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WO2025257090A1 - Process for the preparation of synthesis intermediates of lumateperone and lumateperone analogues - Google Patents

Process for the preparation of synthesis intermediates of lumateperone and lumateperone analogues

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Publication number
WO2025257090A1
WO2025257090A1 PCT/EP2025/065936 EP2025065936W WO2025257090A1 WO 2025257090 A1 WO2025257090 A1 WO 2025257090A1 EP 2025065936 W EP2025065936 W EP 2025065936W WO 2025257090 A1 WO2025257090 A1 WO 2025257090A1
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Prior art keywords
formula
process according
compound
previous
ligand
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French (fr)
Inventor
Francisco De Asís MARQUILLAS OLONDRIZ
Gladys TORIBIO VILLARROYA
Thierry LEÓN SERRANO
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Interquim SA
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Interquim SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems

Definitions

  • the present invention belongs to the field of the process of manufacturing intermediates useful in the synthesis of lumateperone and lumateperone analogues.
  • Lumateperone marketed as Caplyta®, is authorized by the FDA for the treatment of schizophrenia and depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate.
  • Lumateperone has the following chemical formula Illa: and the following chemical name: 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,1 Oa-hexahydro- 1 H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)butan-1-one.
  • A is H or halogen
  • B is a protective group such as -Bn, or -P-Q, wherein P is -C(O)-, -C(O)O-, or -S(O)2- and Q is alkyl or aryl alkyl;
  • R 8 is H, or F
  • R 9 is H, D, or 0-R 1 ;
  • R 10 is H, F, Cl, Br or l.
  • A, B, X, Z, and Y as previously defined and LG is selected from F, Cl, Br, or I:
  • DBU 1,8-diazabicyclo(5.4.0)undec-7-ene
  • DBU 1 ,5-diazabicyclo(4.3.0)non-5-ene
  • DBCO 1 ,4-diazabicyclo[2.2.2]octane
  • DMEDA 1,2-dimethylethylenediamine
  • the most widely use ligands were DBU (8, WO19241278, WQ20131895) and DMEDA (10, WQ08112280).
  • DBU 8, WO19241278, WQ20131895)
  • DMEDA 10, WQ08112280
  • the product obtained in the reaction above is not isolated and the next step is taken in one pot, but when information about the product obtained is included, the resulting product had high level of impurities (5 % in Ex 5 cont 2 of WQ20131895 and 17 % in Ex 5 of WQ08112280).
  • TEDA TMS1A/,A/’,A/’-tetramethylethylenediamine
  • WQ20131895 WO2Q154519, WQ20132605, WQ20132474, WO19183341 , WO23178111 , WO19183546, WO23178113.
  • Example 5 of WQ20131895 it is indicated that the industrial handling of the reaction crude using TMEDA (11) as ligand is complex and results in loss of yields and low purity.
  • DMF Dimethylformamide
  • DBU (8) is corrosive to metals; thus, metal reactors (including industrial metal reactors) cannot be used. Not only that, but the inventors have found that DBU (8) reacts even with non-reactive thermoplastics such as polyvinylidene difluoride (PVDF). DBU (8) is very basic having a pKa of 11 .5-13.5 (Kaupmees 2014).
  • One aspect of the invention is a process for the preparation of a compound of formula I comprising the step of reacting a compound of formula II in the presence of at least a catalyst, at least a ligand, at a least base, and at least an organic solvent to give a compound of formula I; wherein the ligand comprises one or more compounds of formula IV or 2,2'-bipyridyl (13): A is H or halogen;
  • B is a protective group
  • LG is selected from F, Cl, Br, or I; each R 1 , R 3 , R 4 , R 5 , R 6 , R 7 is independently H, D, or linear or branched Ci ealkyl, optionally with one or more H substituted by D; and
  • R 2 is linear or branched Ci ealkyl, optionally with one or more H substituted by D.
  • Another aspect of the invention is a compound of formula lla-Br:
  • Impurity A has the chemical name ethyl (4aS,9bR)-6-iodo-5-(2-(methylamino)-2-oxoethyl)- 1 ,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate. This product has been characterized only by mass spectroscopy (MS).
  • Impurity B is a derivative of la wherein according to its Mw, two hydrogens have been lost. This product has been characterized only by mass spectroscopy (MS).
  • Impurity lla-Br has the chemical name ethyl (4aS,9bR)-5-(2-(methylamino)-2-oxoethyl)-1 , 3, 4, 4a, 5,9b- hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate. This product has been characterized only by mass spectroscopy (MS). Impurity C is a derivative of la wherein according to its Mw, two hydrogens have been lost and one oxygen gained. This product has been characterized only by mass spectroscopy (MS).
  • the process of the invention is a preparation of a compound of formula I comprising the step of reacting a compound of formula II in the presence of at least a catalyst, at least a ligand, at a least base, and at least an organic solvent to give a compound of formula I, wherein the ligand comprises one or more compounds of formula IV or 2,2'-bipyridyl (13):
  • A is H or halogen
  • B is a protective group
  • LG is selected from F, Cl, Br, or I; each R 1 , R 3 , R 4 , R 5 , R 6 , R 7 is independently H, D, or linear or branched Ci ealkyl, optionally with one or more H substituted by D; and
  • R 2 is linear or branched Ci ealkyl, optionally with one or more H substituted by D.
  • A is H.
  • the protective group B is selected from -Bn, and -P-Q, wherein P is -C(O)-, -C(O)O-, or -S(O)2- and Q is alkyl or arylalkyl.
  • the protective group B is -P-Q wherein P is -C(O)O-, and Q is ethyl.
  • R 1 is CH 3 .
  • LG is Br.
  • the compound of formula II is the compound of formula Ila:
  • the ligand comprises a ligand of formula IV selected from 1 -methylimidazole (7), 1 -ethylimidazole, 1 -propylimidazole, 1 -isopropylimidazole (18), 1 -butylimidazole, and mixtures thereof.
  • the ligand comprises a ligand selected from 1 -methylimidazole (7), 1 -isopropylimidazole (18), and mixtures thereof.
  • the ligand comprises 1 -methylimidazole (7).
  • the ligand comprises 2,2'-bipyridyl (13).
  • the process includes removal of water.
  • the removal of water is via azeotropic distillation.
  • the ligand is in a ratio of 0.1 to 0.5 equivalents (eq) in relation to compound of formula II.
  • the ligand in combination with any of the embodiments of the invention, is in a ratio of 0.10 to 0.2 equivalents (eq) in relation to compound of formula II.
  • the ligand in combination with any of the embodiments of the invention, is in a ratio of 0.35 to 0.45 equivalents (eq) in relation to compound of formula II.
  • the catalyst comprises a transition metal catalyst selected from the group consisting of metals of groups 8- 11 of the periodic table of the elements.
  • the elements of group 8 are iron (Fe), ruthenium (Ru), and osmium (Os).
  • the elements of group 9 are cobalt (Co), rhodium (Rh), and iridium (Ir).
  • the elements of group 10 are nickel (Ni), palladium (Pd), and platinum (Pt).
  • the elements of group 11 are copper (Cu), silver (Ag), and gold (Au).
  • the transition metal catalyst is selected from Cu, Pd, Pt, and mixtures thereof.
  • the transition metal catalyst comprises Cu(l).
  • the transition metal catalyst in combination with any of the embodiments of the invention, is in a ratio of 0.1 to 0.3 equivalents (eq) in relation to compound of formula II.
  • the base is selected from IJ2CO3, Na2CO3, K2CO3, Rb2CO3, CS2CO3, Li f BuO, NaTiuO, K f BuO, RbTiuO, CsTiuO, one or more compounds of formula IV as defined in embodiment 1 , 2,2'-bipyridyl (13), and mixtures thereof.
  • the base is selected from IJ2CO3, Na2CO3, K2CO3, Rb2CO3, CS2CO3, and mixtures thereof.
  • the base is K2CO3.
  • the base is in a ratio of 2 to 3 equivalents (eq) in relation to the compound of formula II.
  • At least 50 % of particles of the base have a particle size lower than 58 pm, measured using granulometry with a 270 mesh.
  • the organic solvent is selected from toluene, dioxane, dimethylformamide (DMF), dimethyl sulphoxide (DMSO), dimethylacetamide (DMAc), and mixtures thereof.
  • the organic solvent is selected from toluene, dioxane, and mixtures thereof.
  • the organic solvent is toluene.
  • the organic solvent is in a ratio of 1 to 2 mL/mmol in relation to the compound of formula II.
  • the compound of formula II is Ila and the compound of formula I is la and the ligand is selected from 1 -methylimidazole (7) or 2,2'-bipyridyl (13).
  • the process further comprises reacting a compound of formula la thus obtained with 4-chloro-1-(4- fluorophenyl)butan-1 -one (IV) to yield lumateperone Illa.
  • the invention is as well directed to a compound of formula lla-Br:
  • the invention is as well directed to the use of a compound of formula lla-Br: as analytical standard.
  • the invention is as well directed to a compound of formula A:
  • A is H or halogen
  • B is a protective group
  • LG is selected from F, Cl, Br, or I; each R 1 , R 3 , R 4 , R 5 , R 6 , R 7 is independently H, D, or linear or branched Ci ealkyl, optionally with one or more
  • R 2 is linear or branched Ci ealkyl, optionally with one or more H substituted by D.
  • Clause 3 The process according to any of the previous clauses, wherein the protective group B is selected from -Bn, and -P-Q, wherein P is -C(O)-, -C(O)O-, or -S(O)2- and Q is alkyl or arylalkyl.
  • the ligand comprises a ligand of formula IV selected from 1 -methylimidazole (7), 1 -ethylimidazole, 1 -propylimidazole, 1 -isopropylimidazole (18), 1 -butylimidazole, and mixtures thereof.
  • the ligand comprises a ligand selected from 1 -methylimidazole (7), 1 -isopropylimidazole (18), and mixtures thereof.
  • Clause 15 The process according to the previous clause, wherein the removal of water is via azeotropic distillation.
  • Clause 16 The process according to any of the previous clauses, wherein the ligand is in a ratio of 0.1 to 0.5 equivalents (eq) in relation to compound of formula II.
  • Clause 18 The process according to Clause 16, wherein the ligand is in a ratio of 0.35 to 0.45 equivalents (eq) in relation to compound of formula II.
  • Clause 19 The process according to any of the previous clauses, wherein the catalyst comprises a transition metal catalyst selected from the group consisting of metals of groups 8-11 of the periodic table.
  • transition metal catalyst is selected from Cu, Pd, Pt, and mixtures thereof.
  • Clause 22 The process according to any of the Clause 19 to Clause 21 , wherein the transition metal catalyst is in a ratio of 0.1 to 0.3 equivalents (eq) in relation to compound of formula II.
  • Clause 23 The process according to any of the previous clauses, wherein the base is selected from IJ2CO3, Na2CO3, K2CO3, Rb2CO3, CS2CO3, Li f BuO, NaTiuO, K f BuO, RbTiuO, CsTiuO, one or more compounds of formula IV as defined in claim 1 , 2,2'-bipyridyl (13), and mixtures thereof.
  • Clause 26 The process according to any of the Clause 24 to Clause 25, wherein the base is in a ratio of 2 to 3 equivalents (eq) in relation to the compound of formula II.
  • Clause 27 The process according to any of the Clause 24 to Clause 26, wherein at least 50 % of particles of the base have a particle size lower than 58 pm, measured using granulometry with a 270 mesh.
  • Clause 28 The process according to any of the previous clauses, wherein the organic solvent is selected from toluene, dioxane, dimethylformamide (DMF), dimethyl sulphoxide (DMSO), dimethylacetamide (DMAc), and mixtures thereof.
  • Clause 31 The process according to any of the Clause 28 to Clause 30, wherein the organic solvent is in a ratio of 1 to 2 mL/mmol in relation to the compound of formula II.
  • Clause 32 The process according to any of the previous clauses, wherein the compound of formula II is Ila and the compound of formula I is la and the ligand is selected from 1 -methylimidazole (7) or 2,2'-bipyridyl (13).
  • Kaupmees 2014 Kaupmees, K.; Trummal, A.; Leito, I. (2014). "Basicities of Strong Bases in Water: A
  • Method 1 HPLC method C18 2.5 pm (4.6x75 mm) column eluted with a mixture of ammonia buffer (ammonium formate pH 10.0 adjusted with ammonia) and acetonitrile 85:15 to 30:70 at a flow rate of 1.0mL/min, 40°C of column temperature and 240 nm detection. Finally, 2.0pL are injected into the chromatographic system.
  • ammonia buffer ammonium formate pH 10.0 adjusted with ammonia
  • acetonitrile 85:15 to 30:70 at a flow rate of 1.0mL/min, 40°C of column temperature and 240 nm detection.
  • AD Azeotropic distillation
  • A Intermediate
  • B & C impurities
  • ND Not detected

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention belongs to the field of the process of manufacturing intermediates of formula (I) useful in the synthesis of lumateperone and lumateperone analogues using N-alkyl imidazole and bipyridyl ligands.

Description

Process for the preparation of synthesis intermediates of lumateperone and lumateperone analogues
Field of the Invention
The present invention belongs to the field of the process of manufacturing intermediates useful in the synthesis of lumateperone and lumateperone analogues.
Background of the invention
Lumateperone, marketed as Caplyta®, is authorized by the FDA for the treatment of schizophrenia and depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate. Lumateperone has the following chemical formula Illa: and the following chemical name: 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,1 Oa-hexahydro- 1 H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)butan-1-one.
The compounds of formula I are useful in the synthesis of lumateperone and lumateperone analogues of formula III: wherein
A is H or halogen;
B is a protective group such as -Bn, or -P-Q, wherein P is -C(O)-, -C(O)O-, or -S(O)2- and Q is alkyl or aryl alkyl;
Z is CR5R6, C=0, C=NR7, or C=S; each R1, R3, R4, R5, R6, R7 is independently H, D, or branched Cualkyl, optionally with one or more H substituted by D;
T is 0, C=0, or CR1R9;
R8 is H, or F;
R9 is H, D, or 0-R1; and
R10 is H, F, Cl, Br or l.
Compounds of formula I and III are described in W011133224 A1 , W013155505 A1 , WO15154025 A1 , WO15154030 A1 , WO17165755 A1 , WO17165843 A1 , WO1812614Q A1 , WO17117514 A1 ; and related compounds, such as those of WO1812614Q A1 , WO18126143 A1 ; WO19023062 A1 ; WO19023063 A1 ; WO19183341 A1 ; WO19183546 A1 ; WQ20131899 A1 ; WO21119334 A1 ; WQ22073470 A1 , CN112062767 B, or WO23134711 A1.
In, inter alia, WQ08112280 A1 the conversion of a compound of formula I into lumateperone (Illa) is exemplified.
One convenient way of obtaining a compound of formula I is starting from a compound of formula II. A, B, X, Z, and Y as previously defined and LG is selected from F, Cl, Br, or I:
In the prior art, the following ligands (see Table 1) are disclosed for said reaction:
1 ,8-diazabicyclo(5.4.0)undec-7-ene (DBU, 8) is used in WO2Q131895, WO22195500, IP270692D.
The use of DBU (8), 1 ,5-diazabicyclo(4.3.0)non-5-ene (DBN, 19), or 1 ,4-diazabicyclo[2.2.2]octane (DABCO, 20) is claimed in WO19241278.
1 ,2-dimethylethylenediamine (DMEDA, 10) is used in WQ08112280, WO19241278, WO22195500, CN113024554, IN201741021763, CN114105980, IP270692D.
According to the prior art, the most widely use ligands were DBU (8, WO19241278, WQ20131895) and DMEDA (10, WQ08112280). In most of the examples, the product obtained in the reaction above is not isolated and the next step is taken in one pot, but when information about the product obtained is included, the resulting product had high level of impurities (5 % in Ex 5 cont 2 of WQ20131895 and 17 % in Ex 5 of WQ08112280).
A/,A/,A/’,A/’-tetramethylethylenediamine (TMEDA, 11) is used in WQ20131895, WO2Q154519, WQ20132605, WQ20132474, WO19183341 , WO23178111 , WO19183546, WO23178113.
In Example 5 of WQ20131895 it is indicated that the industrial handling of the reaction crude using TMEDA (11) as ligand is complex and results in loss of yields and low purity.
1 ,3-diphenylpropane-1 , 3-dione (DBM, 17) is used in CN112062767.
Dimethylformamide (DMF, 21) is used in CN113024554.
When the inventors have tried to use the prior art ligands in the reaction above, it was found that either the reactions did not take place, the yield was low, the resulting crude had a high level of impurities (specially with DMEDA (10) the loss of LG to obtain ll-LG or lla-Br which are difficult to remove from the final mixture), and/or the work-up was difficult (see Comparative Example 1).
Furthermore, in the hands of the inventors DBU (8) is corrosive to metals; thus, metal reactors (including industrial metal reactors) cannot be used. Not only that, but the inventors have found that DBU (8) reacts even with non-reactive thermoplastics such as polyvinylidene difluoride (PVDF). DBU (8) is very basic having a pKa of 11 .5-13.5 (Kaupmees 2014).
In the hands of the inventors pure DBU (8) is a very sensitive product and easily degrades resulting in unreliable and slower reactions which gets dark in a short time and makes the handling of the reaction more difficult.
Thus, there is a need in the art to obtain a process to manufacture lumateperone intermediates with high yield, low impurities, and wherein the reaction crude is easy to handle industrially (e.g., considering reactors and work-up) and with safe and mild reactants that are easy to separate from the desired product. Summary of the Invention
One aspect of the invention is a process for the preparation of a compound of formula I comprising the step of reacting a compound of formula II in the presence of at least a catalyst, at least a ligand, at a least base, and at least an organic solvent to give a compound of formula I; wherein the ligand comprises one or more compounds of formula IV or 2,2'-bipyridyl (13): A is H or halogen;
B is a protective group;
Z is CR5R6, C=O, C=NR7, or C=S;
LG is selected from F, Cl, Br, or I; each R1, R3, R4, R5, R6, R7 is independently H, D, or linear or branched Ci ealkyl, optionally with one or more H substituted by D; and
R2 is linear or branched Ci ealkyl, optionally with one or more H substituted by D. Another aspect of the invention is a compound of formula lla-Br:
Detailed description of the invention
In the product obtained using the process of the invention a number of major impurities have been identified:
Impurity A has the chemical name ethyl (4aS,9bR)-6-iodo-5-(2-(methylamino)-2-oxoethyl)- 1 ,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate. This product has been characterized only by mass spectroscopy (MS). Impurity B is a derivative of la wherein according to its Mw, two hydrogens have been lost. This product has been characterized only by mass spectroscopy (MS).
Impurity lla-Br has the chemical name ethyl (4aS,9bR)-5-(2-(methylamino)-2-oxoethyl)-1 , 3, 4, 4a, 5,9b- hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate. This product has been characterized only by mass spectroscopy (MS). Impurity C is a derivative of la wherein according to its Mw, two hydrogens have been lost and one oxygen gained. This product has been characterized only by mass spectroscopy (MS).
The process of the invention is a preparation of a compound of formula I comprising the step of reacting a compound of formula II in the presence of at least a catalyst, at least a ligand, at a least base, and at least an organic solvent to give a compound of formula I, wherein the ligand comprises one or more compounds of formula IV or 2,2'-bipyridyl (13):
A is H or halogen;
B is a protective group;
Z is CR5R6, C=O, C=NR7, or C=S;
LG is selected from F, Cl, Br, or I; each R1, R3, R4, R5, R6, R7 is independently H, D, or linear or branched Ci ealkyl, optionally with one or more H substituted by D; and
R2 is linear or branched Ci ealkyl, optionally with one or more H substituted by D.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, A is H.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the protective group B is selected from -Bn, and -P-Q, wherein P is -C(O)-, -C(O)O-, or -S(O)2- and Q is alkyl or arylalkyl.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the protective group B is -P-Q wherein P is -C(O)O-, and Q is ethyl.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, R1 is CH3.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, Z is C=O.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, R3 and R4 are both H.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, LG is Br.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the compound of formula II is the compound of formula Ila:
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the ligand comprises a ligand of formula IV selected from 1 -methylimidazole (7), 1 -ethylimidazole, 1 -propylimidazole, 1 -isopropylimidazole (18), 1 -butylimidazole, and mixtures thereof.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the ligand comprises a ligand selected from 1 -methylimidazole (7), 1 -isopropylimidazole (18), and mixtures thereof.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the ligand comprises 1 -methylimidazole (7).
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the ligand comprises 2,2'-bipyridyl (13).
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the process includes removal of water.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the removal of water is via azeotropic distillation. In a particular embodiment of the process, in combination with any of the embodiments of the invention, the ligand is in a ratio of 0.1 to 0.5 equivalents (eq) in relation to compound of formula II.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the ligand is in a ratio of 0.10 to 0.2 equivalents (eq) in relation to compound of formula II.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the ligand is in a ratio of 0.35 to 0.45 equivalents (eq) in relation to compound of formula II.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the catalyst comprises a transition metal catalyst selected from the group consisting of metals of groups 8- 11 of the periodic table of the elements.
The elements of group 8 are iron (Fe), ruthenium (Ru), and osmium (Os).
The elements of group 9 are cobalt (Co), rhodium (Rh), and iridium (Ir).
The elements of group 10 are nickel (Ni), palladium (Pd), and platinum (Pt).
The elements of group 11 are copper (Cu), silver (Ag), and gold (Au).
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the transition metal catalyst is selected from Cu, Pd, Pt, and mixtures thereof.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the transition metal catalyst comprises Cu(l).
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the transition metal catalyst is in a ratio of 0.1 to 0.3 equivalents (eq) in relation to compound of formula II.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the base is selected from IJ2CO3, Na2CO3, K2CO3, Rb2CO3, CS2CO3, LifBuO, NaTiuO, KfBuO, RbTiuO, CsTiuO, one or more compounds of formula IV as defined in embodiment 1 , 2,2'-bipyridyl (13), and mixtures thereof.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the base is selected from IJ2CO3, Na2CO3, K2CO3, Rb2CO3, CS2CO3, and mixtures thereof.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the base is K2CO3.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the base is in a ratio of 2 to 3 equivalents (eq) in relation to the compound of formula II.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, at least 50 % of particles of the base have a particle size lower than 58 pm, measured using granulometry with a 270 mesh.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the organic solvent is selected from toluene, dioxane, dimethylformamide (DMF), dimethyl sulphoxide (DMSO), dimethylacetamide (DMAc), and mixtures thereof.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the organic solvent is selected from toluene, dioxane, and mixtures thereof.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the organic solvent is toluene.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the organic solvent is in a ratio of 1 to 2 mL/mmol in relation to the compound of formula II.
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the compound of formula II is Ila and the compound of formula I is la and the ligand is selected from 1 -methylimidazole (7) or 2,2'-bipyridyl (13).
In a particular embodiment of the process, in combination with any of the embodiments of the invention, the process further comprises reacting a compound of formula la thus obtained with 4-chloro-1-(4- fluorophenyl)butan-1 -one (IV) to yield lumateperone Illa.
The invention is as well directed to a compound of formula lla-Br:
The invention is as well directed to the use of a compound of formula lla-Br: as analytical standard. The invention is as well directed to a compound of formula A:
The invention is as well directed to a compound of formula A: as analytical standard. Further aspects and embodiments of the present invention are described in the following clauses below:
Clause 1 . A process for the preparation of a compound of formula I comprising the step of reacting a compound of formula II
B
H
Y Y 7 \j^-N H
LG ZCR3R4
Z
NHR1
(H) in the presence of at least a catalyst, at least a ligand, at a least base, and at least an organic solvent to give a compound of formula I, wherein the ligand comprises one or more compounds of formula IV or 2,2'-bipyridyl (13):
A is H or halogen;
B is a protective group;
Z is CR5R6, C=O, C=NR7, or C=S;
LG is selected from F, Cl, Br, or I; each R1, R3, R4, R5, R6, R7 is independently H, D, or linear or branched Ci ealkyl, optionally with one or more
H substituted by D; and
R2 is linear or branched Ci ealkyl, optionally with one or more H substituted by D.
Clause 2. The process according to the previous clause, wherein A is H.
Clause 3. The process according to any of the previous clauses, wherein the protective group B is selected from -Bn, and -P-Q, wherein P is -C(O)-, -C(O)O-, or -S(O)2- and Q is alkyl or arylalkyl.
Clause 4. The process according to the previous clauses, wherein the protective group B is -P-Q wherein P is -C(O)O-, and Q is ethyl.
Clause 5. The process according to any of the previous clauses, wherein R1 is CH3. Clause 6. The process according to any of the previous clauses, wherein Z is C=O.
Clause 7. The process according to any of the previous clauses, wherein R3 and R4 are both H.
Clause 8. The process according to any of the previous clauses, wherein LG is Br.
Clause 9. The process according to any of the previous clauses, wherein the compound of formula II is the compound of formula Ila:
Clause 10. The process according to any of the previous clauses, wherein the ligand comprises a ligand of formula IV selected from 1 -methylimidazole (7), 1 -ethylimidazole, 1 -propylimidazole, 1 -isopropylimidazole (18), 1 -butylimidazole, and mixtures thereof. Clause 11 . The process according to the previous clauses, wherein the ligand comprises a ligand selected from 1 -methylimidazole (7), 1 -isopropylimidazole (18), and mixtures thereof.
Clause 12. The process according to the previous clauses, wherein the ligand comprises 1 -methylimidazole (7).
Clause 13. The process according to any of the previous clauses, wherein the ligand comprises 2,2'-bipyridyl (13).
Clause 14. The process according to any of the previous clauses, wherein the process includes removal of water.
Clause 15. The process according to the previous clause, wherein the removal of water is via azeotropic distillation. Clause 16. The process according to any of the previous clauses, wherein the ligand is in a ratio of 0.1 to 0.5 equivalents (eq) in relation to compound of formula II.
Clause 17. The process according to the previous clause, wherein the ligand is in a ratio of 0.10 to 0.2 equivalents (eq) in relation to compound of formula II.
Clause 18. The process according to Clause 16, wherein the ligand is in a ratio of 0.35 to 0.45 equivalents (eq) in relation to compound of formula II.
Clause 19. The process according to any of the previous clauses, wherein the catalyst comprises a transition metal catalyst selected from the group consisting of metals of groups 8-11 of the periodic table.
Clause 20. The process according to the previous clause, wherein the transition metal catalyst is selected from Cu, Pd, Pt, and mixtures thereof.
Clause 21 . The process according to the previous clause, wherein the transition metal catalyst comprises Cu(l).
Clause 22. The process according to any of the Clause 19 to Clause 21 , wherein the transition metal catalyst is in a ratio of 0.1 to 0.3 equivalents (eq) in relation to compound of formula II.
Clause 23. The process according to any of the previous clauses, wherein the base is selected from IJ2CO3, Na2CO3, K2CO3, Rb2CO3, CS2CO3, LifBuO, NaTiuO, KfBuO, RbTiuO, CsTiuO, one or more compounds of formula IV as defined in claim 1 , 2,2'-bipyridyl (13), and mixtures thereof.
Clause 24. The process according to the previous clause, wherein the base is selected from IJ2CO3, Na2CO3, K2CO3, Rb2CO3, CS2CO3, and mixtures thereof.
Clause 25. The process according to the previous clauses, wherein the base is K2CO3.
Clause 26. The process according to any of the Clause 24 to Clause 25, wherein the base is in a ratio of 2 to 3 equivalents (eq) in relation to the compound of formula II.
Clause 27. The process according to any of the Clause 24 to Clause 26, wherein at least 50 % of particles of the base have a particle size lower than 58 pm, measured using granulometry with a 270 mesh. Clause 28. The process according to any of the previous clauses, wherein the organic solvent is selected from toluene, dioxane, dimethylformamide (DMF), dimethyl sulphoxide (DMSO), dimethylacetamide (DMAc), and mixtures thereof.
Clause 29. The process according to the previous clauses, wherein the organic solvent is selected from toluene, dioxane, and mixtures thereof.
Clause 30. The process according to the previous clauses, wherein the organic solvent is toluene.
Clause 31 . The process according to any of the Clause 28 to Clause 30, wherein the organic solvent is in a ratio of 1 to 2 mL/mmol in relation to the compound of formula II.
Clause 32. The process according to any of the previous clauses, wherein the compound of formula II is Ila and the compound of formula I is la and the ligand is selected from 1 -methylimidazole (7) or 2,2'-bipyridyl (13).
Clause 33. The process according to any of the previous clauses, further comprising reacting a compound of formula la thus obtained with 4-chloro-1 -(4-fluorophenyl)butan-1 -one (IV) to yield lumateperone Illa.
Clause 34. A compound of formula lla-Br:
Clause 35. The use of a compound of formula lla-Br: as analytical standard. Clause 36. A compound of formula A:
Clause 37. The use of a compound of formula A: as analytical standard. Literature
Kaupmees 2014: Kaupmees, K.; Trummal, A.; Leito, I. (2014). "Basicities of Strong Bases in Water: A
Computational Study". Croat. Chem. Acta. 87 (4): 385-395. doi 10.5562/cca2472. Examples
Table 1: ligands
Method 1: HPLC method C18 2.5 pm (4.6x75 mm) column eluted with a mixture of ammonia buffer (ammonium formate pH 10.0 adjusted with ammonia) and acetonitrile 85:15 to 30:70 at a flow rate of 1.0mL/min, 40°C of column temperature and 240 nm detection. Finally, 2.0pL are injected into the chromatographic system.
Comparative Example 1: Production of ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro- 1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (la)
For each test (T), ethyl (4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1 ,3,4,4a,5,9b-hexahydro- 2H-pyrido[4,3-b]indole-2-carboxylate Ila (1 eq) and potassium carbonate (2.2 eq) are suspended in toluene (1.19 mL/mmol) at 20-25 °C under nitrogen atmosphere. Optionally, the reaction mixture is heated with a Dean-Stark at 110 °C for 2 hours approximately, until no further water is collected by the azeotropic distillation. After cooling the reaction mixture to 25 °C, cooper iodide (0.2 eq) and a ligand L (0.4 eq) indicated in Table 1 according to the following table were added maintaining nitrogen atmosphere. Then, the reaction mixture is heated to reflux until it is substantially complete (<1 % of ethyl (4aS,9bR)-6-bromo-5-(2- (methylamino)-2-oxoethyl)-1 , 3,4,4a, 5, 9b-hexahydro-2H-pyrido[4, 3-b]i ndole-2-carboxylate Ila analysed by Method 1). Once finished, the reaction mixture was cooled to 20-25 °C and 7.5 volumes of heptanes were added with stirring. After 2 hours of stirring, the resulting suspension was filtered. The afforded solid was resuspended in 6 volumes of 25 % ammonium hydroxide solution and stirred for 1 hour. Then, the suspension was filtered and the solid obtained was washed once with 4 volumes of water. This procedure was repeated one additional time under the same conditions. The solid is dried under vacuum to provide ethyl (6bR,10aS)- 3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1 /-/-pyrido[3',4':4,5]pyrrolo[1 ,2,3-cte] quinoxaline-8(7H)- carboxylate la. The mixture was analysed by Method 1 and only purified to obtain the yield when indicated.
None of the tested ligands in the following table resulted in the reaction having good yield, low impurities, and ease of purification of the final products. With DBU (8) the reaction shows good yield but when sampled, the sample, as well as the reaction mixture, turns dark. Furthermore, when the reaction is finished and the reaction mixture contacts air, the mixture turns dark which results in a difficult work-up.
Example 1: Production of ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H- pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (la)
Using the same procedure as in Comparative Example 1 several tests (T) have been carried out using the ligands (L) indicated in the following table. It was found that the use of 1 -methylimidazole (7), 1- isopropylimidazole (18), and 2, 2'-bi pyridyl (13) at a wide range of scales (10 g to 1400 g) resulted in good conversion, yield, and high purity of the resulting product with easier work-up.
AD; Azeotropic distillation; A: Intermediate; B & C: impurities; ND: Not detected; $ 0.15 equivalents of ligand (L); ** % by Method 1 in the final mixture.

Claims

Claims
1 . A process for the preparation of a compound of formula I comprising the step of reacting a compound of formula II in the presence of at least a catalyst, at least a ligand, at a least base, and at least an organic solvent to give a compound of formula I, wherein the ligand comprises one or more compounds of formula IV or 2,2'-bipyridyl (13): A is H or halogen;
B is a protective group;
Z is CR5R6, C=O, C=NR7, or C=S;
LG is selected from F, Cl, Br, or I; each R1, R3, R4, R5, R6, R7 is independently H, D, or linear or branched Ci ealkyl, optionally with one or more H substituted by D; and
R2 is linear or branched Ci ealkyl, optionally with one or more H substituted by D.
2. The process according to any of the previous claims, wherein the compound of formula II is the compound of formula Ila:
3. The process according to any of the previous claims, wherein the ligand comprises a ligand of formula IV selected from 1 -methylimidazole (7), 1 -ethylimidazole, 1 -propylimidazole, 1 -isopropylimidazole (18),
1 -butylimidazole, and mixtures thereof.
4. The process according to the previous claim, wherein the ligand comprises a ligand selected from
1 -methylimidazole (7), 1 -isopropylimidazole (18), and mixtures thereof.
5. The process according to the previous claim, wherein the ligand comprises 1 -methylimidazole (7).
6. The process according to any of the previous claims, wherein the ligand comprises 2,2'-bipyridyl (13).
7. The process according to any of the previous claims, wherein the process includes removal of water.
8. The process according to the previous claim, wherein the removal of water is via azeotropic distillation.
9. The process according to any of the previous claims, wherein the ligand is in a ratio of 0.1 to 0.5 equivalents (eq) in relation to compound of formula II.
10.The process according to any of the previous claims, wherein the catalyst comprises a transition metal catalyst selected from Cu, Pd, Pt, and mixtures thereof.
11 .The process according to the previous claim, wherein the transition metal catalyst comprises Cu(l).
12.The process according to any of the previous claims, wherein the base is selected from IJ2CO3, Na2COs, K2CO3, Rb2CO3, CS2CO3, LifBuO, NaTiuO, KfBuO, RbTiuO, CsTiuO, one or more compounds of formula IV as defined in claim 1 , 2,2'-bipyridyl (13), and mixtures thereof.
13. The process according to any of the previous claims, wherein the organic solvent is selected from toluene, dioxane, dimethylformamide (DMF), dimethyl sulphoxide (DMSO), dimethylacetamide (DMAc), and mixtures thereof.
14.The process according to any of the previous claims, wherein the compound of formula II is Ila and the compound of formula I is la and the ligand is selected from 1 -methylimidazole (7) or 2,2'-bipyridyl (13).
15.The process according to any of the claims 1 -14, further comprising reacting a compound of formula la thus obtained with 4-chloro-1 -(4-fluorophenyl)butan-1 -one (IV) to yield lumateperone Illa.
PCT/EP2025/065936 2024-06-10 2025-06-06 Process for the preparation of synthesis intermediates of lumateperone and lumateperone analogues Pending WO2025257090A1 (en)

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