Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
  • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
  • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
  • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/16—Preparation of optical isomers
  • C07C231/18—Preparation of optical isomers by stereospecific synthesis
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present application relates to a process for preparing a combretastatin (A):
• X is -NH 2 or one of two groups:
• Bioorg. Med. Chem. 2000, ⁇ , 2417-2425 and US 2003/0220404 also describe processes for the preparation of combretastatins.
• Bioorg. Med. Chem. 2006, 14, 3231-3244 describes the preparation of combretastatin of formula (A) with a coupling using DCC, HOBt-H 2 O as the acid activator (step e, compound 10).
• T3P in the preparation of amide bonds; however, T3P is described as leading to more epimerization and lower yields than HAPyU (see Table 3). In these documents, the method forming the subject of claim 1 is not described or suggested. Similarly, the enrichment of the salt of the amino compound with benzyl alcohol and acetonitrile as well as coupling with T3P is not described.
• Combretastatins or stilbene derivatives exhibit high cytotoxic activity and are therefore useful as anticancer agents.
• These compounds are in particular described in US 5731353, US 5561122 or US 6759555.
• the Applicant has improved the process for the preparation of combretastine (A).
• the invention relates to a process for preparing a combretastatin (A):
• the invention also relates to the enrichment of the salt of the amino compound of formula
• the invention also relates to the use of T3P of formula (III)
• the proportion acetonitrile / salts of the compounds (Z) - and (E) -amino expressed by weight is between 5 and 17, preferably between 10 and 12.
• the temperature at which the enrichment is conducted is preferably between 20 and 7O 0 C.
• the proportion benzyl alcohol / salts of the compounds (Z) - and (E) -amino expressed by weight is between 1 and 4, preferably between 2 and 3.
• PG denotes a protective group for the amine function: it may be, for example, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) or 9-fluorenylmethyloxycarbonyl (FMOC);
• Step (i) is described in US 5731353 as well as in Bioorg. Med. Ch ⁇ m. 2000, 8, 2417-2425 (Scheme 1).
• the reaction is carried out in an organic solvent such as for example an aromatic solvent (eg toluene) in the presence of a base, preferably strong such as MeONa or NaH.
• a base preferably strong such as MeONa or NaH.
• the ratio (Z) / (E) is of the order of 75/25.
• (Z) -amino of sufficient purity is then obtained by one or more complicated separation (s).
• the separation following the reduction is carried out by successive crystallizations.
• a 1 st crystallization allows to eliminate the compound (E) -amino, then a 2 nd crystallization allows to isolate the (Z) -amino (see US 6,759,555, ex.1).
• step (iii) is advantageously carried out in the presence of an acid activator such as, for example, 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), PivCl (pivaloyl chloride) or N, N-carbo ⁇ yldiimidazole.
• an acid activator such as, for example, EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide chloride), DCC (dicyclohexylcar
• Coupled agent means a compound whose function is to activate the -COOH acid function in order to promote the formation of a peptide bond.
• acid activators See more details on the acid activators, reference may be made to the review Ch0mFiles 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". The review Tetrahedron 2005, 61, 10827-10852 reveals that there are many available acid activators.
• Step (iv) is conducted in the presence of an acid to promote ring opening and to obtain combretastatin (A) as a salt (-NH 3 + ).
• This is a deprotectio ⁇ / cycle opening.
• hydrochloric acid is advantageously used, for example, in the form of methanolic solution, and the hydrochloride is obtained.
• Combretastatin (A) in the base form is obtained by neutralizing the salt with the aid of a base, for example sodium hydroxide (cf..ex.1-step (Ni)).
• step (ii) the (Z) isomer of the salt of the amino compound is obtained by the process of: "adding benzyl alcohol to a suspension of a mixing the salts of the (Z) - and (E) -amino compounds in acetonitrile; and • mechanically separating the salt of the amino compound enriched in the (Z) isomer.
• the isomer (Z) is thus obtained by "enrichment", this term meaning that at the end of the two steps of the process described above, the proportion of the isomer (Z) is increased relative to the isomer (E); we can also speak of separation process of the (Z) isomer from a mixture of isomers (Z) and (E)). Compared to (re) crystallization, enrichment has the advantage of being both direct and simple to implement. It makes it possible to obtain the amino compound enriched in isomer (Z) with a low content of residual isomer (E) (which can be up to ⁇ 1 mol%, cf ex.1, where the purity of the product is 99.93%). % in (Z) and 0.07% in (E)).
• the mechanical separation may be, for example, filtration or centrifugation. At the end of the mechanical separation, the salt of the isomer (Z) may be optionally washed and dried.
• the suspension preferably has a proportion of aceto ⁇ itrile / salts of the compounds (Z) - and (E) - amino expressed by weight of between 5 and 17, preferably between 10 and 12 (i.e. acetonitrile in the suspension is between 5 to 17 x weight of the compounds (Z) - and (E) -amino).
• the amount of benzyl alcohol which is added is preferably such that the proportion benzyl alcohol / salts of the compounds (Z) - and (E) -amino expressed by weight is between 1 and 4, preferably between 2 and 3 (c). that is, the weight of benzyl alcohol added is from 1 to 4 x weight of the compounds (Z) - and (E) -amino). This proportion makes it possible to maintain a high ratio (Z) / (E) for the final product.
• the benzyl alcohol has the function of preferentially dissolving the salt of the compound (E) -amino.
• Enrichment is preferably carried out at a temperature between 20 and 70 ° C, preferably between 30 and 70 ° C, preferably between 35 and 65 ° C. Beyond 70 0 C, the amino compound begins to degrade slowly.
• a preferred method of preparing the suspension is described below.
• Compounds (Z) - and (E) -nitro are reduced with sodium dithionite (Na 2 S 2 O 4 ) in a solvent which may be a mixture of water and alcohol, for example a mixture water / methanol.
• a strong acid eg HCl or H 2 SO 4
• is introduced into the reaction medium which reacts with the reaction intermediates as well as with the dithionite and disulfite residues.
• a mixture of the salts of the compounds (Z) - and (E) -amino (eg hydrochloride or sulfate) is then obtained.
• DCM dichloromethane
• a strong acid in an alcohol is added to the organic phase, and the alcohol is then displaced with acetonitrile so as to obtain a suspension of the salts of the (Z) - and (E) -amino compounds in acetonitrile.
• the solvent can be displaced by adding acetonitrile after removing the alcohol in a more or less complete vacuum.
• the acetonitrile may also be concomitantly with the removal of the alcohol under vacuum
• the alcohol is preferably a light alcohol such as methanol or ethanol.
• step (iii) the coupling between the salt of the (Z) -amino compound and the doubly protected L-serine derivative of formula (II) is carried out in an organic solvent using anhydride.
• phosphonic propane acid (T3P) as an acid activator in the presence of a base.
• the function of the base is to trap the acid species and move the salt to the free base.
• the amount of base added is between 2 and 3 eq. relative to the salt of the compound (Z) -amino (see ex.1 where 2.7 eq.) were used.
• the base may be a tertiary amine, for example triethylamine (TEA), diisopropylethylamine (DIEA), N-methyl morpholine (NMM) or methylpiperidine.
• the organic solvent may be dichloromethane (DCM), toluene, methyl isobutyl ketone (MIBK), ethyl acetate, acetonitrile, tetrahydrofuran (THF), Me-tetrahydrofuran (Me-THF) or cyclopentylmethyl ether.
• the T3P has the formula:
• T3P does not lead to an epimerization of the asymmetric center, which makes it possible to obtain combretastatin (A) with a good purity and a good yield. It has also been found that T3P makes it possible to obtain a good yield of coupling product (see Table III).
• the coupling reaction is generally conducted at a temperature between 5 ° C and 70 ° C, for example at reflux of DCM.
• the proportion of T3P relative to the (Z) -amino compound is between 1 and 2 eq, preferably between 1.5 and 1.8 eq.
• the isopropyl alcohol (87.6 liters) is then charged and the medium is concentrated and then cooled. The suspension is then filtered at 100 ° C. The isolated product is dried under vacuum (6.46 kg, 52.2%). The purity of the isolated product is of the order of 78% in (Z) and 22% in (E).
• the aqueous phase is removed after re-extraction with DCM (20 ml) then the DCM phase is concentrated under vacuum (about 200 mbar at 35 ° C) and replaced with acetonitrile (160 ml); the solvent is changed from DCM to acetonitrile under reduced pressure so as to keep a reaction volume of about 200 ml.
• the methanolic hydrochloric acid (27 ml, 0.081 mol) is cast and the solvent is then evaporated under reduced pressure (90 mbar) so as to effect the solvent change from methanol-acetonitrile to acetonitrile at a constant volume of about 233 ml. .
• the total volume (solvent + organic compounds) is adjusted to 280 ml.
• the DCM phase is washed with 500 ml of an aqueous solution of 6% sodium hydrogenphosphate (30 g) and then with 500 ml of demineralized water.
• the DCM phase is concentrated under reduced pressure from 360 to 150 mbar at 40-50 ° C. then a HCl solution in methanol at 3 mol / l (379 ml, 8 eq.) and 300 ml of demineralized water. It is allowed to settle and the phases are separated.
• the DCM / methanol phase was re-extracted with deionized water (200 ml) and the phases were separated. 650 ml isopropyl acetate and then 115 ml of 30% sodium hydroxide solution (8.1 eq) are added.
• the mixture is left to settle and the organic phase is washed with 400 ml of demineralised water. It is allowed to settle and the phases are separated.
• the organic phase is then concentrated under reduced pressure from 160 to 60 mbar to 300-350 ml and a change of solvent DCM isopropyl acetate.
• the mixture is then heated to 62 ° C., 35 ml of methanol are added and a solution of hydrochloric acid in 3 mol / l methanol (47.4 ml, 1 eq) is poured. It is then allowed to cool to ambient temperature and the white mud is filtered. We wash the final solid
• step (ii) is repeated with different amounts of (Z) and (E) -nitro compounds initially.
• the proportion acetonitrile / salts of the compounds (Z) - and (E) -amino is fixed at 10.8 and the proportion benzyl alcohol / salts of the compounds (Z) - and (E) -amino is itself variable.
• Examples 10-14 describe coupling results (step (Ni)) using other coupling agents than T3P.
• step (iii) The conditions of step (iii) are repeated but in the presence of TOTU as acid activator (1 eq of TOTU + 5 eq of TEA). The final yield is only 71%.
• BOP-Cl Bis (2-oxo-3-oxazolidinyl) pho
• Example 13 (comparative): use of PyCIOP (chlorotripyrrolidinophosphonium hexafluorophosphate)
• T3P makes it possible to obtain a better yield of coupling product than TOTU, BOP-CI, PyCIOP or PyBROP.

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