DESC:FIELD OF THE INVENTION
The invention relates to novel compounds of the formula (I) and the process for their preparation:

wherein, R1 = H or amine protecting group;
R2 = H or carboxylic acid protecting group

BACKGROUND OF THE INVENTION
Multicomponent Reactions (MCRs) are convergent reactions, in which three or more starting materials react to form a product, where basically all or most of the atoms contribute to the newly formed product. The modified Ugi reaction described in Subhas Chandra Pan and Benjamin List, Angewandte Chemie International Edition (2008), 47 (19), 3622-5 is a multi-component reaction involving a carbonyl component (aldehyde or ketone), an amine derivative and an isocyanide derivative (also called isonitriles) that allows the rapid preparation of a-aminoacyl amide derivatives.

The present invention describe modified Ugi reaction to provide novel compounds (I), which can be effectively used for the synthesis of Quinapril (II) and pharmaceutically acceptable salts thereof.

Quinapril hydrochloride is the active pharmaceutical ingredient in ACCUPRIL® and ACCURETIC®, which are marketed by Pfizer Inc. for treating hypertension and congestive heart failure.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides novel compounds of the formula (I)

wherein, R1 = H or amine protecting group;
R2 = H or carboxylic acid protecting group
In another aspect, the present invention provides a process for the preparation of novel compounds of the formula (I, wherein R1 = H and R2 = carboxylic acid protecting group) comprising:
condensing ethyl 2-amino-4-phenylbutanoate of the formula (III) with acetaldehyde of the formula (IV) and carboxyl protected 2-isocyano-3-phenylpropanoate compound of the formula (V).

wherein, R2 is carboxylic acid protecting group.
In another aspect, the present invention further provides a process for the preparation of novel compounds of the formula (I, wherein R1 = amine protecting group and R2 = H or carboxylic acid protecting group) comprising reaction of compound (I, wherein R1 = H and R2 = H or carboxylic acid protecting group) with amine protecting agent.

DETAILED DESCRIPTION OF THE INVENTION
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.
Unless stated to the contrary, any of the words “including,” “includes,” “comprising,” and “comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
As used herein the term “Amine protecting agent” means compound containing amine protecting group and capable of reacting with primary and secondary amine functionalities with sufficient favorability (thermodynamic, kinetic or otherwise). The protecting agent used for protecting amino group is not particularly limited, and conventional agent may be used. Substituted or unsubstituted for example, an N-alkoxycarbonylating agent, an N-carbamoylating agent, an N-acylating agent, an alkylating or arylating agent may be used. More specifically an alkyl haloformate, a dicarbonic acid dialkyl ester, an isocyanatoalkyl ester, a carbonic anhydride, an alkylcarbonyl halide and an alkyl or aryl halide are preferably used. Among the examples, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, fluorenylmethyloxycarbonyl (FMOC) chloride, dicarbonic acid dimethyl ester, dicarbonic acid diethyl ester, dicarbonic acid di-tert-butyl ester, isocyanato-tert-butyl ester, isocyanatoisopropyl ester, isocyanatophenyl ester, tert-butoxycarbonyl (BOC) chloride, benzoyl chloride, benzyl chloride, methyl iodide, acetyl chloride and acetic anhydride are particularly preferably used.
As used herein the term "carboxylic acid protecting group" means a group which may be used for the protection, i.e. temporary blocking, of the oxygen functionality within a carboxylic acid. Examples of a suitable carboxylic acid protecting group include, but are not limited to, methyl or substituted methyl, allyl, t-butyl, benzyl or substituted benzyl and silyl. Preferably benzyl group is used as carboxylic acid protecting group.
As used herein the term “alkyl” includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, preferably methyl.
Thus, one aspect of the present invention provides novel compounds of the formula (I)

wherein, R1 = H or amine protecting group;
R2 = H or carboxylic acid protecting group
Novel compounds of the formula (I) is selected from
i) ethyl 2-((1-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino) -4-phenylbutanoate;
ii) ethyl 2-((1-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl) (methyl)amino)-4-phenylbutanoate;
iii) ethyl 2-((1-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)(tert-butoxycarbonyl)amino)-4-phenylbutanoate;
iv) ethyl 2-(benzyl(1-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-4-phenylbutanoate.
Novel compounds of the present invention can be effectively used for the synthesis of Quinapril and its pharmaceutically acceptable salts thereof.
Another aspect of the present invention provides a process for the preparation of novel compound of the formula (I, wherein R1 = H and R2 = carboxylic acid protecting group) comprising:
condensing ethyl 2-amino-4-phenylbutanoate of the formula (III) with acetaldehyde of the formula (IV) and carboxyl protected 2-isocyano-3-phenylpropanoate compound of the formula (V).

wherein, R2 is carboxylic acid protecting group.
Yet another aspect of the present invention provides a process for the preparation of novel compounds of the formula (I, wherein R1 = amine protecting group and R2 = H or carboxylic acid protecting group) comprising reaction of compound (I, wherein R1 = H and R2 = H or carboxylic acid protecting group) with amine protecting agent.
Condensation reaction to prepare compound of formula (I, wherein R1 = H and R2 = carboxylic acid protecting group) can be efficiently carried out in a suitable solvent. Suitable solvent used for the above condensation reaction is selected from the group comprising of polar protic solvent, aromatic hydrocarbon, chlorinated hydrocarbons and mixtures thereof. Polar protic solvent is selected from water, C1-C4 alcohols; aromatic hydrocarbon is selected from toluene, xylene, mesitylene; and chlorinated hydrocarbon is selected from chloroform, methylene chloride, dichloroethane, C1-C4 alcohol is selected from methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol or isobutanol. Preferably ethanol is used as solvent. The reaction can be conveniently carried out at 20-50°C.
Condensation reaction to prepare compound of formula (I, wherein R1 = H and R2 = carboxylic acid protecting group) can be more efficiently carried out in presence of catalytic amount (5-10 mole%) of boron compounds (which act as lewis acid) such as BF3, BCl3; boronic acids - e.g. arylboronic acids, their C1–C4-alkyl esters and also C1–C6-alkylboronic acids and their C1-C4-alkyl esters, cyclic boric esters (especially tris(C1–C4-alkoxy)boroxin), boric acid tri(C1–C4-alkyl) esters, boric anhydride, borate (especially sodium borate/borax), and boric acid (H3BO3). More preferably sodium borate is used.
The amine group of compound (I, wherein R1 = H and and R2 = H or carboxylic acid protecting group) is optionally converted to its salt, for example hydrochloride salt, para-toluene sulfonic acid salt or optionally protected with a suitable protecting group by treating with a suitable amino protecting agent in presence of a base and solvent. The base is selected from triethylamine, diisopropylethylamine, 1 ,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4- diazabicycIo[2.2.2]-octane (DABCO), pyridine or 4-(dimethylamino)pyridine (DMAP), preferably DMAP, and the solvent is selected from polar aprotic solvents such as acetone, tetrahydrofuran, methyl ethyl ketone, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide. The protection can be carried out by following the procedure, as described in Theodora W. Greene and Peter G. M. Wuts, "Protecting Groups In Organic Synthesis," third edition, John Wiley and Sons, New York. N.Y.
The compounds of the formula (I, wherein, R1 = H or amine protecting group and R2 = H or carboxylic acid protecting group) can be converted to Quinapril of the formula (II) or its pharmaceutically acceptable salts by Pictet-Spengler reaction of compound of formula (I) to give compound of formula (Ia) followed by deprotection of amine and carboxylic acid protecting group, if any, in any order or simultaneously as depicted in below scheme.

wherein, R1 = H or amine protecting group;
R2 = H or carboxylic acid protecting group
Pictet-Spengler reaction of compound (I) can be efficiently carried out with paraformaldehyade in presence of acid catalyst and a suitable solvent. Acid catalyst is selected from para-toluene sulfonic acid, trifluoro methanesulfonic acid, trifluoro acetic acid, ethanolic.HCl and solvent is selected from group comprising of hydrocarbons like toluene, xylene, 1,3-dioxalane, ethoxy ethane; chlorinated solvents like chloromethyl methyl ether, dichloromethane, chloroform, methylene chloride. Preferred solvent is toluene.
The compounds of the formula (I) in the salt form (when R1 = H and R2 = H or carboxylic acid protecting group) can also be converted to Quinapril of the formula (II) or its pharmaceutically acceptable salts by the above method.
A wide range of procedures exists for removing amine- and carboxyl-protecting groups. Thus, for example an amine-protecting group may be removed by acidoloysis, hydrogenolysis, treatment with dilute ammonium hydroxide, treatment with sodium, treatment with sodium amide, treatment with hydrazine, or enzymatic hydrolysis. The removal of carboxyl protecting groups may, for example, be effected by saponification, acidolysis, hydrogenolysis or enzymatic hydrolysis.
One method of selective deprotection is, for example, (when R1=R2=benzyl) catalytic hydrogenation, conveniently using palladium on carbon, as the catalyst and conveniently in the presence of a solvent e.g. water, methanol, dioxane, acetic acid or t-butanol.
The novel compounds (I) obtained by the above-described processes can be isolated and purified by physical methods (such as distillation, crystallization and chromatography) or by chemical methods (such as the formation of salts followed by the regeneration).

Example 1: Preparation of ethyl 2-((1-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-4-phenylbutanoate (I, R1=H, R2=Benzyl)
1 ml of ethanol was added to a mixture of 1 gm ethyl 2-amino-4-phenylbutanoate and 0.2 gm acetaldehyde and the reaction mas was stirred for 20-30 minutes. To the above reaction mass was added 1.27 gm benzyl 2-isocyano-3-phenylpropanoate, 4 ml of ethanol and 10 mole % of sodium borate, and further stirred the reaction for 24 hrs at 25-30°C. The solvent was evaporated and then 10 ml of ethyl acetate was added. To above mass was added 10 ml brine solution. The organic layer was separated and evaporated to give 2.0 gm title compound as oil which was purified by column chromatography (100-200 mesh Size silica gel, Solvent system: Ethyl Acetate and Hexane, Staining Reagent: KMnO4 solution) to give 0.4 gm of pure title compound as oil.
Analysis:
(M+H) : 517.40 m/z
Infrared Spectroscopy: 1182, 1455, 1604, 1738, 3030, 3368 cm-1
1H NMR :
1H chemical shift
(d ppm) Multiplicity
1.264-1.31 (6H) m
1.743 (3H) m
2.436-2.637 (2H) d
2.974-3.276 (4H) m
4.133-4.157 (2H) q
4.872-4.945 (1H) t
5.161 (2H) s
7.018-7.349 (15H) m
7.681 (1H) s

Example 2: Preparation of ethyl 2-((1-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)amino)-4-phenylbutanoate (I, R1=CH3, R2=Benzyl)
3 ml of DMF was added to 1 gm of compound (I, R1=H) followed by addition of 0.2 gm Na2CO3 and 0.27 gm methyl iodide and was stirred for 10 hrs at 25-30°C. The solvent was evaporated and then 10 ml of ethyl acetate was added and stirred. To above mass was added 10 ml brine solution. The organic layer was separated, dried on Na2SO4 and evaporated to give 1.3 gm title compound as oil which was purified by column chromatography (100-200 mesh Size silica gel, Solvent system: Ethyl Acetate and Hexane, Staining Reagent: KMnO4 solution) to give 0.5 gm of pure title compound as oil.
Analysis:
(M+H) : 531.45 m/z
1H NMR:
1H chemical shift
(d ppm) Multiplicity
1.167-1.290 (6H) m
1.785-1.842 (1H) q
1.950-2.002 (1H) q
2.122-2.178 (3H) d
2.473-2.543 (2H) t
3.073-3.260 (3H) m
3.391-3.436 (1H) q
4.106-4.159 (2H) q
4.860-4.911 (1H) t
5.076-5.207 (2H) m
7.014-7.378 (15H) m
7.634-7.654 (1H) d

Example 3: Preparation of ethyl 2-((1-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)(tert-butoxycarbonyl)amino)-4-phenylbutanoate (I, R1=t-BOC, R2=Benzyl)
10 ml of THF was added to 0.5 gm of compound (I, R1= H) followed by addition of 0.006 gm 4-DMAP. The reaction mixture was cooled to 0-5°C and then 0.23 gm Di-tert-butyl dicarbonate was added and stirred at 25-30°C. 10 ml of water was added and title compound was extracted in 10 ml ethyl acetate and evaporated to give 0.8 gm title compound as oil.
Example 4: Preparation of ethyl 2-(benzyl(1-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-4-phenylbutanoate (I, R1= R2=Benzyl)
5 ml of DMF was added to 0.5 gm of compound (I, R1= H) followed by addition of 0.26 gm Na2CO3 and 0.18 gm benzyl bromide, reaction mixture was then heated and stirred at 45-50°C. The reaction mass was then filtered and title compound was extracted in ethyl acetate, ethyl acetate layer was washed with water, dried on Na2SO4 and evaporated to give 0.7 gm title compound as oil.
Example 5: Preparation of benzyl 2-(N-(1-ethoxy-1-oxo-4-phenylbutan-2-yl)-N-methylalanyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Ia, R1=CH3, R2=Benzyl)
50 ml of toluene was added to 1 gm of N-methylated compound (Example 2) followed by addition of 1 gm of paraformaldehyde and 0.18 gm of para-toluene sulfonic acid monohydrate, the reaction mixture was heated to 110-120°C for 9-12 hrs, reaction mass was then cooled to room temperature and then washed with 10% NaHCO3 solution, organic layer was collected, dried over Na2SO4 and evaporated to give 1.2 gm of title compound which was purified by column chromatography (100-200 mesh Size silica gel, Solvent system: Ethyl Acetate and Hexane, Staining Reagent: KMnO4 solution) to give 0.5 gm of pure title compound as oil.
Analysis:
(M+H) : 543 m/z
1H NMR:

1H chemical shift
(d ppm) Multiplicity
1.139-1.331 (6H) m
1.896-2.140 (2H) m
2.216
2.389 (1H) s
(2H) s
2.561-2.600 (2H) t
3.092-3.147 (1H) t
3.241-3.382 (2H) t
3.789-3.806 (1H) q
3.905-3.938 (2H) q
4.521-4.624
4.913-4.955 (1H) d
(1H) d
5.031-5.102 (2H) m
5.454-5.477 (1H) t
6.947-7.282 (14H) m

Example 6: Preparation of 2-((1-ethoxy-1-oxo-4-phenylbutan-2-yl)alanyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride [Quinapril hydrochloride] from Ia (R1=CH3, R2=Benzyl)
30 ml of dichloroethane was added to 1 gm of 1,2,3,4-tetrahydroisoquinoline-3-carboxylate compound (Example 5) followed by addition of 0.3 gm of K2CO3 and 0.24 gm of ethyl chloroformate dropwise, the reaction mixture was refluxed for 2-4 hrs, then cooled to 10-20°C and 20% aq ammonia was, organic layer was collected and washed with water and brine, dried over Na2SO4, organic layer was evaporated to 1.5 gm of residue, to this residue 50 ml of ethanolic hydrochloride was added and reaction was refluxed for 4 hrs and then evaporated to give residue (2.5 gm) which was dissolved in dichloromethane, pH was adjusted to 7 by saturated NaHCO3, organic layer was evaporated to give 1.5 gm of N-demethylated compound (Ia, R1=H, R2=Benzyl) which was purified by column chromatography (100-200 mesh Size silica gel, Solvent system: Ethyl Acetate and Hexane). 30 ml of ethanol was added to 1.0 gm of N-demethylated compound (Ia, R1=H, R2=Benzyl), followed by 0.1 gm of Pd-C, 6 gm of 35% HCl, applied H2 gas (40-60 psi), reaction was stirred for 5 hrs, filtered on celite bed and washed with 10 ml of ethanol, filtrate was evaporated and crystallised from methyl ter-butyl ether or mixture of toluene and ethyl acetate, filtered and dried under vacuum to give 0.7 gm of title compound.
,CLAIMS:1. Novel compounds of the formula (I)

wherein, R1 = H or amine protecting group;
R2 = H or carboxylic acid protecting group
2. Novel compounds of claim 1, wherein the compound is selected from:
i) ethyl 2-((1-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-4-phenylbutanoate;
ii) ethyl 2-((1-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)amino)-4-phenylbutanoate;
iii) ethyl 2-((1-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)(tert-butoxycarbonyl)amino)-4-phenylbutanoate;
iv) ethyl 2-(benzyl(1-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-4-phenylbutanoate.
3. A process for the preparation of novel compounds of the formula (I, wherein R1 = H and R2 = carboxylic acid protecting group) comprising:
condensing ethyl 2-amino-4-phenylbutanoate of the formula (III) with acetaldehyde of the formula (IV) and carboxyl protected 2-isocyano-3-phenylpropanoate compound of the formula (V; wherein R2 = carboxylic acid protecting group) in presence of a suitable solvent.

4. The process according to claim 3, wherein the suitable solvent is selected from the group comprising of polar protic solvent, aromatic hydrocarbon, chlorinated hydrocarbons and mixtures thereof.
5. The process according to claim 4, wherein the polar protic solvent is water, C1-C4 alcohols; aromatic hydrocarbon is toluene, xylene, mesitylene; and chlorinated hydrocarbons is chloroform, methylene chloride, dichloroethane.
6. A process for the preparation of novel compounds of the formula (I, wherein R1 = amine protecting group and R2 = H or carboxylic acid protecting group) comprising protecting the amine group of compounds of the formula (I, wherein R1 = H and R2 = H or carboxylic acid protecting group) with amine protecting agent.

7. A process for preparation of Quinapril (II) or its pharmaceutically acceptable salts comprising:

a) reaction of compound of formula (I)

wherein, R1 = H or amine protecting group;
R2 = H or carboxylic acid protecting group
with paraformaldehyde in presence of acid catalyst and a suitable solvent to give compound of formula (Ia)

b) optional deprotection of amine and carboxylic acid protecting group to give Quinapril (Ia) or its pharmaceutically acceptable salts.
8. The process according to claim 7, wherein the acid catalyst is para-toluene sulfonic acid, trifluoro methanesulfonic acid, trifluoro acetic acid.
9. The process according to claim 7, wherein the suitable solvent is selected from group comprising of hydrocarbons, chlorinated solvents and mixtures thereof.
10. The process according to claim 9, wherein the hydrocarbon is toluene, xylene, 1,3-dioxalane, ethoxy ethane; chlorinated solvent is chloromethyl methyl ether, dichloromethane, chloroform, methylene chloride.