EA045257B1 - IMPROVED SYNTHESIS METHODS FOR OBTAINING CONDENSED HETEROCYCLIC COMPOUNDS AS OREXIN RECEPTOR MODULATORS - Google Patents

Description

Scope of the invention

The present invention relates to synthetic methods allowing to obtain the compound (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2 -fluoro-6-(2H1,2,3-triazol-2-yl)phenyl)methanone, used to modulate the orexin receptor and to treat diseases, disorders and conditions mediated by orexin receptor activity.

Prerequisites for creating the invention

Orexin (or hypocretin) signaling is mediated by two receptors and two peptide agonists. Two orexin peptides (orexin A and orexin B), hereinafter referred to as orexins, bind to two high-affinity receptors called orexin-1 and orexin-2 receptors. The orexin-1 receptor is selective for orexin A, whereas the orexin-2 receptor binds both orexins with similar affinities. Orexins are cleavage products of the same preproorexin gene. Central nervous system neurons expressing the preproorexin precursor from which orexin is formed are found in the perifornical nucleus, dorsal hypothalamus, and lateral hypothalamus (C. Peyron et al., J. Neurosci., 1998, 18(23), 9996-10015 ). Orexigenic cells in these nuclei project to many areas of the brain and extend rostrally to the olfactory bulbs and caudally to the spinal cord (van den Pol, A.N. et al., J. Neuroscience., 1999, 19(8), 3171-3182) .

The citation of a reference herein should not be construed as an admission that such reference indicates prior art of the present invention. All publications referenced herein are incorporated herein by reference in their entirety.

Substituted diazabicyclic compounds have been described as active agents in the central nervous system (international publication no. WO 2001081347, November 1, 2001; US 2002/0019388, February 14, 2002), and modulators of 7 acetylcholine receptors (US 2005/101602, May 12, 2005 US 2005/0065178, March 24, 2005 and Frost et al, Journal of Medicinal Chemistry, 2006, 49(26), 78437853), proline transporter inhibitors for the treatment of cognitive impairment (WO 2008067121, June 5, 2008 and for improving cognitive function (WO 2006 124897, November 23, 2006 and US 20060258672, November 16, 2006), as androgen receptor ligands for the treatment of androgen receptor-associated conditions, including cancer (WO 2009081197, July 2 2009), and as histone deacetylase inhibitors for the treatment of cancers, neurodegenerative diseases and autoimmune diseases (WO 20060123121, November 23, 2006).

It was found that among the developed compounds (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6- (2H-1,2,3-triazol-2-yl)phenyl)methanone acts as an inhibitor of the orexin-2 receptor and is used to treat sleep disorders and major depressive illness (US 8,653,263 B2).The original synthesis had a linear sequence of eight steps from commercially available 1-benzyl-1H-pyrrole-2,5-dione, including four protecting group manipulation steps (scheme below).

SOCI ₂ , subsequently amide coupling

Other multi-step efforts have been described to prepare the intermediate (3aR,6aS)-2- 1 045257

benzyloctahydropyrrolo[3,4-c]pyrrole, . (Org. Proc. Res. Dev. 2010, 18, 592 and J. Med. Chem.

2015, 55, 5620). However, for economical industrial production of (((3aR,6aS)-5-(4,6dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H -1,2,3-triazol-2yl)phenyl)methanone required an improved synthesis.

The purpose of the invention is to develop a method for producing (((3aR,6aS)-5-(4,6-dimethylpyrimidin2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-( 2H-1,2,3-triazol-2-yl)phenyl)methanone with fewer protecting group steps and a shorter overall reaction sequence to reduce production costs.

Summary of the invention

The invention includes a method for producing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H- 1,2,3-triazol-2-yl)phenyl)methanoneα

wherein the early insertion of the 4,6-dimethylpyrimid-2-yl group eliminates the need for three steps of protecting group manipulation, which reduces the linear sequence from the commercially available 1-benzyl-1H-pyrrole-2,5-dione to four steps.

In other embodiments, the protecting groups are completely eliminated and the linear sequence from the commercially available 1H-pyrrole-2,5-dione is reduced to three steps.

The invention includes a method for producing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2 yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H -1,2,3-triazol-2-yl)phenyl)methanone

wherein said method comprises the step described below: a) oxazolidination of (4,6dimethylpyrimidin-2-yl)glycine

wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

- 2 045257

Detailed Description of the Invention

The invention includes a method for producing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H- 1,2,3-triazol-2-yl)phenyl)methanone

wherein said method comprises the step described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine

wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(III)-ylX2-fluoro-6-( 2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method includes the steps described below:

a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine o ^N HO HN—('N wherein said oxazolidination is distinguished by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5 -she

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

with 1-benzyl-1H-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-Fluoro -6-(2H- 1,2,3-triazol-2yl)phenyl)methanone

wherein said method comprises the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine

- 3 045257 wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one with 1-benzyl-1H-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

c) reduction of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3 (2H,3aH)-dione

with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method comprises the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine

wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one with 1-benzyl-1H-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

- 4 045257

c) reduction of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3 (2H,3aH)-dione

with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4c]pyrrole

d) removal of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4c]pyrrole protecting groups

with the formation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

using 10% (w/w) Pd/C and ammonium formate.

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method comprises the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine

wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one with 1-benzyl-1H-pyrrole-2,5-dione

at temperatures above 250°C with the formation of yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidine-2 -

c) reduction of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

- 5 045257

d) deprotection of yl)octahydropyrrolo[3,4-c]pyrrole

groups (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-

with the formation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole hn 1 /) m—K H X using 10% (w/w) Pd/C and ammonium formate;

f) amidation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole with

HN I _{N_n}

2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

using SOCl ₂ to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-( 2H-1,2,3-triazol-2-yl)phenyl)methanone

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method comprises the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine

wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

with Sh-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5-6 045257 (4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(III)-yl)(2 -fluoro-6-(2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method includes the steps described below: a) oxazolidination of (4,6dimethylpyrimidin-2-yl)glycine

BUT HN^ D ^N= \ wherein the specified oxazolidination is distinguished by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

with Sh-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

c) reduction of (3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole1,3(2H,3aH)-dione

with the formation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method comprises the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine

wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

- 7 045257 with 1H-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

c) reduction of (3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3 (2H,3aR)-dione

with the formation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole n\

f) amidation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole with

2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

using SOCl ₂ to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-( 2H-1,2,3-triazol-2-yl)phenyl)methanone

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(III)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method includes the steps described below:

a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine o, / but this oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one with 1-benzyl-1H-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-8 045257 yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH )-dione

wherein said 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one is not isolated before reacting with said 1-benzyl-1H-pyrrole-2,5-dione.

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method comprises the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine

wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to produce 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one with 1-benzyl-III-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

wherein said 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one is isolated before reacting with said 1-benzyl-1H-pyrrole-2,5-dione.

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method includes the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine o ^N HO HN—N, wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidine-2 -yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

- 9 045257 with 1H-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

wherein said 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one is not isolated before reacting with said 1-benzyl-1H-pyrrole-2,5-dione.

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(III)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method comprises the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine

wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

with 1H-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

Q n/

HN o ^{m 4} and the specified 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one is isolated before reaction with the specified 1-benzyl-1H-pyrrole-2,5-dione.

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method includes the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine o, / but

- 10 045257 wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to produce 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one with 1-benzyl-1H-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-с]pyrrole-1,3(2H,3 aH)-dione

c) reduction of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3 (2H,3aH)-dione

with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

wherein said reduction involves the use of one or more reagents selected from the group consisting of NaBH ₄ , PMHS, TMDS, Et ₃ SiH, Red-Al and BH ₃ .

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-Fluoro -6-(2H- 1,2,3-triazol-2yl)phenyl)methanone

wherein said method comprises the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine

wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to produce 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

with 1-benzyl-1H-pyrrole-2,5-dione

- 11 045257

at temperatures above 250°C with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

c) reduction of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrumidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

wherein said reduction involves the use of one or more reagents selected from the group consisting of NaBH ₄ , PMHS, TMDS, Et ₃ SiH, Red-Al and BH ₃ ;

d) removal of the protecting groups of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4c]pyrrole

with the formation of (3αR,6aS)-2-(4,6-dimethylpyrimudin-2-yl)octahydropyrrolo[3,4-c]pyrrole

using 10% (w/w) Pd/C and ammonium formate.

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(III)-ulχ2-fluoro-6-( 2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method comprises the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine

wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one with 1-benzyl-1H-pyrrole-2,5-dione

- 12 045257 at temperatures above 250°C with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH) -dione

c) reduction of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

wherein said reduction involves the use of one or more reagents selected from the group consisting of NaBH4, PMHS, TMDS, Et ₃ SiH, Red-Al and BH ₃ ;

d) removal of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4c]pyrrole protecting groups

with the formation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

using 10% (w/w) Pd/C and ammonium formate;

f) amidation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole with ζψχ Ν=( ^HN Cp% J

H\

2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

using SOCl ₂ to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-( 2H-1,2,3-triazol-2-yl)phenyl)methanone

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5 (4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2 yl)phenyl)methanone

wherein said method includes the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine o ^N HO HN—( ^z

N wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

- 13 045257

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

with 1H-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

c) reduction of (3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole1,3(2H,3aH)-dione

with the formation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

wherein said reduction involves the use of one or more reagents selected from the group consisting of NaBH ₄ , PMHS, TMDS, Et ₃ SiH, Red-Al and BH ₃ .

Another embodiment of the invention is a method for preparing (((3aR,6aS)-5(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro- 6-(2H-1,2,3-triazol-2yl)phenyl)methanone

wherein said method comprises the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine

wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to obtain 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

with 1H-pyrrole-2,5-dione

at temperatures above 250°C with the formation of (3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

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c) reduction of (3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3 (2H,3aH)-dione

with the formation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

wherein said reduction involves the use of one or more reagents selected from the group consisting of NaBH ₄ , PMHS, TMDS, Et ₃ SiH, Red-Al and BH ₃ .

f) amidation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole with

2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

using SOCl ₂ to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6 -(2H-1,2,3-triazol-2-yl)phenyl)methanone

Another embodiment of the invention is a compound which is 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one

Another embodiment of the invention is a compound which is (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH )-dion

Another embodiment of the invention is a compound which is (3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

The invention may be more fully appreciated by reference to the following description, which includes the following definitions of terms and concluding examples. For brevity, the descriptions of all publications cited herein, including patents, are incorporated herein by reference.

In this document, the terms including, containing, consisting of are used in their open, non-limiting meaning.

Definitions

The term (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2fluoro-6-(2H-1,2 ,3-triazol-2-yl)phenyl)methanone means

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Any of the formulas given herein are intended to represent both compounds with the structures shown by the given structural formula and certain variations or forms of such structures.

The products of the chemical reactions described herein can be directly reacted with additional reagents or separated before subsequent reaction. The term separated means partial or complete separation of the reaction product from other materials in the reaction vessel. These other materials include, but are not limited to, solvents, unreacted starting material, reactants used in the reaction, by-products, impurities and products of reactants used in the reaction.

The term preparation means synthesis by chemical processes.

In addition, each formula given herein, in addition to the compounds themselves, also includes their hydrates, solvates and polymorphs, as well as mixtures thereof, even if such forms are not expressly indicated.

Any of the formulas given herein also represent both unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures shown by the formulas presented herein, the exception being that one or more atoms are replaced by an atom having the selected atomic mass or mass number. Examples of isotopes that may be present in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H, ³ H, ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O respectively. Such isotope-labeled compounds are used in studies of metabolism (preferably using C), reaction kinetics (for example, using ² H or ³ H), detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)), including analysis of the distribution of a drug or substrate in tissues, or during radiotherapy of patients. Substitution with heavier isotopes such as deuterium (ie, ² H) may further provide certain therapeutic benefits due to greater metabolic stability of the compounds, such as greater in vivo half-life or reduced dosage requirements. The isotopically labeled compounds of the present invention and their prodrugs can be prepared substantially by the procedures described below in the Schemes or in the Examples and Preparation Methods described below by replacing a readily available reagent containing no isotope-labeled atoms with a reagent containing isotope-labeled atoms.

Those skilled in the art will appreciate that the compounds and reagents used in the reactions of the invention may exist in the form of salts. The present invention contemplates the use of all salts of any compound used in the reaction exemplified herein.

Examples of salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates , propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butine-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulfonates , phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates.

If the compound or reagent used in the reaction of the invention contains a basic nitrogen atom, the salt can be prepared by any suitable method available in the art, for example by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid , boric acid, phosphoric acid, etc., or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid , fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidylic acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as mandelic acid, citric acid or tartaric acid, an amino acid such as aspartic acid, glutaric acid or glutamic acid, an aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, a sulfonic acid such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid acid, ethanesulfonic acid, any compatible mixture of acids, such as those set forth in the examples herein, and any other acid or mixture of acids that are considered to be equivalent or acceptable substitutes in light of the usual state of knowledge in the art.

Those skilled in the art will appreciate that to remove the benzyl protecting group

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A variety of reagents may be used, and all reagents used in such removal are varied and known to those skilled in the art. The invention provides for the use of all common means of removing benzyl groups, including those described in Protective Groups in Organic Synthesis, by T. W. Green, and P. G. M. Wuts, Wiley-Interscience, New York, 1999, 579-580, 744-747.

Examples of deprotecting reagents include, but are not limited to, ammonium formate in the presence of a palladium catalyst, hydrogen gas in the presence of a palladium catalyst, formic acid, a mixture of formic acid and triethylamine, sodium formate, potassium formate, cyclohexene or cyclohexadiene.

Examples of reactions used in the methods of the invention are described below by reference to the following illustrative synthesis schemes for their general preparation and the following specific examples. Those skilled in the art will appreciate that the reactions can be performed in any suitable solvent. Those skilled in the art will also appreciate that, subject to specific limitations, reactions can be performed over a wide range of temperatures. The reactions can be carried out in the range between the melting point and the reflux temperature of the solvent, and preferably between 0° C. and the reflux temperature of the solvent. Reaction mixtures can be heated traditionally or in a microwave oven. Reactions can also be carried out in sealed pressure vessels at temperatures above the normal reflux temperature of the solvent.

Abbreviations.

Here and throughout the rest of the description, the following abbreviations may be used:_____

Reduction Term asas acetylacetonate VP benzyl VOS tert-Butylcarbamoyl DCM dichloromethane DMSO dimethyl sulfoxide EY Ac or EA ethyl acetate EtOH ethanol _Et3SiH triethylsilane SPLA acetic acid HPLC high performance liquid chromatography KHMDS potassium hexamethyldisilylamide MTBE methyl tert-butyl ether MeOH methanol OAS acetate PMHS poly(methylhydrosiloxane) Red-Al sodium bis(2-methoxyethoxy)aluminum hydride TBAF Tetrabutylammonium fluoride TEA triethylamine T.F.A. trifluoroacetic acid THF tetrahydrofuran TMDS 1,1,3,3-tetramethyldisiloxane UHPLC ultra high pressure liquid chromatography

Examples

Unless otherwise noted, the following experimental and analytical protocols were used to obtain the compounds described in the examples below and the corresponding analytical data.

Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. If mixtures, solutions and extracts were concentrated, they were typically concentrated on a rotary evaporator under reduced pressure. Reactions under microwave conditions were carried out in a Biotage initiator or a CEM Discover instrument.

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Normal phase flash column chromatography (FCC) was performed on silica gel (SiO ₂ ) using prefilled cartridges, eluting with the indicated solvents.

Unless otherwise stated, mass spectra (MS) were acquired on either a Bruker QTOF, Waters QTOF Ultima using electrospray ionization (ESI) in positive mode, or a Waters GC-TOF using electron impact (EI). The calculated (calculated) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker spectrometers. Below is the format for presenting 1H NMR data: chemical shift in ppm. towards a weak field from the signal used as a tetramethylsilane standard (multiplicity, spin-spin interaction constant J in Hz, integral).

Chemical names were generated using ChemDraw Ultra 6.0.2 (CambridgeSoft Corp., Cambridge, Massachusetts, USA) or ACD/Name version 9 (Advanced Chemistry Development, Toronto, Ontario, Canada).

General scheme.

Example 1. Formation of compound 3 from compound 2.

3

Example 1a: batch mode in toluene using paraformaldehyde with release.

Compound 2 (496.10 g) and toluene (7.44 L) were added to a 10 L jacketed reactor. The reaction mixture was heated to 65°C and subsequently charged with paraformaldehyde (1.2 eq., 98.65 g). While stirring under a strong nitrogen flow, the transformation was monitored by FT-IR. After 23 hours the reaction slowed down. Additional paraformaldehyde (0.45 eq., 36.99 g) was added. After 20 hours, the reaction was complete according to FTIR. The reaction mixture was filtered to remove unreacted compound 2 and residual paraformaldehyde. The mother liquor was distilled to dryness to obtain compound 3 (528.97 g, yield: 99%). 1H NMR (400 MHz, CDCl ₃ ) δ 6.48 (s, 1H), 5.64 (s, 2H), 4.27 (s, 2H), 2.33 (s, 6H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 171.5 (C), 167.95 (2 x C), 158.76 (CO), 111.78 (CH), 80.29 (CH ₂ ), 45 .01 (CH2), 24.0 (2 x CH3). High resolution MS (HR, m/z): mass calculated for C9H11N3O2 (M) ⁺ °: 193.0851; measured: 193.0847, m.p. 130-135°C (decomposition).

Example 1b: alternative synthesis - with an aqueous solution of formaldehyde.

A 25 mL reactor was charged with Compound 2 (500 mg), toluene (5 mL), and aqueous formaldehyde (13.31 mol/L, 4 eq.) at room temperature. A DeanStark apparatus was connected to the reactor and the solution was heated to 120°C. After 1 hour, the reaction mixture became a homogeneous solution from a heterogeneous mixture, and it was cooled to 25 °C. The reactor contents were transferred to a separatory funnel and diluted with ethyl acetate (30 ml). The organic layer was washed with water and brine, followed by drying over MgSO ₄ After removal of the solvent in vacuo, product 3 was obtained in 80% yield.

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Example 2. Preparation of compound 5b (R=Bn) from compound 3.

Example 2a. Screening in toluene under different flow conditions A solution of compound 3 and compound 4 b (1 equiv. each) in toluene (4 L/mol) was delivered to the flow set by a syringe pump (Isco 250 D).

The solution was preheated in a 1.7 mm inner diameter (ID) coil and reacted in a 4 mm ID coil at a flow length and flow rate to achieve a residence time of 5 minutes. The reaction temperature was controlled using a heat exchanger. Both the preheating block and the reactor coil were made of stainless steel and placed in a heat exchanger to achieve a uniform reaction temperature. The process pressure was adjusted to 10 bar above the toluene vapor pressure using a back pressure regulator (Swagelock). At the exit, the reaction mixture was cooled in a stainless steel tube at a temperature inside the tube (ID 1.7 mm) of 60°C and the pressure was reduced to atmospheric pressure, after which analysis was carried out using ultra-performance liquid chromatography (UHPLC). A quick temperature screen reveals that the reaction does not proceed until 200°C and requires temperatures above 250°C (see table below). The kinetics are very rapid at 300°C (<2 min) and the product remains stable for at least 5 min.

°C In-situ yield in % (5b) or % unconverted (3, 4b) 3 4b 5b 25 98 2 - 200 97 2 1 250 74 2 21 300 5 - 78 350 5 - 80

Example 2b. Reaction kinetics with 1.5 eq. compounds 4b.

A second set of experiments using the same apparatus as described in Example 2a shows that at 275°C the reaction is complete in approximately 4 minutes, and at 300°C in less than 2 minutes. Compound 5b is stable under these conditions at 300°C for at least 5 minutes (see graphs below).

Temperature: 275 °C min In-situ yield in % (5b) or % unconverted (3, 4b) 3 4b 5b 0 100 100 0 1 46 50 54 1.5 27 35 66 2 17 28 77 2.5 AND 23 83 3 7 19 85 4 3 15 89 5 2 13 90

Temperature: 300°C min In-situ yield in % (5b) or % unconverted (3, 4b) 3 4b 5b 0 100 100 0 1 4 16 86 1.5 1 And 88 2 1 10 88 2.5 0 9 88 3 0 8 88 3.5 0 8 88 4 0 7 88

Example 2c: flow regime in toluene with release.

A solution of compound 3 (1 mol) and compound 4b (1.5 or 1.25 eq.) in toluene (4 l/mol) was passed through the flow system described in example 2a, so as to achieve the required time at the required temperature, as described in the table below. After cooling, the solution was collected, partially evaporated under reduced pressure to a final concentration of 0.8 L/mol, and crystallized at 0°C for 5 hours. The solid (compound 5b) was filtered, washed and dried.

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Temperature (°C) Duration of stay (min) Eq. 4b Yield 5b, % in situ Yield of isolated product 5b, % 275 6 1.5 87.1 82.2 300 3.5 1.5 87.9 73.8 275 6 1.25 92.1 80.7 300 3.5 1.25 89.1 78.2

1H NMR (400 MHz, CDCl ₃ ) δ 7.27-7.29 (m, 2H), 7.22-7.26 (m, 3H), 6.35 (s, 1H), 4.62 (s , 2H), 4.41-4.44 (m, 2H), 3.56-3.62 (m, 2H), 3.42-3.44 (m, 2H), 2.288 (s, 6H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 178.18 (2 x CO), 167.36 (2 x C), 161.08 (C), 135.58 (C), 128.74 (2 x CH ), 128.55 (2 x CH), 127.98 (CH), 110.47 (CH), 48.88 (2 x CH ₂ ), 44.61 (2 x CH), 42.85 (CH ₂ ), 24.08 (2 x CH ₃ ). High resolution MS (ES, m/z): mass calculated for C ₁₉ H ₂₁ N ₄ O ₂ (M+H)+: 337.1665; measured: 337.1666, m.p. = 162°C.

Example 3. Preparation of compound 5a from compound 3 and compound 4a.

1.00 g (5.18 mmol) of compound 3, 777 mg (7.76 mmol) of compound 4a and 12 ml of toluene-d ₈ were placed in a microwave vial. The vial was sealed and heated to 250°C for about an hour, after which it was cooled to room temperature. NMR analysis of the reaction mixture using 1,3,5trimethoxybenzene as an internal standard showed that compound 5a was formed in 45% yield. Compound 5a was isolated and purified as a solid by flash chromatography. 1H NMR (400 MHz, METHANOL-04) δ = 6.47 (s, 1H), 4.83 (br.s, 1H), 4.29 (d, J=10.1 Hz, 2H), 3, 59-3.47 (m, 4H), 2.29 (s, 6H). ¹³ C NMR (101 MHz, METHANOL^) δ = 182.26 (2 x C), 169.15 (2 x C), 162.62 (C), 111.33 (CH), 50.04 (2 x CH2), 47.24 (2 x CH), 23.91 (2 x CH3). High resolution MS (ES, m/z): mass calculated for C ₁₂ H ₁₅ N ₄ O ₂ (M+H)+: 247.1195; measured: 247.1189.

Example 4. Preparation of compound 5b from compound 2.

Example 4a: One-pot reaction in a microwave vial (MW).

Compound 2 (250 mg), compound 4b, paraformaldehyde, and toluene-d ₈ and 1,4-dichlorobenzene (51 mg, 0.25 eq.) were added to a microwave vial (10 mL);

the amounts of compound 4b, paraformaldehyde and toluene-d ₈ are given in the table below.

The tube was sealed with a lid, placed in a Biotage microwave oven and heated to 250°C for 1 hour with stirring. After 1 hour, the reaction vial was cooled to room temperature and the sample was analyzed by 1H NMR to calculate the in-situ yield. Below are the results of various experiments.

No. Eq. 4b Eq. paraformaldehyde Toluene-ds (l/kg) Yield 5b, % in-situ 1 1 1.5 16 81 2 1.25 1.5 16 84 3 1.5 1.5 16 91 4 1 1.5 12 69 5 1 1.5 8 58 6 1 1.2 16 71

Example 4b: One-pot reaction in flow mode.

Mixed suspension of compound 2 (1 mol), paraformaldehyde (1.3 mol/mol) and compound 4b

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The suspension was preheated in a coil (ID 1.7 mm) and the telescopic reaction was carried out in a coil (ID 1.7 mm) with a length determined by the desired residence time and flow rates. The temperature for the first reaction (formation of compound 3) was controlled using the first heat exchanger, and the temperature for the second reaction (formation of compound 5b) was controlled using the second heat exchanger. Both the preheating block and the reactor coil were made of stainless steel and placed in two heating zones of the heat exchanger to obtain a uniform reaction temperature. The process pressure was adjusted to 10 bar above the toluene vapor pressure using a back pressure regulator (Swagelock). At the outlet, the reaction mixture was cooled in a stainless steel tube with an ID of 1.7 mm to a temperature of 60°C and the pressure was released to atmospheric pressure. The product was diluted and analyzed by UHPLC.

The conversion of compound 2 to compound 5b is presented in the table.

Stage 1 Stage 2 Yield, % relative to compound 2 T[°C] min T[°C] min Comp. etc. 3 Comp. Ave. 2 Comp. etc. 5b 180 8 300 3.4 0 0 54.2 180 6 300 2.6 0.2 0.2 54.9 180 4 300 1.7 1.1 2.9 42.0 160 8 300 3.4 0 0 62.1 160 6 300 2.6 0 0 62.6 160 4 300 1.7 1.1 0.8 53.3 200 4 300 2.6 0.1 OD 60.8 200 6 300 1.7 1 0.8 50.7

Example 4c: One-pot reaction in batch flow mode.

A suspension of compound 2 (1 mol), paraformaldehyde (1.5 eq.) and compound 4b (1.4 mol/mol) in toluene (4 L/mol) was heated in a closed vessel to 85 °C (0.5 bar gage). ) and stirred for two hours until complete conversion of 2 to 3 was achieved (see table below). After cooling, the resulting solution (25°C) was dried over MgSO ₄ . It was subsequently used in the next stage.

Conditions UHPLC (mol. rel. / in situ Y) Connection 3 Connection 2 0 min at 85 °C 43 (44) 57 (58.9) 13 min 91.9 (95.2) 5.7 (5.9) 80 min 96.5 (102.2) 1.3 (1.4) 105 min 96.4 (101.4) 1.2 (1.3) dried MgSO ₄ solution 91.4 1

The resulting solution of compound 3 was delivered to the flow unit using a syringe pump (Isco 250D). The suspension was preheated in a coil (ID 1.7 mm) and the reaction was carried out in a coil (ID 1.7 mm) with a length determined by the required residence time of 3 minutes and flow rates. The reaction temperature was controlled at 300°C using a heat exchanger. Both the preheating block and the reactor coil were made of stainless steel and placed in a heat exchanger to achieve a uniform reaction temperature. The process pressure was adjusted to 10 bar above the toluene vapor pressure using a back pressure regulator (Swagelock). At the outlet, the reaction mixture was cooled in a stainless steel tube (ID 1.7 mm) to a tube temperature of 60°C and the pressure was released to atmospheric pressure. Compound 5b was obtained in 66% yield.

As a result of the reaction in chlorobenzene, compound 5b was obtained in a yield similar to that in toluene.

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Example 5. Preparation of compound 5a from compound 2 and compound 4a.

O

250 mg (1.38 mmol) of compound 2, 62 mg (2.07 mmol) of paraformaldehyde, 207 mg (2.07 mmol) of compound 4a and 4 ml of toluene-d ₈ were placed in a microwave vial. The vial was sealed and heated to 250°C for about an hour, after which it was cooled to room temperature. NMR analysis of the reaction mixture using 1,3,5-trimethoxybenzene as an internal standard showed that compound 5a was formed in 28% yield. Compound 5a was isolated and purified as a solid by flash chromatography.

Example 6. Preparation of compound 6b (R=Bn) from compound 5b (R=Bn).

Example 6a: reduction of NaBH4+BF ₃ -THF.

Compound 5b (75 g), NaBH ₄ (19.4 g, 2.25 eq) and THF (375 ml) were placed in a 1 L reactor. The reaction mixture was heated to 50°C with stirring. BF3-THF (78.1 mL, 3.1 eq.) was added to this mixture over 2 hours (caution: strong exotherm at first and decreasing in intensity over time as addition). After the addition of BF3-THF was completed, the reaction was continued for 1 hour. Methanol (108 mL, 12 eq.) was slowly added to the reaction mixture over 2.5 hours. After stirring for an additional 12 hours, the solvents (THF and trimethyl borate) were distilled off to reduce volume to 1/3 and slowly added water (560 ml), and then an aqueous solution of NaOH (47.2 ml, 4 eq., 18.8 M) until the pH of the reaction mixture reached ~ 9.6. MTBE (225 ml) was added to this mixture and after phase separation the aqueous phase was removed. Some of the MTBE was distilled off (150 mL) and ethanol (203 mL) was charged into the reactor, followed by additional distillation to remove more MTBE. After distillation, the reaction mixture was cooled to 30°C, a certain amount of product was added to it and kept for 30 minutes to allow crystallization to begin. After crystallization began, water (450 ml) was added over 4 hours and the reaction mixture was subsequently cooled to 10°C. After stirring for an additional 6 hours, the solids were filtered using a frit funnel and the wet product was dried in an oven at 50°C for 12 hours. Compound 5 (63.3 g, 91% yield) was obtained as a dirty solid. - white color. ^1H NMR (600 MHz, DMSO-d6) δ = 7.327.25 (m, 4H), 7.24-7.19 (m, 1H), 6.37 (s, 1H), 3.67 (dd, J=8.1, 11.5 Hz, 2H), 3.55 (s, 2H), 3.38 (dd, J=3.4, 11.3 Hz, 2H), 2.88-2.81 (m, 2H), 2.60 (dd, J=7.0, 9.3 Hz, 2H), 2.43 (dd, J=3.0, 9.4 Hz, 2H), 2.21 ( s, 6H). ¹³ C NMR (DMSO-d6) δ: 166.4, 160.3, 139.1, 128.3, 128.1, 126.7, 108.3, 60.0, 58.8, 52.3, 41.0, 23.7, mp.: 80°C. High resolution MS (ES, m/z): calculated for C19H ₂₅ N ₄ (M+H)+: 309.2079; measured: 309.2080.

Example 6b: reduction of NaBH ₄ +H ₂ SO ₄ .

A 500 mL reactor was charged with 5b (30 g), NaBH ₄ (14.5 g, 4.2 eq.) and THF (210 mL). The reaction mixture was heated to 50°C with stirring. To this mixture was added H ₂ SO ₄ (10.5 ml, 2.1 eq.) over 2 hours (caution: strong exotherm at first and decreasing in intensity over time as addition). After addition of H2SO4 was completed, the reaction was continued for 0.5 h. Methanol (73 mL, 20 eq.) was slowly added to the reaction mixture over 2 h. After stirring for an additional 12 h, the solvents (THF and trimethyl borate) were distilled off to reduce the volume to 1/3 and water (120 ml) was slowly added, followed by aqueous NaOH (2.4 ml, 0.5 eq, 18.8 M) so that the pH of the reaction mixture reached ~9.6. MTBE (210 ml) was added to this mixture and after phase separation the aqueous phase was removed. A portion of the MTBE was distilled off (150 mL) and ethanol (69 mL) was charged into the reactor, followed by additional distillation to remove more MTBE. After distillation, the reaction mixture was cooled to 30°C, a certain amount of product was added to it and kept for 30 minutes to allow crystallization to begin. Immediately after the start of crystallization, water (207 ml) was added over 4 hours, and the reaction mixture was subsequently cooled to 10°C. After stirring for an additional 6 hours, the solids were filtered using a frit funnel and the wet product was dried in an oven at 50°C for 12 hours. Compound 6b (23.7 g, 82% yield) was obtained as an off-white solid. substances.

Example 6c: reduction of BH ₃ -THF.

A 100 ml reactor was charged with compound 5b (10 g) and THF (60 ml). The reaction mixture was cooled to 10°C with stirring. BH3-THF (89.2 mL, 3 eq., 1M in THF) was added to the resulting mixture over 1 hour. After stirring for 3 days at this temperature, methanol (60 mL) was added over 2 hours. and subsequently raised the temperature to 40°C and stirred for 24 hours. All solvents were removed in vacuo and the crude material was dissolved in a mixture of ethyl acetate and water. After phase separation, the organic layer was concentrated in vacuo to give the desired product 6b (9 g, 98% yield).

Example 6d: Restoration with Red-Al.

Compound 5b (500 mg) and toluene (4 ml) were charged into a 25 ml reactor. The reaction mixture was heated to 60°C with stirring. In another reactor, both Red-Al (1.45 ml, 3 eq., 60% solution in toluene) and toluene (5 ml) were heated to 60° C. with stirring. Subsequently, the hot Red-Al solution was added to the above hot solution of compound 5b over 5 min. Then the temperature of the reaction mixture was raised to 100°C and stirred for 2 hours. After cooling to 20°C, an aqueous solution of NaOH was added dropwise and stirred for 2 hours. Next, phase separation was performed with solvent removal in vacuo to obtain compound 6b (480 mg, 56.7 wt.% by quantitative determination, yield 59%).

Example 6e: reduction with silane (table).

Recovery using the BfCfvFVh/TMDS technique.

A 50 mL reactor was charged with 5b (2 g), 1,1,3,3-tetramethyldisiloxane (TMDS - 6.3 mL, 6 eq.) and toluene (20 mL). The reaction mixture was heated to 60°C with stirring. A solution of B(C ₆ P ₅ ) ₃ (152 mg, 5 mol%) in toluene (1 ml) was added to the mixture and the temperature was raised to 100°C. After stirring for 1 hour, the reaction mixture was cooled to 25°C and the contents were transferred to a round bottom flask. Removal of solvents in vacuo afforded crude 6b (2.07 g, 88.6% quantitation, 95% yield).

Reduction by screening silanes (catalyst/hydride source).

Following the procedure described above, various catalysts and silane reagents were used to reduce 5b (500 mg) to 6b.

No. p/p Catalyst (mol.%) Silane (eq.) 6b (relative LC peak area, %) 1 B(C ₆ F ₅ ) ₃ (1) TMDS (5) 0 2 B(C ₆ F ₅ ) ₃ (2) TMDS (5) 42 3 B(C ₆ F ₅ ) ₃ (3) TMDS (5) 89 4 B(C ₆ F ₅ ) ₃ (4) TMDS (5) 99 5 B(C ₆ F ₅ ) ₃ (5) TMDS (5) 99 6 Fe ₃ (CO) ₁₂ (5) TMDS (5) 38 7 H ₂ PtCl ₆ (1) TMDS (5) 25 8 Zn(OAc) ₂ -2H ₂ O (5) TMDS (5) 0 9 TBAF (1Mb THF) (5) TMDS (5) 0 10 Fe(acac) ₃ (5) TMDS (5) 0 AND Ni(acac) ₂ (5) TMDS (5) 0 12 Co(acac) ₃ (5) TMDS (5) 0 13 Mn(acac) ₃ (5) TMDS (5) 0 14 A1C1 ₃ (5) TMDS (5) 0 15 KHMDS (1Mb THF) (5) TMDS (5) 0 16 B(C ₆ F ₅ ) ₃ (5) PMHS (6) 55 17 Fe ₃ (CO)i ₂ (5) PMHS (6) 57 18 H ₂ PtCl ₆ (1) PMHS (6) 64 19 _H2PtCl6 ( ₄ ) PMHS (6) 76 20 Zn(OAc) ₂ 2H ₂ O (5) PMHS (6) 0 21 B(C ₆ F ₅ ) ₃ (5) _Et3SiH (8) 60

Example 7 Preparation of compound 6a from compound 5a in which R is H.

A 10 mL tubular reactor was charged with compound 5a (75 mg) and THF (2 mL). Reactionary

- 23 045257 the mixture was cooled to 0°C with stirring. BH ₃ -THF (0.91 ml, 3 eq., 1M in THF) was slowly added to this mixture. The reaction mixture was slowly heated to 50°C with stirring and left for 4 hours at this temperature. Methanol (0.3 ml) was slowly added to this mixture and stirred for 2 hours. After cooling to room temperature, the crude mixture was concentrated in vacuo and the residue was redissolved in 2-methyltetrahydrofuran (3 ml) and heated to 50° C. followed by the addition of aqueous solution of H ₂ SO ₄ (0.5 ml, 4 eq., 2.28 M in water). After 2 hours, the solution was neutralized by adding aq. NaOH (0.35 mL, 4.5 eq., 12.5 wt% in water) followed by phase separation and concentration in vacuo to give product 6a (60 mg, 80% quantitation, 72% yield).

Example 8. Preparation of compound 6a from compound 6b.

5.8 g of 10% Pd/C (wet) was added to a solution of 58 g (188 mmol) of compound 6b in 406 ml of methanol. The resulting suspension was heated to 60°C, after which 13 g (206 mmol) of ammonium formate in 174 ml of methanol was added over an hour. Subsequently, the reaction mixture was stirred for 3 hours at 60°C and then cooled to room temperature. The catalyst was filtered and the filtrate was concentrated in vacuo to obtain 40.7 g of compound 6a as a yellowish solid. Yield: 97%. 1H NMR (DMSO4) δ: 6.35 (s, 1H), 3.68 (dd, J=11.3, 7.9 Hz, 2H), 3.32 (dd, J=11.3, 3, 4 Hz, 2H), 2.93 (br. dd, J=10.2, 6.0 Hz, 2H), 2.76 (br. s, 2H), 2.61 (br. d, J=9 .4 Hz, 2H), 2.21 (s, 6H). ¹³ C NMR (DMSO-06) δ: 166.1, 160.2, 107.9, 53.1, 51.6, 42.9, 23.4. High resolution MS (ES, m/z): mass calculated for C ₁₂ H ₁₉ N ₄ (M+H)+: 219.1610; measured: 219.1624. melting point: 99-100°C.

Example 9. Preparation of (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol2(1H)-yl)(2-fluoro-6-(2H- 1,2,3-triazol-2-yl)phenyl)methanone (1) from compound 6a and compound 7

4, 3 ml (60 mmol) of thionyl chloride was added to a suspension of 9.5 g (46 mmol) of compound 7 in 110 ml of toluene, then heated to a temperature of 55 ° C for 2.5 hours, subsequently concentrated in vacuum until a residual volume about 100 ml (about 20 ml of distilled solvent). The resulting solution of the acyl chloride intermediate in toluene was added to a well stirred two-phase mixture of 10.2 g (45.7 mmol) of compound 6a in 44 ml of toluene and 7.26 g (68.5 mmol) of sodium carbonate in 44 ml of water. The resulting two-phase mixture was heated at 30°C for 3.5 hours and then heated to 70°C. The aqueous layer was discarded and the organic phase was washed twice with 57 ml of water and concentrated in vacuo to a residual volume of approximately 64 ml. The concentrated mixture was heated to 90°C to obtain a solution, after which it was cooled to room temperature and 64 ml of cyclohexane was added. The resulting suspension was stirred overnight. 18.1 g of (((3aR,6aS)5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-( 2H-1,2,3-triazol-2yl)phenyl)methanone (1) as a solid after filtration, washing with 12 ml cyclohexane and 11 ml water and drying in vacuo Yield: 97% ¹ H NMR (400 MHz, pyridine-b5) δ ppm 2.33 (s, 12H), 2.81-2.97 (m, 4H), 3.27 (dd, J=10.6, 5.0 Hz, 1H) , 3.33 (dd, J=10.5, 4.7 Hz, 1H), 3.57 (br.t, J=7.1 Hz, 1H), 3.59 (br.t, J=7 ,0 Hz, 1H), 3.67 (dd, J=11.7, 4.5 Hz, 1H), 3.70-3.75 (m, 1H), 3.75-3.82 (m, 2H), 3.82-3.98 (m, 7H), 4.11 (dd, J=12.4, 7.6 Hz, 1H), 6.29 (s, 1H), 6.29 (s , 1H), 7.19 (td, J=8.7, 1.0 Hz, 1H), 7.26 (td, J=8.6, 0.9 Hz, 1H), 7.46 (td, J=8.3, 6.2 Hz, 1H), 7.46 (td, J=8.3, 6.0 Hz, 1H), 7.90 (dt, J=8.2, 0.8 Hz , 1H), 7.90 (s, 2H), 7.98 (dt, J=8.2, 0.8 Hz, 1H), 8.04 (s, 2H). ¹³ C NMR (101 MHz, pyridine -b5) δ ppm 24.47, 24.48, 41.74, 41.82, 42.71, 42.93, 50.76, 50.82, 50.90, 51.03, 51, 43, 51.62, 51.87, 52.06, 109.27, 109.44, 115.88 (br.d, J=22.4 Hz), 115.89 (b.d. d, J=22.4 Hz), 118.82 (br.d, J=3.3 Hz), 118.97 (br.d, J=3.3 Hz), 120.48 (d, J= 24.9 Hz), 120.55 (d, J=24.6 Hz), 131.53 (br. d, J=9.2 Hz), 131.54 (d, J=9.2 Hz), 137.33, 137.47, 138.04 (d, J=7.0 Hz), 138.07 (br. d, J=7.0 Hz), 159.71 (d, J=245.8 Hz ), 159.81 (d, J=245.4 Hz), 161.53, 161.61, 162.99 (d, J=7.3 Hz), 162.99 (d, J=7.3 Hz ), 167.61, 167.63. High resolution MS (ES, m/z): calculated for C ₂₁ H ₂₃ FN ₇ O (M+H)+: 408.1943; measured: 408.1946.

While the foregoing description sets forth the principles of the present invention with examples given for illustrative purposes, it is to be understood that the practice of the invention is intended to embrace all normal variations, adaptations and/or modifications included within the scope of the following claims and their equivalents.

All documents cited herein are incorporated by reference.

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Claims (9)

CLAIM 1. Method for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol2(1H)-yl)(2-fluoro-6-(2H- 1,2,3-triazol-2-yl)phenyl)methanone , wherein said method comprises the steps described below: a) oxazolidination of (4,6-dimethylpyrimidin-2-yl)glycine wherein said oxazolidination is characterized by the use of formaldehyde or paraformaldehyde to produce 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one nV θ' ⁷ N=/ b) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one with 1-benzyl-1Hpyrrole-2,5-dione O at temperatures above 250°C to form (3aR,6aS)-2 -benzyl-5-(4,6dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)dione c) reduction of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole1,3(2H,3aH) dione with the formation of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2yl)octahydropyrrolo[3,4-c]pyrrole wherein said reduction involves the use of one or more reagents selected from the group consisting of NaBH ₄ , PMHS, TMDS, Et ₃ SiH, Red-Al and BH ₃ ; d) removal of (3aR,6aS)-2-benzyl-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4c]pyrrole protecting groups rolo[3,4-c]pyrrole to form (3aR,6aS)-2-(4,6-dimethylnurimidin-2-yl)octahydronur- using 10% (w/w) Pd/C and ammonium formate; And f) amidation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole - 25 045257 with 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid using SOC12 to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol2(1H)-yl)(2-Fluoro-6-( 2H-1,2,3-triazol-2-yl)phenyl)methanone 2. Method of obtaining (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone , wherein said method includes the steps described below: a) reaction of 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one O with Ш-pyrrole-2.5HN | dione θ at temperatures above 250°C to form (3aR,6aS)-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione , b) reduction of (3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole 1,3(2H,3aH)-dione , the formation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2yl)octahydropyrrolo[3,4-c]pyrrole wherein said reduction involves the use of one or more reagents selected from the group consisting of NaBH ₄ , PMHS, TMDS, Ei ₃ SiH, Red-Al and VN ₃ ; and amidation of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole With) with 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid using SOCl ₂ to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol2(1H)-yl)(2-Fluoro-6- (2H-1,2,3-triazol-2-yl)phenyl)methanone 3. The method of claim 1, wherein said 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one is not isolated before reacting with said 1-benzyl-1H-pyrrole-2,5-dione. 4. The method of claim 1, wherein said 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one is isolated before reacting with said 1-benzyl-1H-pyrrole-2,5-dione. 5. The method according to claim 2, wherein said 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one is not isolated before reacting with said N-pyrrole-2,5-dione. 6. The method according to claim 2, in which the specified 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one is isolated - 26 045257 before reacting with the specified 1H-pyrrole-2,5-dione. 7. The compound which is 3-(4,6-dimethylpyrimidin-2-yl)oxazolidin-5-one 8. A compound representing (3AK,6a8)-2-benzyl-5-(4,6-dimethylpyrimidin-2yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3H)dione 9. Compound representing (3AK,6a8)-5-(4,6-dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3H)dione Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2