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US 11,478,481 B2Granted
Process for preparation of optically pure and optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives and their use in preparing pharmaceuticals
AssigneeRhizen Pharmaceuticals SA
InventorsJayaraman V. Raman, Swaroop K. Vakkalanka
Life of this patent
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Abstract
The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives represented by formula (IA) and (IB), processes for preparing the alcohol derivatives and their use in preparing pharmaceuticals.
Claims5
A process for preparing a PI3K inhibitor of formula (I)
- or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
- each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COORx, —C(O)Rx, —C(S)Rx, —C(O)NRxRy, —C(O)ONRxRy, —NRxRy, —NRxCONRxRy, —N(Rx)SORx, —N(Rx)SO2Ry, —NRxC(O)ORy, —NRxC(O)Ry, —NRxC(S)Ry, —NRxC(S)NRxRy, —SONRxRy, —SO2NRxRy, —ORx, —ORxC(O)NRxRy, —ORxC(O)ORx, —OC(O)Rx, —OC(O)NRxRy, —RxNRyC(O)Rz, —RxORy, —RxC(O)ORy, —RxC(O)NRxRy, —RxC(O)Ry, —RxOC(O)Ry, —SRx, —SORx, —SO2Rx, and —ONO2, wherein each occurrence of Rx, Ry and Rz is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of Rx and Ry, when bound to a common atom, are joined to form a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NRz or S, or (ii) any two of Rx and Ry, when bound to a common atom, are joined to form an oxo (═O), thio (═S) or imino (═NRf) (wherein Rf is hydrogen or substituted or unsubstituted alkyl);
- R1 is substituted or unsubstituted C1-6 alkyl;
- Cy1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
- n is an integer selected from 0, 1, 2, 3 or 4;
- Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
- L1 is absent;
- each occurrence of Ra and Rb may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, —NRcRd (wherein Rc and Rd are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, or (C1-6)alkoxy) and —ORc (wherein Rc is substituted or unsubstituted (C1-6)alkyl) or when Ra and Rb are directly bound to a common atom, they may be joined to form an oxo group (═O) or form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring (including the common atom to which Ra and Rb are directly bound), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRd (wherein Rd is hydrogen or substituted or unsubstituted (C1-6)alkyl) or S;
- Y is selected from 0, S, and NRa;
- and
- q is 0, 1 or 2,
- the process comprising
- (a) treating a compound of formula (IA)
- where variables R, n, Cy1, and R1 are as defined above, with Cy2-H to give the desired compound of formula (I) or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof;
- and
- (b) optionally converting the compound of formula (I) to a salt of the compound.
13 more elements
A process for preparing a PI3K inhibitor of formula (I)
- or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
- each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COORx, —C(O)Rx, —C(S)Rx, —C(O)NRxRy, —C(O)ONRxRy, —NRxRy, —NRxCONRxRy, —N(Rx)SORx, —N(Rx)SO2Ry, —NRxC(O)ORy, —NRxC(O)Ry, —NRxC(S)Ry, —NRxC(S)NRxRy, —SONRxRy, —SO2NRxRy, —ORx, —ORxC(O)NRxRy, —ORxC(O)ORx, —OC(O)Rx, —OC(O)NRxRy, —RxNRyC(O)Rz, —RxORy, —RxC(O)ORy, —RxC(O)NRxRy, —RxC(O)Ry, —RxOC(O)Ry, —SRx, —SORx, —SO2Rx, and —ONO2, wherein each occurrence of Rx, Ry and Rz is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of Rx and Ry, when bound to a common atom, are joined to form a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NRz or S, or (ii) any two of Rx and Ry, when bound to a common atom, are joined to form an oxo (═O), thio (═S) or imino (═NRf) (wherein Rf is hydrogen or substituted or unsubstituted alkyl);
- R1 is substituted or unsubstituted C1-6 alkyl;
- Cy1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
- n is an integer selected from 0, 1, 2, 3 or 4;
- Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
- L1 is absent;
- each occurrence of Ra and Rb may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, —NRcRd (wherein Rc and Rd are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, or (C1-6)alkoxy) and —ORc (wherein Rc is substituted or unsubstituted (C1-6)alkyl) or when Ra and Rb are directly bound to a common atom, they may be joined to form an oxo group (═O) or form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring (including the common atom to which Ra and Rb are directly bound), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRd (wherein Rd is hydrogen or substituted or unsubstituted (C1-6)alkyl) or S;
- Y is selected from O, S, and NRa;
- and
- q is 0, 1 or 2,
- the process comprising
- (a) treating a compound of formula (IA)
- where variables R, n, Cy1, and R1 are as defined above, with mesyl halide in the presence of a base to give a compound of formula (8a)
- wherein X1 is —O-Mesyl;
- and
- (b) reacting the compound of formula (8a) with Cy2-H in the presence of a base to give the desired compound of formula (I) or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof;
- and
- (c) optionally, converting the compound of formula (I) to a salt of the compound.
16 more elements
A process for preparing a PI3K inhibitor of formula (III)
- or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
- each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COORx, —C(O)Rx, —C(S)Rx, —C(O)NRxRy, —C(O)ONRxRy, —NRxRy, —NRxCONRxRy, —N(Rx)SORx, —N(Rx)SO2Ry, —NRxC(O)ORy, —NRxC(O)Ry, —NRxC(S)Ry, —NRxC(S)NRxRy, —SONRxRy, —SO2NRxRy, —ORx, —ORxC(O)NRxRy, —ORxC(O)ORx, —OC(O)Rx, —OC(O)NRxRy, —RxNRyC(O)Rz, —RxORy, —RxC(O)ORy, —RxC(O)NRxRy, —RxC(O)Ry, —RxOC(O)Ry, —SRx, —SORx, —SO2Rx, and —ONO2, wherein each occurrence of Rx, Ry and Rz is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of Rx and Ry, when bound to a common atom, are joined to form a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NRz or S, or (ii) any two of Rx and Ry, when bound to a common atom, are joined to form an oxo (═O), thio (═S) or imino (═NRf) (wherein Rf is hydrogen or substituted or unsubstituted alkyl);
- R1 is substituted or unsubstituted C1-6 alkyl;
- Cy1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
- n is an integer selected from 0, 1, 2, 3 or 4;
- Cyt is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
- L1 is absent;
- each occurrence of Ra and Rb may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, —NRcRd (wherein Rc and Rd are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, or (C1-6)alkoxy) and —ORc (wherein Rc is substituted or unsubstituted (C1-6)alkyl) or when Ra and Rb are directly bound to a common atom, they may be joined to form an oxo group (═O) or form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring (including the common atom to which Ra and Rb are directly bound), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRd (wherein Rd is hydrogen or substituted or unsubstituted (C1-6)alkyl) or S;
- Y is selected from O, S, and NRa;
- and
- q is 0, 1 or 2,
- the process comprising
- (a) treating a compound of formula (IB)
- where variables R, n, Cy1, and R1 are as defined above, with Cy2-H to give the desired compound of formula (III) or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof;
- and
- (b) optionally converting the compound of formula (III) to a salt of the compound.
13 more elements
A process for preparing a PI3K inhibitor of formula (III)
- or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
- each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COORx, —C(O)Rx, —C(S)Rx, —C(O)NRxRy, —C(O)ONRxRy, —NRxRy, —NRxCONRxRy, —N(Rx)SORx, —N(Rx)SO2Ry, —NRxC(O)ORy, —NRxC(O)Ry, —NRxC(S)Ry, —NRxC(S)NRxRy, —SONRxRy, —SO2NRxRy, —ORx, —ORxC(O)NRxRy, —ORxC(O)ORx, —OC(O)Rx, —OC(O)NRxRy, —RxNRyC(O)Rz, —RxORy, —RxC(O)ORy, —RxC(O)NRxRy, —RxC(O)Ry, —RxOC(O)Ry, —SRx, —SORx, —SO2Rx, and —ONO2, wherein each occurrence of Rx, Ry and Rz is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of Rx and Ry, when bound to a common atom, are joined to form a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NRz or S, or (ii) any two of Rx and Ry, when bound to a common atom, are joined to form an oxo (═O), thio (═S) or imino (═NRf) (wherein Rf is hydrogen or substituted or unsubstituted alkyl);
- R1 is substituted or unsubstituted C1-6 alkyl;
- Cy1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
- n is an integer selected from 0, 1, 2, 3 or 4;
- Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
- L1 is absent;
- each occurrence of Ra and Rb may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, —NRcRd (wherein Rc and Rd are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, or (C1-6)alkoxy) and —ORc (wherein Rc is substituted or unsubstituted (C1-6)alkyl) or when Ra and Rb are directly bound to a common atom, they may be joined to form an oxo group (═O) or form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring (including the common atom to which Ra and Rb are directly bound), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRd (wherein Rd is hydrogen or substituted or unsubstituted (C1-6)alkyl) or S;
- Y is selected from O, S, and NRa;
- and
- q is 0, 1 or 2,
- the process comprising
- (a) treating the compound of formula (IB)
- where variables R, n, Cy1, and R1 are as defined above, with a phosphorus halide or mesyl halide in the presence of a base to give a compound of formula (8b)
- wherein X1 is halogen or —O-Mesyl;
- and
- (b) reacting the compound of formula (8b) with Cy2-H in the presence of a base to give the desired compound of formula (III) or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable thereof;
- and
- (c) optionally, converting the compound of formula (III) to a salt of the compound.
16 more elements
A process for preparing a PI3K inhibitor of formula (I)
- or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
- each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COORx, —C(O)Rx, —C(S)Rx, —C(O)NRxRy, —C(O)ONRxRy, —NRxRy, —NRxCONRxRy, —N(Rx)SORx, —N(Rx)SO2Ry, —NRxC(O)ORy, —NRxC(O)Ry, —NRxC(S)Ry, —NRxC(S)NRxRy, —SONRxRy, —SO2NRxRy, —ORx, —ORxC(O)NRxRy, —ORxC(O)ORx, —OC(O)Rx, —OC(O)NRxRy, —RxNRyC(O)Rz, —RxORy, —RxC(O)ORy, —RxC(O)NRxRy, —RxC(O)Ry, —RxOC(O)Ry, —SRx, —SORx, —SO2Rx, and —ONO2, wherein each occurrence of Rx, Ry and Rz is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of Rx and Ry, when bound to a common atom, are joined to form a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NRz or S, or (ii) any two of Rx and Ry, when bound to a common atom, are joined to form an oxo (═O), thio (═S) or imino (═NRf) (wherein Rf is hydrogen or substituted or unsubstituted alkyl);
- R1 is substituted or unsubstituted C1-6 alkyl;
- Cy1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
- n is an integer selected from 0, 1, 2, 3 or 4;
- Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
- L1 is absent;
- each occurrence of Ra and Rb may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, —NRcRd (wherein Rc and Rd are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, or (C1-6)alkoxy) and —ORc (wherein Rc is substituted or unsubstituted (C1-6)alkyl) or when Ra and Rb are directly bound to a common atom, they may be joined to form an oxo group (═O) or form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring (including the common atom to which Ra and Rb are directly bound), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRd (wherein Rd is hydrogen or substituted or unsubstituted (C1-6)alkyl) or S;
- Y is selected from O, S, and NRa;
- and
- q is 0, 1 or 2,
- the process comprising
- (a) treating a compound of formula (IA)
- where variables R, n, Cy1, and R1 are as defined above, with a phosphorus halide in the presence of a base to give an intermediate halide compound;
- and
- (b) reacting the intermediate halide compound with Cy2-H in the presence of a base to give the desired compound of formula (I) or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof;
- and
- (c) optionally, converting the compound of formula (I) to a salt of the compound.
15 more elements
Dependencies are inferred from the claim text.