KR20020067490A - Preparation of [4S-(4α,7α,10aβ)]-4-Amino-Octahydro-5-Oxo-7H-Pyrido[2,1-b][1,3]Thiazepine-7-Carboxylic Acid, Methyl Ester and Salts Thereof via Novel Disulfides - Google Patents

Abstract

N-protected-L-homocysteine disulfide of formula (I) or an activated form thereof is reacted with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester to give a disulfide intermediate of formula (II) do.

<Formula I>

<Formula II>

<Formula III>

The disulfide intermediate of formula (II) is reacted to cleave the disulfide bond, and the resulting monomer is subjected to an acid catalyst cyclization reaction to produce an N-protected lactam of formula (III).

N-protecting group was removed to double inhibitor [4S- [4α (R *), 7α, 10aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl) amino] -5 [4S- (4α, 7α, 10aβ)]-4-amino-, useful as an intermediate in the preparation of oxo-7H-pyrido [2,1-b] [1,3] thiazepine-7-carboxylic acid Octahydro-5-oxo-7H-pyrido [2,1-b] [1,3] thiazepine-7-carboxylic acid, methyl ester and salts thereof are produced.

Description

[4S- (4α, 7α, 10αβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2,1-VII] [1,3] thiazepine-7- using novel disulfide Method for preparing carboxylic acid, methyl ester and salts thereof {Preparation of [4S- (4α, 7α, 10aβ)]-4-Amino-Octahydro-5-Oxo-7H-Pyrido [2,1-b] [1,3 Thiazepine-7-Carboxylic Acid, Methyl Ester and Salts Thereof via Novel Disulfides}

Background

Robl discloses compounds of the formula below having neutral endopeptidase and angiotensin converting enzyme inhibitory activity in US Pat. No. 5,508,272.

Where

A is Can be; X can be S; Y can be CH ₂ ; m can be 1; n may be 2. Among these compounds, the recent clinical evaluation is [4S- [4α (R *), 7α, 10aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl) amino ] -5-oxo-7H-pyrido [2,1-b] [1,3] thiazepine-7-carboxylic acid. This compound has been reported in the literature as BMS 186,716 and omapatrilat.

Roble has a chemical formula of BMS 186,716 Aminolactam moiety, that is, the intermediate of formula Of (S) -2-amino-6,6-di-methoxyhexanoic acid, methyl ester, with an N-protected amino acid, wherein P ₁ is an amino protecting group and P ₂ is a sulfur protecting group It is disclosed that it can be prepared by producing a dipeptides of. Removal of the P ₂ protecting group followed by acid catalyst cyclization and removal of the P ₁ protecting group resulted in 4S- (4α, 7α, 10aβ)]-octahydro-4-amino-5-oxo-7H-pyrido [2,1-b ] [1,3] thiazepine-7-carboxylic acid, methyl ester is produced.

Roble disclosed that P ₁ is an amino protecting group such as benzyloxycarbonyl, t-butoxycarbonyl, or a group which forms a protecting group such as phthalimido with N-atoms.

Summary of the Invention

The present invention relates to [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2,1-b] [1,3] thiazepine-7-carboxylic acid , Improved chemical synthesis of methyl esters and salts thereof and novel disulfide intermediates useful in this synthesis.

According to the process of the present invention, the active form of N-protected-L-homocysteine disulfide or N-protected-L-homocysteine of formula (I) is represented by (S) -2-amino-6,6-dimethoxyhexanoic acid. And a methyl ester to produce a disulfide intermediate of formula II.

The disulfide intermediate of formula (II) is then reacted to cleave the sulfur-sulfur bond and the resulting monomers are cyclized to produce an N-protected lactam of formula (III).

Remove the P ₁ protecting group to give the desired lactam [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2,1-b] [1,3] thiazepine- Yields 7-carboxylic acid, methyl ester. This lactam can be converted into a salt such as a hydrohalide salt or the like.

According to another feature of the invention, when the N-protected disulfide of formula (I) and (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester are reacted in ethyl acetate solution, The ethyl acetate solution of) -2-amino-6,6-dimethoxyhexanoic acid is treated with an agent that removes ethylene glycol. This results in less downstream impurities when the monomer is cyclized to the lactam of formula III. Suitable agents for removal of ethylene glycol from the reaction solvent are poly (acrylic acid co-acrylamide), potassium salts and calcium chloride dihydrate.

Detailed description of the invention

As Roble described in US Pat. No. 5,508,272, [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2,1-b] [1, 3] thiazepine-7-carboxylic acid, methyl ester and salts thereof, especially hydrohalide salts thereof, are selected from [4S- [4α (R *), 7α, 10aβ]]-octahydro-4-[( 2-mercapto-1-oxo-3-phenylpropyl) amino] -5-oxo-7H-pyrido [2,1-b] [1,3] thiazepine-7-carboxylic acid as an intermediate useful.

According to the process of the invention, L-homocystine is reacted to introduce a P ₁ group into both nitrogens to produce a disulfide of formula (I). Preferred P ₁ protecting groups are trifluoroacetyl (obtained by treatment of ethyl trifluoroacetate with L-homocystine), phenylmethoxycarbonyl (benzyl chloroformate treated with L-homocystin). ), And formyl (obtained by treating L-homocystine with formic acid and acetic anhydride). Other N-protecting groups such as phthalimido, t-butoxycarbonyl and the like can also be used according to methods known in the art. Most preferred P ₁ protecting group is trifluoroacetyl.

The N-protected disulfide of formula (I) is then reacted with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester to produce the disulfide intermediate of formula (II). The reaction is dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, or carbo It is carried out in the presence of a coupling reagent such as nildiimidazole and the like. Preferred coupling reagent is dicyclohexylcarbodiimide. When P ₁ is trifluoroacetyl, it is preferable to use 1-hydroxybenzotriazole together with dicyclohexylcarbodiimide.

When the N-protected disulfide of formula (I) is reacted with (S) -amino-6,6-dimethoxyhexanoic acid, methyl ester without coupling reagent, a salt of formula (IIa) may be formed. Treatment of this salt with a coupling reagent then yields the disulfide intermediate of formula (II).

Salts of formula (IIa) have a storage stability that can be maintained for a period of at least about 30 days under low temperature and moisture free conditions before conversion to disulfide intermediates of formula (II). This gives flexibility in production run planning and allows different stages of reactions to be carried out at different manufacturing facilities.

Alternatively, the N-protected disulfide of formula (I) may be converted to the activated form prior to reaction with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester. Such activated forms include acid chlorides, mixed anhydrides, symmetric anhydrides, activated esters, and the like. When using an activated form of N-protected disulfide, no coupling reagent is required. The choice of activation form depends on the N-protecting group of the disulfide of formula (I). When the protecting group is trifluoroacetyl, suitable forms of activation are acid chlorides, activated esters and the like, preferably acid chlorides. If the protecting group is phenylmethoxycarbonyl, the suitable form of activation is an activated ester.

Rove discloses a process for the preparation of (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester in US Pat. No. 5,508,272. Another method of making this starting material is disclosed in the co-pending application of the assignee of the present application. According to this co-pending application, dioxolane pentanic acid of formula (VII) is reacted with thionyl chloride in methanol or dimethyl sulfite and chlorotrimethylsilane in methanol to give (S) -2-amino-6,6-dimethoxyhexane Acids, methyl esters can be produced. .

(S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester and the N-protected disulfide of formula (I) or their activated form can be reacted in an organic solvent, preferably n-butyl acetate. If the reaction is carried out in ethyl acetate, (S) -amino-6,6-dimethoxyhexane in ethyl acetate before reacting with the N-protected disulfide of formula (I) to minimize subsequent downstream impurities present The agent is treated to remove ethylene glycol in acid, methyl ester solution. Suitable agents for this purpose include poly (acrylic acid co-acrylamide), potassium salts and calcium chloride dihydrate.

In a biphasic solvent system it is advantageous to react (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester with the acid chloride activated form of the disulfide of formula (I). Under these conditions, first, there is no need to remove ethylene glycol to minimize downstream impurities. Suitable bisolvent systems include mixtures of ethyl and n-butyl acetate as organic phases, mixtures of water and buffers as aqueous phases such as potassium carbonate and potassium bicarbonate, and the like.

The N-protected disulfide intermediate of formula (II) is then reacted to cleave the disulfide bond, and then the resulting monomer is cyclized to produce an N-protected lactam of formula (III). The method for cleaving disulfide bonds includes reacting an intermediate of formula (II) with a bismercaptan, a phosphine reducing agent, a phosphorous acid reducing agent, or a zinc metal powder. Suitable bismercaptans include compounds of the formula

Wherein k is an integer from 1 to 4; Each X ₂ is hydrogen and hydroxy, and 1,2-benzenedimethanethiol, 1,3-butanedithiol meso-α, α'-dimercaptoadipic acid, disodium salt, and Independently from durene-α (1), α (2) -dithiol. Preferably, the bismercaptan is reacted in the presence of a base such as sodium methoxide or 1,8-diazabicyclo [5.4.0] undec-7-ene and the like. Preferred bismercaptans are dithiothritol and dithioerythritol. Suitable phosphine reducing agents include tributyl phosphine, trioctyl phosphine, triphenyl phosphine and the like. Suitable phosphorous acid reducing agents include triethyl phosphorous acid and the like. A preferred reagent for cleaving disulfide bonds is tributyl phosphine.

The resulting monomer is then preferably a strong acid, for example trifluoroacetic acid, chlorosulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl methanesulfo Acid catalyzed cyclization by treatment with a commercially available polystyrene sulfonate polymer type ion exchange resin such as Nate or Amberberst 15 (registered trademark) or the like. This cyclization reaction may be preferably carried out in a non-protonic solvent such as methylene chloride or in a protonic solvent such as methanol or chloroform to produce an N-protected lactam of formula III.

The N-protected lactam of formula III was then treated to remove the P ₁ protecting group [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2 , 1-b] [1,3] thiazepine-7-carboxylic acid, methyl ester. For example, when P ₁ is trifluoroacetyl, potassium carbonate treatment in methanol can be used. When P ₁ is phenylmethoxycarbonyl, iodotrimethylsilane or palladium on carbon and hydrogenation can be used. When P ₁ is formyl or t-butoxycarbonyl, a strong acid treatment such as hydrochloric acid can be used.

Then, lactam [4S- (4α, 7α, 10aβ)]-4-aminoocta-hydro-5-oxo-7H-pyrido [2,1-b] [1,3] thiazepine-7-carboxyl The acid, methyl ester, is reacted with an acylmercaptoalkanoyl side chain of formula IV to produce formula V

Wherein R ₆ is methyl or phenyl.

This coupling reaction is carried out in organic solvents such as methylene chloride and the like and coupling reagents such as 1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide, dicyclohexylcarbodiimide, benzotriazole- It can be carried out in the presence of 1-yloxytris- (dimethylamino) phosphonium hexafluorophosphate, carbonyldiimidazole, or 1-propanephosphonic acid, cyclic anhydride. Alternatively, the acylmercaptoalkanoic acid of formula IV may be converted to an activated form such as acid chloride, mixed anhydride, symmetric anhydride, activated ester, etc. before coupling. Preferably, the lactam is converted to a salt such as a hydrohalide salt or the like followed by a coupling reaction. Suitable hydrohalide salts are preferably hydrochloride salts, including hydrobromide and hydroiodine and the like. The salts can be prepared by treating the lactam solution with the corresponding acid.

The acyl group R ₆ -C (O)-in the compound of formula V is removed and the methyl ester group is converted to a carboxylic acid to give the desired final product of formula VI. For example, when R ₆ is methyl, treatment with methanolic sodium hydroxide followed by treatment with aqueous acid solution gives the desired final product of formula VI.

[4S- [4α (R *), 7α, 10aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl) amino] -5-oxo-7H-pyrido [2 The, 1-b] [1,3] thiazepine-7-carboxylic acid has angiotensin converting enzyme and neutral endopeptidase inhibitory activity. As noted in US Pat. No. 5,508,272 to Roble, the compound and its pharmaceutically acceptable salts are useful for treating cardiovascular diseases such as hypertension and congestive heart failure. The compound may be administered to a mammalian host such as a human from about 0.1 mg to about 100 mg per kg body weight per day, preferably from about 0.5 mg to about 25 mg per kg body weight per day. The compound is preferably administered orally, but parenteral and topical routes may also be employed. The daily dose may be administered at one time or may be divided into two to four times during the day.

The following examples illustrate the invention.

Example 1

[4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido- [2,1-b] [1,3] thiazepine-7-carboxylic acid, methyl Esters, hydrochloride

a) N- (triruoacetyl) -L-homocysteine, (1 → 1 ′)-disulfide

To solid L-homocystine (40 kg) was added a solution of potassium methoxide (32% by weight, 68.8 kg) in methanol and methanol rinse (42 kg). During the addition, the temperature was maintained at 20 ± 5 ° C. and a white aqueous solution was produced. Ethyl trifluoroacetate (43.8 kg) was added to the solution and the reaction temperature was raised to 35-40 ° C. and the reaction mixture was treated with 6 wt% hydrochloric acid (432 kg) and ethyl acetate (270 kg). The layers were separated and the organic phase was washed with an aqueous acidic brine solution (168 kg water, 18 kg sodium chloride, 15 kg concentrated hydrochloric acid). The layers were separated and the upper rich organic phase was washed with 20 wt% aqueous saline solution (183 kg). The layers were separated and the rich ethyl acetate extract was polish filtered and azeotropically distilled to constant volume (110 L) until the water content of the fresh distillate showed KF = 0.5 (400 kg of ethyl acetate was additionally required. ). A portion (6 kg) of this rich ethyl acetate was added to heated (65 ° C.-70 ° C.), stirring heptane, and the resulting slurry was vigorously stirred for 30 minutes. The remaining amount of rich ethyl acetate solution (149 kg) was added over 3.5 hours. After 1 hour at 65 ° C.-70 ° C., the crystal slurry was cooled to 15 ° C.-25 ° C. over 1.5 hours. After 16 hours at 15 ° C.-25 ° C., white crystals were isolated and washed on a centrifugal filter (192 kg heptane, 12 kg ethyl acetate). The tray was dried at 40 ° C. under reduced pressure to give 36.3 kg of the title compound as a white powder (melting point: 123.5 ° C.).

b) (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester

Under nitrogen, chlorotrimethylsilane (28.0 g) was added to a slurry of (S) -α-amino-1,3-dioxolane-2-pentanoic acid (20.9 g) and dimethyl sulfite (12.0 g) in methanol (240 ml). The addition gave a homogeneous solution. An exotherm to 29 ° C. was observed, then heated to 40-45 ° C., stirred at this temperature for 8 hours, and stirred at about 22 ° C. for up to 72 hours. In process HPLC analysis showed that the reaction was complete (about 93 M% converted to product) and the resulting solution was cooled to -5 ° C to -10 ° C. While stirring, 32% (or 4.45 M) methanolic potassium methoxide solution (70 ml) was added slowly and carefully to adjust the apparent pH of the mixture to pH 11.7 to 11.9, with the temperature in the range -5 to 0 ° C. Maintained. Product slurry analysis ( ¹ H NMR) showed that neutralization was complete. First, the thin slurry was concentrated to a volume of 300 ml under vacuum below 30 ° C., and then ethyl acetate was added until GC analysis in the middle of the process determined that methanol was completely removed (below 1 AP). The solvent of the product slurry was exchanged with ethyl acetate. Immediately after completion of the solvent exchange, the batch volume was adjusted to about 400 ml with ethyl acetate and the resulting slurry was filtered. To the filtrate was added poly (acrylic acid co-acrylamide), potassium salt (3.0 to 3.2 g) and water (30-32 ml). The mixture was stirred for about 35 minutes and filtered. In some cases, poly (acrylic acid co-acrylamide) and potassium salts may be repeatedly treated in the filtrate if the amount of ethylene glycol does not exceed 0.15 equivalent, as determined by GC analysis in the middle of the process. After HPLC analysis in the middle of the process, 17.4 g of the title product was obtained in ethyl acetate solution in 80.8 M% yield.

c) 6,6-dimethoxy-N- [N- (trifluoroacetyl) -L-homocysteinyl] -L-norleucine, methyl ester, (1 → 1 ′) disulfide

While stirring (S) -2-amino-6,6-dimethoxyhexanoic acid, an ethyl acetate solution of methyl ester (17.4 g, 328 g solution, 3.5 w% water), thereto was added N- (trifluoroacetyl) -L-homocysteine, (1 → 1 ′)-disulfide (19.5 g), hydroxybenzotriazole (0.7 g, 20 w / w% water) and anhydrous sodium sulfate (15 g) were added. The slurry was cooled to -2 to 2 ° C and dicyclohexylcarbodiimide (19 g) was added to a portion of this mixture (somewhat exothermic). HPLC analysis in the middle of the process after stirring for 5 hours under nitrogen atmosphere showed that the reaction was complete. It washed the cake (wet-cake) with ethyl acetate (2 × 10 ml) - rich dicyclohexyl urea, and sodium sulfate, filtered and the slurry, and the dicyclohexyl urea wet. The combined filtrates were washed with 10% sodium bicarbonate solution (50 ml) and brine saturated solution (50 ml). While maintaining the temperature at 35-40 ° C., the rich ethyl acetate layer was concentrated under vacuum to a volume of 130 ml and a water content of less than 0.1 w / w%.

To the rich ethyl acetate solution was added tert-butyl methyl ether (120 ml) and the resulting opaque solution was filtered filtered. The apparatus was washed with 1: 1 ethyl acetate / tert-butyl methyl ether (2 × 10 ml) and the wash was combined with the rich filtrate. At room temperature, cyclohexane (185 ml) was added to the solution and seed crystals were added. The resulting slurry was shaken for at least 30 minutes and then further cyclohexane (555 ml) was added over 35 minutes. The slurry was shaken for at least 1 hour and the product wet-cake was washed with 6: 1: 1 cyclohexane / tert-butyl methyl ether / ethyl acetate solution (75 ml). The wet-cake was dried under vacuum at about 30 ° C. to give 29.8 g of the title product as a white crystalline solid (melting point: 111-112 ° C.).

d) [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2,1-b] [1,3] thiazepine-7-carboxylic acid, Methyl ester, hydrochloride

To a 1 L five-necked flask equipped with a mechanical stirrer, thermocouple, nitrogen inlet and reflux condenser was added the product of part (c) (41.75 g), methylene chloride (375 ml) and water (2.7 ml). Under nitrogen, tributyl phosphine (13.24 ml) was added thereto while shaking the reaction flask at 18-26 ° C. The reaction mixture was stirred at 18-26 ° C. until HPLC analysis in the middle of the process determined the reaction was complete (1-4 hours). Methanesulfonic acid (6.8 ml) is added to the mercaptan solution, the reaction mixture is heated under reflux for 6-7 hours with stirring, and at room temperature for 12-16 hours until it is determined that the reaction is complete by HPLC analysis in the middle of the process. Stirred at. The solvent of the reaction mixture was exchanged with methanol via distillation and the resulting [4S- (4α, 7α, 10aβ)]-octahydro-5-oxo-4-[(trifluoroacetyl) amino] -7H-pyrido A methanol solution of [2,1-b] [1,3] thiazepine-7-carboxylic acid, methyl ester, buffered (pH 10.5) 1M potassium carbonate while maintaining the pH at pH 10.4 to 10.8 at 40 to 45 ° C Solution (208 ml). The reaction mixture was stirred at 40-45 ° C. until HPLC analysis in the middle of the process determined that deprotection was complete. Below 36 ° C., concentrated HCl (33.5 ml) was added to adjust the pH of the reaction mixture to pH 5.8-6.5. Methanol was removed under vacuum below 37 ° C. until the volume of the quenched deprotection reaction mixture became 300 ml. Methylene chloride was added to the aqueous solution, and concentrated HCl (7 ml) was added to adjust the pH of the abnormal mixture to pH 0.6 to 0.9. The phases were separated and the product rich aqueous layer was washed with additional methylene chloride (60 ml). The methylene chloride extracts were combined and washed again with 3% HCl solution (60 ml) and the aqueous extracts were combined with the product rich aqueous layer. Methylene chloride (80 ml) is added to the product-rich aqueous layer, 10N sodium hydroxide solution (19 ml) is added to the above mixture to adjust the pH to pH 9.0, and then 1N sodium hydroxide solution (3 ml) is added. Addition was adjusted to pH 10.4. The phases were separated and the aqueous layer was extracted with methylene chloride (2 x 80 ml). The product rich methylene chloride layers were combined and methanol (15 ml) and chlorotrimethylsilane were added. At 34-37 ° C., ethyl acetate (50 ml) was slowly added (15 minutes) to the methylene chloride solution of the title compound and the mixture was stirred until crystallization became apparent. Further ethyl acetate (175 ml) was added to complete the crystallization. The resulting product slurry was cooled to 15-25 ° C, the slurry was stirred for at least 1 hour and the product collected on a filter. The wet-cake was washed with ethyl acetate (2 × 50 ml) and the product was dried under vacuum at 45 ° C. (150 mmHg) for 16 hours to give 25.2 g of the title product as white crystalline powder (melting point: 239 ° C. ( Decomposition temperature)).

Example 2

6,6-dimethoxy-N- [N- (trifluoroacetyl) -L-homocysteinyl] -L-norleucine, methyl ester (1 → 1 ′) disulfide

The product of Example 1 (c) may be prepared according to the following method:

a) (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester

Chlorotrimethyl silane (532 g) in a slurry of (S) -α-amino-1,3-dioxolane-2-pentanoic acid (380 g) and dimethyl sulfite (228 g) in methanol (4560 ml) under nitrogen Was added to obtain a homogeneous solution. After exotherm to 29 ° C. was observed, the solution was heated to 42 ° C., stirred at this temperature for 8 hours, and stirred at about 22 ° C. for 16 hours. HPLC analysis in the middle of the process showed that the product was obtained in 93 M% yield. A portion of the resulting solution, containing 53.4 g of the title product, was cooled to -5 to -10 ° C with stirring, and the apparent pH of the mixture was added slowly and carefully with 32% methanolic potassium methoxide solution (2 x 100 ml). Was adjusted to pH -0.38 to about 8.32. While maintaining the temperature below −5 ° C., the potassium methoxide (16 ml) was carefully added to adjust the pH of the mixture back to pH 11.45. ¹ H NMR analysis in the middle of the process of the product slurry showed that neutralization was complete. Through vacuum distillation below 30 ° C., the solvent of the product slurry is exchanged with ethyl acetate (3160 ml total), concentrated to 400 ml volume, diluted with tert-butyl methyl ether (800 ml) and cooled to 0 ° C. And shaken for 30 minutes and filtered. The filtrate was treated with calcium chloride dihydrate (135 g in 9 portions) until GC analysis in the middle of the process indicated that ethylene glycol was removed by the calcium chloride dihydrate. The resulting slurry was filtered to give a filtrate containing 49.7 g of the title product.

b) 6,6-dimethoxy-L-norleucine, methyl ester [S- (R *, R *)] -4,4-dithiobis [2-[(trifluoroacetyl) -amino] butano Eight (2: 1)

N- (trifluoroacetyl) -L-homocysteine, (1 → 1 ′) disulfide (55.8 g) is dissolved in ethyl acetate (200 ml) and the resulting solution is (S) -2- over 10 minutes. To amino-6,6-dimethoxy-hexanoic acid, tert-butyl methyl ether / ethyl acetate solution of methyl ester (about 49.7 g, solution 1787 ml). The resulting mixture was stirred for 1 hour and the product slurry was filtered. The wet-cake was washed with tert-butyl methyl ether / ethyl acetate (2: 1, 250 ml) and dried under vacuum at 30 ° C. to give 98.0 g of the title product (melting point: 129.1-129.7 ° C.).

c) 6,6-dimethoxy-N- [N- (trifluoroacetyl) -L-homocysteinyl] -L-norleucine, methyl ester, (1 → 1 ′) disulfide

The product (95 g), ethyl acetate (750 ml) and water (13.5 ml) in part (b) were charged to a 3 L round bottom flask equipped with a top stirrer, nitrogen inlet, thermocouple, and temperature controller. To the reaction mixture was added hydroxybenzotriazole hydrate (1.5 g), sodium sulfate (34.5 g) and water (3.5 ml). The resulting solution was cooled to -6 ° C and dicyclohexylcarbodiimide (49.1 g) was added to the reaction mixture. The reaction mixture was shaken at -2 to 2 ° C until HPLC analysis in the middle of the process determined the reaction was complete (5.6 hours). The reaction slurry was filtered and the wet-cake was rinsed with ethyl acetate (2 x 50 ml). The filtrates were combined (925 ml) and washed with saturated sodium bicarbonate solution (125 ml) and brine saturated solution (125 ml). The ethyl acetate solution of the resulting title compound was concentrated to oil. The oil was dissolved in ethyl acetate (900 ml) and concentrated to an oil, which was again dissolved in ethyl acetate (300 ml). tert-butyl methyl ether (300 ml) was added, the resulting solution was filtered filtered and the filter-cake was washed with 1: 1 ethyl acetate / tert-butyl methyl ether (2 × 25 ml). The filtrates were combined and cyclohexane (400 ml) and nuclei were added and the mixture was stirred for about 30 minutes. To the resulting low viscosity slurry, cyclohexane (1800 ml) was added over 75 minutes. After stirring for 16 hours, the slurry was filtered through paper and the wet-cake was washed with a solution of ethyl acetate / tert-butyl methyl ether / cyclohexane (1: 1: 6, 175 ml). The wet-cake (194 g) was dried under vacuum at 20 ° C. to give 77.6 g of white title product (melting point: 111-112 ° C.).

Example 3

[4S- (4α, 7α, 10aβ)]-octahydro-5-oxo-4-[[(phenylmethoxy) carbonyl] amino] -7H-pyrido- [2,1-b] [1,3 ] Thiazepine-7-carboxylic acid, methyl ester

a) N-[(phenylmethoxy) carbonyl] -L-homocysteine, (1 → 1 ′)-disulfide

1N sodium hydroxide solution (137 ml) was added to dissolve L-homocystin (15.0 g) in water (90 ml) and the resulting pH 13.3 solution was cooled to 5 ° C. Benzyl chloroformate (21 ml) was added slowly (addition over 135 minutes) while 1N sodium hydroxide solution (192 ml) was added to maintain the pH of the reaction mixture at about pH 13. Once determined by HPLC analysis the reaction was complete, extraction was done using methyl isobutyl ketone (300 ml and 400 ml). Saturated brine solution (60 ml) was added to break up the emulsion formed during the second extraction and to separate the phases. To the rich aqueous solution methanol (50 ml) was added and the concentrated hydrochloric acid solution (24 ml) was added to adjust the pH to about pH 2. The resulting product slurry was filtered, washed with water (100 ml) and 1: 5 methanol / water (vol / vol) and dried under vacuum for 18 hours to give 28.6 g of the title product as crystalline solid (melting point: 110-115 ° C).

b) 6,6-dimethoxy-N- [N-[(phenylmethoxy) carbonyl] -L-homocysteinyl] -L-norleucine, methyl ester, (1 → 1 ′)-disulfide

The product in part (a) above in a tetrahydrofuran (45 ml) solution of (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester (2.4 g) cooled to -4 ° C (3.0 g) ) Was added. Dicyclohexylcarbodiimide (2.53 g) was added to a portion of the resulting solution and the reaction mixture was mechanically stirred under nitrogen atmosphere for 18 hours until judged complete by HPLC analysis. Precipitated dicyclohexylurea was removed by filtration and the wet-cake was washed with tetrahydrofuran (15 ml). The combined filtrates were diluted with ethyl acetate (150 ml) and washed with pH 3.4 phosphate buffer (40 ml) and saturated sodium bicarbonate solution (2 x 60 ml). The organic layer was concentrated to an oil under vacuum, redissolved in ethyl acetate (45 ml) and diluted with sufficient amount of hexane to crystallize the product. At room temperature, the slurry was stirred for 1 hour and then the product wet-cake was collected on a filter and washed with ethyl acetate / heptane (1: 2.5) (80 ml). The wet-cake was dried under vacuum to give 4.22 g of the title product as white crystals (melting point: 109-110 ° C).

c) [4S- (4α, 7α, 10aβ)]-octahydro-5-oxo-4-[[(phenylmethoxy) carbonyl] amino] -7H-pyrido- [2,1-b] [1 , 3] thiazepine-7-carboxylic acid, methyl ester

D, L-dithioerythritol (0.06 g) was added to a nitrogen sparged methyl acetate solution of the product (0.295 g) in part (b) above cooled to -7 ° C. Sodium methoxide solution (25% in methanol, 0.02 ml) was added to the reaction mixture and stirred for about 30 minutes until judged complete by HPLC analysis. The monomer solution was further stirred at −7 ° C. for 60 minutes and chlorosulfonic acid (0.018 ml) was added. Stirring was continued at −7 ° C. for 4 hours, and then the reaction mixture was stored frozen for 16 hours. The reaction mixture was washed with 3% hydrochloric acid solution (2 x 10 ml) and saturated sodium bicarbonate solution (2 x 8 ml). The organic layer was dried and the residue was concentrated to give 0.31 g of the title product as an oil (94.2 M%).

HPLC: Tr = 6.02 min (UV 210 nm): YMC basic 5 micron particle size, 4.6 x 250 mm, 40 v / v% (0.01 M potassium dihydrogen phosphate solution, pH 4.0): 60 v / v% acetonitrile, 20 μl injection volume, spilled at 1.0 ml / min. Dissolve 11.8 mg in 50 ml of mobile phase.

Example 4

[4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido- [2,1-b] [1,3] thiazepine-7-carboxylic acid, methyl Esters, hydrochloride

a) N-formyl-L-homocysteine, (1 → 1 ′)-disulfide

L-homocystine (5.37 g) was dissolved in formic acid (23 ml) to give a viscous solution, which was cooled to 5 ° C. in an ice bath. Acetic anhydride (11.2 ml) was added dropwise to this solution over about 4 minutes, and the temperature of the reaction mixture was raised to about 10 ° C. The reaction mixture was stirred for 6 hours until judged complete by HPLC analysis. Iced water (10 ml) was added to quench the reaction mixture and then concentrated to a white residue on a rotary evaporator. The white residue was further dried under vacuum at room temperature. The resulting dry white powder (6.9 g) was suspended in refluxing chloroform (40 ml) and denatured ethanol (SDA 35A, 8 ml) was added. The mixture was cooled to about 20 ° C, the product was filtered and the wet-cake was washed with cold chloroform. After drying in vacuo, the title product was isolated as a white crystalline powder (5.85 g, 90 M%).

b) N- (N-formyl-L-homocysteinyl) -6,6-dimethoxy-L-norleucine, methyl ester, (1 → 1 ′)-disulfide

To 22 ° C., (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester (2.05 g) was added to a slurry of tetrahydrofuran (45 ml) of the product (1.62 g) in part (a) above. Added. The resulting thick, sticky slurry was shaken for about 10 minutes and dicyclohexylcarbodiimide (2.29 g) was added. After about 15 minutes of shaking, as the reaction proceeded, the sticky slurry turned to a fine white powder. The reaction was shaken for 15 hours until judged complete by TLC analysis. Precipitated dicyclohexylurea was removed by filtration and the wet-cake was washed with tetrahydrofuran (10 ml). The filtrates were combined and concentrated on a rotary evaporator and the residue dissolved in methylene chloride (100 ml). The resulting solution was washed with water (50 ml), 5% citric acid (50 ml) and 5% sodium bicarbonate solution (50 ml). The organic layer was dried over magnesium sulfate and concentrated to dryness on a rotary evaporator to give the product (3.82 g) as a sticky foam. The foam was purified by spinning chromatography using a solvent gradient of 5 vol% methanol in ethyl acetate to 10 vol% methanol in ethyl acetate to give 2.83 g (81 M%) of the product as a yellow glass. The resulting yellow glass was dissolved in reflux ethyl acetate and hexane (30 ml) was added to the cloud point. The resulting mixture was stirred at ambient temperature for 16 hours, the product was filtered and the wet-cake was washed with hexane (2 x 4 ml). The product was dried under vacuum to give 1.3 g (37.2 M%) of the product as an amorphous solid (melting point: 88-92 ° C).

c) [4S- (4α, 7α, 10aβ)]-octahydro-5-oxo-4- (N-formyl) -7H-pyrido [2,1-b] [1,3] thiazepine-7 -Carboxylic acid, methyl ester

D, L-dithioerythritol (0.24 g) was added to a nitrogen sparged methyl acetate solution of the product (1.05 g) in part (b) above cooled to -10 ° C. To the reaction mixture was added sodium methoxide solution (25% in methanol, 0.07 ml) and stirred for about 16 hours. The reaction mixture was analyzed by HPLC, then additional D, L-dithioerythritol (0.03 g) and sodium methoxide solution (25% in methanol, 0.01 ml) were added and the reaction mixture was stirred for 1 hour. The reaction mixture was analyzed by HPLC, then additionally added D, L-dithioerythritol (0.06 g) and sodium methoxide solution (25% in methanol, 0.01 ml), until judged complete by HPLC analysis. The reaction mixture was stirred. The monomer solution was washed with 0.01 M sulfuric acid (10 ml) and saturated sodium bicarbonate solution (10 ml). The organic layer was concentrated on a rotary evaporator to give the crude monomer as a thick liquid (0.84 g, 80 M%). The monomer was dissolved in methyl acetate and the resulting solution was sparged with nitrogen, followed by the addition of Amberlite 15® (2 g). The reaction mixture was stirred at 10-15 ° C. until HPLC analysis determined the reaction was complete (16 hours). The resin was filtered off and washed with methyl acetate (15 ml). The filtrate was washed with saturated sodium bicarbonate solution (2 × 10 ml) and the aqueous wash was extracted again with methyl acetate (2 × 5 ml). The combined organic layers were concentrated in vacuo to yield 0.6 g (87 M%) of the title product as a residue.

HPLC: Tr = 8.42 min. (UV 210 nm); YMC basic 5 micron particle size, 4.6 × 250 mm, 75 v / v% (0.01 M potassium dihydrogen phosphate solution, pH 4.0): 25 v / v% acetonitrile, 20 μl injection volume, eluted at 1.0 ml / min.

d) [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2,1-b] [1,3] thiazepine-7-carboxylic acid, Methyl ester, hydrochloride

Concentrated hydrochloric acid (0.4 ml) was added to a methanol solution (8 ml) of the product (0.6 g) in part (c) above, and the solution was diluted with water (0.4 ml). The reaction mixture was stirred at room temperature until judged complete by HPLC analysis (72 hours). Methanol was removed under vacuum, and the residue was dissolved in 1N hydrochloric acid (10 ml) and washed with methylene chloride (2 x 6 ml). The aqueous layer was basified to pH 10.5 with potassium carbonate and the solution was extracted using methylene chloride (6 x 8 ml). The organic extracts were concentrated in vacuo to give 0.37 g (49 M%) of the title product as a residue.

HPLC: Tr = 3.86 min. (UV 210 nm): YMC basic 5 micron particle size, 4.6 × 250 mm, 75 v / v% (0.01 M potassium dihydrogen phosphate solution, pH 4.0): 25 v / v% acetonitrile, 20 μl injection volume, 1.0 Elution at ml / min.

Example 5

[4S- (4α, 7α, 10aβ)]-octahydro-5-oxo-4-[(trifluoroacetyl) amino] -7H-pyrido- [2,1-b] [1,3] thiazepine -7-carboxylic acid, methyl ester

The product (2.0 g) from Example 1 (c) was dissolved in methylene chloride / methanol (20 ml, 8: 2) and zinc metal powder (0.45 g) was added. Methanesulfonic acid (2.3 g, 10 equiv) was added to this suspension and the mixture was stirred at room temperature until judged complete by HPLC analysis. Typically, the reaction takes about 1 to 2 hours to complete. The product stream was washed with water (10 ml) and the methylene chloride solution was concentrated to dryness to give the desired product as an oil (1.1667 g, 68.7 M%).

As described in Example 1 (d), this oil was dissolved in methanol, reacted with potassium carbonate solution, and then concentrated hydrochloric acid was added to [4S- (4α, 7α, 10aβ)]-4-amino-octahydro. -5-oxo-7H-pyrido [2,1-b] [1,3] thiazepine-7-carboxylic acid, methyl ester, hydrochloride.

Example 6

6,6-dimethoxy-N- [N-trifluoroacetyl) -L-homocysteinyl] -L-norleucine, methyl ester, (1 → 1 ′)-disulfide

The products of Example 1 (c) and Example 2 may be prepared as follows:

a) N- (trifluoroacetyl) -L-homocysteine, (1 → 1 ′)-disulfide

The product of Example 1 (a) may be prepared as follows:

Under nitrogen, L-homocystine (13.34 g) and 32% potassium methoxide in methanol (22.97 g) were placed in a 500 ml 3-necked round bottom flask equipped with a stirrer, thermometer, nitrogen inlet, vent, and addition funnel at the top. Charged. The addition funnel was rinsed with methanol (10.2 g) and rinse solution was added to the mixture. The resulting slurry was thoroughly stirred with rapid shaking at room temperature for 30-40 minutes to obtain a clear solution. To the resulting solution was added ethyl trifluoroacetate (15.2 g) at a rate such that the reaction temperature was maintained at 35-40 ° C. The addition funnel was rinsed with methanol (2.7 g) and the rinse was added to the reaction mixture. The reaction mixture was heated at 38-40 ° C. until judged complete by HPLC analysis in the middle of the process. The reaction mixture was charged with methanol (2.7 g) and cooled to room temperature (about 25 ° C). Acidified saline solution [143.4 g, concentrated hydrochloric acid (12 g) and sodium chloride (1.44 g) dissolved in water (130 g)] and n-butyl acetate (100 ml) were added to the mixture. The phases were separated and the organic phase was washed successively with 12% and 24% brine solutions (60 g each). The washed organic phase was diluted with n-butyl acetate (60 ml) to a total volume of 160 ml and then concentrated at 55-60 ° C. until the water content of the distillate was less than 0.2%. After cooling to about 25 ° C., heptane (80 ml) and some nuclei (30 mg) were added to the product solution. Heptane (200 ml) was further slowly added to the crystallization mixture over 60 minutes. The resulting slurry was stirred at about 25 ° C. for 1-4 hours and the product collected on a filter. The product wet-cake was washed with 9: 1 heptane / n-butyl acetate (50 ml) followed by heptane (50 ml) and then vacuum dried overnight (16-18 hours) (25 torr, 45 ° C.) 20.7 g of the title product were obtained.

HPLC: Tr = 5 min. (UV 210 nm): E. Merck Lichrosorb NH ₂ , 250 × 5 mm, 5 microns, 25 v% 0.025 M NH ₄ OAc, pH = 4.5: 75 v% acetonitrile, 20 μl injection volume, 1.0 ml / min Elution.

b) (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester

The product of Example 1 (b) may be prepared as follows:

Under nitrogen, (S) -α-amino-1,3-dioxolane-2-pentanoic acid (25.0 g), methanol (300 ml) and dimethyl sulfite (12.32 ml) were added to a mechanical stirrer, thermocouple, heater, nitrogen inlet. And a 500 ml three-neck round bottom flask equipped with a foamer. Chlorotrimethylsilane (41.95 ml) was added to the resulting slurry and heated at 40 ° C. for 8 hours to give (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester, hydrochloride salt. After cooling to about 25 ° C., the hydrochloride salt solution was added to a slurry of potassium bicarbonate (52.15 g) in methanol (100 ml) at a rate such that the pH was maintained above pH 7 (total addition time was about 1 hour). . n-butyl acetate (200 ml) was added and the slurry was concentrated under vacuum (110-30 torr) while maintaining the temperature below 30 ° C. to remove methanol. The following steps were performed while maintaining the neutralized (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester slurry at 0-5 ° C.

c) N- (trifluoroacetyl) -L-homocysteine, (1 → 1 ′) disulfide, diacid chloride

Under nitrogen, N- (trifluoroacetyl) -L-homocysteine, (1 → 1 ′) disulfide (25.34 g), ethyl acetate (150 ml) and n-butyl acetate (75 ml) were added to a mechanical shaker, thermocouple. A 500 ml three-necked round bottom flask equipped with a heater, a nitrogen inlet and a foamer was charged. The resulting solution was cooled to -10 ° C. The resulting solution was charged with (chloromethylene) dimethylammonium chloride (Vilsmeier reagent, 16.9 g) and stirred at -5 to -11 ° C until the reaction was judged complete by HPLC analysis in the middle of the process. .

d) 6,6-dimethoxy-N- [N- (trifluoroacetyl) -L-homocysteinyl] -L-norleucine, methyl ester (1 → 1 ′) disulfide

A cold solution of potassium bicarbonate (22.03 g) in water (250 ml) (0-5 ° C.) was added to (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester in part (b) above. The mixture was added to the butyl acetate slurry and vigorously shaken, and the pH was adjusted to pH 8.5 by adding 20 w / v% aqueous potassium carbonate solution. Then, at −1 to 5 ° C., the diacid chloride solution in part (c) was slowly added to a vigorously stirred biphasic mixture of (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester (1 To 2 hours), the pH during the diacid chloride addition was maintained at pH 8.0-8.5 with 20% aqueous potassium carbonate solution. The diacid chloride addition funnel was rinsed with cold (0-5 ° C.) ethyl acetate (12.5 ml) and the rinse was added to the reaction mixture. 30 minutes after completion of the diacid chloride addition, the phases were separated and the organic phase was washed with water (2 × 250 ml). Under vacuum at 60-70 ° C., the rich organic phase was concentrated to about 250 ml volume, then peanut oil (14.5 ml) and heptane (550 ml) were added. The crystallization mixture was stirred at 60-70 ° C. for up to 30 minutes to ensure good crystal formation. Cooling / heating / cooling protocols were alternately applied to the crystalline slurry, cooled at 20-25 ° C., and the product collected on a filter. The resulting wet-cake was washed with 1: 4 n-butyl acetate / heptane (2 × 130 ml) and heptanes (130 ml). The product wet-cake was dried under vacuum below 45 [deg.] C. to give 41 g of the desired product as a white solid with HPLC region percentages of 91-94.

Claims (28)

A compound of formula II <Formula II> Wherein P ₁ is a nitrogen protecting group. The compound of claim 1, wherein P ₁ is selected from the group consisting of trifluoroacetyl, phenylmethoxycarbonyl, formyl, phthalimido, and t-butoxycarbonyl. The compound of claim 1, wherein P ₁ is trifluoroacetyl. The compound of claim 1, wherein P ₁ is phenylmethoxycarbonyl. The compound of claim 1, wherein P ₁ is formyl. A compound of formula IIa <Formula IIa> Wherein P ₁ is a nitrogen protecting group. The compound of claim 6, wherein P ₁ is selected from the group consisting of trifluoroacetyl, phenylmethoxycarbonyl, formyl, phthalimido, and t-butoxycarbonyl. 8. Compounds according to claim 7, wherein P ₁ is trifluoroacetyl. a) reacting L-homocystine to introduce a P ₁ group into both nitrogens to produce a disulfide intermediate of formula (I); And reacting the disulfide of formula I with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester in the presence of a coupling reagent to produce the desired product of formula II: or b) reacting L-homocystine to introduce a P ₁ group into both nitrogens to produce a disulfide intermediate of formula (I); Converting the disulfide intermediate of formula (I) to an activated form; And reacting the activated form of the disulfide of formula (I) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester to produce the desired product of formula (II): or c) reacting L-homocystine to introduce a P ₁ group into both nitrogens to produce a disulfide intermediate of formula (I); Reacting the disulfide of formula (I) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester to produce a compound of formula (IIa); And treating the compound of Formula IIa with a coupling reagent to produce the desired product of Formula II A method for producing a compound of formula (II) comprising a. <Formula I> <Formula IIa> <Formula II> Wherein P ₁ is a nitrogen protecting group. The method of claim 9, wherein in step a) L-homocystine is reacted with ethyl trifluoroacetate and the coupling reagent is dicyclohexylcarbodiimide. The method of claim 9, wherein in step a) L-homocystine is reacted with benzyl chloroformate and the coupling reagent is dicyclohexylcarbodiimide. The method of claim 9, wherein in step a), L-homocystine is reacted with formic acid and acetic anhydride, and the coupling reagent is dicyclohexylcarbodiimide. The process of claim 9, wherein in step b), L-homocystine is reacted with ethyl trifluoroacetate and the resulting disulfide is treated with (chloromethylene) dimethylammonium chloride to produce the corresponding acid chloride. . The method of claim 9, wherein in step c), L-homocystin is reacted with ethyl trifluoroacetate and the compound of formula IIa is treated with dicyclohexylcarbodiimide. a) reacting a product of formula II with a reagent that cleaves disulfide bonds; And b) acid catalyzing the monomer from step (a) to produce the desired product A method for preparing N-protected lactam of formula III, comprising: <Formula II> <Formula III> Wherein P ₁ is a nitrogen protecting group. The method of claim 15, wherein the disulfide of formula (II) is treated with bismercaptan, phosphine reducing agent, phosphite reducing agent, or zinc metal powder to cleave the disulfide bond. The method of claim 16, wherein the disulfide of formula (II) is treated with tributyl phosphine. ai) reacting L-homocystine to introduce a P ₁ group into both nitrogens to produce an intermediate of formula (I); aii) reacting the disulfide of formula (I) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester in the presence of a coupling reagent to produce a compound of formula (II); aiii) reacting the disulfide of formula (II) with a reagent that cleaves disulfide bonds; And aiv) acid catalyst cyclization of the monomer from step (aiii) to produce the desired product; or bi) reacting L-homocystine to introduce a P ₁ group to both nitrogens to produce an intermediate of formula (I); bii) converting the disulfide of formula (I) to an activated form; biii) reacting the activated disulfide from step (bii) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester to produce a compound of formula II; biv) reacting the disulfide of formula II with a reagent that cleaves disulfide bonds; And bv) acid catalyst cyclization of the monomer from step (biv) to produce the desired product; or ci) reacting L-homocystine to introduce a P ₁ group into both nitrogens to produce an intermediate of formula (I); cii) reacting the disulfide of formula (I) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester to produce a compound of formula (IIa); ciii) treating the compound of Formula IIa with a coupling reagent to produce a compound of Formula II; civ) reacting the disulfide of formula (II) with a reagent that cleaves disulfide bonds; And cv) acid catalyst cyclization of the monomer from step (civ) to produce the desired product A method for preparing N-protected lactam of formula III, comprising: <Formula I> <Formula IIa> <Formula II> <Formula III> Wherein P ₁ is a nitrogen protecting group. 19. The process of claim 18, wherein in step (ai), (bi), or (ci), L-homocystin is treated with ethyl trifluoroacetate, benzyl chloroformate, or formic acid and acetic anhydride; in step (aiii), (biv), or (civ), the disulfide of formula (II) is treated with tributyl phosphine. a) reacting a disulfide of formula (II) with a reagent that cleaves disulfide bonds; b) acid catalyzing the monomer from step (a) to produce an N-protected lactam of formula III; And c) subjecting the N-protected lactam of formula (III) to remove the P ₁ protecting group to produce the desired product which can optionally be converted to a salt [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2,1-b] [1,3] thiazepine-7-carboxyl, including Process for the preparation of acids, methyl esters or salts thereof. <Formula II> <Formula III> The method of claim 20, wherein in step (a), the disulfide of formula (II) is treated with dithiothreitol, dithioerythritol, tributyl phosphine, or zinc metal powder to cleave the disulfide bond. ai) reacting L-homocystine to introduce a P ₁ group into both nitrogens to produce an intermediate of formula (I); aii) reacting the disulfide of formula (I) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester in the presence of a coupling reagent to produce a compound of formula (II); aiii) reacting the disulfide of formula (II) with a reagent that cleaves disulfide bonds; aiv) acid catalyzing the monomer from step (aiii) to produce an N-protected lactam of formula III; And av) treating the N-protected lactam of formula III to remove the P ₁ protecting group to produce a desired product that can optionally be converted to a salt; or bi) reacting L-homocystine to introduce a P ₁ group to both nitrogens to produce an intermediate of formula (I); bii) converting the disulfide of formula (I) to an activated form; biii) reacting the activated disulfide from step (bii) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester to produce a compound of formula II; biv) reacting the disulfide of formula II with a reagent that cleaves disulfide bonds; bv) acid catalyzing the monomer from step (biv) to produce an N-protected lactam of formula III; And bvi) subjecting the N-protected lactam of formula (III) to remove the P ₁ protecting group to produce a desired product which can optionally be converted to a salt; or ci) reacting L-homocystine to introduce a P ₁ group into both nitrogens to produce an intermediate of formula (I); cii) reacting the disulfide of formula (I) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester to produce a compound of formula (IIa); ciii) treating the compound of Formula IIa with a coupling reagent to produce a compound of Formula II; civ) reacting the disulfide of formula (II) with a reagent that cleaves disulfide bonds; cv) acid catalyzing the monomer from step (civ) to produce an N-protected lactam of formula III; And cvi) subjecting the N-protected lactam of formula III to remove the P ₁ protecting group to produce the desired product which can optionally be converted to a salt [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2,1-b] [1,3] thiazepine-7-carboxyl, including Process for the preparation of acids, methyl esters or salts thereof. <Formula I> <Formula IIa> <Formula II> <Formula III> The process of claim 22, wherein in step (ai), (bi), or (ci), L-homocystine is reacted with ethyl trifluoroacetate, benzyl chloroformate, or formic acid and acetic anhydride; the coupling reagent in step (aii), or (ciii) is dicyclohexylcarbodiimide; wherein in step (aiii), (biv), or (civ), the disulfide of formula (II) is treated with dithiothritol, dithioerythritol, tributyl phosphine, or zinc metal powder. ai) reacting L-homocystine with ethyl trifluoroacetate, benzyl chloroformate, or formic acid and acetic anhydride to produce a compound of formula (I); aii) reacting the disulfide of formula (I) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester in the presence of dicyclohexylcarbodiimide to produce a compound of formula (II); aiii) cleaving the disulfide bond by reacting the disulfide of formula II with tributyl phosphine; aiv) acid catalyzing the monomer from step (aiii) to produce an N-protected lactam of formula III; And av) when P ₁ is trifluoroacetyl, treating N-protected lactam of formula III with potassium carbonate followed by hydrochloric acid; Or when P ₁ is phenylmethoxycarbonyl, treating N-protected lactam of formula III with iodotrimethylsilane followed by hydrochloric acid; Or when P ₁ is formyl, treating the N-protected lactam of formula III with hydrochloric acid; or bi) reacting L-homocystine with ethyl trifluoroacetate to produce a compound of formula (I); bii) treating the disulfide of formula I with (chloromethylene) dimethylammonium chloride to convert to the corresponding acid chloride; biii) reacting the acid chloride from step (bii) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester to produce a compound of formula II; biv) reacting the disulfide of formula II with tributyl phosphine to cleave the disulfide bond; bv) acid catalyzing the monomer from step (biv) to produce an N-protected lactam of formula III; And bvi) treating the N-protected lactam of formula III with potassium carbonate followed by hydrochloric acid; or ci) reacting L-homocystine with ethyl trifluoroacetate to produce a compound of formula (I); cii) reacting the disulfide of formula (I) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester to produce a compound of formula (IIa); ciii) treating the compound of Formula IIa with dicyclohexylcarbodiimide to produce a compound of Formula II; civ) reacting the disulfide of formula II with tributyl phosphine to cleave the disulfide bond; cv) acid catalyzing the monomer from step (civ) to produce an N-protected lactam of formula III; And cvi) treating N-protected lactam of formula III with potassium carbonate followed by hydrochloric acid [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2,1-b] [1,3] thiazepine-7-carboxyl, including Process for the preparation of acids, methyl esters, hydrochlorides. <Formula I> <Formula IIa> <Formula II> <Formula III> Wherein P ₁ is trifluoroacetyl, phenylmethoxycarbonyl or formyl. a) reacting a disulfide of formula (II) with a reagent that cleaves disulfide bonds; b) acid catalyzing the monomer from step (a) to produce an N-protected lactam of formula III; c) N-protected lactam of formula (III) was treated to remove the P ₁ protecting group, giving [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2 , 1-b] [1,3] thiazepine-7-carboxylic acid, methyl ester; d) coupling the lactam product or salt thereof from step (c) with an acylmercaptoalkanoic acid of formula IV to produce a compound of formula V; And e) treating the compound of formula V to remove the R ₆ -C (O)-group and convert the methyl ester group to a carboxylic acid to give the desired product [4S- [4α (R *), 7α, 10aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl) amino] -5-oxo-7H- containing Process for the preparation of pyrido- [2,1-b] [1,3] thiazepine-7-carboxylic acid. <Formula II> <Formula III> <Formula IV> <Formula V> Wherein P ₁ is a nitrogen protecting group; R ₆ is methyl or phenyl. ai) reacting L-homocystine to introduce a P ₁ group into both nitrogens to produce a disulfide of formula (I); aii) reacting a disulfide of formula (I) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester in the presence of a coupling reagent to produce a disulfide of formula (II) aiii) reacting the disulfide of formula (II) with a reagent that cleaves disulfide bonds; And aiv) acid catalyzing the monomer from step (aiii) to produce an N-protected lactam of formula III; av) N-protected lactam of formula (III) was treated to remove the P ₁ protecting group, giving [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2 , 1-b] [1,3] thiazepine-7-carboxylic acid, methyl ester; avi) coupling the lactam product or salt thereof from step (av) with an acylmercaptoalkanoic acid of formula IV to produce a compound of formula V; And avii) treating the compound of Formula V with the R ₆ -C (O)-group and converting the methyl ester group to a carboxylic acid to give the desired product; or bi) reacting L-homocystine to introduce a P ₁ group into both nitrogens to produce a disulfide of formula (I); bii) converting the disulfide of formula (I) to an activated form; biii) reacting the activated disulfide from step (bii) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester to produce a disulfide of formula II; biv) reacting the disulfide of formula II with a reagent that cleaves disulfide bonds; bv) acid catalyzing the monomer from step (biv) to produce an N-protected lactam of formula III; bvi) The N-protected lactam of formula (III) was treated to remove the P ₁ protecting group, giving [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2 , 1-b] [1,3] thiazepine-7-carboxylic acid, methyl ester; bvii) coupling the lactam product or salt thereof from step (bvi) with an acylmercaptoalkanoic acid of formula IV to produce a compound of formula V; And bviii) subjecting the compound of Formula V to R ₆ -C (O)-group and converting the methyl ester group to a carboxylic acid to give the desired product; or ci) reacting L-homocystine to introduce a P ₁ group into both nitrogens to produce a disulfide of formula (I); cii) reacting the disulfide of formula (I) with (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester to produce a disulfide of formula (IIa); ciii) treating the compound of Formula IIa with a coupling reagent to produce a disulfide of Formula II; civ) reacting the disulfide of formula (II) with a reagent that cleaves disulfide bonds; And cv) acid catalyzing the monomer from step (civ) to produce an N-protected lactam of formula III; cvi) The N-protected lactam of formula (III) was treated to remove the P ₁ protecting group, giving [4S- (4α, 7α, 10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido [2 , 1-b] [1,3] thiazepine-7-carboxylic acid, methyl ester; cvii) coupling the lactam product or salt thereof from step (cvi) with an acylmercaptoalkanoic acid of formula IV to produce a compound of formula V; And cviii) subjecting compound of formula V to R ₆ -C (O)-group and subjecting the methyl ester group to a carboxylic acid to give the desired product [4S- [4α (R *), 7α, 10aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl) amino] -5-oxo-7H- containing Process for the preparation of pyrido- [2,1-b] [1,3] thiazepine-7-carboxylic acid. <Formula I> <Formula IIa> <Formula II> <Formula III> <Formula IV> <Formula V> Wherein R ₆ is methyl or phenyl. The process according to claim 9, wherein the disulfide of formula I or the activated form of disulfide of formula I and (S) -2-amino-6,6-dimethoxyhexanoic acid, methyl ester are reacted in ethyl acetate And (S) -2-amino-6,6-dimethoxyhexanoic acid, an agent for removing ethylene glycol in an ethyl acetate solution of methyl ester. The method of claim 27, wherein the agent used to remove ethylene glycol is poly (acrylic acid co-acrylamide), potassium salt or calcium chloride dihydrate.