Cyclopropyl based O- and N- and S-protecting groups
AssigneeResearch Corporation Technologies, Inc.
InventorsLouis A. Carpino, Hann-Guang Chao
Life of this patent
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Abstract
The present invention is directed to the use of a cyclopropylmethyl derivative as a protecting group for compounds containing an amino group, carboxy group, amido group, mercapto group or hydroxy group and to the compounds formed having the cyclopropylmethyl moiety as the protecting group.
Claims112
A compound of the formula:
- ##STR59## wherein R is one of the side chains of a naturally occurring amino acid;
- Blk is a base labile N .alpha.-amino acid protecting group, a protecting group removed by acid, a protecting group removed by reduction or catalytic hydrogenation, a protecting group removed by a nucleophile or formyl, acetyl, or trifluoroacetyl;
- and ##STR60## R.sub.4 is hydrogen or lower alkyl;
- R.sub.7 and R.sub.5 are independently lower alkyl, aryl, aryl lower alkyl, cycloloweralkyl or cycloloweralkyl lower alkyl;
- R.sub.6 is lower alkyl, aryl lower alkyl, or aryl;
- and
- R.sub.9 is H or lower alkyl.
A compound of the formula ##STR64## wherein BLK is an amino protecting group;
- L is halide, OH or OR.sub.8 ;
- R.sub.a is a side chain of a naturally occurring amino acid having a primary or secondary amino or amido and attached to the nitrogen atom at said amino or amido group is a moiety of the formula:
- ##STR65## wherein R.sub.6 is lower alkyl, aryl lower alkyl or aryl;
- R.sub.7 is lower alkyl, aryl lower alkyl, aryl, lower cycloalkyl or lower cycloalkyl lower alkyl;
- and
- R.sub.8 is hydrogen or lower alkyl.
A compound of the formula:
- ##STR66## wherein BLK is a base labile N .alpha.-amino acid a protecting group, a protecting group removed by acid, a protecting group removed by reduction of catalytic hydrogenation, protecting group removed by nucleophile or formyl, acetyl, or trifluoroacetyl;
- L is halide or OR.sub.8 ;
- R.sub.b is a side chain of a naturally occurring amino acid, said side chain containing a carboxy group, mercapto group or hydroxy group, and attached to said carboxy, mercapto or hydroxy is a moiety of the formula:
- ##STR67## wherein R.sub.4 is hydrogen or lower alkyl;
- R.sub.5 is lower alkyl, aryl, aryl lower alkyl, lower cycloalkyl or lower cycloalkyl lower alkyl;
- and
- R.sub.8 is hydrogen or lower alkyl.
An amino acid moiety of the formula:
- ##STR68## wherein R.sub.a is a side chain of a naturally occurring amino acid having a primary or secondary amine or a primary or secondary amide, and attached to said nitrogen atom of said amine or amide group is a moiety of the formula:
- ##STR69## wherein L is OR.sub.8 or halide;
- R.sub.6 is lower alkyl, aryl, or aryl lower alkyl;
- R.sub.7 is lower alkyl, aryl, aryl lower alkyl, lower cycloalkyl or lower cycloalkyl lower alkyl;
- and R.sub.8 is lower alkyl or hydrogen.
A method for protecting a carboxy group of an organic molecule during a reaction which modifies a portion of the molecule other than the protected carboxy group comprising
- (a) reacting the carboxy group or an acylating derivative thereof with a compound of the formula:
- ##STR70## under esterification conditions to form a protected carboxy group, wherein R.sub.5 is lower alkyl, aryl, lower arylalkyl, lower cycloalkyl or lower cycloalkyl lower alkyl;
- and
- R.sub.4 is hydrogen or R.sub.5 ;
- (b) modifying a portion of the molecule other than the protected carboxy group by chemical reaction;
- and
- (c) removing the protecting group from the carboxy group.
A method of protecting a carboxy group during peptide formation between a first amino acid or peptide having a free amino and carboxy group and a second amino acid or peptide having a free carboxy group and an N.alpha.-protected amino group comprising
- (a) esterifying the carboxy group of the first amino acid, or peptide with a cyclopropylmethanol of the formula:
- ##STR71## wherein R.sub.4 is hydrogen or lower alkyl;
- and
- R.sub.5 is lower alkyl, aryl, aryl lower alkyl, lower cycloalkyl, or lower cycloalkyl lower alkyl to form a cyclopropylmethylester protecting group;
- (b) reacting the product of (a) with said second amino acid or peptide;
- and
- (c) removing the cyclopropylmethyl ester protecting group.
In the synthesis of a peptide wherein a first amino acid or peptide having free amino and carboxy groups is coupled via a peptide linkage to the carboxyl group of a second N .alpha.-amino protected amino acid or peptide and the cycle repeated until the desired peptide has been obtained, the improvement comprising protecting the carboxy group of the first amino acid by (a) esterifying the first amino acid with a cyclopropylmethanol of the formula:
- ##STR72## to provide a carboxy group protected as a cyclopropylmethyl ester, wherein R.sub.4 is hydrogen or lower alkyl;
- and
- R.sub.5 is lower alkyl, aryl, aryl lower alkyl, lower cycloalkyl, or lower cycloalkyl lower alkyl;
- and (b) when the desired peptide is obtained, removing said cyclopropylmethyl ester protecting group with acid hydrolysis.
In the synthesis of a peptide wherein a first amino acid or peptide having a free carboxy group on the side chain thereof is coupled via a peptide linkage to the carboxyl group of a second N .alpha.-amino protected amino acid or peptide and the cycle repeated until the desired peptide has been obtained, the improvement comprising protecting the carboxy group on the side chain by esterifying it with a cyclopropylmethanol of the formula:
- ##STR73## to provide a carboxy group having a cyclopropylmethyl protecting group bonded thereto,
- wherein R.sub.4 is hydrogen or lower alkyl;
- R.sub.5 is lower alkyl, aryl, aryl lower alkyl, lower cycloalkyl or lower cycloalkyl lower alkyl;
- and
- (b) after the desired peptide is obtained, removing said cyclopropylmethyl protecting group with acid hydrolysis.
In the synthesis of a peptide wherein a first amino acid or peptide having a free amino group and a free carboxy group or acylating derivative of said carboxy group is coupled via a peptide linkage to the carboxy group of a second N .alpha.-amino protected amino acid or peptide derivative, and the cycle repeated until the desired peptide has been obtained, the improvement comprising reacting the carboxy group or acylating derivative of the carboxy group on the first amino acid or peptide with a cyclopropylmethylamine of the formula:
- ##STR74## under amide forming conditions to provide an amide protected with a cyclopropylmethyl protecting group, wherein
- R.sub.7 and R.sub.6 independently are lower alkyl, lower cycloalkyl, lower cycloalkyl lower alkyl, aryl or aryl lower alkyl;
- and
- R.sub.11 is hydrogen or lower alkyl;
- and
- (b) after the desired peptide is obtained, removing said cyclopropylmethyl protecting group, thereby converting the free carboxy group of the first amino acid or peptide to an amide.
A process for converting a carboxy group on an organic molecule to an amide and protecting the amide during a reaction which modifies a portion of the molecule other than the protected amide comprising:
- (a) reacting the carboxy group or an acylating derivative thereof with a compound of the formula:
- ##STR75## under amide forming conditions;
- thereby forming a cyclopropylmethyl protected amide,
- wherein R.sub.6 and R.sub.7 are independently lower alkyl, aryl, aryl lower alkyl, lower cycloalkyl, or cycloalkyl lower alkyl;
- and R.sub.11 is hydrogen or lower alkyl,
- (b) modifying a portion of the molecule other than the protected amide by chemical reaction, and
- (c) removing the protecting group from the amide.
The process for converting a carboxy group on the side chain of an amino acid or peptide to an amide and protecting the amide during peptide synthesis which comprises
- (a) reacting the carboxy group on the side chain of a first amino acid or peptide with a cyclopropylmethylamine of the formula:
- ##STR76## under amide forming conditions to form the cyclopropylmethyl protected amide;
- (b) reacting the product of (a) with a second amino acid or peptide under peptide forming conditions;
- and
- (c) removing the cyclopropylmethyl group from the side chain.
In a process for protecting the mercapto group on a cysteine during peptide synthesis wherein a first compound selected from the group consisting of an amino acid and peptide is coupled via a peptide linkage to the carboxyl group of a second compound selected from the group consisting of a second amino acid and second peptide and the cycle repeated until the desired peptide has been obtained and wherein the first compound contains a cysteine, the improvement comprising reacting the first compound with a cyclopropylmethanol of the formula:
- ##STR77## under thioether forming conditions to form a cyclopropylmethyl protected thiol prior to the coupling step
- wherein
- R.sub.4 is hydrogen or lower alkyl;
- and
- R.sub.5 is lower alkyl, lower cycloalkyl, aryl, aryl lower alkyl or lower cycloalkyl;
- and
- (b) after the desired peptide is obtained, removing the cyclopropylmethyl protecting group by acid hydrolysis.
In a process for protecting the amino group on the side chain of a first compound consisting of an amino acid or peptide during peptide synthesis wherein the first compound is coupled via peptide linkage to a second compound consisting of a second amino acid or peptide under peptide forming conditions and the cycle repeated until the desired peptide has been obtained, the improvement comprising reacting the amino group on the side chain of the first compound with a cyclopropylmethyl compound of the formula:
- ##STR78## under substitution reaction conditions prior to said coupling wherein R.sub.6 and R.sub.7 are independently lower alkyl, aryl, aryl lower alkyl, lower cycloalkyl or cycloalkyl lower alkyl, and
- R.sub.10 is a leaving group and
- (b) after the desired peptide is obtained removing the cyclopropylmethyl group from the amine.
A process for protecting an amino acid residue containing an OH group in the side chain which comprises
- (a) reacting an alcohol of the formula:
- ##STR79## with a nitrile of the formula R.sub.13 C.tbd.N under effective conditions to form the corresponding imine ether of the formula:
- ##STR80## and (b) reacting the product of (a) with the amino acid residue containing the hydroxy group in the side chain to form the corresponding cyclopropylmethylether,
- wherein R.sub.13 is lower alkyl which may be unsubstituted or substituted with lower alkyl or an electron donating or electron withdrawing group;
- R.sub.4 is hydrogen or lower alkyl;
- and
- R.sub.5 is lower alkyl, aryl, aryl lower alkyl, lower cycloalkyl or lower cycloalkyl lower alkyl.
A process for protecting a mercapto group on the side chain of a first compound selected from the group consisting of a first amino acid and a first peptide comprising
- (a) reacting said first compound with a cyclopropyl methanol of the formula:
- ##STR81## wherein R.sub.4 is hydrogen or loweralkyl;
- and
- R.sub.5 is lower alkyl, lower cycloalkyl, aryl lower alkyl, aryl, or lower cycloalkyl lower alkyl to form a cyclopropylmethyl protected mercapto group;
- (b) reacting the product of (a) with a second compound selected from the group consisting of a second amino acid and second peptide under peptide forming conditions, and
- (c) removing the cyclopropylmethyl protecting group.
A process for protecting a carboxy group on the side chain of an amino acid or peptide which comprises reacting said amino acid or peptide with a cyclopropyl methanol of the formula:
- ##STR82## under esterification conditions, wherein R.sub.4 is hydrogen or loweralkyl;
- and R.sub.5 is lower alkyl, aryl lower alkyl, aryl, lower cycloalkyl, or lower cycloalkyl lower alkyl.
A process for protecting an amino group on the side chain of an amino acid comprises reacting said amino acid with an effective amount of a compound under conditions effective to form a primary or secondary amine, said compound having the formula:
- ##STR83## wherein R.sub.6 and R.sub.7 are independently lower alkyl, aryl, aryl lower alkyl, lowercycloalkyl or lower cycloalkyl lower alkyl and R.sub.10 is a leaving group.
A process for converting a carboxy group on a first amino acid or first peptide to an amide and protecting said amide which comprises:
- (a) reacting said first amino acid or first peptide with a cyclopropylmethylamine of the formula:
- ##STR84## wherein R.sub.11 is hydrogen or lower alkyl and R.sub.6 and R.sub.7 are independently lower alkyl, aryl, arylloweralkyl, lower cycloalkyl or lower cycloalkyl lower alkyl;
- (b) reacting the product of (a) with a second amino acid or second peptide under amide forming conditions and
- (c) removing the protecting group on said amide.
A process for protecting a primary or secondary amino group on an organic molecule during a reaction which modifies a portion of the molecule other than the protected amino group comprising:
- (a) reacting the amino group with a compound of the formula:
- ##STR85## under effective conditions to react with said amino group, wherein R.sub.6 and R.sub.7 are independently lower alkyl, aryl, aryl lower alkyl, lower cycloalkyl or lower cycloalkyl lower alkyl and
- R.sub.10 is a leaving group;
- (b) modifying a portion of the molecule other than the protected amino group by chemical reaction;
- and
- (c) removing the protecting group from the carboxy group.
Dependencies are inferred from the claim text.