Processes and intermediates for producing diazaspiro lactam compounds
Processes for producing diazaspiro lactam compounds and intermediates useful in the processes.
1. A process of producing a compound of formula I or a pharmaceutically acceptable salt thereof, comprising contacting a compound of formula II with a coupling agent in an organic solvent to obtain a compound of formula I or a pharmaceutically acceptable salt thereof:
wherein:
R b is selected from H, halogen, cyano and C 1 -C 6 alkyl;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H or C 1 -C 6 alkyl;
R 3 is selected from C 1 -C 6 alkyl and C(O)OR 8 ;
R 8 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, and —CH 2 —C 3 -C 10 cycloalkyl, wherein C 3 -C 10 cycloalkyl is optionally substituted with one, two, or three groups selected from C 1 -C 3 alkyl;
R 4 and R 5 are independently selected from H, C 1 -C 6 alkyl, X, and C 1 -C 6 alkylene-X, wherein X is selected from:
(i) C 3 -C 6 cycloalkyl;
(ii) heteroaryl including from 5 to 6 ring atoms wherein one, two, or three of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S;
(iii) heterocyclyl including from three to six ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and
(iv) phenyl;
wherein C 3 -C 6 cycloalkyl, heterocyclyl, heteroaryl, and phenyl are each optionally substituted with one, two, or three substituents independently selected halogen, cyano, C 1 -C 6 alkyl, hydroxyl, and C 1 -C 6 alkoxy:
or R 4 and R 5 together with the nitrogen to which they are attached form heterocyclyl including from 4 to 6 ring atoms; wherein the heterocyclyl includes not more than two ring heteroatoms (including the nitrogen atom attached to R 4 and R 5 ), and the second ring heteroatom, when present, is independently selected from N—C 1 -C 6 alkyl, O and S; and wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
R 6 is selected from —OH, C 1 -C 6 alkoxy, —OC(O)—C 1 -C 6 alkyl, and —OC(O)phenyl; and
R 7 is H or C 1 -C 6 alkyl.
2. The process of claim 1 , wherein the coupling agent comprises at least one selected from (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP—Cl), O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TATU), O-(6-Chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HCTU), O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′-tetra methyluronium tetrafluoroborate (TOTU), (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), O—(N-Suc-cinimidyl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (TSTU), O-(5-Norbornene-2,3-dicarboximido)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TNTU), O-(1,2-Dihydro-2-oxo-1-pyridyl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TPTU), N,N,N′,N′-Tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uranium tetrafluoroborate (TDBTU), N,N,N′,N′-Tetramethylchloroformamidinium Hexafluorophosphate (TCFH), 3-(Diethylphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), and Carbonyldiimidazole (CDI).
3. The process of claim 1 , wherein the coupling agent comprises a carbodiimide optionally together with 1-hydroxybenzotriazole (HOBt) and the carbodiimide selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and ethyl-(N′,N′-dimethylamino) propylcarbodiimide hydrochloride (EDC).
4. The process of claim 1 , wherein the coupling agent comprises a di-C 1 -C 6 alkyl halophosphate, a dialkyl phosphinic halide, or propanephosphonic acid anhydride.
5. The process of claim 4 , wherein the coupling agent comprises diethyl chlorophosphite.
6. The process of claim 1 , wherein the coupling agent is used together with an organic base, the organic base comprising an amine.
7. The process of claim 6 , wherein the amine is triethyl amine, N,N-Diisopropylethylamine (DIPEA), or 4-Dimethylaminopyridine (DMAP).
8. The process of claim 1 , wherein the organic solvent comprises dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF), or 2-methyltetrahydrofuran (2-MeTHF).
9. The process of claim 1 , further comprising contacting a compound of formula IV with a base in a solvent to obtain a compound of formula III, wherein the compound of formula III is subsequently contacted with an alkylating agent or carbamating agent to obtain a compound of formula II, wherein Rb, R 1, R 2, R 3, R 4, R 5, R 6, and R 7 are the same as described in claims 1 , and R 9 is —CCl 3 :
10. The process of claim 9 , wherein the base comprises an amine, the solvent is an aqueous solvent, the alkylating agent is C 1 -C 6 alkyl-halide, and the carbamating agent is di-R 8 -dicarbonate.
11. The process of claim 9 , further comprising contacting a compound of formula VII with an amine of formula VIII to obtain a condensed product of formula V or VI, which is subsequently contacted with a reducing agent to obtain a compound of formula IV, wherein Rb, R 1, R 2, R 3, R 4, R 5, R 6, and R 7 are as defined in claims 1 , and R 9 is —CCl 3 .
12. The process of claim 11 , wherein the solvent for the condensation reaction comprises dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, or toluene.
13. The process of claim 11 , wherein the reducing agent comprises a boron hydride selected from sodium borohydride, lithium borohydride, calcium borohydride, magnesium borohydride, sodium triacetoxyborohydride (NaBH (OAc) 3 ), NBu 4 BH 4 , NaCNBH 3 , and NMe 4 BH (OAc) 3 .
14. The process of claim 11 , further comprising contacting a compound of formula IX with a base to deprotonate the a carbon next to a carbonyl (CO) in a solvent, which is subsequently followed by addition of R 2 COOR to obtain the compound of formula VII, wherein R is methyl or ethyl, R b , R 1, and R 2 are as defined in claim 1 , and R 9 is —CCl 3 :
15. The process of claim 14 , wherein the deprotonation is conducted at a temperature of −80 to −20° C., the base comprises lithium diisopropylamide, and the solvent comprises toluene optionally mixed with methyl tert-butyl ether (MTBE), THE optionally mixed with toluene or MTBE, or 2-MeTHE optionally mixed with toluene or MTBE.
16. The process of claim 14 , further comprising contacting a compound of formula X with an aldehyde R 9 CHO, or hydrate thereof, to obtain a compound of formula IX, wherein R b and R 1 are as defined in claims 1 , and R 9 is —CCl 3 :
17. The process of claim 16 , wherein the solvent used to obtain the compound of formula IX comprises THF, acetonitrile, or toluene.
18. The process of claim 1 , wherein:
R b is selected from H, halogen, cyano and C 1 -C 6 alkyl;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H or C 1 -C 6 alkyl;
R 3 is selected from C 1 -C 6 alkyl and C (O) OR 8 ;
R 8 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, and —CH 2 —C 3 —C 10 cycloalkyl, wherein C 3 -C 10 cycloalkyl is optionally substituted with one, two, or three groups selected from C 1 -C 3 alkyl;
R 4 and R 5 are independently selected from H and C 1 -C 6 alkyl; or R 4 and R 5 together with the nitrogen to which they are attached form heterocyclyl including from 4 to 6 ring atoms; wherein the heterocyclyl includes not more than two ring heteroatoms (including the nitrogen atom attached to R 4 and R 5 ), and the second ring heteroatom, when present, is independently selected from N—C 1 -C 6 alkyl, O and S; and wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
R 6 is selected from —OH, C 1 -C 6 alkoxy, —OC(O)—C 1 -C 6 alkyl, and —OC(O) phenyl; and
R 7 is H or C 1 -C 6 alkyl.
19. A compound of formula II:
wherein:
R b is selected from H, halogen, cyano and C 1 -C 6 alkyl;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H or C 1 -C 6 alkyl;
R 3 is selected from C 1 -C 6 alkyl and C(O)OR 8 ;
R 8 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, and —CH2—C 3 —C 10 cycloalkyl, wherein C 3 -C 10 cycloalkyl is optionally substituted with one, two, or three groups selected from C 1 -C 3 alkyl;
R 4 and R 5 are independently selected from H, C 1 -C 6 alkyl, X, and —C 1 -C 6 alkylene-X, wherein X is selected from
(i) C3-C6 cycloalkyl;
(ii) heteroaryl including from 5 to 6 ring atoms wherein one, two, or three of the ring atoms are independently selected from N, NH, N (C 1 -C 3 alkyl), O, and S;
(iii) heterocyclyl including from three to six ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from N, NH, N (C 1 -C 3 alkyl), O, and S; and
(iv) phenyl;
wherein C 3 -C 6 cycloalkyl, heterocyclyl, heteroaryl, and phenyl are each optionally substituted with one, two, or three substituents independently selected halogen, cyano, C 1 -C 6 alkyl, hydroxyl, and C 1 -C 6 alkoxy;
or R 4 and R 5 together with the nitrogen to which they are attached form heterocyclyl including from 4 to 6 ring atoms; wherein the heterocyclyl includes not more than two ring heteroatoms (including the nitrogen atom attached to R 4 and R 5 ), and the second ring heteroatom, when present, is independently selected from N—C 1 -C 6 alkyl, O and S; and wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
R 6 is selected from-OH, C 1 -C 6 alkoxy, —OC(O) —C 1 -C 6 alkyl, and —OC(O) phenyl; and
R 7 is H or C 1 -C 6 alkyl.
20. A compound of formule III.
wherein:
R b is selected from H, halogen, cyano and C 1 -C 6 alkyl;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H or C 1 -C 6 alkyl;
R 8 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, and —CH 2 -C 3 -C 10 cycloalkyl, wherein C 3 -C 10 cycloalkyl is optionally substituted with one, two, or three groups selected from C1-C3 alkyl;
R 4 and R 5 are independently selected from H, C 1 -C 6 alkyl, X, and —C 1 -C 6 alkylene-X, wherein X is selected from
(i) C3-C6 cycloalkyl;
(ii) heteroaryl including from 5 to 6 ring atoms wherein one, two, or three of the ring atoms are independently selected from N, NH, N (C 1 -C 3 alkyl), O, and S;
(iii) heterocyclyl including from three to six ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from N, NH, N (C 1 -C 3 alkyl), O, and S; and
(iv) phenyl;
wherein C 3 -C 6 cycloalkyl, heterocyclyl, heteroaryl, and phenyl are each optionally substituted with one, two, or three substituents independently selected halogen, cyano, C 1 -C 6 alkyl, hydroxyl, and C 1 -C 6 alkoxy;
or R 4 and R 5 together with the nitrogen to which they are attached form heterocyclyl including from 4 to 6 ring atoms; wherein the heterocyclyl includes not more than two ring heteroatoms (including the nitrogen atom attached to R 4 and R 5 ), and the second ring heteroatom, when present, is independently selected from N—C 1 -C 6 alkyl, O and S; and wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
R 6 is selected from-OH, C 1 -C 6 alkoxy, —OC(O)—C 1 -C 6 alkyl, and —OC(O) phenyl; and
R 7 is H or C 1 -C 6 alkyl.