ITTO990703A1 - PROCEDURE FOR THE PREPARATION OF INTERMEDIATE PRODUCTS IN THE SYNTHESID OF LISINOPRIL. - Google Patents

Description

DESCRIPTION of the industrial invention entitled: "Process for the preparation of intermediate products in the synthesis of Lisinopril",

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

Lisinopril is an important antihypertensive drug, described in US 4 374 829. Its production is carried out via an alkoxycarbonyl dipeptide as an intermediate. In the aforementioned patent, the intermediate N6- (tert-butoxycarbonyl) -L-lysyl-L-proline is used, the synthesis of which is not described. Wu M. T. et al. subsequently described the synthesis of this intermediate in J. Pharm. Sci., 1J \ (3), p. 352-4 (1985). Its synthesis, however, requires complex and expensive reagents.

The Italian application BO 98 A000063 relates to a process for the preparation of alkoxycarbonyl dipeptides of formula I as defined herein comprising

a step (a), wherein the L-lysine is treated in an aqueous alkaline medium with an alkyl chloroform as defined herein,

a step (b) for reacting the product as obtained in step (a) in an inert solvent with thionyl chloride in the presence of N, N-dimethylformamide; And

a step (c) in which the N-carboxyanhydride of N6- (alkoxycarbonyl) -L-lysine as obtained in step (b) is reacted with L-proline in an alkaline hydroacetonic medium.

Although the process claimed herein already represents an improvement of the known prior art processes discussed above for preparing intermediates in the synthesis of lisinopril, an object underlying the present invention has been to provide a further improved process for the preparation of such intermediates.

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

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

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

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

with at least one halogenating agent which produces an acid halide by reaction on the COOX group of the compound of formula II and which is respectively capable of causing the formation of rings, provided 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 aforementioned reaction (b) in which lysine or a derivative thereof is reacted with an aioformat of the general formula I

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

in the presence of an alkaline aqueous medium, which can comprise one or more organic solvents, preferably solvents that can be mixed with water, such as acetone, to obtain compound II.

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

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

The processes according to the present invention will be described below in detail with respect to the individual reactions from (a) to (c).

Reaction (a)

In this step, D-, L-and / or D, L-lysine or a derivative thereof is reacted with an aloformate of the general formula I indicated above, in which R is a linear or branched, saturated or unsaturated alkyl, aryl or aralkyl group , substituted or unsubstituted having 1 to 30, preferably 6 to 20, more preferably 6 to 2 carbon atoms, wherein aralkyl groups having a substituted or unsubstituted phenyl group are preferred. Particularly preferred R residues are those selected from the group comprising allyl, benzyl, ethyl, isopropyl, isobutyl, tert-butyl and trichloroethyl, H1 represents a halogen atom, preferably Cl or Br.

Said reaction is carried out in the presence of an aqueous alkaline medium which can comprise one or more organic solvents, preferably water-miscible solvents such as acetone. Any aqueous alkaline medium can be used in said step and an aqueous sodium hydroxide solution is preferred. Preferably said step (a) is carried out at a pH value between 8 and 14, more preferably between 10 and 12. The temperature at which this reaction is carried out is not specifically limited, but preferably varies between 0 ° C and 50 ° C and more preferably between 10 ° C and 30 ° C. The reaction is carried out for a time sufficient to obtain the complete or almost complete reaction between the reacting substances. Typically the reaction time varies 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 producing an acid halide by reaction on the COOX group of the compound of the formula II and which is respectively capable of causing the formation of rings in order to produce a compound of the formula III.

With respect to the compound of formula II, R is as defined above with respect to the compound of formula I, R 'being COOR, COR or any other protection group known for amino functions and X being hydrogen or a cation of a corresponding acid salt, such as Na <+>, K <+>, NH4 <+>, Mg <2+>. Preferably, X is hydrogen.

With respect to the halogenating agent to be used, there are in principle no limitations, except that the use of thionyl chloride is excluded from this application. The halogenating agent must be capable of causing the ring formation defined above in order to produce compound III. Single compounds to be mentioned are oxalkyl chloride, cyanuric chloride, PC13, P0C13, PCI5 and dichloromethyl ether. Preferably, oxalkyl chloride is used, more preferably together with DMF. The molar ratio of acid chloride and / or chlorinated ether to DMF can be freely chosen.

This reaction can be performed 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; ethyl acetate; MEK; acetone; cyclic and linear ethers are preferred. Again, the reaction is carried out for a time such as to obtain a complete or almost complete conversion and usually reaction periods between 2 and 6 hours are sufficient to achieve this purpose. The temperature involved usually varies 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 ester thereof in an alkaline medium to obtain the compound IV indicated above, wherein R is as defined previously. Also in this reaction, the alkaline medium can be freely chosen. Preferably, an alkaline hydroacetonic medium is used, as well as alkaline means comprising mixtures of water / dioxane; water / THF; water / acetonitrile; or water / ethyl acetate. 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 carry out the complete or almost complete conversion, which generally varies between 1 and 3 h.

Said compound IV can then be converted into lisinopril or a derivative thereof by reactions known in the art. A suitable route is highlighted below.

- Condensation of the dipeptide of the general formula IV with 2-oxo-4-phenylbutyric acid to obtain the Schifi base and subsequent reduction in the presence of sodium borohydride. These transformations are performed by classical techniques known in the art: the condensation reaction is performed in an organic solution with the azeotropic removal of the water formed during the reaction. The reduction step is performed without isolating the Schifi base obtained: the Schifi base solution is dropped directly into the alkaline sodium borohydride solution thus obtaining (N6-phenylmethoxycarbonyl) -N2- (l-carboxy-3-phenylpropyl) - (L) -lisil- (L) -proline, usually called Zà-Lisinopril.

- Deprotection of Zà-Lisinopril to obtain Lisinopril (SSS) and its diastereomer (RSS). The phenylmethoxycarbonyl protecting group is removed by a 5% palladium hydrogenation reaction on a carbon catalyst as reported in the Journal of Pharmaceutical Sciences, Vol.

74, N ° 3, pages 352 to 354, March 1985.

- Separation of the Lisinopril diastereomer by crystallization. The oil containing the mixture of Lisinopril and its diastereomer dissolves in absolute ethanol: the RSS diastereomer crystallizes after sowing, leaving a solution enriched with SSS Lisinopril (SSS / RSS ~ 95/5 in solution). - Further purification of Lisinopril SSS oil on XAD-2 resin to increase the ratio of Lisinopril to its diastereomer, as described in the Journal of Pharmaceutical Sciences, Vol. 74, N ° 3, pages 352 to 354, March 1985 .

- Crystallization of the product from aqueous ethanol.

Thus, the present invention also relates to a process for the preparation of lisinopril or a derivative thereof, such as its dihydrate form, its nitrate, lameate or disulfate salt comprising reaction (b) and optionally reactions (a) and / or (c) as also defined above.

The new path according to the present invention for obtaining compounds of formula III has for example the following advantages:

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

2. This reduction in the amount of catalysts required leads to greater safety of the overall process for obtaining lisinopril;

3. This catalyst can be recycled and / or reused.

4. The whole process is cost effective due to the low costs involved.

Hereinafter, the present invention will be further illustrated with respect to subsequent examples.

EXAMPLES EXAMPLE 1

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

A 5L flask, equipped with mechanical stirrer, thermometer and pH-meter, was loaded in order with water (1040 ml) and lysine hydrochloride (210 g); the mixture was stirred until completely dissolved; the pH was adjusted to 10.5 by adding 30% sodium hydroxide (130 ml); benzylchloroforate (418 g) was added while maintaining the pH at 10.8 while simultaneously adding 30% sodium hydroxide (357 ml). At the end of the addition, the reaction was kept under stirring at 20 ° C for about 1 h. The pH was adjusted to 5.3 with 37% hydrochloric acid (80 ml); ethyl acetate (1020 ml) was added and the pH adjusted to 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 was obtained containing N2, N6-bis ((phenylmethoxy) carbons1) -L-lysine (yield from the 93% HPLC analysis).

EXAMPLE 2

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

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 water content of the mixture was checked to ensure it was less than 0.2%. The mixture was cooled to 0 ° C and oxalyl chloride (151 g) was dropped dropwise for about 1 h while still maintaining the temperature at 0 ° C. The reaction was kept at 0 ° C for 1 h and at 10 ° C for 2 h.

After removing the solvent, 659 g of an oil was obtained.

EXAMPLE 3

1- (N6- (PHENYLMETHOXY) CARBONY- (L) -LYSIL) - (L) -PROLINE A 3L lined flask was filled with water (880ml) and potassium carbonate (K2C03) and the mixture was stirred until to complete dissolution; the solution was cooled to -8 ° C and L-proline (152 g) and acetone (677 ml) were added. The oil from Example 2 was dissolved in acetone (170 ml) and dropped drop the solution in 1 h 30 'in the previously prepared mixture, maintaining the temperature between 0 and 5 ° C. The reaction was maintained at 0 ° C for 1 h and after that the inorganic salts were filtered and washed with water (150 ml). Wash liquors were added to the filtered solution which was extracted twice with toluene (445ml each time) after the pH was adjusted to 6.5 by adding 37% hydrochloric acid (240ml). Butanol (490 ml) was added to the aqueous phase and the pH adjusted to 1.3 by adding 37% hydrochloric acid (130 ml). The aqueous and organic phases separated and the aqueous one was extracted once again with butanol (245 ml). The pH was adjusted to 11 with 30% sodium hydroxide (about 230 ml) and the yield 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 reagent 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 by the addition of 30% sodium hydroxide (130 ml); 95% of benzyl chloroformate (413 g) was added at 20 ° C in 2 h while still maintaining the pH at 10.5 by the simultaneous addition of 30% of sodium hydroxide (340 g).

At the end of the addition the reaction was stirred at 20 ° C for another hour.

Maintaining the temperature at 25 ° C, the pH was adjusted to 5.3 with 37% hydrochloric acid (65 ml). Ethyl acetate (1000ml) was added to the mixture and the pH adjusted to 1.3 with 37% hydrochloric acid (45ml). The reaction was stirred for 15 minutes. The aqueous and organic phases were separated and the organic one was concentrated at reduced pressure until a thick oil was obtained (by HPLC analysis the oil obtained contained 547.8 g of N2, N6-bis ((phenylmethoxy) carbonyls-L-lysine; yield: 96.0%). EXAMPLE 5

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

Half of the oil obtained from Example 4 was dissolved in dichloromethane (280 ml). The water content of the solution was evaluated by a Karl-Fisher analysis and found to be 0.5%. The solvent was evaporated and the oil obtained was dissolved in dichloromethane (280 ml). Karl-Fisher's analysis indicated that the water content of the solution was 0.07%. Dichloromethane (280ml) and dimethylformamide (4.4ml; 0.0574mole) were added. The mixture was cooled to 0 ° C and oxallyl chloride (86.8 g; 0.684 mol) was dropped dropwise for 1 h. The reaction was maintained at 0 ° C for 1 h and at 10 ° C for 4 h and subsequently the solvent was evaporated under reduced pressure.

EXAMPLE 6

1- (N6- (PHENYLMETHOXY) CARBONY- (L) -LYSYL- (L) -PROLINE The oil obtained from example 5 was dissolved in acetone (98 ml) and the solution was cooled to -8 ° C. An IL reagent was loaded with water (520 ml) and potassium carbonate (231.5 g) and the mixture was cooled to -8 ° C and stirred until completely dissolved. L-proline was added. (78.3 g; 0.68 mol) and acetone (390 ml). The solution of N6- (phenylmethoxy) carbonyl-L-lysine, N-carboxyanohydride in acetone was dropped into the reagent for 1 h, while the temperature was allowed to rise to 0 ° C. The reaction was stirred for 30 minutes after completion of the addition. The inorganic salts were filtered and washed with water (90 ml). Wash liquors were added to the filtered solution which was extracted twice with toluene (220ml each time) after adjusting the pH to 6.5 with 37% hydrochloric acid (155ml). The aqueous phase was extracted twice with butanol (366ml each time ) after having rule 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 1 h at 0 ° C. The inorganic salts were filtered and the yield of the product in a methanolic solution was determined by HPLC analysis (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 (210g) was dissolved in water (1720ml) at room temperature. The mixture was kept at 20 ° C and stirred until complete dissolution. The pH was adjusted to 10.5 by the addition of 30% sodium hydroxide (105 ml). Maintaining the temperature between 20 and 23 ° C, benzyl chloroformate (413 g) and 30% sodium hydroxide (350 ml) were dropped at the same time for 2 h, while maintaining the pH between 10.3 and 10.8 . At the end of the addition the reaction was stirred at room temperature for another hour. The pH was adjusted to 5.3 with 37% hydrochloric acid (~ 75ml) and ethyl acetate (1020ml) was added; the pH was adjusted to 1.3 with 37% hydrochloric acid (30 ml) and the reaction was stirred for 15 minutes.

The aqueous and organic phases were separated and the yield of the product in the organic phase was determined by HPLC analysis (by HPLC analysis the solution obtained contained 446 g of N2, N6-bis (phenylmethoxy) carbon!) - L-lysine ; yield: 93.6%).

EXAMPLE 8

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

The solution obtained from example 7 was concentrated under reduced pressure; the oil obtained was dissolved in dichloromethane (550 ml). The water content of the solution was evaluated by means of a Karl-Fisher analysis and found to be 0.27%. The solvent was evaporated and the oil obtained was dissolved in dichloromethane (550 ml). Karl-Fisher's analysis indicated that the water content of the solution was 0.1%. Dichloromethane (550 ml) and dimethylformamide (88.5 ml; 1.15 mol) were added and the water content of the mixture was found to be 0.077%. The mixture was cooled to 0 ° C and the oxalyl chloride (174.1 g; 1.37 moles) was dropped dropwise for 1 h. The reaction was stirred at 0 ° C for 1 h and at 10 ° C for 2 h and after this the solvent was evaporated at 37 ° C under reduced pressure.

EXAMPLE 9

1- (N6- (PHENYLMETHOXY) CARBONY- (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 reagent was charged to IL in order with water (1040 ml) and potassium carbonate (463 g); the mixture was stirred until it was completely dissolved and after this it was cooled to -8 ° C. L-proline (152 g) was added and the mixture was stirred until completely dissolved; acetone (780 ml) was added to obtain a biphasic system. The solution of N6- ((phenylmethoxy) carbonyl) -L-lysine, N-carboxyanhydride in acetone was dropped into the reagent for 1 h, while the temperature was allowed to rise to 0 ° C. The reaction was stirred for 30 minutes after the end of the addition.

The inorganic salts were filtered and the filtrate extracted twice with toluene (445 ml each time) after adjusting the pH to 6.5 with 37% hydrochloric acid (240 ml). Phase separation was performed at 30 ° C. The aqueous phase was extracted twice with butanel (740 ml each time) after adjusting the pH to 1.3 with 37% hydrochloric acid (120 ml). The organic phases were collected and the pH adjusted to 10.7 with 30% sodium hydroxide (200 ml) while maintaining 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)

CLAIMS 1. Process for the preparation of a compound of formula III wherein R is a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl, aryl or aralkyl group having from 1 to 30 carbon atoms, comprising a reaction (b) of a compound according to formula II where R is as defined above and X is hydrogen or a cation of a corresponding salt, R 'is COOR, COR or any other protection group for amino functions, where R is again as defined above, with at least one halogenating agent which produces an acid halide by reaction on the COOX group of the compound of formula II and which is respectively capable of causing the formation of rings, provided that thionyl chloride is excluded from the halogenating agents to be used. 2. A process according to Claim 1, comprising a reaction (a) for reacting lysine or a derivative thereof with an aloformate of the ideal formula I wherein R is defined as in claim 1 and Hai represents a halogen atom, preferably Cl and Br in the presence of an alkaline aqueous medium, which can comprise one or more organic solvents, preferably solvents that can be mixed with water, to obtain compound II. 3. A process according to Claim 1 or 2, further comprising a reaction (c) for reacting the compound of formula III with proline or a derivative thereof in an alkaline medium to obtain a compound IV Γ <X> 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 the preparation of lisinopril or a derivative thereof comprising reaction (b) as defined in claim 1. 5. Process according to any one of Claims 1 to 4, wherein R is selected from the group comprising allyl, benzyl, ethyl, isopropyl, isobutyl, tert-butyl and trichlorethyl. 6. A process according to any one of Claims 1 to 5, wherein the halogenating agents are selected from the group comprising oxalkyl chloride, cyanuric chloride, PC13, POC13, PC15 and dichloromethyl ether respectively. 7. A process according to Claim 6, wherein the halogenating agent is oxyalkyl chloride, which is preferably used together with DMF. 8. Process according to any one of 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 performed 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 performed at a temperature between -10 ° C and 10 ° C for a period of time between 1 and 3 hours in an alkaline hydroacetonic medium. 9. Process substantially as described and for the specified purposes.