Method forming protease inhibitor synthetic intermediates

A method for producing a composition of matter from a N-(tert-butoxycarbonyl)-3-amino-3-substituted-2-oxo-1-nitropropane;

• wherein:
• said composition of matter is represented by the following structural formula:
• ##STR15## wherein:
• R.sup.3 is a side-chain of an amino acid wherein said side-chain is located .alpha. to the amino group of the amino acid and wherein said amino acid is selected from the group consisting of alanine, cysteine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glutamine, glycine, histidine, hydroxylysine, isoleucine, leucine, methionine, phenylalanine, serine threonine, thyroxine, tryptophane, tyrosine, valine and .alpha.-aminobutyric acid;
• R.sup.9 is an alkyl or alkaryl;
• and
• X.sup.2 is an amino, imino acid or ester radical;
• said N-(tert-butoxycarbonyl)-3-amino-3-substituted-2-oxo-1-nitropropane is represented by the following structural formula:
• ##STR16## and said method comprises the steps of:
• a) reacting said N-(tert-butoxycarbonyl)-3-amino-3-substituted-2-oxo-1-nitropropane with a carbonyl reducing agent, thereby forming an N-(tert-butoxycarbonyl)-1-nitro-3-amino-3-substituted-2--propanol represented by the following structural formula:
• ##STR17## b) reacting said N-(tert-butoxycarbonyl)-1-nitro-3-amino-3-substituted-2-propanol with a nitro reducing agent, thereby forming a first chemical intermediate represented by the following structural formula:
• ##STR18## c) reacting said first chemical intermediate with Cl--C(O)--X.sup.2 and with a base to form a second chemical intermediate represented by the following structural formula:
• ##STR19## d) reacting said second chemical intermediate with dimethyl sulfoxide and oxalyl chloride to form a reaction mixture;
• e) reacting said reaction mixture with a base to form a third chemical intermediate represented by the following structural formula:
• ##STR20## f) reacting the third chemical intermediate with an acid to cleave the tert-butoxycarbonyl group from the third chemical intermediate, thereby forming a deprotected third chemical intermediate represented by the following structural formula:
• ##STR21## g) reacting the deprotected third chemical intermediate with a base and Cl--C(O)--N(R.sup.9).sub.2 to form said composition.

A method for producing a protease inhibitor synthetic intermediate from an N-(tert-butoxycarbonyl)-3-amino-3-substituted-2-oxo-1-nitropropane;

• wherein:
• said protease synthetic intermediate is represented by the following structural formula:
• ##STR22## wherein:
• R.sup.3 is a side-chain of an amino acid wherein said side-chain is located to the amino group of the amino acid, and wherein said amino acid is selected from the group consisting of alanine, cysteine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glutamine, glycine, histidine, hydroxylysine, isoleucine, leucine, methionine, phenylalanine, serine, threonine, thyroxine, tryptophane, tyrosine, valine and .alpha.-aminobutyric acid;
• R.sup.8 is selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaralkyl and aminoalkyl;
• and
• X.sup.2 is an amino, imino acid or ester radical;
• said N-(tert-butoxycarbonyl)-3-amino-3-substituted-2-oxo-1-nitropropane is represented by the following structural formula:
• ##STR23## said method comprises the steps of:
• a) reacting said N-(tert-butoxycarbonyl)-3-amino-3-substituted-2-oxo-1-nitropropane with a carbonyl group reducing agent, thereby forming an N-(tert-butoxycarbonyl)-1-nitro-3-amino-3-substituted-2-propanol compound represented by the following structural formula:
• ##STR24## b) reacting said N-(tert-butoxycarbonyl)-1-nitro-3-amino-3-substituted-2-propanol with a nitro reducing agent, thereby forming a first chemical intermediate represented by the following structural formula:
• ##STR25## c) reacting said first chemical intermediate with X.sup.1 --R.sup.8 and a base, wherein X.sup.1 is a halogen, thereby forming a compound represented by the following structural formula:
• ##STR26## d) reacting the compound produced in c) with Cl--C(O)--X.sup.2 and with a base, thereby forming said protease inhibitor synthetic intermediate.

A method for producing a composition of matter from a N-(tert-butoxycarbonyl)-3-amino-3-substituted-2-oxo-1-nitropropane;

• wherein:
• said composition of matter is represented by the following structural formula:
• ##STR27## wherein:
• R.sup.3 is a side-chain of an amino acid wherein said side-chain is located .alpha. to the amino group of the amino acid and wherein said amino acid is selected from the group consisting of alanine, cysteine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glutamine, glycine, histidine, hydroxylysine, isoleucine, leucine, methionine, phenylalanine, serine threonine, thyroxine, tryptophane, tyrosine, valine and .alpha.-aminobutyric acid;
• R.sup.8 is selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaralkyl and aminoalkyl;
• and
• R.sup.9 is an alkyl or alkaryl;
• and
• X.sup.2 is an amino, imino acid or ester radical;
• said N-(tert-butoxycarbonyl)-3-amino-3-substituted-2-oxo-1-nitropropane is represented by the following structural formula:
• ##STR28## said method comprises the steps of:
• a) reacting said N-(tert-butoxycarbonyl)-3-amino-3-substituted-2-oxo-1-nitropropane with an carbonyl reducing agent, thereby forming a N-(tert-butoxycarbonyl)-1-nitro-3-amino-3-substituted-2-propanol compound represented by the following structural formula:
• ##STR29## b) reacting said N-(tert-butoxycarbonyl)-1-nitro-3-amino-3-substituted-2-propanol with a nitro reducing agent, thereby forming a first chemical intermediate represented by the following structural formula:
• ##STR30## c) reacting said first chemical intermediate with X.sup.1 --R.sup.8 and a base, wherein X.sup. is a halogen, thereby forming a compound represented by the following structural formula:
• ##STR31## d) reacting the compound produced in C) with Cl--C(O)--X.sup.2 and with a base to form a second chemical intermediate represented by the following structural formula:
• ##STR32## e) mixing said second chemical intermediate with dimethyl sulfoxide and oxalyl chloride to form a reaction mixture;
• f) reacting said reaction mixture with a base to form a third chemical intermediate represented by the following structural formula:
• ##STR33## g) reacting the third chemical intermediate with an acid to cleave the tert-butoxycarbonyl group from the third chemical intermediate, thereby forming a deprotected third chemical intermediate represented by the following structural formula:
• ##STR34## h) reacting the deprotected third chemical intermediate with a base and Cl--C(O)--N(R.sup.9).sub.2 to form said composition.