WO2001010851A1

WO2001010851A1 - Process for the preparation of lysine-carboxyanhydride intermediates in the synthesis of lisinopril

Info

Publication number: WO2001010851A1
Application number: PCT/EP2000/007743
Authority: WO
Inventors: Barbara Galbiati; Tiziano Ferrario; Valeriano Merli
Original assignee: P.F.C. Italiana S.R.L. Specialty Chemicals
Priority date: 1999-08-09
Filing date: 2000-08-09
Publication date: 2001-02-15
Also published as: WO2001010851B1; ITTO990703A0; IT1307265B1; ITTO990703A1; AU7274200A

Abstract

Process for preparing a compound of formula (III), wherein R is a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl-, aryl-, or aralkyl group having 1 to 30 carbon atoms, comprising a reaction (b) of a compound of formula (II), wherein R is as defined above and X is hydrogen or a cation of a corresponding acid salt, R' is COOR, COR or any other protecting group for amino functions, wherein R is again as defined above, with at least one halogenating agent yielding an acid halide by reacting at the COOX-group of the compound of formula (II) and being respectively capable of causing ring formation, under the proviso that thionyl chloride is excluded from the halogenating agents to be used and process for preparing lisinopril comprising the above reaction.

Description

PROCESS FOR THE PREPARATION OF LYSINE-CARBOXYANHYDRIDE INTERMEDIATES IN THE SYNTHESYS OF LISINOPRIL

5

10

The present invention relates to an improved process for preparing intermediates for the synthesis of lisinopril as well as a process for preparing lisinopril incorporating the new process according to the present invention.

15

Lisinopril is an important antihypertensive drug, described in US 4 374 829. Its production is conducted via an alkoxycarbonyl dipeptide as an intermediate. In the above-referenced patent, the intermediate N6-(tert.-butoxycarbonyl)-L-lysyl-L- proline is used, whose synthesis is not described. Wu M. T. et al. have 0 subsequently described the synthesis of this intermediate in J. Pharm. Sci., 74 (3), p. 352 - 4 (1985). The synthesis thereof, however, requires complex and expensive reagents.

The Italian application BO 98 A000063 relates to a process for preparing 5 alkoxycarbonyldipeptides of formula I as defined therein comprising a step (a), wherein L-lysine is treated in aqueous alkaline medium with an alkylchloroformate as defined therein, a step (b) reacting the product as obtained in step (a) in an inert solvent with thionyl chloride in the presence of N,N-dimethylformamide; and 0 a step (c) wherein the N-carboxyanhydride of the N6-(alkoxycarbonyl)-L-lysine as obtained in step (b) is reacted with L-proline in hydroacetonic alkaline medium.

Although the process claimed therein already represents an improvement of the 5 above discussed known processes of the prior art for preparing intermediates in the synthesis of lisinopril, it was an object underlying the present invention to achieve a further improved process for preparing such intermediates.

Thus, in one aspect, the present invention relates to a process for preparing a compound of formula III

wherein R is a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl-, aryl-, or aralkyl group having 1 to 30 carbon atoms,

comprising a reaction (b) of a compound of formula II

RO— ? C— NH— CH— (CH₂)₄-NH-R' II

COOX

wherein R is as defined above and X is hydrogen or a cation of a corresponding salt, R' is COOR, COR or any other protecting group for amino functions, wherein R is again as defined above,

with at least one halogenating agent yielding an acid halide by reacting at the COOX-group of the compound of the formula II and being respectively capable of causing ring formation, under the proviso that thionyl chloride is excluded from the halogenating agents to be used.

In a further embodiment of the present invention, it relates to a process as defined above comprising a further reaction (a) which is carried out before the above- mentioned reaction (b) of reacting lysine or a derivative thereof with a halo formate of the general formula I

wherein R is defined as in claim 1 and Hal represents a halogen atom, preferably Cl and Br

in the presence of an alkaline aqueous medium, which may comprise one or more organic solvents, preferably water-miscible solvents, such as acetone, to obtain compound II.

Furthermore, the present invention is directed to a process further comprising a reaction (c) of reacting the compound of formula III with proline or a derivative, such as an ester, thereof in an alkaline medium to obtain a compound IN

wherein R is as defined above and R" is H, a cation of an acid salt or a group R.

Hereinunder the processes according to the present invention will be described in detail with regard to the individual reactions (a) to (c).

Reaction (a)

In this step D-, L- and/or D,L-lysine or a derivative thereof is reacted with a haloformate of the above-referenced general formula I, wherein R is a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl-, aryl-, or aralkyl group having 1 to 30, preferably 6 to 20, more preferably 6 to 12 carbon atoms, wherein aralkyl groups having an substituted or unsubstituted phenyl group are preferred. Particularly preferred residues R are those selected from the group consisting of allyl, benzyl, ethyl, isopropyl, isobutyl, tert.-butyl and trichloro ethyl, Hal represents a halogen atom, preferably Cl or Br.

Said reaction is conducted in the presence of an aqueous alkaline medium which may comprise one or more organic solvents, preferably water-miscible solvents such as acetone. In said step any aqueous alkaline medium may be used and an aqueous solution of sodium hydroxide being preferred. Preferably said step (a) is carried out at a pH value of between 8 and 14, more preferably between 10 and 12. The temperature at which this reaction is conducted is not specifically limited, but preferably lies between 0°C and 50°C and more preferably between 10°C and 30°C. The reaction is conducted for a time sufficient to achieve complete or nearly complete reaction between the reactants. Typically the reaction time lies between 2 and 6 h.

Reaction (b)

In this step a compound of the general formula II is reacted with at least one halogenating agent yielding an acid halide by reacting at the COOX-group of the compound of the formula II and being respectively capable of causing ring formation in order to yield a compound of formula III.

With respect to the compound of the formula II, R is as defined above with respect to the compound of the formula I, R' being COOR, COR, or any other known protecting group for amino functions and X being hydrogen or a cation of a corresponding acid salt, such as Na⁺, K⁺, NH ^", Mg²⁺. Preferably, X is hydrogen.

With respect to the halogenating agent to be used, in principle no limitation exists, except that the use of thionyl chloride is excluded from the present application. The halogenating agent must be capable of causing the above-defined ring formation in order to yield compound III. Individual compounds to be mentioned are oxalyl chloride, cyanuric chloride, PC1₃, POCl , PC1₅ and dichloromethyl ether. Preferably, oxalyl chloride is used, more preferably together with DMF. The molar ratio between the acid chloride and/or the chlorinated ether and DMF may be chosen freely.

This reaction may be carried out in the presence or absence of a solvent. In cases, where a solvent is used, said solvent is selected from ketones, cyclic and linear ethers, esters, halogenated hydrocarbons and aromatic hydrocarbons. Halogenated hydrocarbons, such as methylene chloride, tetrachloromethane or chloroform; toluene; ethylacetate; MEK; acetone; cyclic and linear ethers are preferred. Again, the reaction is conducted for such a time that complete or almost complete conversion is achieved and usually reaction periods of between 2 and 6 h are sufficient in order to achieve said purpose. The temperature involved is usually between 0°C and +30°C.

Reaction (c)

According to said step, the above-discussed compound of formula III is reacted with D-,L- or D,L-proline or a salt or an ester thereof in an alkaline medium to obtain the above-referenced compound IV, wherein R is as defined above.

Also in this reaction, the alkaline medium may be freely chosen. Preferably, a hydroacetonic alkaline medium, as well as alkaline media comprising mixtures water/dioxane; water/THF; water/acetonitrile; or water/ethylacetate are used. The reaction is usually carried out at a temperature between -20°C and +50°C, preferably between -10°C and +10°C for a period of time sufficient to achieve complete or almost complete conversion, which generally lies between 1 and 3 h.

Said compound IN may then be converted into lisinopril or a derivative thereof by reactions known in the art. One suitable route is outlined hereinunder.

- Condensation of the dipeptide of general formula IV with 2-oxo-4- phenylbutyric acid to obtain the Schiff base and subsequent reduction in the presence of sodium borohydride. These transformations are performed by means of classical techniques known in the art: the condensation reaction is carried out in organic solution under azeotropical removal of the water formed during the reaction. The reduction step is carried out without isolating the obtained Schiff base: the solution of the Schiff base is directly dropped into the alkaline solution of sodium borohydride thus obtaining (Ν6-phenylmethoxycarbonyl)-Ν2-(l-carboxy- 3-phenylpropyl)-(L)-lysyl-(L)-proline, usually denoted as Zε-Lisinopril. Deprotection of Zε-Lisinopril to obtain Lisinopril (SSS) and its diastereomer (RSS). The phenylmethoxycarbonyl protecting group is removed with a hydrogenation reaction over 5% Palladium on Carbon catalyst as reported in Journal of Pharmaceutical Sciences Vol. 74, N° 3, pag. 352 to 354, March 1985.

Separation of the diastereomer of Lisinopril by crystallization. The oil containing the mixture of Lisinopril and its diastereomer is dissolved in absolute ethanol: the RSS diastereomer crystallizes after seeding, leaving a solution enriched in SSS Lisinopril (SSS/RSS ~ 95/5 in solution).

Further purification of the SSS Lisinopril oil on XAD-2 resin to increase the ration between Lisinopril and its diastereomer, as described in Journal of Pharmaceutical Sciences Vol. 74, N° 3, pag. 352 to 354, March 1985.

Crystallization of the product from aqueous ethanol.

Thus, the present invention also relates to a process for preparing lisinopril or a derivative thereof, such as the dihydrate form thereof, the nitrate, maleate or di- sulfate salt thereof comprising the reaction (b) and optionally the reactions (a) and/or (c) as also defined above.

The novel route according to the present invention for obtaining compounds of formula III has e.g. the following advantages:

1. The amount of the catalysts required to finally obtain lisinopril is relatively low;

2. This reduction in the amount of catalysts required leads to a greater safety of the overall process to obtain lisinopril; 3. This catalyst can be recycled and/or reused.

4. The entire process is economically advantageous due to the low costs involved.

In the following, the present invention is further illustrated with regard to the subsequent examples.

EXAMPLES

EXAMPLE 1 N2,N6-BIS((PHENYLMETHOXY)CARBONYL)-L-LYSINE

A 5L flask, equipped with mechanic stirrer, thermometer and pH-meter was loaded in order with water (1040 ml) and lysine hydrochloride (210 g); the mixture was stirred until complete dissolution; pH was adjusted to 10.5 by addition of 30% sodium hydroxide (130 ml); benzylchloroformiate (418 g) was added while maintaining the pH at 10.8 by adding at the same time 30% sodium hydroxide (357 ml). At the end of the addition, the reaction was kept under stirring at 20°C for about lh. pH was adjusted to 5.3 with 37% hydrochloric acid (80 ml); ethyl acetate was added (1020 ml) and pH was adjusted at 1.3 with 37% hydrochloric acid (60 ml). The mixture was stirred at room temperature for about 30 minutes; the solvent was evaporated until a thick oil containing N2,N6- bis((phenylmethoxy)carbonyl)-L-lysine was obtained (yield by HPLC assay 93%). EXAMPLE 2

N6-((PHENYLMETHOXY)CARBONYL)-L-LYSINE,N- CARBOXYANHYDRIDE

The oil obtained in example 1 was dissolved in dichloromethane (550 ml) and made substantially water-free. Anhydrous dimethylformamide (132 ml) was added to the N2,N6-bis((phenylmethoxy)carbonyl)-L-lysine solution and the mixture water content was checked to be sure that is was less than 0,2%. The mixture was cooled to 0°C and oxalyl chloride (151 g) was dropped in about lh still maintaining the temperature at 0°C. The reaction was kept at 0°C for lh and at lO°C for 2h.

After solvent removal 659 g of an oil were obtained.

EXAMPLE 3 l-(N6-(PHENYLMETHOXY)CARBONYL-(L)-LYSYL)-(L)-PROLINE

A lined 3L flask was loaded with water (880 ml) and potassium carbonate (K CO ) and the mixture was stirred until complete dissolution; the solution was cooled to -8°C and L-proline (152 g) and acetone (677 ml) were added. The oil coming from example 2 was dissolved in acetone (170 ml) and the solution was dropped in lh 30' into the previously prepared mixture, maintaining the temperature between 0 and 5°C. The reaction was kept at 0°C for lh afterwards inorganic salts were filtered and washed with water (150 ml). Washing liquors were added to the filtered solution which was extracted twice with toluene (445 ml each time) after the pH had been adjusted to 6.5 by addition of 37% hydrochloric acid (240 ml). Butanol (490 ml) was added to the aqueous phase and the pH was adjusted to 1.3 by adding 37% hydrochloric acid (130 ml). The aqueous and organic phases were separated and the aqueous one was extracted once again with butanol (245 ml). pH was adjusted to 11 with 30% sodium hydroxide (about 230 ml) and the yield was determined by HPLC. (1-(N6- (phenylmethoxy)carbonyl-(L)-lysyl)-(L)-proline: 314.4 g; yield: 72.4% from L- lysine).

EXAMPLE 4 N2,N6-BIS((PHENYLMETHOXY)CARBONYL)-L-LYSINE

The reactor was loaded in order with water (1720 g) and L-lysine hydrochloride (210 g). The mixture was kept at 20°C and stirred until complete dissolution. The pH was adjusted to 10.5 g by adding 30% sodium hydroxide (130 ml); 95% benzylchloro formate (413 g) was added at 20°C during 2h still maintaining the pH at 10.5 by adding at the same time 30% sodium hydroxide (340 g). At the end of the addition the reaction was stirred at 20°C for an additional hour. Maintaining the temperature at 25°C, the pH was adjusted to 5.3 with 37% hydrochlorid acid (65 ml). Ethyl acetate (1000 ml) was added to the mixture and pH was adjusted to 1.3 with 37% hydrochloric acid (45 ml). The reaction was stirred for 15 minutes. The aqueous and the organic phases were separated and the organic one was concentrated under reduced pressure until a thick oil was obtained, (by HPLC assay the obtained oil contained 547.8 g of N2,N6- bis((phenylmethoxy)carbonyl)-L-lysine; yield: 96,0%).

EXAMPLE 5

N6-((PHENYLMETHOXY)CARBONYL)-L-LYSINE,N-

CARBOXYANHYDRIDE

A half of the oil obtained from example 4 was dissolved in dichloromethane (280 ml). The solution water content was evaluated by means of a Karl-Fisher analysis and it was found to be 0,5%. The solvent was evaporated and the obtained oil was dissolved in dichloromethane (280 ml). The Karl-Fisher analysis indicated the solution water content was 0.07%. Dichloromethane (280 ml) and dimethylformamide (4.4 ml; 0.0574 moles) were added. The mixture was cooled to 0°C and oxalyl choride (86.8 g; 0.684 moles) was dropped during lh. The reaction was kept at 0°C for lh and at 10°C for 4h afterwards the solvent was evaporated under reduced pressure.

EXAMPLE 6 l-(N6-(PHENYLMETHOXY)CARBONYL-(L)-LYSYL-(L)-PROLINE

The oil obtained from example 5 was dissolved in acetone (98 ml) and the solution was cooled to-8°C. A IL lined reactor was loaded with water (520 ml) and potassium carbonate (231.5 g) and the mixture was cooled to -8°C and stirred until complete dissolution. L-proline (78.3 g; 0.68 moles) and acetone (390 ml) were added. The N6-((phenylmethoxy)carbonyl-L-lysine,N-carboxyanhydride solution in acetone was dropped into the reactor during lh, while the temperature was let rise to 0°C. The reaction was stirred for 30 minutes after the end of the addition. Inorganic salts were filtered and washed with water (90 ml). Washing liquors were added to the filtered solution which was extracted twice with toluene (220 ml each time) after having adjusted the pH to 6.5 with 37% hydrochloric acid (155 ml). The aqueous phase was extracted twice with butanol (366 ml each time) after having adjusted the pH to 1.25 with 37% hydrochloric acid (75 ml) The organic phases were collected and the solvent was removed under reduced pressure. Methanol (1150 ml) was added to the oil and the mixture was kept under stirring for lh at 0°C. Inorganic salts were filtered and the yield of the product in methanolic solution was determined by HPLC analyses (1-(N6- (phenylmethoxy)carbonyl-(L)-lysyl)-(L)-proline: yield: 48 % from 1-lysine). EXAMPLE 7

N2,N6-BIS((PHENYLMETHOXY)CARBONYL-L-LYSINE

L-lysine hydrochloride (210 g) was dissolved in water (1720 ml) at room temperature. The mixture was kept at 20°C and stirred until complete dissolution. The pH was adjusted to 10.5 by adding 30% sodium hydroxide (105 ml); Maintaining the temperature between 20 and 23°C, 95% benzylchloroformate (413 g) and 30% sodium hydroxide (350 ml) were dropped at the same time during 2h while keeping the pH between 10.3 and 10.8. At the end of the addition the reaction was stirred at room temperature for an additional hour. The pH was adjusted at 5.3 with 37% hydrochloric acid (~75 ml) and ethyl acetate (1020 ml) was added; pH was adjusted to 1.3 with 37% hydrochloric acid (30 ml) and the reaction was stirred for 15 minutes.

The aqueous and the organic phases were separated and the yield of the product in the organic phase was determined by HPLC analysis (by HPLC assay the obtained solution contained 446 g of N2,N6-bis((phenylmethoxy)carbonyl)-L-lysine; yield: 93,6%).

EXAMPLE 8 N6-((PHENYLMETHOXY)CARBONYL)-L-LYSINE,N- CARBOXYANHYDRIDE

The solution obtained from example 7 was concentrated under reduced pressure; the obtained oil was dissolved in dichloromethane (550 ml). The solution water content was evaluated by means of a Karl-Fisher analysis and it was found to be 0.27%. The solvent was evaporated and the obtained oil was dissolved in dichloromethane (550 ml). The Karl-Fisher analysis indicated the solution water content was 0.1%. Dichloromethane (550 ml) and dimethylformamide (88.5 ml; 1.15 moles) were added and the mixture water content was found to be 0.077%. The mixure was cooled to 0°C and oxalyl chloride (174.1 g; 1.37 moles) was dropped during lh. The reaction was stirred at 0°C for lh and at 10°C for 2h afterwards the solvent was evaporated at 37°C under reduced pressure.

EXAMPLE 9 l-(N6-(PHENYLMETHOXY)CARBONYL-(L)-LYSYL)-(L)-PROLINE

The oil obtained from example 8 was dissolved in acetone (175 ml) and the solution was cooled to -8°C. A IL lined reactor was loaded in order with water (1040 ml) and potassium carbonate (463 g); the mixture was stirred until complete dissolution afterwards it was cooled to -8°C. L-proline (152 g) was added and the mixture was stirred until complete dissolution; acetone (780 ml) was added obtaining a biphasic system. The N6-((phenylmethoxy)carbonyl-L-lysine,N- carboxyanhydride solution in acetone was dropped into the reactor during lh, while the temperature was let rise to 0°C. The reaction was stirred for 30 minutes after the end of the addition. Inorganic salts were filtered and the filtrate was extracted twice with toluene (445 ml each time) after having adjusted the pH to 6.5 with 37 % hydrochloric acid (240 ml). Phases separation was performed at 30°C. The aqueous phase was extracted twice with butanol (740 ml each time) after having adjusted the pH to 1.3 with 37% hydrochloric acid (120 ml). The organic phases were collected and the pH was adjusted to 10.7 with 30% sodium hydroxide (200 ml) while keeping the temperature at 27°C. The yield of the product in the organic solution was determined by HPLC analysis (1-(N6- (phenylmethoxy)carbonyl-(L)-lysyl)-(L)-proline: yield: 55.8 % from 1-lysine).

Claims

1. A process for preparing a compound of formula III

wherein R is a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl-, aryl,- or aralkyl group having 1 to 30 carbon atoms,

comprising a reaction (b) of a compound of formula II

RO— ? C— NH— CH— (CH₂)₄-NH-R II

COOX

wherein R is as defined above and X is hydrogen or a cation of a corresponding acid salt, R' is COOR, COR or any other protecting group for amino functions, wherein R is again as defined above,

with at least one halogenating agent yielding an acid halide by reacting at the COOX-group of the compound of the formula II and being respectively capable of causing ring formation, under the proviso that thionyl chloride is excluded from the halogenating agents to be used and process for preparing lisinopril comprising the above reaction.

2. A process as claimed in claim 1, comprising a reaction (a) of reacting lysine or a derivative thereof with a haloformate of the general formula I

wherein R is defined as in claim 1 and the Hal represents a halogen atom, preferably Cl and Br

in the presence of an alkaline aqueous medium, which may comprise one or more organic sovents, preferably water-miscible solvents to obtain compound II.

3. A process as claimed in claim 1 or 2, further comprising a reaction (c) of reacting the compound of formula III with proline or a derivative thereof in an alkaline medium to obtain a compound IV

wherein R is as defined in claim 1 and R" is H, a cation of an acid salt or a group R.

4. Process for preparing lisinopril or a derivative thereof comprising the reaction (b) as defined in claim 1.

5. Process as claimed in any of the claims 1 to 4, wherein R is selected from the group consisting of allyl, benzyl, ethyl, isopropyl, isobutyl, tert.-butyl and trichloro ethyl.

6. Process as claimed in any of the claims 1 to 5, wherein the halogenating agents are respectively selected from the group consisting of oxalyl chloride, cyanuric chloride, PC1 , POCl₃, PC1₅ and dichloromethyl ether.

7. Process as claimed in claim 6, wherein the halogenating agent is oxalyl chloride, preferably being used together with DMF.

8. Process as claimed in any of the claims 1 to 7, wherein step (a) is carried out at a pH value between 10 and 12 at a temperature between 10°C and 30°C for a period of time between two and six hours, step (b) is carried out in a solvent selected from ketones, cyclic and linear ethers, esters, halogenated hydrocarbons and aromatic hydrocarbons at a temperature between 0°C and +30°C for a period of time between two and six hours, and step (c) is carried out at a temperature between -10°C and +10°C for a period of time between 1 and 3 hours in a hydroacetonic alkaline medium.

9. A process as described in the above-mentioned claims and specified by the scope of protection of said claims.