WO2005120498A2 - Method for synthesis of lonidamine and related indazole derivatives - Google Patents

Method for synthesis of lonidamine and related indazole derivatives Download PDF

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WO2005120498A2
WO2005120498A2 PCT/US2005/019350 US2005019350W WO2005120498A2 WO 2005120498 A2 WO2005120498 A2 WO 2005120498A2 US 2005019350 W US2005019350 W US 2005019350W WO 2005120498 A2 WO2005120498 A2 WO 2005120498A2
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unsubstituted
indazole
lonidamine
solvent
carboxylic acid
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PCT/US2005/019350
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French (fr)
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WO2005120498A3 (en
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Jian-Xin Duan
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Threshold Pharmaceuticals, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

Definitions

  • the present invention provides methods for making lonidamine and related indazole derivatives.
  • the invention relates to the fields of chemistry, biology, pharmacology and medicine.
  • Lonidamine (1a) has been used in cancer therapy.
  • Lonidamine analogs and pharmaceutical formulations of lonidamine and its analogs, as well as methods for their use in treating cancer are described in U.S. Patent Nos. 3,895,026; 6,001,865; 6336,087; 6,319,517; each of which is incorporated herein by reference.
  • Lonidamine and its analogs have also been found to be active as anti-spermatogenic agents (US patents Palazzo et al. 3,895,026 and Silvestrini et al. 6,001,865, each of which is incorporated herein by reference).
  • Lonidamine (1a) and its analogs have been synthesized via alkylation of the indazole moiety with the appropriate benzylic halides (Palazzo and Silvestrini et al.).
  • indazole-3-carboxylic acid (2) was reacted with 3 equivalents of aqueous NaOH and approximately 1 equivalent of a benzylic halide (3a-b) (Scheme 1).
  • Carboxyiic acid 2 was a contaminant in the product that had to be removed by laborious extraction with aqueous NaOH (Corsi et al. 1976, J. Med. Chem., 19(6): 778, incorporated herein by reference. See page 779).
  • R C0 2 Et 5b.
  • the ethyl ester (4b) of indazole-3-carboxylic acid has been subjected to alkylations, including with 4-chlorobenzylchloride as the alkylator.
  • the base was aNH 2 and the solvent xylene, and the reaction was conducted at temperatures between 100 and 135°C.
  • 4b as starting material, a synthetic route utilizing NaOEt as the base in refluxing EtOH has been described.
  • Yet another method employing NaH as the base, in refluxing dioxane has also been described.
  • the benzylated indazole caroboxylic acid esters, like 5b, and the carboxyiic acids derived from them were isolated upon crystallization.
  • the non-aqueous methods are carried out at temperatures where the reaction mixture is refluxed or a high temperature, for example, 135°C, is maintained.
  • the present invention provides a method for synthesizing 1-alkylated indazole-3-carboxylic acid, said method comprising the steps of:
  • a method for synthesizing 1-alkylated indazoIe-3-carboxylic acid comprising the steps of: [0020] (1) performing an alkylation reaction between ArCH 2 -X and indazole-3-carboxylic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; and X is a halogen or OSO 2 R 6 ; wherein R 6 is independently C C6 unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl;
  • the present invention provides a method for synthesizing lonidamine, said method comprising the steps of:
  • said indazole derivative has a structure , wherein R is independently cyano; a halogen; hydrogen; CrC 6 unsubstituted or substituted alkyl; C 2 -Ce unsubstituted or substituted alkenyl; CO2R2, wherein R 2 is C- ⁇ -C 6 unsubstituted or substituted alkyl; C NR3R4, wherein R 3 and R 4 are independently hydrogen or Ci-C ⁇ unsubstituted or substituted alkyl; and CORs, wherein R 5 is hydrogen or C- I - ⁇ unsubstituted or substituted alkyl; and X is a halogen or OS0 2 R6, wherein Re is independently C C ⁇ unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl;
  • the present invention provides a method for synthesizing lonidamine, said method comprising the steps of:
  • said indazole derivative has a structure , wherein R is independently cyano; C r C ⁇ unsubstituted or substituted alkyl; C 2 -C 6 unsubstituted or substituted alkenyl; CO 2 R 2 .
  • R 2 is C ⁇ -C 6 unsubstituted or substituted alkyl; CONR 3 R 4 , wherein R 3 and R 4 are independently hydrogen or C-i-C ⁇ unsubstituted or substituted alkyl; and COR 5 , wherein R5 is hydrogen or C ⁇ -C 6 unsubstituted or substituted alkyl; and X is a halogen or OS0 2 R ⁇ , wherein Re is independently C Ce unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; [0034] (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1 ); (3) crystallizing a lonidamine precursor having a structure
  • the present invention provides a method for synthesizing 1-alkylated indazole-3-carboxylic acids, said method comprising the steps of:
  • the present invention provides a method for synthesis of lonidamine, said method comprising the steps of: [0043] (1) performing an alkylation reaction between 2,4- dichlorobenzyl-X and indazole-3 carboxyiic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein, X is as defined above; [0044] (2) acidifying said reaction mixture; and
  • the invention provides a method for the synthesis of 1-alkylated indazole-3-carboxylic acids, said method comprising the steps of: [0047] (1) performing an alkylation reaction between ArCH 2 -X and indazole-3-carboxylic acid or a salt thereof, in presence of a base and a phase transfer agent in a biphasic solvent, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; and X is a halogen or OS0 2 R 6 , wherein Re is independently Ci-Ce unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; [0048] (2) acidifying said reaction mixture; and
  • the present invention provides a method for synthesizing lonidamine, said method comprising the steps of: [0051] (1) performing an alkylation reaction between 2,4- dichlorobenzyl-X and indazole-3-carboxylic acid or a salt thereof in presence of a base and a phase transfer agent, in a biphasic solvent, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein X is as defined above; [0052] (2) acidifying said reaction mixture; and
  • the present invention provides a method in which lonidamine, which has been synthesized by alkylation, is crystallized from a solvent.
  • the invention provides a method of slow crystallization of lonidamine from acetic acid (AcOH) that can yield lonidamine at 99.97% or greater purity.
  • the invention provides a relatively faster crystallization from AcOH that can yield lonidamine at 99.32% or greater purity.
  • the invention provides a method for the crystallization of lonidamine from EtOH that can yield lonidamine at 99.49% or greater purity.
  • the invention provides a method for synthesizing indazole derivatives, said method comprising the steps of: [0056] (1) performing an alkylation reaction between ArCH 2 -X and an indazole derivative in presence of a base and in a solvent for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein: said indazole derivative has a structure , wherein R is independently cyano; a halogen; hydrogen; C C 6 unsubstituted or substituted alkyl; C 2 -Ce unsubstituted or substituted alkenyl; C0 2 R 2 , wherein R 2 is C ⁇ -C 6 unsubstituted or substituted alkyl; CONR 3 R4, wherein R 3 and R 4 are independently hydrogen or C-t-C ⁇ unsubstituted or substituted alkyl; and COR 5 , wherein R 5 is hydrogen or C-i-Ce unsubstituted or substituted alkyl;
  • this invention provides methods for the synthesis of lonidamine and other indazole derivatives, as described in more detail in the following section.
  • pKa is the negative logarithm of the acid dissociation constant, Ka, in water.
  • a dipolar aprotic solvent is a solvent with a comparatively high relative permittivity (or dielectric constant), greater than approximately 15, and a sizable permanent dipole moment, that cannot donate hydrogen atoms to form strong hydrogen bonds.
  • a “base” is molecule or an ion that can act as an acceptor of proton.
  • a heteroatom is oxygen, sulfur or nitrogen.
  • CrC 6 alkyl is any aliphatic group containing 1 to 6 carbon atoms, and hydrogen, including, straight chain, branched chain, cyclic, carbocycle containing and substituted alkyl groups, and substituted alkyl us an alkyl substituted with one or more heteroatom containing groups.
  • C 2 -C 6 alkenyl refers to straight or branched chain alkene groups having 2 to 6 carbon atoms.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • a "precursor" to a functional group-1 is defined as a moiety or a functional group ⁇ 2 which can be converted into functional group-1 in one step or a combination of steps.
  • "precursors" to a carboxyl group include but are not limited to cyano, ester, CH OH, COCH 3 , CHO, any halogen atom, ethenyl and Ph.
  • Lonidamine is the generic name for 1-(2,4-dichlorobenzyl)-1H- indazole-3-carboxylic acid, and has also been referred to in the literature as 1- [(2,4-dichlorophenyl)methyl]-1 H-indazole-3-carboxylic acid, AF1890, diclondazolic acid (DICA), and Dorida inaTM (ACRAF).
  • the present invention provides a method for synthesizing lonidamine, said method comprising the steps of: [0070] (1) performing an alkylation reaction between 2,4- dichlorobenzyl-X and an indazole derivative in presence of a base and in a solvent for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein:
  • said indazole derivative has a structure , wherein R is independently cyano; a halogen; hydrogen; C C 6 unsubstituted or substituted alkyl; C 2 -C ⁇ unsubstituted or substituted alkenyl; C0 2 R 2 , wherein R 2 is C-i-C.
  • the invention provides a method for the synthesis of lonidamine, said method comprising the steps of:
  • said indazole derivative has a structure , wherein R is independently cyano; C C ⁇ unsubstituted or substituted alkyl; C 2 -C 6 unsubstituted or substituted alkenyl; C0 2 R 2 , wherein R 2 is C ⁇ -C 6 unsubstituted or substituted alkyl; CONR 3 R 4 , wherein R3 and R 4 are independently hydrogen or C Ce unsubstituted or substituted alkyl; and COR 5 , wherein R5 is hydrogen or C ⁇ -C 6 unsubstituted or substituted alkyl; and X is a halogen or OS0 2 R 6 ; wherein R 6 is independently C C 6 unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; [0078] (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1);
  • the present invention provides a method for synthesizing 1-alkylated indazole-3-carboxylic acids, said method comprising the steps of:
  • said invention provides a method for the synthesis of lonidamine, said method comprising the steps of: [0087] (1) performing an alkylation reaction between 2,4- dichlorobenzy(-X and indazole-3 carboxyiic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein, X is as defined above; [0088] (2) acidifying said reaction mixture; and
  • the invention provides a method for the synthesis of 1-alkylated indazole-3-carboxylic acids, said method comprising the steps of:
  • the invention provides a method for the synthesis of lonidamine, said method comprising the steps of:
  • the present invention provides a method wherein lonidamine, which has been synthesized by a process employing an alkylation step, is crystallized from a solvent.
  • the invention provides a method for the slow crystallization of lonidamine from acetic acid (AcOH) that can yield lonidamine at 99.97% or greater purity.
  • the invention provides a relatively faster crystallization of lonidamine from AcOH that can yield lonidamine at 99.32% or greater purity.
  • the invention provides a method for the crystallization of lonidamine from ethanol (EtOH) that can yield lonidamine at
  • the invention provides a method for synthesizing indazole derivatives, said method comprising the steps of: [0100] (1) performing an aikyiation reaction between ArCH 2 -X and an indazole derivative in presence of a base and in a solvent for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein:
  • said indazole derivative has a structure , wherein R is independently cyano; a halogen; hydrogen; Cf-Ce unsubstituted or substituted alkyl; C 2 -C 6 unsubstituted or substituted alkenyl; C0 2 R 2 .
  • R ⁇ is C.-Ce unsubstituted or substituted alkyl; CONR 3 R 4 , wherein R 3 and R 4 are independently hydrogen or C C 6 unsubstituted or substituted alkyl; and COR5, wherein R 5 is hydrogen or C 1 -C-6 unsubstituted or substituted alkyl; wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; and wherein X is a halogen or OS0 2 R 6 , wherein R$ is independently C C 6 unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; [0101] (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1 ); and
  • the invention provides, a method for the
  • R is as defined above and wherein Ar is independently monosubstituted phenyl, said monosubstituted phenyl substituted at the 2, 3, or 4 position; dichloro, dibrom ⁇ , dimethyl, or chloro and methyl disubstituted phenyl, said disubstituted phenyl substituted at the 2 and 3 or 2 and 4 positions; and 2, 4, 5 trichlorophenyl.
  • Ar is independently monosubstituted phenyl, said monosubstituted phenyl substituted at the 2, 3, or 4 position; dichloro, dibrom ⁇ , dimethyl, or chloro and methyl disubstituted phenyl, said disubstituted phenyl substituted at the 2 and 3 or 2 and 4 positions; and 2, 4, 5 trichlorophenyl.
  • Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl.
  • the cyano derivative produced by this method can be converted other indazole derivatives, including derivatives containing functional groups such as, for example, C0 2 H or CONH 2 , by methods known in the art (see, for example, Palazzo et a)., supra; Corsi et al., supra; and Silvestreni et al., supra). [0107] In one embodiment, the methods of the invention are practiced
  • the alkylation step of the synthetic methods of the invention is conducted at temperatures below the refluxing temperature of the solvent in the reaction mixture. In one embodiment, this step is performed at temperatures below 100°C, in another embodiment, this step is performed at room temperature or below room temperature.
  • the alkylation step employs a base selected from the group consisting of metal hydrides; metal or quaternary ammonium hydroxides or alkoxides; amides; primary or secondary amides; and hexaalkyldisylazides.
  • strong bases that are insoluble in the solvent used are employed, and the temperature of the alkylation step is below the refluxing temperature of the solvent in the reaction mixture,
  • the solvents employed in the alkylation step are dipolar aprotic solvents.
  • the solvents used are selected from the group consisting of acetone, 2-butanone, cyclopentanone, cyclohexanone, dimethylf ⁇ r amide, dimethylsulfoxide, acetonitriie, and tetrahydrofuran.
  • the temperature of the alkylation step is a temperature at which the solvent in the reaction mixture is not refluxing.
  • the solvent is acetone, and the temperature of the alkylation step is at or about the refluxing temperature of the mixture.
  • the base used for the alkylation reaction is a metal carbonate base having the formula M n (C ⁇ 3) q , wherein M is a metal, and wherein n and q can have values from 1-10.
  • examples of such bases include, but are not limited to, K 2 C0 3 , Na 2 C0 3 , Cs 2 C0 3 , Li 2 C0 3 and CaC0 3 .
  • a metal carbonate base such as K2CO3, a 2 C03, or Cs 2 C0 3
  • an aprotic dipolar solvent such as acetone, acetonitriie, dimethylforma ide, or dimethyisu.f x.de
  • the alkylation step employing a metal carbonate base and an aprotic dipolar solvent is performed at temperatures below 100°C.
  • the alkylation step is performed at or below room temperature.
  • the solvent of crystallization is a solvent such as an ester solvent or an alcoholic solvent.
  • the solvent of crystallization is selected from the group consisting of ethyl acetate, ethanol, and acetic acid.
  • lonidamine having purity of 99.97% or more
  • indazole-3-carboxylic acid is converted into lonidamine employing a solvent other than water, as shown in Scheme 5 below.
  • indazole-3-carboxylic acid is converted into lonidamine employing a dipolar aprotic solvent such as dimethylformamide (DMF) as solvent, as shown in Scheme 5 below.
  • DMF dimethylformamide
  • reaction mixture was diluted with 500 mL ethyl acetate and filtered. The filtrate was washed with brine (3x100 mL) and the solvent removed under vacuum. The residue was taken up into hot ethyl acetate and product D crystallized as a white solid (13 g, 0.039 mole, 68% yield).
  • the crude product was filtered from the mixture and collected as a white solid after washing with water (12.5 g, 100% yield).
  • the pure product E can be obtained by either crystallization from hot ethanol (2 g /
  • Example 2 Alkylation of 1 -H-indazole-3-carbbxylic esters in acetone using K 2 C0 3 as the base
  • Example 4 Alkylation of 1-H-indazole-3-carboxyl/c acid in DMF using NaH as the base
  • Example 5 Instructions for the Synthesis of Lonidamine [0130]
  • This example illustrates a step-by-step process for synthesis of lonidamine in accordance with one embodiment of the invention.
  • the bolded letters following compounds designated in the process refer to the compounds designated by letter in Table 1 above.
  • 1. To prepare a saturated sodium chloride solution, dissolve 60 g sodium chloride in 300 mL water. Use the supernatant for the process. 2. To prepare 1N sodium hydroxide solution, dissolve 10 g sodium hydroxide in 250 mL water. 3. Set up a round-bottomed flask (500-mL) with stirrer and reflux condenser. 4.

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Abstract

Methods are provided for making highly pure preparations of lonidamine and related indazole derivatives.

Description

PATENT APPLICATION
METHOD FOR SYNTHESIS OF LONIDAMINE AND RELATED INDAZOLE DERIVATIVES
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims benefit under 35 U.S.C. 119 of provisional application No. 60/588,694, filed July 15, 2004, and provisional application No. 60/576,968, filed June 3, 2004, the disclosures of each of which are incorporated herein by reference.
FIELD OF THE INVENTION [0002] The present invention provides methods for making lonidamine and related indazole derivatives. The invention relates to the fields of chemistry, biology, pharmacology and medicine.
BACKGROUND OF THE INVENTION [0003] Lonidamine (1a) has been used in cancer therapy. Lonidamine analogs and pharmaceutical formulations of lonidamine and its analogs, as well as methods for their use in treating cancer are described in U.S. Patent Nos. 3,895,026; 6,001,865; 6336,087; 6,319,517; each of which is incorporated herein by reference. Lonidamine and its analogs have also been found to be active as anti-spermatogenic agents (US patents Palazzo et al. 3,895,026 and Silvestrini et al. 6,001,865, each of which is incorporated herein by reference). For use in a drug product, lonidamine and its analogs need to be prepared in a pure form Other therapeutic uses of lonidamine and its analogs, including for the treatment of benign prostatic hyperplasia, are described in co-pending, commonly assigned, U.S. patent application Serial No. 10/759,337, filed 16 Jan. 2004, incorporated herein by reference. [0004] Lonidamine (1a) and its analogs have been synthesized via alkylation of the indazole moiety with the appropriate benzylic halides (Palazzo and Silvestrini et al.). In one approach, indazole-3-carboxylic acid (2) was reacted with 3 equivalents of aqueous NaOH and approximately 1 equivalent of a benzylic halide (3a-b) (Scheme 1). Carboxyiic acid 2 was a contaminant in the product that had to be removed by laborious extraction with aqueous NaOH (Corsi et al. 1976, J. Med. Chem., 19(6): 778, incorporated herein by reference. See page 779).
Figure imgf000003_0001
2H 3 a. Ar = 2,4- iclιlorop enyl la. Ar = 2,4-dichlorophenyl 3b. Ar = 4-chlorophenyl
Scheme 1 [0005] In other synthetic methods described in Palazzo et al. as well as
Corsi et al. (supra), the synthesis of lonidamine and its analogs is divided into multiple steps (Scheme 2). In these multi-step syntheses, one of the steps is the alkylation of an indazole moiety possessing a precursor of the 3-carboxyl group. The transformation of the ester or cyano precursor into the carboxyiic acid is performed following acidic or alkaline hydrolysis. The esters can be synthesized in one step reactions from commercial material. Some of these approaches are illustrated in Scheme 2 below.
Figure imgf000003_0002
4a. R = CN Ar = 4-chlorophenyl 5a. R: CN 4b. R= C02Et 5b. R : CO2Et
Scheme 2 [0006] In one approach 3-cyano-1 H-indazole (4a) was alkylated with a benzylic halide in the presence of NaOEt in refluxing anhydrous ethanol to yield 5a. The cyano group of 5a was hydrolyzed in aqueous alkali to yield the 1-N-alkylated indazole-3-carboxylic acid.
[0007] Also, the ethyl ester (4b) of indazole-3-carboxylic acid has been subjected to alkylations, including with 4-chlorobenzylchloride as the alkylator. In one example, the base was aNH2 and the solvent xylene, and the reaction was conducted at temperatures between 100 and 135°C. With 4b as starting material, a synthetic route utilizing NaOEt as the base in refluxing EtOH has been described. Yet another method employing NaH as the base, in refluxing dioxane, has also been described. The benzylated indazole caroboxylic acid esters, like 5b, and the carboxyiic acids derived from them were isolated upon crystallization.
[0008] Compounds like 1 have been made using 5,6,7,8- tetrahydroindazoles as starting materials (Scheme 3). Alkylation of such a tetrahydroindazole-3-carboxylic acid with the necessary benzylic halide, followed by dehydrogenation using Pd or S, and hydrolysis, yields the desired indazole derivatives (see Palazzo and Corsi et al., supra).
Figure imgf000004_0001
R
4,5,6,7-tetrahydroindazole -carboxyiic acid
Scheme 3 [0009] The aqueous reaction condition (Scheme 1) did not reliably produce the desired products, as indicated by the following statement from Corsi et al., supra: Ali the new 1 -substituted 1 H-indazole-3-carboxyiic acids were prepared by two methods. The first one consisted of the direct alkylation of the corresponding 1 H-indazole-3-carboxyIic acids with a benzyl halide in aqueous sodium hydroxide. en this method failed, a second one was used in which the benzylation was carried out on the ethyl ester in an ethanol or dioxane solution.
[0010] The non-aqueous methods, recommended in cases where the aqueous method failed, are carried out at temperatures where the reaction mixture is refluxed or a high temperature, for example, 135°C, is maintained.
In all the methods described above the bases used were very strong, like
NaOEt, NaNH or NaH, with the conjugate acids having a pKa 15. The combination of high temperatures and strong bases leads to formation of byproducts. Strong bases are also highly sensitive to moisture, a common atmospheric constituent. Such combination with moisture forms hydroxide anion and can lead to hydrolysis of the intermediates. [0011] There remains a need for new methods for preparing lonidamine and its analogs in highly pure form. The present invention meets this need.
SUMMARY OF THE INVENTION [0012] In one aspect, the present invention provides a method for synthesizing 1-alkylated indazole-3-carboxylic acid, said method comprising the steps of:
[0013] (1) performing an alkylation reaction between ArCH2-X and indazole-3-carboxylic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; and X is a halogen or OS02R6; wherein Re is independently d-Ce unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl;
[0014] (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1);
[0015] (3) crystallizing a first 1-alkylated indazole-3-carboxylic acid precursor from said mixture resulting from step (1) or (2);
[0016] (4) reacting, if necessary, said first precursor, to yield a second precursor, said second precursor hydrolyzable or oxidizable to said 1- alkylated indazole-3-carboxylic acid;
[0017] (5) hydrolyzing or oxidizing said 1-alkylated indazole-3- carboxylic acid precursor resulting from step (3) or (4) to yield 1-alkylated indazoie-3-carboxylic acid; and
[0018] (6) recrystallizing said 1-alkylated indazole-3-carboxylic acid.
[0019] A method for synthesizing 1-alkylated indazoIe-3-carboxylic acid, said method comprising the steps of: [0020] (1) performing an alkylation reaction between ArCH2-X and indazole-3-carboxylic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; and X is a halogen or OSO2R6; wherein R6 is independently C C6 unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl;
[0021] (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1 );
[0022] (3) crystallizing a 1-alkylated indazole-3-carboxylic acid precursor from said mixture resulting from step (1) or (2);
[0023] (4) hydrolyzing or oxidizing said 1-alkylated indazole-3- carboxylic acid precursor resulting from step (3) to yield 1-alkylated indazole- 3-carboxylic acid; and
[0024] (5) recrystallizing said 1-alkylated indazole-3-carboxylic acid. /
[0025] In one aspect, the present invention provides a method for synthesizing lonidamine, said method comprising the steps of:
[0026] (1) performing an alkylation reaction between 2,4- dichlorobenzyl-X and an indazole derivative in presence of a base and in a solvent for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein:
said indazole derivative has a structure
Figure imgf000006_0001
, wherein R is independently cyano; a halogen; hydrogen; CrC6 unsubstituted or substituted alkyl; C2-Ce unsubstituted or substituted alkenyl; CO2R2, wherein R2 is C-ι-C6 unsubstituted or substituted alkyl; C NR3R4, wherein R3 and R4 are independently hydrogen or Ci-Cβ unsubstituted or substituted alkyl; and CORs, wherein R5 is hydrogen or C-I- Θ unsubstituted or substituted alkyl; and X is a halogen or OS02R6, wherein Re is independently C Cβ unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl;
[0.027] (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1);
[0028] (3) crystallizing a first lonidamine precursor having a
structure
Figure imgf000007_0001
, wherein Ar and R are as defined above, from said mixture resulting from step (1) or (2);
[0029] (4) reacting, if necessary, said first precursor, to yield a second precursor, said second precursor hydrolyzable or oxidizable to said lonidamine;
[0030] (5) hydrolyzing or oxidizing said first or second lonidamine precursor resulting from step (3) or (4) to yield lonidamine; and
[0031] (6) recrystallizing said lonidamine.
[0032] In one aspect, the present invention provides a method for synthesizing lonidamine, said method comprising the steps of:
[0033] (1) performing an alkylation reaction between 2,4- dichlorobenzyl-X and an indazole derivative in presence of a base and in a solvent for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein:
said indazole derivative has a structure
Figure imgf000007_0002
, wherein R is independently cyano; CrCβ unsubstituted or substituted alkyl; C2-C6 unsubstituted or substituted alkenyl; CO2R2. wherein R2 is Cι-C6 unsubstituted or substituted alkyl; CONR3R4, wherein R3 and R4 are independently hydrogen or C-i-Cβ unsubstituted or substituted alkyl; and COR5, wherein R5 is hydrogen or Cι-C6 unsubstituted or substituted alkyl; and X is a halogen or OS02Rδ, wherein Re is independently C Ce unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; [0034] (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1 ); (3) crystallizing a lonidamine precursor having a structure
Figure imgf000008_0001
, wherein Ar and R are as defined above, from said mixture resulting from step (1) or (2);
[0036] (4) hydrolyzing or oxidizing said lonidamine precursor resulting from step (3) to yield lonidamine; and [0037] (5) recrystallizing said lonidamine.
[0038] In one aspect, the present invention provides a method for synthesizing 1-alkylated indazole-3-carboxylic acids, said method comprising the steps of:
[0039] (1) performing an alkylation reaction between ArCH2-X and indazole-3-carboxylic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent mixture, one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein: Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; X is a halogen or OS02Rβ, wherein Re is independently C-i-Ce unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; [0040] (2) acidifying said reaction mixture; and
[0041] (3) crystallizing 1-alkylated indazole-3-carboxylic acids.
[0042] In one embodiment, the present invention provides a method for synthesis of lonidamine, said method comprising the steps of: [0043] (1) performing an alkylation reaction between 2,4- dichlorobenzyl-X and indazole-3 carboxyiic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein, X is as defined above; [0044] (2) acidifying said reaction mixture; and
[0045] (3) crystallizing lonidamine.
[0046] In one aspect, the invention provides a method for the synthesis of 1-alkylated indazole-3-carboxylic acids, said method comprising the steps of: [0047] (1) performing an alkylation reaction between ArCH2-X and indazole-3-carboxylic acid or a salt thereof, in presence of a base and a phase transfer agent in a biphasic solvent, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; and X is a halogen or OS02R6, wherein Re is independently Ci-Ce unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; [0048] (2) acidifying said reaction mixture; and
[0049] (3) crystallizing 1-alkylated indazole-3-carboxylic acids.
[0050] In one embodiment, the present invention provides a method for synthesizing lonidamine, said method comprising the steps of: [0051] (1) performing an alkylation reaction between 2,4- dichlorobenzyl-X and indazole-3-carboxylic acid or a salt thereof in presence of a base and a phase transfer agent, in a biphasic solvent, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein X is as defined above; [0052] (2) acidifying said reaction mixture; and
[0053] (3) crystallizing lonidamine.
[0054] In another aspect, the present invention provides a method in which lonidamine, which has been synthesized by alkylation, is crystallized from a solvent. In one embodiment, the invention provides a method of slow crystallization of lonidamine from acetic acid (AcOH) that can yield lonidamine at 99.97% or greater purity. In one embodiment, the invention provides a relatively faster crystallization from AcOH that can yield lonidamine at 99.32% or greater purity. In one embodiment, the invention provides a method for the crystallization of lonidamine from EtOH that can yield lonidamine at 99.49% or greater purity.
[0055] In another aspect, the invention provides a method for synthesizing indazole derivatives, said method comprising the steps of: [0056] (1) performing an alkylation reaction between ArCH2-X and an indazole derivative in presence of a base and in a solvent for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein: said indazole derivative has a structure
Figure imgf000010_0001
, wherein R is independently cyano; a halogen; hydrogen; C C6 unsubstituted or substituted alkyl; C2-Ce unsubstituted or substituted alkenyl; C02R2, wherein R2 is Cι-C6 unsubstituted or substituted alkyl; CONR3R4, wherein R3 and R4 are independently hydrogen or C-t-Cβ unsubstituted or substituted alkyl; and COR5, wherein R5 is hydrogen or C-i-Ce unsubstituted or substituted alkyl; wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; and wherein X is a halogen or OS02R6, wherein Re is independently Ci-Cβ unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; [0057] (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1); and
[0058] (3) crystallizing a compound having a structure
Figure imgf000010_0002
wherein Ar and R are as defined above, from said mixture resulting from step
(2).
[0059] Thus, this invention provides methods for the synthesis of lonidamine and other indazole derivatives, as described in more detail in the following section.
DETAILED DESCRIPTION OF THE INVENTION [0060] As used herein, "pKa" is the negative logarithm of the acid dissociation constant, Ka, in water.
[0061] As used herein, "a dipolar aprotic" solvent is a solvent with a comparatively high relative permittivity (or dielectric constant), greater than approximately 15, and a sizable permanent dipole moment, that cannot donate hydrogen atoms to form strong hydrogen bonds. [0062] As used herein, a "base" is molecule or an ion that can act as an acceptor of proton.
[0063] As used herein, a "heteroatom," is oxygen, sulfur or nitrogen. [0064] As used herein, "CrC6 alkyl," is any aliphatic group containing 1 to 6 carbon atoms, and hydrogen, including, straight chain, branched chain, cyclic, carbocycle containing and substituted alkyl groups, and substituted alkyl us an alkyl substituted with one or more heteroatom containing groups. [0065] As used herein, "C2-C6 alkenyl" refers to straight or branched chain alkene groups having 2 to 6 carbon atoms. Within an alkenyl group, one or more unsaturated carbon-carbon double bonds are present, and may occur at any stable point along the chain (e.g., ethenyl, ally! and isopropenyl). [0066] As used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine.
[0067] As used herein, a "precursor" to a functional group-1 is defined as a moiety or a functional group~2 which can be converted into functional group-1 in one step or a combination of steps. For example, "precursors" to a carboxyl group include but are not limited to cyano, ester, CH OH, COCH3, CHO, any halogen atom, ethenyl and Ph.
[0068] Lonidamine is the generic name for 1-(2,4-dichlorobenzyl)-1H- indazole-3-carboxylic acid, and has also been referred to in the literature as 1- [(2,4-dichlorophenyl)methyl]-1 H-indazole-3-carboxylic acid, AF1890, diclondazolic acid (DICA), and Dorida ina™ (ACRAF). [0069] In one aspect, the present invention provides a method for synthesizing lonidamine, said method comprising the steps of: [0070] (1) performing an alkylation reaction between 2,4- dichlorobenzyl-X and an indazole derivative in presence of a base and in a solvent for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein:
said indazole derivative has a structure
Figure imgf000011_0001
, wherein R is independently cyano; a halogen; hydrogen; C C6 unsubstituted or substituted alkyl; C2-Cδ unsubstituted or substituted alkenyl; C02R2, wherein R2 is C-i-C. unsubstituted or substituted alkyl; C NR3R4, wherein R3 and R4 are independently hydrogen or C Cβ unsubstituted or substituted alkyl; and COR5, wherein R5 is hydrogen or C1.-C6 unsubstituted or substituted alkyl; and X is a halogen or OS02R6, wherein R6 is independently CI-CQ unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl;
[0071] (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1);
[0072] (3) crystallizing a first lonidamine precursor having a
structure
Figure imgf000012_0001
, wherein Ar and R are as defined above, from said mixture resulting from step (1) or (2);
[0073] (4) reacting, if necessary, said first precursor, to yield a second precursor, said second precursor hydrolyzable or oxidizable to said lonidamine;
[0074] (5) hydrolyzing or oxidizing said first or second lonidamine precursor resulting from step (3) or (4) to yield lonidamine; and
[0075] (6) recrystallizing said lonidamine.
[0076] In one aspect, the invention provides a method for the synthesis of lonidamine, said method comprising the steps of:
[0077] (1) performing an alkylation reaction between 2,4- dichlorobenzyl-X and an indazole derivative in presence of a base and in a solvent for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein:
said indazole derivative has a structure
Figure imgf000012_0002
, wherein R is independently cyano; C Cβ unsubstituted or substituted alkyl; C2-C6 unsubstituted or substituted alkenyl; C02R2, wherein R2 is Cι-C6 unsubstituted or substituted alkyl; CONR3R4, wherein R3 and R4 are independently hydrogen or C Ce unsubstituted or substituted alkyl; and COR5, wherein R5 is hydrogen or Cι-C6 unsubstituted or substituted alkyl; and X is a halogen or OS02R6; wherein R6 is independently C C6 unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; [0078] (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1);
[0079] (3) crystallizing a lonidamine precursor having a structure
Figure imgf000013_0001
wherein Ar and R are as defined above, from said mixture resulting from step (1) or (2);
[0080] (4) hydrolyzing or oxidizing said lonidamine precursor resulting from step (3) to yield lonidamine; and [0081] (5) recrystallizing said lonidamine.
[0082] In one aspect, the present invention provides a method for synthesizing 1-alkylated indazole-3-carboxylic acids, said method comprising the steps of:
[0083] (1) performing an alkylation reaction between ArCH2~X and indazole-3-carboxylic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; wherein X is a halogen or OS02Rβ, wherein R6 is independently C-ι-C6 unsubstituted or substituted alkyl; unsubstituted or substituted ary); and unsubstituted or substituted heteroaryl; [0084] (2) acidifying said reaction mixture; and
[0085] (3) crystallizing 1-alkylated indazole-3-carboxylic acids.
[00863 In one embodiment, said invention provides a method for the synthesis of lonidamine, said method comprising the steps of: [0087] (1) performing an alkylation reaction between 2,4- dichlorobenzy(-X and indazole-3 carboxyiic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein, X is as defined above; [0088] (2) acidifying said reaction mixture; and
[0089] (3) crystallizing lonidamine. [0090] In another aspect, the invention provides a method for the synthesis of 1-alkylated indazole-3-carboxylic acids, said method comprising the steps of:
[00913 (1) performing an alkylation reaction between ArCH2-X and indazole-3-carboxylic acid or a salt thereof, in presence of a base and a phase transfer agent in a biphasic solvent, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; wherein X is a halogen or OS02R6, wherein Re is independently C-i-Cβ unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl;
[0092] (2) acidifying said reaction mixture; and
[0093] (3) crystallizing 1-alkylated indazole-3-carboxylic acids.
[0094] In another emobodiment, the invention provides a method for the synthesis of lonidamine, said method comprising the steps of:
[0095] (1) performing an alkylation reaction between 2,4- dichiorobenzyl-X and indazole-3-carboxylic acid or a salt thereof, in presence of a base and a phase transfer agent in a biphasic solvent, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein X is as defined above;
[0096] (2) acidifying said reaction mixture", and
[0097] (3) crystallizing 1-alkylated indazole-3-carboxylic acids.
[0098] In another aspect, the present invention provides a method wherein lonidamine, which has been synthesized by a process employing an alkylation step, is crystallized from a solvent. In one embodiment, the invention provides a method for the slow crystallization of lonidamine from acetic acid (AcOH) that can yield lonidamine at 99.97% or greater purity. In another embodiment, the invention provides a relatively faster crystallization of lonidamine from AcOH that can yield lonidamine at 99.32% or greater purity. In another embodiment, the invention provides a method for the crystallization of lonidamine from ethanol (EtOH) that can yield lonidamine at
99.49% or greater purity.
[0099] In another aspect, the invention provides a method for synthesizing indazole derivatives, said method comprising the steps of: [0100] (1) performing an aikyiation reaction between ArCH2-X and an indazole derivative in presence of a base and in a solvent for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein:
said indazole derivative has a structure
Figure imgf000015_0001
, wherein R is independently cyano; a halogen; hydrogen; Cf-Ce unsubstituted or substituted alkyl; C2-C6 unsubstituted or substituted alkenyl; C02R2. wherein R≥ is C.-Ce unsubstituted or substituted alkyl; CONR3R4, wherein R3 and R4 are independently hydrogen or C C6 unsubstituted or substituted alkyl; and COR5, wherein R5 is hydrogen or C1-C-6 unsubstituted or substituted alkyl; wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; and wherein X is a halogen or OS02R6, wherein R$ is independently C C6 unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; [0101] (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1 ); and
[0102] (3) crystallizing a compound having a structure
Figure imgf000015_0002
wherein Ar and R are as defined above, from said mixture resulting from step
(2).
[0103] In one embodiment, the invention provides, a method for the
Figure imgf000015_0003
synthesis of an indazole derivative R , wherein, R is as defined above and wherein Ar is independently monosubstituted phenyl, said monosubstituted phenyl substituted at the 2, 3, or 4 position; dichloro, dibromσ, dimethyl, or chloro and methyl disubstituted phenyl, said disubstituted phenyl substituted at the 2 and 3 or 2 and 4 positions; and 2, 4, 5 trichlorophenyl. [0104] In one embodiment, the methods of the invention are used to
Figure imgf000016_0001
synthesize an indazole derivative having the structure R , wherein R is the carboxylate anion of formula -COO", and wherein the indazole derivative is associated with a counter ion, Z+, wherein Z+ is a pharmaceutically acceptable cation.
[0105] In one embodiment, the methods of the invention are used to
synthesize an indazole derivative
Figure imgf000016_0002
, wherein Ar is as defined above, and wherein R is independently -COOH; -CONH2; ~CONHNH2; - CONHN(CH3)2; -CH2CH2OH; -CH2CH(OH)CH2OH; or CH2(CH2OH)2; - CH2COOH; and -CH=CH-C02H. [0106] In one embodiment, the methods of the invention are used to
synthesize a lonidamine derivative having the structure
Figure imgf000016_0003
, wherein
Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl. The cyano derivative produced by this method can be converted other indazole derivatives, including derivatives containing functional groups such as, for example, C02H or CONH2, by methods known in the art (see, for example, Palazzo et a)., supra; Corsi et al., supra; and Silvestreni et al., supra). [0107] In one embodiment, the methods of the invention are practiced
using a starting material having the structure
Figure imgf000016_0004
2R2> wherein R2 is as defined above. In one embodiment, R2 is methyl or ethyl. [0108] In one embodiment, the alkylation step of the synthetic methods of the invention is conducted at temperatures below the refluxing temperature of the solvent in the reaction mixture. In one embodiment, this step is performed at temperatures below 100°C, in another embodiment, this step is performed at room temperature or below room temperature. In one embodiment, the alkylation step employs a base selected from the group consisting of metal hydrides; metal or quaternary ammonium hydroxides or alkoxides; amides; primary or secondary amides; and hexaalkyldisylazides. In another embodiment, strong bases that are insoluble in the solvent used are employed, and the temperature of the alkylation step is below the refluxing temperature of the solvent in the reaction mixture,
[0109] In one embodiment, the solvents employed in the alkylation step are dipolar aprotic solvents. In one embodiment, the solvents used are selected from the group consisting of acetone, 2-butanone, cyclopentanone, cyclohexanone, dimethylfαr amide, dimethylsulfoxide, acetonitriie, and tetrahydrofuran. In one embodiment, the temperature of the alkylation step is a temperature at which the solvent in the reaction mixture is not refluxing. In another embodiment, the solvent is acetone, and the temperature of the alkylation step is at or about the refluxing temperature of the mixture. [0110] In one embodiment, the base used for the alkylation reaction is a metal carbonate base having the formula Mn(Cθ3)q, wherein M is a metal, and wherein n and q can have values from 1-10. Examples of such bases include, but are not limited to, K2C03, Na2C03, Cs2C03, Li2C03 and CaC03. [0111] In one embodiment, a metal carbonate base, such as K2CO3, a2C03, or Cs2C03, and an aprotic dipolar solvent, such as acetone, acetonitriie, dimethylforma ide, or dimethyisu.f x.de is employed for the alkylation step. In one embodiment, the alkylation step employing a metal carbonate base and an aprotic dipolar solvent is performed at temperatures below 100°C. In another embodiment, the alkylation step is performed at or below room temperature. An important step in the isolation of pure product in accordance with certain methods of the invention is the crystallization of crude reaction product. In one embodiment of the invention, the solvent of crystallization is a solvent such as an ester solvent or an alcoholic solvent. In one embodiment, the solvent of crystallization is selected from the group consisting of ethyl acetate, ethanol, and acetic acid. [0112] In one embodiment, lonidamine having purity of 99.97% or more
is synthesized starting from
Figure imgf000018_0001
a e,
[0113] In one embodiment of the invention, methods for converting lonidamine precursors into lonidamine are provided in which hydrolysis and/or oxidation steps are employed in the synthesis. Exemplary syntheses employing such steps are shown in scheme 4 below:
Figure imgf000018_0002
Scheme 4
[0114] In one embodiment of the invention, indazole-3-carboxylic acid is converted into lonidamine employing a solvent other than water, as shown in Scheme 5 below. In another embodiment, indazole-3-carboxylic acid is converted into lonidamine employing a dipolar aprotic solvent such as dimethylformamide (DMF) as solvent, as shown in Scheme 5 below.
Ar, Cf CQ2H
Figure imgf000018_0003
ArCH2Cl Scheme 5 [0115] These and other embodiments of the Invention are exemplified in the examples below. EXAMPLES Example 1 : Synthesis of lonidamine [0116] Lonidamine was prepared in three steps from lndazole-3- carboxylic acid in 33% overall yield according to the following procedure described in this example: [0117] The following solvents and reagents, all of which were of ACS reagent grade, were used: glacial acetic acid, acetone, ethanol (95%), ethyl acetate, concentrated hydrochloric acid, methanol, potassium carbonate, sodium chloride solution, 1 molar sodium hydroxide and sulfuric acid. Table 1 shows the structures of certain compounds used in the example.
Table 1
Figure imgf000019_0001
[0118] The reactions employed in this example can be depicted in a series of steps, as shown below.
Step l
H3
Figure imgf000020_0001
B
Step 2
Figure imgf000021_0001
reflux
Figure imgf000021_0002
CH3 B C D
Figure imgf000021_0003
D E
[0119] These steps, schematically illustrated above, are described in more detail below.
Step 1
[0120] A 500 mL round-bottomed flask was charged sequentially with A
(20 g, 0.12 mole), methanol (350 mL), and H2S04 (50 mL). The mixture was heated at reflux with stirring by magnetic stirrer for 10 hrs. The reaction was monitored by TLC on silica gel plates.
[0121] Upon complete consumption of A, the mixture was poured into ice water (1 L) and methyl ester precipitated out as light yellow solid. White crystals of the product B (10 g, 0.057 mole, 48% yield) were obtained by recrystallization from ethyl acetate. Step 2
[0122] A mixture of B (10 g, 0.057 mole), C (11 g), potassium carbonate (15 g), and acetone (350 L) was heated at reflux for 5 hrs with stirring by magnetic stirrer in a 500 mL round-bottomed flask. The reaction was monitored by TLC on silica gel plates.
[0123] The reaction mixture was diluted with 500 mL ethyl acetate and filtered. The filtrate was washed with brine (3x100 mL) and the solvent removed under vacuum. The residue was taken up into hot ethyl acetate and product D crystallized as a white solid (13 g, 0.039 mole, 68% yield).
Step 3
[0124] A mixture of D (13 g, 0.039 mole), sodium hydroxide solution
(1 , 250 mL), and methanol (250 mL) was heated at 60 °C for 18 hr. The reaction was monitored by TLC on silica gel plates.
[0125] The reaction mixture was acidified to pH = 1 and stirred at room temperature for 30 min. The crude product was filtered from the mixture and collected as a white solid after washing with water (12.5 g, 100% yield). The pure product E can be obtained by either crystallization from hot ethanol (2 g /
10 mL) or from hot glacial acetic acid (10 g / 200 mL).
Example 2: Alkylation of 1 -H-indazole-3-carbbxylic esters in acetone using K2C03 as the base
[0126] One equivalent of the 1-H-indazole-3-carboxylic ester, 1 equivalent of the benzylic halide ArCH2-X and 2 equivalents of K2CO3 are reacted in anhydrous acetone at room temperature, and the reaction is monitored by TLC. When the starting ester is completely consumed (this may require additional halide) the insoluble part is filtered off and volatiles removed in a rotary evaporator to yield a solid. Pure product is obtained upon recrystallization from ethyl acetate.
[0127] The resulting ester is hydrolyzed using aqueous or methanolic
KOH to yield the carboxyiic acid. The conversion of this carboxyiic acid to a number of lonidamine analogs can be accomplished by methods known in the art (see Palazzo et al., supra; Corsi et al., supra; and Silvestreni et al., supra, each of which is incorporated herein by reference). Example 3: Alkylation of methyl 1-H-indazole-3-carboxyIate in DMF using K2C03 as the base
[0128] A mixture of 1 equivalent of methyl 1-H-indazole-3-carboxylate acid, 1 equivalent of 2,4-dichlorobenzylchloride, and 2 equivalent of K2C03 are reacted in anhydrous dimethylformamide (DMF) at room-temperature. After filtering to remove the base, the reaction mixture is poured into water. The precipitated solid is isolated by filtration, dried in vacuo, and recrystallized from ethyl acetate to yield the pure ester. The ester-precursor to lonidamine is hydrolyzed to yield lonidamine.
Example 4: Alkylation of 1-H-indazole-3-carboxyl/c acid in DMF using NaH as the base
[0129] To a mixture of 1 equivalent of 1-H-indazole-3-carboxylic acid in
DMF kept at 0°C is added 2 equivalent of NaH and said mixture stirred for 30 minutes. 1 equivalent of 2,4-dichlorobenzylchloride dissolved in DMF was added dropwise into the reaction mixture. After ascertaining the completion of the alkylation by TLC, the reaction mixture was added into dilute aqueous hydrochloric acid. The precipitated solid is filtered off, dried in vacuo and recrystallized from acetic acid to yield the pure 1-alkylated indazole-3- carboxylic ester.
Example 5: Instructions for the Synthesis of Lonidamine [0130] This example illustrates a step-by-step process for synthesis of lonidamine in accordance with one embodiment of the invention. The bolded letters following compounds designated in the process refer to the compounds designated by letter in Table 1 above. 1. To prepare a saturated sodium chloride solution, dissolve 60 g sodium chloride in 300 mL water. Use the supernatant for the process. 2. To prepare 1N sodium hydroxide solution, dissolve 10 g sodium hydroxide in 250 mL water. 3. Set up a round-bottomed flask (500-mL) with stirrer and reflux condenser. 4. Add 20 g indazole-3-carboxylic acid, 350 mL methanol and 50 mL sulfuric acid. 5. Heat the reaction mixture to reflux and stir for about 10 hours. Monitor the reaction by TLC on silica gel plates developed with methylene chloride. lndazole-3-carboxylic acid; Rf = 0.0 lndazole-3-carboxy(ic acid, methyl ester; Rf = 0.5 6 Pour the mixture into 1 L ice water to form the light yellow precipitate. > 7 Filter the crude product and transfer into 100 mL hot ethyl acetate (90-100°C). 8. Add 1 g decolorizing charcoal to the hot solution. Stir for about 30 minutes. 9. Filter the discolored mixture and cool the filtrate to room temperature yielding white crystalline. 10. Filter to collect the white product (B). 11. Set up a round-bottomed flask (500-mL) with stirrer and reflux condenser. 12. Add 10 g indazole-3-carboxylic acid, methyl ester (B) and 11 g dichlorobenzyl chloride. 13. Add 15 g potassium carbonate and 350 mL acetone. 14 Heat the reaction mixture to reflux and stir for about 5 hours. Monitor the reaction by TLC on silica gel plates developed with methylene chloride. lndazole-3-carboxy)ic acid, methyl ester (B), Rf = 0.5 1 -(2,4-Dichlorobenzyl)-1 H-indazole-3-carboxylic acid, methyl ester (D), Rf = 0.8 15. Add 500 mL ethyl acetate and stir the mixture for about 10 minutes. 16. Filter the mixture to remove insoluble solids. 17. Transfer the solution to a separate funnel and wash with 3 x 100 mL of saturated sodium chloride solution. 18. Add 1 g decoioring charcoal to the filtrate and stir for 30 minutes. 19. Filter the mixture and remove the solvent under vacuum resulting a white solid residue. 20. Add 100 mL hot ethyl acetate to dissolve the white residue. Cool to room temperature and a white crystal is precipitated out. 21. Collect the product 1-(2,4-dichlorobenzyl)-1H-indazole-3- carboxylic acid, methyl ester (D) by filtration. 22. Set up a round-bottomed flask (500 mL) with stirrer and reflux condenser. 23. Add 13 g 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid, methyl ester (D). 24. Add 250 mL sodium hydroxide solution and 150 mL methanol. 25. Heat the reaction mixture at 60°C and stir for about 18 hours. Monitor the reaction by TLC on silica gel plates developed with methylene chloride. 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid, methyl ester, R = 0.8; Lonidamine, Rf = 0.0. 26. Acidify the reaction mixture by adding hydrochloric acid to pH ~1 and stir for about 30 minutes. 27. Filter the reaction mixture to collect the product as white solid. 28. Wash the collected solid with water (3 x 500 mL). 29. Dissolve the white solid in hot glacial acetic acid (200 mL/10 g) and cool slowly to room temperature. 30. Collect the lonidamine product by filtration. 31. Place the product in a funnel with a sintered glass filter disc or suitable filter paper. 32. Wash the product with water (3 x 35 mL). Do not pull a vacuum on the funnel between washes (allows more thorough wash). 33. Apply a vacuum to the funnel to remove excess water. 34. Transfer the washed product to a container and dry under high vacuum at 80°C for at least 48 hours. The lonidamine product is obtained as a white solid. [0131] Although the present invention has been described in detail with reference to specific embodiments, those of skill in the art will recognize that modifications and improvements are within the scope and spirit of the invention, as set forth in the claims which follow. AH publications and patent documents (patents, published patent applications, and unpublished patent applications) cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any such document is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description and example, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples are for purposes of illustration and not limitation of the following claims.

Claims

1. A method for synthesizing 1 -alkylated indazole-3- carboxylic acid, said method comprising the steps of: (1 ) performing an alkylation reaction between ArCH2-X and indazole-3-carboxylic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; and X is a halogen or OSO2R6; wherein Re is independently Cι-C6 unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1 ); (3) crystallizing a first 1-alkylated indazole-3- carboxylic acid precursor from said mixture resulting from step (1) or (2); (4) reacting, if necessary, said first precursor, to yield a second precursor, said second precursor hydrolyzable or oxidizable to said 1-alkylated indazole-3-carboxylic acid; (5) hydrolyzing or oxidizing said 1-alkylated indazole- 3-carboxylic acid precursor resulting from step (3) or (4) to yield 1-alkylated indazole-3-carboxylic acid; and (6) recrystallizing said 1-alkylated indazole-3- carboxylic acid.
2. A method for synthesizing lonidamine, said method comprising the steps of: (1 ) performing an alkylation reaction between 2,4- dichlorobenzyl-X and an indazole derivative in presence of a base and in a solvent for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein: said indazole derivative has a structure
Figure imgf000028_0001
, wherein R is independently cyano; a halogen; hydrogen; Ci-Cβ unsubstituted or substituted alkyl; C2-C6 unsubstituted or substituted alkenyl; C02R2, wherein R2 is CrC6 unsubstituted or substituted alkyl; CONR3R4, wherein R3 and R4 are independently hydrogen or Ci-Cβ unsubstituted or substituted alkyl; and COR5, wherein R5 is hydrogen or Cι-C6 unsubstituted or substituted alkyl; and X is a halogen or OS02R6, wherein R6 is independently Ci-Cβ unsubstituted or substituted alkyl; and unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1 ); (3) crystallizing a first lonidamine precursor having a
structure
Figure imgf000028_0002
, from said mixture resulting from step (1 ) or (2); (4) reacting, if necessary, said first precursor, to yield a second precursor, said second precursor hydrolyzable or oxidizable to said lonidamine; (5) hydrolyzing or oxidizing said lonidamine precursor resulting from step (3) or (4) to yield lonidamine; and (6) recrystallizing said lonidamine.
3. A method for synthesizing 1-alkylated indazole-3- carboxylic acid, said method comprising the steps of: (1) performing an alkylation reaction between ArCH2-X and indazole-3-carboxylic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; and X is a halogen or OS02R6; wherein R6 is independently Cι-C6 unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1 ); (3) crystallizing a 1-alkylated indazole-3-carboxylic acid precursor from said mixture resulting from step (1) or (2); (4) hydrolyzing or oxidizing said 1-alkylated indazole- 3-carboxylic acid precursor resulting from step (3) to yield 1-alkylated indazole-3-carboxylic acid; and (5) recrystallizing said 1-alkylated indazole-3- carboxylic acid.
4. A method for synthesizing lonidamine, said method comprising the steps of: (1 ) performing an alkylation reaction between 2,4- dichlorobenzyl-X and an indazole derivative in presence of a base and in a solvent for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein:
said indazole derivative has a structure
Figure imgf000029_0001
, wherein R is independently cyano;
Figure imgf000029_0002
unsubstituted or substituted alkyl; C2-C6 unsubstituted or substituted alkenyl; C02R2, wherein R2 is CrC6 unsubstituted or substituted alkyl; CONR3R4, wherein R3 and R4 are independently hydrogen or Cι-C6 unsubstituted or substituted alkyl; and COR5, wherein R5 is hydrogen or Cι-C6 unsubstituted or substituted alkyl; and X is a halogen or OS02R6, wherein R6 is independently
Figure imgf000029_0003
unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1 ); (3) crystallizing a lonidamine precursor having a
Figure imgf000030_0001
structure R , from said mixture resulting from step (1 ) or (2); (4) hydrolyzing or oxidizing said lonidamine precursor resulting from step (3) to yield lonidamine; and (5) recrystallizing said lonidamine.
5. The method of claim 4, wherein said indazole derivative
has a structure
Figure imgf000030_0002
2Mej said 2,4-dichlorobenzyl-X is 2,4- dichlorobenzylchloride, said solvent is acetone, said base is K2C03, said temperature is the temperature wherein acetone refluxes in the mixture, said crystallization step (3) is performed employing ethyl acetate, said step (4) is a hydrolysis employing NaOH and MeOH, and said lonidamine resulting from step (5) is crystallized employing acetic acid.
6. A method for synthesizing 1-alkylated indazole-3- carboxylic acid, said method comprising the steps of: (1 ) performing an alkylation reaction between ArCH2-X and indazole-3-carboxylic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; and X is a halogen or OS02RΘ; wherein RQ is independently
Figure imgf000030_0003
unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; (2) acidifying said reaction mixture; and (3) crystallizing 1-alkylated indazole-3-carboxylic acid.
7. A method for synthesizing lonidamine, said method comprising the steps of: (1 ) performing an alkylation reaction between 2,4- dichlorobenzyl-X and indazole-3 carboxyiic acid or a salt thereof, in presence of a base, and in a solvent other than water, or a biphasic solvent one of which is water, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein, X is a halogen or OS02Rβ; (2) acidifying said reaction mixture; and (3) crystallizing lonidamine.
8. The method of claim 6, wherein for every molar equivalent of said ArCH2-X, a maximum of 1 equivalent of said indazole-3- carboxylic acid or a salt thereof, and a minimum of 2 equivalents of said base, are used.
9. The method of claim 8, wherein said solvent is selected from the group consisting of dimethylformamide, dimethylsulfoxide, and tetrahydrofuran.
10. The method of claim 7, wherein said temperature of step (1 ) is less than the refluxing temperature of the solvent in the reaction mixture, the solvent is a dipolar aprotic solvent and said base is independently a metal hydride, an amide or an alkoxide.
11. A method for synthesizing 1 -alkylated indazole-3- carboxylic acid, said method comprising the steps of: (1) performing an alkylation reaction between ArCH2- X and indazole-3-carboxylic acid or a salt thereof in presence of a base and a phase transfer agent in a biphasic solvent, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; X is a halogen or OS02R6, wherein R6 is independently d-Ce unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; (2) acidifying said reaction mixture; and (3) crystallizing said 1-alkylated indazole-3-carboxylic acid.
12. A method for synthesizing lonidamine, said method comprising the steps of: (1 ) performing an alkylation reaction between 2,4- dichlorobenzyl-X and indazole-3-carboxylic acid or a salt thereof in presence of a base and a phase transfer agent, in a biphasic solvent, for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein X is a halogen or OS02RΘ; (2) acidifying said reaction mixture; and (3) crystallizing lonidamine.
13. The method of claim 11 or claim 12, wherein said biphasic solvent comprises water and a second solvent.
14. The method of claim 13, wherein the second solvent is selected from the group consisting of dichloromethane, 1 ,2 dichloroethane, benzene, toluene, dioxane, and THF.
15. The method of claim 13, wherein the phase transfer agent is selected from the group consisting of a quaternary ammonium salt, a phosphonium salt, and a crown ether.
16. The method of claim 15 , wherein said phase transfer agent is selected from the group consisting of benzyltriethylammonium chloride, tetrabutylammonium iodide, and tetrabutylammonium bisulfate.
17. The method of claim 13, wherein said base is a metal hydroxide.
18. A method for synthesizing indazole derivatives, said method comprising the steps of: (1 ) performing an alkylation reaction between ArCH2- X and an indazole derivative in presence of a base and in a solvent for a sufficient time and at a temperature such that said reaction is greater than 90% complete, wherein: said indazole derivative has a structure
Figure imgf000033_0001
, wherein R is independently cyano; a halogen; hydrogen; Cι-C6 unsubstituted or substituted alkyl; C2-C6 unsubstituted or substituted alkenyl; C02R2, wherein R2 is Cι-C6 unsubstituted or substituted alkyl; CONR3R4, wherein R3 and R4 are independently hydrogen or Ci-Cβ unsubstituted or substituted alkyl; and COR5, wherein R5 is hydrogen or C Cβ unsubstituted or substituted alkyl; Ar is independently unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; and X is a halogen or OS02Rβ, wherein R6 is independently Ci-Cε unsubstituted or substituted alkyl; unsubstituted or substituted aryl; and unsubstituted or substituted heteroaryl; (2) removing insoluble materials, if any, from said reaction mixture resulting from step (1 ); and (3) crystallizing a compound having a structure
Figure imgf000033_0002
from said mixture resulting from step (2).
19. The method of claim 18, further comprising the step of hydrolyzing or oxidizing said indazole derivative resulting from step (3).
20. The method of claim 18, wherein said indazole derivative
has a structure
Figure imgf000034_0001
Mej said ArCH2-X is 2,4-dichlorobenzylchloride, said solvent is acetone, said base is K2C03, said temperature is the temperature at which acetone refluxes, and said crystallization resulting from step (3) performed employing ethyl acetate.
21. The method of claim 1 or claim 3 wherein said precursor is hydrolyzed to yield 1-alkylated indazole-3-carboxylic acid.
22. The method of claim 2 or claim 4 wherein said precursor is hydrolyzed to yield lonidamine.
23. The method of claim 1 or claim 3 wherein said precursor is oxidized to yield 1-alkylated indazole-3-carboxylic acid.
24. The method of claim 2 or claim 4 wherein said precursor is oxidized to yield lonidamine.
25. The method of any one of claims 1-4, 6, 7, 11, 12 and 18, wherein said temperature of step (1 ) is less than the refluxing temperature of the solvent in the reaction mixture.
26. The method of any one of claims 1-4, 6, 7, 11 , 12 and 18, wherein said temperature of step (1) is less than 100°C.
27. The method of any one of claims 1-4, 6, 7, 11 , 12 and 18, wherein said temperature of step (1) is room temperature or lower.
28. The method of any one of claims 1-4, 6, 7, 11 , 12 and 18, wherein said solvent is a dipolar aprotic solvent.
29. The method of claim 28, wherein said solvent is selected from the group consisting of acetone, 2-butanone, cyclopentanone, cyclohexanone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and acetonitriie.
30. The method of any one of claims 3, 4 and 18, wherein said base is Mn(COs)2, wherein M is a metal, and q can have values from 1-3.
31. The method of claim 30, wherein said base is M2C03.
32. The method of claim 31 , wherein said M is selected from the group consisting of Li, Na, K and Cs.
33. The method of claim 25, wherein said base is selected from metal hydrides; metal or quaternary ammonium hydroxides or alkoxides; amides, primary; and secondary amides and hexaalkyldisylazides.
34. The method of claim 3 or claim 4, wherein said lonidamine precursor resulting from step (3) is crystallized from ethyl acetate.
35. The method of claim 3 or claim 4, wherein said lonidamine resulting from step (5) is crystallized slowly from acetic acid.
36. The method of claim 3 or claim 4, wherein said lonidamine resulting from step (5) is crystallized from ethyl alcohol.
PCT/US2005/019350 2004-06-03 2005-06-02 Method for synthesis of lonidamine and related indazole derivatives WO2005120498A2 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7208611B2 (en) 2005-02-23 2007-04-24 Xenoport, Inc. Platinum-containing compounds exhibiting cytostatic activity, synthesis and methods of use
CN103497156A (en) * 2013-09-18 2014-01-08 苏州岚云医药科技有限公司 1-N-substitution method of fused ring pyrazole compounds
CN112778203A (en) * 2021-01-29 2021-05-11 兰州交通大学 Process for the preparation of 1H-indazole-3-carboxylic acid derivatives and granisetron and lonidamine

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US3895026A (en) * 1972-02-29 1975-07-15 Acraf Substituted 1-benzyl-1h-indazole-3-carboxylic acids and derivatives thereof

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US3895026A (en) * 1972-02-29 1975-07-15 Acraf Substituted 1-benzyl-1h-indazole-3-carboxylic acids and derivatives thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7208611B2 (en) 2005-02-23 2007-04-24 Xenoport, Inc. Platinum-containing compounds exhibiting cytostatic activity, synthesis and methods of use
CN103497156A (en) * 2013-09-18 2014-01-08 苏州岚云医药科技有限公司 1-N-substitution method of fused ring pyrazole compounds
CN112778203A (en) * 2021-01-29 2021-05-11 兰州交通大学 Process for the preparation of 1H-indazole-3-carboxylic acid derivatives and granisetron and lonidamine

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