WO2006067416A1 - Procedes chimiques et produits intermediaires - Google Patents

Procedes chimiques et produits intermediaires Download PDF

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WO2006067416A1
WO2006067416A1 PCT/GB2005/004941 GB2005004941W WO2006067416A1 WO 2006067416 A1 WO2006067416 A1 WO 2006067416A1 GB 2005004941 W GB2005004941 W GB 2005004941W WO 2006067416 A1 WO2006067416 A1 WO 2006067416A1
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compound
alkyl
formula
transition metal
formation
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Simon Daniel Broady
Michael David Golden
John Leonard
David Michael Glanville Martin
James Campbell Muir
Robin Fieldhouse
Mickael Louis Pierre Maudet
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Astrazeneca Ab
Astrazeneca Uk Limited
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    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/44—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
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    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/86—Ketones containing a keto group bound to a six-membered aromatic ring containing —CHO groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/141—Esters of phosphorous acids
    • C07F9/142—Esters of phosphorous acids with hydroxyalkyl compounds without further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
    • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes
    • 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

  • This invention relates to a chemical process and particularly to a chemical process for making vascular damaging agents.
  • vascular damaging agents are useful, for example, for the treatment of diseases involving angiogenesis.
  • colchinol derivatives for the preparation of compositions for the treatment of diseases involving angiogenesis has been described in Patent Application WO 99/62506, WO 00/40529 and WO 02/04434.
  • the compounds described therein are made by chemical modification of compounds whose basic carbon framework may be derived from the natural products such as colchicine (I).
  • Patent Application WO 99/62506 describes inter alia compounds of the formula (A), which, may in general be made in a number of steps which include a rearrangement of colchicine (I).
  • Colchicine has been known as a starting material for chemical synthesis of colchinol derivatives for a number of years, see for example, V. Fernholz Justus, Liebigs Ann., 1950, 568, 63-72.
  • the functional groups present in colchicine provide useful means of interconversion or introduction of functional groups, and one chiral centre is also present.
  • Colchicine occurs naturally in the lily Gloriosa Superba, which is a native flower of
  • a key step in forming the basic carbon framework of compounds of the formula (A) from colchicine is the rearrangement which transforms the [6,7,7] tricyclic ring system into a [6,7,6] ring system.
  • the most direct method of achieving this is by oxidative rearrangement, which is generally found to be low yielding.
  • the synthesis of N-Acetyl colchinol from colchicine which has been described in the literature is low yielding (F Santavy, Collect. Czech. Chem.
  • enamide (III) A convenient possible precursor to (II) to consider as a synthetic target is the enamide (III).
  • Such an enamide derivative can be converted into (II) by a stereoselective hydrogenation process in the presence of a suitable catalyst such as a rhodium, ruthenium or iridium complex, particularly a complex which comprises one or more chiral ligand(s).
  • each R is independently selected from (l- ⁇ C)alkyl, benzyl and -C(O)(I -6C)alkyl, or two RO groups together form a (l-4C)alkylenedioxy group, comprising the steps of reductive acylation of an oxime of formula (IX)
  • each R is independently selected from (l-6C)alkyl, benzyl and -C(O)(I -6C)alkyl, or two RO groups together form a (l-4C)alkylenedioxy group, and the hydroxy group may optionally be protected by a hydroxy protecting group; and thereafter if necessary, removal of any protecting groups.
  • An oxime of formula (IX) may be prepared according to the invention by the following steps: 1) formation of a keto-aldehyde compound (IV)
  • each R is independently selected from (l- ⁇ C)alkyl, benzyl and -C(O)(I -6C)alkyl, or two RO groups together form a (l-4C)alkylenedioxy group, and wherein P is a suitable hydroxy protecting group; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group;
  • R 1 is an imine; X 1 is halide; X 2 is halide; R 2 is an acetal or thioacetal; the transition metal is copper; P and R are as hereinbefore defined; or b) R 1 is an acetal; one OfX 1 and X 2 is halide and the other is -B(OH) 2 or -B(OR 3 ) 2 (wherein each R 3 is independently (l-4C)alkyl or wherein the two -OR 3 groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons; R 2 is a ketone; the transition metal is palladium; P and R are as hereinbefore defined;
  • each R is independently selected from (l- ⁇ C)alkyl, benzyl and -C(O)(I -6C)alkyl. In one aspect, the R groups are all the same.
  • each R is independently selected from (l-4C)alkyl, benzyl and -C(O)(I -4C)alkyl.
  • each R is independently selected from (l-4C)alkyl and benzyl.
  • each R is independently selected from (l-4C)alkyl.
  • each R group is methyl.
  • Suitable hydroxy protecting groups include, for example a group selected from (1-
  • P is selected from (l- ⁇ C)alkyl, -SiL 3 (wherein each group L is independently selected from (l-6C)alkyl and aryl), benzyl and -CO 2 (l-6C)alkyl.
  • P is selected from (l- ⁇ C)alkyl, -SiL 3 (wherein each group L is independently selected from (l-6C)alkyl and aryl), benzyl and -CO 2 (I -6C)alkyl.
  • P is selected from (l-4C)alkyl and -SiL 3 (wherein each group L is independently selected from (l-6C)alkyl and aryl).
  • Suitable values for -SiL 3 include -SiMe 3 , -SiEt 3 , -SiPhMe 2 , -Si 1 Pr 3 , -Si 1 BuMe 2 and -Si 4 BuPh 2 .
  • P is selected from benzyl, -SiMe 3 , -SiPhMe 2 , and -CO 2 Me.
  • P is benzyl.
  • keto-aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group, is the first stage in forming the key carbon-carbon bonds of the carbon framework, in this case, the aryl-aryl bond.
  • This invention provides two methods suitable for formation of keto-aldehyde (IV) as described in a) and b) hereinbelow.
  • acetal/thioacetal group shown in (XI) and (XII) above is a 5-membered ring
  • the process of the invention may be applied to compounds wherein the acetal/thioacetal group is a 6 membered ring or is acyclic, and wherein the carbon atoms of the acetal/thioacetal group may be substituted with one or more methyl groups.
  • a selective procedure has been described in the art for coupling certain aromatic components, each of which contain nitrogen or sulfur based functionality that can co-ordinate with copper (see for example, Ziegler et al, J. Am. Chem. Soc, 1980, 102, p790).
  • a lithiated aromatic compound bearing a nitrogen containing group (e.g. an imine) ortho to the lithium is reacted with copper iodide-triethyl phosphate complex to provide a copper reagent in which the copper is coordinated to the nitrogen function.
  • the coupling partner is an aromatic iodide bearing a thioacetal ring ortho to the iodide. Co-ordination of the sulfur to the copper in the other component facilitates the selective coupling of the aromatic rings at ambient temperature.
  • X 1 and X 2 are both bromide.
  • the reaction wherein X 1 and X 2 are both bromide may be carried out between 20 and 50°C, preferably between 30 and 50°C, more preferably between 40 and 50°C, for example at about 45°C.
  • the use of a lower temperature generally results in a slower reaction.
  • transition metal containing reagent used in this invention to achieve the coupling reaction namely CuBr 1 P(OEt) 3
  • the transition metal containing reagent used in this invention to achieve the coupling reaction may conveniently be prepared by heating triethylphosphite with a suspension of copper (I) bromide in toluene.
  • CuLP(OEt) 3 may also be used as a coupling reagent.
  • a methoxime functional group replaces the acetal/thioacetal, (XIV),
  • (XII) is an acetal
  • conversion to the ketone and the aldol reaction to make (XII) can be combined together in the same reaction vessel and solvent, without isolation of the intermediate (FV).
  • a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R 1 is an imine, X 1 is halide, X 2 is halide, R 2 is an acetal and the transition metal is copper.
  • a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R 1 is an imine, X 1 is bromide, X 2 is bromide, R 2 is an acetal and the transition metal is copper.
  • a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R 1 is an imine, X 1 is halide, X 2 is halide, R 2 is a thioacetal and the transition metal is copper.
  • a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R 1 is an imine, X 1 is bromide, X 2 is bromide, R 2 is a thioacetal and the transition metal is copper.
  • R 1 is an acetal; one OfX 1 and X 2 is halide and the other is - B(OH) 2 or B(OR 3 ) 2 (wherein each R 3 is independently (l-4C)alkyl or wherein the two -OR 3 groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R 2 is a ketone; and the transition metal is palladium is shown in detail in Scheme 6 below:
  • acetal group shown in (XVa), (XVb) and (XVII) above is a 5-membered ring
  • the process of the invention may be applied to compounds wherein the acetalgroup is a 6 membered ring or is acyclic, and wherein the carbon atoms of the acetal group may be substituted with one or more methyl groups.
  • the coupling reaction shown in Scheme 6 is generally known in the art as a Suzuki Coupling, which is generally a highly efficient method of coupling together two aryl substrates (See A. Suzuki, Handbook of Organopalladium Chemistry for Organic Synthesis, (2002), 1, 249-262. Publisher John Wiley).
  • One substrate in a Suzuki coupling is a halide and the other substrate is a boronic acid or ester derivative thereof.
  • a number of transition metal catalysts are known in the art to be generally useful in Suzuki couplings and for compounds of the formula (XV) an (XVI), the catalyst Pd(PPh 3 ) 4 was found to be effective.
  • the coupling reaction may be carried out using either the boronic acid derivative (XVIc) or a boronic ester for example (XVId), wherein P is a protecting group as defined herein.
  • a boronic ester is used.
  • the boronic ester is (XVId).
  • keto acetal (XVII) may be converted to the keto aldehyde (IV) without isolation in the reaction mixture resulting from the Suzuki coupling reaction.
  • the keto aldehyde (IV) may be used in the next stage of the process of the invention without isolation.
  • a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R 1 is an acetal; one OfX 1 and X 2 is halide and the other is -B(OH) 2 or B(OR 3 ) 2 (wherein each R 3 is independently (l-4C)alkyl or wherein the two -OR 3 groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R 2 is a ketone; and the transition metal is palladium.
  • a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R 1 is an acetal; X 1 is Bromide and X 2 is -B(OH) 2 ; R 2 is a ketone; and the transition metal is palladium.
  • a process for the formation of a keto- aldehyde compound (IV) by transition metal mediated coupling of a compound of the formula (V) and a compound of the formula (VI), followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R 1 is an acetal; X 2 is halide and X 1 is
  • each R 3 is independently (l-4C)alkyl or wherein the two -OR 3 groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons);
  • R 2 is a ketone; and the transition metal is palladium.
  • Intramolecular cyclisation of the keto-aldehyde compound (V) to form an enone (VIII) is the second stage in forming the key carbon-carbon bonds of the carbon framework and completes formation of the tricyclic ring system.
  • the process of the invention achieves intramolecular cyclisation by the use of an aldol condensation reaction (see for example, Comprehensive Organic Chemistry, ed. Trost and Fleming). This may be carried out under any conditions known in the art, for example those shown in Scheme 8 below.
  • the base used may be any base known to be useful in aldol reactions, for example an aqueous base.
  • the base is potassium carbonate. It will be appreciated by those skilled in the art that such an aldol reaction may also be carried out using acid catalysis instead of base catalysis.
  • a further aspect of the invention comprises conversion of the keto-aldehyde compound (IV) to the enone (VII) by an intramolecular aldol condensation reaction.
  • a further aspect of the invention comprises conversion of the keto-aldehyde compound (IV) to the enone (VII) by an intramolecular aldol condensation reaction in the presence of aqueous potassium carbonate.
  • Reduction of the enone (VII) to form a cyclic ketone (VIII) may be carried out using any suitable processes well known in the art for reduction of enones, for example by hydrogenation using a palladium catalyst such as Pd(OH) 2 .
  • the protecting group P may be removed by any conventional means known in the art. Conveniently, when the protecting group P is benzyl, hydro genolysis of the benzyl group may be carried out simultaneously as sho ⁇ vn below in Scheme 9. Alternatively, when Pd/C is used as the catalyst, enone reduction occurs without hydrogenolysis of the benzyl group.
  • a further aspect of the invention comprises conversion of the enone compound (Vila) to the cyclic ketone (VIII) by simultaneous palladium catalysed hydrogenolysis.
  • the formation of the oxime derivative (IX) of the cyclic ketone (VIII) may be carried out by any process known in the art for the formation of oximes, for example by reaction with hydroxylamine hydrochloride, as shown in Scheme 10.
  • a further aspect of the invention comprises conversion of the cyclic ketone compound (VIII) to the oxime (IX).
  • Step 5 Reductive acylation of the oxime (IX) to form the enamide (III) may be carried out by processes known in the art.
  • a suitable method for the reductive acylation uses iron and acetic anhydride in acetic acid as shown in Scheme 11.
  • a further aspect of the invention comprises conversion of the oxime (IX) to the enamide (III).
  • the protecting group P is not removed during step 3, but is instead removed during step 5, according to Scheme 12.
  • the protecting group P may conveniently be removed before or after the reductive acylation reaction, by any suitable process known in the art depending on the nature of P.
  • keto-aldehyde compound (IV) wherein each R is (l-6C)alkyl and wherein P is selected from (l-6C)alkyl, -SiL 3 (wherein each group L is independently selected from (l-6C)alkyl and aryl), benzyl and -CO 2 (I- 6C)alkyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein either a) R 1 is an imine; X 1 is halide; X 2 is halide; R 2 is an acetal or thioacetal; the transition metal is copper; P and R are as hereinbefore defined; or b) Ri is an acetal; one OfX 1 and X 2 is halide and the other is -B(OH) 2 or B(OR 3 ) 2 (wherein each R 3 is independently (l-4C)alkyl
  • enamide (III) reductive acylation and deprotection to form the enamide (III).
  • a process for the formation of an enamide (III) comprising the steps 1) to 5):
  • keto-aldehyde compound (IV) wherein each R is methyl and wherein P is selected from (l-6C)alkyl, -SiL 3 (wherein each group L is independently selected from (l-6C)alkyl and aryl), benzyl and -CO 2 (I -6C)alkyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group;
  • R 1 is an imine; X 1 is halide; X 2 is halide; R 2 is an acetal or thioacetal; the transition metal is copper; P and R are as hereinbefore defined;
  • a process for the formation of an enamide (III) comprising the steps 1) to 5): 1) formation of a keto-aldehyde compound (IV) wherein each R is methyl and wherein P is selected from (l- ⁇ C)alkyl, -SiL 3 (wherein each group L is independently selected from (l-6C)alkyl and aryl), benzyl and -CO 2 (I -6C)alkyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein Ri is an acetal; one of Xi and X 2 is halide and the other is -B(OH) 2 or B(OR 3 ) 2 (wherein each R 3 is independently (l-4C)alkyl or wherein the two -OR 3 groups together with the B atom to which they are attached form a ring, and wherein such
  • a process for the formation of an enamide (III) comprising the steps 1) to 5): 1) formation of a keto-aldehyde compound (FV) wherein each R is (l-6C)alkyl and wherein P is benzyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein either a) R 1 is an imine; Xi is halide; X 2 is halide; R 2 is an acetal or thioacetal; the transition metal is copper; P and R are as hereinbefore defined; or b) R 1 is an acetal; one OfX 1 and X 2 is halide and the other is -B(OH) 2 or B(OR 3 ) 2 (wherein each R 3 is independently (l-4C)alkyl or wherein the two -OR 3 groups together with the B atom to which
  • a process for the formation of an enamide (III) comprising the steps 1) to 5): 1) formation of a keto-aldehyde compound (IV) wherein each R is methyl and wherein P is benzyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R 1 is an imine; X 1 is halide; X 2 is halide; R 2 is an acetal or thioacetal; the transition metal is copper; P and R are as hereinbefore defined;
  • keto-aldehyde compound (IV) wherein each R is methyl and wherein P is benzyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group; wherein R 1 is an acetal; one OfX 1 and X 2 is halide and the other is -B(OH) 2 or B(OR 3 ) 2 (wherein each R 3 is independently (l-4C)alkyl or wherein the two -OR 3 groups together with the B atom to which they are attached form a ring, and wherein such a ring may contain methyl substituents on the carbons); R 2 is a ketone; the transition metal is palladium; P and R are as hereinbefore defined;
  • a process for the formation of an enamide (III) comprising the steps 1) to 5): 1) formation of a keto-aldehyde compound (IV) wherein each R is methyl and wherein P is benzyl; by transition metal mediated coupling of a compound of the formula (V) with a compound of the formula (VI) followed by conversion of any carbonyl group derivative into its parent carbonyl group;
  • R 1 is an imine; X 1 is bromide; X 2 is bromide; R 2 is an acetal or thioacetal; the transition metal is copper;
  • Suitable values for (l-4C)alkyl include methyl, ethyl, isopropyl, propyl, butyl, isobutyl and tertiarybutyl; suitable values for (l-6C)alkyl include (l-4C)alkyl, pentyl, cyclopentyl, hexyl and cyclohexyl; suitable values for -CO 2 (I -4C)alkyl include -CO 2 CH 3 , -CO 2 CH 2 CH 3 and -CO 2 tBu; suitable values for -CO 2 (I -6C)alkyl include -CO 2 (I -4C)alkyl and -C0 2 pentyl, suitable values for -C(O)(I -4C)alkyl include -C(O)CH 3 , and -C(O)CH 2 CH 3 ; suitable values for -C(O)(I -6C)alkyl include -C(0)(l-4C)alkyl
  • 'aryl' means an aromatic carbocyclic ring, optionally substituted by 1, 2, or 3 substituents independently selected from (l-4C)alkyl, halo.
  • the (1- 4C)alkylenedioxy group is, for example, methylenedioxy -(0CH 2 O)- or ethylenedioxy - (OCH 2 CH 2 O)-.
  • the enamide of formula (III) is of the formula (Ilia) or (IHb):
  • the ring so formed may be, for example a 5 to 7 membered ring that contains a group of the formula — O-B-O- in the ring and which is linked to the group to which it is attached via the B group, he ring so formed is optionally substituted on carbon by one or more methyl groups.
  • Representative examples of such rings include but are not limited to:
  • VoIs refers to the relative amount of solvent used in millilitres, relative to the amount of the main reaction substrate in grams.
  • each intermediate was purified to the standard required for the subsequent stage and was characterised in sufficient detail to confirm that the assigned structure was correct; purity was assessed by HPLC, TLC, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate;
  • Step l Compound 1 : l-(4-Benzyloxy-6'-fl,31dioxoIan-2-vI-2',3',4'-trimethoxy-biphenyl-2-yl)- ethanone
  • Potassium phosphate (1.54 g, 7.25 mmol) was added to a solution of l-[5-benzyloxy-2- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-ethanone (Intermediate 1, 2.55 g, 7.24 mmol) and 2-(2-bromo-3,4,5-trimethoxy-phenyl)-[l,3]dioxolane (Intermediate 2, 1.54 g, 4.83 mmol) in DMF (38 ml, 490.7 mmol).
  • the reaction mixture was allowed to warm to ambient temperature, and held for 18 hours.
  • the solvent was removed by vacuum distillation, and the residue partitioned between toluene (50ml) and 20% aq. acetic acid (50ml) for 1 hour.
  • the organic phase was separated and washed with saturated NaHCO 3 solution (50ml) and then brine (50ml), then dried over MgSO 4 .
  • the solvent was removed under vacuum distillation and the residue purified by chromotography (petroleum ether/diethyl ether) to yield a yellow oil (2.0Og, 76%), which crystallised on standing.
  • Step 2 Compound 6: 3rBenzyloxy-940Jl-trimethoxy-dibenzofa.,clcvcloheptan-5-one
  • the filter cake was washed with aqueous ethanol (1:3, EtOH, H 2 0, 1 x 20 ml) and then dried in a vacuum oven (40°C) overnight.
  • the product was obtained as an off white solid (major isomer >90%) (10.72 g, 93%).
  • Acetic anhydride (10.74ml, 0.114 mol) was added in one portion to a stirred slurry of 3 ⁇ hydroxy-9,10,11-trimethoxy-dibenzo [a,c] cycloheptan-5-one oxime (Compound 8, 15.35g, 0.046 mol) in glacial acetic acid (150ml) at room temperature and the resulting mixture was stirred for 40 minutes.
  • Iron powder (3.09g, 0.054 mol) was then added in one portion and stirring was continued for a further 4 hours.
  • Pinacol (1.62 g, 13.7 mmol) was added to a solution of 2-acetyl-4-benzyloxyphenyl boronic acid (3.7 g, 13.7 mmol) in toluene (35 ml). The reaction mixture was stirred at ambient temperature for 16 hours then concentrated under vacuum to yield the product as a solid [3.6 g, 75% (by HPLC area %)] .
  • n-Butyllithium in hexane 28.45 ml, 2.5M, 71 mmol was added dropwise to a cooled (-70 0 C) 20 solution of 2-(5-benzyloxy-2-bromoplienyl)-2-methyl-[l,3]dioxolane (21.6 g, 62 mmol) in THF (100 ml) over 30 minutes.
  • the reaction mixture was stirred at -70°C for 1 hour before the dropwise addition of trimethylborate (7.95 ml, 71 mmol) over 2 minutes.
  • the mixture was then allowed to warm to ambient temperature and stir for 18 hours. Water and t- butylmethylether were then added to the mixture and the organic layer separated.
  • N-Bromosuccinimide (69.8 g, 0.39 mol) was added to a solution of 3-benzyloxyacetophenone (80 g, 0.35 mol) in acetonitrile (300 ml) under nitrogen.
  • the initial slurry was warmed to 6O 0 C with stirring, slowly becoming a homogeneous black solution.
  • the acetonitrile was distilled off, the residue diluted with toluene (50 ml) and the solvent again distilled off.
  • the mixture was then diluted with toluene (200 ml) and washed with IM sodium thiosulfate (2 x 300 ml).
  • CDCh CDCh ⁇ : 1.19-1.45 (3H, m), 1.51-1.63 (2H, m), 1.64-1.79 (3H, m), 1.79- 1.88 (2H, m), 3.23-3.33 (IH, m), 3.89 (3H, s), 3.91 (3H, s) 5 3.92 (3H, s), 7.41 (IH, s), 8.63 (IH, s).
  • N-Bromosuccinimide (143 g, 0.80mol) was added to a solution of 3,4,5- trimethoxybenzaldehyde (150 g, 0.76 mol), in acetonitrile (750 ml). The reaction mixture was heated to 5O 0 C for 1 hour cooled and left at ambient temperature for 54 hours. On completion, sodium thiosulfate solution [24 g, 0.152 mol; in water (115 ml)] was added. The reaction mixture was then concentrated, diluted with dichloromethane (400 ml) and washed with water (2x 200 ml). The organic layer was then separated, dried (MgSO 4 ), concentrated and recrystallised from iso-propanol (50 ml).
  • Triethyl phosphite (183g, 1.1 mol) was added to a suspension of copper(I) bromide (164.5 g, 1.15 mol) in toluene (500 ml). The mixture was heated at 80°C for 3 h with stirring, then left to cool and settle. The clear solution was decanted from the solid residue and the solvent evaporated on a rotary evaporator at 60°C, to provide copper(I) bromide triethyl phosphite complex as a clear colourless oil, 336g (94% crude yield).

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Abstract

La présente invention concerne un procédé pour produire un énamide de formule (III) dans laquelle chaque R est indépendamment choisi parmi (1-6C)alkyle, benzyle et C(O)(1-6C)alkyle ou deux groupes RO forment ensemble un groupe (1-4C)alkylènedioxy. Ce procédé consiste à effectuer une acylation réductrice d'une oxime de formule (IX), dans laquelle chaque R est indépendamment choisi parmi (1-6C)alkyle, benzyle et C(O)(1-6C)alkyle ou deux groupes RO forment ensemble un groupe (1-4C)alkylènedioxy et le groupe hydroxy peut éventuellement être protégé par un groupe protecteur d'hydroxy, puis ensuite, si cela est nécessaire, à retirer tous les groupes protecteurs. Cette invention concerne également des produits intermédiaires à l'énamide (III) et des procédés pour les préparer.
PCT/GB2005/004941 2004-12-23 2005-12-19 Procedes chimiques et produits intermediaires WO2006067416A1 (fr)

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US8227622B2 (en) 2009-07-06 2012-07-24 Astrazeneca Ab Pharmaceutical process and intermediates 714

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2000040529A1 (fr) * 1999-01-07 2000-07-13 Angiogene Pharmaceuticals Ltd. Derives de colchinol utilises comme agents de degradation vasculaire

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000040529A1 (fr) * 1999-01-07 2000-07-13 Angiogene Pharmaceuticals Ltd. Derives de colchinol utilises comme agents de degradation vasculaire

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BERGEMANN, SILKE ET AL: "Novel B-ring modified allocolchicinoids of the NCME series: design, synthesis, antimicrotubule activity and cytotoxicity", BIOORGANIC & MEDICINAL CHEMISTRY , 11(7), 1269-1281 CODEN: BMECEP; ISSN: 0968-0896, 2003, XP002371234 *
GUAN, JIAN ET AL: "Antitumor agents. 192. Antitubulin effect and cytotoxicity of C(7)-oxygenated allocolchicinoids", COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS , 64(2), 217-228 CODEN: CCCCAK; ISSN: 0010-0765, 1999, XP008060922 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8227622B2 (en) 2009-07-06 2012-07-24 Astrazeneca Ab Pharmaceutical process and intermediates 714

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