Enantiomerically pure amines
A compound of formula wherein PROT is an amine protecting group and PROT′ is hydrogen; or PROT and PROT′ together with the nitrogen atom to which they are attached form a heterocyclic ring as an amine protecting group, and PROT″ is a thiol protecting group, processes for its production, intermediates in their production and production of intermediates in stereoisomerically pure form, and their use for the production of pharmaceutically active compounds.
1. A compound of formula I
wherein
PROT is selected from
ethoxycarbonyl,
2,2,2-trifluoroacetyl, and
PROT′ is hydrogen; or
PROT and PROT′ together with the nitrogen atom to which they are attached form a heterocyclic ring as an amine protecting group, and
PROT″ is a thiol protecting group.
2. A compound according to claim 1 , wherein
PROT is selected from
ethoxycarbonyl,
2,2,2-trifluoroacetyl, and
PROT′ is hydrogen.
3. A compound according to claim 1 , wherein PROT and PROT′ together with the nitrogen atom to which they are attached form phthalimido-N-yl.
4. A compound according to claim 1 , wherein PROT″ is benzoyl or trityl.
5. A compound according to claim 1 , wherein the compound is of formula
wherein PROT is selected from
ethoxycarbonyl,
2,2,2-trifluoroacetyl, and.
6. A compound according to claim 5 , which is of formula
wherein R together with the C═O to which it is attached is ethoxycarbonyl or 2,2,2-trifluoroacetyl.
7. A compound according to claim 1 , selected from the group consisting of:
{(1R, 2R, 4R)-4-[(2,2,2-Trifluoro-acetyl)-amino]-2-hydroxy-cyclohexyl}-benzene-carbothioate,
tert-Butyl [(1R, 3R, 4R)-3-hydroxy-4-tritylsulfanyl-cyclohexyl]-carbamate, and
2,2,2-Trifluoro-N-((1R, 3R, 4R)-3-hydroxy-4-tritylsulfanyl-cyclohexyl)-acetamide.
8. A compound according to claim 1 , which is of formula
9. A process for the preparation of a compound of formula I according to claim 1 , comprising
performing oxiran ring opening in a compound of formula
or in a compound of formula
or in a compound of formula
or in a compound of formula
respectively, wherein PROT, PROT′ and R are as defined in claim 1 ,
optionally by reaction with an optionally protected or activated thiol,
isolating a compound of formula I in the form of a single regioisomer and a single diastereomer from the reaction mixture;
wherein optionally a compound of formula II, II S , II SS or II SSS is obtained by epoxidation of the double bond in a compound of formula
and
isolating a compound formula II, II S , II SS or II SSS , wherein PROT, PROT′ and R are as defined in claim 1 , obtained from the reaction mixture.
10. A process according to claim 9 wherein formula II, IIs, IIss or IIsss is selected from the group consisting of
tert-Butyl (1R, 3R, 6R)-(7-oxa-bicyclo[4.1.0]hept-3-yl)-carbamate, and
2,2,2-Trifluoro-N-(1R, 3R, 6S)-(7-oxa-bicyclo[4.1.0]hept-3-yl)-acetamide.
11. A process for the production of a compound of formula I according to claim 1 , wherein PROT′ is hydrogen, comprising
a) either reacting a compound of formula
with an azidoyl forming agent, optionally diphenylphosphoryl azide, optionally in the presence of a base, or
reacting compound of formula V with an acid chloride forming agent, optionally oxalyl chloride or thionyl chloride, to obtain a compound of formula IX
and
further reacting a compound of formula IX with sodium azide, to obtain the acyl azide of formula
b) subjecting the acyl azide of formula VI to a Curtius rearrangement to obtain an isocyanate of formula
c) either reacting the isocyanate of step b) either via addition of an alcohol or via reaction with an strong organic acid and optionally in the presence of CuCl, or
subjecting a compound of formula VII to hydrolysis with subsequent loss of carbon dioxide to obtain a compound of formula IV
and
further reacting a compound of formula IV with an amino protecting group, optionally in the presence of base, to obtain a compound of formula III, III S , III SS or III SSS , respectively,
wherein PROT and R are as defined in claim 1 and PROT′ is hydrogen,
d) subjecting a compound of formula III, III S , III SS or III SSS , respectively, to epoxidation by use of an oxidation agent to obtain a corresponding oxiran of formula II, II S , II SS or II SSS , respectively,
wherein PROT, PROT′ and R are as defined in claim 1 , and PROT′ is hydrogen, in solution,
e) subjecting a compound obtained in step d) to oxiran ring opening under introduction of a sulfur group in the side chain of the cyclohexyl ring via a sulfur donating agent, and
f) directly isolating a compound of formula I according to claim 1 , wherein PROT, PROT″ and R are as defined in claim 1 , and PROT′ is hydrogen,
optionally by addition of an appropriate anti solvent,
optionally whereby the reaction a) to e) is performed in a single solvent (system), and/or whereby none of the intermediates obtained in a) to d) is isolated, and
isolating a compound of formula I in the form of a crystalline solid, from the reaction mixture.
12. A process according to claim 11 , wherein none of the intermediates obtained in a) to d) is isolated.
13. A process according to claim 11 , wherein the reaction a) to e) is performed in a single solvent (system).
14. A process for the preparation of a compound of formula I S according to claim 5 , comprising
performing oxiran ring opening in a compound of formula
wherein PROT is an amine protective group,
optionally by reaction with an optionally protected or activated thiol, and isolating a compound of formula in the form of a single regioisomer and a single diastereomer from the reaction mixture;
wherein optionally the compound of formula II S is obtained by epoxidation of the double bond in a compound of formula
wherein PROT is an amine protecting group, and
isolating a compound formula II S obtained from the reaction mixture.
15. A process for the preparation of a compound of formula I SS according to claim 6 , comprising
performing oxiran ring opening in a compound of formula
wherein R is as defined in claim 6 ,optionally by reaction with an optionally protected or activated thiol, and isolating a compound of formula I SS in the form of a single regioisomer and a single diastereomer from the reaction mixture;
wherein optionally the compound of formula II SS is obtained by epoxidation of the double bond in a compound of formula
wherein R is as defined in claim 6 , and
isolating a compound formula II SS obtained from the reaction mixture.
16. A process for the preparation of a compound of formula I SSS according to claim 8 , comprising
performing oxiran ring opening in a compound of formula
optionally by reaction with an optionally protected or activated thiol, and isolating a compound of formula I SSS in the form of a single regioisomer and a single diastereomer from the reaction mixture;
wherein optionally the compound of formula II SSS is obtained by epoxidation of the double bond in a compound of formula
and
isolating a compound formula II SSS obtained from the reaction mixture.
17. A process for the production of a compound of formula I S according to claim 5 , comprising
a) either reacting a compound of formula
with an azidoyl forming agent, optionally diphenylphosphoryl azide, optionally in the presence of a base, or
reacting compound of formula V with an acid chloride forming agent, optionally oxalyl chloride or thionyl chloride, to obtain a compound of formula IX
and
further reacting a compound of formula IX with sodium azide, to obtain the acyl azide of formula
b) subjecting the acyl azide of formula VI to a Curtius rearrangement to obtain an isocyanate of formula
c) either reacting the isocyanate of step b) either via addition of an alcohol or via reaction with an strong organic acid and optionally in the presence of CuCl, or
subjecting a compound of formula VII to hydrolysis with subsequent loss of carbon dioxide to obtain a compound of formula IV
and
further reacting a compound of formula IV with an amino protecting group, optionally in the presence of base, to obtain a compound of formula III S ,
wherein PROT is an amine protective group,
d) subjecting a compound of formula III S to epoxidation by use of an oxidation agent to obtain a corresponding oxiran of formula II S
wherein PROT is an amine protective group, in solution,
e) subjecting a compound obtained in step d) to oxiran ring opening under introduction of a sulfur group in the side chain of the cyclohexyl ring via a sulfur donating agent, and
f) directly isolating a compound of formula I S according to claim 5 ,
optionally by addition of an appropriate anti solvent,
optionally whereby the reaction a) to e) is performed in a single solvent (system), and/or whereby none of the intermediates obtained in a) to d) is isolated,
and isolating a compound of formula I S in the form of a crystalline solid, from the reaction mixture.
18. A process for the production of a compound of formula I SS according to claim 6 , comprising
a) either reacting a compound of formula
with an azidoyl forming agent, optionally diphenylphosphoryl azide, optionally in the presence of a base, or
reacting compound of formula V with an acid chloride forming agent, optionally oxalyl chloride or thionyl chloride, to obtain a compound of formula IX
and
further reacting a compound of formula IX with sodium azide, to obtain the acyl azide of formula
b) subjecting the acyl azide of formula VI to a Curtius rearrangement to obtain an isocyanate of formula
c) either reacting the isocyanate of step b) either via addition of an alcohol or via reaction with an strong organic acid and optionally in the presence of CuCl, or
subjecting a compound of formula VII to hydrolysis with subsequent loss of carbon dioxide to obtain a compound of formula IV
and
further reacting a compound of formula IV with an amino protecting group, optionally in the presence of base, to obtain a compound of formula III SS ,
wherein R is as defined in claim 6 ,
d) subjecting a compound of formula III SS to epoxidation by use of an oxidation agent to obtain a corresponding oxiran of formula II SS
wherein R is as defined in claim 6 , in solution,
e) subjecting a compound obtained in step d) to oxiran ring opening under introduction of a sulfur group in the side chain of the cyclohexyl ring via a sulfur donating agent, and
f) directly isolating a compound of formula I SS according to claim 6 ,
optionally by addition of an appropriate anti solvent,
optionally whereby the reaction a) to e) is performed in a single solvent (system), and/or whereby none of the intermediates obtained in a) to d) is isolated,
and isolating a compound of formula I SS in the form of a crystalline solid, from the reaction mixture.
19. A process for the production of a compound of formula I SSS according to claim 8 , comprising
a) either reacting a compound of formula
with an azidoyl forming agent, optionally diphenylphosphoryl azide, optionally in the presence of a base, or
reacting compound of formula V with an acid chloride forming agent, optionally oxalyl chloride or thionyl chloride, to obtain a compound of formula IX
and
further reacting a compound of formula IX with sodium azide, to obtain the acyl azide of formula
b) subjecting the acyl azide of formula VI to a Curtius rearrangement to obtain an isocyanate of formula
c) either reacting the isocyanate of step b) either via addition of an alcohol or via reaction with an strong organic acid and optionally in the presence of CuCl, or
subjecting a compound of formula VII to hydrolysis with subsequent loss of carbon dioxide to obtain a compound of formula IV
and
further reacting a compound of formula IV with an amino protecting group, optionally in the presence of base, to obtain a compound of formula III SSS ,
d) subjecting a compound of formula III SSS to epoxidation by use of an oxidation agent to obtain a corresponding oxiran of formula II SSS
e) subjecting a compound obtained in step d) to oxiran ring opening under introduction of a sulfur group in the side chain of the cyclohexyl ring via a sulfur donating agent, and
f) directly isolating a compound of formula I SSS according to claim 8 ,
optionally by addition of an appropriate anti solvent,
optionally whereby the reaction a) to e) is performed in a single solvent (system), and/or whereby none of the intermediates obtained in a) to d) is isolated,
and isolating a compound of formula I SSS in the form of a crystalline solid, from the reaction mixture.