WO2012045007A1 - Method of preparation of (4 - {4 -acetylamino- 2 - [3- ( 2 - isopropyl - thiazol - 4 - ylmethyl) - 3 -methyl - ureido] - butyryl amino} -1 -benzyl- 5 -phenyl- pentyl) -carbamic acid thiazol - 5 - ylmethyl ester - Google Patents

Abstract

The invention provides methods and intermediates that are useful for preparing a compound of formula I: and salts thereof.

Description

METHOD OF PREPARATION OF (4 - {4 -ACETYLAMINO- 2 - [3- ( 2 - ISOPROPYL - THIAZOL - 4 - YLMETHYL) - 3 -METHYL - UREIDO] - BUTYRYL AMINO} -1 -BENZYL- 5 -PHENYL- PENTYL) -CARBAMIC ACID THIAZOL - 5 -

YLMETHYL ESTER

Related Application

This patent document claims the benefit of priority of U.S. application serial No.

61/388,928, filed October 1, 2010, which application is herein incorporated by reference.

Background of the Invention

International Patent Application Publication Number WO 2008/010921 and

International Patent Application Publication Number WO 2008/103949 disclose certain compounds that are reported to be useful to modify the pharmacokinetics of a coadministered drug, e.g. by inhibiting cytochrome P450 monooxygenase. One specific compound identified therein is a compound of the following formula I:

There is currently a need for improved synthetic methods and intermediates that can be used to prepare the compound of formula I and its salts. There is also a need for improved methods for preparing intermediate compounds that can be used to prepare the compound of formula I and its salts. The improved methods and intermediates may reduce the cost, time, and or the amount of waste associated with the existing methods for preparing the compound of formula I and its salts.

Summary of the Invention

An improved synthetic route for preparing the compound of formula I and its salts has been identified. This improved synthetic route utilizes novel intermediates of formulae XIX, XX, XXI, XXVI, XXVII, XXVIII, XL, XLI, XLII, and XLIII identified herein below. This route reduces the cost, the time, and the amount of waste associated with the preparation of the compound of formula I and its salts.

Accordingly in one embodiment, the invention provides a method for preparing a compound of formula I:

comprising reacting a compound of formula XXVIII:

wherein Y is a suitable counter ion;

with a compound of formula XXIII:

XXIII

or a salt thereof; to provide the compound of formula I.

In another embodiment the invention provides a compound of formula XIX, XXa, XXI, XXVI, XXVII, XXVIII, XL, XLI, XLII, or XLIII:



wherein Y is a suitable counter ion; Ri is -S(=0)₂NR_aR_b, wherein each of R_a and R_b is independently (C₁-C₈)alkyl; or R_a and R_b together with the nitrogen to which they are attached form a 3 or 4 membered saturated ring or a 5, 6, or 7 membered saturated or partially unsaturated ring comprising 1 or 2 heteroatoms (e.g. aziridine, azetidine, piperidine, morpholine, thiomorpholine, pyrrolidine, homopiperazine, homopiperidine, or piperazine); and R₂ is (C₁-C₈)alkyl; or a salt thereof.

In another embodiment the invention provides a method for preparing a compound of formula I:

a salt thereof, wherein a compound of formula XIX:

XIX wherein Rj is a suitable protecting group, or a salt thereof is prepared and converted into the compound of formula I, characterized in that the compound of formula XIX is prepared by protecting a corresponding compound of formula XXXI:

H N

Ph

XXXI

or a salt thereof to provide the compound of formula XIX.

In another embodiment the invention provides a method for preparing a compound of formula I:

I

or a salt thereof, wherein a compound of formula XX:

wherein each R_\ is a protecting group, or a salt thereof is prepared and converted into the compound of formula I, characterized in that the compound of formula XX is prepared by dimerizing a corresponding compound of formula XIX:

XIX or a salt thereof to provide the compound of formula XX.

In another embodiment the invention provides a method for preparing a compound of formula I:

or a salt thereof, wherein a compound of formula XXI:

XXI or a salt thereof is prepared and converted into the compound of formula I,

characterized in that the compound of formula XXI is prepared by deprotecting a corresponding compound of formula XX:

XX wherein each R_\ is a protecting group, or a salt thereof to provide the compound of formula XXI.

In another embodiment the invention provides a method for preparing a compound of formula I:

or a salt thereof, wherein a compound of formula XXVI:

wherein R₂ is (C₁-C₈)alkyl, or a salt thereof is prepared and converted into the compound of formula I, characterized in that the compound of formula XXVI is prepared by acylating a corresponding compound of formula XXX:

to provide the compound of formula XXVI.

In another embodiment the invention provides a method for preparing a compound of formula I:

I

or a salt thereof, wherein an acid of formula XXVII:

or a salt thereof is prepared and converted into the compound of formula I,

characterized in that the acid of formula XXVII is prepared by hydrolyzing an ester of formula XXVI:

wherein R₂ is (C₁-C₈)alkyl to provide the compound of formula XXVII.

In another embodiment the invention provides a method for preparing a compound of formula I:

I

thereof, wherein a compound of formula XXVIII:

XXVIII wherein Y is a suitable counter ion, or a salt thereof, is prepared and converted into the compound of formula I, characterized in that the compound of formula XXVIII or the salt thereof is prepared by converting an acid of formula XXVII:

or a salt thereof to the compound of formula XXVIII or the salt thereof.

In another embodiment the invention provides a method for preparing a compound of formula I:

XL or a salt thereof is prepared and converted into the compound of formula I or the thereof, characterized in that the compound of formula XL or the salt thereof is prepared by reacting an amine formula XXI:

or a salt thereof, with a carbonate of formula VIII:

wherein R³ is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl, to provide the compound of formula XL.

In another embodiment the invention provides a method for preparing a compound of formula I:

or a salt thereof, wherein a compound of formula XLI:

is prepared and converted into the compound of formula I or the salt thereof, characterized in that the compound of formula XLI is prepared by coupling an amine of formula XXI:

or a salt thereof, with a com ound of formula XXVII:

to provide the compound of formula XLI.

In another embodiment the invention provides a method for preparing a compound of formula I:

or a salt thereof, comprising hydrogenating a compound of formula XLII:

to provide the compound of formula I or the salt thereof.

In another embodiment the invention provides a method for preparing a compound of formula I:

I

or a salt thereof, comprising reacting an amine formula XLIII:

or a salt thereof, with a carbonate of formula VIII:

wherein R is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl, to provide the compound of formula I or the salt thereof.

In another embodiment the invention provides a method for preparing a compound of formula XIX:

XIX wherein R_\ is a suitable protecting group, or a salt thereof comprising protecting a corresponding compound of formula XXXI:

XXXI

or a salt thereof to provide the compound of formula XIX or the salt thereof.

In another embodiment the invention provides a method for preparing a compound of formula XX:

or a salt thereof, wherein each R₁ is a protecting group, or a salt thereof comprising dimerizing a corresponding compound of formula XIX:

XIX or a salt thereof to provide the compound of formula XX.

In another embodiment the invention provides a method for preparing a compound of formula XXI:

wherein each Ri is a protecting group, or a salt thereof comprising deprotecting a corresponding compound of formula XX:

XX wherein each Ri is a protecting group, or a salt thereof, to provide the compound of formula XXI or the salt thereof.

In another embodiment the invention provides a method for preparing a compound of formula XXVI:

wherein R₂ is (C₁-C₈)alkyl, or a salt thereof comprising acylating a compound of formula XXX:

wherein R₂ is (Ci-Cg)alkyl, or a salt thereof to provide the compound of formula XXVI or the salt thereof. In another embodiment the invention provides a method for preparing a compound of formula XXVII:

a salt thereof comprising hydrolyzing an ester of formula XXVI:

XXVI wherein R₂ is (C₁-C₈)alkyl to provide the compound of formula XXVII or the salt thereof.

In another embodiment the invention provides a method for preparing a compound of formula XXVIII:

wherein Y is a suitable counter ion or a salt thereof comprising converting an acid of formula XXVII:

or a salt thereof to the compound of formula XXVIII or the salt thereof.

In another embodiment the invention provides a method for preparing a compound of formula XL:

XL or a salt thereof comprising reacting an amine formula XXI:

or a salt thereof, with a carbonate of formula

to provide the compound of formula XL or the salt thereof.

In another embodiment the invention provides a method for preparing a compound of formula XLI:

comprising coupling an amine of formula XXI:

or a salt thereof, with a com ound of formula XXVII:

to provide the compound of formula XLI.

In another embodiment the invention provides a method for preparing a compound of formula XLII:

or a salt thereof, with a carbonate of formula VIII:

wherein R³ is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl, to provide the compound of formula XLII.

In another embodiment the invention provides a method for preparing an amine formula XLIII:

or a salt thereof, comprising hydrogenating a compound of formula XLI:

to provide the amine of formula XLIII or the salt thereof. In another embodiment the invention provides a method for preparing an amine formula ofXLIII:

or a salt thereof, comprising coupling an amine of formula XXII:

or a salt thereof, with a com ound of formula XXVII:

to provide the amine of formula XLIII or the salt thereof.

The invention also provides novel synthetic intermediates described herein as well as methods for preparing such intermediates.

Detailed Description

As used herein alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual group such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.

Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. Specifically, (C₁-C )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, or octyl.

Another specific value for R_x is -S(=0)₂NR_aR_b, -S(=0)₂R_c, -C(=0)Rc, or

-C(=0)NR_aR_b wherein each of R_a and R_b is independently (C]-C8)alkyl; or R_a and R_b together with the nitrogen to which they are attached form a 3 or 4 membered saturated ring or a 5, 6, or 7 membered saturated or partially unsaturated ring comprising 1 or 2 heteroatoms (e.g. aziridine, azetidine, piperidine, morpholine, thiomorpholine, pyrrolidine, homopiperazine, homopiperidine, or piperazine); and Rc is aryl, (C_\- C₈)alkyl, halo(C₁-C₈)alkyl (Ci-C8)alkoxy, or aryl-(C₁-C₈)alkoxy, wherein any aryl can optionally be substituted with one or more (C₁-C₈)alkyl. In one embodiment of the invention Ri is not fert-butylsulfonyl.

Another specific value for Ri is -S(=0)₂NR_aR_b wherein each of R_a and R_b is independently (C₁-C₈)alkyl; or R_a and R_b together with the nitrogen to which they are attached form a 3 or 4 membered saturated ring or a 5, 6, or 7 membered saturated or partially unsaturated ring comprising 1 or 2 heteroatoms (e.g. an aziridine, azetidine, piperidine, morpholine, thiomorpholine, pyrrolidine, homopiperazine, homopiperidine, or piperazine ring.

A specific value for R] is an NN-disubstituted aminosulfonyl group.

Another specific value for R is an NN-dialkyl aminosulfonyl group.

Another specific value for Ri is:

Another specific value for R¹ is -S(0)₂N(CH₃)₂.

Another specific value for R¹ is benzyloxycarbonyl.

A specific value for R₂ is methyl.

In one specific embodiment the invention provides a compound of formula XIX, XX, XXI, XXVI, XXVII, or XXVIII; or a salt thereof.

In one specific embodiment the invention provides a compound of formula XL, XLI, XLII, or XLIII; or a salt thereof.

A compound of formula I or a salt thereof can be prepared as illustrated in

Schemes 1-5 below. Scheme 1

f/? 2-Benzylaziridine XIX

VIII XXIII Scheme 3

Scheme 4

Scheme 5

XXVIII + XXIII

I

An intermediate compound of formula XXIII or a salt thereof can be prepared as illustrated in Scheme 6 below. The compound of formula XXIII or the salt thereof can be carried on to a compound of formula I as described herein.

Scheme 6

XXIII

A compound of formula I or a salt thereof can also be prepared as illustrated in Schemes 7-9 below. Scheme 7

XLII

Scheme 8

In one embodiment the invention provides a method for preparing a compound of formula I:

a salt thereof comprising

1) protecting (R)-2-benzylaziridine to provide a compound of formula XIX:

XIX wherein Ri is a protecting group, or a salt thereof.

2) dimerizing the compound of formula XIX or the salt thereof to provide a corresponding compound of formula XX:

or a salt thereof;

3) deprotecting the compound of formula XX or the salt thereof to provide compound of formula XXI:

or a salt thereof;

4) reducing the compound of formula XXI or the salt thereof to provide compound of formula XXII:

or a salt thereof;

5) reacting the compound of formula XXII or the salt thereof with a carbonate of formula VIII:

wherein R is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl, to provide a compound of formula XXIII:

XXIII

or a salt thereof;

6) reacting the compound of formula XXIII or the salt thereof with a compound of formula XXVIII:

wherein Y is a suitable counter ion to provide the compound of formula I or the salt thereof.

In another embodiment, the invention also provides the above method for preparing a compound of formula I which further comprises preparing the compound of formula XXVIII by:

7) reacting a compound of formula XXIV:

XXIV wherein Pg is a suitable protecting group and R₂ is (C₁-C )alkyl or a salt thereof with methyl aminomethylthiazole to provide a corresponding compound of formula XXV:

or a salt thereof;

8) deprotecting the compound of formula XXV to provide an amine of formula XXX:

XXX or a salt thereof;

9) acylating the amine of formula XXX or the salt thereof to provide an ester of formula XXVI:

XXVI or a salt thereof;

10) hydrolyzing the ester of formula XXVI or the salt thereof to provide an acid of formula XVII:

XXVII

or a salt thereof;

11) treating the acid of formula XXVII or the salt thereof with a base to provide the compound of formula XXVIII:

wherein Y is a suitable counter ion.

Preparation of a compound of formula XIX

f?J-2-Benzylaziridine XIX

The starting aziridine can be protected with any suitable protecting group (K_\) under standard conditions to provide the corresponding compound of formula XIX. For example, the reaction can be carried out in a suitable solvent in the presence of a base. Suitable solvents include aprotic solvents such as, dichloromethane, tetrahydrofuran, ethyl ether, tert-butyl methyl ether, tetrahydropyran, 1,4-dioxane, 1,2-dichloroethane, and mixtures thereof. Suitable bases include trialkylamines such as: triethylamine, N- methyl morpholine, quinuclidine, N-methylpiperidine, N,N-diisopropylethylamine, and iV-methyl pyrrolidine; as well as other weak non-nucleophilic bases such as, potassium carbonate and sodium bicarbonate. The reaction can conveniently be carried out at a temperature from about -10 °C to 40 °C.

The resulting compound of formula XIX can be purified by recrystallization from a suitable solvent or mixture of solvents. For example, combinations of ethereal and non-polar solvents, such as ethyl ether, «-butyl ether, tetrahydrofuran, tetrahydropyran, 1,2-dimethoxyethane, hexanes, tert-butyl methyl ether, heptane, pentane, cyclohexane, toluene can be used.

Preparation of a compound of formula XX

XIX XX

The starting aziridine XIX can be dimerized by treatment with a suitable base in a suitable solvent to provide the corresponding compound of formula XX. Suitable solvents include ethyl ether, tert-butyl methyl ether, w-butyl ether, tetrahydropyran, hexanes, tetrahydrofuran, 1 ,2-dimethoxyethane, and mixtures thereof. Suitable bases include 2,2,6,6-tetramethylpiperidine (TMP); w-butyllithium («-BuLi), as well as other hindered non-nucleophilic amine bases such as diisopropylamine,

hexamethyldisilazane, di-t-butylamine, isopropylcyclohexyl-amine, and

dicyclohexylamine; and other organolithium bases such as: rc-hexyllithium, s- butyllithium, and t-butyllithium. The reaction can conveniently be carried out at a temperature from about -78 °C to 22 °C.

The resulting compound of formula XX can be purified by recrystallization from a suitable solvent or mixture of solvents. For example, combinations of ethereal and non-polar solvents, such as ethyl ether, n-butyl ether, tetrahydrofuran, tetrahydropyran, 1,2-dimethoxyethane, and fert-butyl methyl ether can be used. Preparation of a compound of formula XXI

XX

The starting compound of formula XX can be deprotected under standard conditions to provide the corresponding compound of formula XXI. The reaction can be carried out in a solvent that comprises an amine; for example, a diamine such as 1,3-diaminopropane, ethylenediamine, 1,2-diaminocyclohexane, 1,2-phenylenediamine, putrescene, or cadaverine; also for example, an amino alcohol, such as 2-aminoehanol or 3-amino-l-propanol. The solvent can also comprise toluene, anisole, or the like, or mixtures thereof. The reaction can conveniently be carried out at a temperature from about 100 °C to about 140 °C.

Hydrogenation to provide a compound of formula XXII

The starting alkene XXI can be hydrogenated under standard conditions to provide the corresponding compound of formula XXII. For example, the

hydrogenation can be carried out using a metal-containing catalyst in an alcoholic solvent. Suitable solvents include methanol, ethanol, isopropanol, «-propanol, butanol, ethyl acetate, isopropyl acetate, toluene, dioxane, and anisole, and mixtures thereof. Suitable catalysts include palladium on carbon, platinum on carbon, Raney nickel, Wilkinson's catalyst, and palladium hydroxide The reaction can conveniently be carried out at a pressure from about ambient pressure to about 60 psi.

The compound of formula XXII can be isolated by treatment with an acid in an organic solvent to provide a corresponding salt. Suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid. Suitable solvents include dichloromethane, ethyl ether, tetrahydrofuran, t-butyl methyl ether, 1,4-dioxane, 1,2- dimethoxyethane, chloroform, 1 ,2-dichloroethane, toluene, and anisole, and mixtures thereof. The conversion to the salt can conveniently be carried out at a temperature from about -10 °C to about 40 °C.

Preparation of a compound of formula XXIII or a salt thereof

VIII XXIII

A compound of formula XXIII can be prepared from a compound of formula XXII by treatment with a carbonate of formula VIII wherein R³ is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl, in the presence of a suitable base in a suitable solvent. Suitable bases include carbonate bases (e.g. potassium carbonate) and trialkylamines (e.g. diisopropylethylamine, or N-methyl morpholine). Suitable solvents include solvents such as dichloromethane, tetrahydrofuran, 1,2- dichloroethane, isopropyl acetate, and diethylether, and mixtures thereof. Subsequent treatment with an acid source provides a salt of the compound of formula XXIII.

Suitable acid sources include 1) non-aqueous acid solutions such as hydrochloric acid in ether, hydrochloric acid in methanol, or hydrochloric acid in isopropanol; 2) other mineral acids such as: hydrobromic acid, hydroiodic acid, sulfuric acid, in similar solvents; and in situ generated acid sources such as TMSCl/methanol and acetyl chloride/methanol. Preparation of a compound of formula VIII

VIII

The mixed carbonate of formula VIII can be prepared by treating 5-hydroxy- methylthiazole with a suitable carbonate or carbonate equivalent having a leaving group adjacent to the carbonyl carbon, such as phosgene in the presence of a base. For example, suitable carbonates include bis-(4-nitrophenyl)carbonate and disuccinimidyl carbonate. The reaction can conveniently be carried out in a suitable aprotic organic solvent, such as dichloromethane, tetrahydrofuran, 1 ,2-dichloro-ethane, or diethylether, or a mixture thereof. Suitable bases include trialkylamine bases, such as

diisopropylethylamine, N-methyl morpholine, and triethylamine.

Preparation of a compound of formula XXV

aminomethylthiazole

The compound of formula XXV can be prepared by treating methyl

aminomethylthiazole with a compound of formula XXIV wherein Pg is a suitable protecting group; and R₂ is (C₁-C₈)alkyl, or a salt thereof, in the presence of a suitable coupling agent. When a salt of the compound of formula XXIV is used, the reaction can be carried out in the presence of a base. The reaction can conveniently be carried out in a suitable aprotic organic solvent, such as dichloromethane, tetrahydrofuran, 1 ,2- dichloroethane, or diethylether, or a mixture thereof. Suitable coupling agents include carbonyl diimidazole. Suitable bases include trialkylamine bases, such as

diisopropylethylamine, N-methyl morpholine, and triethylamine. The reaction can conveniently be carried out at a temperature from about 0 °C to about 22 °C. Suitable protecting groups (Pg) include carbamates such as a Boc group as well as acetates.

Preparation of a com ound of formula XXVI:

The compound of formula XXVI can be prepared by deprotecting a

corresponding compound of formula XXV wherein Pg is a suitable protecting group other than acetate and R₂ is (CrC₈)alkyl followed by treatment of the resulting primary amine with a acetic anhydride or acetyl chloride in the presence of a suitable base. The deprotection reaction can conveniently be carried out under standard conditions for removing the group Pg. When Pg is a Boc group, the deprotection can be carried out in a suitable aprotic organic solvent, such as dichloromethane, tetrahydrofuran, 1,2- dichloroethane, or diethylether, or a mixture thereof, in the presence of an anhydrous acid source (e.g. methanesulfonic acid). The acetylation reaction can conveniently be carried out at a temperature from about 0 °C to about 22 °C.

Preparation of an acid of formula XXVII

XXVII

An acid of formula XXVII or a salt thereof can be prepared by hydrolyzing a corresponding ester of formula XXVI wherein R₂ is (C₁-C₈)alkyl or a salt thereof under standard conditions. For example, the hydrolysis can be carried out in an aqueous solvent (e.g. water and dichloromethane, 2-methyltetrahydrofuran, or tetrahydrofuran) in the presence of a base (e.g. potassium hydroxide or lithium hydroxide) at a temperature from about -10 °C to about -30 °C. Preparation of a salt of formula XXVIII

XXVII XXVIII

A salt of formula XXVIII wherein Y is counterion can be prepared by treating an acid of formula XXVII with a base. The reaction can be carried out in a suitable solvent (e.g. acetone, 2-methyl tetrahydrofuran, tetrahydrofuran, methylethylketone, other keytones, methyl tert-butyl ether, and other ethers, and mixtures thereof) in the presence of a suitable base (e.g. an amine base such as dicyclohexylamine). The reaction salt formation can conveniently be carried out at a temperature from about 20 °C to about 50 °C. Preparation of a compound of formula I

A compound of formula I or a salt thereof can be prepared by coupling an acid salt of formula XXVIII with an amine of formula XXIII to form the corresponding amide. This amide forming reaction can be carried out under standard conditions. For example, it can be carried out in a suitable organic solyent (e.g. dichloromethane, tetrahydrofuran, diethylether, 1 ,2-dichloroethane, N,N-dimethylformamide, or a mixture thereof) in the presence of a suitable coupling agent, such as an onium salt reagent (e.g. BOP, PyBOP, PyBroP, BOI, HBTU, HATU, or TBTU) or a carbodiimide reagent (e.g. DCC or DICI) and in the presence of a suitable base (e.g. a trialkylamine base such as diisopropylethylamine triethylamine or N-methyl morpholine).

Preparation of a compound of formula XL or a salt thereof

XXI VIII XL

A compound of formula XL can be prepared from a compound of formula XXI by treatment with a carbonate of formula VIII wherein R³ is nitrophenyl (e.g. 4- nitrophenyl), succinimidyl, or thiazol-5-ylmethyl (in the presence of a suitable base in a suitable solvent. Suitable bases include carbonate bases (e.g. potassium carbonate) and trialkylamines (e.g. diisopropylethylamine, or N-methyl morpholine). Suitable solvents include solvents such as dichloromethane, tetrahydrofuran, 1 ,2-dichloroethane, isopropyl acetate, and diethylether, and mixtures thereof. Subsequent treatment with an acid source provides a salt of the compound of formula XL. Suitable acid sources include 1) non-aqueous acid solutions such as hydrochloric acid in ether, hydrochloric acid in methanol, or hydrochloric acid in isopropanol; 2) other mineral acids such as: hydrobromic acid, hydroiodic acid, sulfuric acid, in similar solvents; and in situ generated acid sources such as TMSCl/methanol and acetyl chloride/methanol.

Reduction of a compound of formula XL or a salt thereof to provide a compound of formula XXIII

The starting alkene XL or a salt thereof can be hydrogenated under standard conditions. For example, the hydrogenation can be carried out using a metal containing catalyst in a suitable solvent. Suitable solvents include methanol, ethanol, isopropanol, w-propanol, butanol, ethyl acetate, isopropyl acetate, toluene, dioxane, and anisole, and mixtures thereof. Suitable catalysts include palladium on carbon, platinum on carbon, Raney nickel, Wilkinson's catalyst, and palladium hydroxide. The reaction can conveniently be carried out at a pressure from about ambient pressure to about 60 psi.

The compound of formula XXIII can be isolated by treatment with an acid in an organic solvent to provide a corresponding salt. Suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid. Suitable solvents include dichloromethane, ethyl ether, tetrahydrofuran, t-butyl methyl ether, 1,4-dioxane, 1,2- dimethoxyethane, chloroform, 1,2-dichloroethane, toluene, and anisole, and mixtures thereof. The conversion to the salt can conveniently be carried out at a temperature from about -10 °C to about 40 °C.

Preparation of a compound of formula XLI or a salt thereof

XXI XXVII XLI

A compound of formula XLI or a salt thereof can be prepared by coupling a compound of formula XXVII (or a salt of formula XXVIII) with an amine of formula XXI to form the corresponding amide. This amide forming reaction can be carried out under standard conditions. For example, it can be carried out in a suitable organic solvent (e.g. dichloromethane, tetrahydrofuran, diethylether, 1 ,2-dichloroethane, N,N- dimethylformamide, or a mixture thereof) in the presence of a suitable coupling agent, such as an onium salt reagent (e.g. BOP, PyBOP, PyBroP, BOI, HBTU, HATU, or TBTU) or a carbodiimide reagent (e.g. DCC or DICI) and in the presence of a suitable base (e.g. a trialkylamine base such as diisopropylethylamine triethylamine or N-methyl morpholine).

Preparation of a compound of formula XLII or a salt thereof

A compound of formula XLII can be prepared from a compound of formula XLI by treatment with a carbonate of formula VIII (wherein R³ is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl) in the presence of a suitable base in a suitable solvent. Suitable bases include carbonate bases (e.g. potassium carbonate) and trialkylamines (e.g. diisopropylethylamine, or N-methyl morpholine). Suitable solvents include solvents such as dichloromethane, tetrahydrofuran, 1 ,2- dichloroethane, isopropyl acetate, and diethylether, and mixtures thereof.

Reduction of a compound of formula XLII or a salt thereof to provide a compound of formula I

XLII

The starting alkene XLII can be hydrogenated under standard conditions. For example, the hydrogenation can be carried out using a metal containing catalyst in a suitable solvent. Suitable solvents include methanol, ethanol, isopropanol, «-propanol, butanol, ethyl acetate, isopropyl acetate, toluene, dioxane, and anisole, and mixtures thereof. Suitable catalysts include palladium on carbon, platinum on carbon, Raney nickel, Wilkinson's catalyst, and palladium hydroxide. The reaction can conveniently be carried out at a pressure from about ambient pressure to about 60 psi. Preparation of a compound of formula XLIII or a salt thereof

A compound of formula XLIII or a salt thereof can be prepared by

hydrogenating a corresponding compound of formula XLI or a salt thereof under standard conditions. For example, the hydrogenation can be carried out using a metal containing catalyst in an alcoholic solvent. Suitable solvents include methanol, ethanol, isopropanol, «-propanol, butanol, ethyl acetate, isopropyl acetate, toluene, dioxane, and anisole, and mixtures thereof. Suitable catalysts include palladium on carbon, platinum on carbon, Raney nickel, Wilkinson's catalyst, and palladium hydroxide The reaction can conveniently be carried out at a pressure from about ambient pressure to about 60 psi.

The compound of formula XLIII can be isolated by treatment with an acid in an organic solvent to provide a corresponding salt. Suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid. Suitable solvents include dichloromethane, ethyl ether, tetrahydrofuran, i-butyl methyl ether, 1,4-dioxane, 1,2- dimethoxyethane, chloroform, 1 ,2-dichloroethane, toluene, and anisole, and mixtures thereof. The conversion to the salt can conveniently be carried out at a temperature from about -10 °C to about 40 °C.

The compound of formula XLIII or a salt thereof can be converted to a compound of formula I by treatment with a carbonate of formula VIII (wherein R³ is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl) in the presence of a suitable base in a suitable solvent. Suitable bases include carbonate bases (e.g.

potassium carbonate) and trialkylamines (e.g. diisopropylethylamine, or N-methyl morpholine). Suitable solvents include solvents such as dichloromethane,

tetrahydrofuran, 1,2-dichloroethane, isopropyl acetate, and diethylether, and mixtures thereof.

Alternative preparation of a compound of formula XLIII or a salt thereof

A compound of formula XLIII or a salt thereof can also be prepared by coupling a compound of formula XXVII or a salt thereof with an amine of

formula XXII or a salt thereof to form the corresponding amide. This amide forming reaction can be carried out under standard conditions. For example, it can be carried out in a suitable organic solvent (e.g. dichloromethane, tetrahydrofuran, diethylether, 1,2-dichloroethane, N,N-dimethylformamide, or a mixture thereof) in the presence of a suitable coupling agent, such as an onium salt reagent (e.g. BOP, PyBOP, PyBroP, BOI, HBTU, HATU, or TBTU) or a carbodiimide reagent (e.g. DCC or DICI) and in the presence of a suitable base (e.g. a trialkylamine base such as diisopropylethylamine triethylamine or N-methyl morpholine).

The invention will now be illustrated by the following non-limiting Examples.

Examples

Example 1. Preparation of (i?)-2-benzyl-N,N-dimethylaziridine-l -sulfonamide (XlXa)

? -2-Benzylaziridine XlXa

To a cooled (-10 °C) solution of (i?)-2-benzylaziridine (152 g, 1.14 mol) and N,N-dimethylsulfamoyl chloride (128.5 mL, 1.20 mol) in dichloromethane (762 mL) was added N.N-diisopropylethylamine (198.5 mL, 1.14 mol). The resulting yellow solution was stirred at -10 °C for a minimum of 16 hours. A 0.5M solution of citric acid (300 mL) was then added and the phases were separated. The organic phase was washed with 1.0 M sodium bicarbonate solution (300 mL). The organic phase was solvent exchanged into fert-butyl methyl ether (760 mL). The solution was cooled to 0 °C, and heptane (1.5 L) was added dropwise over a period of 2 hours. The mixture was aged for an additional 2 hours at 0 °C, then cooled to -10 °C, allowing the compound of formula XlXa to precipitate out as a white, crystalline solid (209 g, 76%). R_f: 0.53 (Si0₂; 1 :1 heptane:ethyl acetate, KMn0₄). 1H NMR (400 MHz, CDC1₃): δ 7.20-7.29 (m, 5H), 2.94 (dd, J= 14, 5 Hz, 1H), 2.80-2.88 (m, 1H), 2.70 (dd, J= 14, 7 Hz, 1H), 2.66 (s, 6H), 2.56 (d, J= 7 Hz, 1H), 2.14 (d, J= 4 Hz, 1H). ¹³C NMR (100 MHz, CDC1₃): δ 137.4, 129.3, 128.9, 127.2, 40.6, 38.3, 38.1, 33.0. Example 2. Preparation of Diamine (XXa)

To a cooled (-9 °C) slurry of XlXa (lOg, 0.041 mol) and 2,2,6,6-tetra- methylpiperidine (2.1 mL, 0.012 mol) in 1 :3 tetrahydrofuramheptane (30 mL) was added «-butyllithium (2.6M in hexanes, 19 mL, 0.050 mol), dropwise, maintaining an internal temperature below -7.2 °C (total addition time: 120 minutes). The resulting red-brown mixture was quenched with glacial acetic acid (4 mL) at which time the reaction turned bright-yellow. The solution was warmed to 5 °C and the suspension was filtered cold, and the yellow solids were subsequently washed with 3:1

MTBE:heptane (2 x 30 mL), water (3 x 30 mL), then again with 3:1 MTBE:heptane (2 x 30 mL) to give XXa as a pale-yellow powder (7.2g, 72%). R_f: 0.32 (Si0₂, 1 : 1 heptane:ethyl acetate, ΚΜη0₄). Ή NMR (400 MHz, CDC1₃): δ 7.10-7.35 (m, 10H), 5.59 (s, 2H), 3.95-4.10 (m, 4H), 2.80 (ddd, J = 22, 13, 6 Hz, 4H), 2.59 (s, 12H). ¹³C NMR (100 MHz, CDC1₃): δ 136.7, 132.0, 129.9, 128.9, 127.2, 57.0, 42.4, 38.1.

Example 3. Preparation of Diamine (XXI)

A solution of XXa (3.05 g, 0.00635 mol) in ethylene diamine (6 mL) was heated to 110 °C (internal temp) for 18-24 hours. After cooling the yellow solution to 22 °C, water (15 mL) was added followed by isopropyl acetate (15 mL). The phases were separated. The organic layer was carried forward as a solution of isopropyl acetate/XXI into the next hydrogenation step. R_f: 0.61 (Si0₂, 4:1 CH₂C1₂:CH₃0H w/ 5% Et₃N, KMn0₄). 1H NMR (400 MHz, CDC1₃): δ 7.10-7.35 (m, 10H), 5.60 (dd, J = 4, 2 Hz, 2H), 3.50-3.60 (br, 2H), 2.85 (dd, J = 13, 5 Hz, 2H), 2.60 (13, 8 Hz, 2H), 1.15 (br, 4H). 1³C NMR (100 MHz, CDC1₃): δ 139.0, 134.1, 129.7, 128.6, 126.5, 54.9, 44.9.

Example 4. Preparation of Diamine (XXII)

XXI XXII

To a solution of XXI (th. 1.69 g, th. moles, 0.00635 mol) in isopropyl acetate was added 10% palladium on carbon (168 mg, 10 wt%). The resulting black suspension was purged with hydrogen gas and held under a hydrogen atmosphere (balloon) for 4-12 hours. The reaction was then filtered through celite, the cake was rinsed with isopropyl acetate (15 mL) and the solution was dried via distillation then diluted up to 30 vols (50 mL) (KF of solution < 0.1% water). This solution was used the next step. _f: 0.60 (Si0₂, 4: 1 CH₂C1₂:CH₃0H w/ 5% Et₃N, KMn0₄).

1H NMR (400 MHz, CDC1₃): δ 7.15-7.35 (m, 10H), 2.95-3.05 (m, 2H),

2.82 (dd, J = 13, 5 Hz, 2H), 2.50 (dd, J = 13, 9 Hz, 2H), 1.45-1.66 (m, 4H), 1.36

(br, 4H). ¹³C NMR (100 MHz, CDC1₃): δ 139.7, 129.5, 128.7, 126.5, 53.2, 45.1, 34.6.

Example 5. Preparation of Mono-Carbamate Hydrochloride (XXIIIa)

XXII + T Π N i. DIPEA (1 .5 equiv)

ii- 4M HCI in dioxane

Villa XXIIIa To a solution of XXII (th, 11.9 g, 0.0044 mol) in isopropylacetate (375 mL) was added Villa (12.4 g, 0.0044 mol) followed by diisopropylethylamine (8.6 g, 0.0066 mol). The resulting yellow solution was stirred for 18 hours and was then quenched with the addition of 0.25M sodium hydroxide (120 mL). The phases were split and the organic layer was washed with 0.5M sodium hydroxide (1 x 120 mL) followed by l.OM sodium hydroxide (1 x 120 mL). The organic layer was then washed with water (120 mL), dried over sodium sulfate (48 g), filtered, and diluted with dichloromethane (180 mL). To this solution was charged HCI (12.2 mL, 4M HCI in dioxane, about 0.0048) to induce precipitation. The product, XXIIIa, was filtered, rinsed with isopropyl acetate, and dried under vacuum to afford a white powder (16.1 g, 82% yield). 1H NMR (CD₃OD) δ 9.0 (s, 1H), 7.8 (s, 1H), 7.4-7.14 (m, 10H), 5.2 (d, 1H), 4.8 (s, 5 H) 3.7 (m, 1H), 3.6 (m, 1H), 3.3 (s, 1H), 2.6-2.8 (m, 2H), 1.8-1.4 (m, 4H). ¹³C NMR (CD₃OD) δ 154.4, 143.2, 129.6, 128.0, 126.0, 58.0, 52.4, 44.3, 41.6, 33.8, 30.5. Example 6. Preparation of Urea XXVa

Methyl XXIVa

aminomethylthiazole

Compound XXIVa (104.8 g, 390.0 mmol), carbonyl diimidazole (63.2 g, 390.0 mmol) and dichloromethane (1.02 L) were charged to 2 liter flask. The mixture was cooled to 0 °C and diisopropylethylamine (135.9 mL, 780.0 mmol) was added slowly while keeping the temperature between 0-5 °C. After the addition was complete, the mixture was warmed to 22 °C and stir for 2 hours. Methyl aminomethylthiazole (66.4 g, 380.0 mmol) was added and the resulting mixture was stirred for 6-12 hours until the coupling was complete. The reaction was quenched by pouring it into 10% citric acid (1 L). The phases were separated and the organic phase was washed with water (1 L). Sodium sulfate (105 g) was added to the organic layer and it was stirred for 10 minutes and filtered. The solution was used directly in the next step. Compound XXVa can also be isolated as an oil by concentrating in vacuo (99% yield). Ή NMR (400 MHz,

CDC1₃): δ 7.04 (s, IH), 6.15 (bs, IH), 5.07-5.21 (bs, IH), 4.58 (m, IH), 4.53 (s, 2H), 3.73 (s, 3H), 3.38-3.40 (m, 2H), 3.0-3.1 (m, IH), 3.02 (s, 3H), 2.12-2.05 (m, IH), 1.77- 1.78 (m, IH), 1.39-1.42 (m, 15H).

Example 7. Preparation of Compound XXVIa

Methanesulfonic acid (25.3 mL, 390.0 mmol) was added to a solution of XXVa (167.0 g, 390.0 mmol) in dichloromethane (1 L) at 22 °C and the resulting solution was allowed to stir for 1 hour. A second equivalent of MSA was added and the solution was stirred for 1 hour. A third equivalent of MSA was added and the solution was stirred for 1 hour. This was repeated until no starting material remained. The solution was cooled to 0 °C and diisopropylethylamine (340.0 mL, 1,950.0 mmol) was added slowly while keeping the temperature between 0-5 °C. Acetic anhydride (59.0 mL, 624 mmol) was added and the solution was stirred for 15 minutes at 0 °C. The reaction was quenched by pouring it into 9% sodium bicarbonate (3.4 L) and stirring vigorously for 1 hour. The layers were separated and the organic layer was washed with 10% citric acid (300 mL) and concentrate in vacuo to yield 81% (2 steps) of XXVIa as yellow oil. Compound XXVIa was typically carried onto the next step without further purification.

1H NMR (400 MHz, CDC1₃): δ 6.41 (s, 1H), 6.75 (bs, 1H), 6.22 (bs, 1H), 4.34-4.51 (m, 3H), 3.67 (s, 3H), 3.20 (ddd, J= 6.8, 6.8, 13.9 Hz, 1H), 2.94 (s, 3H), 2.84 (ddd, J= 3.7, 9.0, 17.8 Hz, 1H), 2.04 (ddd, J= 4.3, 9.4, 18.2 Hz, 1H), 1.90 (s, 3H), 1.60 (ddd, J= 4.5, 9.6, 18.6 Hz, 1H), 1.32 (d, J= 6.8 Hz, 6H). Example 8. Pre aration of compound XXVII

XXVII

Acetamide XXVIa (117.0 g, 316.22 mmol) was dissolved in tetrahydrofuran (910 mL) and cooled to 0 °C. NaOH (347.8 mL, 347.8 mmol, 1M) was added to the solution such that the internal temperature did not exceed 5 °C. The reaction was allowed to stir for a total of 1 hour and then HC1 (205.5 mL, 411.0 mmol, 2M) was added to pH 3.2-3.5. The resulting solution was extracted with dichloromethane (1.8 L). The layers were separated and the aqueous layer was washed a second time with dichloromethane (440 mL). The combined organic layers were concentrated in vacuo to provide 93% of XXVII as white foam. 1H NMR (400 MHz, D₂0): δ 7.20 (s, IH), 4.45 (s, 2H), 4.15 (ddd, J= 4.7, 9.4 Hz, IH), 3.20-3.25 (m, IH), 3.12-3.17 (m, 2H), 2.87 (s, 3H), 1.93-1.97 (m, IH), 1.83 (s, 3H), 1.73-1.80 (m, IH), 1.24 (d, J= 7.0 Hz, 6H).

Example 9. Preparation of compound XXVIIIa

A solution of XXVII (25.0 g, 0.0701 moles) in dichloromethane was distilled to a minimal stirring volume. Acetone (1000 mL) was added then and distilled to 7 vols (175 mL) and cooled to 50 °C (KF < 0.4% water, 1H NMR showed less than 5% CH₂C1₂). Dicyclohexylamine (12.97 g, 0.0715 moles) and isopropyl ether (750 mL) was charged to a separate flask and heated to 50 °C. The dicyclohexlyamine/ IPE solution was charged to the acetone solution at such a rate to maintain 45-50 °C. The reaction was seeded and cooled from 50 °C to 20 °C over 3 hours then held at 20 °C for 10 hours. The reaction was then cooled to 0 °C for at least 1 hour followed by filtration. The wet cake was rinsed with the mother liquor and the solids were dried in the vac oven at 35 °C to provide compound XXVIIIa (30.75 g, 81% yield). 1H NMR (400 MHz, D₂0): δ 7.00 (s, 1H), 4.4 (s, 2H), 4.01-3.97 (dd, J= 4, 9Hz 1H), 3.04-3.19 (m, 5H), 2.86 (s, 3H), 1.82-1.9 (m, 8H), 1.68 (m, 5H), 1.51-1.54 (m, 2H), 1.03-1.22 (m, 16H). Example 10. Preparation of compound I

XXIIIa

To a slurry of XXIIIa (0.829 g, 0.0019 mol), XXVIIIa (1.0 g, 0.0019 mol), and HBTU (0.712 g, 0.0019 mol) in CH₂C1₂ (8 mL) was added diisopropylethyl-amine (0.680 mL, 0.0039 mol). After stirring at 22 °C for 1 hour, the mixture was quenched with half-saturated sodium bicarbonate (8 mL) at which time the slurry became homogeneous. The layers were separated and the aqueous layer was washed with ethyl acetate (2 x 8 mL). The combined organic solution was then washed with brine (1 x 8 mL). The resulting golden-yellow solution was concentrated out of ethyl acetate (1 x 10 mL). The crude mixture was diluted with ethyl acetate (15 mL), heated, seeded with previously formed I, and allowed to slowly cool to 22 °C. After stirring at 22 °C for 4 days the resulting thick slurry was filtered and the white, crystalline solids were washed with ethyl acetate. A typical yield for this reaction is about 82%. R_f: 0.24 (Si0₂, 9:1 EtOAc:CH₃OH, ΚΜη0₄). Ή NMR (400 MHz, CDC1₃): δ 8.80 (s, 1H), 7.85 (s, 1H), 7.10-7.40 (m, 10H), 6.90 (s, 1H), 6.15-6.25 (m, 2H), 5.65 (d, J= 8.6 Hz, 1H), 5.25 (dd, J= 12.5, 12.5 Hz, 2H), 4.50 (dd, J= 15.9, 15.9 Hz, 2H), 3.96-4.15 (m, 3H), 3.70-3.80 (m, 1H), 3.35-3.50 (m, 1H), 3.25 (ddd, J= 7.6, 7.6, 7.6 Hz, 1H), 2.95 (s, 3H), 2.80-2.90 (m, 2H), 2.55-2.75 (m, 2H), 2.98 (s, 3H), 1.40-1.80 (m, 6H), 1.35 (d, J= 7.0 Hz, 6H).

All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

What is claimed is:

1. A method for preparing a compound of formula I:

I

comprising reacting a compound of formula XXVIII:

wherein Y is a suitable counter ion;

with a compound of formula XXIII:

XXIII

or a salt thereof to provide the compound of formula I.

2. The method of claim 1 wherein the compound of formula XXIII or the salt thereof is a salt of formula XXIIIb:

XXI I lb

wherein W is dicyclohexylammonium. 3. The method of claim 1 or 2 wherein the reaction is carried out in a suitable organic solvent, in the presence of a suitable coupling agent, and in the presence of a suitable base.

4. The method of any one of claims 1-3 further comprising preparing the compound of formula XVIII by treating a corresponding compound of

formula XXVII:

with a base to provide the compound of formula XXVIII.

5. The method of claim 4 further comprising preparing the compound of formula XXVII by hydrolyzing a corresponding ester of formula XXVI:

XXVI wherein R₂ is (C₁-C₈)alkyl to provide the compound of formula XXVI.

6. The method of claim 5 further comprising preparing the ester of formula XXVI by acylating a corresponding amine of formula XXX:

XXX to provide the compound of formula XXVI.

7. The method of claim 6 further comprising preparing the amine of formula XXX by deprotecting a correspondin compound of formula XXV:

wherein Pg is a protecting group to provide the compound of formula XXX.

8. The method of claim 7 wherein Pg is tert-butoxycarbonyl.

9. The method of claim 7 or 8 further comprising preparing the compound of formula XXV by reacting a corresponding compound of formula XXIV:

or a salt thereof with methyl aminomethylthiazole to provide the compound of formula XXV.

10. The method of claim 9 wherein the compound of formula XXIV or the salt thereof is a salt of formula XXIVb:

11. The method of any one of claims 1-10 further comprising preparing the compound of formula XXIII:

^¹¹¹ or a salt thereof by reacting a compound of formula XXII:

XXII or a salt thereof with a carbonate of formula VIII:

wherein R³ is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl, to provide the compound of formula XXIII or the salt thereof.

12. The method of claim 11 further comprising preparing the compound of formula XXII or the salt thereof by reducing a compound of formula XXI:

or a salt thereof to provide the compound of formula XXII or the salt thereof.

13. The method of claim 12 further comprising preparing the compound of formula XXI or the salt thereof by deprotecting a corresponding compound of formula XX:

XX or a salt thereof wherein each R] is a protecting group, to provide the compound of formula XXI or the salt thereof. 14. The method of claim 13 wherein each R] is -S(=0)₂NR_aRb wherein each of Ra and R_b is independently (Ci-C₈)alkyl; or R_a and Rb together with the nitrogen to which they are attached form a 3 or 4 membered saturated ring or a 5, 6, or 7 membered saturated or partially unsaturated ring comprising 1 or 2 heteroatoms. 15. The method of claim 13 or 14 further comprising preparing the compound of formula XX or the salt thereof by dimerizing a corresponding compound of formula XIX:

XIX or a salt thereof to provide the compound of formula XX or the salt thereof.

16. The method of claim 15 further comprising preparing the compound of formula XIX or the salt thereof by protecting (i?)-2-benzylaziridine to provide the compound of formula XIX or the salt thereof. 17. A compound of formula XIX, XXa, XXI, XXVI, XXVII, XXVIII, XL, XLI, XLII, or XLIII:

XIX XXa XXI

XXVI XXVII

wherein Y is a suitable counter ion; R] is -S(=0)₂NR_aR_b, wherein each of R_a and R_b is independently (C₁-C₈)alkyl; or R_a and R_b together with the nitrogen to which they are attached form a 3 or 4 membered saturated ring or a 5, 6, or 7 membered saturated or partially unsaturated ring comprising 1 or 2 heteroatoms (e.g. aziridine, azetidine, piperidine, morpholine, thiomorpholine, pyrrolidine, homopiperazine, homopiperidine, or piperazine); and R₂ is (C₁-C )alkyl; or a salt thereof. 18. The compound of claim 17 which is a compound of formula XIX, XXa, XXI, XXVI, XXVII, or XXVIII, wherein Y is a suitable counter ion; Ri is a suitable protecting group; and R₂ is (C₁-C )alkyl; or a salt thereof.

19. A method for preparing a compound of formula I:

or a salt thereof, wherein a compound of formula XIX:

XIX wherein Ri is a suitable protecting group, or a salt thereof is prepared and converted into the compound of formula I or the salt thereof, characterized in that the compound of formula XIX or the salt thereof is prepared by protecting a corresponding compound of formula XXXI:

XXXI

or a salt thereof to provide the compound of formula XIX or the salt thereof. 20. A method for preparing a compound of formula I:

I

or a salt thereof, wherein a compound of formula XX:

XX wherein each R_\ is a protecting group, or a salt thereof is prepared and converted into the compound of formula I or the salt thereof, characterized in that the compound of formula XX or the salt thereof is prepared by dimerizing a corresponding compound of formula XIX:

XIX or a salt thereof to provide the compound of formula XX or the salt thereof.

A method for preparing a compound of formula I

or a salt thereof, wherein a compound of formula XXI:

wherein each R is a protecting group, or a salt thereof is prepared and converted into the compound of formula I or the salt thereof, characterized in that the compound of formula XXI or the salt thereof is prepared by deprotecting a corresponding compound of formula XX:

XX wherein each ¾ is a protecting group, or a salt thereof to provide the compound of formula XXI or the salt thereof.

A method for preparing a compound of formula I

or a salt thereof, wherein a compound of formula XXVI:

XXVI wherein R₂ is (C₁-C₈)alkyl or a salt thereof is prepared and converted into the compound of formula I or the salt thereof, characterized in that the compound of formula XXVI or the salt thereof is prepared by acylating a corresponding compound of formula XXX:

or a salt thereof, to provide the compound of formula XXVI or the salt thereof.

A method for preparing a compound of formula I

I

a salt thereof, wherein an acid of formula XXVII

XXVII or a salt thereof is prepared and converted into the compound of formula I or the salt thereof, characterized in that the compound of formula XXVII or the salt thereof is prepared by hydrolyzing an ester of formula XXVI:

XXVI wherein R₂ is (C₁-Cg)alkyl or a salt thereof, to provide the compound of

formula XXVII.

A method for preparing a compound of formula I

or a salt thereof, wherein a compound of formula XXVIII:

wherein Y is a suitable counter ion, or a salt thereof, is prepared and converted into the compound of formula I or the salt thereof, characterized in that the compound of formula XXVIII or the salt thereof is prepared by converting an acid of

formula XXVII:

XXVII salt thereof to the compound of formula XXVIII or the salt thereof. A method for preparing a compound of formula XIX:

XIX wherein is a suitable protecting group, or a salt thereof comprising protecting corresponding compound of formula XXXI:

XXXI

or a salt thereof to provide the compound of formula XIX or the salt thereof.

26. A method for preparing a compound of formula XX:

XX wherein each R_\ is a protecting group, or a salt thereof comprising dimerizing a corresponding compound of formula XIX:

or a salt thereof to provide the compound of formula XX or the salt thereof.

A method for preparing a compound of formula XXI:

wherein each R_\ is a protecting group, or a salt thereof comprising deprotecting corresponding compound of formula XX:

XX wherein each Ri is a protecting group, or a salt thereof, to provide the compound of formula XXI or the salt thereof.

28. A method for preparing a compound of formula XXVI:

wherein R₂ is (CrC₈)alkyl or a salt thereof comprising acylating a corresponding compound of formula XXX:

or a salt thereof to provide the compound of formula XXVI or the salt thereof. 29. A method for preparing a compound of formula XXVII:

XXVII or a salt thereof comprising hydrolyzing an ester of formula XXVI:

wherein R₂ is (C₁-C₈)alkyl or a salt thereof, to provide the compound of formula XXVII or the salt thereof. 30. A method for preparing a compound of formula XXVIII:

wherein Y is a suitable counter ion or a salt thereof comprising converting an acid of formula XXVII:

XXVII or a salt thereof to the compound of formula XXVIII or the salt thereof. 31. A method for preparing a compound of formula I:

I

or a salt thereof, wherein a com ound of formula XL:

XL or a salt thereof is prepared and converted into the compound of formula I or the thereof, characterized in that the compound of formula XL or the salt thereof is prepared by reacting an amine formula XXI:

or a salt thereof, with a carbonate of formula VIII:

wherein R³ is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl, to provide the compound of formula XL or the salt thereof.

32. A method for preparing a compound of formula I:

I

or a salt thereof, wherein a compound of formula XLI:

is prepared and converted into the compound of formula I or the salt thereof, characterized in that the compound of formula XLI is prepared by coupling an amine formula XXI:

or a salt thereof, with a com ound of formula XXVII:

to provide the compound of formula XLI.

33. A method for preparing a compound of formula I:

or a salt thereof, comprising hydrogenating a compound of formula XLII:

to provide the compound of formula I or the salt thereof.

A method for preparing a compound of formula I

I

a salt thereof, comprising reacting an amine formula XLIII:

or a salt thereof, with a carbonate of formula VIII:

wherein R³ is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl,to provide the compound of formula I or the salt thereof.

A method for preparin a compound of formula XL

XL or a salt thereof comprising reacting an amine formula XXI:

a salt thereof, with a carbonate of formula VIII

wherein R³ is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl,to provide the compound of formula XL or the salt thereof. 36. A method for preparing a compound of formula XLI:

comprising coupling an amine formula XXI:

or a salt thereof, with a compound of formula XXVII:

to provide the compound of formula XLI.

A method for preparing a compound of formula XLII

or a salt thereof, with a carbonate of formula VIII:

wherein R³ is nitrophenyl (e.g. 4-nitrophenyl), succinimidyl, or thiazol-5-ylmethyl,to provide the compound of formula XLII.

A method for preparing an amine formula XLIII

or a salt thereof, comprising hydrogenating a compound of formula XLI:

to provide the amine of formula XLIII or the salt thereof.

39. A method for preparing an amine formula XLIII:

or a salt thereof, comprising couplin an amine formula XXII:

or a salt thereof, with a compound of formula XXVII:

to provide the amine of formula XLIII or the salt thereof.