JP2008069163A - Solid-phase synthesis method for aldehyde, ketone, oxime, amine and hydroxamic acid compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for synthesizing each of aldehydes, ketones, oximes, amines and hydroxamic acid compounds. <P>SOLUTION: Provided is a solid-phase synthesis method for each of aldehydes, ketones, oximes, amines and hydroxamic acid compounds. A polymer hydroxylamine resin compound useful for the method is also provided. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

FIELD OF THE INVENTION The present invention relates to a solid phase synthesis process for aldehydes, ketones, oximes, amines and hydroxamic acid compounds and polymeric hydroxylamine resin compounds useful for these.

BACKGROUND OF THE INVENTION Solid-phase synthesis techniques (fixed to a polymer material that is not only inert to the reagents and reaction conditions used, but also insoluble in the medium used) prepare amides, peptides and hydroxamic acids. It is an important means to do. For solid phase peptide synthesis, many technical summaries can be found in JM Stewart and JD Young, Solid Phase Peptide Synthesis, 2nd. Ed., Pierce Chemical Co. (Chicago, IL, 1984); J. Meienhofer, Hormonal Proteins and Peptides, vol. 2, p. 46, Academic Press (New York), 1973; and E. Atherton and RC Sheppard, Solid Phase Peptide Synthesis: A Practical Approach, IRL Press at Oxford University Press (Oxford, 1989). For the use of solid phase methods in the preparation of non-peptide molecules, see Leznoff, CC, Acc. Chem. Res., 11 , 327-333 (1978).

Several polymer reagents have synthetic uses for simple functional group transformations. A. Akelah and DC Sherrington, Application of Functionalized Polymers in Organic Synthesis, Chem Rev., 81 , 557-587 (1981) and WT Ford and EC Blossey, Polymer Supported Reagents, Polymer supported Catalysts, and Polymer Supported Coupling Reactions, in Preparative See Chemistry using Supported Reagents, Pierre Laszlo, ed., Academic Press, Inc, 193-212 (1987). Regarding the use of polymer reagents in oxidation reactions, JMJ Frechet et al., J. Org. Chem., 43 , 2618 (1978) and G. Cainelli et al., J. Am. Chem. Soc., 98 , 6737 (1976 )checking. For the use of polymeric reagents in halogenation reactions, see JMJ Frechet et al., J. Macromol. Sci. Chem., A-11 , 507 (1977) and DC Sherrington et al., Eur. Polym. J., 13 , 73. , (1977). For the use of polymeric reagents in epoxidation reactions, see JMJ Frechet et al., Macromolecules, 8 , 130 (1975) and CR Harrison et al., J. Chem. Soc. Chem. Commun., 1009 (1974). . See MB Shambhu et al., Tet. Lett., 1627 (1973) and MB Shambhu et al., J. Chem. Soc. Chem. Commun., 619 (1974) for the use of polymeric reagents in acylation reactions. thing. For the use of polymeric reagents in the Wittig reaction, see SV McKinley et al., J. Chem. Soc. Chem. Commun., 134 (1972).

The polymeric reagents also have a wide range of uses in combinatorial synthesis and preparation of combinatorial libraries. See F. Balkenhohl et al., Angew. Chem. Int. Ed. Engl., 35 , 2288-2337 (1996) and LA Thompson et al., Chem Rev., 96 , 555-600 (1996).

  Polymeric reagents have advantages for easy separation from low molecular weight reactants or products by filtration or selective precipitation. Polymeric reagents can also be used excessively to perform rapid and quantitative reactions as in acylation, or a large excess of reactants can be directed toward product formation, as seen in solid phase peptide synthesis. Can be used to induce an equilibrium of the reaction to obtain a quantitative conversion to the product. A further advantage of supported reagents and catalysts is that they can be circulated and that they are easily adapted to automated methods. In addition, supported analogues of toxic and odorous reagents are safer to use.

  PCT application publication WO 96/26223 discloses the synthesis of hydroxamic acid compounds using solid phase hydroxylamine substrates.

Prasad et al. Discloses an O-methylhydroxylamine-polystyrene resin compound in J. Steroid Biochem., 18 , 257-261 (1983).

SUMMARY OF THE INVENTION
Formula (a)

(Where

Is a solid support, L is absent or a linking group, and R _b is aliphatic or aryl)
A N-alkylated polymeric hydroxamic acid resin compound of the formula R _c M where R _{c is an} aliphatic or aryl anion and M is a metal cation; and

  (b) a formula characterized by liberating a ketone compound from a resin

(Wherein R _c and R _a are independently aliphatic or aromatic)
The present invention relates to a method for preparing a ketone compound.

In another aspect, the present invention provides
Formula (a)

(Where

, L and R _a and R _b are defined above)
Reacting a N-alkylated polymer hydroxamic acid resin compound with a reducing agent; and

(b) The present invention relates to a method for preparing an aldehyde compound of R _a CHO (wherein R _a is defined above), wherein the aldehyde compound is released from a resin.

In another aspect, the present invention provides
(a) a carboxylic acid compound of the formula R _a CO ₂ H

Coupling with a polymer hydroxylamine resin compound of formula

A polymer hydroxamic acid resin compound, and
(b) a formula characterized by reacting a polymeric hydroxamic acid resin compound with an alkylating agent of the formula R _b LG where LG is a leaving group

(Where

, L and R _a and R _b are defined above)
The present invention relates to a method for preparing N-alkylated polymer hydroxamic acid resin compounds.

In another aspect, the present invention provides
Formula (a)

(Wherein P is an amine protecting group)
Of the N-protected polymer hydroxamic acid resin compound is reacted with an alkylating agent of R _b LG where LG is as defined above.

Producing a polymer N-protected N-alkylated hydroxylamine resin compound of

  (b) Formula with the amine protecting group removed

A polymer N-alkylated hydroxylamine resin compound, and

(c) a formula characterized by coupling _a polymer N-alkylated hydroxylamine resin compound with a carboxylic acid compound of formula R _a CO ₂ H

(Where

, L and R _a and R _b are defined above)
The present invention relates to a method for preparing N-alkylated polymer hydroxamic acid resin compounds.

  In another aspect, the invention provides a formula

(Where
A ² is a direct bond or alkylene, or NR ¹³ (wherein R ¹³ is hydrogen or alkyl);

R ⁹ has the formula -L ¹ -R ¹⁴ (wherein L ¹ is a direct bond or optionally substituted by alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl, hydroxyl, or oxo). Represents a chain or branched C _1-6 alkylene chain, and R ¹⁴ is hydrogen, aryl, carboxy, cyano, cycloalkyl, cycloalkenyl, cyclocarbamoyl, cycloimidyl, heterocycloalkyl, heteroaryl, —NH—C (═O) -NH ₂ , (N-carbamoyl) cyclic amine, -C = NOC (= O) -NH ₂ , -C (= O) -NY ¹ Y ^{2 wherein} Y ¹ and Y ² are independently hydrogen, alkyl , Arylalkyl, and aryl, or the substituent Y ¹ Y ² N- may optionally contain an additional heteroatom selected from O, S, NH 3 or NR ¹³ -NY ¹ SO ₂ aryl, -NHR ¹³ , -SR ¹³ or -OR ^{1 3} is a) a group, or in group L ² -R ¹⁵ (wherein, straight or branched carbon L ² contains carbon atoms from the two which may optionally be substituted by carboxy or cyano necessary up to about 6 A chain (which contains a double or triple carbon-carbon bond or is interrupted by an oxygen or sulfur atom, a phenylene bond, an imino (-NH-) bond or an alkylimino bond, 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 are the atoms to which they are attached. Together to form a ring, or R ⁹ and R ¹¹ together with the atoms to 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 is a group -L ³ -R ¹⁶ , wherein L ³ is a direct bond or optionally substituted by alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl, hydroxyl, or oxo. Represents a chain or a branched C _1-6 alkylene chain, or L ³ is a straight or branched carbon chain containing from 2 to about 6 carbon atoms (this includes a double carbon-carbon bond or a triple carbon-carbon bond). Or is interrupted by an oxygen or sulfur atom, a phenylene bond, an imino (-NH-) bond or an alkylimino bond, or a sulfinyl group or a sulfonyl group), and R ¹⁶ is hydrogen, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-carbamoyl, Shikuroimijiru, heterocycloalkyl, heteroaryl, -NH-C (= O) -NH 2, (N- carbamoyl) cyclic amine, -C = NOC (= O) - NH ₂ , —C (═O) —NY ¹ Y ^{2 wherein} Y ¹ and Y ² are independently hydrogen, alkyl, arylalkyl, and aryl, or the substituent Y ¹ Y ² N— is required Represents a 4-6 membered cyclic amine which may contain additional heteroatoms selected from O, S, NH 3 or NR ¹³ ], —NY ¹ SO ₂ aryl), or R ¹¹ and R ⁹ together with the atom to which they are attached forms a ring, or R ¹¹ and R ¹² together with the atom to which they are attached form a ring;

  Ar is

(i)

Or (ii)

A group selected from
Wherein R ¹⁷ is a linear or branched alkyl group of 1 to about 6 carbon atoms optionally substituted with one or more halogen atoms, or when Z ³ is a direct bond R ¹⁷ may also represent a hydrogen atom, an alkenyl group or an alkynyl group,

R ¹⁸ represents an optionally substituted cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, aryl group, partially saturated bicycloaryl group or heteroaryl group,

R ¹⁹ is R ²⁰ , -OR ²⁰ , -SR ²⁰ , -SOR ²⁰ , -SO ₂ R ²⁰ , -SO ₂ NR ²⁰ R ²¹ , -NR ²⁰ SO ₂ R ²¹ , -NR ²⁰ R ²¹ , -O (C ^{= O) NR 20 R 21,} -NR 20 C (= O) R 2 1, -N (OH) C (= O) R 20, or -C (= O) N (OH ) R 21 ( wherein, R ²⁰ and R ²¹ (which may be the same or different) are each a hydrogen atom, or an alkyl group, alkenyl group, heterocycloalkyl group, cycloalkyl group, cycloalkenyl group, aryl group Represents a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, or the group NR ²⁰ R ²¹ may optionally contain one or more additional heteroatoms selected from O, N or S 5 When it represents a 7-membered cyclic amine and R ¹⁸ represents a substituted cycloalkyl group, the cycloalkyl group is OR ²³ , SR ²⁴ , SOR ²⁴ , SO ₂ R ²⁴ , NH ₂ , NR ¹³ R ²⁴ , = NOR ²⁴ , = NOH, = NNHR ²⁴ , = NOCONHR ²⁴ , = NCO ₂ R ²⁴ , SOR ²⁴ , N One or more selected from HCOR ²⁴ , NHSO ₂ R ²⁴ , SO ₂ NR ¹³ R ²⁴ , R ²³ , CONHR ²⁴ , CONHCH ₂ CO ₂ R ¹³ , CONR ²⁴ R ¹³ , or N ₃ (for example, 1 or 2 R ²³ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, and R ²⁴ is alkyl, cycloalkyl, cyclo Alkenyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or the substituent NR ¹³ R ²⁴ optionally contains an additional heteroatom selected from O, S, NH or NR ¹³ When a 4-7 membered cyclic amine is formed and R ¹⁸ represents a substituted heterocycloalkyl group containing a nitrogen atom, the ring is one or more of the ring carbon atoms (eg, 1, 2 or 3 ) Position) The substituent oxo, _{^{cyano, CO 2 R 13, CONHCH 2}} CO 2 R 13, aryl, arylalkyl, selected from alkyl or hydroxyalkyl, and / or is substituted at the position of the ring nitrogen atoms, the substituent Is R ¹³ , (CH ₂ ) _n CO ₂ H, (CH ₂ ) _n CO ₂ R ²⁴ , (CH ₂ ) _n CONR ¹³ R ²⁴ , (CH ₂ ) _n COR ²⁴ , CONH ₂ , CONHR ²⁴ , COR ²⁴ , Selected from SO ₂ R ²⁴ or OR ²⁴ ,

A ³ represents a direct bond, optionally a linear or branched C 1-6 alkylene chain optionally substituted by halogen, hydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroaryl, or A ³ is 2 to about A straight or branched carbon chain containing up to 6 carbon atoms (including double or triple carbon-carbon bonds, or oxygen or sulfur atoms, phenylene bonds, imino (-NH-) bonds or alkylimino bonds, Or is interrupted by a sulfinyl group or a sulfonyl group)

Z ¹ and Z ³ each represents an oxygen atom or a sulfur atom, a direct bond or NH,

Z ² represents an oxygen atom or a sulfur atom, or a direct bond,

B, C, D, and E are independently carbon or O, S, N, NOR ²² or NR ²² (wherein R ²² is hydrogen or a C _1-4 linear or branched alkyl group, aryl group, aryl C _1-4 alkyl group, heteroaryl group or heteroaryl C _1-4 alkyl group), or three of B, C, D or E are carbon or O, N, NR ²² , Or a hetero atom selected from S, and the other represents a direct bond, except for compounds in which two O atoms or S atoms are adjacent to each other, and a bond that binds B, C, D and E is a single bond. May be a bond or a double bond,

Q ¹ , Q ² and Q ³ (which may be the same or different) each represent a CH bond or a CX ¹ bond or a nitrogen atom, X ¹ represents a halogen atom, and

n is 0, 1 or 2)
A process for preparing a hydroxamic acid compound of the formula: or an N-oxide, prodrug, acid isostere, pharmaceutically acceptable salt, or solvate thereof, comprising:
formula

The present invention relates to a preparation method characterized in that the polymer hydroxamic acid resin compound is treated with an acid.
In another aspect, the invention provides a formula

The polymer hydroxylamine resin compound of formula

Characterized by reacting with a carbonyl compound of

(Where

And L are as defined herein, and R _d and _Re are independently H, aliphatic or aromatic)
The present invention relates to a method for preparing the polymer oxime ether resin compound.

In another aspect, the invention provides a formula

(Where

And L are as defined herein)
A reductive cleavage of the polymer oxime ether resin compound of

(Wherein R _d and R _e are independently H, aliphatic or aryl, provided that R _d and R _e are not both H)
The present invention relates to a method for preparing the α-amine compound.

  In another aspect, the present invention provides

  Formula (a)

(Where

And L are as defined herein)
Is reacted with an organometallic reagent of the formula R _f M where Rf is an aliphatic or aromatic anion and M is a metal cation.

A polymer α-substituted hydroxylamine resin compound, and

(b) a formula characterized by reductive cleavage of an α-substituted hydroxylamine resin compound

(Wherein, R _d and R _e are independently are H, aliphatic or aromatic the proviso that not both are R _d and R _e H, and R _f is an aliphatic or aromatic)
Of the substituted α-amine compound.

In another aspect, the present invention provides
Formula (a)

(Where

And L are as defined herein)
The α, β-unsaturated polymer hydroxamic acid ester resin compound of the formula is treated with thiophenol and a free radical initiator.

Wherein the polymer oxymyl lactone compound is treated with an aqueous acid solution.

_Where R _g , R _h and R _i are aliphatic or aromatic and Ph is phenyl.
It relates to a process for preparing the lactone compound.

In another aspect, the invention provides a formula

The polymer hydroxylamine resin compound of formula

Characterized by reacting with an α, β-unsaturated carboxylic acid ester compound of

(Where

, L and R _g and R _h and R _i are as defined herein)
Relates to a process for the preparation of α, β-unsaturated polymer hydroxamic acid ester resin compounds.

In another aspect, the present invention provides
Formula (a)

(Where

And L are as defined herein)
The polymer acetophenone oxime compound was treated with trialkyltin hydride and a free radical initiator to formula

A polymer α-cyclic hydroxylamine resin compound, and

(b) a formula characterized by treating a polymer α-cyclic hydroxylamine resin compound with an aqueous acid solution

Wherein R _j and R _k are aliphatic or aromatic and Q is —O— or —CH 2 —.
To an α-cyclic hydroxylamine compound.

In another aspect, the invention provides a formula

(Where

And L are as defined herein)
Wherein the polymer α-cyclic hydroxylamine resin compound is reductively cleaved

Wherein R _j and R _k are aliphatic or aromatic and Q is —O— or —CH ₂ —.
To an α-cyclic amino compound.

In another aspect, the present invention provides
Formula (a)

(Where

And L are as defined herein)
The polymer acetophenone oxime compound was treated with trialkyltin hydride and a free radical initiator to formula

A polymer α-cyclic hydroxylamine resin compound, and

(b) a formula characterized by treating a polymer α-cyclic hydroxylamine resin compound with an aqueous acid solution

Wherein R _j , R _k and R _l are aliphatic or aromatic and Q is —O— or —CH ₂ —.
To an α-cyclic hydroxylamine compound.

In another aspect, the invention provides a formula

(Where

And L are as defined herein)
Wherein the polymer α-cyclic hydroxylamine resin compound is reductively cleaved

Wherein R _j , R _k and R _l are aliphatic or aromatic and Q is —O— or —CH ₂ —.
To an α-cyclic amino compound.

  In another aspect, the invention provides a formula

(Where

And L is as defined herein and P is an amine protecting group provided that P is other than 4-methoxybenzyl or 2,4-dimethoxybenzyl). Protected hydroxylamine resin compound.

  In another aspect, the invention provides a formula

(Where

, A, R ³ and R ⁴ are as defined herein and P ¹ is an amine protecting group)
The polymer tetrafluorophenylhydroxylamine resin compound.

DETAILED DESCRIPTION OF THE INVENTION Definitions of Terms The following terms used above and used in the description of the invention should be understood to have the following meanings unless otherwise indicated.

  “Solid support” means a support that is not only inert to the reagents and reaction conditions described herein, but is substantially insoluble in the medium used. Typical solid supports include inorganic supports such as diatomaceous earth, silica gel, and controlled pore glass; 1-2% copolystyrenedivinylbenzene (gel form) and 20-40% copolystyrenedivinylbenzene. Organic polymers including polystyrene, polypropylene, polyethylene glycol, polyacrylamide, cellulose, etc. (macroporous form); and composite inorganic / polymer compositions, such as polyacrylamide supported in a matrix of diatomaceous earth particles It is done. See J.M. Stewart and J.D. Young, Solid Phase Peptide Synthesis, 2nd. Ed., Pierce Chemical Co. (Chicago, IL, 1984).

In addition, as a “solid support”, a second inert support such as pins described in the Technical Manual, Multipin ^™ SPOC, Chiron Technologies (1995) and references therein (these are grafted with amino-functionalized methacrylate copolymers). And a solid carrier that is fixed to a removable polyethylene or polypropylene-based head and an inert trunk.

In addition, as "solid carriers", polymer carriers such as those described by Janda et al., Proc. Natl. Acad. Sci. USA, 92 , 6419-6423 (1995) and S. Brenner, WO 95/16918 Polyethylene glycol carriers, which are soluble in many solvents, but can be precipitated by the addition of a precipitation solvent.

“Polymer hydroxylamine resin compound” refers to a solid support that is chemically modified as known in the art to include multiple hydroxylamine groups (—ONH ₂ ) or protected hydroxylamine groups (—ONHP). means. The hydroxylamine group or protected hydroxylamine group is covalently bonded directly to the solid support or is covalently bonded to the solid support through the linking group. The polymeric hydroxylamine resin compound of the process aspect of the present invention is herein incorporated by reference.

Or

(Where

Is a solid support as defined herein, L is absent or linking group, and P is an amine protecting group)
It is called.

  “Binding group” and “linker” mean a group to which an amino or aminomethyl functional group can be covalently bonded to a solid support. The linking group is generally inert to the reagents and reaction conditions described herein.

"Amine protecting group" means an easily removable group known in the art that protects amino groups against undesired reactions during synthetic operations and can be selectively removed. The use of amine protecting groups is known in the art to protect against undesired reactions during synthetic operations, and many such protecting groups are known, for example, TH included herein by reference. See Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). Typical amine protecting groups include formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl , Acyl isothiocyanate, aminocaproyl, benzoyl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc), vinyloxycarbonyl, allyl Oxycarbonyl, t-butyloxycarbonyl (BOC), 1,1-dimethylpropynyloxycarbonyl, benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, allyloxycarboni (Aloc), 2- (p-biphenyl) isopropyloxycarbonyl (Bpoc), adamantyloxycarbonyl (Adoc), 2- (3,5-dimethoxyphenyl) -propyl-2-oxycarbonyl (Ddz), t-butyl (t-Bu), p-methoxybenzyloxycarbonyl (Moz), p-nitrobenzyloxycarbonyl (4-NO ₂ -Z), 2- (phenylsulfonyl) ethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, o -Nitrobenzyloxycarbonyl, 1- (2-oxo-1,2-diphenylethyl) methyloxycarbonyl, (1,3-dithion-2-yl) methoxycarbonyl (Dmoc), pyridylethyl (Pyoc), 4-nitro Phenylallyloxycarbonyl (Noc), 2-nitro-4,5-dimethoxybenzyloxycarbonyl, dimethyl-t-butylsilyl, o-nitrobenzylsulfonyl (o-Nbs), p-nitrobenzylsulfonyl (p-Nbs), 2 -Nitro-4-trifluoro Chill benzenesulfonyl and the like.

“Natural amino acid” is a carboxylic acid compound having an amino group at the alpha position in the carboxylate group, ie, the formula H ₂ N—CHR—CO ₂ H, wherein R is aliphatic or as defined herein Compound) which is aromatic. Preferred amino acids have L stereochemistry at the α-carbon. The most preferred natural amino acids are so-called natural α-amino acids, namely alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine. And histidine.

  “Peptide” and “polypeptide” refer to a polymer in which the monomers are natural or unnatural amino acid residues joined together by amide bonds. The term “peptide backbone” refers to a series of amide bonds to which amino acid residues are attached. The term “amino acid residue” means an individual amino acid unit incorporated into a peptide or polypeptide.

  “Unnatural amino acid” means a carboxylic acid compound having an amino group therein at a position other than α relative to the carboxylate group. Representative non-natural amino acids include β-alanine and γ-aminobutyric acid.

  “Aliphatic” means a compound or group that does not contain an aromatic ring. Representative aliphatic groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and the like.

  “Aromatic” means a compound or group containing at least one aromatic ring. “Aromatic ring” includes both aryl and heteroaryl rings as defined herein. Representative aromatic groups include aryl, arylalkenyl, arylalkyl, arylalkynyl, benzyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylalkynyl and the like.

“Acid bioisosteres” means groups with chemical and physical similarities that give rise to broadly similar biological properties (Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p283 “Bioisosterism In Drug Design”; Yun, Hwahak Sekye, 1993,33, p576-579 "Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995, p34-38 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham, Theochem, 1995 , 343, p105-109 "Theoretical Studies Applied To Drug Design: ab initio Electronic Distributions In Bioisosteres"). Examples of suitable acid bioisosteres include -C (= O) -NH-OH, -C (= O) -CH ₂ OH, -C (= O) -CH ₂ SH, -C (= O)- NH-CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1, Examples include 2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl.

  “Acyl” means an H—CO— or alkyl-CO— group, the alkyl group of which is as defined herein. Preferred acyls include lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.

  “Acylamino” is an acyl-NH— group wherein acyl is as defined herein.

  “Alkenyl” means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have from 2 to about 12 carbon atoms in the chain, and more preferably from about 2 to about 4 carbon atoms in the chain. Branching means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. “Lower alkenyl” means about 2 to about 4 carbon atoms in the chain which may be straight or branched. An alkenyl group may be substituted by one or more halo or cycloalkyl. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methyl-2-butenyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.

  “Alkoxy” means an alkyl-O— group in which the alkyl group is as defined herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.

  “Alkoxyalkyl” means an alkyl-O-alkyl- group in which the alkyl group is independently as defined herein. Exemplary alkoxy groups include methoxyethyl, ethoxymethyl, n-butoxymethyl and cyclopentylmethyloxyethyl.

  “Alkoxycarbonyl” means an alkyl-O—CO— group in which the alkyl group is as defined herein. Exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.

“Alkyl” means a straight or branched aliphatic hydrocarbon group having about 1 to about 15 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. “Lower alkyl” means about 1 to about 4 carbon atoms in the chain which may be straight or branched. The alkyl group may be substituted by one or more halo, cycloalkyl or cycloalkenyl. Exemplary alkyl groups include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl , Heptyl, octyl, nonyl, decyl and dodecyl. Preferred alkyl groups for R ⁹ include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, and ethyl.

  “Alkylsulfinyl” means an alkyl-SO— group in which the alkyl group is as defined herein. Preferred groups are those in which the alkyl group is lower alkyl.

“Alkylsulfonyl” means an alkyl-SO ₂ − group in which the alkyl group is as defined herein. Preferred groups are those in which the alkyl group is lower alkyl.

  “Alkylthio” means an alkyl-S— group in which the alkyl group is as previously described herein. Exemplary alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.

  “Alkynyl” means a straight or branched aliphatic hydrocarbon group containing about 2 to about 15 carbon atoms in the chain that contains a carbon-carbon triple bond. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain, and more preferably have about 2 to about 4 carbon atoms in the chain. Branching means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methyl-2-butynyl, and n-pentynyl.

  “Aroyl” means an aryl-CO— group in which the aryl group is as described herein. Exemplary groups include benzoyl and 1-naphthoyl and 2-naphthoyl.

  “Aroylamino” is an aroyl-NH— group wherein aroyl is as defined herein.

“Aryl” as a group or part of a group represents an optionally substituted monocyclic or polycyclic aromatic carbocyclic moiety of from about 6 to about 10 carbon atoms. Exemplary aryls include phenyl or naphthyl, or phenyl or naphthyl substituted with one or more aryl group substituents, which may be the same or different. As the aryl group substituent ”, acyl, acylamino, alkoxy, alkoxycarbonyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkoxy, arylalkoxycarbonyl, arylalkyl, arylalkylthio, aryloxy, aryloxy Carbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyl, heteroarylamino Heteroaryloxy, hydrogen, hydroxy, hydroxyalkyl, nitro, Y ¹ Y ² N-, Y ¹ Y ² NCO-- or Y ¹ Y _² NSO ² - (wherein, Y ¹ and Y ² are independently hydrogen, alkyl, Arylalkyl, and aryl, or Y ¹ and Y ² together with the N atom to which Y ¹ and Y ² are attached are 4-7 membered heterocycles (which may be O, S, NH or NR if necessary) Which may contain additional heteroatoms selected from ¹³ ). Preferred aryl group substituents include acyl, acylamino, alkoxycarbonyl, alkyl, alkylthio, aroyl, cyano, halo, hydrogen, hydroxy, nitro, Y ¹ Y ² N-, Y ¹ Y ² NCO- or Y ¹ Y ² NSO ₂ -In which Y ¹ and Y ² are independently hydrogen and alkyl.

  “Arylalkenyl” means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred arylalkenyls contain a lower alkenyl moiety. Exemplary arylalkenyl groups include styryl and phenylallyl.

  “Arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred arylalkyls contain a lower alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthalenemethyl.

  “Arylalkyloxy” means an arylalkyl-O— group in which the arylalkyl group is as previously described. Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.

  “Arylalkyloxyalkenyl” means an arylalkyl-O-alkenyl group in which the arylalkyl and alkenyl groups are as previously described. An exemplary arylalkyloxyalkenyl group is 3-benzyloxyallyl.

  “Arylalkyloxyalkyl” means an arylalkyl-O-alkyl group in which the arylalkyl and alkyl groups are as previously described. An exemplary arylalkyloxyalkyl group is benzyloxyethyl.

  “Arylalkoxycarbonyl” means an arylalkyl-O—CO— group. An exemplary arylalkoxycarbonyl group is benzyloxycarbonyl.

  “Arylalkylthio” means an arylalkyl-S— group in which the arylalkyl group is as previously described. An exemplary arylalkylthio group is benzylthio.

  “Arylalkynyl” means an aryl-alkynyl- group in which the aryl and alkynyl are as previously described. Preferred arylalkynyls contain a lower alkynyl moiety. An exemplary arylalkynyl group is phenylacetylenyl.

  “Aryloxy” means an aryl-O— group in which the aryl group is as previously described. Exemplary aryloxy groups include phenoxy and naphthoxy.

  “Aryloxyalkenyl” means an aryl-O-alkenyl- group in which the aryl or alkenyl group is as previously described. An exemplary aryloxyalkenyl group is phenoxyallyl.

  “Aryloxyalkyl” means an aryl-O-alkyl- group in which the aryl or alkyl group is as previously described. An exemplary aryloxyalkyl group is phenoxypropyl.

  “Aryloxycarbonyl” means an aryl-O—CO— group in which the aryl group is as previously described. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.

  “Arylsulfinyl” means an aryl-SO— group in which the aryl group is as previously described.

“Arylsulfonyl” means an aryl-SO ₂ − group in which the aryl group is as previously described.

  “Arylthio” means an aryl-S— group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.

“(N-carbamoyl) cyclic amine” means a 5-7 membered cycloalkyl ring system wherein one of the ring carbon atoms is replaced by NC (═O) —NH ₂ . An exemplary (N-carbamoyl) cyclic amine is N-carbamoylpiperidinyl.

“Benzyl” means a phenyl-CH ₂ — group in which the phenyl ring is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, halogen, and haloalkyl.

“Cycloalkenyl” means a non-aromatic mono- or polycyclic ring system containing carbon-carbon double bonds and having from about 3 to about 10 carbon atoms. Preferred monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. More preferred is cyclopentenyl. A preferred polycyclic cycloalkenyl ring is norbornenyl. A cycloalkenyl group may be substituted by one or more halo, methylene (H ₂ C═) or alkyl.

“Cycloalkyl” means a non-aromatic mono- or polycyclic ring system of about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred monocyclic cycloalkyl rings for R ¹⁸ include cyclopentyl and cyclohexyl. A preferred monocyclic cycloalkyl ring for R ¹⁹ is cyclopropyl. Exemplary polycyclic cycloalkyl rings include perhydronaphthyl, adamant- (1- or 2-) yl and norbornyl groups and spironicyclic groups such as spiro [4,4] non-2-yl. It is done. Cycloalkyl groups may be substituted by one or more halo, methylene (H ₂ C═) groups or alkyl groups. Preferred monocyclic cycloalkyl rings for R ¹⁸ include cyclopentyl and cyclohexyl. A preferred cycloalkyl group for R ¹⁹ includes cyclopropyl.

  “Cycloalkoxy” means a cycloalkyl-O— group in which the cycloalkyl group is as previously described. Exemplary cycloalkoxy groups include cyclopentyloxy and cyclohexyloxy.

  “Cyclocarbamoylalkyl” is a compound of the formula

(Wherein the cyclocarbamoyl group consists of an oxooxaza heterocyclic moiety, and the alkyl group is as already described)
Means a compound of The alkyl moiety may be attached to the carbamoyl via a carbon atom or a nitrogen atom of the carbamoyl moiety. An exemplary cyclocarbamoylalkyl group is N-oxazolidinylpropyl.

  “Cycloimidyl” is a formula

(Wherein the imide group comprises an oxodiazaheterocyclic moiety and the alkyl group is as already described)
Means a compound of The alkyl moiety may be attached to the carbamoyl via a carbon atom or a nitrogen atom of the carbamoyl moiety. An exemplary imidoalkyl group is N-phthalimidopropyl.

  “Halo” and “halogen” refer to fluoro, chloro, bromo, or iodo. Fluoro, chloro or bromo is preferred, and fluoro or chloro is more preferred.

  “Haloalkyl” means an alkyl group, as defined herein, substituted with one or more halogen atoms. Representative haloalkyl groups include chloromethyl, bromoethyl, trifluoromethyl and the like.

  “Heteroaroyl” means a heteroaryl-CO— group in which the heteroaryl group is as defined herein. An exemplary heteroaroyl group is pyridylcarbonyl.

  "Heteroaryl" as a group or part of a group is an aromatic monocyclic or polycyclic hydrocarbon ring system (one of the ring members) optionally substituted from about 5 to about 10 atoms. The above represents an element other than carbon, such as nitrogen, oxygen, or sulfur. Also, “heteroaryl” may be substituted with one or more aryl group substituents. Examples of suitable optionally substituted heteroaryl groups include furyl, isoxazolyl, isoquinolinyl, isothiazolyl, optionally substituted with one or more aryl substituents as defined above. 1,2,3-oxadiazole group, 1,2,4-oxadiazole group, 1,2,5-oxadiazole group, 1,3,4-oxadiazole group, pyrazinyl group, pyridazinyl group , Pyridyl group, pyrimidinyl group, quinolinyl group, 1,3,4-thiadiazolyl group, thiazolyl group, thienyl group, 1,2,3-triazolyl group and 1,2,4-triazolyl group.

Where R ¹⁸ or R ¹⁹ contains an optionally substituted heteroaryl group, this is specifically an optionally substituted “azaheteroaryl” group (where “azaheteroaryl” is a ring member) Represents a heteroaryl group of about 5 to about 10 ring members in which one or more of the above are nitrogen. Examples of the optional substituent of the heteroaryl group in R ¹⁸ or R ¹⁹ include a halogen atom and an alkyl group, aryl group, arylalkyl group, hydroxy group, oxo group, hydroxyalkyl group, haloalkyl group (for example, trifluoromethyl group). Group), an alkoxy group, a haloalkoxy group (for example, trifluoromethoxy group), an aryloxy group, and an arylalkyloxy group. Preferred heteroaryl groups in R ¹⁸ include optionally substituted thienyl, thiazolyl, pyridyl, 1,2,4-oxadiazole or 1,3,4-oxadiazole. A preferred heteroaryl group in R ¹⁹ is optionally substituted pyridyl.

  “Heteroarylalkenyl” means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl are as previously described. Preferred heteroarylalkenyls contain a lower alkenyl moiety. An exemplary heteroarylalkenyl group is 4-pyridylvinyl.

  “Heteroarylalkyl” means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroarylalkyls contain a lower alkyl moiety. An exemplary heteroarylalkyl group is 4-pyridylmethyl.

  “Heteroarylalkyloxy” means a heteroarylalkyl-O— group in which the heteroarylalkyl group is as previously described. An exemplary heteroarylalkyloxy group is 4-pyridylmethyloxy.

  “Heteroarylalkyloxyalkenyl” means a heteroarylalkyl-O-alkenyl group in which the heteroarylalkyl and alkyl groups are as previously described. An exemplary heteroarylalkyloxyalkenyl group is 4-pyridylmethyloxyallyl.

  “Heteroarylalkyloxyalkyl” means a heteroarylalkyl-O-alkyl group in which the heteroarylalkyl and alkyl groups are as previously described. An exemplary heteroarylalkyloxy group is 4-pyridylmethyloxyethyl.

  “Heteroarylalkynyl” means a heteroaryl-alkynyl- group in which the heteroaryl and alkynyl are as previously described. Preferred heteroarylalkynyls contain a lower alkynyl moiety. An exemplary heteroarylalkynyl group is 4-pyridylethynyl.

  “Heterocycle” means a monocyclic or polycyclic ring system of about 4 to about 10 members, wherein one or more of the atoms in the ring system is other than carbon selected from nitrogen, oxygen or sulfur Elements. The heterocycle may be optionally substituted with one or more alkyl group substituents. Exemplary heterocyclic moieties include quinuclidine, pentamethylene sulfide, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, or tetrahydrofuranyl.

  “Heterocycle alkyl” means a heterocycle-alkyl-group in which the heterocycle and alkyl are as previously described. Preferred heterocyclic alkyls contain a lower alkyl moiety. An exemplary heteroarylalkyl group is tetrahydropyranylmethyl.

  “Heterocyclealkyloxyalkyl” means a heterocycle-alkyl-O-alkyl- group in which the heterocycle and alkyl are independently as previously described. An exemplary heteroarylalkyl group is tetrahydropyranyl-methyloxymethyl.

  “Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyl include lower alkyl. Exemplary hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

  “Partially saturated bicycloaryl” refers to a group in which an aryl and cycloalkyl group are fused together to form a bicyclic structure. Exemplary arylalkyl groups include indanyl and tetrahydronaphthyl, particularly indanyl.

Preferred Embodiments The process for preparing the aldehydes and ketones of the present invention is outlined in Scheme 1, where R _a and R _b are any aliphatic groups or aromatics that are amenable to treatment with the solvents and reagents used in the processes described herein. A group is represented independently. The groups R _a and R _b may be further substituted and may contain functional groups suitable for further chemical transformations while attached to the hydroxylamine resin. It is understood that if these functional groups are reactive so that they can potentially interfere with the reactions described below, such functional groups should be appropriately protected. . For a comprehensive paper on the protection and deprotection of common functional groups, see TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991) (included herein by reference) )checking. R _c represents any aliphatic group or aromatic group that can be easily used as an organometallic reagent.

Scheme 1

According to Scheme 1 above, polymeric hydroxylamine resin compound 1 is coupled with a carboxylic acid derivative of formula R _a CO ₂ H to produce polymeric hydroxamic acid resin compound 2. The coupling reaction is carried out in the presence of an active agent as is known in the field of peptide synthesis. Typical activators include isopropyl chloroformate, diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), 1-hydroxybenzotriazole (HOBT), bis (2-oxo -3-Oxazolidinyl) -phosphonic acid chloride (BOP-Cl), benzotriazol-1-yloxy-tris ((dimethylamino) phosphonium) hexafluorophosphate (BOP), benzotriazol-1-yloxy-tris-pyrrolidino-phosphonium hexa Fluorophosphate (PyBROP), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), 2- (1H-benzotriazol-1-yl) -1.1.3.3-tetramethyluronium tetrafluoroborate (TBTU), 2- (1H-benzotriazol-1-yl) -1.1.3.3-tetramethyluronium hexafluoroborate (HBTU), 2 -[2-oxo-1- (2H) -pyridyl] -1,1,3,3-bispentamethyleneuronium tetrafluoroborate (TOPPipU), N, N'-dicyclohexylcarbodiimide (DCC), etc. . Suitable solvents for the coupling reaction include dichloromethane, DMF, DMSO, THF and the like. Coupling times range from about 2 hours to about 24 hours, depending on the resin to be coupled and the carboxylic acid derivative, activator, solvent and temperature. Coupling is performed from about −10 ° C. to about 50 ° C., preferably at about ambient temperature.

  The coupling reaction is preferably carried out using 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride for about 12 hours in DMF at ambient temperature.

Then the polymer hydroxamic acid resin compound 2 is non-nucleophilic base, for example, 1,8-diazabicyclo [5.4.0] wherein R _b in such a toluene inert organic solvent in the presence of a undec-7-ene (DBU) Alkylation with an alkylating agent of LG, where LG is a leaving group produces N-alkylated polymeric hydroxamic acid resin compound 3. The alkylating agent R _b LG may be added in an equimolar amount to an excess of about 25 molar equivalents. About 15 molar equivalents are preferred. The non-nucleophilic base may be added in an equimolar amount to an excess of about 10 molar equivalents. About 5 molar equivalents are preferred. The leaving group LG is any group susceptible to nucleophilic substitution by the nitrogen atom of the polymer hydroxamic acid resin compound 2 under the above reaction conditions. A preferred leaving group is halogen. A sample of N-alkylated polymer hydroxamic acid resin compound 3 may be subjected to acidolysis to cleave the substituted hydroxamic acid to ensure that the reaction proceeds satisfactorily.

Reaction of polymeric N-alkylated hydroxamic acid resin compound 3 with an organometallic reagent of R _c M where R _c is an aliphatic or aromatic anion and M is a metal cation, followed by Acid hydrolysis gives ketone 4. Preferred organometallic reagents are organolithium reagents of the formula R _c Li and Grignard reagents of the formula R _c MgX where X is a halogen. In a preferred preparation of the ketone of this aspect of the invention, the polymeric N-alkylated hydroxamic acid resin compound 3 is treated with R _c MgX in diethyl ether at ambient temperature for about 18 hours, and then the reaction mixture is either aqueous HCl or KHSO ₄ The reaction is stopped by addition of aqueous solution to liberate ketone 4.

The aldehyde is prepared by treatment of polymeric N-alkylated hydroxamic acid resin compound 3 with a hydride reducing agent as shown in Scheme 1 above, followed by acid hydrolysis. Typical hydride reducing agents include LiAlH ₄ , (iso-Bu) ₂ AlH, LiAlH (Ot—Bu) ₃ , LiAlH ₄ —EtOH, LiAlH ₄ —MeOH and the like. Preferred reducing agents are LiAlH ₄ and LiAlH ₄ —MeOH. Acid hydrolysis is preferably performed in KHSO _4. aqueous.

  As shown in Scheme 1, N-alkylated polymer hydroxamic acid resin compound 3 is a wine lev-like amide useful for the synthesis of aldehydes and ketones (S. Nahm and S. Weinreb, Tet Lett. 1981, 22, 3815- 3818). This N-alkylated polymer hydroxamic acid resin compound is a N-alkylated polymer with a bulky lipophilic group, such as a benzyl group, a substituted benzyl group, a naphthyl group, or any alkyl group that it needs to optimize the solid phase reaction. Conventional examples of resin-bound winelev-like amides in terms of alkylation (J.-A. Fehrentz, M. Paris, A. Heitz, J. Velek, C.-F. Liu, F. Winternitz, and J. Martinez. B) It has advantages over TQ Dinh and RW Armstrong, Tet. Lett., 1996, 37, 1161-1164). For example, the N-benzyl-O-methylpolystyrenyl moiety is suitable for generating stable metal chelating intermediates. The lipophilic benzyl group is believed to help mask the chelate and increase its stability.

  A preferred method for preparing aldehydes and ketones is outlined in Scheme 2. In Scheme 2, “P” represents an amine protecting group as defined herein.

Scheme 2

As shown in Scheme 2 above, the polymeric hydroxylamine resin compound is protected with an amine protecting group to produce the N-protected polymeric hydroxylamine resin compound 6. N-protected polymer hydroxylamine resin compound 6 is then alkylated as described in Scheme 1 above to produce N-alkylated N-protected polymer hydroxylamine resin compound 7. Removal of the amine protecting group gives the mono N-alkylated polymer hydroxylamine resin compound 8. Coupling of 8 with a carboxylic acid compound of the formula R _a CO ₂ H gives the polymer N-alkylated hydroxamic acid resin compound 3, which is converted to ketone 4 or aldehyde 5 as described in Scheme 1 above.

Preferred amine protecting groups include allyloxycarbonyl (Aloc), benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl (Moz), p-nitrobenzyloxycarbonyl (4-NO ₂ -Z), trimethylsilylethoxycarbonyl (Teoc ), 2,4-dimethoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, o-nitrobenzylsulfonyl (o-Nbs), p-nitrobenzylsulfonyl (p-Nbs), and 2-nitro-4-trifluoromethyl Benzenesulfonyl is mentioned.

  The most preferred amine protecting group is allyloxycarbonyl.

Preferred polymer N-protected hydroxylamine resin compounds include:
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-amineoxyethyl) -2-methoxy-5-nitrophenoxy]-(N-4-methylbenzhydryl) -butyramide-copoly (styrene-1% divinylbenzene ) Resin,
N-allyloxycarbonyl-O-hydroxylamine-2'-chlorotrityl-copolystyrene-1% divinylbenzene) resin,
N-allyloxycarbonyl-O-hydroxylamine-trityl-copolystyrene-1% divinylbenzene resin,
N-allyloxycarbonyl-5- (4-O-methylhydroxylamine-3,5-dimethoxyphenoxy) -valeric acid-copolystyrene-1% divinylbenzene resin,
N-allyloxycarbonyl-4-O-methylhydroxylamine-3-methoxyphenoxy-copolystyrene-1% 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 and
N-allyloxycarbonyl-3-hydroxy-xanthidolamine-copolystyrene-1% divinylbenzene) resin.

  The most preferred polymeric N-protected hydroxylamine resin compound is N-allyloxycarbonyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin.

When the carboxylic acid compound R _a CO ₂ H represents a natural or non-natural amino acid or peptide, the procedure described in Schemes 1 and 2 above is an easy route that it has been difficult in the past to obtain an amino acid or peptide aldehyde compound. give.

The process for preparing the amines of the present invention is outlined in Scheme 3. In Scheme 3, R _d and R _e independently represent H or any aliphatic or aromatic group amenable to treatment with the solvents and reagents used in the methods described herein, provided that R _d and R _provided that both _e are not H. The groups R _a , R _b and R _c may be further substituted and may contain functional groups suitable for further chemical transformations while attached to the hydroxylamine resin. It will be appreciated that if these functional groups are reactive so that they can potentially interfere with the following reactions, such functional groups should be appropriately protected. For a comprehensive paper on the protection and deprotection of common functional groups, see TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991), included here for reference. See R _f represents any aliphatic or aromatic group that is easy to use as an organometallic reagent.

Scheme 3

According to Scheme 3 above, the reaction of the polymer hydroxylamine resin compound 1 and the aldehyde or ketone 9 gives the polymer oxime ether resin compound 10 . Oxime formation is preferably performed by swelling polymer hydroxylamine resin compound 1 in a suitable inert organic solvent, such as dichloromethane, at about ambient temperature, followed by addition of excess aldehyde or ketone. For example, NaCNBH ₃ or BH ^_3. THF, followed by reductive cleavage of the resin by reaction with LiAlH ₄ provides the amine 11. Organometallic reagent of polymer oxime ether resin compound 10 and formula R _f M, wherein R _f is an aliphatic or aromatic anion, and M is a metal cation as defined herein. This gives the polymer α-substituted hydroxylamine resin compound 12 . Cleavage of α- amine 13 from the resin is performed, for example, using a BH ^_3. THF or LiAlH _4. See Y. Ukaji et al., Chem. Lett., 173, (1991) and RP Dieter et al., Can. J. Chem. 71 , 814 (1993). Preferred metal cations are Li and MgX where X is a halogen. With the aid of a chiral auxiliary, such as a chiral benzylhydroxylamine linker, a chiral α-substituted amine will be generated.

A method for preparing lactones by free radical cyclization is shown in Scheme 4. In Scheme 4, R _g , R _h and R _i are aliphatic or aryl as defined herein.

Scheme 4

As shown in Scheme 4 above, the polymer hydroxylamine resin compound 1 is reacted with an α, β unsaturated carboxylic ester compound 14 to produce a polymer oxymil resin compound 15 . For example, fifteen free radical cyclizations by heating in the presence of 2,2′-azobisisobutyronitrile (AIBN) and thiophenol in an inert organic solvent such as benzene may result in polymer g-lactone resin compound 16 Resulting in the generation of. For example, 16 acid hydrolysis using 10% aqueous HCl gives lactone 17 . See O. Miyata et al., Tet. Lett., 37 , 229-232, (1996).

A method for preparing carbocyclic or heterocyclic compounds by free radical cyclization is shown in Scheme 5. In Scheme 5, R _j , R _k and R _l are aliphatic or aryl as defined herein. The method described in Scheme 1 can be applied to the preparation of 5-membered, 6-membered or 7-membered rings. A carbocycle is formed when the oxygen atom of the phenol is replaced with a carbon atom.

Scheme 5

Scheme 5, continued

According to Scheme 5 above, polymeric hydroxylamine resin compound 1 is reacted with acetophenone compound 18 and a bromoalkene compound or o-bromobenzyl compound to produce polymeric acetophenone oxime compound 19 or 23 . For example, free radical cyclization of 19 or 23 by heating in the presence of AIBN and tri-n-butyltin hydride in an inert organic solvent such as benzene may result in the formation of polymer N-cyclic hydroxylamine resin compound 20 or 24 . Bring about generation. Treatment of 20 or 24 with an acid, preferably trifluoroacetic acid, results in the formation of the cyclic hydroxamic acid compound 21 or 25 . For example, reductive cleavage of 20 or 24 using LiAlH ₄ as described in Scheme 3 above results in the formation of cyclic amine compounds 22 or 26 . See SE Booth et al., J. Chem. Soc. Commun., 1248-1249, (1991).

A process for the preparation of a hydroxamic acid compound of formula 29 wherein n and the groups Ar, A ² , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined above is shown in Scheme 6.

Scheme 6

a) 3- (4-Methoxyphenylsulfonyl) propionic acid (5 eq); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI 5 eq); DMF; 25 ° C; 12 hours. b) 50% in CH ₂ Cl ₂ TFA (100 eq); 30 min.

According to Scheme 6 above, the carboxylic acid compound 27 is coupled to the polymer hydroxylamine resin compound 1 described in Scheme 1 above to produce the polymer hydroxamic acid resin compound 28 . Polymeric hydroxamic acid resin compound 28 is then treated with an acid such as trifluoroacetic acid (TFA) in an inert solvent such as dichloromethane to liberate hydroxamic acid compound 29 . A high proportion of TFA (trifluoroacetic acid) and longer reaction times are required to cleave the hydroxamic acid from the one variant compared to the link variant of the resin. It can be seen that during evaporation of the TFA during the process to isolate the hydroxamic acid, heating the sample during concentration produces a significant amount of the parent hydroxamic acid N, O-diacylated dimer as a byproduct. In order to minimize this side reaction, the reaction mixture is concentrated below room temperature with toluene used as the azeotrope.

A solid phase synthesis method of carboxylic acid compound 27 is shown in Scheme 7. In scheme 7, Ar, A ² , n, R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined above.

Scheme 7

For example, polymer hydroxy resin compound 30 is treated with diethyl phosphonoacetic acid at about room temperature in the presence of 2,6-dichlorobenzoyl chloride and pyridine in an inert solvent such as dimethylformamide to give polymer diethyl phosphonoacetoxy resin compound 31 . Arise.

The polymer diethylphosphonoacetoxy resin compound 31 is prepared in an inert solvent such as toluene at a temperature of about 0 ° C. at a base such as potassium bis (trimethylsilyl) amide, followed by R ¹¹ CHO (where R ¹¹ is To give a polymeric alkenoate resin compound 32 .

The polymeric alkenoate resin compound 32 is then reacted with a thiol of formula Ar—A ² —SH, where Ar ² and A ² are as previously defined, to yield the polymeric alkanoate resin compound 33 . The addition can be conveniently performed at mild ambient conditions, for example, at about ambient temperature in the presence of lithium hydroxide.

The polymeric alkanoate resin compound 33 is then hydrolyzed by treatment with an acid such as trifluoroacetic acid in an inert solvent such as dichloromethane to prepare acid 35 (where n is 0).

Alternatively, the polymer alkanoate resin compound 33 may be treated with an oxidant such as m-chloro-perbenzoic acid in an inert solvent such as dioxane at about ambient temperature to yield polymer sulfoxide (n = 1) or sulfone (n = 2). Resin compound 34 may be produced. The 34 hydrolysis described above gives the carboxylic acid compound 35 .

The preparation of polymeric hydroxylamine resin compound 1 is shown in Scheme 8.

Scheme 8

According to Scheme 8 above, the polymer hydroxy resin compound 30 is coupled with N-hydroxyphthalimide under Mitsunobu conditions (Mitsunobu, O., Synthesis 1981, 1), conversion of the hydroxy group to a leaving group such as mesylate, Subsequent conversion to polymer N-hydroxyphthalimide resin compound 36 by nucleophilic substitution or reaction of the polymer hydroxy resin compound with N-hydroxyphthalimide in the presence of an acid such as benzenesulfonic acid. Removal of the phthalimide group gives the polymer hydroxylamine resin compound 1 .

For example, if 30 is 4- (hydroxymethyl) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (one resin), N-hydroxyphthalimide is diisopropyl azodicarboxylate and triphenylphosphine in DMF. Coupled to the resin in the presence of The phthalimide protection is removed by methylaminolysis in THF at 40 ° C. The reaction is complete in about 2 hours. The use of methylamine to cleave the phthalimide protection provides significant advantages over the commonly used hydrazinolysis procedure (Wolf et al., Can. J. Chem., 48 , 3572, (1970).

When 4- (2 ', 4'-dimethoxyphenyl-O-methylhydroxylamine) -phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (link resin) is used, 1 is the catalyst in DMF The polymer N-hydroxyphthalimide resin compound 36 is preferably prepared by reaction of the polymer hydroxy resin compound with N-hydroxyphthalimide in the presence of benzenesulfonic acid. The phthalimide protecting group is then removed by reaction with hydrazine hydrate in tert-butanol at about 60 ° C. to give the corresponding polymeric hydroxylamine resin compound.

  Another route to polymeric N-protected hydroxylamine resin 6 is outlined in Scheme 9.

Scheme 9

According to Scheme 9 above, the polymer hydroxy resin compound 30 is coupled with the N, N-diprotected hydroxylamine compound 37 (wherein P 1 and P ′ are amine protecting groups) as described in Scheme 8 to form a polymer. N, N-diprotected hydroxylamine resin compound 38 is produced. The amine protecting group P ′ is then selectively removed to produce the polymer N-protected hydroxylamine resin compound 6 .

  In a preferred embodiment of the synthesis described in Scheme 9, P is benzyl and P ′ is allyloxycarbonyl. Selective removal of the allyloxycarbonyl protecting group is effected by treatment with tetrakis (triphenylphosphine) palladium (0).

N, N-diprotected hydroxylamine compound 37 is prepared by sequential introduction of protecting groups P 1 and P ′ into an O-protected hydroxylamine compound of formula H ₂ NOP ² , where P ² is a hydroxy protecting group. The A preferred hydroxy protecting group is alkyl. Amine protecting groups P 1 and P ′ are then introduced using reagents and reaction conditions known in the field of organic synthesis. For example, the reaction of O-tert-butylhydroxylamine with allyloxychloroformate results in the formation of N-allyloxycarbonyl-O-tert-butylhydroxylamine, which is then reacted with benzyl bromide to produce N-benzyl-N -Allyloxycarbonyl-O-tert-butylhydroxylamine is produced. Treatment of N-benzyl-N-allyloxycarbonyl-O-tert-butylhydroxylamine with trifluoroacetic acid yields N-benzyl-N-allyloxycarbonylhydroxylamine.

  The preparation of the polymer 4- (O-methylhydroxylamine) -2,3,5,6-tetrafluorophenoxymethyl resin compound is shown in Scheme 10.

Scheme 10

According to Scheme 10 above, a polymeric chloromethyl resin compound, such as chloromethylpolystyrene ( 39 , Merrifield resin), is reacted with 4-hydroxy-2,3,5,6-benzoic acid in the presence of a base. 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl resin compound 40 is produced. For example, reduction of the carboxylic acid group using LiAlH 4, diisobutylaluminum hydride, or BH ₃ —THF gives 4-hydroxymethyl-2,3,5,6-tetrafluorophenoxymethyl resin compound 41 . Conversion of 41 to hydroxyphthalimide resin compound 42 followed by removal of the phthalimide group described in Scheme 8 is 4- (O-methylhydroxylamine) -2,3,5,6-tetrafluorophenoxymethyl-copoly (styrene -1% divinylbenzene) resin compound 43 .

  The preparation of the polymer 4- (2 ′, 4′-dimethoxyphenyl-O-methylhydroxylamine) -2,3,5,6-tetrafluorophenoxymethyl resin compound is shown in Scheme 11.

Scheme 11

According to Scheme 11 above, the polymeric chloromethyl resin compound reacts with 4-phenoxy-2,3-5,6-tetrafluorophenyl 2,4-dimethoxyphenyl ketone 44 in the presence of the base described in Scheme 10 above. To yield 4- (2 ′, 4′-dimethoxyphenylcarbonyl) -2,3,5,6-tetrafluorophenoxymethyl-resin compound 45 . For example, reduction of the carbonyl using LiBH 4 provides 4- (hydroxymethyl-2 ′, 4′-dimethoxyphenyl) -2,3,5,6-tetrafluorophenoxymethyl resin compound 46 . Conversion of 46 to hydroxyphthalimide resin compound 47 followed by removal of the phthalimide group described in Scheme 8 above is 4- (2 ′, 4′-dimethoxyphenyl-O-methylhydroxylamine) -2,3,5, 6-Tetrafluorophenoxymethyl-resin compound 48 is obtained.

Preferred polymeric hydroxylamine resin compounds have the formula 1 where L is a linking group.

  Preferred linking groups L are of the formula

Have
Where
A is absent or a group of formula -X ¹ -Z-
X ¹ is —CHR— or —CHR—Y—CO— (CH ₂ ) _n — (wherein R is substituted with H, alkyl, phenyl, or —H, alkyl, alkoxy, halogen, nitrile or —NO _2. And phenyl
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 —NO ₂ 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 —NO ₂ , or
One of R ¹ and R ² together with one of R ³ and R ⁴ and the carbon atom to which they are attached

(Where
R ^{1 ′} is —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ and
R ⁶ , R ⁷ and R ⁸ are independently selected from —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ )
To form a linking group.

As a typical preferred polymer hydroxylamine resin compound,
In this specification,

4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin, represented as
In this specification,

4- [4- (O-methylhydroxylamine) -3-methoxyphenoxy]-(N-4-methylbenzohydryl) -butyramide-copoly (styrene-1% -divinylbenzene) -resin, represented as
In this specification,

4- (2 ', 4'-dimethoxyphenyl-O-methylhydroxylamine) -phenoxymethyl-copoly (styrene-1% divinylbenzene) resin represented as
In this specification,

4- [4- (1-Amineoxyethyl) -2-methoxy-5-nitrophenoxy]-(N-4-methylbenzohydryl) -butyramide-copoly (styrene-1% divinylbenzene) resin represented as ,
In this specification,

O-hydroxylamine-2'-chlorotrityl-copolystyrene-1% -divinylbenzene-resin, represented as
In this specification,

O-hydroxylamine-trityl-copolystyrene-1% -divinylbenzene-resin, represented as
In this specification,

5- (4-O-methylhydroxylamine-3,5-dimethoxyphenoxy) -valeric acid-copolystyrene-1% -divinylbenzene resin represented as
In this specification,

4-O-methylhydroxylamine-3-methoxyphenoxy-copolystyrene-1% -divinylbenzene resin represented as
In this specification,

3-hydroxy-xanthoxylamine-copolystyrene-1% -divinylbenzene resin represented as
In this specification,

4- (O-methylhydroxylamine) -2,3,5,6-tetrafluorophenoxymethyl-copoly (styrene-1% divinylbenzene) resin represented as:

4- (2 ′, 4′-dimethoxyphenyl-O-methylhydroxylamine) -2,3,5,6-tetrafluorophenoxymethyl-copoly (styrene-1% divinylbenzene) resin represented by

The most preferred polymer hydroxylamine resin compound is
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) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin, and
4- (2 ′, 4′-dimethoxyphenyl-O-methylhydroxylamine) -phenoxymethyl-copoly (styrene-1% divinylbenzene) resin.

  Link handle (H. Rink, Tet. Lett., 28, 3787-3790, 1987) is cleaved under mild acidosis (ie 10% TFA in DCM for 10-15 minutes) over a short period of time Has the advantage. However, due to the cost of the resin, the corresponding functional resin can be replaced with a single solid support ((a) SS Wang, J. Am. Chem. Soc., (1973), 95, 1328.b) G. Lu, S. It is desirable to synthesize by Mojsov, JP Tam, and RB Merrifield, J. Org. Chem., (1981), 46, 3433).

  A tetrafluorophenyl phenyl handle is particularly useful. This is because it is compatible with easy quantification of the reaction monitoring performed on the resin using resin loading and fluorine NMR.

  The methods described herein are also useful for the preparation of peptide aldehydes, ketones and hydroxamic acids. In general, this method involves coupling the carboxyl group of a suitably N-protected first amino acid to a resin to produce a polymeric N-protected amino acid hydroxamic acid resin compound. The amino acid N-protecting group is then removed and the unprotected polymeric amino acid hydroxamic acid resin compound is coupled with a second suitably N-protected amino acid. This process is then repeated until the desired amino acid residue is incorporated into the peptide.

  Alternatively, peptides containing multiple amino acids are prepared by coupling appropriately N-protected peptide subunits containing two or more amino acids to produce polymeric N-protected peptide hydroxamic acid resin compounds. The amino acid N-protecting group is then removed and the unprotected polymeric peptide hydroxamic acid resin compound is coupled with a second suitably N-protected amino acid or peptide. Thus, in addition to the sequential addition of the individual amino acid subunits, polypeptides can be prepared by coupling of peptide subunits.

  Once the desired amino acid is incorporated into the peptide, the polymeric peptide hydroxamic acid compound is reacted with an organometallic reagent, followed by acid hydrolysis to produce a peptide ketone compound, which is reductively cleaved to produce a peptide aldehyde compound. Or cleaved with an acid to produce a peptide hydroxamic acid compound. Residual protecting groups may be removed before or after cleavage of the peptide from the resin.

  N-protecting groups suitable for use in the peptide synthesis described herein are stable to the conditions of coupling to the polymeric hydroxylamine resin compound and break down the growing peptide chain or the chiral center contained therein. It should have the property that it can be easily removed without causing any racemization. Suitable protecting groups are 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), biphenylisopropyloxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl, (a, a) Dimethyl-3,5-dimethoxybenzyloxycarbonyl, o-nitrophenylsulfenyl, 2-cyano-t-butyloxycarbonyl and the like.

  In addition, this resin can be used for an array of aldehyde, ketone or amine combinatorial libraries or reagents in combinatorial library synthesis, such as Ugi 4-component condensation (Ivar Ugi, in Isonitrile Chemistry, 1971, p. 145, Academic Press). Useful for constructing arrays of aldehydes and ketones as reagents. Hydroxylamine binding resins may be used not only for single functional group transformations, but also for multi-step solid phase synthesis to generate combinatorial libraries.

The functionalized resins of the present invention are also useful for parallel synthesis of a number of different aldehyde, ketone or amine end products as outlined for ketone compounds in Schemes 12a and 12b. In schemes 12a and 12b, R _b and R _c are as defined above. n is a number representing the total number of different aldehyde, ketone or amine products prepared. R _a1 -R _an independently represents an aliphatic group or an aromatic group as defined herein.

Scheme 12a

A parallel synthesis of a variety of ketone compounds using a variety of carboxylic acid compounds R _a1 CO ₂ HR _an CO ₂ H and a single organometallic compound R _c MgX is shown in Scheme 12a. According to Scheme 12a, an N-alkylated hydroxylamine resin compound 8 prepared as described in Scheme 2 is divided into n moieties. Each portion of the resin is then coupled with a different carboxylic acid compound to yield the n portion of the polymeric N-alkylated hydroxamic acid resin compound. Each portion of the polymer N-alkylated hydroxamic acid resin compound is then reacted with a Grignard reagent of the formula R _c X and subjected to acid hydrolysis to yield the n portion of the ketone derived from a single organometallic reagent.

Scheme 12b

A parallel synthesis of n different ketone compounds derived from _a single carboxylic acid compound R _a CO ₂ H and n different organometallic compounds R _c1 MgBr to R _cn MgBr is outlined in Scheme 12b above. According to Scheme 12b, a polymer N-alkylated hydroxylamine resin compound is coupled with a carboxylic acid of formula R _a CO ₂ H. The resulting polymer N-alkylated hydroxamic acid resin compound is then divided into n moieties and then each portion of the polymer N-alkylated hydroxamic acid resin compound is reacted with a different Grignard reagent R _c1 -R _cn MgBr to produce acid hydrolysates. Degradation yields n different ketone compounds derived from a single carboxylic acid compound.

  Also, the functionalized resin of the present invention provides a combinatorial library of ketones or amines as described for a ketone library derived from four carboxylic acid compounds and four Grignard reagents as outlined in Scheme 13. Useful for building.

Scheme 13

Scheme 13, continued

According to Scheme 13 above, the polymer N-alkylated hydroxylamine resin compound 8 is divided into 4-parts and each part is coupled with a different carboxylic acid compound to provide four different polymer N-alkylated hydroxamic acid resins. A compound is prepared. The four parts of the polymer N-alkylated hydroxamic acid resin compound are then mixed together to form a single part, which is then divided into four parts of the polymer N-alkylated hydroxamic acid resin compound, each part being in an approximately equal amount. Each of the individual polymer N-alkylated hydroxamic acid resin compounds. Each of the four parts is then reacted with a different Grignard reagent R _c1 -R _c4 MgBr and subjected to acid hydrolysis to give four parts of the ketone compound, each of these four different polymer N-alkylated hydroxamic acid resins. Contains four compounds corresponding to the product of the reaction of each compound with a single Grignard reagent. In this way, a combinatorial library containing various ketone compounds can be rapidly constructed.

Similarly, combinatorial libraries of peptides can be constructed by repeating the split-recombination order for each amino acid or peptide building block.

  The foregoing is better understood with reference to the following examples, which are presented for purposes of illustration and are not intended to limit the scope of the invention.

Example 1
Preparation of 4- (2 ', 4'-dimethoxyphenyl-O-methylhydroxylamine) -phenoxymethyl-copoly (styrene-1% divinylbenzene) resin

Rink acid resin (1 g; 0.63 mmol) is swollen in DMF (10 mL) for 15 minutes at ambient temperature. N-hydroxyphthalimide (514 mg; 3.15 mmol) is added to the resin suspension followed by benzenesulfonic acid (19 mg; 0.13 mmol). The mixture is stirred with a mechanical stirrer and heated at 50 ^° C. for 5 hours. The mixture was then cooled to ambient temperature and stirred for an additional 12 hours after which the resin was filtered and DMF (5 x 25 mL); DMF: H ₂ O (70:30; 5 x 25 mL); THF (10 x 25 mL); and thoroughly with diethyl ether (10 x 25 mL). The resin is then dried overnight at 40 ° C. under high vacuum. The IR spectrum shows carbonyl absorption at 1733 cm ⁻¹ , which corresponds to phthalimidocarbonyl stretching. Elemental analysis: Calculated .: 0.28% N. Found: 0.26% N. Loading = 0.18 mmol / g.

The resin is swelled in 20 mL of tert-butanol for 10 minutes. Hydrazine hydrate (10 mL) is added to the mixture and the reaction is warmed to 60 ^° C. with mechanical stirring for 12 hours. The reaction is then cooled to ambient temperature. The resin is filtered and washed thoroughly with DMF (10 × 25 mL), THF (10 × 25 mL), and diethyl ether (10 × 25 mL), then dried at 40 ° C. under high vacuum overnight. The IR spectrum of Resin III shows a loss of carbonyl stretching at 1733 cm ⁻¹ , which is present in the starting material.
Elemental analysis:% N found = 0.43; 0.42 (corresponding to a loading level of 0.3 mmol / g).

Example 2
N- [3-((4-Methoxyphenyl) sulfonyl) prop-1-ylcarbonyl] 4- (2 ', 4'-dimethoxyphenyl-O-methylhydroxylamine) -phenoxymethyl-copoly (styrene-1% divinyl Preparation of benzene) resin.

4- (2 ′, 4′-dimethoxyphenyl-O-methylhydroxylamine) -phenoxymethyl-copoly (styrene-1% divinylbenzene) resin (200 mg) is swollen in DMF (3 mL). To this suspension, 3- (4-methoxyphenylsulfonyl) propionic acid (610 mg; 2.5 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI; 477 mg; 2.5 mmol) Is added at ambient temperature. Shake the reaction mixture at ambient temperature for 12 hours using a vortex shaker, then filter the resin, DMF: H ₂ O (80:20; 5 x 5 mL), DMF (5 x 5 mL) Wash thoroughly with THF (5 x 5 mL), and diethyl ether (5 x 5 mL). The resin IV is dried at 40 ° C. for 12 hours under high vacuum. The IR spectrum shows a carbonyl absorption at 1675 cm ⁻¹ , which corresponds to the bound hydroxamate.

Example 3
Preparation of N-hydroxy-3- (4-methoxyphenylsulfonyl) propionamide Dry N- [3-((4-methoxyphenyl) sulfonyl) prop-1-ylcarbonyl] 4- (2 ', 4'-Dimethoxyphenyl-O-methylhydroxylamine) -phenoxymethyl-copoly (styrene-1% divinylbenzene) resin (200 mg) is swollen in 3 mL of methylene chloride for 10 minutes. Trifluoroacetic acid (TFA; 0.3 mL) is added dropwise to the mixture at ambient temperature and the resulting mixture is stirred for 30 minutes. The resin turned dark blue after the addition of TFA. The mixture is then filtered and washed twice with 5 mL portions of methylene chloride. The filtrate is evaporated by rotary evaporation to give 20 mg of crude product. An LC / MS trace of the crude reaction mixture showed that it contained the desired product better than 75 area% (3- (4-methoxyphenylsulfonyl) propionic acid is present at 6 area%). ¹ H NMR (MeOH-d ₄ ) δ 2.45 (t, 2H); 3.45 (t, 2H); 3.90 (s, 3H), 7.15 (d, 2H); 7.85 (d, 2H).

Example 4
Preparation of 4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (100-200 mesh)

  A 1-L jacketed reactor equipped with a bottom valve and an overhead stirrer (Ace catalog # 8090) is charged with one resin (18.35 g, 20 meq) and anhydrous tetrahydrofuran (THF, 450 mL). The mixture is gently stirred for about 15 minutes and then as much solvent as possible is removed by vacuum suction through a tube fitted with a porous glass frit. Fresh THF is added followed by triphenylphosphine (15.74 g, 60 mmol) and N-hydroxyphthalimide (16.31 g, 100 mmol). The resulting mixture is stirred and cooled to -5-0 ° C. Diisopropyl azodicarboxylate (11.8 mL, 60 mmol) is added slowly to keep the temperature <5 ° C. When the addition is complete, the stirred mixture is gradually warmed to room temperature and stirred overnight. As much reaction solution as possible is removed by suction with a dip tube as described above. The resin is washed by charging N, N-dimethylformamide (DMF, 200 mL), stirring the mixture for 3-5 minutes, and then removing as much washing solution as possible by suction. Similarly, the resin is washed sequentially with additional portions of DMF and portions of methanol (2 times), THF (2 times), and methanol (1 time). Part of the resin may be removed for analysis: IR 1734 cm-1 (C = O).

To the resin remaining in the reactor is added 200 mL of a 40% aqueous solution of THF (400 mL) and methylamine (2.31 mol). The reaction mixture is gently stirred at 40 ° C. for 2 hours and then cooled to room temperature (the mixture may be kept at this temperature overnight). As much of the reaction as possible is removed by aspiration and the resin is washed with the solvent array as described above. After the final methanol wash, additional methanol is used to flush the resin from the bottom of the reactor, which is isolated by filtration. The filtered resin is dried in vacuo at 40 ° C. Yield 18-18.5 g Resin: Amine Road 1.02 meq / g (based on potentiometric titration of THF suspension with p-toluenesulfonic acid); IR (microscopy) 3316 cm ^-1 (w, -NH ₂ ). Analysis , Measured C, 87.07%; H, 7.77%; N, 1.58% (this corresponds to 1.13 nitrogen atoms / g resin).

Assay: Preparation of 4-nitrophenylethanehydroxamic acid A 200 mg sample (approximately 0.2 mmol) of dry resin is charged to a 5- or 10-mL resin reactor (a polypropylene syringe barrel fitted with a polypropylene frit). The resin is allowed to swell in dry DMF for about 15 minutes, then 115 mg (EDCI, 0.6 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is added. To this mixture is then added 4-nitrophenylacetic acid (115 mg, 0.6 mmol). Cap the reactor and stir the mixture slowly overnight (using a rocker bed apparatus). Remove the reaction by vacuum filtration (insert the resin reactor into a small rubber vacuum flask adapter) and wash the resin with several small portions (2-3 mL) of the following solvent: DMF (4-5 portions), MeOH or 50% aqueous DMF (3-4 parts), THF (3-4 parts), and MeOH (2-3 parts). The resin (still in the syringe reactor) is dried at 40 ° C. in vacuo for at least 4 hours.

To this dried resin is added 2 mL dichloromethane followed by 2 mL trifluoroacetic acid (TFA). An additional 20 mL of water is added (it is thought to reduce “anhydride” formation from the hydroxamic acid product). The mixture is allowed to react for about 1 hour, and the reaction solution is discharged to a tare collection device. The resin is washed 1-2 times with 1 mL of dichloromethane followed by 1-2 times with 1 mL of toluene. The combined filtrate is concentrated to about 2 mL at 30 ° C., an additional 2 mL of toluene is added, and the resulting solution is concentrated in vacuo and dried (rotary evaporator at 30 ° C. followed by vacuum; heating in the presence of TFA is “ Note that it promotes the formation of “anhydride” impurities). The residue is weighed and analyzed for weight percent purity (HPLC, carboxylic acid is used as response factor standard). Typical results for 4-nitrophenylethanehydroxamic acid: 60-70 wt% purity, 90-97 A% purity (261 nm) solid 29-30 mg; ¹ H NMR (CD ₃ OD) δ8.13 (d, 2H ), 7.25 (d, 2H), 4.85 (bs, OH, NH), 3.55 (s, 2H); ¹³ C NMR δ169.4, 144.3, 131.3, 124.6, 40.2. This is 1 meq / g from the resin. Reflects 50-55% load / clip chemical yield.

Example 5
Preparation of N-4-phenylbut-1-oil-4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

Dry 4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (2 g, 1.5 mmol) prepared in Example 4 was swollen in DMF (8 mL) for 10 minutes. Then treated with 4-phenylbutyric acid and EDC (0.86 g, 4.5 mmol). The mixture is shaken for 24 hours and filtered. The resin was washed with DMF, DMF / H ₂ O, DMF, THF and Et ₂ O and dried in vacuo at 40 ° C. to give N-4-phenylbut-1-oil-4-O-methylhydroxylamine) phenoxymethyl -Copoly (styrene-1% -divinylbenzene) -resin (2.2 g) is obtained. IR: C = O 1670 cm ^-1 . Elemental analysis: Calculated; N, 1.05%. Found: N, 1.07%.

Example 6
Preparation of N- (4-bromo-3-methylbenzoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

Dry 4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (4 g, 3 mmol) prepared in Example 4 was swollen in DMF (32 mL) for 10 minutes. Followed by treatment with 4-bromo-3-methylbenzoic acid and EDC (1.725 g, 9 mmol). The mixture is shaken for 24 hours and filtered. The resin was washed with DMF, DMF / H ₂ O, DMF, THF and Et ₂ O and dried in vacuo at 40 ° C. to give N- (4-bromo-3-methylbenzoyl) -4-O-methylhydroxylamine) Phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (4.5 g) is obtained. IR: C = O 1677.5cm ^-1 . Elemental analysis: Calculated: Br, 5.2%; N, 1.05%. Found: Br, 5.3%; N, 0.91%.

Example 7
Preparation of N-hydroxy-4-bromo-3-methylbenzamide N- (4-Bromo-3-methylbenzoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1%) prepared in Example 6 -Divinylbenzene) -resin is suspended in 50% TFA / CH ₂ Cl ₂ for 2 hours. The resin is filtered and washed 3 times with CH ₂ Cl ₂ to give N-hydroxy-4-bromo-3-methylbenzamide. LC MS: m / z 230/232 (Br) [M + H] ⁺ area = 78%; ¹ H NMR (300 Mhz, CDCl ₃ ) δ: 2.42 (s, 3H), 7.4 (bd J = 7.89, 1H ) 7.58 (bd J = 7.89 1H), 7.62 (bs, 1H).

Example 8
Preparation of N-4-bromobenzyl-N-4-phenylbut-1-ylcarbonyl-4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

N-4-phenylbut-1-oil-4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (1.46 g, 1.095 mmol) prepared in Example 5 was dissolved in toluene ( Suspend in 26 mL) for 10 minutes. DBU (0.83 mL; 5.5 mmol) is added and the mixture is stirred for 2 hours on a wrist shaker. Bromobenzyl bromide (4.1 g, 16.425 mmol) is added and the reaction mixture is stirred vigorously over 4 days. The resin was filtered, washed with DMF, DMF / H ₂ O, DMF, THF and Et ₂ O and dried in vacuo at 40 ° C. to give N-4-bromobenzyl-N-4-phenylbut-1-ylcarbonyl 4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (1.4 g) is obtained. IR C = O 1668 cm ^-1 . Elemental analysis: Calculated: Br, 5.3%; N, 0.94%. Found: Br, 5.4%; N, 0.85%.

Example 9
Preparation of 4-phenylbutyraldehyde
N-4-bromobenzyl-N-4-phenylbut-1-oil-4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (0.2 g, 0.6 mmol / g 0.12 Mmol) is suspended in diethyl ether for 10 minutes and then cooled to 5 ° C. in an orbital shaker. The suspension is treated with LiAlH ₃ OMe (0.46 M in diethyl ether, 0.22 mL, 0.1 mmol) and stirred at this temperature for 30 minutes. The reaction mixture is quenched by the addition of 2 M HCL (aq) and stirred for 30 minutes. Potassium sodium tartrate is added and the mixture is stirred for an additional 10 minutes. Sodium sulfate is added and the mixture is filtered through a plug of silica gel and washed thoroughly with dichloromethane. The filtrate is concentrated to give 4-phenylbutyraldehyde. GC: Area = 91%; ¹ H NMR (CDCl ₃ ) δ9.75 (1H, s), 7.05-7.30 (5H, m), 2,58-2.68 (2H, m), 2,41-2,50 (2H, t), 1,91-2.02 (2H, m); MS (EI): m / z = 149 [M + H ⁺ ].

Example 10
Preparation of 6-phenylhexane-3-one
N-4-bromobenzyl-N-4-phenylbut-1-oil-4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (0.15 g, approx.0.75 mmol / g 0.11 mmol) is suspended in diethyl ether (1 mL) and treated with a 1 M solution of ethylmagnesium bromide in tetrahydrofuran (0.34 mL, 0.34 mmol). The reaction mixture is stirred for 18 hours and then quenched by the addition of 2 M HCl (aq) (approximately pH 3 is obtained). The mixture is stirred for 30 minutes. Sodium sulfate is added and the mixture is filtered through a plug of silica gel, washed thoroughly with dichloromethane and concentrated to give 6-phenylhexane-3-one. GC MS (EI) area = 97.1%, m / z 176.2 (M) ⁺ ; MS (EI-LRP) m / z 176 (M) ⁺ ; NMR (300 Mhz, CDCl ₃ ) δ 1.02 (t, 3H), 1.9 (m, 2H), 2.4 (m, 4H) 2.6 (m, 2H), 7.2-7.3 (m, 5H).

Example 11
Preparation of N-4-chlorobenzyl-N- (4-bromo-3-methylbenzoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

N- (4-Bromo-3-methylbenzoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (2.8 g, 2.1 mmol) prepared in Example 6 Suspend in toluene (27 mL) and stir the mixture for 10 min. DBU (1.6 g, 10.5 mmol) is added and the mixture is stirred on a wrist shaker for 2 hours. Chlorobenzyl bromide (6.47 g, 31.5 mmol) is added and the reaction mixture is then stirred vigorously over 3 days. The resin was filtered, washed with DMF, DMF / H ₂ O, DMF, THF and Et ₂ O, dried in vacuo at 40 ° C. and N-4-chlorobenzyl-N- (4-bromo-3-methylbenzoyl) ) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (3 g). IR C = O 1644 cm ^-1 ; Elemental analysis: Calculated: Br, 4.2%; Cl, 1.9%; N, 0.8%. Found: Br, 3.8%; Cl, 2.0%; N, 0.9%.

Example 12
Preparation of N- (4-chlorobenzyl) -N-hydroxy-3-methyl-4-bromobenzamide

N-4-chlorobenzyl-N- (4-bromo-3-methylbenzoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin prepared in Example 11 Suspend in 50% TFA / CH ₂ Cl ₂ for 2 hours. The resin is filtered and washed 3 times with CH ₂ Cl ₂ to give N- (4-chlorobenzyl) -N-hydroxy-3-methyl-4-bromobenzamide. LC MS (H-ISP) m / z 354/356 (Cl / Br) [M + H] ⁺ area 64%; ¹ H NMR (300 Mhz, CDCl ₃ ) δ 2.3 (bs, 3H), 4.65 (bs, 2H), 7.2-7.6 (m, 7H).

Example 13
Preparation of 4-bromo-3-methylbenzaldehyde

N-4-chlorobenzyl-N- (4-bromo-3-methylbenzoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin prepared in Example 11 0.2 g, 0.5 mmol / g 0.1 mmol) is suspended in diethyl ether for 10 minutes and then cooled to 5 ° C. in an orbital shaker. The suspension is treated with LiAlH ₃ OMe (0.46 M in diethyl ether, 0.2 mL, 0.092 mmol) and stirred at this temperature for 30 minutes. The reaction mixture is quenched by the addition of 2 M aqueous HCL and stirred for 30 minutes. Potassium sodium tartrate is added and the mixture is stirred for an additional 10 minutes. Sodium sulfate is added and the mixture is filtered through a plug of silica gel and washed thoroughly with dichloromethane. The filtrate is concentrated to give 4-bromo-3-methylbenzaldehyde. GC MS: EI area = 99.5%, m / z 179/199 (Br) [M] ⁺ ; ¹ H NMR (CDCl ₃ ) δ 9.94 (1H, s), 7.70 (2H, d), 7.52 (1H, d ), 2.45 (3H, s); MS (EI): m / z = 199 [M + H ⁺ ].

Example 14
Preparation of 1- (4-bromo-3-methylphenyl) propan-1-one N-4-chlorobenzyl-N- (4-bromo-3-methylbenzoyl) -4-O-methyl prepared in Example 11 Hydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (0.23 g, 0.5 mmol / g 0.115 mmol) was suspended in diethyl ether (1 mL) and ethyl magnesium bromide (1.0 M in THF). , 0.23 mL, 0.23 mmol). The reaction mixture is stirred for 18 hours and then quenched by the addition of 2 M aqueous HCL solution (approximately pH 3 is obtained). The mixture is stirred for 30 minutes. Sodium sulfate is added and the mixture is filtered through a plug of silica gel and washed thoroughly with dichloromethane. The residue is concentrated to give 1- (4-bromo-3-methylphenyl) propan-1-one. GC area = 78.7%; MS (EI) m / z 226 Br [M ⁺ -H]; NMR (300 Mhz, CDCl ₃ ) δ 1.22 (t J = 7.89, 3H), 2.96 (q J = 7.89, 2H) , 7.6 (bs, 2H), 7.8 (s, 1H).

Example 15
Preparation of N-3-bromobenzaldehyde oxime-4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (105 mg; 0.08 mmol) is swollen in dichloromethane (DCM) (@ mL) for 10 minutes. Trimethylorthoformate (1 mL) and 3-bromo-benzaldehyde (500 mg; 2.7 mmol; 34 equiv.) Are added to the resin and the mixture is shaken overnight. The slurry is then filtered and rinsed with dichloromethane (5 mL), DMF (5 mL x 3), H ₂ O (5 mL x 4), THF (5 mL x 10), and Et ₂ O (5 mL x 10). . The resin is dried in vacuum at 40 ° C. for 12 hours. IR oxime stretching 1602 cm ^-1 . Elemental analysis: Calculated: Br, 5.52%; N, 1.04%. Found: Br, 5.76%; N, 1.08%.

Example 16
Preparation of N-3- (4-methoxyphenyl) propane-1-oil-4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (1 g, 0.73 mmol) was swollen in DMF for 10 minutes and then 3- (4-methoxyphenyl) propion Treat with acid (0.658 g, 3.65 mmol) and DIC (0.46 g, 3.65 mmol). The mixture was shaken for 24 hours, then filtered, the residue washed with DMF, DMF / H ₂ O, DMF, THF and ET ₂ O, dried in vacuo at 40 ° C. and N-3- (4-methoxy Phenyl) propane-1-oil-4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin is obtained. IR: C = O 1698 cm ^-1 . Elemental analysis: Calculated: N, 1.02%. Found: N, 1.21%.

Example 17
Preparation of N-hydroxy-3- (4-methoxyphenyl) propionamide Using the procedure of Example 7, N-hydroxy-3- (4-methoxyphenyl) propionamide was converted to N-3- (4-methoxyphenyl). It is prepared by the reaction of TFA with propane-1-oil-4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin. ¹ H NMR 300MHz (CDCl _{3 /,} CD ₃ OD) δ 2.25 (t, 2H), 2.78 (t, 2H), 3.68 (s, 3H), 6.72 (d, 2H), 7.04 (d, 2H).

Example 18
Preparation of N-2- (4-bromophenyl) ethane-1-oil-4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

The title resin is prepared using the method of Example 16, except that 4-bromophenylacetic acid is used in place of 3- (4-methoxyphenyl) propionic acid. IR C = O 1713.9 cm ^-1 . Elemental analysis: Calculated: Br, 5.8%; N, 1.02%. Found: Br, 8.29%, 8.18%; N, 0.97%, 0.96%.
EDS: Net X-ray count
K line L line M line
O: 969 1024
C: 2662 3003
Br: 12855 10436

Example 19
Preparation of N-4-bromocinnamoyl-4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

The title resin is prepared using the method of Example 16 except that 4-bromocinnamic acid is used in place of 3- (4-methoxyphenyl) propionic acid. IR: C = O 1671.7 cm ^-1 (broad). Elemental analysis: Calculated: Br, 5.8%; N, 1.02%. Found: Br, 4.45%, 4.54%.
EDS: Net X-ray count
K line L line M line
O: 818 1365
C: 4549 5059
Br: 6384 5271

Example 20
Preparation of N-hydroxy-4-bromocinnamamide Using the procedure of Example 7, N-4-bromocinnamoyl-4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene ) -N-hydroxy-4-bromocinnamamide is prepared by treating the resin with TFA. LC MS (H-ISP) m / z 241/243 Br [M ⁺ ], Area = 84%; ¹ H NMR (300 Mhz, CDCl _{3 /} CD ₃ OD) δ: 3.23 (s, 1H), 6.35 (d , J = 15.8), 7.3 (d, J = 7.9), 7.4 (d, J = 7.9), 7.6 (d, J = 15.8).

Example 21
Preparation of N- (4-chlorobenzoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

  The title resin is prepared using the method of Example 16 except that 4-chlorobenzoic acid is used in place of 3- (4-methoxyphenyl) propionic acid. IR: C = O 1678 cm-1. Elemental analysis: Calculated: Cl, 2.66%; N, 1.05%. Found: Cl, 2.39%; N, 1.02%.

Example 22
Preparation of N-hydroxy-4-chlorobenzamide N- (4-Chlorobenzoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene)-using the procedure of Example 7 N-hydroxy-4-chlorobenzamide is prepared by treating the resin with TFA. LC MS (H-ISP) m / z 172,174 (Cl) [M + H] ⁺ , Area = 96%; ¹ H NMR (300 Mhz, DMSO-d ₆ ) δ 7.48 (d J = 9.42, 2H), 7.69 (d J = 9.42, 2H), 8.9-9.2 (broad, 1H), 11.28 (s, 1H).

Example 23
Preparation of N-methyl-N- (4-chlorobenzoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

N- (4-Chlorobenzoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (0.1 g, 0.075 mmol, 0.75 mmol / g) in toluene (2 mL) Suspend in and cool to 5 ° C. The mixture is treated with methyl iodide (1.5 mmol, 0.21 g, 93 μl) followed by DBU (0.22 mL, 0.228 g, 1.5 mmol). The reaction mixture is placed in a vortexer and warmed to ambient temperature. Within a few minutes, a large amount of white precipitate is formed and the mixture is further diluted with toluene (2 mL). Stirring of the reaction mixture is continued for 18 hours. N-methyl-N- (4-chlorobenzoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin was filtered and DMF, DMF / H ₂ O, DMF, Wash with THF, Et ₂ O and dry in vacuo at 40 ° C.

Example 24
Preparation of 1- (4-chlorophenyl) propan-1-one
N-methyl-N- (4-chlorobenzoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin is suspended in diethyl ether (0.7 mL) and ethyl Treat with magnesium bromide (1.0 M in THF, 0.225 mL, 0.225 mmol). The reaction mixture is stirred for 18 hours on a wrist shaker and then quenched by the addition of 5% HCl in ethanol. Stirring is maintained for an additional 30 minutes, and the mixture is then filtered through a small plug of silica to remove inorganic material. The filtrate is concentrated to give 1- (4-chlorophenyl) propan-1-one. MS (EI-LRP) m / z 168/170 Cl [M ⁺ ], 169/171 Cl [M + H] ⁺ ; ¹ H NMR (300Mhz, CDCl ₃ ) δ 1.22 (t, 3H), 2.98 (q. 2H), 7.42 (d, 2H), 7.9 (d, 2H).

Example 25
Preparation of N- [3-((4-methoxyphenyl) sulfonyl) propane-1-oilcarbonyl] -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

Using the method of Example 16, except that 3- (4-methoxyphenylsulfonyl) propionic acid was added instead of 3- (4-methoxyphenyl) propionic acid, N- [3-((4-methoxyphenyl) was used. ) Sulfonyl) propane-1-oilcarbonyl] -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin is prepared. IR C = O 1691.6 cm ^-1 (broad). Elemental analysis: Calculated: N, 1.02%; S, 2.34%. Found: N, 1.03%; S, 2.5%.

Example 26
Preparation of N-hydroxy-3- (4-methoxyphenylsulfonyl) propionamide Using the procedure of Example 7, N- [3-((4-methoxyphenyl) sulfonyl) propane-1-oilcarbonyl] -4- N-hydroxy-3- (4-methoxyphenylsulfonyl) propionamide is prepared by treating O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin with TFA. ¹ H NMR (300Mhz, DMSO-d ₆ ) δ 2.25 (t, 2H), 3.42 (t, 2H) 3.85 (s, 3H), 7.13 (d, 2H), 7.79 (d, 2H); LC MS (ion Spray) m / z 259 [M ⁺ ], area = 44%

Example 27
Preparation of N-allyloxycarbonyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin

  4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin (2 g, 2 mmol) is suspended in 15 ml of dichloromethane, shaken with a wrist shaker for 10 minutes, and diisopropylethylamine 284 mg (383 ul, 2.2 mmol) are added. Shake the mixture for 30 minutes. Allyl chloroformate (265 mg, 233ul, 2.2 mmol) is added and the mixture is shaken overnight. N-allyloxycarbonyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin is washed with 15 ml dichloromethane, THF (3x) and dichloromethane (3x) and dried in vacuo .

Example 28
Preparation of N-4-bromobenzyl-N-allyloxycarbonyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin

  The N-allyloxycarbonyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin prepared in Example 27 is suspended in 15 mL of toluene. DBU (1,522 g, 1.5 ml, 10 mmol) and 4-bromobenzyl bromide (2.5 g, 10 mmol) are added and the mixture is shaken for 70 hours. N-4-Bromobenzyl-N-allyloxycarbonyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin in 15 mL DMF (3x), THF (3x) and dichloromethane Wash with (3x) and dry in vacuo.

Example 29
Preparation of N-4-bromobenzyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin

N-4-bromobenzyl, N-allyloxycarbonyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin prepared in Example 28 was added to 6 mL of THF, 6 mL of Swell in DMSO, 3 mL 0.5 n Hcl. Pd (Ph ₃ P) ₄ (347 mg, 15% by weight) is added and the mixture is shaken for 5 minutes. Morpholine (4.3 mL) is added and the mixture is shaken overnight. Drain the reagent and add N-4-bromobenzyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin to DMF (2x), THF (2x), dichloromethane (2x), Wash with 0.5% diisopropylethylamine (3x) in dichloromethane, 0.5% sodium diethyldithiocarbamate (3x), DMF (3x), THF (3x) and dichloromethane (3x) in DMF and dry overnight in vacuo.

Example 30
Preparation of N- (Indol-2-ylcarbonyl) -N-4-bromobenzyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin

N-4-bromobenzyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin (1.17 g, 1 mmol) prepared in Example 29 was suspended in 15 ml DMF. Let Indole-2-carboxylic acid (483 mg, 3 mmol) and 15.1 (3-dimethylaminopropyl) -3-diethylcarbodiimide hydrochloride 575.1 mg (3 mmol) are added and the mixture is shaken for 16 hours. N- (Indol-2-ylcarbonyl) -N-4-bromobenzyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin is drained and 15 ml DMF (3x ), THF / 20% H ₂ O (3x), THF (3x), and dichloromethane (3x) and dried in vacuo.

Example 31
Preparation of indole-2-carboxaldehyde Dry N- (Indol-2-ylcarbonyl) -N-4-bromobenzyl-4- (O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% divinylbenzene) resin Swell in 12 mL of THF, shake and cool at 0 ° C. for 30 minutes. LiAlH ₄ (0.62 ml, 3 eq) is added and the mixture is shaken at 0 ° C. for 30 minutes. Saturated KHSO ₄ solution (0.5 mL) and 0.3 mL of potassium, sodium tartrate solution are added and the mixture is shaken for 30 minutes while warming to room temperature. Add dry Na ₂ SO ₄ and dry excess H ₂ O by shaking for more than 15 minutes. The mixture is filtered under low nitrogen pressure, washed three more times with 8 mL of dichloromethane and subsequently filtered. The filtrate was dried over Na ₂ SO ₄ and filtered twice through a short bed (1 inch) of silica gel 60 (particle size 0.040-0.063 mm) for column chromatography and the solvent was removed in vacuo to remove indole-2-carboxyl. Obtain an aldehyde. ¹ H NMR (CDCl ₃ ) δ 9.84 (1H, s), 9.22 (1H, brs), 7.75 (1H, d), 7.14-7.48 (4H, m); MS (EI): m / z = 146 [M + H ⁺ ].

Example 32
Preparation of N- (tert-butoxycarbonyl) phenylalanine aldehyde Prepare the desired compound according to the methods of Examples 30 and 31 except that N- (tert-butoxycarbonyl) phenylalanine was used instead of indole-2-carboxaldehyde. .

Example 33
Preparation of N- (3,4-dimethoxycinnamoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin (1 g, 1 mmol) was washed with DMF (15 mL) and then suspended in 15 mL DMF, 624.6 mg (3 mmol, 3 x excess) 3,4-dimethoxycinnamic acid and 575.1 mg (3 mmol, 3 x excess) 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added. Shake the mixture for 16 hours. Drain the resin and wash with 15 mL DMF (1x), THF / 20% H ₂ O (3x), THF (3x), dichloromethane (3x) and dry in vacuo overnight.

Example 34
Preparation of N-4-bromobenzyl-N- (3,4-dimethoxycinnamoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin

  Dry N- (3,4-dimethoxycinnamoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin is shaken in 15 mL of toluene for 10 minutes and then 0.9. Add mL (6 mmol, 6 x excess) of DBU and shake the mixture for 2 h. p-Bromobenzyl bromide (1.5 g, 6 mmol, 6 x excess) is added and the mixture is shaken for 3 days. The resin is dried overnight in vacuo.

Example 35
Preparation of 3-4-dimethoxycinnamaldehyde Dry N-4-bromobenzyl-N- (3,4-dimethoxycinnamoyl) -4-O-methylhydroxylamine) phenoxymethyl-copoly (styrene-1% -divinylbenzene) -Swell the resin in 12 mL dry THF, shake and cool at 0 ° C for 30 min. LiAlH _{4 in} THF (0.5 mL, 2 eq) is added and the mixture is shaken at 0 ° C. for 30 min. Saturated aqueous KHSO ₄ solution (0.5 mL) and potassium and sodium tartrate solution (0.3 mL) are added and the mixture is shaken for 30 minutes while warming to ambient temperature. Dry Na ₂ SO ₄ is added and excess H ₂ O is dried by shaking for 15 minutes. The mixture is filtered with low nitrogen pressure, washed 3 times with 8 mL of dichloromethane and filtered. The filtrate was further dried over Na ₂ SO ₄ , filtered through a short bed (1 inch) of silica gel 60 (particle size 0.040-0.063 mm) for column chromatography, the solvent was removed in vacuo and 3,4-dimethoxycinna Obtains mualdehyde. ¹ H NMR (CDCl ₃ ) δ 9.65 (1H, d), 7.40 (1H, d), 7.12 (1H, d), 7.06 (1H, s), 6.87 (1H, d), 6.60 (1H, dd), 3.90 (6H, s); MS (EI): m / z = 193 [M + H ⁺ ].

Examples 36-43
The compounds of Examples 36-43 are prepared from the desired carboxylic acid starting material using the procedures of Examples 33-35.

Example 36
Preparation of anthranialdehyde
¹ H NMR (CDCl ₃ ) δ 9.88 (1H, s), 7,52-7.58 (1H, d), 7.11-7.38 (7H, m), 6.81 (1H, t); MS (EI): m / z = 198 [M + H ⁺ ].

Example 37
Preparation of 2-bibenzylaldehyde
¹ H NMR (CDCl ₃ ) δ 10.18 (1H, s), 7.83 (1H, d), 7.14-7.52 (8H, m), 3.30 (2H, t), 2.87 (2H, t); MS (EI): m / z = 211 [M + H ⁺ ].

Example 38
Preparation of 4-methoxy-2-quinolinaldehyde
¹ H NMR (CDCl ₃ ) δ 10.17 (1H, s), 8.27 (1H, d), 8.18 (1H, d), 7.78 (1H, t), 7.62 (1H, t), 7.38 (1H, s), 4.12 (3H, s); MS (EI): m / z = 188 [M + H ⁺ ]

Example 39
Preparation of 3-acetamidobenzaldehyde
¹ H NMR (CDCl ₃ ) δ 9.98 (1H, s), 7.97 (1H, s), 7.86 (1H, d), 7.62 (1H, d), 7.48 (1H, t), 2.21 (3H, s). MS (EI): m / z = 164 [M + H ⁺ ].

Example 40
Preparation of 4- (4-N-propylphenyl) benzaldehyde
¹ H NMR (CDCl ₃ ) δ 10.02 (1H, s), 7,92 (2H, d), 7.72 (2H, d), 7.53 (2H, d), 7.26 (2H, d), 2.65 (2H, t ), 1.68 (2H, dt), 0.95 (3H, t); MS (EI): m / z = 225 [M + H ⁺ ].

Example 41
Preparation of 3-quinoline aldehyde
¹ H NMR (CDCl ₃ ) δ 10.26 (1H, s), 9.38 (1H, s), 8.64 (1H, s), 8.20 (1H, d), 7.98 (1H, t), 7.89 (1H, t), 7.65 (1H, t); MS (EI): m / z = 158 [M + H ⁺ ].

Example 42
Preparation of 3- (3,4-methylenedioxy) propionaldehyde
¹ HNMR (CDCl ₃ ) δ 9.80 (1H, s), 7.60-7.74 (3H, m), 5.92 (2H, s), 2.88 (2H, t), 2,74 (2H, t); MS (EI) : m / z = 179 [M + H ⁺ ].

Example 43
Preparation of 2-phenyl-4-quinolinaldehyde
¹ H NMR (CDCl ₃ ) δ 10.58 (1H, s), 9.00 (1H, d) 8.19-8.30 (4H, m), 7.82 (1H, t), 7.70 (1H, t), 7.47-7.59 (3H, m); MS (EI): m / z = 234 [M + H ⁺ ].

Example 44
Preparation of 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl-copoly (styrene-1% divinylbenzene) resin

Merrifield resin (2 mmol / g, 600 mg, 1.2 mmol) is swollen in anhydrous DMF (20 mL). 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid hydrate (2.28 g, 10 mmol) and cesium carbonate (3.26 g, 10 mmol) were added and the reaction mixture was stirred with gentle stirring. Heat at ℃ 12 hours. The reaction mixture was filtered and 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl-copoly (styrene-1% divinylbenzene) resin was added to DMF (5x), 20% aqueous DMF (5x), THF (5x ) And dichloromethane and dried in vacuo overnight. IR (microscope, cm-1): 1640 (C = O); ¹⁹ F NMR (nanoprobe) -144.4 ppm, -160.2 ppm.

EDS

  Energy dispersive x-ray measurements are performed using an electroscan scanning electron microscope with a PGT digital detector. The beads are mounted on an aluminum stub and tested without a conductive coating. Net x-ray counts are reported after correction for background. No correction is made for atomic number, fluorescence or absorbance.

Claims (42)

formula

(Where
A ² is a direct bond or alkylene, or NR ¹³ (wherein R ¹³ is hydrogen or alkyl);
R ⁹ is a group of formula -L ¹ -R ¹⁴ (wherein L ¹ is a direct bond or optionally substituted by alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl, hydroxyl, or oxo. Represents a chain or branched C _1-6 alkylene chain, and R ¹⁴ is hydrogen, aryl, carboxy, cyano, cycloalkyl, cycloalkenyl, cyclocarbamoyl, cycloimidyl, heterocycloalkyl, heteroaryl, —NH—C (═O) -NH ₂ , (N-carbamoyl) cyclic amine, -C = NOC (= O) -NH ₂ , -C (= O) -NY ¹ Y ^{2 wherein} Y ¹ and Y ² are independently hydrogen, alkyl , Arylalkyl, and aryl, or the substituent Y ¹ Y ² N— may optionally contain an additional heteroatom selected from O, S, NH or NR ¹³ forming a], - NY ¹ SO ₂ aryl, -NHR ^13, -SR ¹³ or -OR ¹³ der Group), or a group L ² -R ¹⁵ (wherein, L ² represents a linear or branched carbon chain containing carbon atoms from the two which may optionally be substituted by carboxy or cyano necessary up to about six (which Contains a double carbon-carbon bond or triple carbon-carbon bond, or is interrupted by an oxygen or sulfur atom, a phenylene bond, an imino (-NH-) bond or an alkylimino bond, or a sulfinyl group or a sulfonyl group) And R ¹⁵ is hydrogen, aryl, carboxy, cyano, cycloalkyl, cycloalkenyl, heterocycloalkyl or heteroaryl, or R ⁹ and R ¹⁰ together with the atoms to which they are attached To form a ring, or R ⁹ and R ¹¹ together with the atoms to 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 is a group -L ³ -R ¹⁶ , wherein L ³ is a direct bond or optionally substituted by alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl, hydroxyl, or oxo. Represents a chain or a branched C _1-6 alkylene chain, or L ³ is a straight or branched carbon chain containing from 2 to about 6 carbon atoms (this includes a double carbon-carbon bond or a triple carbon-carbon bond). Or is interrupted by an oxygen or sulfur atom, a phenylene bond, an imino (-NH-) bond or an alkylimino bond, or a sulfinyl group or a sulfonyl group), and R ¹⁶ is hydrogen, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-carbamoyl, Shikuroimijiru, heterocycloalkyl, heteroaryl, -NH-C (= O) -NH 2, (N- carbamoyl) cyclic amine, -C = NOC (= O) -NH ₂ , -C (= O) -NY ¹ Y ^{2 wherein} Y ¹ and Y ² are independently hydrogen, alkyl, arylalkyl, and aryl, or the substituent Y ¹ Y ² N- is optionally O , S, NH or NR ^13, which forms a 4-6 membered cyclic amine that may contain additional heteroatoms], —NY ¹ SO ₂ aryl), or R ¹¹ and R ⁹ together with the atom to which they are attached forms a ring, or R ¹¹ and R ¹² together with the atom to which they are attached form a ring;
Ar

A group selected from
Wherein R ¹⁷ is a linear or branched alkyl group of 1 to about 6 carbon atoms optionally substituted with one or more halogen atoms, or when Z ³ is a direct bond R ¹⁷ may also represent a hydrogen atom, an alkenyl group or an alkynyl group,
R ¹⁸ represents an optionally substituted cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, aryl group, partially saturated bicycloaryl group or heteroaryl group,
R ¹⁹ is ^{R 20, -OR 20, -SR 20} , -SOR 2 0, -SO 2 R 20, -SO 2 NR 20 R 2 1, -NR 20 SO 2 R 21, -NR 20 R 21, -O (C = O) NR ²⁰ R ²¹ , -NR ²⁰ C (= O) R ²¹ , -N (OH) C (= O) R ²⁰ , or -C (= O) N (OH) R ²¹ (wherein , R ²⁰ and R ²¹ (which may be the same or different) are each a hydrogen atom, or an alkyl group, alkenyl group, heterocycloalkyl group, cycloalkyl group, cycloalkenyl group, aryl group Represents a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, or the group NR ²⁰ R ²¹ may optionally contain one or more additional heteroatoms selected from O, N or S 5 When it represents a 7-membered cyclic amine and R ¹⁸ represents a substituted cycloalkyl group, the cycloalkyl group is OR ²³ , SR ²⁴ , SOR ²⁴ , SO ₂ R ²⁴ , NH ₂ , NR ¹³ R ²⁴ , = NOR ²⁴ , = NOH, = NNHR ²⁴ , = NOCONHR ²⁴ , = NCO ₂ R ²⁴ , SOR ²⁴ , NHCOR ²⁴ , N One or more selected from HSO ₂ R ²⁴ , SO ₂ NR ¹³ R ²⁴ , R ²³ , CONHR ²⁴ , CONHCH ₂ CO ₂ R ¹³ , CONR ²⁴ R ¹³ , or N ₃ (for example, 1, 2 or 3 Wherein R ²³ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, and R ²⁴ is alkyl, cycloalkyl, cycloalkenyl, hetero Cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or the substituent NR ¹³ R ²⁴ may optionally contain additional heteroatoms selected from O, S, NH or NR ¹³ When a 4-7 membered cyclic amine is formed and R ¹⁸ represents a substituted heterocycloalkyl group containing a nitrogen atom, the ring is one or more of the ring carbon atoms (eg, 1, 2 or 3). Is replaced at the position Group oxo, _{^{cyano, CO 2 R 13, CONHCH 2}} CO 2 R 13, aryl, arylalkyl, selected from alkyl or hydroxyalkyl is substituted and / or position of the ring nitrogen atoms, the substituent R ¹³ , (CH ₂ ) _n CO ₂ H, (CH ₂ ) _n CO ₂ R ²⁴ , (CH ₂ ) _n CONR ¹³ R ²⁴ , (CH ₂ ) _n COR ²⁴ , CONH ₂ , CONHR ²⁴ , COR ²⁴ , SO ₂ Selected from R ²⁴ or OR ²⁴ ;
A ³ represents a direct bond, optionally a linear or branched C _1-6 alkylene chain optionally substituted by halogen, hydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroaryl, or A ³ from 2 Linear or branched carbon chain containing up to about 6 carbon atoms (this includes double or triple carbon-carbon bonds, or oxygen or sulfur atoms, phenylene bonds, imino (-NH-) bonds or alkylimino bonds) Or is interrupted by a sulfinyl or sulfonyl group)
Z ¹ and Z ³ each represents an oxygen atom or a sulfur atom, a direct bond or NH,
Z ² represents an oxygen atom or a sulfur atom, or a direct bond,
B, C, D, and E are independently carbon or O, S, N, NOR ²² or NR ²² (wherein R ²² is hydrogen or a C _1-4 linear or branched alkyl group, aryl group, aryl C _1-4 alkyl group, heteroaryl group or heteroaryl C _1-4 alkyl group), or three of B, C, D or E are carbon or O, N, NR ²² , Or a hetero atom selected from S, and the other represents a direct bond, except for compounds in which two O atoms or S atoms are adjacent to each other, and a bond that binds B, C, D and E is a single bond. May be a bond or a double bond,
Q ¹ , Q ² and Q ³ (which may be the same or different) each represent a CH bond or a CX ¹ bond or a nitrogen atom, X ¹ represents a halogen atom, and n is 0, 1 or 2)
Or a N-oxide, prodrug, acid isostere, pharmaceutically acceptable salt, or solvate thereof, comprising:

A carboxylic acid compound of the formula

Coupling to a polymer hydroxylamine resin compound of formula

A polymer hydroxamic acid resin compound, and
(b) A method for preparing the hydroxamic acid compound, wherein the polymer hydroxamic acid resin compound is treated with an acid.   2. A process according to claim 1 wherein the acid is trifluoroacetic acid. formula

(Where

Is a solid support and L is absent or a linking group)
The polymer hydroxylamine resin compound of formula

Characterized by reacting with a carbonyl compound of

(Where

Is a solid support, L is absent or a linking group, and R _a and R _b are independently H, aliphatic or aromatic)
Of preparing a polymer oxime ether resin compound of   The method according to claim 3, wherein L is a linking group. L is the formula

The method according to claim 4, wherein the bonding group is
(Where
A is absent or a group of formula -X ¹ -Z-
X ¹ is —CHR— or —CHR—Y—CO— (CH ₂ ) _n — (wherein R is substituted with H, alkyl, phenyl, or —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ And phenyl
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 ² a are independently —H, alkyl, alkoxy, halogen, nitrile, or —NO ₂ 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 —NO ₂ , or
One of R ¹ and R ² together with one of R ³ and R ⁴ and the carbon atom to which they are attached

(Where
R ^{1 ′} is —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ and
R ⁶ , R ⁷ and R ⁸ are independently selected from —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ )
Form a linking group) formula

(Where

Is a solid support and L is absent or a linking group)
A reductive cleavage of an α-amine compound from the polymer oxime ether resin compound of

(Wherein R _d and R _e are independently H, aliphatic or aryl, provided that R _d and R _e are not both H)
Of the α-amine compound.   The method according to claim 6, wherein L is a linking group. L is the formula

The method according to claim 7, wherein the linking group is.
(Where
A is absent or a group of formula -X ¹ -Z-
X ¹ is —CHR— or —CHR—Y—CO— (CH ₂ ) _n — (wherein R is substituted with H, alkyl, phenyl, or —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ And phenyl
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 ² a are independently —H, alkyl, alkoxy, halogen, nitrile, or —NO ₂ 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 —NO ₂ , or
One of R ¹ and R ² together with one of R ³ and R ⁴ and the carbon atom to which they are attached

(Where
R ^{1 ′} is —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ and
R ⁶ , R ⁷ and R ⁸ are independently selected from —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ )
Form a linking group)   9. A process according to claim 8 wherein reductive cleavage is performed using a hydride reducing agent. The method according to claim 9, wherein the reductive cleavage is performed by continuous treatment of the polymer oxime ether resin compound with NaBH ₃ CN and LiAlH ₄ . (a) Expression

(Where

Is a solid support and L is absent or a linking group)
Is reacted with an organometallic reagent of the formula R _f M where R _f is an aliphatic or aromatic anion and M is a metal cation.

A polymer α-substituted hydroxylamine resin compound, and
(b) a formula characterized by reductive cleavage of an α-substituted hydroxylamine resin compound

Of (in the formula, R _d and R _e are independently are H, aliphatic or aromatic the proviso that not both are R _d and R _e H, and R _f is an aliphatic or aromatic) A method for preparing a substituted α-amine compound.   The method according to claim 11, wherein M is Li or MgX (wherein X is Br or Cl).   13. A process according to claim 12 wherein reductive cleavage is performed using a hydride base. The method according to claim 13 hydride base is BH ₃ THF or LiAlH _4.   The method according to claim 14, wherein L is a linking group. L is the formula

The method according to claim 15, which is a linking group.
(Where
A is absent or a group of formula -X ¹ -Z-
X ¹ is —CHR— or —CHR—Y—CO— (CH ₂ ) _n — (wherein R is substituted with H, alkyl, phenyl, or —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ And phenyl
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 ² a are independently -H, alkyl, alkoxy, halogen, nitrile, or -NO ₂ 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 —NO ₂ , or
One of R ¹ and R ² together with one of R ³ and R ⁴ and the carbon atom to which they are attached

(Where
R ^{1 ′} is —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ and
R ⁶ , R ⁷ and R ⁸ are independently selected from —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ )
Form a linking group) (a) Expression

(Where

Is a solid support and L is absent or a linking group)
The α, β-unsaturated polymer hydroxamic acid ester resin compound of the formula is treated with thiophenol and a free radical initiator.

A polymer oxymyl lactone compound, and
(b) A formula characterized by treating a polymer oxymillactone compound with an aqueous acid solution

A process for preparing a lactone compound wherein R _g , R _h and R _i are aliphatic or aromatic and Ph is phenyl.   The process according to claim 17, wherein the free radical initiator is 2,2'-azobisisobutyronitrile.   The method according to claim 18, wherein the aqueous acid solution is an aqueous HCl solution. formula

The polymer hydroxylamine resin compound of formula

By reacting with an α, β-unsaturated carboxylic acid ester compound of

(Where

, L and R _g and R _h and R _i are as defined herein)
18. A process according to claim 17 for preparing an [alpha], [beta] -unsaturated polymeric hydroxamic acid ester resin compound.   21. The method of claim 20, wherein L is a linking group. L is the formula

The method according to claim 21, which is a linking group.
(Where
A is absent or a group of formula -X ¹ -Z-
X ¹ is —CHR— or —CHR—Y—CO— (CH ₂ ) _n — (wherein R is substituted with H, alkyl, phenyl, or —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ And phenyl
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 ² a are independently —H, alkyl, alkoxy, halogen, nitrile, or —NO ₂ 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 —NO ₂ , or
One of R ¹ and R ² together with one of R ³ and R ⁴ and the carbon atom to which they are attached

(Where
R ^{1 ′} is —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ and
R ⁶ , R ⁷ and R ⁸ are independently selected from —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ )
Form a linking group) (a) Expression

(Where

Is a solid support and L is absent or a linking group)
The polymer acetophenone oxime compound was treated with trialkyltin hydride and a free radical initiator to formula

A polymer α-cyclic hydroxylamine resin compound of formula (b) and (b) treating the polymer α-cyclic hydroxylamine resin compound with an aqueous acid solution.

Wherein R _j and R _k are aliphatic or aromatic and Q is —O— or —CH ₂ —.
Of the preparation of an α-cyclic hydroxylamine compound.   24. The method of claim 23, wherein L is a linking group. L is the formula

The method according to claim 24, wherein the linking group is.
(Where
A is absent or a group of formula -X ¹ -Z-
X ¹ is —CHR— or —CHR—Y—CO— (CH ₂ ) _n — (wherein R is substituted with H, alkyl, phenyl, or —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ And phenyl
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 ² a are independently —H, alkyl, alkoxy, halogen, nitrile, or —NO ₂ 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 —NO ₂ , or
One of R ¹ and R ² together with one of R ³ and R ⁴ and the carbon atom to which they are attached

(Where
R ^{1 ′} is —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ and
R ⁶ , R ⁷ and R ⁸ are independently selected from —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ )
Form a linking group)   26. The method of claim 25, wherein the trialkyltin hydride is tri-n-butyltin hydride.   27. The method of claim 26, wherein the free radical initiator is 2,2′-azobisisobutyronitrile. formula

(Where

Is a solid support and L is absent or a linking group)
Wherein the polymer α-cyclic hydroxylamine resin compound is reductively cleaved

A process for preparing an α-cyclic amino compound wherein R _j and R _k are aliphatic or aromatic and Q is —O— or —CH ₂ —.   29. The method of claim 28, wherein reductive cleavage is performed using a hydride reducing agent. The method according to paragraph 29 claims hydride reducing agent is LiAlH _4.   The method according to claim 30, wherein L is a linking group. L is the formula

32. The method according to claim 31, wherein the linking group is.
(Where
A is absent or a group of formula -X ¹ -Z-
X ¹ is —CHR— or —CHR—Y—CO— (CH ₂ ) _n — (wherein R is substituted with H, alkyl, phenyl, or —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ And phenyl
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 —NO ₂ 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 —NO ₂ , or
One of R ¹ and R ² together with one of R ³ and R ⁴ and the carbon atom to which they are attached

(Where
R ^{1 ′} is —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ and
R ⁶ , R ⁷ and R ⁸ are independently selected from —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ )
Form a linking group) (a) Expression

(Where

Is a solid support and L is absent or a linking group)
The polymer acetophenone oxime compound was treated with trialkyltin hydride and a free radical initiator to formula

A polymer α-cyclic hydroxylamine resin compound, and
(b) a formula characterized by treating a polymer α-cyclic hydroxylamine resin compound with an aqueous acid solution

(Wherein R _j , R _k and R _l are aliphatic or aromatic and Q is —O— or —CH ₂ —)
Of preparing an α-cyclic bidoxylamine compound.   34. The method of claim 33, wherein L is a linking group. L is the formula

35. The method of claim 34, wherein the linking group is
(Where
A is absent or a group of formula -X ¹ -Z-
X ¹ is —CHR— or —CHR—Y—CO— (CH ₂ ) _n — (wherein R is substituted with H, alkyl, phenyl, or —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ And phenyl
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 —NO ₂ 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 —NO ₂ , or
One of R ¹ and R ² together with one of R ³ and R ⁴ and the carbon atom to which they are attached

(Where
R ^{1 ′} is —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ and
R ⁶ , R ⁷ and R ⁸ are independently selected from —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ )
Form a linking group)   36. The method of claim 35, wherein the trialkyltin hydride is tri-n-butyltin hydride.   The process according to claim 36, wherein the free radical initiator is 2,2'-azobisisobutyronitrile. formula

(Where

Is a solid support and L is absent or a linking group)
Wherein the polymer α-cyclic hydroxylamine resin compound is reductively cleaved

(Wherein R _j , R _k and R _l are aliphatic or aromatic and Q is —O— or —CH ₂ —)
Of the α-cyclic amino compound.   40. The method of claim 38, wherein reductive cleavage is performed using a hydride reducing agent. The method according to paragraph 39 claims hydride reducing agent is LiAlH _4.   41. The method of claim 40, wherein L is a linking group. L is the formula

71. The method of claim 70, wherein the linking group is
(Where
A is absent or a group of formula -X ¹ -Z-
X ¹ is —CHR— or —CHR—Y—CO— (CH ₂ ) _n — (wherein R is substituted with H, alkyl, phenyl, or —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ And phenyl
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 —NO ₂ 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 —NO ₂ , or
One of R ¹ and R ² together with one of R ³ and R ⁴ and the carbon atom to which they are attached

(Where
R ^{1 ′} is —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ and
R ⁶ , R ⁷ and R ⁸ are independently selected from —H, alkyl, alkoxy, halogen, nitrile or —NO ₂ )
Form a linking group)