HK1147751B - Carbamoylglycine derivatives - Google Patents

Description

Carbamoylglycine derivatives

Technical Field

The present invention relates to carbamoylglycine derivatives, a process for the preparation of carbamoylglycine derivatives and the use of carbamoylglycine derivatives for the preparation of enantiomerically enriched alpha-amino acids.

Background

General formula [1]]The carbamoylglycine derivatives of (i) are versatile building blocks in many synthetic pathways for the synthesis of a wide variety of drugs, some of which also have therapeutic properties themselves. An example of the latter is carglumic acid (N- (aminocarbonyl) -L-glutamic acid; [1]]，R＝-CH₂CH₂CO₂H) For use in the treatment of hyperammonemia (hypermamonaea) in patients deficient in N-acetylglutamate synthase.

A particularly attractive application of carbamoylglycine derivatives is for enzyme-mediated synthesis of enantiomerically pure α -amino acids. For example, Ogawa et al (Eur.J.biochem.212, 685-.

Unfortunately, not all carbamoylglycine derivatives are equally readily available, but many of them are highly desirable as chemical building blocks. For example, carbamoylglycine derivatives [1] wherein R is methyl substituted with a cycloalkanone moiety (motif) are a class of compounds not described. However, such compounds are suitable candidates for enzyme-mediated synthesis of enantiomerically pure α -amino acids as described above, since the resulting α -amino acids can be used as building blocks for several active pharmaceutical ingredients.

There is therefore a need for the carbamoylglycine derivatives described above, for processes for their preparation and for the use of these carbamoylglycine derivatives in the synthesis of active pharmaceutical ingredients.

Detailed Description

In a first aspect of the present invention, there is provided a novel class of carbamoylglycine derivatives, i.e., compounds of the general formula [1] or salts thereof

Wherein R ism and n are 0, 1, 2, 3 or 4, and m + n.gtoreq.1.

In a preferred embodiment, the compound of the invention is the compound [1] wherein R is as defined above and m is 3 and n is 0(3- (2-oxocyclopentyl) -2-ureido-propionic acid), which is useful as an intermediate for the synthesis of the Angiotensin Converting Enzyme (ACE) inhibitor ramipril (ramipril). In another preferred embodiment, the compound of the invention is the following compound [1], wherein R is as defined above and m is 4, n is 0(3- (2-oxocyclohexyl) -2-ureido-propionic acid), which is useful as an intermediate for the synthesis of the ACE inhibitor perindopril (perindopril).

In a second aspect of the invention, there is provided a process for the preparation of a compound of the first aspect of the invention. It has been found that the carbamoylglycine derivatives of the present invention can be successfully prepared starting from readily available compounds, such as amino acids.

In a first embodiment, a suitable amino acid, for example cysteine or serine, is converted into an ester of the general formula [2] or a salt thereof according to methods known to the skilled person:

wherein R is₁is-CH₂OH or-CH₂SH。R₂Is selected from-CH₃、-CH₂X、-CHX₂、-CX₃、-C₆H₆、-C₆H₅X、-C₆H₄X₂-SiY 'Y', lower alkyl and aryl, wherein X represents Br, CH₃、C₂H₅、NO₂Cl, F or I, Y 'and Y' independently represent lower alkyl or aryl. Preferably, R₂is-CH₃or-CH₂CH₃or-CH₂CH₂CH₃. Other preferred R₂Groups are those known to the skilled worker for protecting amino acids, such as, for example, allyl, benzyl, tert-butyl, tert-butyldimethylsilyl, p-methoxybenzyl, methoxyethoxy-methyl, p-nitrobenzyl, pentafluorophenyl, trimethylsilyl and derivatives thereof. Optionally, R₁is-CH₂OR₁₁or-CH₂SR₁₁Wherein R is₁₁Is selected from-CH₃、-CH₂X、-CHX₂、-CX₃、-C₆H₆、-C₆H₅X、-C₆H₄X₂T-butyl, lower alkyl and aryl, wherein X represents Br, CH₃、C₂H₅、NO₂Cl, F or I.

In a second embodiment, the compound of formula [2] is converted into a compound of general formula [3] according to methods known to the skilled person

Wherein R is₂Have the same meaning as defined in the first embodiment of the second aspect of the invention. R₁May be as defined above, but advantageously R₁is-CH₂X, wherein X is a leaving group, preferably halogen, more preferably BrOr Cl. R₃Is selected from-CH₃、-CH₂X、-CHX₂、-CX₃、-C₆H₆、-C₆H₅X、-C₆H₄X₂-SiY 'Y', lower alkyl and aryl, wherein X represents Br, CH₃、C₂H₅、NO₂Cl, F or I, and Y', Y "and Y" independently represent lower alkyl or aryl. Preferably, R₃is-CH₃or-CH₂CH₃or-CH₂CH₂CH₃. Can be prepared by using a compound of the formula [2]]With a halogenating agent followed by reaction with an acylating agent to prepare said compound [3]. Suitable examples of halogenating agents are thionyl bromide and thionyl chloride; suitable examples of acylating agents are acetyl chloride and propionyl chloride. The halogenation and acylation steps may be carried out as two separate steps, the intermediate product may be purified or not purified, or the two steps may be combined into one step.

In a third embodiment, the compound of formula [3] is converted to a compound of formula [4],

wherein R ism and n are 0, 1, 2, 3 or 4, and m + n.gtoreq.1, and R₂And R₃Have the same meaning as defined above. Preferably, the compound [3]R in (1)₁is-CH₂X, wherein X is Br, Cl, OH or SH, more preferably Br or Cl, and then reacting said compound [3]With cycloalkanone enamines, preferably in the presence of a base. Suitably, cycloalkanone enamines are, for example, 1-morpholinyl-1-cyclohexene, 1-morpholinyl-1-cyclopentene, 1-piperidine-1-cyclohexene, 1-piperidine-1-cyclopentene, 1-pyrrolidinyl-1-cyclohexene, 1-pyrrolidinyl-1-cyclopentene and similarly activated cyclopentene and cyclohexene. Suitable bases are N, N-diethylmethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine, N-dimethylethylamine, N-methylmorpholine, imidazole, lutidine (e.g. 3, 5-lutidine), N-methylpiperidine, morpholine, pyridine, N' -tetramethyl-ethylenediamine, triethylamine and trimethylamine, preferably N, N-dimethylethylamine and triethylamine. Suitable solvents are inert solvents, for example, alkylnitriles, esters, ethers, (halo) hydrocarbons, and the like. Preferred solvents are acetonitrile, tetrahydrofuran, toluene and the solvents also used in the first and second embodiments. Preferably the temperature is from-20 to 60 deg.C, more preferably from 0 to 40 deg.C, most preferably from 10 to 30 deg.C.

In a fourth embodiment, the general formula [4] is prepared by hydrolysis of the ester and amide functions followed by reaction with cyanate]Is converted into a compound of the general formula [1]]The compound of (1). The hydrolysis is preferably carried out with a catalyst suitable for removing the particular R₂Radical reagents. For example, when R is₂In the case of alkyl groups, the hydrolysis is carried out using an acid, such as hydrochloric acid or sulfuric acid, in the presence of at least one equivalent of water. The hydrolysis of the amide function is preferably carried out using the same medium as the hydrolysis of the ester function, although other methods known to the skilled person are also within the scope of the invention. The hydrolysis of the amide functional group should also preferably be carried out in the presence of at least one equivalent of water. Preferably, the reaction mixture is neutralized by adding a base, such as lithium hydroxide, potassium hydroxide or sodium hydroxide, prior to reaction with the cyanate. Preferred cyanates are potassium cyanate and sodium cyanate. After adjusting the pH, R is hydrolyzed₂And R₃The step of hydrolysis of the group may be carried out as two separate steps, the intermediate product may be purified or not purified, or the two steps may be combined into one step.

In a fifth embodiment, the method described in the fourth embodiment is further extended by biotransformation of said compound of general formula [1] to yield a compound of general formula [5 ]:

wherein p has a value of 0, 1, 2, 3, 4, 5 or 6, having the S-configuration at the nitrogen-substituted carbon atom, preferably with an ee value of > 95%, more preferably > 98%, most preferably > 99.5%. Preferred p values are 1 and 2, since the products [5] with these values can be used as optically pure intermediates for the preparation of the ACE inhibitors ramipril and perindopril, respectively.

Preferably, the biotransformation is carried out by the action of a carbamoylase (carbamoylase). The enzyme may be used in vitro or in vivo. Alternatively, the carbamoylase is part of a system of enzymes (e.g., hydantoinases, carbamoylases, and hydantoin racemases).

In a sixth embodiment, the process described in the fifth embodiment is further extended by hydrogenating said compound of formula [5] to yield a compound of general formula [6]

Wherein p has the value described above, having predominantly the S, S, S-configuration, preferably > 85%, more preferably > 90%, most preferably > 95%. Preferably, the hydrogenation is carried out in the presence of a suitable heterogeneous or homogeneous metal-based catalyst. The metal-based heterogeneous catalyst may be, for example, Pd on carbon or Pt on carbon. The metal-based homogeneous catalysts may be based, for example, on Ru, Rh, Ir, etc., with or without ligands. The hydrogenation can be carried out in a polar solvent, such as water, methanol, ethanol, acetic acid or mixtures thereof, under a hydrogen pressure of 1 to 10bar, preferably 3 to 6bar, at a temperature of 0 to 60 c, preferably 10 to 30 c. Alternatively, the hydrogenation of the compound of formula [5] is carried out by selecting conditions such that the main product is an isomer of the compound of formula [6], which the skilled person is capable of carrying out. A most preferred example of the latter aspect is a compound of formula [6] with p ═ 2, which predominantly has the 2S, 3R, 7S-configuration, i.e. wherein the bridges in the bicyclic system have trans orientation ((2S, 3aR, 7aS) -octahydro-1H-indole-2-carboxylic acid).

In a seventh embodiment, the process described in the sixth embodiment is further extended by reacting said compound of formula [6] with a carboxylic acid or an activated carboxylic acid (preferably with an "activated" form of the compound of formula [7] or with a compound of formula [8 ])

Wherein R is₄Is alkyl or aryl, preferably-CH₃Or phenyl, to give the formula [9]]The compound of (a) to (b),

wherein p has the value defined above. Preferably, p has a value of 1, and R₄Is phenyl (ramipril), or has a p value of 2, and R₄is-CH₃(perindopril). Or, p has a value of 2, R₄Is phenyl, the compound [9]The overall configuration of (a) is 2S, 3R, 7S (trandolapril). Optionally, in the presence of a compound [7]]Or its activated form or [8]Before reaction, on compound [6]]The carboxylic acid groups of (a) are protected in order to avoid unwanted side reactions. Those skilled in the art are aware of a variety of protecting groups suitable for this purpose. Particularly suitable is the compound [6]]The protection is benzyl ester or substituted benzyl ester. And compound [7]]Or [8]]After the reaction, the resulting compound [9] can be reacted using standard techniques]To provide a compound [9] by deprotection of the carboxylic acid protecting derivative of (a)]. When the protecting group is a benzyl ester or a substituted benzyl ester, deprotection can be carried out, for example, using hydrogenation.

In a third aspect of the invention, the compounds of the first aspect of the invention are useful for the preparation of a medicament. Preferably, 3- (2-oxocyclopentyl) -2-ureidopropionic acid is used for the preparation of ramipril and 3- (2-oxocyclohexyl) -2-ureidopropionic acid is used for the preparation of perindopril. Said use may be achieved by the process and intermediates of the second aspect of the invention.

Examples

Example 1

Preparation of 3- (2-oxocyclopentyl) -2-ureidopropionic acid from methyl 2-acetylamino-3- (2-oxocyclopentyl) propionate

Methyl 2-acetylamino-3- (2-oxocyclopentyl) propanoate (52.0g, 229mmol, prepared as described in US 5,061,722) was dissolved in 120mL of 6N aqueous HCl (720mmol) and heated at 90-95 ℃ for 4 hours. The resulting reaction mixture was cooled in an ice bath and neutralized to pH 7.0 with 86mL of 10N aqueous NaOH (860mmol) maintaining a temperature of 15-25 ℃. Potassium cyanate (22.6g, 278mmol) was then added and the mixture heated to 60 ℃. After 3 hours, the solution was cooled to 50 ℃. Decolorizing carbon (3.0g, Norit SX) was added, stirred for 0.5h, then the carbon was filtered off with suction. The remaining solution (pH 8.9) was cooled in an ice bath and acidified with 6N aqueous HCl, maintaining the temperature below 10 ℃. The solution was inoculated with 0.1g of product at pH 4.5. The slurry was stirred for 0.5 hours at pH 1.8, and the product was collected on a filter under suction. The filter residue was washed with MTBE (2X 50mL) and dried under vacuum. Weight 35.8g, 73% yield.¹H NMR：(DMSO-d₆，300MHz)：12.57(br s，1H)，6.22(dd，1H)，5.60(br s，2H)，4.23-4.04(m，1H)，2.27-1.40(m，9H)。

Example 2

From 2-acetamido-3-Preparation of 3- (2-oxocyclopentyl) -2-ureidopropionic acid from propyl (2-oxocyclopentyl) propionate

1. Preparation of (R) -2-acetylamino-3-chloropropionic acid propyl ester

The (S) -propyl 2-amino-3-hydroxypropionate HCl salt (18.2g, 99.1mmol) was suspended in toluene (96mL) and thionyl chloride (8.20mL, 13.3g, 112mmol) was added over 15 minutes via an addition funnel. The homogeneous reaction was stirred at 20 ℃ for 2 hours. The temperature was then raised to 60 ℃ over 45 minutes and the reaction was held at this temperature for 45 minutes. Acetyl chloride (15.1mL, 16.7g, 213mmol) was then added over 2 hours via the addition funnel while the temperature reached 80 ℃ and the reaction was stirred at this temperature for 30 minutes. The reaction was allowed to cool to 5 ℃ at which time a precipitate formed. The precipitate was collected on a glass funnel under suction and washed with petroleum benzene (3X 25 mL). The filter residue was dried under vacuum overnight to a final weight of 9.19 g. Some of the crystals of the filter residue were used to inoculate the mother liquor, which was further diluted with petroleum benzene (25mL) and stirred overnight at 20 ℃. The resulting suspension was cooled to 5 ℃ and the product collected on a glass funnel under suction and washed with petroleum benzene (3X 25 mL). The filter residue was dried under vacuum overnight to a final weight of 6.48 g. The combined weight (two filter residues) was 15.7g, about 76% yield.¹H NMR：(CDCl₃，300MHz)：6.40(br s，1H)，4.99(dt，1H)，4.27-4.11(m，2H)，3.95(dq，2H)，2.09(s，3H)，1.77-1.65(m，2H)，0.97(t，3H)。

2. Preparation of propyl 2-acetylamino-3- (2-oxocyclopentyl) propionate

(R) -propyl 2-acetylamino-3-chloropropionate (2.50g, 12.0mmol) was dissolved in acetonitrile (25mL), and 1-pyrrolidino-1-cyclopentene (2.27mL, 2.14g, 15.6mmol) was added. The reaction was maintained at 20 ℃ and dimethylethylamine (1.70mL, 1.14g, 15.6 mmo) was added over 10 minutes via an addition funnell). The homogeneous reaction was stirred at 20 ℃ for 21 hours. Water (0.50mL) was then added and the reaction stirred for 2.5 hours. The solvent was removed under vacuum at 50 ℃ using EtOAc: petroleum benzene gradient, purification of residual oil by silica gel flash chromatography. The product was a pale yellow oil. Weight 2.67g, approximately 87% yield (two diastereomers).¹H NMR：(CDCl₃，300MHz)：6.62(br d，0.5H)，6.38(br d，0.5H)，4.61-4.49(m，1H)，4.05-4.00(m，2H)，2.38-1.92(m，8H)，1.80-1.47(m，6H)，0.90-0.84(m，3H)。

3. Preparation of 3- (2-oxocyclopentyl) -2-ureidopropionic acid

3- (2-Oxocyclopentyl) -2-ureidopropionic acid was prepared as described in example 1 above, but using 2-acetamido-3- (2-oxocyclopentyl) -propionic acid propyl ester instead of 2-acetamido-3- (2-oxocyclopentyl) propionic acid methyl ester as starting material in a similar yield.

Example 3

Preparation of (S) -2-amino-3- (2-oxocyclopentyl) propionic acid

1. Transformation of pKECARoP-hyu1 construct into Escherichia coli RV308

● Small aliquots of Escherichia coli RV308 (200. mu.l, super-competent) were thawed on ice

● Add 15. mu. lLR of the reaction mixture (see above)

● incubation on ice for 30 min

Heat shock at ● 42 deg.C for 1 min

● cells were cooled on ice for 2 minutes

● Add 1mL LB medium (5g/l NaCl, 5g/l yeast extract, 10g/l tryptone)

Incubation at ● 37 ℃ for 1 hour

● were spread on LB agar plates supplemented with kanamycin (5g/l NaCl, 5g/l yeast extract, 10g/l tryptone, 15g/l agar, 50mg/l kanamycin)

Incubation at ● 28 ℃ for 24 hours

● Individual colonies were isolated.

2. Expression of Hyu Gene in Escherichia coli RV308

Single clones obtained by transformation (see above) were inoculated with 0.05g/l kanamycin and 1mM MnCl respectively₂Or CoCl₂5mL of 2xTY medium (10g/l yeast extract, 16g/l tryptone, 5g/1 NaCl). The cultures were incubated at 28 ℃ and 150rpm for 24 hours and then inoculated with a solution supplemented with 0.05g/l kanamycin and 1mM MnCl, respectively₂Or CoCl₂100mL of 2xTY medium. The cultures were then incubated for 24-28 hours under the conditions mentioned above and harvested by centrifugation (20min, 5000rpm, 4 ℃). The cell pellet was resuspended in 5mL Tris-HCl (100mM, pH 7), centrifuged again (20min, 5000rpm, 4 ℃) and the cells frozen at-20 ℃.

3. Biotransformation

3- (2-Oxocyclopentyl) -2-ureidopropionic acid (10.0g, 46.7mmol) was suspended in water (80mL) and the pH adjusted to 8.0 with 10.8N aqueous NaOH. Then adding MnCl₂Solution (5mL, 100mmol/L) was treated with N₂Purge for 15 minutes. 40g of the wet cell slurry obtained according to "expression of Hyu gene in Escherichia coli RV 308" (see above) was then added. The reaction was stirred at 38 ℃ for 16 h, after which TLC showed complete conversion to the product. During this time, 5N H was added₃PO₄The aqueous solution kept the pH constant at 8.0. The reaction mixture was then centrifuged (12000rpm) and the clear liquid was separated from the remaining cell materialAnd opening. The liquid pH was adjusted to about 1.0 with 37% aqueous HCl, which precipitated the protein. The mixture was centrifuged a second time (12000rpm) and the clear solution was collected. After charcoal treatment (0.5g activated charcoal) and microfiltration (0.45. mu.) the solution was loaded onto an ion exchange resin (Amberlyst 15, 80mL/144 meq.). Initially eluted with water to neutral pH to remove impurities. Then using 2N NH₃The amino acid is eluted with water to neutral pH. The aqueous fractions were combined, the pH adjusted to about 7 with 37% aqueous HCl and water removed under vacuum at 50 ℃ to yield a light brown solid. The product amino acid has the S configuration at C2 and > 99% ee (the other chiral center, C4, is promiscuous).

Example 4

Preparation of 3- (2-oxocyclohexyl) -2-ureidopropionic acid

Methyl 2-acetylamino-3- (2-oxocyclohexyl) propionate (15.0g, 62.2mmol, prepared as described in EP 84164) was dissolved in 30mL of 6N aqueous HCl (180mmol) and heated at 90-95 ℃ for 4 h. The resulting reaction mixture was cooled in an ice bath and neutralized to pH 7.0 with 23mL of 10N aqueous NaOH (230mmol) maintaining the temperature at 15-25 ℃. Potassium cyanate (4.8g, 69mmol) was then added and the mixture heated to 60 ℃. After 3 hours, the solution was cooled to 50 ℃. Decolorizing carbon (1.0g, Norit SX) was added, stirred for 0.5h, then the carbon was filtered off with suction. The remaining solution (pH 8.9) was cooled in an ice bath, acidified with 6N aqueous HCl and kept at a temperature below 10 ℃. The solution was inoculated with 0.1g of product at pH 4.5. The slurry was stirred for 0.5 hours at pH 1.8, and the product was collected on a filter under suction. The beige crystals were dried under vacuum. Weight 4.20g, approximately 30% yield.¹H NMR：(DMSO-d₆，300MHz)：12.45(br s，1H)，6.22(dd，1H)，5.60(br s，2H)，4.19-3.95(m，1H)，2.45-1.15(m，11H)。

Example 5

Preparation of (S) -2-amino-3- (2-oxocyclohexyl) propionic acid

The biotransformation described in example 3 was repeated, but using 3- (2-oxocyclohexyl) -2-ureidopropionic acid instead of 3- (2-oxocyclopentyl) -2-ureidopropionic acid as starting material.

Example 6

Preparation of (2S, 3aS, 6aS) -octahydrocyclopenta [ b ] from (S) -2-amino-3- (2-oxocyclopentyl) propionic acid]Pyrrole-2-carboxylic acids

(S) -2-amino-3- (2-oxocyclopentyl) propionic acid (130mg, 0.76mmol) obtained in example 3 was dissolved in water (2mL) with 25% NH₃The aqueous solution was adjusted to pH 9. 10% Pd/C (5mg) was then added and the hydrogenation was carried out under 5bar of hydrogen for 16 hours. At the end of the reaction, the catalyst was filtered off under suction over a pad of celite, the aqueous layer was evaporated under vacuum at 80 ℃ and the product (2S, 3aS, 6aS) -octahydrocyclopenta [ b ] was isolated]Pyrrole-2-carboxylic acid. The weight was 118 mg. 100% yield. Diastereomeric excess > 95% (determined by chiral HPLC).¹H NMR：(DMSO-d₆，300MHz)：10.54(br s，1H)，8.71(br s，1H)，4.22(dd，1H)，3.98(t，1H)，2.86-2.76(m，1H)，2.49-2.42(m，1H)，2.00-1.96(m，1H)，1.80-1.40(m，6H)。

Example 7

From (2S, 3aS, 6aS) -octahydrocyclopenta [ b]Preparation of (2S, 3aS, 6aS) -octahydrocyclopenta [ b ] using pyrrole-2-carboxylic acid]Pyrrole-2-carboxylic acid, 4-toluenesulfonic acid (1: 1) benzyl ester

(2S, 3aS, 6aS) -octahydrocyclopenta [ b ] pyrrole-2-carboxylic acid (5.00g, 32.2mmol) obtained in example 6 was suspended in toluene (100mL) in a round-bottom flask equipped with a Dean-Stark trap, p-toluenesulfonic acid monohydrate (6.60g, 34.7mmol) and benzyl alcohol (15.0mL, 15.6g, 144mmol) were added and the mixture was refluxed. The reaction was refluxed for 8 hours and then allowed to cool to room temperature. A colorless solid precipitated. Most of the solvent was then removed under vacuum at 65 ℃. To the remaining thick suspension was added diethyl ether (200mL), and the solid was collected on the filter (#3 wells) under suction, then washed with diethyl ether (4X 50 mL). The colorless product was allowed to air dry. Weight 12.1g, 90% yield.

Example 8

From N- [ (S) -1- (ethoxycarbonyl) -3-phenyl-propyl]Preparation of N- [ (S) -1- (ethoxycarbonyl) -3-phenyl-propyl ] -L-alanine]-L-alanyl chloride HCl

At 0. + -. 3 ℃ in CH as described in US 2006/0079698₂Cl₂From N- [ (S) -1- (ethoxycarbonyl) -3-phenyl-propyl]-L-alanine and PCl₅Synthesis of N- [ (S) -1- (ethoxycarbonyl) -3-phenyl-propyl]-L-alanyl chloride HCl, precipitated by slow addition of cyclohexane. Filtration was performed under nitrogen.

Example 9

From (2S, 3aS, 6aS) -octahydrocyclopenta [ b]Preparation of benzyl pyrrole-2-carboxylate (2S, 3aS, 6aS) -octahydrocyclopenta [ b [ -b ]]Pyrrole-2-carboxylic acid, 1- [ (2S) -2- [ [ (1S) -1- (ethoxycarbonyl) -3-phenylpropyl]Amino group]-1-oxopropyl radical]Phenyl methyl ester

The tosylate salt prepared in example 7 (6.00g, 14.4mmol) was suspended in CH₂Cl₂To (60mL) was added triethylamine (1.46g, 14.4mmol) at 0 ℃. The slurry was stirred for 30 minutes, then imidazole (2.94g, 43.1mmol) was added in small portions, followed by the addition of N- [ (S) -1- (ethoxycarbonyl) -3-phenyl-propyl prepared in example 8]L-alanyl chloride HCl (5.28g, 15.8 mmol). The reaction mixture was stirred at 0 ℃ for 2 hours and then allowed to warm to 20 ℃ over 30 minutes at which temperatureStirred for 2 hours. Then water (60mL) was added, the phases were mixed vigorously, the organic layer was separated and washed with CH₂Cl₂The aqueous layer was washed once more (60 mL). With saturated NaHCO₃The combined organic layers were washed with aqueous solution (60mL), treated with charcoal (1g) over anhydrous Na₂SO₄(5g) And drying. After filtration of the salts and evaporation of the solvent in vacuo at 40 ℃, the product was obtained as a pale yellow oil. The oil was redissolved in methanol (90mL), 5% Pd/C (0.50g) was added and the hydrogenation was carried out under 2bar of hydrogen pressure. After about 4 hours, the hydrogen consumption was stopped and the catalyst was filtered off on a celite pad. Celite (20mL) was washed with additional methanol. The organic layer was removed under vacuum at 50 ℃. The residue was recrystallized from ether (100mL) at 0 ℃. Product ramipril ([ 9]]，p＝1，R₄Phenyl) is a colorless solid. Weight 4.56g, 70% yield.

Claims (9)

1. A compound of the general formula [1] or a salt thereof

Wherein R ism and n are 0, 1, 2, 3 or 4, and m + n.gtoreq.1.

2. A compound according to claim 1 which is 3- (2-oxocyclopentyl) -2-ureido-propionic acid or 3- (2-oxocyclohexyl) -2-ureido-propionic acid, or a salt thereof.

3. A process for preparing a compound according to any one of claims 1 to 2, the process comprising: treating the compound of the formula [4] with an acid followed by a cyanate,

wherein R ism and n are 0, 1, 2, 3 or 4, and m + n.gtoreq.1, and R₂And R₃Is independently selected from-CH₃、-CH₂X、-CHX₂、-CX₃Wherein X represents Br or CH₃、C₂H₅、NO₂Cl, F or I.

4. A process according to claim 3, wherein the cyanate is potassium cyanate or sodium cyanate or a mixture thereof.

5. A process for producing a compound of the general formula [5 ]:

wherein p is 1 or 2, the method comprising: preparing a compound of general formula [1] according to the process of any one of claims 3 to 4; and contacting a compound of the general formula [1] wherein m is 3 or 4 and n is 0 with a carbamoylating enzyme.

6. A process for producing a compound of the formula [6]

Wherein p is 1 or 2, the method comprising: the process according to claim 5 for preparing a compound of the formula [5], and hydrogenating the compound of the formula [5 ].

7. A process for producing a compound of the general formula [9],

wherein p is 1 or 2, the method comprising: the method according to claim 6, wherein the compound of the formula [6] is prepared, and the compound of the formula [6] is contacted with the compound of the formula [7] or the compound of the formula [8]

Wherein R is₄is-CH₃Or a phenyl group.

8. The method according to claim 7, wherein R₄is-CH₃P has a value of 2, or wherein R₄Is phenyl and has a p value of 1.

Use of 3- (2-oxocyclopentyl) -2-ureido-propionic acid in the preparation of ramipril or 3- (2-oxocyclohexyl) -2-ureido-propionic acid in the preparation of perindopril or trandolapril.