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US 6,204,398 B1Granted
Preparation of cyclohexene carboxylate derivatives
AssigneeGilead Sciences, Inc.
InventorsKenneth M. Kent, Choung U. Kim, Lawrence R. McGee, John D. Munger, Ernest J. Prisbe, Michael J. Postich, John C. Rohloff, Daphne E. Kelly, Matthew A. Williams, Lijun Zhang
Life of this patent
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Abstract
The present invention provides new synthetic methods and compositions. In particular, new methods of preparing intermediates such as those having formulas (I)-(IV), useful in the synthesis of neuraminidase inhibitors and compositions useful as intermediates that are themselves useful in the synthesis of neuraminidase inhibitors are provided.
Claims26
A process for preparation of compounds of the formula:
- wherein:
- R1 is a cyclic hydroxy protecting group;
- R2 is a carboxylic acid protecting group;
- R3 is a hydroxy protecting group;
- and
- each R20 is independently H or an alkyl of 1 to 12 carbon atoms;
- which process comprises reaction of a compound of the formula:
- with a dehydrating reagent.
5 more elements
A process for preparation of compounds of the formula:
- wherein:
- R2 is a carboxylic acid protecting group;
- R3 is a hydroxy protecting group;
- R4 is —C(R30)3;
- R5 is H or R3;
- R7 is H or an amino protecting group;
- R8 is H or R2;
- R9 is H or a thiol protecting group;
- each R20 is independently H or an alkyl of 1 to 12 carbon atoms;
- each R21 is independently R20, Br, Cl, F, I CN, NO2 or N3;
- each R22 is independently F, Cl, Br, I, —CN, N3, —NO2, —OR5, —OR20, —N(R20)2, —N(R20)(R7), —N(R7)2, —SR20, —SR9, —S(O)R20, —S(O)2R20, —S(O)OR20, —S(O)OR8, —S(O)2OR20, —S(O)2OR8, —C(O)OR20, —C(O)OR8, —OC(O)R20, —N(R20)(C(O)R20), —N(R7)(C(O)R20), —N(R20)(C(O)OR20), —N(R7)(C(O)OR20), —C(O)N(R20)2, —C(O)N(R7)(R20), —C(O)N(R7)2, —C(NR20)(N(R20)2), —C(N(R7))(N(R20)2), —C(N(R20))(N(R20)(R7)), —C(N(R7))(N(R20)(R7)), —C(N(R20))(N(R7)2), —C(N(R7))(N(R7)2), —N(R20)C(N(R20))(N(R20)2), —N(R20)C(N(R20))(N(R20)(R7)), —N(R20)C(N(R7))(N(R20)2), —N(R7)C(N(R20))(N(R20)2), —N(R7)C(N(R7))(N(R20)2), —N(R7)C(N(R20))(N(R20)(R7)), —N(R20)C(N(R7))(N(R20)(R7)), —N(R20)C(N(R20))(N(R7)2), —N(R7)C(N(R7))(N(R20)(R7)), —N(R7)C(N(R20))(N(R7)2), —N(R20)C(N(R7))(N(R7)2), —N(R7)C(N(R7))(N(R7)2), ═O, ═S, ═N(R20), ═N(R7) or W;
- R23 is independently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or alkynyl of 2 to 11 carbon atoms;
- R24 is independently R23 wherein each R23 is substituted with 0 to 3 R22 groups;
- R24a is independently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R22 groups;
- R28 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
- R29 is independently R22 or R28 wherein each R28 is substituted with 0 to 3 R22 groups;
- each R30 is independently H, R24, W or —R24aW;
- W is carbocycle or heterocycle wherein any one of which carbocycle or heterocycle is substituted with 0 to 3 R29 groups;
- which process comprises reaction of a compound of the formula:
- with a reducing reagent;
- provided that R4, taken as a whole, contains:
- 0 to 3 W groups substituted with 0 to 3 R29 groups;
- and, in addition,
- 1 to 12 carbon atoms substituted with 0 to 3 R22 groups.
21 more elements
A process for preparation of compounds of the formula:
- wherein:
- R2 is a carboxylic acid protecting group;
- R3 is a hydroxy protecting group;
- R4 is —C(R30)3;
- R5 is H or R3;
- R7 is H or an amino protecting group;
- R8 is H or R2;
- R9 is H or a thiol protecting group;
- each R20 is independently H or an alkyl of 1 to 12 carbon atoms;
- each R21 is independently R20, Br, Cl, F, I CN, NO2 or N3;
- each R22 is independently F, Cl, Br, I, —CN, N3, —NO2, —OR5, —OR20, —N(R20)2, —N(R20)(R7), —N(R7)2, —SR20, —SR9, —S(O)R20, —S(O)2R20, —S(O)OR20, —S(O)OR8, —S(O)2OR20, —S(O)2OR8, —C(O)OR20, —C(O)OR8, —OC(O)R20, —N(R20)(C(O)R20), —N(R7)(C(O)R20), —N(R20)(C(O)OR20), —N(R7)(C(O)OR20), —C(O)N(R20)2, —C(O)N(R7)(R20), —C(O)N(R7)2, —C(NR20)(N(R20)2), —C(N(R7))(N(R20)2), —C(N(R20))(N(R20)(R7)), —C(N(R7))(N(R20)(R7)), —C(N(R20))(N(R7)2), —C(N(R7))(N(R7)2), —N(R20)C(N(R20))(N(R20)2), —N(R20)C(N(R20))(N(R20)(R7)), —N(R20)C(N(R7))(N(R20)2), —N(R7)C(N(R20))(N(R20)2), —N(R7)C(N(R7))(N(R20)2), —N(R7)C(N(R20))(N(R20)(R7)), —N(R20)C(N(R7))(N(R20)(R7)), —N(R20)C(N(R20))(N(R7)2), —N(R7)C(N(R7))(N(R20)(R7)), —N(R7)C(N(R20))(N(R7)2), —N(R20)C(N(R7))(N(R7)2), —N(R7)C(N(R7))(N(R7)2), ═O, ═S, ═N(R20), ═N(R7) or W;
- R23 is independently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or alkynyl of 2 to 11 carbon atoms;
- R24 is independently R23 wherein each R23 is substituted with 0 to 3 R22 groups;
- R24a is independently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R22 groups;
- R28 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
- R29 is independently R22 or R28 wherein each R28 is substituted with 0 to 3 R22 groups;
- each R30 is independently H, R24, W or —R24aW;
- W is carbocycle or heterocycle wherein any one of which carbocycle or heterocycle is substituted with 0 to 3 R29 groups;
- and
- Y1 is a mono-, di- or unsubstituted amino group;
- which process comprises reaction of a compound of the formula:
- with an oxidizing reagent;
- provided that R4, taken as a whole, contains:
- 0 to 3 W groups substituted with 0 to 3 R29 groups;
- and, in addition,
- 1 to 12 carbon atoms substituted with 0 to 3 R22 groups.
23 more elements
A process for preparation of a compound of the formula:
- wherein:
- R2 is a carboxylic acid protecting group;
- R3 is a hydroxy protecting group;
- R4 is —C(R30)3;
- R5 is H or R3;
- R7 is H or an amino protecting group;
- R8 is H or R2;
- R9 is H or a thiol protecting group;
- each R20 is independently H or an alkyl of 1 to 12 carbon atoms;
- each R21 is independently R20, Br, Cl, F, I CN, NO2 or N3;
- each R22 is independently F, Cl, Br, I, —CN, N3, —NO2, —OR5, —OR20, —N(R20)2, —N(R20)(R7), —N(R7)2, —SR20, —SR9, —S(O)R20, —S(O)2R20, —S(O)OR20, —S(O)OR8, —S(O)2OR20, —S(O)2OR8, —C(O)OR20, —C(O)OR8, —OC(O)R20, —N(R20)(C(O)R20), —N(R7)(C(O)R20), —N(R20)(C(O)OR20), —N(R7)(C(O)OR20), —C(O)N(R20)2, —C(O)N(R7)(R20), —C(O)N(R7)2, —C(NR20)(N(R20)2), —C(N(R7))(N(R20)2), —C(N(R20))(N(R20)(R7)), —C(N(R7))(N(R20)(R7)), —C(N(R20))(N(R7)2), —C(N(R7))(N(R7)2), —N(R20)C(N(R20))(N(R20)2), —N(R20)C(N(R20))(N(R20)(R7)), —N(R20)C(N(R7))(N(R20)2), —N(R7)C(N(R20))(N(R20)2), —N(R7)C(N(R7))(N(R20)2), —N(R7)C(N(R20))(N(R20)(R7)), —N(R20)C(N(R7))(N(R20)(R7)), —N(R20)C(N(R20))(N(R7)2), —N(R7)C(N(R7))(N(R20)(R7)), —N(R7)C(N(R20))(N(R7)2), —N(R20)C(N(R7))(N(R7)2), —N(R7)C(N(R7))(N(R7)2), ═O, ═S, ═N(R20), ═N(R7) or W;
- R23 is independently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or alkynyl of 2 to 11 carbon atoms;
- R24 is independently R23 wherein each R23 is substituted with 0 to 3 R22 groups;
- R24a is independently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R22 groups;
- R28 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
- R29 is independently R22 or R28 wherein each R28 is substituted with 0 to 3 R22 groups;
- each R30 is independently H, R24, W or —R24aW;
- W is carbocycle or heterocycle wherein any one of which carbocycle or heterocycle is substituted with 0 to 3 R29 groups;
- and
- Y1 is a mono-, di- or unsubstituted amino group;
- which process comprises reaction of a compound of the formula:
- with a base;
- provided that R4, taken as a whole, contains:
- 0 to 3 W groups substituted with 0 to 3 R29 groups;
- and, in addition,
- 1 to 12 carbon atoms substituted with 0 to 3 R22 groups.
23 more elements
A process for preparation of compounds of the formula:
- wherein:
- R2 is a carboxylic acid protecting group;
- R3 is a hydroxy protecting group;
- R4 is —C(R30)3;
- R5 is H or R3;
- R7 is H or an amino protecting group;
- R8 is H or R2;
- R9 is H or a thiol protecting group;
- each R20 is independently H or an alkyl of 1 to 12 carbon atoms;
- each R21 is independently R20, Br, Cl, F, I CN, NO2 or N3;
- each R22 is independently F, Cl, Br, I, —CN, N3, —NO2, —OR5, —OR20, —N(R20)2, —N(R20)(R7), —N(R7)2, —SR20, —SR9, —S(O)R20, —S(O)2R20, —S(O)OR20, —S(O)OR8, —S(O)2OR20, —S(O)2OR8, —C(O)OR20, —C(O)OR8, —OC(O)R20, —N(R20)(C(O)R20), —N(R7)(C(O)R20), —N(R20)(C(O)OR20), —N(R7)(C(O)OR20), —C(O)N(R20)2, —C(O)N(R7)(R20), —C(O)N(R7)2, —C(NR20)(N(R20)2), —C(N(R7))(N(R20)2), —C(N(R20))(N(R20)(R7)), —C(N(R7))(N(R20)(R7)), —C(N(R20))(N(R7)2), —C(N(R7))(N(R7)2), —N(R20)C(N(R20))(N(R20)2), —N(R20)C(N(R20))(N(R20)(R7)), —N(R20)C(N(R7))(N(R20)2), —N(R7)C(N(R20))(N(R20)2), —N(R7)C(N(R7))(N(R20)2), —N(R7)C(N(R20))(N(R20)(R7)), —N(R20)C(N(R7))(N(R20)(R7)), —N(R20)C(N(R20))(N(R7)2), —N(R7)C(N(R7))(N(R20)(R7)), —N(R7)C(N(R20))(N(R7)2), —N(R20)C(N(R7))(N(R7)2), —N(R7)C(N(R7))(N(R7)2), ═O, ═S, ═N(R20), ═N(R7) or W;
- R23 is independently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or alkynyl of 2 to 11 carbon atoms;
- R24 is independently R23 wherein each R23 is substituted with 0 to 3 R22 groups;
- R24a is independently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R22 groups;
- R28 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
- R29 is independently R22 or R28 wherein each R28 is substituted with 0 to 3 R22 groups;
- each R30 is independently H, R24, W or —R24a W;
- W is carbocycle or heterocycle wherein any one of which carbocycle or heterocycle is substituted with 0 to 3 R29 groups;
- and
- Y1 is a mono-, di- or unsubstituted amino group;
- which process comprises reaction of a compound of the formula:
- with a reductive amination reagent;
- provided that R4, taken as a whole, contains:
- 0 to 3 W groups substituted with 0 to 3 R29 groups;
- and, in addition,
- 1 to 12 carbon atoms substituted with 0 to 3 R22 groups.
23 more elements
A process according to any one or sequential combination of processes AA, AB, AC, AD, AE, AF, AG, AH, AI, AJ, or AK of Schemes 1 and 2.
A process according to any one or sequential combination of the processes of Example 1, Example 2, Example 3, Example 4, Example 5, Example 6, Example 7, Example 8, Example 9, Example 10, Example 11, Example 12 or Example 13.
A process according to any one or sequential combination of processes AL, AM, AN, AO, or AP of Scheme 3.
A process for preparation of compounds of the formula:
- wherein:
- R1 is a cyclic hydroxy protecting group;
- R2 is a carboxylic acid protecting group;
- R3 is a hydroxy protecting group;
- and
- each R20 is independently H or an alklyl of 1 to 12 carbon atoms;
- which process comprises reaction of a compound of the formula:
- with a dehydrating reagent;
- provided that excluded is the process of converting a compound of the formula:
- to a compound of the formula:
- by reaction with POCl3 in pyridine.
8 more elements
A process for the preparation of a compound of the formula:
- which process comprises reaction of a compound of the formula:
- with a dehydrating reagent and a noble metal complex.
A process for the preparation of a compound of the formula:
- which process comprises reaction of a compound of the formula:
- with a Lewis acid reagent.
A process for the preparation of a compound of the formula:
- wherein R is a mono-, di- or unsubstituted amino group, which process comprises reaction of a compound of the formula:
- with an amine reagent.
A compound of the formula:
A process for preparing the compound of the formula 116
- which comprises
- a) converting the compound of formula 110
- to the compound of formula 111:
- b) converting the compound of formula 111 to the compound of formula 113:
- c) converting the compound of formula 113 to the compound of formula 114:
- d) converting the compound of the formula 114 to the compound of formula 115:
- e) converting the compound of formula 115 to the compound of formula 116.
4 more elements
A process for preparing the compound of formula 116:
- which comprises
- a) converting the compound of formula 201
- to the compound of formula 202
- b) converting the compound of formula 202 to the compound of formula 203
- c) converting the compound of formula 203 to the compound of formula 204
- d) converting the compound of formula 204 to the compound of formula 205
- e) converting the compound of formula 205 to the compound of formula 116.
4 more elements
A compound of the formula:
Dependencies are inferred from the claim text.