RU2813137C2 - Methods of obtaining cytotoxic benzodiazepine derivatives - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to the method of preparation of a compound of formula (IIA). The method involves introduction of a compound of formula (IA) with 0.6 to 1.0 molar equivalent of cyanuric acid chloride into the reaction to form a compound of formula (IIA). The invention also relates to a method of preparing a compound of formula (IIB) from a compound of formula (IB).

(IIA) (IA)

(IIB) (IB)

EFFECT: proposed methods make it possible to selectively introduce one chlorine atom into the starting diol compounds with a higher yield and can be used for the preparation of synthetic precursors of benzodiazepine dimeric compounds.

34 cl, 19 dwg, 4 ex

Description

RELATED APPLICATION

This application claims benefit of filing date under 35 U.S.C. § 119(e) of US Provisional Application No. 62/758814, filed November 12, 2018. The entire contents of the above application are incorporated herein by reference.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to new methods for producing cytotoxic indolinobenzodiazepine derivatives.

BACKGROUND OF THE ART

Cell-binding agent conjugates with indolinobenzodiazepine compounds that have one imine functional group and one amine functional group have been shown to exhibit a much higher therapeutic index (the ratio of the maximum tolerated dose to the minimum effective dose) in vivo compared to previously described benzodiazepine derivatives containing two imine functional groups. See for example WO 2012/128868. A previously disclosed method for preparing indolinobenzodiazepine compounds having one imine functionality and one amine functionality involves partial reduction of indolinobenzodiazepine compounds having two imine functionality. The partial reduction step typically results in a fully reduced by-product and unreacted starting material, requiring cumbersome purification steps.

Thus, there is a need for improved methods that are more efficient and suitable for large-scale production of indolinobenzodiazepine compounds.

SUMMARY OF THE INVENTION

In one embodiment of the present invention there is provided a method for preparing a compound of formula (IIA):

comprising reacting a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA).

In another embodiment, the present invention provides a method for preparing a compound of formula (IVA):

including stages:

1) introducing into the reaction a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA):

2) reacting a compound of formula (IIA) with a compound of formula (a):

to form a compound of formula (IIIA):

And

3) reacting a compound of formula (IIIA) with a compound of formula (b):

to form a compound of formula (IVA).

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

including stages:

1) introducing into the reaction a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA):

2) reacting a compound of formula (IIA) with a sulfonating agent to form a compound of formula (VIA):

3) reacting a compound of formula (VIA) with a compound of formula (a):

to form a compound of formula (IIIA):

And

4) reacting a compound of formula (IIIA) with a compound of formula (b):

to form a compound of formula (IVA).

In another embodiment, the present invention provides a method for preparing a compound of formula (IIB):

comprising reacting a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB).

In yet another embodiment, the present invention provides a method for preparing a compound of formula (IVB):

including stages:

1) introducing into the reaction a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB):

2) reacting a compound of formula (IIB) with a compound of formula (a):

to form a compound of formula (IIIB):

And

3) reacting a compound of formula (IIIB) with a compound of formula (b):

to form a compound of formula (IVB).

In yet another embodiment, the present invention provides a method for preparing a compound of formula (IVB):

including stages:

1) introducing into the reaction a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB):

2) reacting a compound of formula (IIB) with a sulfonating agent to form a compound of formula (VIB):

3) reacting a compound of formula (VIB) with a compound of formula (a):

to form a compound of formula (IIIB):

And

4) reacting a compound of formula (IIIB) with a compound of formula (b):

to form a compound of formula (IVB).

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

In fig. 1A-1D show HPLC chromatograms of the reactions of compound (IA) and cyanuric acid chloride.

In fig. 2-19 depict exemplary synthesis schemes of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. Although the invention will be described in connection with the numbered embodiments, it should be understood that they are not intended to limit the invention to these embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials, similar or equivalent to those described herein, that can be used in the practice of the present invention.

It should be understood that any of the embodiments described herein may be combined with one or more other embodiments of the invention unless expressly stated or otherwise inappropriate. The combination of embodiments is not limited to those specific combinations claimed in the several dependent claims.

DEFINITIONS

As used herein, the term “compound” is intended to include compounds for which the structure or formula or any derivative thereof has been disclosed in the present invention, or the structure, formula or any derivative thereof is incorporated by reference. The term also includes stereoisomers, geometric isomers or tautomers. The specific listing of "stereoisomers", "geometric isomers", "tautomers" in certain aspects of the invention described in this application should not be interpreted as the intended exclusion of these forms in other aspects of the invention where the term "compound" is used without listing these other forms.

As used herein, the term “stereoisomer” refers to compounds that have identical chemical structure and connectivity, but different orientations of their atoms in space that cannot be interconverted by rotation around single bonds.

As used herein, the term “diastereomer” refers to a stereoisomer with two or more centers of chirality, the molecules of which are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical procedures such as crystallization, electrophoresis and chromatography.

As used herein, the term “enantiomers” refers to two stereoisomers of a compound that are non-matching, superimposed mirror images of each other.

Stereochemical definitions and conventions used herein generally follow from S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule relative to its chiral center(s). The prefixes d and 1 or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or 1 indicating that the compound is left-handed. The connection with the prefix (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be called an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselection or stereospecificity in a chemical reaction or process. The terms racemic mixture and racemate refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

As used herein, the term “tautomer” or “tautomeric form” refers to structural isomers of different energies that are interconvertible through a low energy barrier. For example, protic tautomers (also known as prototropic tautomers) involve interconversions via proton migration, such as the isomerization of keto-enol and imine-enamine. Valence tautomers involve interconversions due to the reorganization of some of the bonding electrons.

As used herein, the term “alcohol activating agent” refers to a reagent that increases the reactivity of a hydroxyl group, thereby making the hydroxyl group a more removable group.

As used herein, the term “sulfonating reagent” refers to a reagent that converts an alcohol group to a sulfonate ester group. Preferably, the sulfonating agent is a sulfonic anhydride such as methanesulfonic anhydride ( _MS2O ) or a sulfonyl chloride such as methanesulfonyl chloride (MsCl).

As used herein, the term “imine reducing reagent” refers to a reagent that is capable of reducing an imine functional group to an amine functional group. In certain embodiments, the imine reducing reagent is a hydride reducing reagent. Examples of such imine reducing reagents include, but are not limited to, borohydrides (e.g., sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium borohydride ( _LiBH4 ), potassium borohydride ( _KBH4 )), hydrogen gas and lithium aluminum hydride, ammonium formate, borane, 9-borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminum hydride (DIBAL) and sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al). In certain embodiments, the imine reducing reagent is sodium triacetoxyborohydride.

As used herein, the term "cyanuric acid chloride" or "2,4,6-trichloro-1,3,5-triazine" refers to a compound of the following formula (CAS number 108-77-0):

As used herein, quantity by volume means the ratio of the volume of solvent (in ml) to the quantity by weight (in g) of the compound. For example, a volume of 40 means that 40 ml of solvent is used per 1 g of compound.

METHODS OF THE PRESENT INVENTION

The present invention provides a method for selectively introducing a single chlorine atom to produce synthetic precursors of benzodiazepine dimeric compounds. Surprisingly, it has been found that using a specific molar equivalent of cyanuric acid chloride relative to the starting diol compound provides the monochloride product in higher yield.

In a first embodiment of the present invention there is provided a method for preparing a compound of formula (IIA'):

comprising introducing into the reaction a compound of formula (IA’):

with cyanuric acid chloride to form the compound of formula (IIA’).

In ^one specific embodiment of the present invention, there is provided a method for preparing a compound of formula (IIA):

comprising reacting a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA).

In a second embodiment, the method of the first embodiment further comprises reacting a compound of formula (IIA') with a compound of formula (a):

to form a compound of formula (IIIA’):

In ^{the 2nd} specific embodiment, the method of ^{the 1st} specific embodiment further comprises reacting a compound of formula (IIA) with a compound of formula (a):

to form a compound of formula (IIIA):

In a third embodiment, the method of the second embodiment further comprises reacting a compound of formula (IIIA') with a compound of formula (b):

to form a compound of formula (IVA’):

In ^{the 3rd} specific embodiment, the method of ^{the 2nd} specific embodiment further comprises reacting a compound of formula (IIIA) with a compound of formula (b):

to form a compound of formula (IVA):

In a fourth embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA'):

including stages:

1) introducing into the reaction a compound of formula (IA’):

with cyanuric acid chloride to form a compound of formula (IIA’):

2) reacting a compound of formula (IIA’) with a compound of formula (a):

to form a compound of formula (IIIA’):

And

3) reacting a compound of formula (IIIA’) with a compound of formula (b):

to form a compound of formula (IVA’).

In a ^4th specific embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA):

including stages:

1) introducing into the reaction a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA):

2) reacting a compound of formula (IIA) with a compound of formula (a):

to form a compound of formula (IIIA):

And

3) reacting a compound of formula (IIIA) with a compound of formula (b):

to form a compound of formula (IVA).

In a fifth embodiment of the present invention, a method for producing a compound (IVA') is provided:

including stages:

1) introducing into the reaction a compound of formula (IA’):

with cyanuric acid chloride to form a compound of formula (IIA’):

2) reacting a compound of formula (IIA’) with a compound of formula (b):

to form a compound of formula (VA’):

And

3) reacting a compound of formula (VA’) with a compound of formula (a):

to form a compound of formula (IVA’).

In a ^5th specific embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA):

including stages:

1) introducing into the reaction a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA):

2) reacting a compound of formula (IIA) with a compound of formula (b):

to form a compound of formula (VA):

And

3) reacting a compound of formula (VA) with a compound of formula (a):

to form a compound of formula (IVA).

In a sixth embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA'):

including stages:

1) introducing into the reaction a compound of formula (IA’):

with cyanuric acid chloride to form a compound of formula (IIA’):

2) reacting a compound of formula (IIA’) with a compound of formula (b):

to form a compound of formula (VA’):

3) reacting a compound of formula (VA') with an imine-reducing agent to form a compound of formula to form a compound of formula (IIIA'):

And

4) reacting a compound of formula (IIIA’) with a compound of formula (b):

to form a compound of formula (IVA’).

In the ^6th specific embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA):

including stages:

1) introducing into the reaction a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA):

2) reacting a compound of formula (IIA) with a compound of formula (b):

to form a compound of formula (VA):

3) reacting a compound of formula (VA) with an imine-reducing agent to form a compound of formula to form a compound of formula (IIIA):

And

4) reacting a compound of formula (IIIA) with a compound of formula (b):

to form the compound of formula (IVA).

In a seventh embodiment of the present invention, there is provided a method for preparing the compound of formula (IVA'):

including stages:

1) introducing into the reaction a compound of formula (IA’):

with cyanuric acid chloride to form a compound of formula (IIA’):

2) reacting a compound of formula (IIA’) with a sulfonating agent to form a compound of formula (VIA’):

3) reacting a compound of formula (VIA’) with a compound of formula (b):

to form a compound of formula (VA’):

4) reacting a compound of formula (VA’) with a compound of formula (a):

to form a compound of formula (IVA'), where X ₁ is a sulfonic acid ester.

In the ^7th specific embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA):

including stages:

1) introducing into the reaction a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA):

2) reacting a compound of formula (IIA) with a sulfonating agent to form a compound of formula (VIA):

3) reacting a compound of formula (VIA) with a compound of formula (b):

to form a compound of formula (VA):

4) reacting a compound of formula (VA) with a compound of formula (a):

to form a compound of formula (IVA), where X ₁ is a sulfonic acid ester.

An eighth embodiment of the present invention provides a method for preparing a compound of formula (IVA'):

including stages:

1) introducing into the reaction a compound of formula (IA’):

with cyanuric acid chloride to form a compound of formula (IIA’):

2) reacting a compound of formula (IIA’) with a sulfonating agent to form a compound of formula (VIA’):

3) reacting a compound of formula (VIA’) with a compound of formula (a):

to form a compound of formula (IIIA’):

And

4) reacting a compound of formula (IIIA’) with a compound of formula (b):

to form a compound of formula (IVA'), where X ₁ is a sulfonic acid ester.

In the ^8th specific embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA):

including stages:

1) introducing into the reaction a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA):

2) reacting a compound of formula (IIA) with a sulfonating agent to form a compound of formula (VIA):

3) reacting a compound of formula (VIA) with a compound of formula (a):

to form a compound of formula (IIIA):

And

4) reacting a compound of formula (IIIA) with a compound of formula (b):

to form a compound of formula (IVA), where X ₁ is a sulfonic acid ester.

In a ninth embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA'):

including stages:

1) introducing into the reaction a compound of formula (IA’):

with cyanuric acid chloride to form a compound of formula (IIA’):

2) reacting a compound of formula (IIA’) with a sulfonating agent to form a compound of formula (VIA’):

3) reacting a compound of formula (VIA’) with a compound of formula (b):

to form a compound of formula (VA’):

4) reacting a compound of formula (VA’) with an imine-reducing agent to form a compound of formula (IIIA’):

And

5) reacting a compound of formula (IIIA’) with a compound of formula (b):

to form a compound of formula (IVA'), where X ₁ is a sulfonic acid ester.

In the ^9th specific embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA):

including stages:

1) introducing into the reaction a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA):

2) reacting a compound of formula (IIA) with a sulfonating agent to form a compound of formula (VIA):

3) reacting a compound of formula (VIA) with a compound of formula (b):

to form a compound of formula (VA):

4) reacting a compound of formula (VA) with an imine-reducing agent to form a compound of formula (IIIA):

And

5) reacting a compound of formula (IIIA) with a compound of formula (b):

to form a compound of formula (IVA), where X ₁ is a sulfonic acid ester.

A tenth embodiment of the present invention provides a method for preparing a compound of formula (IVA'):

including stages:

1) introducing into the reaction a compound of formula (IA’):

with cyanuric acid chloride to form a compound of formula (IIA’):

2) reacting a compound of formula (IIA’) with a compound of formula (b):

to form a compound of formula (VIIA’):

3) reacting a compound of formula (VIIA’) with a sulfonating agent to form a compound of formula (VIIIA’):

4) reacting a compound of formula (VIIIA’) with a compound of formula (a):

to form a compound of formula (IVA'), where X ₁ is a sulfonic acid ester.

In the ^10th specific embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA):

including stages:

1) introducing into the reaction a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA):

2) reacting a compound of formula (IIA) with a compound of formula (b):

to form a compound of formula (VIIA):

3) reacting a compound of formula (VIIA) with a sulfonating agent to form a compound of formula (VIIIA):

4) reacting a compound of formula (VIIIA) with a compound of formula (a):

to form a compound of formula (IVA), where X ₁ is a sulfonic acid ester.

In an eleventh embodiment, the present invention provides a method for preparing a compound of formula (IVA'):

including stages:

1) introducing into the reaction a compound of formula (IA’):

with cyanuric acid chloride to form a compound of formula (IIA’):

2) reacting a compound of formula (IIA’) with a compound of formula (a):

to form a compound of formula (IXA’):

3) reacting a compound of formula (IXA’) with a sulfonating agent to form a compound of formula (XA’):

4) reacting a compound of formula (XA’) with a compound of formula (b):

to form a compound of formula (IVA'), where X ₁ is a sulfonic acid ester.

In the ^11th specific embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA):

including stages:

1) introducing into the reaction a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA):

2) reacting a compound of formula (IIA) with a compound of formula (a):

to form a compound of formula (IXA):

3) reacting a compound of formula (IXA) with a sulfonating agent to form a compound of formula (XA):

4) reacting a compound of formula (XA) with a compound of formula (b):

to form a compound of formula (IVA), where X ₁ is a sulfonic acid ester.

In a twelfth embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA'):

including stages:

1) introducing into the reaction a compound of formula (IA’):

with cyanuric acid chloride to form a compound of formula (IIA’):

2) reacting a compound of formula (IIA’) with a compound of formula (b):

to form a compound of formula (VIIA’):

3) reacting a compound of formula (VIIA’) with an imine-reducing agent to form a compound of formula (IXA’):

4) reacting a compound of formula (IXA’) with a sulfonating agent to form a compound of formula (XA’):

5) reacting a compound of formula (XA’) with a compound of formula (b):

to form a compound of formula (IVA'), where X ₁ is a sulfonic acid ester.

In the ^12th specific embodiment of the present invention, there is provided a method for preparing a compound of formula (IVA'):

including stages:

1) introducing into the reaction a compound of formula (IA):

with cyanuric acid chloride to form a compound of formula (IIA):

2) reacting a compound of formula (IIA) with a compound of formula (b):

to form a compound of formula (VIIA):

3) reacting a compound of formula (VIIA) with an imine-reducing agent to form a compound of formula (IXA):

4) reacting a compound of formula (IXA) with a sulfonating agent to form a compound of formula (XA):

5) reacting a compound of formula (XA) with a compound of formula (b):

to form a compound of formula (IVA'), where X ₁ is a sulfonic acid ester.

In a thirteenth embodiment of the present invention, there is provided a method for preparing a compound of formula (IIB):

comprising reacting a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB).

In the fourteenth embodiment, the method of the thirteenth embodiment further comprises reacting a compound of formula (IIB) with a compound of formula (a):

to form a compound of formula (IIIB):

In the fifteenth embodiment, the method of the fourteenth embodiment further comprises reacting a compound of formula (IIIB) with a compound of formula (b):

to form a compound of formula (IVB):

In a sixteenth embodiment of the present invention, there is provided a method for preparing the compound of formula (IVB):

including stages:

1) introducing into the reaction a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB):

2) reacting a compound of formula (IIB) with a compound of formula (a):

to form a compound of formula (IIIB):

And

3) reacting a compound of formula (IIIB) with a compound of formula (b):

to form a compound of formula (IVB).

In a seventeenth embodiment of the present invention, there is provided a method for preparing the compound of formula (IVB):

including stages:

1) introducing into the reaction a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB):

2) reacting a compound of formula (IIB) with a compound of formula (b):

to form a compound of formula (VB):

And

3) reacting a compound of formula (VB) with a compound of formula (a):

to form a compound of formula (IVB).

An eighteenth embodiment of the present invention provides a method for producing a compound of formula (IVB):

including stages:

1) introducing into the reaction a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB):

2) reacting a compound of formula (IIB) with a compound of formula (b):

to form a compound of formula (VB):

3) reacting a compound of formula (VB) with an imine-reducing agent to form a compound of formula (IIIB):

And

4) reacting a compound of formula (IIIB) with a compound of formula (b):

to form a compound of formula (IVB).

In a nineteenth embodiment of the present invention, there is provided a method for preparing a compound of formula (IVB), comprising the steps of:

1) introducing into the reaction a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB):

2) reacting a compound of formula (IIB) with a sulfonating agent to form a compound of formula (VIB):

3) reacting a compound of formula (VIB) with a compound of formula (b):

to form a compound of formula (VB):

4) reacting a compound of formula (VB) with a compound of formula (a):

to form a compound of formula (IVB) wherein X ₁ is a sulfonic acid ester.

In a twentieth embodiment of the present invention, there is provided a method for preparing a compound of formula (IVB), comprising the steps of:

1) introducing into the reaction a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB):

2) reacting a compound of formula (IIB) with a sulfonating agent to form a compound of formula (VIB):

3) reacting a compound of formula (VIB) with a compound of formula (a):

to form a compound of formula (IIIB):

4) reacting a compound of formula (IIIB) with a compound of formula (b):

to form a compound of formula (IVB), where X ₁ is a sulfonic acid ester.

In the twenty-first embodiment of the present invention, there is provided a method for preparing a compound of formula (IVB) comprising the steps of:

1) introducing into the reaction a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB):

2) reacting a compound of formula (IIB) with a sulfonating agent to form a compound of formula (VIB):

3) reacting a compound of formula (VIB) with a compound of formula (b):

to form a compound of formula (VB):

4) reacting a compound of formula (VB) with an imine-reducing agent to form a compound of formula (IIIB):

5) reacting a compound of formula (IIIB) with a compound of formula (b):

to form a compound of formula (IVB) wherein X ₁ is a sulfonic acid ester.

In a twenty-second embodiment of the present invention, there is provided a method for preparing a compound of formula (IVB), comprising the steps of:

1) introducing into the reaction a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB):

2) reacting a compound of formula (IIB) with a compound of formula (b) to form a compound of formula (VIIB):

3) reacting a compound of formula (VIIB) with a sulfonating agent to form a compound of formula (VIIIB):

4) reacting a compound of formula (VIIIB) with a compound of formula (a) to form a compound of formula (IVB), wherein X ₁ is a sulfonic acid ester.

In a twenty-third embodiment of the present invention, there is provided a method for preparing a compound of formula (IVB) comprising the steps of:

1) introducing into the reaction a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB):

2) reacting a compound of formula (IIB) with a compound of formula (a) to form a compound of formula (IXB):

3) reacting a compound of formula (IXB) with a sulfonating agent to form a compound of formula (XB):

4) reacting a compound of formula (XB) with a compound of formula (b):

to form a compound of formula (IVB), where X ₁ is a sulfonic acid ester.

In a twenty-fourth embodiment of the present invention, there is provided a method for preparing a compound of formula (IVB) comprising the steps of:

1) introducing into the reaction a compound of formula (IB):

with cyanuric acid chloride to form a compound of formula (IIB):

2) reacting a compound of formula (IIB) with a compound of formula (b) to form a compound of formula (VIIB):

3) reacting a compound of formula (VIIB) with an imine-reducing agent to form a compound of formula (IXB):

4) reacting a compound of formula (IXB) with a sulfonating agent to form a compound of formula (XB):

And

5) reacting a compound of formula (XB) with a compound of formula (b) to form a compound of formula (IVB), wherein X ₁ is a sulfonic acid ester.

In a twenty-fifth embodiment, to react a compound of formula (IA) or (IA') with cyanuric acid chloride in the methods described herein (e.g., first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment or 1 ^ohm , 2 ^ohm , 3 ^ohm , 4 ^ohm , 5 ^ohm , 6 ^ohm , 7 ^ohm , 8 ^ohm , 9 ^ohm , 10 ^ohm , 11 ^ohm or 12 ^ohm particular embodiment), used from 0.5 to 0.9 molar equivalent of cyanuric acid chloride, based on the amount of compound of formula (IA) or (IA'). In specific embodiments, 0.6 to 1.0 molar equivalent of cyanuric acid chloride is used, relative to the amount of compound of formula (IA) or (IA'). In particular embodiments, 0.6 to 0.8 molar equivalent of cyanuric acid chloride is used, relative to the amount of compound of formula (IA) or (IA'). In specific embodiments, 0.7 to 0.8 molar equivalent of cyanuric acid chloride is used, relative to the amount of compound of formula (IA) or (IA'). In even more specific embodiments, 0.75 molar equivalent of cyanuric acid chloride is used relative to the amount of compound of formula (IA) or (IA'). In even more specific embodiments, 0.85 molar equivalent of cyanuric acid chloride is used relative to the amount of compound of formula (IA) or (IA').

In some embodiments, the reaction between a compound of formula (IA) or (IA') and cyanuric acid chloride is carried out in a polar solvent. In specific embodiments, the polar solvent is dimethylformamide (DMF).

In some embodiments, a compound of formula (IA) or (IA') is used as a solution or suspension in dichloromethane (DCM). In some other embodiments, a compound of formula (IA) or (IA') is used as a solution or suspension in dimethylformamide (DMF).

In some embodiments, the reaction between a compound of formula (IA) or (IA') and cyanuric acid chloride is carried out in dimethylformamide (DMF). In some other embodiments, a compound of formula (IA) or (IA') is used as a solution or suspension in dichloromethane (DCM), and the reaction between the compound of formula (IA) or (IA') and cyanuric acid chloride is carried out in dimethylformamide (DMF) .

In some other embodiments, a compound of formula (IA) or (IA') is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IA) or (IA') and cyanuric acid chloride is carried out in dimethylformamide (DMF). .

In some embodiments, the amount of solvent is between 5 volumes and 40 volumes relative to the amount of compound of formula (IA) or (IA'). In other embodiments, the amount of solvent is between 10 volumes and 30 volumes relative to the amount of compound of formula (IA) or (IA'). In other embodiments, the amount of solvent is about 5 volumes relative to the amount of compound of formula (IA) or (IA'). In other embodiments, the amount of solvent is about 10 volumes relative to the amount of compound of formula (IA) or (IA'). In other embodiments, the amount of solvent is about 15 volumes relative to the amount of compound of formula (IA) or (IA'). In other embodiments, the amount of solvent is about 20 volumes relative to the amount of compound of formula (IA) or (IA'). In other embodiments, the amount of solvent is about 25 volumes relative to the amount of compound of formula (IA) or (IA'). In other embodiments, the amount of solvent is about 30 volumes relative to the amount of compound of formula (IA) or (IA').

In some embodiments, the compound of formula (IA) or (IA') is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IA) or (IA') and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is between 5 volumes and 40 volumes relative to the amount of the compound of formula (IA) or (IA').

In some embodiments, the compound of formula (IA) or (IA') is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IA) or (IA') and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 5 volumes relative to the amount of the compound of formula (IA) or (IA').

In some embodiments, the compound of formula (IA) or (IA') is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IA) or (IA') and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 10 volumes relative to the amount of the compound of formula (IA) or (IA').

In some embodiments, the compound of formula (IA) or (IA') is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IA) or (IA') and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 15 volumes relative to the amount of the compound of formula (IA) or (IA').

In some embodiments, the compound of formula (IA) or (IA') is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IA) or (IA') and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 20 volumes relative to the amount of the compound of formula (IA) or (IA').

In some embodiments, the compound of formula (IA) or (IA') is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IA) or (IA') and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 25 volumes relative to the amount of the compound of formula (IA) or (IA').

In some embodiments, the compound of formula (IA) or (IA') is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IA) or (IA') and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 30 volumes relative to the amount of the compound of formula (IA) or (IA'). In some embodiments, a compound of formula (IA) or (IA') is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula

(IA) or (IA') and cyanuric acid chloride are carried out in dimethylformamide (DMF), and the amount of DMF is 35 volumes relative to the amount of the compound of formula (IA) or (IA').

The reaction between a compound of formula (IA) or (IA') and cyanuric acid chloride in a polar solvent can be carried out at a suitable temperature. In some embodiments, the reaction is carried out at a temperature between -5 °C and 50 °C. In some embodiments, the reaction is carried out at a temperature between 0°C and 50°C. In some embodiments, the reaction is carried out at a temperature between 5°C and 50°C. In some embodiments, the reaction is carried out at a temperature between 10°C and 40°C. In some embodiments, the reaction is carried out at a temperature of -5 °C to 5 °C. In more specific embodiments, the cyanuric acid chloride and the polar solvent are mixed at a temperature of -5°C to 10°C. In more specific embodiments, the cyanuric acid chloride and the polar solvent are mixed at a temperature of from 0°C to 10°C. In more specific embodiments, the cyanuric acid chloride and the polar solvent are mixed at a temperature of 2°C to 5°C. In other more specific embodiments, the reaction between a compound of formula (IA) or (IA') and cyanuric acid chloride in a polar solvent is carried out at a temperature of from 20 °C to 30 °C. In other more specific embodiments, the reaction between a compound of formula (IA) or (IA') and cyanuric acid chloride in a polar solvent is carried out at 25 ± 3 °C. In other embodiments, the cyanuric acid chloride and the polar solvent are mixed at a temperature between -5°C and 10°C, and the reaction between the compound of formula (IA) or (IA') and the cyanuric acid chloride in the polar solvent is carried out at a temperature between 20°C up to 30 °C. In other embodiments, the cyanuric acid chloride and the polar solvent are mixed at a temperature of 2 °C to 5 °C, and the reaction between the compound of formula (IA) or (IA') and the cyanuric acid chloride in the polar solvent is carried out at 25 ± 3 °C.

The reaction between a compound of formula (IA) or (IA') and cyanuric acid chloride in a polar solvent can be carried out for a period of time until a sufficient amount of the compound of formula (IIA) or (IIA'), respectively, is formed. As used herein, the term “significant amount” refers to an amount of a compound of formula (IIA) or (IIA') that is greater than 40%, greater than 45%, greater than 50%, greater than 55%, or greater than 60% of the product formed. In some embodiments, the reaction time between the compound of formula (IA) or (IA') and cyanuric acid chloride in a polar solvent is from 10 minutes to 48 hours. In some embodiments, the reaction time between the compound of formula (IA) or (IA') and cyanuric acid chloride in a polar solvent is from 20 minutes to 5 hours. In some embodiments, the reaction time between the compound of formula (IA) or (IA') and cyanuric acid chloride in a polar solvent is from 30 minutes to 5 hours. In some embodiments, the reaction time between the compound of formula (IA) or (IA') and cyanuric acid chloride in a polar solvent is from 1 hour to 5 hours. In some embodiments, the reaction time between the compound of formula (IA) or (IA') and cyanuric acid chloride in a polar solvent is from 1 hour to 4 hours. In some embodiments, the reaction time between the compound of formula (IA) or (IA') and cyanuric acid chloride in a polar solvent is from 2 hours to 4 hours. In some embodiments, the reaction time between the compound of formula (IA) or (IA') and cyanuric acid chloride in a polar solvent is from 16 hours to 24 hours.

In a twenty-sixth embodiment, for the reaction between a compound of formula (IB) and cyanuric acid chloride in the methods described herein (e.g., thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third or twenty-fourth embodiment), 0.6 to 1.0 molar equivalent of cyanuric acid chloride is used relative to the compound of formula (IB). In a specific embodiment, 0.7 to 0.8 molar equivalent of cyanuric acid chloride is used relative to the compound of formula (IB). In more specific embodiments, 0.65 molar equivalent of cyanuric acid chloride is used, relative to the amount of compound of formula (IB). In even more specific embodiments, 0.75 molar equivalent of cyanuric acid chloride is used, relative to the amount of compound of formula (IB). In even more specific embodiments, 0.85 molar equivalent of cyanuric acid chloride is used, relative to the amount of compound of formula (IB).

In some embodiments, the reaction between compound (IB) and cyanuric acid chloride is carried out in a polar solvent. In specific embodiments, the polar solvent is dimethylformamide (DMF).

In some embodiments, the compound of formula (IB) is used as a solution or suspension in dichloromethane (DCM). In some other embodiments, the compound of formula (IB) is used as a solution or suspension in dimethylformamide (DMF).

In some embodiments, the reaction between a compound of formula (IB) and cyanuric acid chloride is carried out in dimethylformamide (DMF). In some other embodiments, the compound of formula (IB) is used as a solution or suspension in dichloromethane (DCM), and the reaction between the compound of formula (IB) and cyanuric acid chloride is carried out in dimethylformamide (DMF).

In some other embodiments, the compound of formula (IB) is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IB) and cyanuric acid chloride is carried out in dimethylformamide (DMF).

In some embodiments, the amount of solvent is between 5 volumes and 40 volumes relative to the amount of compound of formula (IB). In other embodiments, the amount of solvent is between 10 volumes and 30 volumes relative to the amount of compound of formula (IB). In other embodiments, the amount of solvent is about 5 volumes relative to the amount of compound of formula (IB). In other embodiments, the amount of solvent is about 10 volumes relative to the amount of compound of formula (IB). In other embodiments, the amount of solvent is about 15 volumes relative to the amount of compound of formula (IB).

In other embodiments, the amount of solvent is about 20 volumes relative to the amount of compound of formula (IB). In other embodiments, the amount of solvent is about 25 volumes relative to the amount of compound of formula (IB). In other embodiments, the amount of solvent is about 30 volumes relative to the amount of compound of formula (IB). In some embodiments, the compound of formula (IB) is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IB) and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is from 5 volumes to 40 volumes relative to the amount of compound of formula (IB). In some embodiments, the compound of formula (IIB) is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IIB) and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 5 volumes relative to the amount of the compound of formula (IIB). In some embodiments, the compound of formula (IIB) is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IIB) and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 10 volumes relative to the amount of the compound of formula (IIB). In some embodiments, the compound of formula (IIB) is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IIB) and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 15 volumes relative to the amount of the compound of formula (IIB). In some embodiments, the compound of formula (IIB) is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IIB) and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 20 volumes relative to the amount of the compound of formula (IIB). In some embodiments, the compound of formula (IIB) is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IIB) and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 25 volumes relative to the amount of the compound of formula (IIB). In some embodiments, the compound of formula (IIB) is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IIB) and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 30 volumes relative to the amount of the compound of formula (IIB). In some embodiments, the compound of formula (IIB) is used as a solution or suspension in dimethylformamide (DMF), and the reaction between the compound of formula (IIB) and cyanuric acid chloride is carried out in dimethylformamide (DMF), and the amount of DMF is 35 volumes relative to the amount of the compound of formula (IIB).

The reaction between compound (IB) and cyanuric acid chloride in a polar solvent can be carried out at a suitable temperature. In some embodiments, the reaction is carried out at a temperature between -5 °C and 50 °C. In some embodiments, the reaction is carried out at a temperature between 0°C and 50°C. In some embodiments, the reaction is carried out at a temperature between 5°C and 50°C. In some embodiments, the reaction is carried out at a temperature between 10°C and 40°C. In some embodiments, the reaction is carried out at a temperature of -5 °C to 5 °C. In more specific embodiments, the cyanuric acid chloride and the polar solvent are mixed at a temperature of -5°C to 10°C. In more specific embodiments, the cyanuric acid chloride and the polar solvent are mixed at a temperature of from 0°C to 10°C. In more specific embodiments, the cyanuric acid chloride and the polar solvent are mixed at a temperature of 2°C to 5°C. In other more specific embodiments, the reaction between a compound of formula (IB) and cyanuric acid chloride in a polar solvent is carried out at a temperature of from 20°C to 30°C. In another more specific embodiment, the reaction between a compound of formula (IB) and cyanuric acid chloride in a polar solvent is carried out at 25±3°C. In other embodiments, the cyanuric acid chloride and the polar solvent are mixed at a temperature of -5°C to 10°C, and the reaction between the compound of formula (IB) and the cyanuric acid chloride in the polar solvent is carried out at a temperature of 20°C to 30°C. In other embodiments, the cyanuric acid chloride and the polar solvent are mixed at a temperature of 2°C to 5°C, and the reaction between the compound of formula (IB) and the cyanuric acid chloride in the polar solvent is carried out at 25±3°C. In other embodiments, the cyanuric acid chloride and the polar solvent are mixed at a temperature of -5°C to 10°C, and the reaction between the compound of formula (IIB) and the cyanuric acid chloride in the polar solvent is carried out at a temperature of 20°C to 30°C. In other embodiments, the cyanuric acid chloride and the polar solvent are mixed at a temperature of 2°C to 5°C, and the reaction between the compound of formula (IIB) and the cyanuric acid chloride in the polar solvent is carried out at 25±3°C.

The reaction of compound (IB) and cyanuric acid chloride in a polar solvent can be carried out for a period of time until a sufficient amount of compound (IIB) is formed. As used herein, the term “significant amount” refers to an amount of a compound of formula (IIB) that constitutes more than 40%, more than 45%, more than 50%, more than 55%, or more than 60% of the product formed. In some embodiments, the reaction time between the compound of formula (IB) and the cyanuric acid chloride in a polar solvent ranges from 10 minutes to 48 hours. In some embodiments, the reaction time between the compound of formula (IB) and the cyanuric acid chloride in a polar solvent is from 20 minutes to 5 hours. In some embodiments, the reaction time between the compound of formula (IB) and the cyanuric acid chloride in a polar solvent is from 30 minutes to 5 hours. In some embodiments, the reaction time between the compound of formula (IB) and the cyanuric acid chloride in a polar solvent is from 1 hour to 5 hours. In some embodiments, the reaction time between the compound of formula (IB) and the cyanuric acid chloride in a polar solvent is from 1 hour to 4 hours. In some embodiments, the reaction time between the compound of formula (IB) and the cyanuric acid chloride in a polar solvent is from 2 hours to 4 hours. In some embodiments, the reaction time between the compound of formula (IB) and the cyanuric acid chloride in a polar solvent is from 16 hours to 24 hours.

In a twenty-seventh embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (a) in the methods described herein (for example, in the second, third, fourth or twenty-fifth embodiment or ^2nd , ^3rd or ^4th specific embodiment), the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (b) in the methods described herein (for example, in the fifth, sixth or twenty-fifth embodiment or 5th or 6th ^{embodiment om} particular embodiment), the reaction between a compound of formula (IIB) and a compound of formula (a) in the methods described herein (for example, in the fourteenth, fifteenth, sixteenth or twenty-sixth embodiment), or the reaction between a compound of formula (IIB) and a compound of formula (b) in the methods described herein (eg, the seventeenth, eighteenth or twenty-sixth embodiment) is carried out in the presence of an alcohol activating agent and an azodicarboxylate. In one embodiment, the alcohol activating agent is a trialkylphosphine, triarylphosphine, or triheteroarylphosphine. In specific embodiments, the alcohol activating agent is trimethylphosphine, tri-n-butylphosphine, tri(o-tolyl)phosphine, tri(m-tolyl)phosphine, tri(p-tolyl)phosphine, tri(2-pyridyl)phosphine, tri(3-pyridyl)phosphine, tri(4-pyridyl)phosphine or [4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10, 10,10-heptadecafluorodecyl)phenyl]diphenylphosphine. In other specific embodiments, the alcohol activating agent may be a phosphine-like reagent such as (tri-n-butylphosphoranylidene)acetonitrile, (cyanomethylene)tributylphosphorane (CMBP), or (cyanomethylene)trimethylphosphorane (CMMP). In more specific embodiments, the alcohol activating agent is triphenylphosphine. In yet other more specific embodiments, the alcohol activating agent is tri-n-butylphosphine. In some embodiments, the alcohol activating agent may be bound to or supported by a polymer, such as a polymer bound or supported trialkylphosphine, triarylphosphine (eg, triphenylphosphine), or triheteroarylphosphine.

In some embodiments, for the method described in the twenty-seventh embodiment, the azodicarboxylate is selected from diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1'-(azodicarbonyl)dipiperidine (ADDP), ditertbutyl azodicarboxylate (DTAD), 1,6-dimethyl -1,5,7-hexahydro-1,4,6,7-tetrazocine-2,5-dione (DHTD), di-(4-chlorobenzyl)azodicarboxylate (DCAD), azodicarboxylic acid dimorpholide, N,N,N' ,N'-tetramethylazodicarboxamide (TMAD), N,N,N',N'-tetraisopropyl azodicarboxamide (TIPA), 4,4'-azopyridine, bis(2,2,2-trichloroethyl)azodicarboxylate, o-(tert-butyldimethylsilyl) -N-tosylhydroxylamine, di-(4-chlorobenzyl)azodicarboxylate, cyclic 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazocine-2,5-dione (DHTD), dimethylacetylenedicarboxylate ( DMAD), di-2-methoxyethyl azodicarboxylate, di-(4-chlorobenzyl) azodicarboxylate and bis(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl) azodicarboxylate. More specifically, azodicarboxylate is DIAD. In one embodiment, the azodicarboxylate is polymer-bound or supported on a polymer, such as a polymer-supported alkyl azodicarboxylate (eg, polymer-bound DEAD, DIAD, DTAD, or ADDP).

In some specific embodiments, for the method described in the twenty-seventh embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (a), the reaction between a compound of formula (IIA') or (IIA) and a compound of formula ( b), the reaction between a compound of formula (IIB) and a compound of formula (a) or the reaction between a compound of formula (IIB) and a compound of formula (b) is carried out in the presence of tri-n-butylphosphine or triphenylphosphine and azodicarboxylate. In some embodiments, the azodicarboxylate is selected from diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1'-(azodicarbonyl)dipiperidine (ADDP), and ditertbutyl azodicarboxylate (DTAD). More specifically, azodicarboxylate is DIAD.

In some more specific embodiments, for the method described in the twenty-seventh embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (a) is carried out in the presence of triphenylphosphine and DIAD. In some more specific embodiments, for the method described in the twenty-seventh embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (b) is carried out in the presence of triphenylphosphine and DIAD. In some more specific embodiments, for the method described in the twenty-seventh embodiment, the reaction between a compound of formula (IIB) and a compound of formula (a) is carried out in the presence of triphenylphosphine and DIAD. In some more specific embodiments, for the method described in the twenty-seventh embodiment, the reaction between a compound of formula (IIB) and a compound of formula (b) is carried out in the presence of triphenylphosphine and DIAD.

In other more specific embodiments, for the method described in the twenty-seventh embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (a) is carried out in the presence of tri-n-butylphosphine and DIAD. In other more specific embodiments, for the method described in the twenty-seventh embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (b) is carried out in the presence of tri-n-butylphosphine and DIAD. In some more specific embodiments, for the method described in the twenty-seventh embodiment, the reaction between a compound of formula (IIB) and a compound of formula (a) is carried out in the presence of tri-n-butylphosphine and DIAD. In some more specific embodiments, for the method described in the twenty-seventh embodiment, the reaction between a compound of formula (IIB) and a compound of formula (b) is carried out in the presence of tri-n-butylphosphine and DIAD.

In certain embodiments of the method described in the twenty-seventh embodiment, the alcohol activating agent and azodicarboxylate are mixed together to form an alcohol activating agent-azodicarboxylate complex. In some embodiments, a compound of formula (IIA') or (IIA) is first mixed with an activating agent-azodicarboxylate complex before contacting the compound of formula (a). In some embodiments, the compound of formula (IIA') or (IIA) is first mixed with the activating agent-azodicarboxylate complex before contacting the compound of formula (b). In some other embodiments, the compound of formula (a) is first mixed with the activating agent-azodicarboxylate complex before contacting the compound of formula (IIA') or (IIA). In some other embodiments, the compound of formula (b) is first mixed with the activating agent-azodicarboxylate complex before contacting the compound of formula (IIA') or (IIA). In some embodiments, the compound of formula (IIB) is first mixed with the activating agent-azodicarboxylate complex before contacting the compound of formula (a). In some embodiments, the compound of formula (IIB) is first mixed with the activating agent-azodicarboxylate complex before contacting the compound of formula (b). In some other embodiments, the compound of formula (a) is first mixed with the activating agent-azodicarboxylate complex before contacting the compound of formula (IIB). In some other embodiments, the compound of formula (b) is first mixed with the activating agent-azodicarboxylate complex before contacting the compound of formula (IIB). In certain embodiments of the method of the twenty-seventh embodiment or any of the specific embodiments described herein, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (a) is carried out in a solvent(s). In certain embodiments of the method of the twenty-seventh embodiment or any of the specific embodiments described herein, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (b) is carried out in solvent(s). In certain embodiments of the method of the twenty-seventh embodiment or any of the specific embodiments described herein, the reaction between a compound of formula (IIB) and a compound of formula (a) is carried out in a solvent(s). In certain embodiments of the method of the twenty-seventh embodiment or any of the specific embodiments described herein, the reaction between a compound of formula (IIB) and a compound of formula (b) is carried out in a solvent(s). Any suitable solvent(s) described herein may be used. In some embodiments, a suitable solvent is selected from dichloromethane (CH ₂ Cl ₂ ), acetonitrile (MeCN), tetrahydrofuran (THF), toluene, N-methylmorpholine (NMM), or any combination thereof. In some more specific embodiments, the solvent is THF.

In certain embodiments of the method of the twenty-seventh embodiment or any specific embodiments described herein, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (a) is carried out at a temperature of from 0 °C to 50 °C °C, 0 °C to 40 °C, 5 °C to 30 °C, 10 °C to 30 °C or 15 °C to 25 °C. In certain specific embodiments, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (a) is first carried out at a temperature of from 0°C to 10°C, and then carried out at a temperature of from 20°C to 30°C. In certain embodiments of the method of the twenty-first embodiment or any specific embodiments described herein, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (b) is carried out at a temperature of from 0 °C to 50 °C °C, 0 °C to 40 °C, 5 °C to 30 °C, 10 °C to 30 °C or 15 °C to 25 °C. In some specific embodiments, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (b) is first carried out at a temperature of from 0 °C to 10 °C, and then carried out at a temperature of from 20 °C to 30 °C. In certain embodiments of the method of the twenty-first embodiment or any specific embodiments described herein, the reaction between a compound of formula (IIB) and a compound of formula (a) is carried out at a temperature of from 0 °C to 50 °C, from 0 °C to 40 °C, 5 °C to 30 °C, 10 °C to 30 °C or 15 °C to 25 °C. In some specific embodiments, the reaction between a compound of formula (IIB) and a compound of formula (a) is first carried out at a temperature of from 0°C to 10°C, and then carried out at a temperature of from 20°C to 30°C. In certain embodiments of the method of the twenty-seventh embodiment or any specific embodiments described herein, the reaction between a compound of formula (IIB) and a compound of formula (b) is carried out at a temperature of from 0 °C to 50 °C, from 0 °C to 40 °C, 5 °C to 30 °C, 10 °C to 30 °C or 15 °C to 25 °C. In some specific embodiments, the reaction between a compound of formula (IIB) and a compound of formula (b) is first carried out at a temperature of 0°C to 10°C and then carried out at a temperature of 20°C to 30°C.

In a twenty-eighth embodiment, the reaction between a compound of formula (IIIA') or (IIIA) and a compound of formula (b) in the methods described herein (for example, in the third, fourth, sixth, eighth, ninth, twenty-fifth or twenty-seventh embodiment implementation or 3 ^ohm , 4 ^ohm , 6 ^ohm , 8 ^ohm or 9 ^ohm specific embodiment) is carried out in the presence of a base. In the twenty-eighth embodiment, the reaction between a compound of formula (VA') or (VA) and a compound of formula (a) in the methods described herein (for example, in the fifth, seventh, twenty-fifth or twenty-seventh embodiment or ⁵ or 7 ^{in this} particular embodiment) is carried out in the presence of a base. In a twenty-eighth embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (b) in the methods described herein (for example, in the tenth, twelfth or twenty-fifth embodiment or ^{the 10th} or ^12th particular embodiment implementation) is carried out in the presence of a base. In a twenty-eighth embodiment, the reaction between a compound of formula (IIA) and a compound of formula (a) in the methods described herein (eg, the eleventh or twenty-fifth embodiment or the ^11th specific embodiment) is carried out in the presence of a base. In the twenty-eighth embodiment, the reaction between the compound of formula (IIIB) and the compound of formula (b) in the methods described herein (for example, in the fifteenth, sixteenth, eighteenth, twentieth, twenty-first, twenty-sixth or twenty-seventh embodiment) is carried out in the presence of a base. In the twenty-eighth embodiment, the reaction between the compound of formula (VB) and the compound of formula (a) described herein (eg, in the seventeenth, nineteenth, twenty-sixth or twenty-seventh embodiment) is carried out in the presence of a base. In a twenty-eighth embodiment, the reaction between a compound of formula (IIB) and a compound of formula (b) in the methods described herein (eg, the twenty-second, twenty-fourth or twenty-sixth embodiment) is carried out in the presence of a base. In a twenty-eighth embodiment, the reaction between a compound of formula (IIB) and a compound of formula (a) in the methods described herein (eg, in the twenty-third or twenty-sixth embodiment) is carried out in the presence of a base. In certain specific embodiments, the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. In some more specific embodiments, the base is potassium carbonate.

In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIIA') or (IIIA) and a compound of formula (b) further comprises potassium iodide and cesium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (VA') or (VA) and a compound of formula (a) further comprises potassium iodide and cesium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (b) further comprises potassium iodide and cesium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (a) further comprises potassium iodide and cesium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIIB) and a compound of formula (b) further comprises potassium iodide and cesium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (VB) and a compound of formula (a) further includes potassium iodide and cesium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIB) and a compound of formula (b) further comprises potassium iodide and cesium iodide.

In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIB) and a compound of formula (a) further includes potassium iodide and cesium iodide. In some specific embodiments, the reaction between a compound of formula (IIIA') or (IIIA) and a compound of formula (b) involves potassium iodide. In some specific embodiments, the reaction between a compound of formula (VA') or (VA) and a compound of formula (a) involves potassium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (b) further involves potassium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (a) further involves potassium iodide. In some specific embodiments, the reaction between a compound of formula (IIIB) and a compound of formula (b) involves potassium iodide. In some specific embodiments, the reaction between a compound of formula (VB) and a compound of formula (a) involves potassium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIB) and a compound of formula (b) further involves potassium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIB) and a compound of formula (a) further involves potassium iodide.

In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIIA') or (IIIA) and a compound of formula (b) is carried out in the presence of potassium carbonate and potassium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (VA') or (VA) and a compound of formula (a) is carried out in the presence of potassium carbonate and potassium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (b) is carried out in the presence of potassium carbonate and potassium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIA') or (IIA) and a compound of formula (a) is carried out in the presence of potassium carbonate and potassium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIIB) and a compound of formula (b) is carried out in the presence of potassium carbonate and potassium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (VB) and a compound of formula (a) is carried out in the presence of potassium carbonate and potassium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIB) and a compound of formula (b) is carried out in the presence of potassium carbonate and potassium iodide. In certain embodiments of the method described in the twenty-eighth embodiment, the reaction between a compound of formula (IIB) and a compound of formula (a) is carried out in the presence of potassium carbonate and potassium iodide.

Any suitable solvents can be used for the methods of the twenty-eighth embodiment. In some embodiments, the solvent is a polar aprotic solvent. Examples of solvents include, but are not limited to, dimethylformamide (DMF), dichloromethane (DCM or CH ₂ Cl ₂ ), dichloroethane (DCE), tetrahydrofuran (THF), dimethyl acetamide (DMA or DMAc), etc. In particular embodiments, the solvent is dimethylformamide or dimethylacetamide.

In a twenty-ninth embodiment, for a reaction between a compound of formula (VA') or (VA) and an imine-reducing agent, or for a reaction between a compound of formula (VIIA') or (VIIA) and an imine-reducing agent, or for a reaction between a compound of formula (VB) and an imine-reducing agent, or for the reaction between a compound of formula (VIIB) and an imine-reducing agent in the methods described herein (for example, in the sixth, ninth, twelfth, eighteenth, twenty-first, twenty-fourth, twenty-fifth , twenty-sixth, twenty-seventh or twenty-eighth embodiment or the ^6th , ^9th or ^12th particular embodiment), the imine reducing agent is selected from sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogen gas, ammonium formate, borane , diborane, borane-tetrahydrofuran complex (borane-THF), borane-dimethyl sulfide complex (BMS), borane-1,4-oxatain complex, 9-borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminum hydride (DIBAL ), lithium borohydride (LiBEH ₄ ), potassium borohydride (KBH ₄ ), or sodium bis(2-methoxyethoxy) aluminum hydride (Red-Al). In specific embodiments, the imine reducing reagent is sodium triacetoxyborohydride (NaBH(OAc) ₃ ).

In certain embodiments of the methods of the twenty-ninth embodiment, a reaction between a compound of formula (VA') or (VA) and an imine-reducing agent, or a reaction between a compound of formula (VIIA') or (VIIA) and an imine-reducing agent, or a reaction between a compound of formula (VB) and an imine-reducing agent, or the reaction between a compound of formula (VIIB) and an imine-reducing agent can be carried out in a suitable solvent selected from alcohols, ethers, a halogenated solvent. In some specific embodiments, the solvent is selected from methanol, ethanol, THF, or DCM. In some more specific embodiments, the solvent is dichloromethane.

In the thirtieth embodiment, for a compound of formula (VIA'), (VIA), (VIIIA'), (VIIIA), (XA'), (XA), (VIB), (VIIIB) or (XB), X ₁ is mesylate , tosylate, brosylate or triflate. In some specific embodiments, X ₁ is a mesylate.

In some embodiments, the sulfonating agent is a sulfonic anhydride, such as methanesulfonic anhydride, or a sulfonyl chloride, such as methanesulfonyl chloride (MsCl). In some specific embodiments, the sulfonating agent is methanesulfonic anhydride. In some specific embodiments, the sulfonating agent is methanesulfonyl chloride.

In some embodiments, the reaction between a compound of formula (IIA'), (IIA), (VIIA'), (VIIA), (IXA'), (IXA), (IIB), (VIIB) or (IXB) with a sulfonating agent in methods described herein (for example, the seventh, eighth, ninth, tenth, eleventh, twelfth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-four, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, or twenty-ninth embodiment) is carried out in the presence of a base. In some embodiments, the base is a non-nucleophilic base.

Examples of non-nucleophilic bases include, but are not limited to, triethylamine, imidazole, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or tetramethylpiperidine. In some specific embodiments, the base is triethylamine or diisopropylethylamine. In some more specific embodiments, the base is triethylamine. In some more specific embodiments, the base is diisopropylethylamine.

Any suitable solvents may be used to react a compound of formula (IIA'), (IIA), (VIIA'), (VIIA), (IXA'), (IXA), (IIB), (VIIB) or (IXB) with a sulfonating agent agent. In one embodiment, the solvent is dichloromethane.

In the thirty-first embodiment, the reaction between a compound of formula (VIA') or (VIA) and a compound of formula (b) in the methods described herein (for example, in the seventh, ninth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth or the thirtieth embodiment or the ^7th or ^9th particular embodiment) is carried out in the presence of a base. In the thirty-first embodiment, the reaction between a compound of formula (VIA') or (VIA) and a compound of formula (a) in the methods described herein (for example, in the eighth, twenty-fifth, twenty-seventh, twenty-eighth, twenty-ninth or thirtieth embodiment or ^8th specific embodiment) is carried out in the presence of a base. In the thirty-first embodiment, the reaction between a compound of formula (VIIIA') or (VIIIA) and a compound of formula (a) in the methods described herein (for example, in the tenth, twenty-fifth, twenty-seventh, twenty-eighth, twenty-ninth or thirtieth embodiment implementation or the ^10th specific embodiment) is carried out in the presence of a base. In the thirty-first embodiment, the reaction between a compound of formula (XA') or (XA) and a compound of formula (b) in the methods described herein (for example, in the eleventh, twelfth, twenty-fifth, twenty-seventh, twenty-eighth, twenty-ninth or the thirtieth embodiment or the ^11th or ^12th particular embodiment) is carried out in the presence of a base. In the thirty-first embodiment, the reaction between a compound of formula (VIB) and a compound of formula (b) in the methods described herein (e.g., in the nineteenth, twenty-first, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, or thirtieth embodiment) , carried out in the presence of a base. In the thirty-first embodiment, the reaction between a compound of formula (VIB) and a compound of formula (a) in the methods described herein (for example, in the twentieth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth or thirtieth embodiment) is carried out in the presence of grounds. In the thirty-first embodiment, the reaction between a compound of formula (VIIIB) and a compound of formula (a) in the methods described herein (for example, in the twenty-second, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth or thirtieth embodiment) is carried out in the presence of a base. In the thirty-first embodiment, the reaction between a compound of formula (XB) and a compound of formula (b) in the methods described herein (for example, in the twenty-third, twenty-fourth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, or thirtieth embodiment ) is carried out in the presence of a base. Examples of the base include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. In certain embodiments, the base is potassium carbonate.

Any suitable solvents may be used for the methods of the thirty-first embodiment. In some embodiments, the solvent is a polar aprotic solvent. Examples of solvents include, but are not limited to, dimethylformamide (DMF), dichloromethane (DCM or CH ₂ Cl ₂ ), dichloroethane (DCE), tetrahydrofuran (THF), dimethyl acetamide (DMA or DMAc), etc. In particular embodiments, the solvent is dimethylformamide or dimethylacetamide.

In certain embodiments of the methods described herein, a compound of formula (IVB) is reacted with a reducing agent to form a compound of formula (VIIB):

Any suitable reducing agent that can reduce a disulfide group to a thiol group can be used in the reaction. Examples of reducing agents include, but are not limited to, dithiothreitol (DTT), tris(2-carboxyethyl)phosphine (TCEP), or 2-mercaptoethanol. In some specific embodiments, the reducing agent is TCEP.

In some embodiments, for the methods described herein, a compound of formula (VIIB) is reacted with sodium bisulfite, sodium hydrogensulfite, or sodium metabisulfite to form a compound of formula (VIIIB):

In some embodiments, a compound of formula (VIIB) is reacted with sodium bisulfite to form a compound of formula (VIIIB). Any suitable solvent can be used for the reaction. Examples of solvents include, but are not limited to, water, DMA, acetone, DMF, etc., or a mixture thereof. In some embodiments, the reaction is carried out in a mixture of water and DMA.

EXAMPLES

Example 1. Synthesis of methyl-6-(((S)-1-(((S)-1-((3-(chloromethyl)-5-(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl) amino)-1-oxopropan-2-yl)amino)-6-oxohexanoate (compound 2)

DMF (5.0 mL, 5 vol.) was charged into a dry 100 mL round bottom flask equipped with a magnetic stirrer and thermocouple under an inert nitrogen atmosphere. Cyanuric acid chloride (0.274 g, 0.65 eq., 1.49 mmol) was added portionwise over 10 minutes. The solution was stirred for 60 ± 10 minutes, and a solution of DMF (5.0 ml, 5 vol.) methyl-6-(((S)-1-(((S)-1-((3,5-bis( Hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)amino)-6-oxohexanoate (compound 1, 1.0 g, 2.29 mmol, 1.0 eq. .) was then added dropwise until the reaction mixture cooled in an ice bath. The reaction mixture was stirred for 16 to 24 hours and a sample of the reaction mixture was analyzed by HPLC (see Fig. 1A, peak at ~1.0 min corresponds to starting material 1; peak at ~1.3 min corresponds to monochloride product 2 ; and the peak at ~1.5 min corresponds to the dichlorinated by-product 2a). The reaction mixture was cooled to 2-5 °C and 0.1 M NaOH (5.0 ml, 5 vol.) was slowly added to the reaction mixture. The resulting mixture was stirred for 30 ± 5 min. and then extracted with ethyl acetate (50.0 ml, 50.0 vol). The organic layer was separated and washed with water (2 x 10.0 mL, 2 x 10 vol). The combined aqueous layer was extracted with ethyl acetate (50.0 ml, 50.0 vol). The organic phases were combined and concentrated. The crude material was purified by silica gel column chromatography, eluting with a 0-30% gradient (where the solvent system consists of (i) 20% methanol in dichloromethane) and (ii) dichloromethane) over 25 minutes. Fractions containing the product were combined and concentrated in vacuo to obtain the desired product.

The experiment was repeated with 0.316 g (0.75 eq, 1.71 mmol) or 0.358 g (0.85 eq, 1.94 mmol) of cyanuric acid chloride and HPLC analysis of the reaction mixture is shown in FIG. 1B or FIG. 1C, respectively. A similar experiment was also carried out with 0.427 g (1.0 eq., 2.29 mmol) cyanuric acid chloride and 1.0 g (1.0 eq., 2.20 mmol) methyl-6-(((S)-1 -(((S)-1-((3,5-bis(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)amino)-6-oxohexanoate ( 1.0 g, 2.29 mmol, 1.0 eq.). In fig. 1D shows the HPLC curve of the reaction mixture. As shown in FIG. 1A-1D, the use of 0.85 molar equivalents (or equiv) of cyanuric acid chloride provided the most optimal yield for the monochloride product, compound 2.

Example 2. Synthesis of (3-(chloromethyl)-5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)(2-methyl-2-(methyldisulfanyl)propyl)amino)phenyl)methanol (compound 4)

(5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)(2-methyl-2-(methyldisulfanyl)propyl)amino)-1,3-phenylene)dimethanol (compound 3, 5.0911 g, 11.74 mmol, 1.0 eq) was dissolved in DMF (30 ml, 3.0 vol) in a dry 50 ml round bottom flask and the resulting solution was transferred to a dry 500 ml round bottom flask filled with nitrogen. A 50 ml round bottom flask was washed with DMF (2 x 20.0 ml, 2 x 2.0 vol) and the solution was added to a 500 ml round bottom flask. The combined solution of compound 3 in DMF was stirred for 2 hours at 25 ± 2 °C until a homogeneous solution was obtained. Cyanuric acid chloride (1.6557 g, 0.75 eq, 8.805 mmol) was added to a separate dry round bottom flask under nitrogen and DMF (30.0 mL, 3.0 vol) was added to the flask. The resulting mixture was stirred for 30 ± 10 minutes at 3 ± 2 °C to obtain a yellow-brown suspension, which was then transferred to a dropping funnel and added dropwise to a solution of compound 3 in DMF at a rate of 1 ml/minute, maintaining the temperature at 25 ± 3 °C. The resulting reaction mixture was stirred for 20 minutes and the reaction was monitored by UV-HPLC analysis. The reaction was considered complete after 50 ± 5 minutes. Ethyl acetate was added to the reaction mixture, followed by the slow addition of 0.5 M NaOH (25.0 mL, 2.5 vol). The resulting mixture was stirred for 30 ± 5 minutes and then transferred to a separatory funnel. Another portion of ethyl acetate (400 ml, 40 vol.) was added to the separatory funnel, followed by the addition of deionized water (100 ml, 10 vol.). Separate the organic phase and the aqueous phase, and if the aqueous phase has a pH <4, the organic phase is then washed again with 0.5 M NaOH. The organic phase was washed with water (2×100 ml, 2×10 vol.) and then concentrated. The crude product was purified by silica gel column chromatography, eluting with a gradient of 5-55% ethyl acetate/hexane over 40 minutes followed by increasing to 100% ethyl acetate over 5 minutes. The desired product, compound 4, was eluted with 47% to 53% ethyl acetate. Fractions containing product were combined and concentrated to give the desired product (2.96 g, 56%).

Similar experiments were carried out with 0.65 eq., 0.85 eq. or 1 eq. cyanuric acid chloride. The reaction yields of the required product are listed below.

Equivalents Conn. 3 Conn. 4 Conn. 4a Practical solution 0.65 41 42 14 41.3% 0.85 14 51 34 40.3% 1.0 17 49 33 40.3%

Example 3 Synthesis of Compound 5

Tetrahydrofuran (10.0 mL, 20 vol) was added to a dry 100 mL round bottom flask equipped with a magnetic stirrer and thermocouple under a nitrogen atmosphere, followed by cooling to 5 ± 3 °C. Tri-n-butylphosphine (0.332 mL, 1.32 mmol) was added, followed by dropwise addition of diisopropyl azodicarboxylate (0.261 mL, 1.32 mmol) through the addition funnel over 10 ± 2 minutes. The resulting mixture was stirred at 5 ± 3 °C for 2 hours. (S)-9-hydroxy-8-methoxy-11,12,12a,13-tetrahydro-6H-benzo[5,6][1,4]diazepino[1,2- a]indol-6-one (0.328 g, 1.10 mmol, 1.00 eq.) followed by the addition of tetrahydrofuran (10.0 ml, 20 vol.). The resulting mixture was stirred under a nitrogen atmosphere at 20 °C ± 5 °C to obtain a slightly cloudy solution. (3-(chloromethyl)-5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)(2-methyl-2-(methyldisulfanyl)propyl)amino)phenyl)methano (0.5 g) was added to the solution , 1.10 mmol) and the resulting mixture was stirred at 20 °C ± 5 °C until a slightly cloudy solution was obtained, which was cooled to 5 ± 3 °C and added dropwise through a dropping funnel over 10 ± 2 minutes, maintaining the temperature at 5 °C ± 3 °C in a round bottom flask containing a mixture of tri-n-butylphosphine and diisopropyl azodicarboxylate. The resulting reaction mixture was stirred overnight with slow heating to 20 °C ± 5 °C for 16 to 24 hours. The reaction was monitored by HPLC analysis and the reaction was considered complete when ≥60% of the starting material was converted to product. Upon completion of the reaction, silica gel supported by potassium carbonate (1.0 g) was added to the reaction mixture and stirred for 30 ± 5 min. and filtered to remove solids. The filtrate was concentrated to dryness and redissolved in dichloromethane (3.0 ml, 6 vol). The crude product was purified by silica gel column chromatography, eluting with a gradient of 0-100% ethyl acetate/hexanes over 40 minutes. Fractions containing pure product were combined and concentrated to dryness to give the desired product 5 (0.140 g, 17.3% yield). The yield of the reaction is due to the imprecise mass of starting material 4 because it contains DMF.

Example 4 Synthesis of Compound 8

Stage 1.

A dry 250 mL round bottom flask (RBF) equipped with a magnetic stirrer and thermocouple was slowly charged with nitrogen. In a dry 50 mL round bottom flask, 10.12 g (22.26 mmol) (5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)(2-methyl-2-(methyldisulfanyl)propyl)amino) -1,3-phenylene)dimethanol (compound 3) was dissolved in DMF (40 ml, 4.0 vol). The resulting solution was transferred into RBF with a volume of 500 ml. The 50 mL RBF containing Compound 3 was washed with DMF (30.0 mL, 3.0 vol) and the solution was added to the 500 mL RBF. A 500 mL solution in RBF was stirred at 600 rpm for over 1 hour at 25 ± 2 °C to obtain a homogeneous suspension. To a separate 100 mL dry RBF, 3.14 g (16.70 mmol) of 2,4,6-trichloro-1,3,5-triazine (TCT) was added. The RBF was charged with nitrogen and 20.0 ml (2.0 vol) DMF was added. The resulting mixture was stirred for 30 ± 5 minutes at 3 ± 2 °C to form a solution, which was transferred to an additional funnel and RBF was added dropwise to a 500 ml round bottom flask over 20 ± 3 minutes, maintaining the temperature at 25 ± 3 °C . The resulting reaction mixture was stirred for 50±5 minutes. Upon completion of the reaction, ethyl acetate (100.0 mL, 10 vol) was added to the reaction mixture through an additional funnel to quench the reaction mixture, followed by the addition of 0.5 M NaOH (50.0 ml, 5 vol), maintaining the reaction temperature below 30°C. The resulting mixture was stirred for 30 ± 5 min. and transferred to a separatory funnel. An additional 800 ml (80 vol) of ethyl acetate was added to the separatory funnel, followed by 100 ml (10 vol) of deionized water. The organic phase was separated and washed with water (2 x 200.0 ml, 2 x 20 vol). The combined organic phase was concentrated using a rotary evaporator. The crude product was purified by silica gel column chromatography, eluting with a gradient of 0-55% ethyl acetate/hexanes over 40 minutes, then increased to 100% ethyl acetate over 5 minutes to give the desired product (3-(chloromethyl)-5 ((2- (2-(2-methoxyethoxy)ethoxy)ethyl)(2-methyl-2-(methyldisulfanyl)propyl)amino)phenyl)methanol (compound 4) (4.9429 g, 10.72 mmol, 48.1% yield) .

Stage 2

Compound 4 (4.0788 g, 8.81 mmol) was dissolved in dichloromethane (20.0 ml, 5 vol). The resulting clear yellow solution was cooled to -10 °C and methanesulfonic anhydride (4.90 g, 27.3 mmol) was added. N-ethyl-N-isopropylpropan-2-amine (9.23 ml, 52.9 mmol) was dissolved in dichloromethane (20.0 ml, 5 vol) and the resulting solution was slowly added to a mixture of compound 4 and methanesulfonic anhydride, maintaining the reaction temperature at -10 °C. After 15 minutes, the reaction mixture was quenched by adding a 1:1 mixture of ice water and methanol (20.0 mL, 5 vol) and stirred at 1000 rpm for 5 minutes at -10 °C. The mixture was then added to pre-cooled (5 °C) water (36.0 ml, 9.0 vol.) and stirred at -10 °C, followed by the addition of an aqueous solution of methanesulfonic acid (5% solution, 10.0 ml, 2. 5 vol.). The resulting solution was stirred at 0 °C for 5 minutes, DCM (16.0 mL, 40.0 volume) was added and the mixture was stirred for 1 minute. The organic layer was separated and returned back to the reaction reactor, and pre-cooled (5 °C) water (36.0 mL, 9.0 vol) and an aqueous solution of methanesulfonic acid (5% solution, 13.2 mL, 3 ,3 vol.). The mixture was stirred for 8 minutes and the organic layer was separated and washed with ice water (2 x 42.7 mL, 2 x 10.5 vol). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the solvent was removed in a vacuum oven to give the desired product 3-(chloromethyl)-5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)(2-methyl-2- (methyldisulfanyl)propyl)amino)benzylmethanesulfonate (compound 5) (4.8740 g, 8.81 mmol, 100% yield).

Stage 3

(S)-9-Hydroxy-8-methoxy-11,12,12a,13-tetrahydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-6-one (compound 5) (0.124 g, 0.418 mmol) and N,N-dimethylacetamide (1.0 mL, 4 vol) were added to a 100 mL round bottom flask equipped with a magnetic stirrer and thermocouple, and the solution was sonicated. Potassium carbonate (0.114 g, 0.828 mmol) was added to the solution. In a 20 ml glass vessel, compound 5 (0.2263 g, 0.414 mmol) was dissolved in N,N-dimethylacetamide (1.5 ml, 6 vol) and the resulting solution was slowly added to a 100 ml RBF reaction vessel over an hour. The reaction mixture was stirred at 800 rpm for 11 hours, maintaining the reaction temperature at 20 °C ± 3 °C. Water (3 mL, 10 vol) was slowly added and stirred for 15 ± 5 minutes to quench the reaction. Ethyl acetate (9 ml, 30 vol) was then added to the reaction mixture and stirred for 15 ± 5 minutes. The resulting mixture was transferred to a separatory funnel and the organic phase was separated. The aqueous layer was washed with ethyl acetate (3 x 12 ml, 3 x 40 vol). The combined organic layers were washed with semi-saturated brine (1 x 9 mL, 1 x 30 vol) and concentrated to give the crude product. The crude product was purified by silica gel column chromatography, eluting with a gradient of 0-70% ethyl acetate/hexane over 35 minutes to give the desired product (S)-9-((3-(chloromethyl)-5-((2-(2 -(2-methoxyethoxy)ethoxy)ethyl)(2-methyl-2-(methyldisulfanyl)propyl)amino)benzyl)oxy)-8-methoxy-11,12,12a,13-tetrahydro-6H-benzo[5,6 ][1,4]diazepino[1,2-a]indol-6-one (compound 6) (0.1549 g, 0.212 mmol, 51.2% yield).

Stage 4

(S)-9-((3-(chloromethyl)-5-((2-(2-(2-methoxyethoxy)ethoxy) )ethyl)(2-methyl-2-(methyldisulfanyl)propyl)amino)benzyl)oxy)-8-methoxy-11,12,12a,13-tetrahydro-6H-benzo[5,6][1,4]diazepino [1,2-a]indol-6-one (0.150 g, 0.195 mmol). N,N-Dimethylacetamide (3.0 mL, 6 volumes) was added and the resulting mixture was stirred at 20 °C ± 5 °C to obtain a clear light brown solution. Potassium iodide (0.032 g, 0.195 mmol) was added to the light brown solution, followed by potassium carbonate (0.054 g, 0.390 mmol). In a 20 ml glass bottle (S)-9-hydroxy-8-methoxy-12a,13-dihydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-6-one (0.071 g, 0.234 mmol) was dissolved in N,N-dimethylacetamide (2.0 ml, 4 vol). The resulting solution was slowly added to the reaction mixture in RBF, and the reaction solution turned brownish yellow. The reaction mixture was stirred for 24 hours while heating to 30 °C ± 3 °C and then cooled to 20 °C ± 5 °C.

Deionized water (6 mL, 20 vol) was added to the reaction mixture to quench the reaction and precipitate the product. The product was filtered, washed with deionized water (2x3 ml, 10 vol.) and redissolved in dichloromethane (12 ml, 40 vol.). The dichloromethane solution was mixed with deionized water (6 ml, 20 vol.), and the organic phase was separated, washed with semi-saturated brine (2 x 6 ml, 2 x 20 vol.) and water (2 x 6 ml, 2 x 20 vol.) . The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to about 0.45 ml (1.5 vol). The crude product is purified by silica gel column chromatography, eluting with a gradient of 0-100% ethyl acetate/hexanes over 50 minutes, then increased to 100% ethyl acetate over 5 minutes to give the desired product (S)-8-methoxy-9-((3 -((((S)-8-methoxy-6-oxo-11,12,12a, 13-tetrahydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indole-9 -yl)oxy)methyl)-5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)(2-methyl-2-(methyldisulfanyl)propyl)amino)benzyl)oxy)-12a,13-dihydro -6H-benzo[5,6][1,4]diazepino[1,2-a]indol-6-one (0.1033 g, 0.105 mmol, 53.6% yield).

Stage 5

TCEP (3.1 g) was moistened with a few drops of water. Saturated NaHCO ₃ (85 ml) was added until pH 6.5 was reached. Freshly prepared 0.1 M phosphate buffer (34 mL) was adjusted to pH 6.5 and then added to the TCEP solution. Compound 7 (10.1 g) was dissolved in acetonitrile (588 ml) and MeOH (257 ml) and mixed with the TCEP solution. After 2 hours, additional TCEP (310 mg) (dissolved in NaHCO3 solution and adjusted to pH 6.5) was added and the mixture was stirred for about 2 hours. DCM (1.3 L) and water (600 ml) were added. After separation, the aqueous phase was extracted with DCM (250 ml). The combined organic phases were washed with water (2×250 ml) and evaporated to dryness to obtain 9.6 g of the reduced compound.

The reduced compound (9.5 g) was suspended under argon in 2-propanol (522 ml) and water (261 ml) at room temperature. To the above suspension was added sodium bisulfite (6.78 g) as a solid. The mixture was stirred at room temperature for 1 hour, after which a clear solution was obtained. The yellowish solution was filtered. The resulting solution was then diluted with water (500 ml) and divided into two equal parts of 593 g each. They were transferred to 3 L round bottom flasks, frozen in a dry ice bath, and lyophilized to a dry powder (flasks were kept at ambient temperature during lyophilization). The output fractions provided 7.2 g and 7.4 g of compound 8, respectively, as an off-white lyophilized powder.

Claims (121)

1. Method for preparing the compound of formula (IIA) (IIA), comprising reacting a compound of formula (IA) (IA) with from 0.6 to 1.0 molar equivalent of cyanuric acid chloride to form a compound of formula (IIA). 2. The method according to claim 1, characterized in that from 0.7 to 0.8 molar equivalent of cyanuric acid chloride is used. 3. The method according to claim 1, characterized in that 0.75 molar equivalent or 0.85 molar equivalent of cyanuric acid chloride is used. 4. Method according to any one of paragraphs. 1-3, characterized in that the reaction is carried out in DMF. 5. Method according to any one of paragraphs. 1-4, characterized in that the method additionally includes reacting a compound of formula (IIA) with a compound of formula (a) to form a compound of formula (IIIA) (IIIA). 6. The method according to claim 5, characterized in that the method further includes reacting a compound of formula (IIIA) with a compound of formula (b) to form a compound of formula (IVA) 7. Method according to claim 5 or 6, characterized in that the reaction between the compound of formula (IIA) and the compound of formula (a) is carried out in the presence of an alcohol activating agent and an azodicarboxylate. 8. The method according to claim 7, characterized in that the alcohol activating agent is tributylphosphine or triphenylphosphine and the azodicarboxylate is selected from the group consisting of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1'-(azodicarbonyl)dipiperidine (ADDP) ) and ditert-butyl azodicarboxylate (DTAD). 9. The method according to claim 7, characterized in that the alcohol activating agent is triphenylphosphine and the azodicarboxylate is diisopropyl azodicarboxylate (DIAD). 10. The method of claim 9, wherein triphenylphosphine and diisopropyl azodicarboxylate are first mixed together to form a triphenylphosphine-azodicarboxylate complex before mixing the complex with the compound of formula (IIA) and the compound of formula (a). 11. Method according to any one of paragraphs. 6-10, characterized in that the compound of formula (IIIA) is reacted with a compound of formula (b) in the presence of a base. 12. The method according to claim 11, characterized in that the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride or potassium hydride. 13. The method according to claim 12, characterized in that the base is potassium carbonate. 14. Method according to any one of paragraphs. 6-13, characterized in that the reaction between the compound of formula (IIIA) and the compound of formula (b) is carried out in the presence of potassium iodide or cesium iodide. 15. Method according to any one of paragraphs. 1-4, characterized in that the method additionally includes the stages: i) reacting a compound of formula (IIA) with a sulfonating agent to form a compound of formula (VIA): (VIA); ii) reacting a compound of formula (VIA) with a compound of formula (b) to form a compound of formula (VA) iii) reacting a compound of formula (VA) with a compound of formula (a) to form a compound of formula (IVA) where X ₁ represents a sulfonic acid ester. 16. Method according to any one of paragraphs. 1-4, additionally including the stages: i) reacting a compound of formula (IIA) with a sulfonating agent to form a compound of formula (VIA) (VIA); ii) reacting a compound of formula (VIA) with a compound of formula (a) to form a compound of formula (IIIA) (IIIA); And ii) reacting a compound of formula (IIIA) with a compound of formula (b) to form a compound of formula (IVA) where X ₁ represents a sulfonic acid ester. 17. Method according to any one of paragraphs. 1-4, additionally including the stages: i) reacting a compound of formula (IIA) with a sulfonating agent to form a compound of formula (VIA) (VIA); ii) reacting a compound of formula (VIA) with a compound of formula (b) to form a compound of formula (VA) iii) reacting a compound of formula (VA) with an imine reducing agent to form a compound of formula (IIIA) (IIIA); And iv) reacting a compound of formula (IIIA) with a compound of formula (b) to form a compound of formula (IVA) where X ₁ represents a sulfonic acid ester. 18. Method for preparing the compound of formula (IIB) comprising reacting a compound of formula (IB) with from 0.6 to 1.0 molar equivalent of cyanuric acid chloride to form a compound of formula (IIB). 19. The method according to claim 18, characterized in that from 0.7 to 0.8 molar equivalent of cyanuric acid chloride is used. 20. The method according to claim 18, characterized in that 0.75 molar equivalent of cyanuric acid chloride is used. 21. Method according to any one of paragraphs. 18-20, characterized in that the reaction is carried out in DMF. 22. Method according to any one of paragraphs. 18-21, characterized in that the method additionally includes reacting a compound of formula (IIB) with a compound of formula (a) to form a compound of formula (IIIB) 23. The method according to claim 22, characterized in that the method further includes reacting a compound of formula (IIIB) with a compound of formula (b) to form a compound of formula (IVB) 24. Method according to claim 22 or 23, characterized in that the reaction between the compound of formula (IIB) and the compound of formula (a) is carried out in the presence of an alcohol activating agent and an azodicarboxylate. 25. The method according to claim 24, characterized in that the alcohol activating agent is tributylphosphine or triphenylphosphine and the azodicarboxylate is selected from the group consisting of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1'-(azodicarbonyl)dipiperidine (ADDP) ) and ditert-butyl azodicarboxylate (DTAD). 26. The method according to claim 25, characterized in that the alcohol activating agent is triphenylphosphine and the azodicarboxylate is diisopropyl azodicarboxylate (DIAD). 27. The method of claim 26, wherein triphenylphosphine and diisopropyl azodicarboxylate are first mixed together to form a triphenylphosphine-azodicarboxylate complex before mixing the complex with the compound of formula (IIB) and the compound of formula (a). 28. Method according to any one of paragraphs. 23-27, characterized in that the compound of formula (IIIB) is reacted with a compound of formula (b) in the presence of a base. 29. The method according to claim 28, characterized in that the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride or potassium hydride. 30. The method according to claim 29, characterized in that the base is potassium carbonate. 31. Method according to any one of paragraphs. 23-30, characterized in that the reaction between the compound of formula (IIIB) and the compound of formula (b) is carried out in the presence of potassium iodide or cesium iodide. 32. Method according to any one of paragraphs. 18-21, characterized in that the method additionally includes the stages: i) reacting a compound of formula (IIB) with a sulfonating agent to form a compound of formula (VIB) (VIB); ii) reacting a compound of formula (VIB) with a compound of formula (b) to form a compound of formula (VB) iii) reacting a compound of formula (VB) with a compound of formula (a) to form a compound of formula (IVB) 33. Method according to any one of paragraphs. 18-21, additionally including the stages: i) reacting a compound of formula (IIB) with a sulfonating agent to form a compound of formula (VIB) ii) reacting a compound of formula (VIB) with a compound of formula (a) to form a compound of formula (IIIB) iii) reacting a compound of formula (IIIB) with a compound of formula (b) to form a compound of formula (IVB) where X ₁ represents a sulfonic acid ester. 34. Method according to any one of paragraphs. 18-21, additionally including the stages: i) reacting a compound of formula (IIB) with a sulfonating agent to form a compound of formula (VIB) (VIB); ii) reacting a compound of formula (VIB) with a compound of formula (b) to form a compound of formula (VB) iii) reacting a compound of formula (VB) with an imine-reducing agent to form a compound of formula (IIIB) iv) reacting a compound of formula (IIIB) with a compound of formula (b) to form a compound of formula (IVB).