MXPA00006014A - Deprotection and recrystallization processes - Google Patents

Abstract

Acylmercaptoalkanoylamino lactam esters or acids are converted to the corresponding mercaptoalkanoylamino lactam ester or acid under basic conditions by including an agent which minimizes the amount of disulfides. Suitable agents are bismercaptans, phosphine or phosphite reducing agents, zinc metal powder, and sodium hydrosulfite. Such agents are also employed in the recrystallization and reprocessing of the mercaptoalkanoylamino lactam acids.

Description

PROCESSES OF DESPROTEOCTÓN AND RFCRISALIZACTÓN BACKGROUND OF THE INVENTION Ercaptoalkanoylamino lactams have. have been described as possessing useful cardiovascular properties as a result of their activity as a double angiotesine that converts enzyme inhibitors and neutral metalloendopeptidase inhibitors. The lactam can be a monocyclic, bicyclic fused or a tricyclic fused as was thought by Karane sky et al. in U.S. Patent 5,552,397, Karanewsky et al. in US Patent 5,504,080, Robl in US Patent 5,508,272, Robl in US Patent 5,525,723, Robl in US Patent 5,362,727, Robl in US Patent 5,587,375, Robl et al, in Serial No. 443,278 registered in May 17, 1995 and EP 744,319, Ryono. et al in U.S. Patent 5,635,504 and Karanewsky et al, in U.S. Patent 5,650,408. These references describe the attachment of a side chain acylmercaptoalkanoic acid to the amino lactam ester followed by a deprotection by treatment with a sodium hydroxide or lithium hydroxide in aqueous alcohol or tetrahydrofuran followed by a treatment with aqueous acid to provide the products of mercaptoalkanoylamino lactams.

BRIEF DESCRIPTION OF THE INVENTION This invention is directed to improve the processes of deprotection used to convert an acylmercaptoalkanoylaminolactamic acid or ester of formula (II) O O II R2-C S- (CH2) u- • C * H-C11 Xi Ri to a mercaptoalkanoylamino lactamic acid or ester of formula (I) ti HS- (CH2) n CH-C- • Xi I and an improvement in the deprotection process used to convert the mercaptoalkanoylamino lactam ester of formula I to the mercaptoalkanoylamino lactam acid of formula I. These protective reactions are performed under basic conditions. The mercapto group in the acid or lactam ester of formula I under such conditions is susceptible to the formulation of disulfides of formula (III) Such disulfides are an undesired impurity in the pharmaceutically active mercaptoalkylaminolactamyl lactam products of formula I. Also, the disulfides of formula III can be converted to other undesirable by-products. In particular, when Ri is other than hydrogen, the disulfide of formula III can be converted to the mercaptoalkanoyl lactam of formula I having the undesired chirality in the optically active carbon in the mercaptoalkanoyl side chain.

Likewise, the formation of the disulfide impurity of formula III can occur during the recrystallization of the mercaptoalkanoylamino lactam product of formula I. The improvements of this invention resides in that it includes within the aforementioned preservation and the recrystallization processes an agent that minimizes the amount of the disulfides of the formula III and, in turn, minimizes the formation of the unwanted epimer of the pharmaceutically active compound of the formula I. Preferred agents for this purpose are bismercaptans as well as reducing agents such as phosphines and phosphites, metallic zinc powder, and sodium hydrosulfite.

DETAILED DESCRIPTION OF THE INVENTION The amino lactam acids and esters Xi shown above include: (virr) , (xii) (XIV) (XV) (XVI) (XVIII) (XIX) (XX) (XXI) In the formulas above, the various symbols have the definitions listed below. Ri and R2 are independently selected from straight or branched chain alkyl of 1 to 6 carbon atoms - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl. m is zero or an integer from 1 to 6. n is zero or one. R and R5 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, (CH2) m-cycloalkyl, - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl, or one of R4 and Rs is hydrogen and the other is hydroxy or R4 and Rs taken together with the carbon to which they are bound completely to a saturated cycloalkyl ring of 3 to 7 carbon atoms, or R and Rs taken together with the carbon to which they are bound completely to a keto substituent. e, Rβ and Rio are independently selected from hydrogen, alkyl, saturated alkyl, alkenyl (CH2) m-cycloalkyl, - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl. R7, R9 and R11 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl - (CH2) m-cycloalkyl, - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl , or Re and R7 taken together with the carbon to which they are fully bonded to a saturated cycloalkyl ring of 3 to 7 carbon atoms, or R8 and R9 taken together with the carbon to which they are completely attached to a saturated cycloalkyl ring of 3 to 1 carbon atoms. b is zero or one. d is zero or one. q is an integer from 1 to 4. r is one or two. t is an integer from 1 to 3. v is one or two. w is one or two.

Yi is -CH2-, - (CH) 2-, - (CH2) 3-, -O-, -S-, -CHc-0-, or -CH2-S-. Y2 is -CH2-, -S-, or -O-. Y3 is -CH2-, - (CH2) 2, - (CH2) 3-, -O-, or -CH? -O-. z is O or two hydrogens. Ri7 is hydrogen, alkyl, substituted alkyl, alkenyl, - (CH2) m-cycloalkyl, - (CH) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl. Y5 is -CH2-, -S-, or -O- provided that Y5 is -S- or -O- only when d is one. Y6 is -S- or -0-. The dashed line represents an optional double bond between the two carbons.

Represents an aromatic heteroatom containing a ring selected from Y7 is -S- or -NH-. Y8 is -S-, -O-, or -NH-. Ris and 19 are independently selected from hydrogen, alkyl, - (CH2) m-aryl, or R1 and R19 together with the carbon and nitrogen atoms to which they are fully attached to a ring having five to six members.

R 12 is a hydrogen or an acid protecting group such as methyl, ethyl, propyl, phenyl or benzyl. The term "alkyl" refers to straight or branched open radicals of 1 to 7 carbon atoms, preferably 1 to 4 carbons. The term "substituted alkyl" refers to straight or branched open chain radicals of 1 to 7 carbon atoms wherein one, two or three hydrogens have been replaced by a hydroxy, amino, cyano, Cl, Br, F, trifluoromethyl- NH (alkyl of 1 to 4 carbon atoms), -N (alkyl of 1 to 4 carbon atoms) 2, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, or carboxy. The preferred "substituted alkyl" is from 1 to 4 carbon atoms with a hydrogen replaced by a hydroxy, amino, Cl, or Br. The term "alkenyl" refers to straight or branched open chain radicals of 3 to 7 carbon atoms. carbon that have one or two double bonds. Preferred "alkenyl" groups are straight or branched open chain radicals of 3 to 5 carbon atoms having a double bond. The term "cycloalkyl" refers to saturated rings of 3 to 7 carbon atoms with cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl being preferred. The term "aryl" refers to phenyl, 1-naphthyl and 2-naphthyl with phenyl being preferred. v The term "substituted aryl" refers to phenyl, 1-naphthyl and 2-naphthyl having a substituent selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms. carbon, Cl, Br, F, hydroxy, trifluoromethyl, amino, NH (alkyl of 1 to 4 carbon atoms), or -N (alkyl of 1 to 4 carbon atoms) 2, phenyl di and tri-substituted, 1- naphthyl, or 2-naphthyl wherein said substituents are selected from methyl, methoxy, Cl, Br, methylthio, hydroxy or amino. The term "heteroaryl" refers to unsaturated rings of 5 to 6 atoms containing one or two O and S atoms and / or one or four N atoms provided that the total number of heteroatoms in the ring is 4 or less. The heteroaryl ring is attached by passing through an available carbon or a nitrogen atom. Preferred heteroaryl groups include 2-, 3-, or 4-pyridyl, 4-imidazole, 4-thiazolyl, 2- and 3-thienyl and 2- and 3-furyl. The term "heteroaryl" also includes bicyclic rings wherein the ring having five or six members contains atoms of O, S and N as defined above is fused to a benzene or pyridyl ring. Preferred bicyclic rings are 2-and 3-indolyl and 4- and 5-quinolinyl.

The acylmercaptoamino lactam esters of formula II are prepared by joining the acylmercapto containing the side chain of formula (XXIV) With the amino lactam ester (XXV) H-Xa. The above reaction can be carried out in an organic solvent such as methylene chloride and in the presence of a linking reagent such as l-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, benzotriazol-1-yloxytris- (dimethylamino) hexafluorophosphate ) phosphate, or carbonyldiimidazole.

Alternatively, the acylmercapto carboxylic acid of formula XXIV can be converted to an activated form such as hydrochloric acid, mixed anhydride, symmetrical anhydride, activated ester, etc., before joining. The starting materials of formulas XXIV and XXV and the resultant acylmercaptoalkanoylaminolactam esters of formula II are described in the prior art. For example, the above compounds wherein Xi is as defined in formulas IV to XIV are described by Karanewsky et al. in U.S. Patent 5,552,397 whose description is hereby incorporated by reference. The above __compounds wherein Xi is as defined in formula XV are described by Robl in U.S. Patent 5,508,272 whose description is hereby incorporated by reference. The above compounds wherein Xi is as defined in formula XVI are described by Karanewsky in U.S. Patent 5,504,080 whose description is hereby incorporated by reference. The above compounds wherein Xi is as defined in formula XVII are described by Robl in U.S. Patent 5, 525, 723, the disclosure of which is hereby incorporated by reference. The above compounds wherein Xi is co or defined in formula XVIII are described by Robl in U.S. Patent 5,362,727, the disclosure of which is hereby incorporated by reference. The above compounds wherein Xi is as defined in the formula. XIX and XX are described by Robl in U.S. Patent 5,587,375, the description of which is hereby incorporated by reference. The above compounds wherein Xi is as defined in formula XXI are described by Ryono et al, in U.S. Patent 5,635,504, the disclosure of which is hereby incorporated by reference. The above compounds wherein Xi is as defined in formula XXII are described by Karanewsky et al in U.S. Patent 5,650,408, the disclosure of which is hereby incorporated by reference. The above compounds wherein Xi is as defined in formula XXIII are described by Robl et al. in EP 743,319 and in U.S. Serial No. 443,278 registered May 17, 1995 whose description is hereby incorporated by reference. The deprotection processes of this invention include the conversion of the acylmercaptoalkanoylamino lactam acid or ester of formula II to the mercaptoalkylaminolamino lactam of formula I. The improvement in this process resides in that it includes in the basic hydrolysis reaction which eliminates the acyl functional group R2- C (0) - an agent that minimizes the amount of disulfides of formula III and, in turn, minimizes the formation of the undesired epimer of the pharmaceutically active compound of formula I. When the acylmercaptoalkanoylamino lactam of formula II is a carboxylic acid, ie Ri2 in the definition of Xi in formula II is hydrogen, then the acyl protecting group R2-C (O) - is eliminated in a single step to provide the pharmaceutically active lactam of formula I. This process of deprotection involves the treatment of the lactam carboxylic acid of formula II with an alkali metal or an alkali earth metal hydroxide or carbonate or with an amine in a suitable solvent containing a sufficient amount of a group that minimizes the amount of disulfide of formula III. Suitable agents for this purpose include bismercaptans as well as phosphine and phosphite reducing agents, metallic zinc powder, and sodium hydrosulfite. Such agents can be presented in an amount of from about 1 to about 20 mole percent, preferably from about 5 mole percent to about 10 mole percent in the reaction mixture. This protection reaction can be carried out at a temperature of about -20 ° C to about 45 ° C. Following the termination, the reaction is acidified with an aqueous acid such as HCl, acetic acid, propanic acid, sulfuric acid, phosphoric acid, or oxalic acid to precipitate the pharmaceutically active lactam of formula I.

An alkali metal and hydroxide and alkali metal earth carbonates suitable for this protection process include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and lithium carbonate. Amines useful in this process of deprotection include H2H-alkyl, H2N- (CH2) m-aryl, and hydroxyalkylamines wherein alkyl, aryl and m are as defined above. Methylamine, ethylamine, benzylamine, and ethanolamine are preferred. Suitable solvents for this deprotection process include methanol, aqueous methanol, ethanol, aqueous ethanol, tetrahydrofuran, aqueous tetrahydrofuran, isopropanol, aqueous isopropanol, acetonitrile, aqueous acetonitrile, and water. When the acylmercaptoalkanoylamino lactam of formula II is an ester of the carboxylic acid, i.e. R12 in the definition of Xi in formula II is an acid protecting group such as methyl, ethyl, propyl, phenyl or benzyl, then the acyl protecting group R2-C (0) - and the protective carboxylic acid group can be eliminated in a single step or in two steps to provide pharmaceutically active lactam of formula I. In the single-step deprotection process, the lactam carboxylic acid ester of formula II is treated under aqueous conditions with an alkali metal or a hydroxide or carbonate of alkali metal earth in a suitable solvent containing a sufficient amount of an agent that minimizes the amount of the disulfide of formula III. Suitable agents for this purpose include bismercaptans as well as phosphine and phosphite reducing agents, metallic zinc powder and sodium hydrosulfite. Such agents can be presented in an amount of about 1 mole percent to about 20 mole percent preferably from about 5 mole percent to about 10 mole percent in the reaction mixture. This protection reaction can be performed at a temperature of about -20 ° C to about 45 ° C. Following the termination, the reaction is acidified with an aqueous acid such as HCl, acetic acid, propanic acid, sulfuric acid, phosphoric acid or oxalic acid to precipitate pharmaceutically active lactam of formula I. An alkali metal and the hydroxides and carbonates of the alkali metal earths for this single-step de-protection process are as defined above. Suitable solvents for this single-step deprotection process include methanol, ethanol, isopropanol, acetonitrile, and tetrahydrofuran. This reaction is carried out under aqueous conditions, that is, the water is present in the solvent and / or in the reactants. The improved deprotection processes of this invention also include the process wherein the acylmercaptoalkanoylamino lactam ester of formula II is converted to the mercaptoalkanoylamino lactam ester of formula I. This process involves the removal of the acyl group R2-C (0) - by treating the ester acylmercaptoalkanoylamino lactam of formula II with an alkali metal or an alkaline earth hydroxide or carbonate with an amine in a suitable solvent containing a sufficient amount of an agent that minimizes the amount of disulfide of formula III and, in turn, minimizes the formation of the undesired epimer of the pharmaceutically active compound of formula I. Suitable agents for this purpose include bismercaptans as well as phosphine and phosphite reducing agents, metallic zinc powder and sodium hydrosulfite. Such agents can be presented in an amount of about 1 percent to about 20 mole percent, preferably from about 5 mole percent to about 10 mole percent in the reaction mixture. When an alkali metal or an alkali metal hydroxide or carbonate is employed, the reaction is carried out under no. watery When the amine is used, the reaction is carried out under aqueous conditions. This protection reaction is carried out at a temperature of about -20 ° C to about 45 ° C. Following the termination, the reaction is acidified with an aqueous acid such as HCl, acetic acid, propanic acid, sulfuric acid, phosphoric acid, or oxalic acid to precipitate the mercaptoalkanolaminolactam ester of formula I. An alkali metal and hydroxides and carbonates and amines of metal earths alkaline suitable for this first stage of protection are as defined above. Suitable solvents include methanol, ethanol, isopropanol, acetonitrile, and tetrahydrofuran. The improved deprotection processes of this invention also include the process wherein the mercaptoalkylaminolactamyl lactam ester of formula I is converted to the pharmaceutically active mercaptoalkanoylamino lactam of formula I wherein R 2 is hydrogen. This process involves the removal of the protective carboxylic acid group by treating the lactam ester of formula I with an alkali metal or a hydroxy or alkali metal carbonate under aqueous conditions in a suitable solvent containing a sufficient amount of an agent that minimizes the amount of the disulfide of formula III and in turn, minimizes the formation of the unwanted epimer of the pharmaceutically active compound of formula I. Suitable agents for this purpose include bismercaptans as well as phosphine and phosphite reducing agents and metallic zinc powder. Such agents can be presented in about 1 mole percent to about 20 mole percent, preferably about 5 mole percent to about 10 mole percent in the reaction mixture. This protection is carried out at a temperature of about -20 ° C to about 45 ° C. Following the termination, the reaction is acidified with an acid such as HCl, acetic acid, propanic acid, sulfuric acid, phosphoric acid, or oxalic acid to precipitate the pharmaceutically active lactam of formula I. The alkali metal and alkali metal earth metal hydroxides and carbonates for this protection step are as defined above. Suitable solvents include water, methanol, ethanol, isopropanol, acetonitrile and tetrahydrofuran. The recrystallization and improved reprocessing process of this invention, the mercaptoalkanoylamino lactam product of formula I is added to a suitable solvent containing a sufficient amount of an agent that minimizes the amount of the disulfide of formula III, and in turn, minimizes the formation of the unwanted epimer of the pharmaceutically active compound of formula I. Suitable agents for this purpose include bismercaptans as well as phosphine and phosphite reducing agents, metallic zinc powder, and sodium hydrosulfite. Such agents can be presented at about 1 mole percent to about 20 percent mole, preferably from about 5 mole percent to about 10 mole percent in the recrystallization mix. The resulting slurry is subject to changes in temperature and / or pH, optionally filtered, and then subject to further changes in temperature and / or pH to effect recrystallization. For example, the slurry can be heated to about 25 ° C at the reflux temperature to dissolve the solids, the solution is then filtered, the combined filtrates are cooled to about room temperature, and the desired product is collected. Alternatively, the slurry is treated to raise the above pH to about 8 by adding a basic material such as an alkali metal or an alkali metal hydroxide or carbonate, then the pH is lowered to at least below about 8. and preferably below about 6 and the product is precipitated by the addition of an acid such as HCl, acetic acid, propanic acid, sulfuric acid, phosphoric acid, or oxalic acid, the product is filtered, washed with water and ether ether. Butyl methyl, and dried in vaccuo. Suitable solvents for the recrystallization process include methanol, ethanol, isopropanol, and mixtures thereof. Bismercaptans used in the process of preserving and recrystallization are compounds which in the presence of the disulfide of formula III will open such disulfides to form a stable ring. Suitable bimercaptans are those of formula (XXVI) wherein K is an integer from 1 to 4 and each X2 is independently selected from hydrogen and hydroxy as well as 1, 2-benzenedimethanetiol, 1,3-butanedithiol meso-a, a'-dimercaptoadipic, disodium salt, and durene -a (l), cc (2) -dithiol. The preferred bismercaptans are dithiothreitol and dithioerythritol. Suitable phosphine reducing agents include tributyl phosphine and triphenyl phosphine. Suitable phosphite reducing agents include triethyl phosphite. Preferred reagents for use in the recrystallization and preservation reactions of this invention are dithiothreitol. To minimize the amount of disulfide of formula III in the reaction mixture according to the improved recrystallization and preservation processes of this invention, the disulfide byproducts of formula III are minimized. Said by-products include when Ri is other than hydrogen, the mercaptoalkanyl amino lactams of formula I having the undesired chirality in the optically active carbon in the side chain. In the preferred aspects of this invention, Xi in the acid or ester of the acylmercaptoalkanoylamino lactam of formula II is of formula IV or formula XV, n is zero, Ri is benzyl, and R2 is methyl. When Xi is of formula IV, q is preferably two, R4, R5 Rio and R11 are preferably hydrogen, b is preferably zero, R12 is preferably hydrogen or ethyl, and R6 and R7 are preferably independently selected from hydrogen and alkyl from 1 to 4. carbon atoms, especially where R6 and R7 are both methyl. When Xi is of formula XV, V is preferably two, d is preferably one, Y5 is preferably -CH2-, Y6 is preferably -S-, and R12 is preferably hydrogen or methyl. The asterisk (*) in formulas I, II and XXIV represents an asymmetric carbon in the acylmercaptoalkanoyl and mercaptoalkanoyl side chain. In the preferred compounds, this asymmetric center has the absolute configuration S. As shown in formula IV to XXXIII, another asymmetric center is represented in the various amino lactam rings. The pharmaceutically active products of the formula I wherein R 2 is hydrogen are useful cardiovascular agents particularly useful in the treatment of hypertension congestive heart attack. The pharmaceutically active products can be formulated in effective amounts to treat hypertension or a congestive heart attack as described by Karanewsky in U.S. Patents 5,552,397, Karanewsky in U.S. Patents 5,504,080 and 5,650,408, Robl in U.S. Patents 5,508,272, 5,525,723, 5,587,375. and 5,362,727, Robl in non-successive No. 443,278 recorded May 17, 1995 and EP 743,319 and Ryono et al in US Patent 5,635,504. The following examples are illustrative of the invention.

EXAMPLE 1 Acid [4S- [4a (R *), 7a lOaβ]] -octahydro-4- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -5-oxo-7H-pyrido [2, 1 -b] [1,3] thiazepine-7-carboxylic acid. [4S- [4a (R *), 7a-10aß]] - octahydro-4- [[2- (acetylthio) -l-oxo-3-phenylpropyl] amino] -5-oxo-7H-pyrido methyl ester 2, 1-b] [1, 3] thiazepine-7-carboxylic, (5.0 g, 10.76 mmol) [prepared as described in any of Examples 3 (c), 11 (i), 22 (b), 23 (i), or 24 of US Patent 5,508,272] is dissolved in methanol (45 ml) in a 250 ml flask equipped with an addition funnel, an internal temperature test and an argon inlet. To the solution is added DL-dithiothreitol (83 mg, 0.538 mmol). The solution is sprayed with argon for 15 minutes and then maintained under an argon atmosphere. The solution is cooled to 0 ° C in an ice bath. In the addition funnel, a solution of IN sodium hydroxide (65 ml, 64.57 mol) is sprayed with argon for 30 minutes. The sprayed sodium hydroxide solution is added to the reaction flask for 20 minutes so that the internal temperature does not exceed 5 ° C. The reaction is allowed to stir at 0 ° C for 30 minutes and then the ice bath is removed to allow the reaction to warm to room temperature for one hour. The reaction is stirred at room temperature for two additional hours at which point the TLC confirms that the reaction is complete. A pH test and a reflux condenser are attached to the reaction flask. The reaction previously sprayed with argon is acidified with a 3N HCl solution at a pH between 8 and 9. The mixture is warmed to 40 ° C (internal temperature test) and further acidified to a pH of 2 with vigoroza agitation. The resulting slurry is stirred at a temperature of 40 ° C for 30 minutes and then allowed to cool to room temperature for 1 hour. The product is collected by filtration and washed with distilled water (80 ml volumes) until the wash water negative test for chloride with a silver nitrate solution. The product is washed with additional water (2x25 ml) and air-dried for 30 minutes. The product is washed with methyl tert-butyl ether (2x10 ml) and hexane (2x10 ml)., dried with air, and dried under high vacuum overnight to provide 4.0 g of the title product (94% yield) as a white crystalline solid; p.f. 205-207 ° C (decomp.); [α] D = -68.0 ° C (c = 1, dimethylformamide). TLC: Rf = 0.63 (silica gel, 2% acetic acid / ethyl acetate, visualized by UV light and ceric sulfate / ammonium molybdate). Analysis calculated for C? 9H24N2? 4S2 * l .1 H20: C, 55.25; H, 5.98; N, 6.78; S, 15.52 Found: C, 55.10; H, 5.87; N, 6.74; S, 15.33 EXAMPLE 2 Acid [S- (R *, R *)] -hexahydro-6- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -2,2-dimethyl-7-oxo-lH-azepine- l-acetic Ethyl esters of [S- (R *, R *)] -hexahydro-6- [(2- (acetylthio) -l-oxo-3-phenylpropyl) amino] -2, 2-dimethyl-7-oxo-lH azepine-1-acetic, (2.0 g, 4.46 mmol) [prepared as described in Example 66 (g) of US Patent 5 / 552,397] is dissolved in methanol (9 ml) in a 100 ml flask equipped with an addition funnel, an internal temperature test and an argon inlet. To the solution is added DL-dithiothreitol (34 mg, 0.22 mmol). The solution is sprayed with argon for 15 minutes and then maintained under an argon atmosphere. The solution is cooled to 0 ° C in an ice bath. In the addition funnel, a solution of IN sodium hydroxide (26.8 ml, 26.8 mol) is sprayed with argon for 30 minutes. The sprayed sodium hydroxide solution is added to the reaction flask for 30 minutes so that the internal temperature does not exceed 5 ° C. The reaction is allowed to stir at 0 ° C for 30 minutes and then the ice bath is removed to allow the reaction to warm to room temperature for one hour. The reaction is stirred at room temperature for an additional 1.5 hours at which point the TLC confirms that the reaction is complete. A pH test and a reflux condenser are attached to the reaction flask. The reaction previously sprayed with argon is acidified with a 3N HCl solution to a pH of 6. A little bit of seeded crystals are added and the mixture is stirred for 5 minutes. The mixture is then acidified to a pH of 2. The resulting slurry is stirred at room temperature for 1 hour. The product is collected by filtration and washed with distilled water until the wash water negative test for chloride with a silver nitrate solution. The product is air-dried for 30 minutes, washed with tert-butyl methyl ether (2 × 4, 1) and hexane (2 × 4 ml), air dried, and dried under high vacuum to provide 1.5 g of the title product as a white crystalline solid (89% yield), mp from 176 ° C to 177 ° C; [a] D = -18.1 ° C (c = 1.0, chloroform). TLC: Rf = 0.51 (silica gel, 2% acetic acid / ethyl acetate, visualized by UV light and ceric sulfate / ammonium molybdate). Analysis calculated for: C? 9H26N2? 4S «2.6 H20: C, 60.30; H, 6.92; N, 7.40; S, 8.47. Found: C, 60.02; H, 6.81; N, 7.34; S, 8.60.

EXAMPLE 3 Methyl ester of [4S- [4a (R *) / la, lOaß]] -octahydro-4- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -5-oxo-7H-pyrido acid [2, 1-b] [1,3] thiazepine-7-carboxylic acid.

Methyl ester of [4S- [4a (R *), la, 10aß]] - octahydro-4- [(2- (acetylthio) -l-oxo-3-phenylpropyl) amino] -5-oxo-7H-pyrido acid [2, 1-b] [1, 3] thiazepine-7-carboxylic acid (700 g, 1.51 mol) is dissolved in methanol (7.7 L) in a 10 L flask equipped with an internal temperature test and an Argon inlet . To the solution is added D, L-dithiothreitol (24.6 g, 0.16 mol). The solution is completely purged with argon for 30 minutes. The solution is cooled to -15 ° C and finally ground potassium carbonate (311.6 g, 2.25 moles) is added with stirring. After completion of the reaction (no starting material was detected by either TLC or HPLC), the potassium carbonate is removed by filtration. The filter cake is washed with methanol (400 ml). The filtrate temperature is maintained at 0 ° C while it is transferred to another 10 L flask. Concentrated HCl (280 ml) which has been purged with argon is added rapidly with stirring. The desired product immediately crystallized and the resulting suspension is stirred at 10 ° C for 30 minutes. Ice water (3.5 L) are added and the suspension is stirred at 0 ° C for one hour. The crystals are collected by filtration. The product is washed with 1.8 L of methanol / water (2: 1) at 0 ° C followed by 1 L of ice water and finally washed twice with 1 L portions of tert-butyl methyl ether and dried to give 594 g (93.5%) of the title compound as a solid.

EXAMPLE 4 [4S- [4cc (R *), la, IQaß]] -octahydro-4- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -5-oxo-7H-pyrido methyl ester. [2, 1-b] [1, 3] thiazepine-7-carboxylic acid.

A slurry of the hydroiodide of the methyl ester of [4S- [4a (R *), la, lOaß]] -4-aminooctahydro-5-oxo-7H-pyrido [2, 1-b] [1, 3] thiazepine- 7-carboxylic (150 g, 0.388 mol) and dicyclohexylamine salt of a- (acetylthio) benzene-prppanic acid, (181.2 g, 0.447 mol) in methylene chloride (525 ml) is cooled to about -20 ° C and treated with a slurry of N-ethyl-N'-dimethylaminopropylcarbodiimide (100.5 g, 0.524 mol) in methylene chloride (500 ml) while maintaining the crucible temperature at less than -5 ° C. Additional methylene chloride (175 ml) is used to complete the carbodiimide transfer. The reaction is stirred at -5 ° C. at -12 ° C until complete, determined by HPLC (about 18 hours). The cold reaction is filtered in dilute phosphoric acid (450 ml, 1: 3 v / v 85% phosphoric acid in water) and the filter cake is washed with methylene chloride (3x100 ml). The filtrate phases are separated and the terbutyl methyl ether (1000 ml) is added to the organic layer. The solvents removed under vacuum at a crucible volume of about 900 ml and the slurry is filtered. The filter cake is washed with tert-butyl methyl ether (3x55 ml) and the filtrate is diluted with tert-butyl methyl ether (750 ml). The organic phase is washed with dilute phosphoric acid (450 ml 1: 3 v / v 85% phosphoric acid in water), aqueous sodium bisulfite (3% w / v, 450 ml) and 5% aqueous sodium chloride (450 ml). The organic solution is filtered to remove any insoluble material and treated with D, L-dithiothreitol (6g). Gated methanol (2000 ml) is added and the solvents are distilled to about 20 mm of mercury until the crucible volume is about 2200 ml. The solution of methyl ester of [4S- [4a (R *), la, lOaß]] -octahydro-4- [(2- (acetylthio) -l-oxo-3-phenylpropyl] amino] -5-oxo- 7H-pyrido [2, 1-b] [1, 3] thiazepine-7-carboxylic acid is cooled from 0 ° C to 5 ° C and treated with 40% aqueous methylane (150 ml) while maintaining the temperature of crucible at less than 5 ° C. The reaction is stirred for about 30 minutes and the pH is adjusted to 7.5-8.3 using concentrated HCl (155 ml) containing D, L-dithiothreitol (2% w / v). The resulting product is stirred for 30 minutes at 5 ° C, the pH is readjusted to 7.5-8.3, if necessary, and the product is filtered and washed with cold methanol / water 3: 1 (3x300 ml). 1 g of the title product The above procedure is also carried out with the following modifications: A wash of sodium bicarbonate is used before treatment with D, L-dithiothreitol, acetonitrile is completed in place of methanol after treatment with D , L-dithiothrethol, and the pH is just using D, L-dithiothreitol in acetic acid instead of concentrated HCl.

EXAMPLE 5 Acid [S- (R *, R *), hexahydro-6- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -2, 2-dime i1-7-oxo-lH-azepine- 1-acetic a) 1, 1-dimethylethyl ester of [S- (R *, R *) -6- [(2- (acetylthio) -l-oxo-3-phenylpropyl) amino] hexahydro-2, 2-dimethyl-7 -oxo-lH-azepina-l-acetic.

A solution of 1, 1-dimethylethyl acid ester (S) -6-aminohexahydro-2, 2-dimethyl-7-oxo-lH-azepine-1-acetic acid (0.781 g, 2.8 mmol) in methylene chloride (11 ml) is cooled in an ice water bath and triturated, (S) -2- (acetylthio) benzene-phoraoic acid (0.641 g, 2.86 mol) is added. A clear solution is obtained in one minute. The 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.642 g, 3351 moles) are added and the mixture is stirred for 2.5 hours.

The solvent is evaporated and the residue is taken up in ethyl acetate (25 ml) and IN HCl (15 ml). The aqueous layer is separated and extracted with ethyl acetate (25 ml). The combined organic extracts are washed thoroughly with IN HCl (2x15 ml), brine, saturated aqueous sodium bicarbonate (2x10 ml) and brine (10 ml). The solution is dried with sodium sulfate and evaporated to provide 1.32 g (93% yield) of the title product as a white foam. [α] D = -48.9 ° (c = 1, ethyl acetate). Analysis calculated for C25H36N2Os * 0.4H2 ?: C, 62.06; H, 7.67; N, 5.79; S, 6.63 Found: C, 62.28; H, 7.63; N, 5.75; S, 6.44. b) [S- (R *, R *) -6- [(2- (acetylthio) -l-oxo-3-phenylpropyl) amino] hexahydro-2, 2-dimethyl-7-oxo-lH-azepine- l- acetic The trifluoroacetic acid (9.0 ml, 126 mmol) is added to a solution of the product from part (a) (3.75 g ', 7.88 mmole) in methylene chloride (30 ml). After 5 hours, dibasic sodium phosphate (8.4 g, 59.1 mmol) dissolved in water (50 ml) is added to the cooled reaction mixture in an ice bath. The pH of the mixture drops to 1.4 and is adjusted to 2.9 with sodium hydroxides ION. The layers are separated and the organic layer is washed with a solution of sodium dibasic phosphate (0.5 g) in water (25 ml) then the pH is adjusted to 2.9 with concentrated HCl. The layers are washed again with methylene chloride (5 ml). The combined organic layers are dried with sodium sulfate and evaporated. The residue is dissolved in methylene chloride (6 ml) and heptane (24 ml), this is added slowly with stirring for 20 minutes. The resulting mass of crystals is stirred overnight, filtered, washed with methylene chloride / heptane (1: 9), and heptane, and dried under vacuum to provide 3.08 (93% yield) of the title product as crystals. colorful; p.f. 160-161 ° C; [a] D = -46.6 ° (c = 0.7, chloroform). Analysis calculated for C2? H28N2? S »0.023H2O: C, 59.47; H, 6.67; N, 6.59; S, 7.54 Found: C, 59.29; H, 6.61; N, 6.55; S, 7.56. c) [S- (R *, R *) -hexahydro-6- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -2,2-dimethyl-7-oxo-lH-azepine-1 acid -acetic In a 100 ml flask equipped with an additional funnel, an internal temperature test, an argon inlet, the product title of part (b) (2.0 g, 4.76 mmol) and D, L-dithiothreitol (0.037 g, 0.24) mmoles) are stirred in methanol (6.4 ml). The suspension is sprayed with argon for 10 minutes, cooled to 1 ° C, and then kept under argon. In the additional funnel, a solution of IN sodium hydroxide (19 ml, 19 mmol) was sprayed with argon for 15 minutes. The sprayed sodium hydroxide solution is added to the reaction flask for 20 minutes so that the internal temperature does not exceed 5 ° C. The reaction is stirred at 1 ° C for 30 minutes, and then the ice bath is removed to allow the reaction to warm to room temperature for 1 hour. A pH test and a reflux condenser is attached to the reaction flask. The reaction is acidified with a 3N HCl solution previously sprayed to a pH of 6. The reaction is warmed to 0 ° C (internal temperature test). Seed crystals of the desired product are added, and the mixture is further acidified with 3N HCl with stirring at pH 2. The resulting slurry is stirred at 40 ° C for 30 minutes and then allowed to cool to room temperature for 1 hour. The product is collected by filtration and washed with distilled water (about 30 ml) until the wash water negative test for chloride with a silver nitrate solution. The product is air-dried for 30 minutes, washed with tert-butyl methyl ether (2 × 4 ml) and hexane (2 × 4 ml), dried with air, and under high vacuum overnight to provide 1.67 g (93%) of the title product. as a white solid having the same analytical values as in Example 2.

EXAMPLE 6 Acid [4S- [4a (R *), la, IQaß]] -octahydro-4- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -5-oxo-7H-pyrido [2, 1- b] [1,3] thiazepine-7-carboxylic acid.

The D, L-dithiothreitol (10.4 g) is dissolved in methanol (3250 ml) and purged with inert gas to remove the oxygen. The solution is cooled to 0 to -5 ° C and the methyl ester product of Example 4 (296 g) is added. While stirring, 3N sodium hydroxide (1400 ml) is added at a rate such that the temperature is maintained at 0-5 ° C. After stirring for an additional 30 minutes, the reaction is warmed to room temperature. When the reaction is complete, the pH is adjusted to 1.6-2.0 by the addition of 3N HCl (1500 ml) resulting in the crystallization of the product. During the addition of HCl the temperature rises to 30-35 ° C. The water (2800 ml) is then added, the slurry is cooled to room temperature in about 1 hour, and stirred for an additional hour. The product is filtered and washed with water (4 × 500 ml) and the terbutil methyl ether (4 × 500 ml). The product is then dried to provide 272.4 g of the title product having the same analytical values as in Example 1.

EXAMPLE 7 Acid [4S- [4a (R *) la, lOaß]] -octahydro-4- [(2-mercato-l-oxo-3-phenylpropyl) amino] -5-oxo-7H-pyrido [2 , 1- b] [1,3] thiazepine-7-carboxylic acid.

All operations are carried out in an argon atmosphere and all transfers are made using cannulas to minimize the exposure of the substrate and the product to the oxygen atmosphere.Insugar dehydrated hydroxide (376 g, the level of dissolved oxygen is less than or equal to 5%) is added to a 1-liter four-necked flask equipped with a mechanical stirrer, a pH electrode, a thermocouple and an argon inlet, which contains the methyl ester product of Example 4 (50 g) and D, L-dithiitritol (1.8 g) The reaction solution is stirred at 20 ° ± 10 ° C until the hydrolysis is considered complete (HPLC assay, hydrolysis is completed in about one hour after the addition Sodium hydroxide is completed.) The product solution is filtered by refining to remove any particles, and the hydrolysis vessel and the refinement filter are washed with water (50 g) .The filtrates are combined in a four-necked flask of 1 liter equipped with a mechanical agitator, a pH electrode, a thermocouple and an argon inlet. With vigorous stirring, the title compound is crystallized at 20 ° ± 10 ° C by the addition of degassed IN acetic acid (401 g, the dissolved oxygen level is less than or equal to 5%), at a final pH of 5.5 ± 0.5 The glass slurry is stirred at 20 ± 10 ° C for at least one hour, collected on a filter (an inert atmosphere is no longer used), and the wet cake is washed with water (3 × 100 g). The wet cake is dried in vacuo to yield 45.1 g of the title product as a white crystalline powder having the same analytical values as in Example 1.

EXAMPLE 8 Recrystallization of the acid [4S- [4a (R *), la, 10aß]] - octahydro-4- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -5-oxo-7H-pyrido [ 2, 1-b] [1,3] thiazepine-7-carboxylic acid.

All operations are carried out in an argon atmosphere and all transfers are made using cannulas to minimize the exposure of the substrate and the product to the oxygen atmosphere. A solution of degassed alcohol (302 g of concentrated ethanol and 87 g of methanol, containing less than or equal to 5% of oxygen) is added to a 1 liter flask equipped with a mechanical stirrer, a reflux condenser, thermocouple, and an argon inlet containing the acid [4S- [4a (R *), la, lOaß]] -octahydro-4- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -5-oxo-7H [2, 1-b] [1,3] thiazepine-7-carboxylic acid (11 g) and D, L-dithiothreitol (1.1 g). The resulting slurry is heated to reflux (about 75 ° C) for about two hours to dissolve the solids. After cooling the solution to about 60 ° C, refinement filtration is performed to this in a 1-liter four-necked flask equipped with a mechanical stirrer, a reflux condenser, a thermocouple and an argon inlet. The dissolution vessel and the cooling filter are washed with methanol (5g). With stirring, the combined filtrates are cooled to 20 ° + 10 ° C, and kept at this temperature for at least one hour. The product is collected on a filter (no further time is required in the inert atmosphere) and the wet cake is washed with methanol (3x15 g). The wet cake is dried in vacuo to yield 8.74 g of the title product as a white crystalline powder.

EXAMPLE 9 Reprocessing the acid [S- (R *, R *) -hexahydro-6- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -2, 2-dimethyl-7-oxo-lH-azepine -1-acetic The acid [S- (R *, R *) -hexahydro-6- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -2, 2-dimethyl-7-oxo-lH-azepine-l- acetic acid (5 g, 13.2 mmol), HPLC 99.6 percent area), and D, L-dithiothreitol (180 mg, 1.67 mmol) are charged to a three-necked flask. The flask is filled with nitrogen and placed in an ice bath. A solution of cold deoxygenated sodium hydroxide (2 ° C) (1.22 N, 40 ml) is added slowly while maintaining the reaction temperature below 10 ° C. After the addition is complete, the cooling is removed and the resulting solution is allowed to warm to room temperature. The solution is heated to about 45 ° C and a solution of deoxygenated acetic acid (1.06 N, 50 ml) is added while maintaining the temperature of the mixture at about 45 ° C. The glass slurry is stirred at about 45 ° C for 30 minutes and then allowed to cool to room temperature. After stirring at room temperature for 30 minutes, the product is filtered, washed with water (50 ml) and dried in a vacuum oven at 51 ° C / 4.9 inches Hg to yield 4.65 g of the title compound having a Laboratory HPLC of 99.9 percent area.

EXAMPLE 10 Acid [S- (R *, R *) -hexahydro-6- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -2,2-dimethyl-7-oxo-lH-azepine-1 -acetic A three-necked flask is charged with acid [S- (R *, R *) -6- [(2- (acetylthio) -l-oxo-3-phenylpropyl) amino] hexahydro-2, 2-dimethyl-7- oxo-lH-azepine-1-acetic acid (10 g, 23.78 mmol) and D, L-dithiothreitol (390 mg, 2.5 mmol). The flask is filled with nitrogen. Deoxygenated water (20 ml) is added to the flask and the mixture is cooled to 1 ° C. A solution of cold deoxygenated sodium hydroxide (1 ° C) (1.22 N, 70 ml, 84 mmol) is added slowly while maintaining the temperature of the reaction mixture between 1 ° C and 4 ° C. After the addition of 10% v / v of the sodium hydroxide solution, the remaining solution is added, keeping the reaction temperature between -2 ° C to 3 ° C. After stirring the reaction mixture at -2 ° C to 6 ° C for 30 minutes, the reaction mixture is allowed to warm to room temperature. A refining filtration is performed on the reaction mixture in a crystallization flask and heated to 45 ° C. A solution of deoxygenated acetic acid (1.06 N, 90 ml, 95 mmol) is added while maintaining the reaction temperature between 41 ° C and 46 ° C. The glass slurry is stirred at 41 ° C and 46 ° C for 20 minutes and then allowed to cool to room temperature. After stirring at room temperature for 30 minutes, the product is filtered and washed with water (100 ml) and dried in a vacuum oven at 51 ° C / 4.1 inches Hg to produce 8.45 g of the title product having a Laboratory HPLC of 99.75 percent area.

EXAMPLE 11 Acid [S- (R *, R *) -hexahydro-6- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -2,2-dimethyl-7-oxo-lH-azepine-1 -acetic a) [S- (R *, R *) -hexahydro-6- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -2,2-dimethyl-7-oxo-lH- ethyl ester azepine-1-acetic.

Under an inert atmosphere, a methylene chloride solution (25 ml) of (S) -2- (acetylthio) benzenepropanoic acid (4.8 g) is cooled to -11 ° C and chloride (chloromethylene) dimethylammonium (3.9 g) is added. The reaction mixture is stirred between -14 ° C and -5 ° C for 2 hours. To a separate reaction vessel, the camphorsulfonic acid salt of (S) -6-aminohexahydro-2,2-dimethyl-7-oxo-lH-azepine-1-acetic acid ethyl ester (10 g), potassium bicarbonate (12 g), methylene chloride (25 ml), and water (50 ml) are charged. After 10 minutes of stirring a biphasic solution is obtained and cooled to 0 ° C. With vigorous stirring, a (S) -2- (acetylthio) benzenepropanoyl methylene chloride solution is added to the biphasic reaction mixture maintaining the pH in the range of 6.8 to 8.5 and the temperature between 0 to 5 ° C. Once the reaction is considered completed by the HPLC assay in the process, the phases are separated and the product rich in the organic phase is concentrated to an oily residue under reduced pressure. The oily residue is dissolved in isopropanol (50 ml), concentrated to a residue one more time and the resulting residue is dissolved in isopropanol (40 ml). The resulting solution is cooled to 0 ° C and deoxygenated by spraying it with nitrogen for at least 15 minutes. D, L-dithiothreitol (220 mg) and ethanolamine (4 ml) are charged and the reaction mixture is stirred at 0 ° C until the reaction is considered to have completed an HPLC analysis. The pH of the reaction mixture (at 10 ° C) is adjusted to 8.56 using an IN-deoxygenated acetic acid solution (40 ml) to produce a glass slurry. The pH of the glass slurry is further adjusted to 7.36 using glacial acetic acid (6 drops). After cooling, the glass slurry is stirred at 0 ° C for 30 minutes, filtered, and the wet cake is washed with cold (3%) aqueous isopropanol (1: 1, 4.4 ml). Initially the product is dried by suction for 1.5 hours under a nitrogen atmosphere and finally dried in a vacuum oven at 41 ° C to produce 7.51 g (87.6%) of the title compound. b) [S- (R *, R *) -hexahydro-6- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -2, 2-dimethyl-7-oxo-lH-azepine-l acid -acetic The product of part (a) (5 g), D, L-dithiothreitol (130 mg) and deoxygenated water (18 ml) are charged to a reaction vessel. Under an inert atmosphere, the mixture is stirred at room temperature and a solution of sodium hydroxide (17.5 ml, 2.2 N approximately) is charged while maintaining the temperature between 21 ° and 25 ° C. A clear solution is observed for 5 minutes after sodium hydroxide has been added and the reaction mixture is stirred until the reaction is considered complete by an HPLC assay. The solution is heated to 45 ° C and deoxygenated acetic acid (43 ml, approximately 1 N) is added to adjust the pH of the product slurry to 5.9. The product slurry is stirred at 45 ° C for 30 minutes, cooled to room temperature, filtered and washed with water (50 ml). The wet cake is dried in a vacuum oven at 61 ° C to yield 4.2 g (90.3% M) of the title compound.

EXAMPLE 12 Recrystallization of the acid [4S- [4a (R *), la, IQaß]] - octahydro-4- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -5-oxo-7H-pyrido [ 2, 1-b] [1,3] thiazepine-7-carboxylic acid.

A flask containing [4S- [4a (R *), la, 10aß]] - octahydro-4- [(2-mercapto-l-oxo-3-phenylpropyl) amino] -5-oxo-7H-pyrido [ 2, 1-b] [1, 3] thiazepine-7-carboxylic acid (50.42 g, 123.42 irimoles) and D, L-dithiothreitol (1.915 g, 12.41 mmol) is deoxygenated and treated with a deoxygenated sodium hydroxide solution (0.5N, 1.3 eq). The product dissolves between 3 to 5 minutes to provide a solution with a pH of 8-8.5. The resulting pale pink colored solution is filtered under nitrogen in a crystallizer, and the solution flask and filter are washed with deoxygenated water. The product is crystallized by the addition of deoxygenated aqueous acetic acid (1.5 equivalents) which is prepared by dissolving glacial acetic acid (11.11 g, 10.59 ml, 186.8 mmol) in deionized water (175.7 ml) and then deoxygenated by bubbling with nitrogen. The resulting acetic acid solution is added between 10-15 minutes and the pH drops from 8.1 to 7.2. After the initial crystallization, additional deoxygenated IN acid is added 10 to 15 minutes to complete the crystallization. The final pH of the slurry is 5.3. The product slurry is stirred for 1 hour at 15-25 ° C, filtered and washed with water and tert-butyl methyl ether. The desired product is dried under vacuum at 35-45 ° C for 16 hours to yield 49.39 g of the product (98% yield by weight) having a purity greater than 99%.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (16)

CLAIMS 1. A process of deprotection to convert an acylmercaptoalkanoylaminolactamic acid or ester of formula (II) 0 0 II * II R2-C S-. { 2) u CH-C-Xi Ri to a mercaptoalkanoylamino lactam acid or ester of formula or to convert the mercaptoalkanoyl lactamyl ester of formula I to the corresponding lactam acid of formula I characterized in that: Xi is a lactam selected from (IV) (V) (VIII) W (XII) (CH2), II COOR12 (XV) (XVT) (XVIII) - 59 (XIX) (XX) (XXI) (XXIII) Ri and Re are independently selected from straight or branched chain alkyl of 1 to 6 carbon atoms - (CH 2) m -aryl, - (CH 2) m-substituted aryl, or - (CH 2) m -heteroaryl; m is zero or an integer from 1 to 6; n is zero or one; R4 and Rs are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, - (CH2) m-cycloalkyl, - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl, or one of R4 and Rs is hydrogen and the other is hydroxy or R4 and R5 taken together with the carbon to which they are bound completely to a saturated cycloalkyl ring of 3 to 7 carbon atoms, or R4 and R5 taken together with the carbon to which they are bonded completely to a keto substituent. Re, Re and Rio are independently selected from hydrogen, alkenyl, saturated alkyl, alkenyl - (CH2) m-cycloalkyl, - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH) m-heteroaryl. R, Rg and Rn are independently selected from hydrogen, alkyl, saturated alkyl, alkenyl - (CH2) m-cycloalkyl, - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl, or Re and R7 taken together with the carbon to which they are fully attached to a cycloalkyl ring saturated with 3 to 7 carbon atoms, R8 and Rg taken together with the carbon to which they are completely attached to a saturated cycloalkyl ring of 3 to 7 carbon atoms, b is zero or one; d is zero or one; q is-an integer from 1 to 4; r is one or two; t is an integer from 1 to 3; v is one or two; w is one or two; Yi is -CH2-, - (CH) 2-, - (CH2) 3-, -O-, -S-, -CH2-0-, or -CH2-S-; Y2 is -CH2-, -S-, or -O-; Y3 is -CH2-, - (CH2) 2, - (CH2) 3- / -O-, or -CH2-0-; Z is O or two hydrogens; Ri7 is hydrogen, alkyl, substituted alkyl, alkenyl, - (CH2) m-cycloalkyl, - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl. Y5 is -CH2-, -S-, or provided that Y5 is -S- or -O- only when d is one; Y6 is -S- or -O-; The dashed line represents an optional double bond between the two carbons; Represents an aromatic heteroatom containing a ring selected from Y7 is -S- or -NH-; Y8 is -S-, -O-, or -NH-; Ri8 and R19 are independently selected from hydrogen, alkyl, - (CH2) m-aryl, or R? 8 and Ri9 together with the carbon and nitrogen atoms to which they are fully attached to a ring having five to six members; Ri2 is a hydrogen or an acid protecting group such as methyl, ethyl, propyl, phenyl or benzyl; which comprises; a) when Ri2 in the definition of Xi in formula II is hydrogen, the treatment of acylmercaptoalkanoylaminolactamic acid of formula II with an alkali metal or an alkali metal hydroxide or carbonate or an amine in a suitable solvent containing a sufficient amount of an agent that minimizes the amount of disulfide of the formula (III) followed by treatment with an aqueous acid to precipitate the desired lactam acid of formula I; or b) when Ri2 in the definition of Xi in formula II is an acid protecting group, the treatment of the acylmercaptoalkylaminolactamyl ester of the formula ir- under aqueous conditions with an alkali metal or an alkali metal hydroxide or carbonate in a suitable solvent which contains a sufficient amount of an agent which minimizes the amount of disulfides of formula III followed by a treatment with an aqueous acid to precipitate the desired lactam acid of formula I; or c) when Rl2 in the definition of Xj. in formula II is an acid protecting group, the treatment of the acylmercaptoalkanoylaminolactam ester of formula II under non-aqueous conditions with an alkali metal or an alkali metal hydroxide or carbonate in a suitable solvent containing a sufficient amount of a minimizing agent the amount of disulfides of formula III or the treatment of the acylmercaptoalkanoylaminolactamyl ester of formula II under aqueous conditions with an amine in a suitable solvent containing a sufficient amount of an agent that minimizes the amount of disulfides of formula III to remove the acyl protecting group R2-C (0) - and provide the mercaptoalkanoylamino lactam ester of formula I; or d) treatment of the mercaptoalkanoyl lactam ester of formula I under aqueous conditions with an alkali metal or an alkali metal hydroxide or carbonate in a suitable solvent containing a sufficient amount of an agent that minimizes the amount of disulfides of formula III followed by treatment with an aqueous acid to precipitate the desired mercaptoalkanoyl lactam acid of formula
1. I.
2. 2. The process according to claim 1 characterized in that the agent that minimizes the amount of disulfides of formula III is a bismercaptan of formula (XXVI) wherein K is an integer from 1 to 4 and each X2 is independently selected from a hydrogen and hydroxy, or bismercaptan in 1,2-benzenedimethanethiol, 1,3-butanedithiol meso-a, a'-dimercaptoadipic, disodium, or durene-a (1), a (2) -dithiol, or the agent is a reducing agent is a phosphine or phosphite, or the agent is a zinc metal powder, or the agent is a sodium hydrosulfite.
3. 3. The process according to claim 2 characterized in that: Xi is a lactam of the formula (IV) R4 and Rs are both hydrogen; R6 and R7 are both methyl; Rio and R11 are both hydrogen; b is zero; That is two; - in the acylmercaptoalkanoylamino lactam of formula II is hydrogen, methyl, ethyl, propyl, phenyl or benzyl and R 12 in the mercaptoalkanoylamino lactam of formula I is hydrogen; n is zero; Ri is benzyl and; the agent that minimizes the amount of disulfide of formula III and, in turn, minimizes the formation of the unwanted epimer of the pharmaceutically active compound of formula I is dithiothreitol bismercaptan or dithioerythritol.
4. 4. The process according to claim 3 characterized in that: a) the acylmercaptoalkanoylaminolactamic acid of formula II is the acid [S- (R *, R *)] -hexahydro-6- [[2- (acetylthio) -l-oxo-3-phenylpropyl] amino] -2, 2 -dimethyl-7-oxo-lH-azepine-1-acetic acid which is dissolved in methanol and treated with D, L-dithiothreitol and sodium hydroxide; Y b) Following with the termination, the above reaction mixture is treated with aqueous hydrochloric acid to precipitate the acid [S- (R *, R *)] -hexahydro-6- [[2-mercapto-l-oxo-3-] phenylpropyl] amino] -2,2-dimethyl-7-oxo-lH-azepine-1-acetic acid; or the process according to claim 3, characterized in that: a) the acylmercaptoalkanoylaminolactamyl ester of formula II is the ethyl ester of [S- (R *, R *) j-hexahydro-6- [[2- (acetylthio) -l-oxo-3-phenylpropyl] amino] - 2, 2-dimethyl-7-oxo-lH-azepine-1-acetic acid which is dissolved in methanol and treated with D, L-dithiothreitol and sodium hydroxide under aqueous conditions; and b) following the termination, the above reaction mixture is treated with aqueous hydrochloric acid to precipitate the acid [S- (R *, R *)] -hexahydro-6- [[2-mercapto-l-oxo-3-] phenylpropyl] amino] -2,2-dimethyl-7-oxo-lH-azepine-1-acetic acid; or the process according to claim 3, characterized in that: a) the acylmercaptoalkanoylaminolactamic acid of formula II is the acid [S- (R *, R *)] -hexahydro-6- [[2- (acetylthio) -l] -oxo-3-phenylpropyl] amino] -2, 2-dimethyl-7-oxo-lH-azepine-1-acetic which is mixed in water and treated with D, L-dithiothreitol and sodium hydroxide; and b) following the termination, the above reaction mixture is treated with acetic acid to precipitate the acid [S- (R *, R *)] -hexahydro-6- [[2-mercapto-l-oxo-3-phenylpropyl] ] amino] -2,2-dimethyl-7-oxo-lH-azepine-1-acetic acid; or the process according to claim 3, characterized in that; a) the acylmercaptoalkanoylaminolactamyl ester of formula II is the ethyl ester of [S- (R *, R *)] ~ hexahydro-6- [[2- (acetylthio) -l-oxo-3-phenylpropyl] amino] - 2, 2-dimethyl-7-oxo-lH-azepine-1-acetic acid which is dissolved in isopropanol and treated with D, L-dithiothreitol and hydroxide and ethanolamine under aqueous conditions to provide ethyl ester of [S- (R *, R *)] -hexahydro-6- [[2-mercapto-l-oxo-3-phenylpropyl] amino] -2,2-dimethyl-7-oxo-lH-azepine-1-acetic; and b) the product of part (a) is mixed in water and treated with D, L-dithiothreitol and sodium hydroxide and following completion, the above reaction mixture is treated with acetic acid to precipitate the acid [S- ( R *, R *)] -hexahydro-6- [[2-mercapto-l-oxo-3-phenylpropyl] amino] -2,2-dimethyl-7-oxo-lH-azepine-1-acetic; or
5. 5. The process according to claim 2, characterized in that: Xi is a lactam of formula (XV) Ye is S; Y5 is CH2; d is one; v is two; and R 12 in the acylmercaptoalkanoylamino lactam of formula II is hydrogen or methyl and R 12 in the mercaptoalkanoylamino lactam of formula I is hydrogen.
6. 6. The process according to claim 5 characterized in that: a) the acylmercaptoalkanoylaminolactamyl ester of formula II is the methyl ester of [4S- [4a (R *), la, lOaß]] -octahydro-4- [[2- (acetylthio) -l-oxo-3-phenyl-propyl] amino] -5-oxo-7H-pyrido [2, 1-b] [1, 3] thiazepine-7-carboxylic acid, which is dissolved in methanol and treated under aqueous conditions with D, L-dithiothreitol and sodium hydroxide; and b) following the termination, the above reaction mixture is treated with hydrochloric acid to precipitate the acid [4S- [4a (R *), la, lOaß]] -octahydro-4- [[2- mercapto-l-oxo] -3-phenylpropyl] amino] -5-oxo-7H-pyrido [2, 1-b] [1, 3] thiazepine-7-carboxylic acid.
7. 7. The process according to claim 2 characterized in that: Xi is a lactam of the formula (XV) d Y6 is S; Y5 is CH2; d is one; v is two; and R 12 in the lactam esters of formula I and II is the same and is methyl, ethyl, propyl, phenyl or benzyl; n is zero;; Ri is benzyl; and the agent that minimizes the amount of the disulfide of formula III and, in turn, minimizes the formation of the undesired epimer of the pharmaceutically active compound of formula I is dithiothreitol bismercaptan or dithioerythritol.
8. 8. The process according to claim 7 characterized in that: a) the acylmercaptoalkanoylaminolactamyl ester of formula II is the methyl ester of [4S- [4a (R *), 7a, lOaß]] -octahydro-4- [[2- (acetylthio) -l-oxo-3-phenyl-propyl] amino] -5-oxo-7H-pyrido [2, 1-b] [1, 3] thiazepine-7-carboxylic acid, which is dissolved in methanol and treated under non-aqueous conditions with D, L-dithiothreitol and potassium carbonate to provide the mercaptoalkanoylaminolactamyl ester of formula I the methyl ester of the acid Í4S- [4a (R *), 1a, lOaβ]] -octahydro-4- [( 2-mercapto-l-oxo-3-phenyl-propyl] amino] -5-oxo-7H-pyrido [2, 1-b] [1, 3] thiazepine-7-carboxylic acid, or the process according to the claim 7 characterized in that: the acylmercaptoalkanoylaminolactamyl ester of formula II is the methyl ester of [4S- [4a (R *), la, lOaß]] -octahydro-4- [[2- (acetylthio) -l-oxo-3] methyl ester phenylpropyl] amino] -5-oxo-7H-pyrido [2, 1-b] [1, 3] thiazepine-7-carboxyl co, which is dissolved in methanol or acetonitrile and treated under aqueous conditions with D, L-dithiothreitol and methylamine to give the mercaptoalkanoylamino lactam ester of formula I the methyl ester of [4S- [4a (R *), 7a, lOaß]] -octahydro-4- [(2-mercapto-l-oxo-3-phenyl-propyl] amino] -5-oxo-7H-pyrido [2, 1-b] [1, 3] thiazepine-7 carboxylic
9. 9. The process according to claim 2 characterized in that: Xi is a lactam of the formula (XV) ej Y6 is S; Y5 is CH2; d is one; v is two; R 12 in the mercaptoalkanoylamino lactam ester of formula I is methyl, ethyl, phenyl or benzyl and R 2 in the mercaptoalkanoylamino lactam acid of formula I is hydrogen; n is zero; Ri is benzyl; and The agent that. minimizes the amount of disulfide of formula III and, in turn, minimizes the formation of the undesired epimer of the pharmaceutically active compound of formula I is dithiothreitol bismercaptan or dithioerythriol.
10. 10. The process according to claim 9 characterized in that: a) the mercaptoalkanoylamino lactam ester of formula I is the methyl ester of [4S- [4a (R *), la, 10aß]] - octahydro-4- [(2- mercapto-l-oxo-3-phenyl-propyl] amino] -5-oxo-7H-pyrido [2, 1-b] [1,3] thiazepine-7-carboxylic acid, which is dissolved in methanol and treated aqueous conditions with D, L-dithiothreitol and sodium hydroxide followed by aqueous acetic acid or hydrochloric acid to precipitate the acid [4S- [4a (R *), 1a, lOaβ]] -octahydro-4- [(2- mercapto-l-oxo-3-phenyl-propyl) amino] -5-oxo-7H-pyrido [2, 1-b] [1,3] thiazepine-7-carboxylic acid; or b) the mercaptoalkanoylamino lactam ester of formula I is the methyl ester of [4S- [4a (R *), la, 10aß]] - octahydro-4- [(2-mercapto-l-oxo-3-phenyl-propyl) ) amino] -5-oxo-7H-pyrido [2, 1-b] [1, 3] thiazepine-7-carboxylic acid, which is mixed in water and treated with D, L-dithiothreitol and sodium hydroxide followed by aqueous acetic acid or hydrochloric acid to precipitate the acid [4S- [4a (R *), la, 10aß]] - octahydro-4- [(2-mercapto-l-oxo-3-phenyl-propyl) amino] -5 -oxo-7H-pyrido [2, 1-b] [1,3] thiazepine-7-carboxylic acid.
11. 11. A recrystallization and reprocessing process for the mercaptoalkanoylamino lactam acid of formula (I) OR II HS. { CH2) "~ CH- c-x1 Rl Characterized porgue Xi is a lactam selected from (VIII) 78 (IX) (X) (XI) (XV) (XVI) 80 (XVIII) (xrx) (XX) (XXI) (XXIII) Ri and R6 are independently selected from the straight or branched chain open alkyl of 1 to 6 carbon atoms - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl; m is zero or an integer from 1 to 6; n is zero or one; R4 and R5 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, - (CH2) m-cycloalkyl, - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl, or one of R4 and R5 is hydrogen and the other is hydroxy or R4 and R5 taken together with the carbon to which they are bound completely to a saturated cycloalkyl ring of 3 to 7 carbon atoms, or R4 and Rs taken together with the carbon to which they are bonded completely to a keto substituent. Re, Rs and Rio are independently selected from hydrogen, alkyl, saturated alkyl, alkenyl - (CH2) m-cycloalkyl, - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl. R ?, R9 and Rn are independently selected from hydrogen, alkyl, saturated alkyl, alkenyl - (CH2) m-cycloalkyl, - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl, or R6 and R7 taken together with the carbon to which they are fully attached to a saturated cycloalkyl ring of 3 to 7 carbon atoms, R8 and R9 taken together with the carbon to which they are completely attached to a saturated cycloalkyl ring of 3 to 7 carbon atoms; b is zero or one; d is zero or one; q is an integer from 1 to 4; r is one or two; t is an integer from 1 to 3; v is one or two; w is one or two; Yi is -CH2-, - (CH) 2-, - (CH2) 3-, -O-, -S-, -CH2-0-, OR -CH2-S-; Y2 is -CH2-, -S-, or -O-; Y3 is -CH2-, - (CH2) 2, - (CH2) 3-, -O-, or -CH2-0-; Z is O or two hydrogens; R17 is hydrogen, alkyl, substituted alkyl, alkenyl, - (CH2) m-cycloalkyl, - (CH2) m-aryl, - (CH2) m-substituted aryl, or - (CH2) m-heteroaryl; Y5 is -CH2-, -S-, or provided that Y5 is -S- or -O- only when d is one; Ye is -S- or -O-; The dashed line represents an optional double bond between the two carbons. Represents an aromatic heteroatom containing a ring selected from is -S- or -NH-; Ys is -S-, -O-, or -NH-; and R1 and R19 are independently selected from hydrogen, alkyl, - (CH2) m-aryl, or R8 and R19 together with the carbon and nitrogen atoms to which they are fully attached to a ring having five to six members; comprising the addition of the mercaptoalkanoylamino lactam acid of formula I to a solvent containing a sufficient amount of an agent that minimizes the amount of disulfide of formula (III) And then subject the resulting slurry to changes in temperature and / or pH, optionally filtered, and then changing the temperature and / or pH to perform the recrystallization.
12. 12. The process according to claim 11, characterized in that the agent that minimizes the amount of disulfide of formula III and, in turn, minimizes the formation of the unwanted epimer of the pharmaceutically active compound of formula I is a bismercaptan of the formula ( XXVI) wherein K is an integer from 1 to 4 and each X2 is independently selected from hydrogen and hydroxy, or the bismercaptan is 2, 2-benzenedimethanethiol, 1,3-butanedithiol meso-a, a'-dimercaptoadipic, disodium salt , or durenoa (1), a (2) -dithiol, or the agent is a phosphine or phosphite reducing agent, or the agent is zinc metal powder, or the agent is sodium hydrosulfite.
13. 13. The process according to claim 12 characterized in that the mercaptoalkanoylamino lactam acid of formula I is the acid [4S- [4a (R *), la, 10aß]] - octahydro-4- [(2-mercapto-l-oxo -3-phenylpropyl] amino] -5-oxo-7H-pyrido [2, 1-b] [1,3] thiazepine-7-carboxylic acid, and the agent that minimizes the amount of the disulfide of formula III, and its time, it minimizes the formation of the undesired epimer of the pharmaceutically active compound of formula I is dithiothreitol bismercaptan or dithioerythritol.
14. 14. The process according to claim 13 characterized in that the acid [4S- [4a (R *), la, 10aß]] - octahydro-4- [(2-mercapto-l-oxo-3-phenyl-propyl] amino] -5-oxo-7H-pyrido [2, 1-b] [1, 3] thiazepine-7-carboxylic acid, is treated with aqueous sodium hydroxide and D, L-dithiothreitol to provide a pH greater than about 8, the The solution is filtered, and the desired product is crystallized by adding aqueous acetic acid to adjust the pH below 8, and the product is then filtered, washed and dried; the process according to claim 13 characterized in that the acid [4S- [4a (R *), la, 10aß]] - octahydro-4- [(2-mercapto-l-oxo-3-phenyl-propyl] amino] -5-oxo-7H-pyrido [2, 1-b] [1, 3] thiazepine-7-carboxylic acid, is dissolved in an alcoholic solution containing D, L-dithiothreitol, the resulting slurry is heated to reflux to dissolve the solids, followed by a filtration, a cooling of the combined filtrates, and the collection of the product.
15. 15. The process according to claim 12 characterized in that the mercaptoalkanoylamino lactam acid of formula I is acid [S- (R *, R *)]] -hexahydro-6- [(2-mercapto-l-oxo-3-phenyl- propyl] amino] -2, 2-dimethyl-7-oxo-lH-azepine-1-acetic, and the agent that minimizes the amount of the disulfide of formula III, and in turn, minimizes the formation of the desired epimer of the pharmaceutically active compound of formula I is dithiothreitol bismercaptan or dithioerythritol.
16. 16. The process according to claim 15 characterized in that, the acid [S- (R *, R *)]] -hexahydro-6- [(2-mercapto-l-oxo-3-phenyl-propyl] amino] -2 , 2-dimethyl-7-oxo-lH-azepine-1-acetic acid, treated with aqueous sodium hydroxide and D, L-dithiothreitol at a temperature below 10 ° C, the reaction mixture is allowed to warm to room temperature, it is filtered, heated, treated with an acetic acid solution cooled to room temperature causing the desired product to crystallize, the product is filtered, washed and dried.