# US 12,215,114 B2 · Processes and intermediates for producing diazaspiro lactam compounds

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- Number: US 12,215,114 B2
- Document ID: US12215114B2
- Status: Granted
- Kind: B2
- Application number: 17/621,905
- Filed: 2020-06-23
- Published: 2022-08-18
- Granted: 2025-02-04
- Earliest claimed: 2019-06-24
- Assignees: Naurex, Inc.
- Applicants: Naurex Inc.
- Inventors: Danny T. Dinh; William R. Perrault; Khalid Diker
- Web page: https://patentgrep.com/patent/US12215114B2

## CPC

- C07D 487/10: Spiro-condensed systems
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 498/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Processes for producing diazaspiro lactam compounds and intermediates useful in the processes.

## Claims

### Claim 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:
Rb is selected from H, halogen, cyano and C1-C6 alkyl;
R1 is H or C1-C6 alkyl;
R2 is H or C1-C6 alkyl;
R3 is selected from C1-C6 alkyl and C(O)OR8;
R8 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, and —CH2—C3-C10 cycloalkyl, wherein C3-C10 cycloalkyl is optionally substituted with one, two, or three groups selected from C1-C3 alkyl;
R4 and R5 are independently selected from H, C1-C6 alkyl, X, and C1-C6 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(C1-C3 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(C1-C3alkyl), O, and S; and
(iv) phenyl;
wherein C3-C6 cycloalkyl, heterocyclyl, heteroaryl, and phenyl are each optionally substituted with one, two, or three substituents independently selected halogen, cyano, C1-C6 alkyl, hydroxyl, and C1-C6 alkoxy:
or R4 and R5 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 R4 and R5), and the second ring heteroatom, when present, is independently selected from N—C1-C6 alkyl, O and S; and wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy;
R6 is selected from —OH, C1-C6 alkoxy, —OC(O)—C1-C6 alkyl, and —OC(O)phenyl; and
R7 is H or C1-C6 alkyl.

### Claim 2 (depends on 1)

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).

### Claim 3 (depends on 1)

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).

### Claim 4 (depends on 1)

The process of claim 1, wherein the coupling agent comprises a di-C1-C6 alkyl halophosphate, a dialkyl phosphinic halide, or propanephosphonic acid anhydride.

### Claim 5 (depends on 4)

The process of claim 4, wherein the coupling agent comprises diethyl chlorophosphite.

### Claim 6 (depends on 1)

The process of claim 1, wherein the coupling agent is used together with an organic base, the organic base comprising an amine.

### Claim 7 (depends on 6)

The process of claim 6, wherein the amine is triethyl amine, N,N-Diisopropylethylamine (DIPEA), or 4-Dimethylaminopyridine (DMAP).

### Claim 8 (depends on 1)

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).

### Claim 9 (depends on 1)

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, R1, R2, R3, R4, R5, R6, and R7 are the same as described in claims 1, and R9 is —CCl3:

### Claim 10 (depends on 9)

The process of claim 9, wherein the base comprises an amine, the solvent is an aqueous solvent, the alkylating agent is C1-C6 alkyl-halide, and the carbamating agent is di-R8-dicarbonate.

### Claim 11 (depends on 1, 9)

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, R1, R2, R3, R4, R5, R6, and R7 are as defined in claims 1, and R9 is —CCl3.

### Claim 12 (depends on 11)

The process of claim 11, wherein the solvent for the condensation reaction comprises dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, or toluene.

### Claim 13 (depends on 11)

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), NBu4BH4, NaCNBH3, and NMe4BH (OAc)3.

### Claim 14 (depends on 1, 11)

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 R2COOR to obtain the compound of formula VII, wherein R is methyl or ethyl, Rb, R1, and R2 are as defined in claim 1, and R9 is —CCl3:

### Claim 15 (depends on 14)

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.

### Claim 16 (depends on 1, 14)

The process of claim 14, further comprising contacting a compound of formula X with an aldehyde R9CHO, or hydrate thereof, to obtain a compound of formula IX, wherein Rb and R1 are as defined in claims 1, and R9 is —CCl3:

### Claim 17 (depends on 16)

The process of claim 16, wherein the solvent used to obtain the compound of formula IX comprises THF, acetonitrile, or toluene.

### Claim 18 (depends on 1)

The process of claim 1, wherein:
Rb is selected from H, halogen, cyano and C1-C6 alkyl;
R1 is H or C1-C6 alkyl;
R2 is H or C1-C6 alkyl;
R3 is selected from C1-C6 alkyl and C (O) OR8;
R8 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, and —CH2—C3—C10 cycloalkyl, wherein C3-C10 cycloalkyl is optionally substituted with one, two, or three groups selected from C1-C3 alkyl;
R4 and R5 are independently selected from H and C1-C6 alkyl; or R4 and R5 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 R4 and R5), and the second ring heteroatom, when present, is independently selected from N—C1-C6 alkyl, O and S; and wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy;
R6 is selected from —OH, C1-C6 alkoxy, —OC(O)—C1-C6 alkyl, and —OC(O) phenyl; and
R7 is H or C1-C6 alkyl.

### Claim 19

A compound of formula II:
wherein:
Rb is selected from H, halogen, cyano and C1-C6 alkyl;
R1 is H or C1-C6 alkyl;
R2 is H or C1-C6 alkyl;
R3 is selected from C1-C6 alkyl and C(O)OR8;
R8 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, and —CH2—C3—C10 cycloalkyl, wherein C3-C10 cycloalkyl is optionally substituted with one, two, or three groups selected from C1-C3 alkyl;
R4 and R5 are independently selected from H, C1-C6 alkyl, X, and —C1-C6 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 (C1-C3 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 (C1-C3 alkyl), O, and S; and
(iv) phenyl;
wherein C3-C6 cycloalkyl, heterocyclyl, heteroaryl, and phenyl are each optionally substituted with one, two, or three substituents independently selected halogen, cyano, C1-C6 alkyl, hydroxyl, and C1-C6 alkoxy;
or R4 and R5 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 R4 and R5), and the second ring heteroatom, when present, is independently selected from N—C1-C6 alkyl, O and S; and wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy;
R6 is selected from-OH, C1-C6 alkoxy, —OC(O) —C1-C6 alkyl, and —OC(O) phenyl; and
R7 is H or C1-C6 alkyl.

### Claim 20

A compound of formule III.
wherein:
Rb is selected from H, halogen, cyano and C1-C6 alkyl;
R1 is H or C1-C6 alkyl;
R2 is H or C1-C6 alkyl;
R8 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, and —CH2-C3-C10 cycloalkyl, wherein C3-C10 cycloalkyl is optionally substituted with one, two, or three groups selected from C1-C3 alkyl;
R4 and R5 are independently selected from H, C1-C6 alkyl, X, and —C1-C6 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 (C1-C3 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 (C1-C3 alkyl), O, and S; and
(iv) phenyl;
wherein C3-C6 cycloalkyl, heterocyclyl, heteroaryl, and phenyl are each optionally substituted with one, two, or three substituents independently selected halogen, cyano, C1-C6 alkyl, hydroxyl, and C1-C6 alkoxy;
or R4 and R5 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 R4 and R5), and the second ring heteroatom, when present, is independently selected from N—C1-C6 alkyl, O and S; and wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy;
R6 is selected from-OH, C1-C6 alkoxy, —OC(O)—C1-C6 alkyl, and —OC(O) phenyl; and
R7 is H or C1-C6 alkyl.