -L-alanine and 65 ml of methylene chloride The mixture was stirred for 65 minutes, raising the temperature to 20-25 ° C.

Silylated L-proline was added to the reaction mixture containing only NSA. The acylation control is performed by IR spectroscopy, where it is found that the -C = O- vibration at 1820 cm ^-1 disappears. The reaction is complete within a few hours depending on the reaction temperature. The light yellow solution was then rotavaped and the solvent removed, 36 ml of water, 12 g of NaCl and 18 ml of ethyl acetate were added to the residue. The pH of 2.66 was changed to pH 4.22 with 33% NaOH. Separate the organic phase and extract the aqueous phase twice with 10 ml of ethyl acetate. The combined ethyl acetate was dried with anhydrous sodium sulfate, which was filtered off with suction and washed twice with 10 ml of ethyl acetate each and then added 14 ml of methyl acetate. 2.14 g (0.01844 moles) of maleic acid were added. The mixture was stirred at room temperature for 20 minutes and then at -25 ° C for 20 minutes. The precipitate was filtered off, washed with ethyl acetate to give 7.8 g of enalapril maleate (88% yield), m.p. 144-146 ° C (in literature 143-144,5 ° C), [α] _2θ ° 1% MeOH -44,16 (in literature -42,2).

Example 3

Synthesis of SSS trandolapril

7 ml of anhydrous methylene chloride and 0.18 ml (0.0025 mol) of SOCl _{2 are} mixed. The solution was cooled to -5 ° C and 0.68 g (0.01 mol) of imidazole (white suspension) was added. The system was stirred for 1 hour, allowing the temperature to rise from -5 ° C to room temperature. It is then filtered and the solid is washed with 5 ml of CH ₂ C1 _{2> The} liquid is cooled to -5 ° C and 0.18 ml of SOC1 _{2 is added} , stirring the system for 1 hour and allowing the temperature to rise from -5 ° C to room temperature temperature. The system was then cooled to -15 ° C and 1.25 g of N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine (0.0045 moles) and 16 ml of anhydrous CH ₂ Cl _{2 were added} . The system was stirred for 65 minutes, allowing the temperature to rise from -15 ° C to room temperature. The solid was then filtered and washed with 5 ml of anhydrous CH ₂ Cl ₂ . An opalescent solution A (preparation described below) of silylated (2S, 3aS, 7aS) -octahydro-1H-indole-2carboxylic acids was added to the filtrate to give an opalescent yellow solution. This solution was stirred for 1 to 6 hours at room temperature (21 ° C). Then a solution of 10 ml of H ₂ O and 3 g of NaCl was added and 35% HCl was added to pH 0.8. Decant and wash the organic phase with 5 ml of water. A solution of 10 ml of H ₂ O and 3 g of NaCl was added to the organic phase and 33% was added

NaOH to pH 4.33. The aqueous phase was then decanted and washed with 5 ml of CH ₂ Cl ₂ . The organic phase was dried with anhydrous Na ₂ SO ₄ , filtered and evaporated on a rotary evaporator. After evaporation of CH ₂ Cl _2, about 20 ml of methyl tert-butyl ether is added and evaporated again on a rotary evaporator. 1.94 g of 2S, 3aS, 7aS-1 {2S - [(1R-ethoxycarbonyl-3-phenylpropyl) amino] -1-oxopropyl} octahydro-1H-indole-2-carboxylic acid (trandolapril base) is obtained in 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 C ₂₄ H ₃₄ N ₂ O ₅ :

% H % C % N 7.96 66.95 6.51 8.13 66.55 6.31

Preparation of solution A

0.90 g (2S, 3aS, 7aS) -octahydro-1H-indole-2-carboxylic acid (0.0053 mol) is mixed with 25 ml of anhydrous CH 2 Cl 2 0.73 ml of triethylamine (0.0053 mol) and 0 , 67 ml (CH 2 SiCl (0.0053 mol). The system was stirred for 1.5 to 2 hours at room temperature (21 ° C).

Example 4

Synthesis of SRS trandolapril

Proceed as in Example 3 except that the 2S, 3aR, 7aS isomer is taken instead of the SSS octahydro-1H-indole-214 carboxylic acid. 1.72 g of SRS trandolapril 2S, 3aR, 7aS-1 {2S - [(1R-ethoxycarbonyl-3-phenylpropyl) amino] -1-oxopropyl} octahydro-1-H-indole-2-carboxylic acid are obtained from m.p. 140-143 ° C.

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

Mix 0.5 g (0.00116 mol) of trandolapril obtained in Example 3 and 10 ml of methyl tert-butyl ether to give a yellow solution. To this solution was added 0.5 ml (0.00036 mol) of sulfuric acid solution in 1 hour (this solution was obtained by diluting 1 ml of 96% sulfuric acid to 25 ml with methyl tert-butyl ether) at room temperature (22 ° C). and with good mixing. 0.3 ml (0.000216 moles) of the above sulfuric acid solution were added at -15 to -20 ° C for 20 minutes. The system was filtered at -20 ° C and the solid was washed with 5 ml of methyl tert-butyl ether at -20 ° C. 0.41 g of beige solid is obtained, which is trandolapril sulfate, in a yield of 74.5%, m.p. 86 to 90 ° C.

Example 6

Synthesis of trandolapril hydrochloride

Mix 0.5 g (0.00116 mol) of trandolapril obtained in Example 3 and 10 ml of methyl tert-butyl ether to give a yellow solution. This solution is cooled to -15 to -20 ° C and gas HC1 is passed through. The title product begins to turn. Since the suspension is very dense, 3 ml of methyl tert-butyl ether is added and gas HC1 is passed through (HC1 gas is introduced for a total of 5 to 10 minutes). The system was stirred at -15 to -20 ° C for another 10 minutes and then filtered at this temperature. The solid was washed with 5 ml of methyl tert-butyl ether at -20 ° C. 0.43 g of a beige solid, which is trandolapril hydrochloride, is obtained in a yield of 80%, m.p. 105-110 ° C.

Example 7

Synthesis of trandolapril (process variant b)

0.9 g (0.0053 mol) of a racemic mixture of 2S, 3aS, 7aS and 2R, 3aR, 7aR octahydro-1H-indole-2-carboxylic acid, 22 ml of anhydrous methylene chloride and 1.56 ml (0.0124 mol) are mixed. tetramethylguanidine (TMG). The mixture was stirred at 20 ° C for 2 hours.

The mother liquors obtained in Example 1, cooled to -5 ° C, were added some 4-N, N-dimethylaminopyridine as catalyst, and the above solution was added dropwise at -5 to 0 ° C for 15 minutes. The system was then stirred at -5 to 0 ° C for 25 minutes, then a solution of 10 ml of H ₂ O and 3 g of NaCl were added. 1N HCl was added to pH 4.21 and decanted. The aqueous phase was washed with 5 ml of methylene chloride and the final organic phase was dried with anhydrous sodium sulfate, filtered and evaporated on rotavap. A yellow solid paste is obtained. Add 15 ml of methyl, tert-butylether and evaporate again on rotavap. 2 g of a mixture of trandolapril and a compound of formula VII are obtained.

Claims (5)

1. N-sulfoxy-anhydrides of formula (III) (NSA) COOEt H Ri-CH-NCR ₂ sc OOO (ΙΠ) where R _x is PhCH ^ CH ^ or CE ^ CH ^ H ^ -, and R ^ is methyl or R _{3 is} -NH- (CH ₂ ) ₃ -CH ₂ -, wherein R _{3 is an} amino protecting group, preferably CF ₃ CO 2. Process for the preparation of N-sulfoxy-anhydrides of formula (III) according to claim 1, characterized in that the compound of formula (IV) COOEt R <—CH — NH — CH— (Π) * 1 COOH where R ₃ and R _{2 have} the above meaning, is reacted with an N- (chlorosulfinyl) -heterocyclic compound of general formula (V) Ο α - i ¹ - r ₄ in which R _{4 represents the} residue of imidazole, alkylimidazole, benzimidazole, tetrazole and the like other heterocyclic compounds, operating in dry organic solvents. 3. A process for the preparation of ACE inhibitors of the formula COOEt R ₂ R 1 - CH - N - CH - CO - R ¹ H in the form of racemates as well as pure stereoisomers, and their pharmaceutically acceptable salts, such as hydrochloride, maleate, sulfate, wherein R ₁ is as defined in claim 1 and R has the following meanings H N 'OOCH H H N • uicooH S is characterized in that the compound NSA of formula III is metabolised a) with mono- or disilylated amino acids or mixtures of mono- and disilylated amino acids selected from the group consisting of &lt; 1 &gt; OOOH at pH 2 to 6, preferably 2 to 3, or b) with inorganic or organic salts of amino acids defined as a) at a pH above 7, or c) with a free amino acid defined as in a), preferably with L-proline, and then the compounds obtained are conventionally converted into their pharmaceutically acceptable salts, such as hydrochloride, maleinate, sulfate. Process according to claim 3, characterized in that enalapril and trandolapril are prepared. Process according to claim 3 or 4, characterized in that the synthesized ACE inhibitor is purified by recrystallization from acetonitrile or by conversion to ethyl acetate.