DESC:Field of the invention:
The present invention relates to a process for the preparation of 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione (M-Dione), a key intermediate of Sotorasib which is represented by the following structural formula:

Formula-2

Further, the said key intermediate of formula-2 is useful in the preparation of Sotorasib compound of formula-1 which is represented by the following structural formula:

Formula-1

Background of the Invention:
Sotorasib has been approved by U.S. Food and Drug Administration (FDA) in May, 2021 which is an inhibitor of the RAS GTPase family indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Sotorasib is marketed by Amgen Inc under the brand name Lumakras and Lumykras.

US10519146B2 disclosed a process for the preparation of Sotorasib which is illustrated in below Scheme-I:

The process disclosed in US10519146B2 involves the usage of corrosive chemicals and also involves the column purification techniques for the isolation of Sotorasib which is not suitable for the commercial scale production.
Moreover, the said process involves the usage of racemic-Dione compound for the preparation of Sotorasib which is a mixture of (M) and (P)-atropisomers. To obtain the desired isomer, the process further required SFC (chiralpack column) to separate the (M)-atropisomer of Sotorasib from the mixture. Whereas, the separation of the compound by chiral column may drastically decrease the yield of the desired compound which is not viable for commercial scale process.

In view of the above, there remains a need to develop a cost effective and commercially viable process for the preparation of (M)-atropisomer of Sotorasib.

The present inventors have developed a process for the preparation of 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (M-Dione), a key intermediate of Sotorasib which is useful in the preparation of (M)-atropisomer of Sotorasib. Further, by the usage of said intermediate avoids the above said column purifications such as SFC (chiralpack column) of prior-art process and provides the (M)-atropisomer of Sotorasib directly with high purity and yield.

Brief description of the Invention:
The first aspect of the present invention is to provide a process for the preparation of 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl] pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (M-Dione) compound of formula-2 from racemic-Dione.

The second aspect of the present invention is to provide M-Dione DTTA salt of formula-3 and its novel crystalline form as well as its process for the preparation.

Description of Diagrams:

FIG-1: Illustrates the X-ray powder diffractogram of crystalline Form-N of M-Dione
DTTA salt of formula-3.
Detailed description of the Invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether and aromatic hydrocarbon solvents such as toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether (MTBE), 1,2-dimethoxyethane, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, monoxime, dioxime and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as N, N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane/methylene chloride, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert.amyl alcohol, t-butanol and the like; "polar solvents" such as water or mixtures thereof.

As used herein the present invention, the term "anti-solvent" refers to a solvent which is used to precipitate the solid from a solution.

As used herein the present invention the term “suitable acid” refers to organic acids or inorganic acids. The “inorganic acid” is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and “organic acid” is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, aspartic acid, tartaric acid, di-toluoyl-D-tartaric acid [(+)-DTTA], mandelic acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like or mixtures thereof.

As used herein the present invention the term “suitable base” refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; alkali metal phosphates such as disodium hydrogen phosphate; Ammonia; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.

The first aspect of the present invention is to provide a process for the preparation of 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl] pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (M-Dione) compound of formula-2, comprising of:
a) Treating the racemic-Dione with di-toluoyl-D-tartaric acid [(+)-DTTA] in a suitable solvent to provide M-Dione DTTA salt of formula-3,
b) treating the compound of formula-3 with a suitable base and a suitable solvent to provide (M-Dione) compound of formula-2.
Wherein in step-a) & b), the suitable solvent is selected from ether solvents, hydrocarbon solvents or mixtures thereof.
In step-b), the suitable base is inorganic base.

In a preferred embodiment of the present invention provides a process for the preparation of 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl] pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (M-Dione) compound of formula-2, comprising of:
a) Treating the racemic-Dione with di-toluoyl-D-tartaric acid [(+)-DTTA] in 2-methyl tetrahydrofuran to provide M-Dione DTTA salt of formula-3,
b) treating the compound of formula-3 with aqueous sodium hydroxide in methyl tert-butyl ether to provide (M-Dione) compound of formula-2.

The second aspect of the present invention is to provide M-Dione DTTA salt of formula-3 and its novel crystalline form as well as its process for the preparation.

In a preferred embodiment of the present invention provides M-Dione DTTA salt of formula-3 having the following structure:

In a further aspect of the present invention provides novel crystalline form of M-Dione DTTA salt of formula-3 hereinafter designated as “Form-N”, which is characterized by:
i) Its powder X-ray diffractogram having peaks at about 6.6, 8.6, 12.6, 13.2, 15.1, 18.0, 18.8, 20.4, 24.4 and 26.8 ± 0.2 degrees 2-theta.
ii) powdered X-ray diffraction pattern as shown in Figure-1.

In a further aspect of the present invention provides a process for the preparation of crystalline form-N of M-Dione DTTA salt of formula-3, comprising of:
a) Treating the racemic-Dione with di-toluoyl-D-tartaric acid [(+)-DTTA] in a suitable solvent,
b) heating the reaction mixture to a suitable temperature,
c) stirring and cooling the reaction mixture to a suitable temperature,
d) adding a suitable anti-solvent to the reaction mixture,
e) filtering the obtained solid and washing with a solvent to get the crystalline form-N of M-Dione DTTA salt of formula-3.

Wherein in step-a), d) & e), the suitable solvent & anti-solvent is selected from ether solvents, hydrocarbon solvents or mixtures thereof.
In step-b) & c), the suitable temperature used is ranging from 20°C to the reflux temperature of the solvent used;

In a preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of M-Dione DTTA salt of formula-3, comprising of:
a) Treating the racemic-Dione with di-toluoyl-D-tartaric acid [(+)-DTTA] in 2-methyl tetrahydrofuran,
b) heating the reaction mixture to 75-80°C,
c) stirring and cooling the reaction mixture to 20-25°C,
d) adding n-Heptane to the reaction mixture,
e) filtering the obtained solid and washing with a mixture of 2-methyl tetrahydrofuran & n-Heptane to get the crystalline form-N of M-Dione DTTA salt of formula-3.

The racemic-Dione used as a starting material in the present invention can be prepared from the processes known in the art.

The M-Dione DTTA salt of formula-3 and its crystalline form-N of the present invention are useful in the preparation of pure (M-Dione) compound of formula-2.

Further, the (M-Dione) compound of formula-2 obtained from the present invention is a key intermediate which is useful in the preparation of (M)-atropisomer Sotorasib compound of formula-1 with high yield & purity.

The process for the preparation of 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (M-Dione) compound of formula-2 from racemic-Dione is schematically represented as below:

Scheme-II:

PXRD method of analysis:

PXRD analysis of the M-Dione DTTA salt of formula-3 was carried out using Panlytical Expert Pro DY3248 X-ray powder diffractometer using Cu-Ka radiation of 10 wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples provide as illustration only and hence should not be construed as limitation of the scope of the invention.
Examples:

Exampe-1: Process for the preparation of M-Dione DTTA salt of formula-3 from Racemic Dione
To a solution of rac. Dione (20 g) in 2-Methyltetrahydrofuran (140 mL) was added Di-toluoyl-D-tartaric acid [(+)-DTTA] (44.28 g). The suspension was heated to 75 °C, stirred up to clear solution and filtered at 75 °C. Thereafter, filtrate was cooled to 65-70 °C and n-heptane (40 mL) was added slowly to the filtrate. Reaction mass was further cooled to 20-25 °C over a period of 4 hours with slow rpm. M-Dione DTTA salt seed (0.2 g) was added to the reaction mass and stirred for 15 min at 20-25 °C.
n-Heptane (60 mL) was added slowly to the reaction mass and stirred for 4 hours at 20-25 °C. The precipitated solid was filtered, washed with 2-Methyltetrahydrofuran and n-heptane solvent mixture and dried the material under vacuum to get the M-Dione DTTA salt of formula-3 (12 g).
Chiral purity: M-Dione DTTA: 99.11% and P-Dione DTTA: 0.89
1H NMR (CDCl3, 400 MHz): d 9.29 (br, s, 1H), 8.70-8.69 (d, J = 5.2 Hz, 2H), 8.23-8.21 (d, J = 6.4 Hz, 2H), 7.99-7.97 (d, J = 8.0 Hz, 8H), 7.22-7.20 (m, 10H), 6.04 (s, 4H), 3.99-3.85 (m, 2H), 3.74-3.68 (m, 1H), 2.70-2.63 (m, 2H), 2.39 (s, 12H), 2.08 (s, 6H), 01.21-1.6 (m, 10H), 1.05-1.03 (d, J = 6.8 Hz, 6H).
The PXRD of the obtained compound of formula-3 is illustrated in figure-1.

Exampe-2: Process for the preparation of M-Dione of formula-2 from M-Dione DTTA salt (Formula-3)
A mixture of M-Dione DTTA salt, MTBE (240 mL) and DM water (180 mL) were stirred for 10 min at 25-30 °C. Reaction mass pH was adjusted to 7.0-7.5 with aqueous NaOH solution (12 mL) and stirred for 30 min at 25-30 °C to get clear solution. Both layers were separated and aq. layer was extracted with MTBE (24 mL). Both organic layers were combined and solvent was concentrated under reduced pressure and co-distilled with n-heptane at = 45 °C. Product was dried under vacuum to get M-Dione of formula-2 (5.5 g).
Chiral purity: M-Dione: 99.09% and P-Dione: 0.91%
1H NMR (CDCl3, 400 MHz): d 9.85 (br, s, 1H), 8.62-8.60 (d, J = 4.8 Hz, 1H), 8.26-8.24 (d, J = 6.8 Hz, 1H), 7.17-7.15 (d, J = 5.2 Hz, 1H), 2.74-2.67 (m, 1H), 2.09 (s, 3H), 1.23-1.21 (d, J = 6.8 Hz, 3H), 1.14-1.12 (d, J = 6.8 Hz, 3H).
,CLAIMS:We Claim:

1. A process for the preparation of 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (M-Dione) compound of formula-2, comprising of:

a) Treating the racemic-Dione with di-toluoyl-D-tartaric acid [(+)-DTTA] in a suitable solvent to provide M-Dione DTTA salt of formula-3,
b) treating the compound of formula-3 with a suitable base and a suitable solvent to provide (M-Dione) compound of formula-2.

2. The process as claimed in claim-1, wherein
In step-a) & b), the suitable solvent is selected from ether solvents, hydrocarbon
solvents or mixtures thereof.
In step-b), the suitable base is inorganic base.

3. The process as claimed in claim-1, comprising of:
a) Treating the racemic-Dione with di-toluoyl-D-tartaric acid [(+)-DTTA] in 2-methyl tetrahydrofuran to provide M-Dione DTTA salt of formula-3,
b) treating the compound of formula-3 with aqueous sodium hydroxide in methyl tert-butyl ether to provide (M-Dione) compound of formula-2.

4. The M-Dione DTTA salt of formula-3 having the following structure:

5. A novel crystalline form-N of M-Dione DTTA salt of formula-3, which is characterized by:
i) Its powder X-ray diffractogram having peaks at about 6.6, 8.6, 12.6, 13.2, 15.1, 18.0, 18.8, 20.4, 24.4 and 26.8 ± 0.2 degrees 2-theta.
ii) powdered X-ray diffraction pattern as shown in Figure-1.

6. A process for the preparation of crystalline form-N of M-Dione DTTA salt of formula-3, comprising of:
a) Treating the racemic-Dione with di-toluoyl-D-tartaric acid [(+)-DTTA] in a suitable solvent,
b) heating the reaction mixture to a suitable temperature,
c) stirring and cooling the reaction mixture to a suitable temperature,
d) adding a suitable anti-solvent to the reaction mixture,
e) filtering the obtained solid and washing with a solvent to get the crystalline form-N of M-Dione DTTA salt of formula-3.

7. The process as claimed in claim-6, wherein
In step-a), d) & e), the suitable solvent & anti-solvent is selected from ether solvents,
hydrocarbon solvents or mixtures thereof.
In step-b) & c), the suitable temperature used is ranging from 20°C to the reflux
temperature of the solvent used;
8. The process as claimed in claim-6, comprising of:
a) Treating the racemic-Dione with di-toluoyl-D-tartaric acid [(+)-DTTA] in 2-methyl tetrahydrofuran,
b) heating the reaction mixture to 75-80°C,
c) stirring and cooling the reaction mixture to 20-25°C,
d) adding n-Heptane to the reaction mixture,
e) filtering the obtained solid and washing with a mixture of 2-methyl tetrahydrofuran & n-heptane to get the crystalline form-N of M-Dione DTTA salt of formula-3.

9. The M-Dione DTTA salt of formula-3 and its crystalline form-N as claimed in claim-4 & 5 are useful in the preparation of pure (M-Dione) compound of formula-2.

10. The (M-Dione) compound of formula-2 obtained according to the process claimed in claims 1-3, is a key intermediate which is useful in the preparation of high pure (M)-atropisomer of Sotorasib compound of formula-1.