US 2025/0101006 A1 · PROCESS FOR THE SYNTHESIS OF PYRAZOLYL DERIVATIVES USEFUL AS ANTI-CANCER AGENTS

Abstract

The invention provides a novel process, novel process steps and novel intermediates useful in the synthesis of pharmaceutically active compounds, especially KRAS G12C inhibitors. The present invention provides a direct enantioselective chemical manufacturing method of making Compound A, or a pharmaceutically acceptable hydrate or solvent thereof: (I). The invention provides a process for preparing Intermediate B6* comprising reacting Intermediate B4* with Intermediate B5* in an atroposelective coupling reaction, using a chiral catalyst.

Claims20

Dependent claims

A process for preparing a compound of formula (I), or a salt, or hydrate or a solvate thereof,

comprising reacting Compound B11b*, or a salt thereof,
with acrylic acid or a reactive derivative of acrylic acid to form a compound of formula (Ia) and optionally subsequently forming a salt or hydrate or solvate of the compound of formula (Ia).

A process according to any one of the previous claims or a process for preparing Intermediate B6*, comprising coupling Intermediate B4*,

wherein Pr1 is a nitrogen-protecting group and
(a) Xb is hydrogen, halogeno, —OSO2RA in which RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl, or ORB wherein RB is C1-C4-alkyl, if Lb is borono (—B(OH)2), a boronic diester moiety, BF3K, MgX, in which X is Cl, Br or I, Zn(RZ), in which RZ is halogen or alkyl;
Sn(RD)(RE)(RF), in which each of RD, RE, RF is methyl, n-butyl;
Si(RG)(RH)(RI), in which each of RG, RH, RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li;
or (b) Xb is borono (—B(OH)2), a boronic diester moiety, BF3K, MgX, in which X is Cl, Br or I, Zn(RZ), in which RZ is halogen or alkyl;
Sn(RD)(RE)(RF), in which each of RD, RE, RF is methyl, n-butyl;
Si(RG)(RH)(RI), in which each of RG, RH, RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li;
if Lb is hydrogen, halogeno, —OSO2RA in which RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl, or ORB wherein RB is C1-C4-alkyl,
in the presence of a chiral (enantiomerically pure) mono- or (especially) bisphosphine ligand catalyst and a palladium source reagent with an Intermediate B5*,
wherein Q is formyl or in particular a formyl group in the form of an acetal or a Schiff base,
Lb is (a′) (in particular) borono (—B(OH)2), a boronic diester moiety, BF3K, MgX, in which X is Cl, Br or I, Zn(RZ), in which RZ is halogen or alkyl;
Sn(RD)(RE)(RF), in which each of RD, RE, RF is methyl, n-butyl;
Si(RG)(RH)(RI), in which each of RG, RH, RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li, if Xb is as just defined above for Xb under (a),
or (b′) Lb is hydrogen, halogeno, —OSO2RA in which RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl, or ORB wherein RB is C1-C4-alkyl, if Xb is as just defined under (b) for Xb above;
and
Xc is halogeno or pseudohalogeno, to form Intermediate B6*.

13 more elements

The process of any one of the preceding claims, or a process for preparing Intermediate B4*, wherein (a) Xb is halogeno, —OSO2RA in which RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl, or ORB wherein RB is C1-C4-alkyl, if Lb is borono (—B(OH)2), a boronic diester moiety, BF3K, MgX, in which X is Cl, Br or I, Zn(RZ), in which RZ is halogen or alkyl;

Sn(RD)(RE)(RF), in which each of RD, RE, RF is methyl, n-butyl;
Si(RG)(RH)(RI), in which each of RG, RH, RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li;
or (b) Xb is borono (—B(OH)2), a boronic diester moiety, BF3K, MgX, in which X is Cl, Br or I, Zn(RZ), in which RZ is halogen or alkyl;
Sn(RD)(RE)(RF), in which each of RD, RE, RF is methyl, n-butyl;
Si(RG)(RH)(RI), in which each of RG, RH, RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li;
if Lb is hydrogen, halogeno, —OSO2RA in which RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl, or ORB wherein RB is C1-C4-alkyl,
comprising reacting an Intermediate B3*,
wherein Pr1 is a nitrogen-protecting group, with a reagent capable of inserting the group Xb wherein Xb is Xb is halogeno, —OSO2RA in which RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl, or ORB wherein RB is C1-C4-alkyl, if Lb is borono (—B(OH)2), a boronic diester moiety, BF3K, MgX, in which X is Cl, Br or I, Zn(RZ), in which RZ is halogen or alkyl;
Sn(RD)(RE)(RF), in which each of RD, RE, RF is methyl, n-butyl;
Si(RG)(RH)(RI), in which each of RG, RH, RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li;
or (b) Xb is borono (—B(OH)2), a boronic diester moiety, BF3K, MgX, in which X is Cl, Br or I, Zn(RZ), in which RZ is halogen or alkyl;
Sn(RD)(RE)(RF), in which each of RD, RE, RF is methyl, n-butyl;
Si(RG)(RH)(RI), in which each of RG, RH, RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li;
if Lb is hydrogen, halogeno, —OSO2RA in which RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl, or ORB wherein RB is C1-C4-alkyl.

11 more elements

The process of any one of the preceding claims, wherein in the Intermediate B4*

Pr1 is a nitrogen-protecting group selected from the group consisting of tert-butyoxycarbonyl, carbobenzoxycarbonyl (Cbz), benzyl (Bn), methoxybenzyl (MPM), trifluoroacetyl, acetyl, fluoren-9-yl-methoxycarbonyl (Fmoc) and trityl (Tr);
and Xb is hydrogen, halogeno, a mesylate moiety, a triflate moiety or a tosylate moiety;
and in the Intermediate B5*, Q is selected from the group consisting of
in which R1 and R2 are independently selected from alkyl or arylalkyl or together form an alkenyl bridge that may be unsubstituted or substituted with one or more moieties selected from alkyl, aryl and arylalkyl;
some preferred moities are
in which R1 and R2 are independently selected from hydrogen and alkyl and further aryl,
in which R1 and R2 are independently selected from hydrogen, alkyl and further aryl;
the following groups are special examples:
and further
—CH═N—R′ in which R′ is selected from the group consisting of alkyl, aryl, alkoxy and S(═O)—R″ wherein R″ is selected from alkyl, aryl and alkoxy, such as —S(═O)-alkyl (e.g. tert-butyl) or —S(═O)phenyl;
the chiral (enantiomerically pure) mono- or (especially) bisphosphine ligand catalyst is selected from the group consisting of
and especially from the
Group 1 consisting of
Group 1:
from
the Group 2 consisting of:
Group 2:
BINAP and related ligands:
(most important are Ligand 21, 22, 23 or 24)
and
from the Group 3 consisting of:
Group 3:
Other ligands:
the palladium source reagent is selected from the group consisting of palladium source, any Pd salt or complex can be employed, such as Pd(OAc)2, Pd(OPiv)2, Pd(OCOEt)2, PdCl2, PdBr2, PdI2, Pd(OH)2, PdSO4, Pd(TFA)2, Pd(dba)2, Pd2(dba)3, Pd(acac)2, Pd2(dba)3·CHCl3, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, [Pd(π-allyl)Cl]2, [Pd(π-cinnamyl)Cl]2, Pd[P(o-Tol)3]2, Pd/C, Pd(OH)2/C, [Pd-G1]2, [Pd-G2]2, [Pd-G3]2, [Pd-G4]2, Pd(BINAP)Cl2, Pd(dppe)Cl2, Pd(dppp)Cl2, Pd(dppb)Cl2, and Pd(dppf)Cl2;
Pd(II) salts or complexes selected, e.g. for bisphosphone ligands Pd(II), for example selected from Pd(OAc)2, Pd(TFA)2 and Pd(PhCN)2Cl2;
or for bisphosphine monoxide ligands Pd(0) can be used, e.g. Pd2(dba)3 or Pd(dba)2;
where the reaction is preferably conducted in the presence of a base, such as selected from the group consisting of Cs2CO3, CsOH·H2O, CsHCO3, CsOPiv, CsF, CsOAc, K3PO4, K2CO3, KHCO3, KF, TMSOK, NaOH, NaHCO3, KOH, NaOMe, KOMe, NaOEt, KOEt, KOtBu, NaOtBu, NaOAc, KOAc, DABCO, DBU, TEA, DIPEA, Cy2NMe, pyridine, 2,6-lutidine, or the like. Cs2CO3, especially in micronized form, is a preferred example;
in one or more solvents selected from the group consisting of DMF, DMSO, NMP, water, MeOH, EtOH, i-PrOH, tert-amyl alcohol, toluene, o-xylene, m-xylene, p-xylene, 1,3,5-trimethylbenzene, 1,3,5-trifluorobenzene, chlorobenzene, trifluoromethylbenzene, 1,2-difluorobenzene, n-heptane, n-hexane, c-hexane, n-pentane, THF, 2-MeTHF, 1,4-dioxane, MTBE, CPME, i-Pr2O, n-Bu2O, Ph2O, DME (1,2-dimethoxyethane), MeO(CH2CH2O)2Me, cyclohexane, acetonitrile, DCM, Et3N, DIPEA, 2,6-lutidine, ethyl acetate, i-propyl acetate, t-butyl acetate, MIBK and sulfolane;
can, for example, be used;
where the sum of water in the reaction mixture preferably is kept at about 1.5 (e.g. 1.2 to 1.8) equivalents per mol of Intermediate B4*;
where the reaction preferably takes place at temperatures in the range from 0° C. to the boiling temperature of the reaction mixture, especially at an elevated temperature in the range from 25 to 90° C., such as in the range from 50 to 75° C., e.g. at 60 to 70° C.

28 more elements

Dependencies are inferred from the claim text.

Process for the synthesis of pyrazolyl derivatives useful as anti-cancer agents

Life of this patent

Process for the synthesis of pyrazolyl derivatives useful as anti-cancer agents

Life of this patent

Abstract

Claims20