EP1045831A1 - Solid supported synthesis of hydroxamic acids - Google Patents
Solid supported synthesis of hydroxamic acidsInfo
- 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- Withdrawn
Links
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.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
Description
Claims
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)
Publication Number | Publication Date |
---|---|
EP1045831A1 true EP1045831A1 (en) | 2000-10-25 |
Family
ID=22098530
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98959113A Withdrawn EP1045831A1 (en) | 1998-01-09 | 1998-12-28 | Solid supported synthesis of hydroxamic acids |
Country Status (7)
Country | Link |
---|---|
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9503749D0 (en) * | 1995-02-24 | 1995-04-12 | British Biotech Pharm | Synthesis of hydroxamic acid derivatives |
WO1998018754A1 (en) * | 1996-10-28 | 1998-05-07 | Versicor, Inc. | Methods for solid-phase synthesis of hydroxylamine compounds and derivatives, and combinatorial libraries thereof |
-
1998
- 1998-12-28 EP EP98959113A patent/EP1045831A1/en not_active Withdrawn
- 1998-12-28 CA CA002318487A patent/CA2318487A1/en not_active Abandoned
- 1998-12-28 AU AU15029/99A patent/AU1502999A/en not_active Abandoned
- 1998-12-28 IL IL13721798A patent/IL137217A0/en unknown
- 1998-12-28 JP JP2000527528A patent/JP2002500216A/en not_active Withdrawn
- 1998-12-28 WO PCT/IB1998/002117 patent/WO1999035126A1/en not_active Application Discontinuation
-
2000
- 2000-07-10 NO NO20003541A patent/NO20003541L/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9935126A1 * |
Also Published As
Publication number | Publication date |
---|---|
JP2002500216A (en) | 2002-01-08 |
NO20003541D0 (en) | 2000-07-10 |
IL137217A0 (en) | 2001-07-24 |
NO20003541L (en) | 2000-08-31 |
CA2318487A1 (en) | 1999-07-15 |
AU1502999A (en) | 1999-07-26 |
WO1999035126A1 (en) | 1999-07-15 |
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