EP1045831A1 - Solid supported synthesis of hydroxamic acids - Google Patents

Solid supported synthesis of hydroxamic acids

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Publication number
EP1045831A1
EP1045831A1 EP98959113A EP98959113A EP1045831A1 EP 1045831 A1 EP1045831 A1 EP 1045831A1 EP 98959113 A EP98959113 A EP 98959113A EP 98959113 A EP98959113 A EP 98959113A EP 1045831 A1 EP1045831 A1 EP 1045831A1
Authority
EP
European Patent Office
Prior art keywords
resin
acid compound
side chain
hydroxamic acid
moiety
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98959113A
Other languages
German (de)
French (fr)
Inventor
Adam Golebiowski
Sean Rees Klopfenstein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Procter and Gamble Co
Original Assignee
Procter and Gamble Co
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Filing date
Publication date
Application filed by Procter and Gamble Co filed Critical Procter and Gamble Co
Publication of EP1045831A1 publication Critical patent/EP1045831A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • 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
    • C07B2200/11—Compounds covalently bound to a solid support
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the subject invention relates to methods for synthesizing hydroxamic acid compounds using a solid-support resin to facilitate purification of intermediates.
  • Hydroxamic acids are an important class of organic molecules playing a key role in many biologically relevant interactions.
  • MMPs matrix metalloproteinases
  • FIG. 732 Rockwell, A.; Melden, M.; Copeland, R. A.; Hardman, K.; Decicco, C. P.; DeGrado, W. F.; J. Am. Chem. Soc., vol. 118 (1996), p.
  • R can be virtually any organic radical. It is limited only by stability and solubility factors during processing and as part of the final product.
  • the subject invention processes use a solid-support resin having an oxime moiety as the linking moiety of the resin.
  • a preferred resin is an oxime (Kaiser) resin available commercially from Novabiochem, San Diego, California, having the structure:
  • the first step of the subject invention processes involves treating the resin with a carboxylic acid compound:
  • R can be virtually any organic radical that provides a stable and soluble compound (3), and will not react preferentially (to the acid moiety) with the oxime moiety of the resin. R can be the same or different from R.
  • the carboxylic acid becomes attached to the resin by a simple condensation reaction between the carboxyl moiety of the carboxylic acid and the oxime moiety of the resin. Preferably the reaction is carried out with the resin suspended in dichloromethane (DCM) in the presence of one equivalent of 1,3- diisopropylcarbodiimide (DIC) and a catalytic amount of 4-dimethylaminopyridine (DMAP).
  • DCM dichloromethane
  • DIC 1,3- diisopropylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • reaction and purification procedures can be used to modify the structure of the side chain R .
  • This second step is optional since R and R may be the same moiety, or no modification of R may be desired at this stage of the process. However, this second step is preferably used, since the ease of modifying R during this step is one of the primary advantages of the subject processes.
  • Linkage of the material undergoing modification to the solid-support resin provides the advantage of easy purification of intermediates by simply washing excess reagents and impurities from the resin-bound materials using appropriate solvents.
  • An advantage of the subject invention process is that the linkage of the product to the oxime resin is typically both acid and base stable to a sufficient extent that a wide variety of reactions can be utilized in modifying the side chain of the product. This includes the use of both acid and base labile protecting groups during these reaction and purification steps.
  • Resin:C NOC(O)R* (4) where R* is R or R or R .
  • a product is cleaved from the resin in a third step by treating structure (4) with O-tert-butyldimethylsilylhydroxylamine:
  • the O-TBS -protected product (5) may be useful in its own right, if further modifications of the material are desired to be made with the O-protecting group in place. If R* is R or R , it is modified in an optional fourth step through one or more reaction and purification procedures to produce side chain R of the target hydroxamic acid compound:
  • This step is optional since it is not needed if R* is R.
  • the corresponding unprotected hydroxamic acid compound is produced in a fifth step by treating structure (6) with acid, producing the target compound:
  • This step is optional, because it may be desirable to retain the hydroxamic acid compound produced in its O-TBS -protected state.
  • inorganic acids such as HC1 or HBr can be used in this fifth step to produce the hydroxamic acid
  • a volatile organic acid such as trifluoroacetic acid (TFA)
  • TFA trifluoroacetic acid
  • Both TBSONH2 and an acid such as TFA are generally more volatile than the unprotected hydroxamic acid product, so that excess amounts of them are readily separated from the unprotected hydroxamic acid compound by evaporation.
  • the subject invention processes provide easy purification of intermediates which are bonded to the resin, and easy purification of the final product due to the volatility of the reagents used. This makes the processes amenable to automation.
  • a preferred exemplary synthetic route which is outlined in Scheme 1, utilizes oxime (Kaiser) resin (1) which is reacted with carboxylic acid to produce esters (2). After side chain modification, the product is cleaved as an O-protected hydroxamic acid (3), using O-tert-butyldimethylsilylhydroxylamine. (At this stage the crude product can be purified by silica gel chromatography.) Finally, the silyl group is removed with trifluoroacetic acid at room temperature to afford pure hydroxamic acid (4).
  • N- tosyl-proline hydroxamic acid (8) is prepared according to Scheme 2 and the following described procedure:
  • Reagents a) Boc-Pro-OH, DIC, DMAP, DCM; b) 25% TFA/DCM ; c) TsCl, DIPEA, DCM; d) TBSONH2, DCE; e) 95% TFA/H2O.
  • Oxime resin (1.0 g, 1.17 mmol/g, 1.17 mmol; Novabiochem, product number 01-64-0022) is rinsed several times with DCM.
  • Boc-proline (5eq, 1.28 g, 5.85 mmol) in DCM (12 mL) is added, followed by DIC (737 mg, 5.85 mmol) and a catalytic amount of DMAP (5 mg).
  • the reaction mixture is shaken for 17 hours, and the resin is filtered and washed (DCM, 2-propanol, DMF).
  • the reaction mixture is shaken for 6 h, then filtered, washed (DCM, 2-propanol and again DCM several times) and vacuum dried (room temperature, 48h).
  • the resin is swelled in DCE (10 mL) and TBSONH2 (0.107 mg, 0.730 mmol 5 eq) is added, and the reaction mixture is refluxed for 20 h (ca. 90°C).
  • the resin is filtered and washed (DCM); the filtrate is collected and evaporated.
  • the oily residue is vacuum dried and co-evaporated with chloroform several times to give 55.2 mg of oily product (95% yield).
  • the oily product is dissolved in TFA:water (95:5; v:v) and stirred for 16 h, then evaporated to yield a yellowish, waxy solid.

Abstract

The subject invention involves processes for making hydroxamic acid compounds using a solid-support resin having an oxime moiety as the linking moiety of the resin, comprising the steps of (a) treating the resin with a carboxylic acid compound, such that it is attached to the resin by a condensation reaction between the oxime and carboxyl moieties; (b) optionally modifying the side chain; (c) cleaving a product from the resin by treating with O-tert-butyldimethylsilylhydroxylamine; (d) optionally modifying the side chain; and (e) optionally treating the resulting O-TBS-protected material with acid to produce an unprotected hydroxamic acid compound.

Description

Solid Supported Synthesis of Hydroxamic Acids
TECHNICAL FIELD
The subject invention relates to methods for synthesizing hydroxamic acid compounds using a solid-support resin to facilitate purification of intermediates.
BACKGROUND OF THE INVENTION Hydroxamic acids are an important class of organic molecules playing a key role in many biologically relevant interactions. Inhibition of matrix metalloproteinases (MMPs) (see Greenwald, R. A.; Golub, L. M., Eds.; Inhibition of Matrix Metalloproteinases: Therapeutical Potential; New York Academy of Sciences, vol. 732 (1994), and Rockwell, A.; Melden, M.; Copeland, R. A.; Hardman, K.; Decicco, C. P.; DeGrado, W. F.; J. Am. Chem. Soc., vol. 118 (1996), p. 10337 and references therein) or a unique deacetylase of lipid A biosynthesis (see Onishi, R. H.; Pelak, B. A.; Gerckens, L. S.; Silver, L. L.; Kahan, F. M.; Chen, M-H.; Patchett, A. A.; Galloway, S. M.; Hyland, S. A.; Anderson, M S.; Raetz C. R. H.; Science, vol. 274 (1996), p. 980) testify to the significance of this class of compounds.
Synthesis on solid support is a crucial technology for combinatorial chemistry efforts. It allows for easy automation of processes and convenient handling of polar molecules throughout the synthetic protocol. It also provides a reliable method for the preparation of mixtures of compounds (split-mix synthesis). The solid supported synthesis of hydroxamic acids, based on Wang, Sasrin, or the 2-chlorotrityl O-hydroxylamine bound resin have recently been reported. (See Richter, L. S.; Desai, M. C; Tetrahedron Lett., vol. 38 (1997), p. 321; Gordeev, M. F.; Hui, H. C; Gordon, E. M.; Patel, D. V.; Tetrahedron Lett., vol. 38 (1997), p. 1729; Mellor, S. L.; McGuire, C; Chan, W. C; Tetrahedron Lett., vol. 38 (1997), p. 3311; and Bauer, U.; Ho, W-B.; Koskinen, A. M. P.; Tetrahedron Lett., vol. 38 (1997), p. 7233.) Another alternative synthetic approach, based on resin N-linked hydroxylamine has been reported. (See Ngu, K.; Patel, D. V.; J. Org. Chem., vol. 62 (1997), p. 7088.)
We have found two major limitations of the reported methods for making hydroxamic acids using solid-support resins. First, during side chain modifications we sometimes observed undesired functionalization of the nitrogen which ultimately is part of the hydroxylamino moiety of the hydroxamic acid: Resin-ONHCOR. Second, none of the above reported methods allows application of acid labile protecting groups (e.g. Boc) during side-chain synthesis.
SUMMARY OF THE INVENTION The subject invention involves processes for making hydroxamic acid compounds: RC(O)NHOH, using a solid-support resin having an oxime moiety: Resin:C=N-OH, as the linking moiety of the resin, comprising the following steps:
(a) treating the resin with a carboxylic acid compound: R C(O)OH, having a carboxyl moiety: C(O)OH, and a side chain moiety: R , whereby the carboxylic acid compound becomes attached to the resin due to a condensation reaction between the oxime and carboxyl moieties;
(b) optionally modifying the side chain R to produce side chain R of the target hydroxamic acid compound or an intermediate side chain R , through one or more reaction and purification procedures, whereby a resin, linking, and attached moiety has the structure: Resin:C=NOC(O)R or Resin: C=NOC(O)R or Resin: C=NOC(O))R;/;
(c) cleaving a product from the resin by treating with O-tert- butyldimethylsilylhydroxylamine: TBSONH2, to produce a TBS- protected hydroxamic acid compound: R C(O)NHOTBS or
RC(O)NHOTBS or R//C(O)NHOTBS;
(d) optionally modifying the side chain R or R to produce the side chain R of the target hydroxamic acid compound, whereby RC(O)NHOTBS is produced; and (e) optionally treating the RC(O)NHOTBS with acid to produce an unprotected hydroxamic acid compound: RC(O)NHOH.
DETAILED DESCRIPTION OF THE INVENTION The subject invention involves processes for making hydroxamic acid compounds:
RC(O)NHOH (1)
Many hydroxamic acids are known. In structure (1), R can be virtually any organic radical. It is limited only by stability and solubility factors during processing and as part of the final product. The subject invention processes use a solid-support resin having an oxime moiety as the linking moiety of the resin. A preferred resin is an oxime (Kaiser) resin available commercially from Novabiochem, San Diego, California, having the structure:
where ^ is the resin backbone. The first step of the subject invention processes involves treating the resin with a carboxylic acid compound:
R/C(O)OH (3)
Many carboxylic acids are known. R can be virtually any organic radical that provides a stable and soluble compound (3), and will not react preferentially (to the acid moiety) with the oxime moiety of the resin. R can be the same or different from R. The carboxylic acid becomes attached to the resin by a simple condensation reaction between the carboxyl moiety of the carboxylic acid and the oxime moiety of the resin. Preferably the reaction is carried out with the resin suspended in dichloromethane (DCM) in the presence of one equivalent of 1,3- diisopropylcarbodiimide (DIC) and a catalytic amount of 4-dimethylaminopyridine (DMAP).
If R is different from the desired R of the hydroxamic acid being produced, one or more reaction and purification procedures can be used to modify the structure of the side chain R . This second step is optional since R and R may be the same moiety, or no modification of R may be desired at this stage of the process. However, this second step is preferably used, since the ease of modifying R during this step is one of the primary advantages of the subject processes.
Linkage of the material undergoing modification to the solid-support resin provides the advantage of easy purification of intermediates by simply washing excess reagents and impurities from the resin-bound materials using appropriate solvents. An advantage of the subject invention process is that the linkage of the product to the oxime resin is typically both acid and base stable to a sufficient extent that a wide variety of reactions can be utilized in modifying the side chain of the product. This includes the use of both acid and base labile protecting groups during these reaction and purification steps.
Ultimately these reaction and purification steps provide a resin-bound material having the structure:
Resin:C=NOC(O)R* (4) where R* is R or R or R . A product is cleaved from the resin in a third step by treating structure (4) with O-tert-butyldimethylsilylhydroxylamine:
TBSONH2 where TBS is tert-butyldimethylsilyl, producing an O-tert-butyldimethylsilyl- protected hydroxamic acid compound:
R*C(O)NHOTBS (5)
The O-TBS -protected product (5) may be useful in its own right, if further modifications of the material are desired to be made with the O-protecting group in place. If R* is R or R , it is modified in an optional fourth step through one or more reaction and purification procedures to produce side chain R of the target hydroxamic acid compound:
RC(O)NHOTBS (6)
This step is optional since it is not needed if R* is R.
The corresponding unprotected hydroxamic acid compound is produced in a fifth step by treating structure (6) with acid, producing the target compound:
RC(O)NHOH (1)
This step is optional, because it may be desirable to retain the hydroxamic acid compound produced in its O-TBS -protected state.
While inorganic acids such as HC1 or HBr can be used in this fifth step to produce the hydroxamic acid, the use of a volatile organic acid, such as trifluoroacetic acid (TFA), is highly preferred. Both TBSONH2 and an acid such as TFA are generally more volatile than the unprotected hydroxamic acid product, so that excess amounts of them are readily separated from the unprotected hydroxamic acid compound by evaporation. The subject invention processes provide easy purification of intermediates which are bonded to the resin, and easy purification of the final product due to the volatility of the reagents used. This makes the processes amenable to automation.
They are readily used for providing mixed-compound or isolated-compound combinatorial libraries of compounds. The subject processes also minimize undesired functionalization of the nitrogen which ultimately is part of the hydroxylamino moiety of the hydroxamic acid produced.
A preferred exemplary synthetic route, which is outlined in Scheme 1, utilizes oxime (Kaiser) resin (1) which is reacted with carboxylic acid to produce esters (2). After side chain modification, the product is cleaved as an O-protected hydroxamic acid (3), using O-tert-butyldimethylsilylhydroxylamine. (At this stage the crude product can be purified by silica gel chromatography.) Finally, the silyl group is removed with trifluoroacetic acid at room temperature to afford pure hydroxamic acid (4).
Scheme 1
TBS0N^ RCONHOTBS-IFA_ RCONHOH 4
A small exemplary set of hydroxamic acids prepared by the process of Scheme 1 is shown in Table 1 :
Table 1
The following description details the making of 2-furoic hydroxamate, Example A in Table 1. Oxime resin (1.0 g, 1.17 mmol/g, 1.17 mmol; Novabiochem, product number 01-64-0022) is rinsed several times with dichloromethane (DCM). 2-Furoic acid (5eq, 655 mg, 5.85 mmol) in DCM (12 mL) is added, followed by 1,3-diisopropylcarbodiimide (DIC; 737 mg, 5.85 mmol) and a catalytic amount of 4-dimethylaminopyridine (DMAP, 5 mg). The reaction mixture is shaken for 17 hours and the resin is filtered and washed (DCM, 2- propanol, dimethylformamide (DMF)). Alternate washing with DCM and 2- propanol is repeated several times, and finally the resin is dried under vacuum for several hours at room temperature. The resin is swelled in 1 ,2-dichloroethane (DCE, 10 mL). TBSONH2 (107 mg, 0.730 mmol, 5 eq) is added and the reaction mixture is refluxed for 20 h (ca. 90°C). The resin is filtered and washed (DCM); the filtrate is collected and evaporated. The oily residue is vacuum dried and co- evaporated with chloroform several times to give 198 mg of oily product. This residue is dissolved in TFA:water (95:5; v:v) and stirred for 16 h, then evaporated to yield a yellowish, waxy solid, 131 mg (95% purity).
To demonstrate the possibility of using acid labile protecting groups, N- tosyl-proline hydroxamic acid (8) is prepared according to Scheme 2 and the following described procedure:
Scheme 2
7 8
Reagents: a) Boc-Pro-OH, DIC, DMAP, DCM; b) 25% TFA/DCM ; c) TsCl, DIPEA, DCM; d) TBSONH2, DCE; e) 95% TFA/H2O.
Oxime resin (1.0 g, 1.17 mmol/g, 1.17 mmol; Novabiochem, product number 01-64-0022) is rinsed several times with DCM. Boc-proline (5eq, 1.28 g, 5.85 mmol) in DCM (12 mL) is added, followed by DIC (737 mg, 5.85 mmol) and a catalytic amount of DMAP (5 mg). The reaction mixture is shaken for 17 hours, and the resin is filtered and washed (DCM, 2-propanol, DMF). Alternate washing with DCM and 2-propanol is repeated several times, and finally the resin is dried under vacuum for several hours at room temperature to give 1.188 g of Boc-proline loaded resin (yield 96.5%, new loading 0.78 mmol/g). The Boc-proline oxime resin ester (158 mg, 0.146 mmol) is treated with 25% TFA in DCM and shaken for lh. The resin is filtered and washed several times with DCM and 10% DIPEA/DCM. DCE and N,N-diisopropylethylamine (DIPEA) are added (2:1, total 5 mL), followed by tosyl chloride (TsCl, 140 mg, 0.730 mmol, 5 eq). The reaction mixture is shaken for 6 h, then filtered, washed (DCM, 2-propanol and again DCM several times) and vacuum dried (room temperature, 48h). The resin is swelled in DCE (10 mL) and TBSONH2 (0.107 mg, 0.730 mmol 5 eq) is added, and the reaction mixture is refluxed for 20 h (ca. 90°C). The resin is filtered and washed (DCM); the filtrate is collected and evaporated. The oily residue is vacuum dried and co-evaporated with chloroform several times to give 55.2 mg of oily product (95% yield). The oily product is dissolved in TFA:water (95:5; v:v) and stirred for 16 h, then evaporated to yield a yellowish, waxy solid.
While particular embodiments of the subject invention have been described, it will be obvious to those skilled in the art that various changes and modifications of the subject invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.

Claims

WHAT IS CLAIMED IS:
1. A process for making a hydroxamic acid compound using a solid-support resin having an oxime moiety as the linking moiety of the resin, comprising the following steps:
(a) treating the resin with a carboxylic acid compound having a carboxyl moiety and a side chain moiety, whereby the resin is loaded by attachment of the carboxylic acid compound to the resin due to a condensation reaction between the oxime and carboxyl moieties;
(b) optionally, while on the loaded resin, modifying the side chain from the carboxylic acid compound through one or more reaction and purification procedures;
(c) cleaving a product from the loaded resin of step (b) by treating with O-tert-butyldimethylsilylhydroxylamine: TBSONH2, to produce an O- TBS-protected hydroxamic acid compound;
(d) optionally modifying the side chain from step (b) through one or more reaction and purification procedures; and
(e) optionally treating the O-TBS-protected hydroxamic acid compound from step (d) with acid to produce an unprotected hydroxamic acid compound.
2. The process of Claim 1 wherein step (b) is not optional.
3. The process of Claim 1 or 2 wherein step (e) is not optional.
4. The process of any of Claims 1-3 wherein step (b) comprises a reaction where the side chain has an acid-labile protecting group.
5. The process of any of Claims 1-4 wherein step (b) comprises a reaction where the side chain has a base-labile protecting group.
6. The process of any of Claims 1-5 wherein the acid used in step (e) is a volatile organic acid, preferably trifluoroacetic acid.
7. The process of any of Claims 1-6 wherein the side chain from the carboxylic acid compound is modified producing the side chain of the hydroxamic acid compound in step (b), and step (d) is not used, so that in step (e), the O-TBS- protected hydroxamic acid compound from step (c) is treated.
The process of any of Claims 1-7 wherein the resin has the structure:
9. The process of any of Claims 1-8 wherein the process is used to make a combinatorial library of compounds.
EP98959113A 1998-01-09 1998-12-28 Solid supported synthesis of hydroxamic acids Withdrawn EP1045831A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US7098098P 1998-01-09 1998-01-09
US70980P 1998-01-09
PCT/IB1998/002117 WO1999035126A1 (en) 1998-01-09 1998-12-28 Solid supported synthesis of hydroxamic acids

Publications (1)

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EP1045831A1 true EP1045831A1 (en) 2000-10-25

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EP (1) EP1045831A1 (en)
JP (1) JP2002500216A (en)
AU (1) AU1502999A (en)
CA (1) CA2318487A1 (en)
IL (1) IL137217A0 (en)
NO (1) NO20003541L (en)
WO (1) WO1999035126A1 (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9503749D0 (en) * 1995-02-24 1995-04-12 British Biotech Pharm Synthesis of hydroxamic acid derivatives
AU5426398A (en) * 1996-10-28 1998-05-22 Versicor Inc Methods for solid-phase synthesis of hydroxylamine compounds and derivatives, and combinatorial libraries thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9935126A1 *

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AU1502999A (en) 1999-07-26
WO1999035126A1 (en) 1999-07-15
NO20003541L (en) 2000-08-31
IL137217A0 (en) 2001-07-24
NO20003541D0 (en) 2000-07-10
CA2318487A1 (en) 1999-07-15

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