Methods for making thiazolypyrazole carboxylic acids and intermediates therefor
This disclosure relates generally to improved methods of preparing pyrazolylthiazole-containing compounds and their intermediates.
1. A method for preparing a halopyrazolylthiazole of formula (Ia)
wherein
X is a halogen;
L 1 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, —NR 6 —, —C(O)NR 6 —, —NR 6 C(O)—, —C(S)NR 6 —, —NR 6 C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O) 1-2 O—, —OS(O) 1-2 —, —S(O) 1-2 NR 6 — and —NR 6 S(O) 1-2 —;
R 1 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkenyl and C 1 -C 8 alkynyl, each unsubstituted or fluorinated;
Q 1 is selected from the group consisting of —C(O)OR 2C , —C(O)NR 2B R 2C , —C(O)NR 2B S(O) 2 R 2C , —C(O)NR 2B S(O) 2 NR 2B R 2C , —S(O) 2 R 2C , —N(R 2B )S(O) 2 R 2C , —S(O) 2 NR 2B R 2C , and —C(O)NH—O(C 1 -C 3 alkyl), in which
each R 2B is independently selected from H and C 1 -C 3 alkyl, and
each R 2C is independently selected from C 1 -C 3 alkyl and a protecting group;
R 3 is phenyl or heteroaryl each (i) optionally substituted with a single substituent selected from -L 3C -(phenyl optionally substituted with 1-5 R 3D ), -L 3C -(heteroaryl optionally substituted with 1-5 R 3D ), -L 3C -(cycloalkyl optionally substituted with 1-5 R 3D ), -L 3C -(heterocycloalkyl optionally substituted with 1-5 R 3D ) and (ii) optionally substituted with 1-5 R 3E ,
in which
each L 3C is a bond, methylene, ethylene, —C(O)—, —S—, —S(O) 1-2 —, —O—, or —NR 3G —;
each R 3D is independently selected from oxo optionally-substituted C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, halogen, —CN, —SF 5 , —N 3 , —C(O)R 3F , —SR 3F , —S(O) 1-2 R 3F , —OR 3F , —NR 3G R 3F , —C(O)R 3F , —C(O)NR 3G R 3F , —NR 3G C(O)R 3F , —C(S)NR 3G R 3F , —NR 3G C(S)R 3F , —C(O)OR 3F , —OC(O)R 3F , —C(O)SR 3F , —SC(O)R 3F , —C(S)OR 3F , —OC(S)R 3F , —C(S)SR 3F , —SC(S)R 3F , —S(O) 1-2 OR 3F , —OS(O) 1-2 R 3F , —S(O) 1-2 NR 3G R 3F , and —NR 3G S(O) 1-2 R 3F ;
each R 3E is independently selected from oxo, optionally-substituted C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, halogen, —CN, —SF 5 , —N 3 , —C(O)R 3F , —SR 3F , —S(O) 1-2 R 3F , —OR 3F , —NR 3G R 3F , —C(O)R 3F , —C(O)NR 3G R 3F , —NR 3G C(O)R 3F , —C(S)NR 3G R 3F , —NR 3G C(S)R 3F , —C(O)OR 3F , —OC(O)R 3F , —C(O)SR 3F , —SC(O)R 3F , —C(S)OR 3F , —OC(S)R 3F , —C(S)SR 3F , —SC(S)R 3F , —S(O) 1-2 OR 3F , —OS(O) 1-2 R 3F , —S(O) 1-2 NR 3G R 3F , and —NR 3G S(O) 1-2 R 3F ;
each R 3F is independently selected from H, C 1 -C 3 alkyl and C 1 -C 3 fluoroalkyl and
each R 3G is independently selected from H, C 1 -C 3 alkyl, and C 1 -C 3 fluoroalkyl; and
R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally-substituted C 1 -C 8 alkenyl and optionally substituted C 1 -C 8 alkynyl;
wherein
each R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl and —C(O)(C 1 -C 3 alkyl);
each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups;
each cycloalkyl has 3-10 ring carbons and is saturated or partially unsaturated;
each heterocylcloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and is saturated or partially unsaturated; and
each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur,
the method comprising:
reacting a thiazolylhydrazine of formula (Ib)
wherein X, R 1 , and L 1 are as described for formula (Ia),
with a dione of formula (II)
wherein R 3 and R 4 are as described for formula (Ia),
optionally in a solvent, under conditions sufficient to form a hydrazone; and
contacting the hydrazone with an compound of formula X 1 —CH 2 -Q 1 wherein Q 1 is as described for formula (Ia), and X 1 is a halogen or a leaving group, to obtain the halopyrazolylthiazole of formula (Ia).
2. The method of claim 1 , wherein the hydrazone and the alkylhalogenide are reacted in presence of an inorganic iodide and a base.
3. The method of claim 2 , wherein the inorganic iodide is KI or NaI.
4. The method of claim 2 , wherein the amount of inorganic iodide at least 1 molar equivalent based on the amount of the thiazole.
5. The method of claim 2 , wherein the base is a carbonate.
6. A halopyrazolylthiazole of formula (Ia)
wherein
X is a halogen;
L 1 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, —NR 6 —, —C(O)NR 6 —, —NR 6 C(O)—, —C(S)NR 6 —, —NR 6 C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O) 1-2 O—, —OS(O) 1-2 —, —S(O) 1-2 NR 6 — and —NR 6 S(O) 1-2 —;
R 1 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkenyl and C 1 -C 8 alkynyl, each unsubstituted or fluorinated;
Q 1 is selected from the group consisting of —C(O)OR 2C , —C(O)NR 2B R 2C , —C(O)NR 2B S(O) 2 R 2C , —C(O)NR 2B S(O) 2 NR 2B R 2C , —S(O) 2 R 2C , —N(R 2B )S(O) 2 R 2C , —S(O) 2 NR 2B R 2C , and —C(O)NH—O(C 1 -C 3 alkyl), in which
each R 2B is independently selected from H and C 1 -C 3 alkyl, and
each R 2C is independently selected from C 1 -C 3 alkyl and a protecting group;
R 3 is phenyl or heteroaryl each (i) optionally substituted with a single substituent selected from -L 3C -(phenyl optionally substituted with 1-5 R 3D ), -L 3C -(heteroaryl optionally substituted with 1-5 R 3D ), -L 3C -(cycloalkyl optionally substituted with 1-5 R 3D ), -L 3C -(heterocycloalkyl optionally substituted with 1-5 R 3D ) and (ii) optionally substituted with 1-5 R 3E ,
in which
each L 3C is a bond, methylene, ethylene, —C(O)—, —S—, —S(O) 1-2 —, —O—, or —NR 3G —;
each R 3D is independently selected from oxo optionally-substituted C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, halogen, —CN, —SF 5 , —N 3 , —C(O)R 3F , —SR 3F , —S(O) 1-2 R 3F , —OR 3F , —NR 3G R 3F , —C(O)R 3F , —C(O)NR 3G R 3F , —NR 3G C(O)R 3F , —C(S)NR 3G R 3F , —NR 3G C(S)R 3F , —C(O)OR 3F , —OC(O)R 3F , —C(O)SR 3F , —SC(O)R 3F , —C(S)OR 3F , —OC(S)R 3F , —C(S)SR 3F , —SC(S)R 3F , —S(O) 1-2 OR 3F , —OS(O) 1-2 R 3F , —S(O) 1-2 NR 3G R 3F , and —NR 3G S(O) 1-2 R 3F ;
each R 3E is independently selected from oxo, optionally-substituted C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, halogen, —CN, —SF 5 , —N 3 , —C(O)R 3F , —SR 3F , —S(O) 1-2 R 3F , —OR 3F , —NR 3G R 3F , —C(O)R 3F , —C(O)NR 3G R 3F , —NR 3G C(O)R 3F , —C(S)NR 3G R 3F , —NR 3G C(S)R 3F , —C(O)OR 3F , —OC(O)R 3F , —C(O)SR 3F , —SC(O)R 3F , —C(S)OR 3F , —OC(S)R 3F , —C(S)SR 3F , —SC(S)R 3F , —S(O) 1-2 OR 3F , —OS(O) 1-2 R 3F , —S(O) 1-2 NR 3G R 3F , and —NR 3G S(O) 1-2 R 3F ;
each R 3F is independently selected from H, C 1 -C 3 alkyl and C 1 -C 3 fluoroalkyl and
each R 3G is independently selected from H, C 1 -C 3 alkyl, and C 1 -C 3 fluoroalkyl; and
R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl,
optionally-substituted C 1 -C 8 alkenyl and optionally substituted C 1 -C 8 alkynyl;
wherein
each R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl and —C(O)(C 1 -C 3 alkyl);
each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups;
each cycloalkyl has 3-10 ring carbons and is saturated or partially unsaturated;
each heterocylcloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and is saturated or partially unsaturated; and
each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
7. The compound of claim 6 , wherein X is Cl or Br.
8. The compound of claim 6 , wherein the halopyrazolylthiazole of formula (Ia) is C 1 -C 3 alkyl 1-(4-halo-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate.
9. A method for preparing a compound of formula (I)
optionally in the form of a pharmaceutically acceptable salt or N-oxide, and/or a solvate or hydrate, wherein
L 1 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, —NR 6 —, —C(O)NR 6 —, —NR 6 C(O)—, —C(S)NR 6 —, —NR 6 C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O) 1-2 O—, —OS(O) 1-2 —, —S(O) 1-2 NR 6 — and —NR 6 S(O) 1-2 —;
R 1 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkenyl and C 1 -C 8 alkynyl, each unsubstituted or fluorinated;
Q is selected from the group consisting of —C(O)OR 2A , —C(O)NR 2B R 2A , —C(O)NR 2B S(O) 2 R 2A , —C(O)NR 2B S(O) 2 NR 2B R 2A , —S(O) 2 R 2A , —N(R 2B )S(O) 2 R 2A , —S(O) 2 NR 2B R 2A , and —C(O)NH—O(C 1 -C 3 alkyl), in which
each R 2A is independently selected from H, C 1 -C 3 alkyl, and a protecting group, and
each R 2B is independently selected from H and C 1 -C 3 alkyl;
R 3 is phenyl or heteroaryl each (i) optionally substituted with a single substituent selected from -L 3C -(phenyl optionally substituted with 1-5 R 3D ), -L 3C -(heteroaryl optionally substituted with 1-5 R 3D ), -L 3C -(cycloalkyl optionally substituted with 1-5 R 3D ), -L 3C -(heterocycloalkyl optionally substituted with 1-5 R 3D ) and (ii) optionally substituted with 1-5 R 3E ,
in which
each L 3C is a bond, methylene, ethylene, —C(O)—, —S—, —S(O) 1-2 —, —O—, or —NR 3G —;
each R 3D is independently selected from oxo optionally-substituted C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, halogen, —CN, —SF 5 , —N 3 , —C(O)R 3F , —SR 3F , —S(O) 1-2 R 3F , —OR 3F , —NR 3G R 3F , —C(O)R 3F , —C(O)NR 3G R 3F , —NR 3G C(O)R 3F , —C(S)NR 3G R 3F , —NR 3G C(S)R 3F , —C(O)OR 3F , —OC(O)R 3F , —C(O)SR 3F , —SC(O)R 3F , —C(S)OR 3F , —OC(S)R 3F , —C(S)SR 3F , —SC(S)R 3F , —S(O) 1-2 OR 3F , —OS(O) 1-2 R 3F , —S(O) 1-2 NR 3G R 3F , and —NR 3G S(O) 1-2 R 3F ;
each R 3E is independently selected from oxo, optionally-substituted C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, halogen, —CN, —SF 5 , —N 3 , —C(O)R 3F , —SR 3F , —S(O) 1-2 R 3F , —OR 3F , —NR 3G R 3F , —C(O)R 3F , —C(O)NR 3G R 3F , —NR 3G C(O)R 3F , —C(S)NR 3G R 3F , —NR 3G C(S)R 3F , —C(O)OR 3F , —OC(O)R 3F , —C(O)SR 3F , —SC(O)R 3F , —C(S)OR 3F , —OC(S)R 3F , —C(S)SR 3F , —SC(S)R 3F , —S(O) 1-2 OR 3F , —OS(O) 1-2 R 3F , —S(O) 1-2 NR 3G R 3F , and —NR 3G S(O) 1-2 R 3F ;
each R 3F is independently selected from H, C 1 -C 3 alkyl and C 1 -C 3 fluoroalkyl and
each R 3G is independently selected from H, C 1 -C 3 alkyl, and C 1 -C 3 fluoroalkyl;
R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally-substituted C 1 -C 8 alkenyl and optionally substituted C 1 -C 8 alkynyl; and
R 5 is phenyl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted with 1-5 R 5E ,
in which
each R 5E is independently selected from oxo, optionally-substituted C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, halogen, —CN, —SF 5 , —N 3 , —C(O)R 5F SR 5F , —S(O) 1-2 R 5F , —OR 5F , —NR 5G R 5F , —C(O)R 5F , —C(O)NR 5G R 5F , —NR 5G C(O)R 5F , —C(S)NR 5G R 5F , —NR 5G C(S)R 5F , —C(O)OR 5F , —OC(O)R 5F , —C(O)SR 5F , —SC(O)R 5F , —C(S)OR 5F , —OC(S)R 5F , SC(S)SR 5F , SC(S)R 5F , —S(O) 1-2 OR 5F , —OS(O) 1-2 R 5F , —S(O) 1-2 NR 5G R 5F , and —NR 5G S(O) 1-2 R 5F ;
each R 5F is independently selected from H, C 1 -C 3 alkyl and C 1 -C 3 fluoroalkyl and
each R 5G is independently selected from H and C 1 -C 3 alkyl;
wherein
each R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl and —C(O)(C 1 -C 3 alkyl);
each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups;
each cycloalkyl has 3-10 ring carbons and is saturated or partially unsaturated;
each heterocylcloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and is saturated or partially unsaturated;
each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur,
the method comprising:
coupling a halopyrazolylthiazole of formula (Ia)
wherein X is a halogen (e.g., Cl, Br or I);
Q 1 is selected from the group consisting of —C(O)OR 2C , —C(O)NR 2B R 2C , —C(O)NR 2B S(O) 2 R 2C , —C(O)NR 2B S(O) 2 NR 2B R 2C , —S(O) 2 R 2C , —N(R 2B )S(O) 2 R 2C , —S(O) 2 NR 2B R 2C , and —C(O)NH—O(C 1 -C 3 alkyl), in which
each R 2B is independently selected from H and C 1 -C 3 alkyl, and
each R 2C is independently selected from C 1 -C 3 alkyl and a protecting group;
and L 1 , R 1 , R 3 , and R 4 are as described for formula (I),
with an organoboron comprising R 5 moiety to obtain the compound of formula (I).
10. The method of claim 9 , wherein the organoboron is an boronic acid or boronic ester having R 5 substituted on the boron atom.
11. The method of claim 10 , wherein the organoboron has the formula:
wherein
R 5 is as described for formula (I), and
Y 1 and Y 2 are independently hydroxy or C 1 -C 4 alkoxy, or Y 1 and Y 2 together with B atom form a 5- or 6-membered ring having one or two oxygens in the ring bound to the boron.
12. The method of claim 10 , wherein the halopyrazolylthiazole of formula (Ia) and the organoboron are coupled in presence of a palladium catalyst and a base.
13. The method of claim 10 , wherein the compound of formula (I) is
14. A method for preparing a thiazolylhydrazine of formula (Ib)
wherein
X is a halogen;
L 1 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, —NR 6 —, —C(O)NR 6 —, —NR 6 C(O)—, —C(S)NR 6 —, —NR 6 C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O) 1-2 O—, —OS(O) 1-2 —, —S(O) 1-2 NR 6 — and —NR 6 S(O) 1-2 —;
R 1 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkenyl and C 1 -C 8 alkynyl, each unsubstituted or fluorinated;
wherein
each R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl and —C(O)(C 1 -C 3 alkyl);
the method comprising:
reacting a dihalothiazole of formula
wherein X, R 1 , and L 1 are as described for formula (Ib), and X a is halogen, optionally in a solvent, with an aqueous solution of hydrazine to obtain a crude product; and
crystallizing the crude product from a hydrocarbon solvent to obtain the thiazolylhydrazine of formula (Ib).
15. The method of claim 14 , wherein X a is chloro or bromo.
16. The method of claim 1 , wherein
R 1 is unsubstituted C 1 -C 5 alkyl or fluorinated C 1 -C 5 alkyl;
L 1 is —S—;
R 3 is optionally substituted with 1-5 R 3E , in which each R 3E is independently selected from C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, halogen, —OR 3F , and —NR 3G R 3F ; or wherein R 3E is independently selected from halogen, —OR 3F , and —NR 3G R 3F ;
R 4 is hydrogen or unsubstituted C 1 -C 6 alkyl;
R 5 is partially unsaturated cycloalkyl or phenyl, each optionally substituted with 1-5 R 5E ; and
Q 1 is —C(O)OR 2C .
17. The method of claim 1 , wherein the compound of formula (Ia) is:
18. The method of claim 1 , wherein the compound of formula (Ia) is:
wherein R 1 is C 1 -C 8 alkyl, and R 3E is independently selected from C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, halogen, —OR 3F , and —NR 3G R 3F .
19. Ethyl 1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate.
20. The method of claim 14 , wherein L 1 is —S— and R 1 is isopropyl.