Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/22—Separation; Purification; Stabilisation; Use of additives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
  • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated

Definitions

• the present application relates to a process for preparing a combretastatin derivative of formula (I) or (II):
• the Applicant has developed an alternative method of preparing compounds (I) or (II) which is based on the use of the intermediates P 2 or P ' 2 described below.
• This method has the advantage of postponing the step during which a cytotoxic intermediate is formed.
• This alternative method therefore has fewer steps including toxic compounds, which facilitates its management from an industrial point of view.
• the invention relates to a process for preparing a combretastatin derivative of formula (I) or (II):
• a " designating the anion associated with an acid AH, comprising the following steps:
• Ar denotes an aryl group chosen from phenyl or thienyl, optionally substituted with a (CrC 4 ) alkyl, (CrC 4 ) alkoxy or halogen group, with:
• R represents a phenyl group optionally substituted with a (CrC 4 ) alkoxy group and R 'represents a hydrogen atom;
• the invention also relates to a compound of formula P2:
• R represents a phenyl group optionally substituted with a (CrC 4 ) alkoxy group and R 'represents a hydrogen atom;
• X represents boc, Fmoc or CBZ.
• the invention also relates to the compound of formula P'2:
• PGi represents a protecting group of the alcohol function and X represents boc, Fmoc or CBZ.
• R and R ' may for example both represent a methyl group (Me) or may together with the carbon atom to which they are connected form the cyclohexyl group.
• X can for example represent boc.
• PG1 may for example represent one of the following protective groups: THP (tetrahydropyran), MEM (methoxyethoxymethyl), boc, trityl or acetyl (Ac).
• Ar may be phenyl or thienyl, optionally substituted with (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy.
• a " may denote CI " .
• the invention also relates to the use of one of the two compounds P2 and P'2 as an intermediate compound in the preparation of a compound of formula (I) or (II).
• the invention also relates to the use of one of the two compounds P4 and P'4 as an intermediate compound in the preparation of a compound of formula (I) or (II). [Detailed description of the invention]
• the general scheme 1 describes the steps (i) to (iv) of the process:
• R and R ' represent:
• R represents a phenyl group optionally substituted with a (CrC 4 ) alkoxy group, e.g. methoxy, and R 'represents a hydrogen atom; o or else R and R 'together with the carbon atom to which they are attached form a (C 3 -C 7 ) cycloalkyl group; Or else of formula ⁇ in which PGi represents a protecting group of the alcohol function. At the end of this coupling, P 2 or P 2 are respectively obtained.
• X represents boc, Fmoc or CBZ.
• PG1 denotes a group protecting the alcohol function
• boc, Fmoc and CBZ respectively denote the tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl and benzyloxycarbonyl groups.
• a protecting group is a chemical entity which is introduced on a molecule during a so-called protection step by modification of a chemical group making it possible to improve the chemo-selectivity of a reaction by avoiding undesired side reactions at the level of said chemical group and which is released in a subsequent deprotection step.
• PG1 may be for example THP (tetrahydropyran), MEM (methoxyethoxymethyl), boc, trityl or acetyl group (Ac).
• Coupling is advantageously carried out in the presence of an acid activator.
• acid activator denotes a compound whose function is to make the -COOH acid function of Pi or ⁇ more reactive in order to promote the formation of an amide bond.
• acid activators reference may be made to ChemFiles Vol.7, No. 2, page 3 edited by Aldrich Chemical or Tetrahedron report No. 672, 2004, 60, 2447- 2467, "Recent Development of Peptide Coupling Reagents in Organic Synthesis".
• EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide chloride), DCC (dicyclohexylcarbodiimide), TOTU (o- [ethoxycarbonyl] cyanomethyleneamino) -N, N, N ', N'-tetramethyluronium tetrafluoroborate), HBTU (o-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate), N, N- carbonyldiimidazole are examples of acid activators or the anhydride of propane phosphonic acid (T3P). In the presence of the acidic activator, an intermediate, isolable or otherwise, may be formed comprising an activated acid function of the form -COZ; for example, in the case of pivaloyl chloride, Z represents -OtBu.
• the coupling may be conducted in a solvent such as for example a chlorinated solvent, e.g. dichloromethane (DCM), an ether, e.g. THF or an aromatic solvent, e.g. toluene at a temperature of between 0 ° C and 20 ° C.
• a solvent such as for example a chlorinated solvent, e.g. dichloromethane (DCM), an ether, e.g. THF or an aromatic solvent, e.g. toluene at a temperature of between 0 ° C and 20 ° C.
• Ar denotes an aryl group selected from phenyl or thienyl, optionally substituted by a (CrC 4 ) alkyl or (CrC 4
• P 3 is obtained by the reaction of the 3,4,5-trimethoxybenzyl halide with the corresponding triarylphosphine PAr 3 .
• a chloride or bromide is preferably used.
• An example of P 3 is triphenyl (3,4,5-trimethoxybenzyl) phosphonium chloride which is described in p.102 of J. Fluor. Chem. 2003, 123, 101-108 or its bromide equivalent which is described in p.15-16 of WO 02/06279.
• the solvent of this reaction may be, for example, toluene, THF, dimethylformamide (DM F), chloroform, DCM, trifluorotoluene, a mixture of these solvents or an aqueous biphasic mixture, for example the chloroform / water.
• the base used is preferably a strong base such as, for example, NaHMDS (sodium bis (trimethylsilyl) amide CAS [1070-89-9]), KHMDS (potassium bis (trimethylsilyl) amide, CAS [ 40949-94-8]), sodium methoxide, sodium amide, sodium hydroxide.
• the base may be brought into contact with the phosphonium salt P 3 , and then the aldehyde P 2 or P ' 2 may be cast on the phosphonium salt P 3 , which has been brought into contact with the base beforehand.
• the base is cast on the mixture formed by the aldehyde and the phosphonium salt.
• the skilled person may refer to "Greene's Protective Groups in Organic Synthesis", 4th edition, isbn 978-0-471 -69,754 to 1 to find if any of these conditions.
• the deprotection can be conducted in the presence of an organic or inorganic HA acid. In this case, the deprotection leads to the compound P 5 in salt form.
• the deprotection can be conducted in the presence of a base B, organic or mineral. In this case, the deprotection leads to the compound P ' 5 in base form.
• the temperature of the deprotection reaction is preferably from 0 ° C to 50 ° C.
• the acid may be a strong acid such as for example hydrochloric acid, which leads to the hydrochloride.
• the base may be, for example, sodium hydroxide.
• a purification technique known in organic synthesis. This may be the purification by recrystallization using as solvent a mixture containing an alcohol and a ketone or an ester and more particularly the methyl ethyl ketone (MEK) / water mixture.
• MEK methyl ethyl ketone
• Pi is obtained according to Scheme 2 by reaction of a ketone and an L-serine derivative whose amino function has been protected by X.
• Figure 2 P'i is obtained by protecting the -OH function of a derivative of L-serine whose amino function has been protected by X.
• the L-serine derivative of Schemes 2 and 2 ' can be commercial (eg, N-boc-L-serine) or easily accessible by at least one chemical reaction known to those skilled in the art (similar, for example, to the preparation of N-boc-L-serine). [Examples]
• 3-Amino-4-methoxybenzaldehyde is obtained by reduction of the corresponding nitro compound according to Tetrahedron Letters 1993, 34 (46), 7445-1446.
• the reactor Before being used, the reactor is freed from DCM, dried under vacuum and purged with nitrogen for 15 to 30 minutes, the Erlenmeyer flask is rinsed with stabilized DCM and then dried under nitrogen.
• 95 ml of DCM and 34.0 g of Boc-L-serine-acetonide are charged into the reactor, cooled to 4-10 ° C. and added by means of a dropping funnel while maintaining the temperature at 4 ° C. -10 ° C, 14.3 g of N-methylmorpholine.
• the ampoule is rinsed with 2.5 ml of DCM. 17.1 g of pivaloyl chloride are added by means of the dropping funnel while maintaining the temperature at 4-10 ° C., the ampoule is rinsed with 2.5 ml of DCM. Stirring is maintained at 4-10 ° C for 2 h.
• a solution of aminobal (20.0 g) in DCM (95 mL) was prepared with stirring and this solution was poured into the reactor while maintaining the temperature at 4-10 ° C.
• the mixture is then heated at 20 ° C. for 1 hour and stirred at 20 ° C. for at least 16 hours.
• 100 ml of demineralized water are added to the reactor at 20-25 ° C., the mixture is stirred for 20 minutes and decanted.
• the lower organic phase containing the product is withdrawn as well as the upper phase (predominantly aqueous).
• the organic phase containing the product is recharged in the reactor.
• 140 ml of a 1.0 N aqueous sodium hydroxide solution are added. The mixture is stirred at 20-25 ° C.
• the organic phase containing the product is withdrawn.
• the organic phase containing the product is recharged in the reactor. 100 ml of demineralized water are added. Stirring is maintained at 20-25 ° C for about 20 min and then allow to settle.
• the lower organic phase, containing the product is withdrawn.
• the organic phase containing the product is recharged in the reactor. 100 ml of isopropanol are added.
• the mixture is decanted and the yellow-orange organic phase is withdrawn (volume 4250 ml containing 346.0 g of Z and 136.7 g of E).
• the Z / E ratio is 72/28 and the yield of Z + E relative to the aldehyde is 96.2%.
• the organic phase is decanted and the yellow-orange organic phase (mass 470.4 g containing 26.7 g of Z and 1 1, 2 g of E).
• the ratio Z / E is 70/30, the yield of Z + E relative to the aldehyde is 98% and the yield of Z relative to the aldehyde 69.0%.

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