Patent EA-002478-B1 (EA)
Title: Method for the solid phase synthesis of aldehydes, ketines, oximes, amines and hydroxamic acid compounds
Inventor: SALVINO JOSEPH M
IPC: C07C/
Filed: 1997-12-17
Abstract: 1. A process for the preparation of a ketone compound of formula   wherein Rc and Ra are independently aliphatic or aromatic group, comprising: (a) i) reacting a carboxylic acid of formula RaCHO and polymeric hydroxamine resin of formula   with forming polymeric reisin of hydroxamic acid of the formula   with further reacting polymeric reisin of hydroxamic acid with alkylating or arylating agent of the formula RbLG, wherein LG is a leaving group, with forming polymeric reisin of N-alkylated or N-arylated hydroxamic acid of the general formula:   or ii) reacting polymeric reisin of N-protected hydroxylamine of the formula   wherein P is aminoprotective group with alkylating or arylating reagent of the formula RbLG, wherein LG is a leaving group, with forming polymeric reisin of N-protected, N-alkylated or N-arylated hydroxylamine of the formula:   with further removal aminoprotective group with forming polymeric reisin of N-alkylated or N-arylated hydroxylamine of the formula:   and combination of polymeric reisin of N-alkylated or N-arylated hydroxylamine with carboxylic acid of the formula RaCOOH with formation of polymeric reisin of N-alkylated or N-arylated hydroxamic acid of formula:   b) reacting polymeric reisin of N-alkylated or N-arylated hydroxamic acid of formula:   wherein   is a solid support, L is absent or a linking group and Ra and Rb are independently aliphatic or aryl group with an organometallic reagent of formula RcM wherein Rc is an aliphatic or aryl anion and M is a metal cation; and (c) liberating the ketone compound from the resin. 2. A process for the preparation of an aldehyde compound of formula RaCHO wherein Ra is aliphatic or aryl group, comprising: (a) reacting an N-alkylated polymeric hydroxamic acid resin compound of formula     is a solid support, L is absent or a linking group and Ra and Rb are independently aliphatic or aryl group with hydride regenerative agent, and b) isolation of aldehyde from the resin. 3. A process for the preparation of polymeric reisin of N-alkylated hydroxamic acid of formula:   wherein   is a solid support, L is absent or a linking group and Ra and Rb are independently aliphatic or aryl group, comprising a) reacting a carboxylic acid of formula RaCHO and polymeric hydroxamine resin of formula   with forming polymeric reisin of hydroxamic acid of the formula   b) reacting polymeric reisin of hydroxamic acid with alkylating agent of the formula RbLG, wherein LG is a leaving group. 4. The process of Claim 3 wherein polymeric hydroxamine resin is 4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-[4-(O-methylhydroxylamine)-3-methoxyphenoxy]-(N-4-methylbenzhydryl)-butyramide-copoly(styrene-1%-divinylbenzene) resin, 4-(2',4'-dimethioxyphenyl-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin, 4-[4-(1-aminoxyethyl)-2-methoxy-5-nitrophenoxy]-(N-4-methylbenzhydryl)-butyramide-copoly(styrene-1% divinylbenzene) resin, O-hydroxylamine-2' -chlorotrityl-copoly(styrene-1%-divinylbenzene) resin, O-hydroxylaminetrityl-copoly(styrene-1%-divinylbenzene) resin, 5-(4-O-methylhydroxylamine-3,5-dimethoxyphenoxy)-valeric acid-copoly(styrene-1%-divinylbenzene) resin, 4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-O-methylhydroxylamine-3-methoxyphenoxy-copoly(styrene-1%-divinylbenzene) resin, or 3-hydroxyxanthydrolamine-copoly(stryene-1 %-divinylbenzene) resin. 5. A process for the preparation of polymeric resin of N-alkylated hydroxamic acid of formula:   wherein   is a solid support, L is absent or a linking group and Ra and Rb are independently aliphatic or aryl group, comprising a) reacting a N-protected hydroxylamine polymeric resin of formula   wherein P is aminoprotective group, with alkylating agent of the formula RbLG, wherein LG is a leaving group, with forming polymeric resin of N-protected, N-alkylated hydroxylamine of the formula:   b) removal aminoprotective group with forming polymeric resin of N-alkylated hydroxylamine of the formula:   c) combination of polymeric resin of N-alkylated hydroxylamine with carboxylic acid of the formula RaCOOH. 6. The process of Claim 5, wherein P is allyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trimethylsilylethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, o-nitrobenzolsulfonyl, p-nitrobenzolsulfonyl, and 2-nitro-4-trifluoromethylbenzenesulfonyl. 7. A polymeric resin of N-protected hydroxylamine of the formula    wherein   is a solid support; L is absent or a linking group;and P is an amine protecting group, provided that P is other than 4-methoxybenzyl or 2,4-dimethoxybenzyl. 8. A polymeric N-protected hydroxylamine resin compound according to Claim 7 wherein L is a linking group. 9. A polymeric N-protected hydroxylamine resin compound according to Claim 8 wherein L is a linking group of formula   wherein A is absent or a group of formula -X<1>-Z- wherein X<1> is -CHR- or -CHR-Y-CO-(CH2)n- wherein R is H, alkyl, phenyl, or phenyl substituted with -H, alkyl, alkoxy, halogen, nitrile or -NO2, Y is -O- or -NH-, n is an integer from 1 to 6, and Z is -O- or -NH-; R<1>, R<1a>, R<2>, and R<2a> are independently -H, alkyl, alkoxy, halogen, nitrile or -NO2; and R<3> and R<4> are independently -H, alkyl, phenyl, or phenyl substituted with one or more substituents selected from alkyl, alkoxy, halogen, nitrile and -NO2; or one of R<1> and R<2> taken together with one of R<3> and R<4> and the carbon atoms to which they are attached define a linking group of formula   wherein R<1>' is -H, alkyl, alkoxy, halogen, nitrile or -NO2; and R<6>, R<7> and R<8> are independently selected from -H, alkyl, alkoxy, halogen, nitrile or -NO2. 10. A polymeric N-protected hydroxylamine resin compound according to Claim 9 wherein P is allyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trimethylsilylethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, o-nitrobenzolsulfonyl, p-nitrobenzolsulfonyl, and 2-nitro-4-trifluoromethylbenzenesulfonyl. 11. A polymeric N-protected hydroxylamine resin compound according to Claim 10 which is N-allyloxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1% divinylbenzene) resin, N-allyloxycarbonyl-4-[4-(O-methylhydroxylamine)-3-methoxyphenoxy]-(N-4-methylbenzhydryl)butyramide-copoly(styrene-1%-divinylbenzene) resin, N-allyloxycarbonyl-4-(2',4' -dimethoxyphenyl-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1% divinylbenzene) resin, N-allyloxycarbonyl-4-[4-(1-aminoxyethyl)-2-methoxy-5-nitrophenoxy]-(N-4-methylbenzhydryl) butyramide-copoly(styrene-1% divinylbenzene) resin, N-allyloxycarbonyl-O-hydroxylamine-2'-chlorotrityl-copoly(styrene-1% divinylbenzene) resin, N-allyloxycarbonyl-O-hydroxylaminetrityl-copoly(styrene-1% divinylbenzene) resin, N-allyloxycarbonyl-5-(4-O-methylhydroxylamine-3,5-dimethoxyphenoxy) valeric acid-copoly(styrene1% divinylbenzene) resin, N-allyloxycarbonyl-4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, N-allyloxycarbonyl-4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, N-allyloxycarbonyl-4-O-methylhydroxylamine-3-methoxyphenoxycopoly(styrene-1% divinylbenzene) resin, or N-allyloxycarbonyl-3-hydroxyxanthydrolamine-copoly(stryene-1% divinylbenzene) resin. 12. A process for preparing a hydroxamic acid compound of formula   wherein A<2> is a direct bond or an alkylene group, or NR<13> wherein R<13> is hydrogen or alkyl; R<9> is a group of formula -L<1>-R<14>, where L<1> represents a direct bond or a straight- or branched C<1-6>alkylene chain optionally substituted by alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl, hydroxyl, or oxo, and R<14> is hydrogen, aryl, carboxy, cyano, cycloalkyl, cycloalkenyl, cyclocarbamoyl, cycloimidyl, heterocycloalkyl, heteroaryl, -NH-C(=O)-NH2, (N-carbamoyl)cyclic amine, -C=N-O-C(=O)-NH2, -C(=O)-NY<1>Y<2> [where Y<1> and Y<2> are independently hydrogen, alkyl, arylalkyl, and aryl, or the substituent Y<1>Y<2>N- forms a 4-6 membered cyclic amine which optionally contains an additional heteroatom selected from O, S, NH or NR<13>], -NY<1>SO2-aryl, -NHR<13>, -SR<13> or -OR<13>; or a group -L<2>-R<15> where L<2> represents a straight- or branched-carbon chain comprising from 2 to about 6 carbon atoms, optionally substituted with carboxy- or cyano, which contains a double or triple carbon-carbon bond, or is interrupted by an oxygen or sulfur atom, a phenylene, imino (-NH-) or alkylimino group, or a sulfinyl or sulfonyl group, and R<15> is hydrogen, aryl, carboxy, cyano, cycloalkyl, cycloalkenyl, heterocycloalkyl or heteroaryl; or R<9> and R<10> taken together with the atom to which they are attached form a ring; or R<9> and R<11> taken together with the atoms through which they are attached form a ring; R<10> and R<12> are independently hydrogen or alkyl; or R<10> and R<12> together form a bond; R<11> represents a group -L<3>-R<16> where L<3> represents a direct bond or a straight or branched C1-6alkylene chain optionally substituted by by alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl, hydroxyl, or oxo; or L<3> represents a straight or branched carbon chain comprising from 2 to about 6 carbon atoms which contains a double or triple carbon-carbon bond, or is interrupted by an oxygen or sulfur atom, a phenylene, imino (-NH-) or alkylimine, or a sulfinyl or sulfonyl group; and R<16> is hydrogen, aryl, cycloalkyl, cycloalkenyl, cyclocarbamoyl, cycloimidyl, heterocycloalkyl, heteroaryl, -NH-C(=O)-NH2, (N-carbamoyl)cyclic amine, -C=N-O-C(=O)-NH2, -C(=O)-NY<1>Y<2> [where Y<1> and Y<2> are independently hydrogen, alkyl, arylalkyl, and aryl, or the substituent Y<1>Y<2