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Amcenestrant (SAR 439859)

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Amcenestrant Chemical Structure
Amcenestrant.png

Amcenestrant  (SAR 439859)

アムセネストラント

Molecular Weight554.48
FormulaC31H30Cl2FNO3
CAS No.2114339-57-8

6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

Amcenestrant

8-(2,4-dichlorophenyl)-9-(4-{[(3 S )-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro  5H- Benzo[7]annulene-3-carboxylic acid

8-(2,4-Dichlorophenyl)-9-(4-{[(3 S )-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5 H -benzo [7]annulene-3-carboxylic acid

C31H30Cl2FNO3  : 554.48 [ 2114339-57-8 ] _ _ _ _ _

EfficacyAntineoplastic, Selective estrogen receptor downregulator
CommentSelective estrogen receptor downregulator (SERD)
Treatment of breast cancer

SAR439859 (compound 43d) is an orally active, nonsteroidal and selective estrogen receptor degrader (SERD). SAR439859 is a potent ER antagonist and has ER degrading activity with an EC50 of 0.2 nM for ERα degradation. SAR439859 demonstrates robust antitumor efficacy and limited cross-resistance in ER+ breast cancer.

Amcenestrant is an orally available, nonsteroidal selective estrogen receptor degrader/downregulator (SERD), with potential antineoplastic activity. Upon oral administration, amcenestrant specifically targets and binds to the estrogen receptor (ER) and induces a conformational change that promotes ER degradation. This prevents ER-mediated signaling and inhibits both the growth and survival of ER-expressing cancer cells.

Amcenestrant is reported to be a selective estrogen receptor degrader (SERD) which has estrogen receptor antagonist properties and accelerates the proteasomal degradation of the estrogen receptor. Amcenestrant is under clinical investigation as an anticancer agent, in particular for treatment of breast cancer.

The compound and processes for preparation thereof are described in International Publication No. WO 2017/140669.

Crystalline forms are described in International Publication No. WO 2021/116074.

PAPER

Journal of Medicinal Chemistry (2020), 63(2), 512-52

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01293

6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3- yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic Acid (43d).

To a solution of 6-(2,4-dichloro-phenyl)-5-[4-[1-(3-fluoropropyl)-pyrrolidin-3-yloxy]-phenyl]-8,9-dihydro-7H-benzocycloheptene-2-carboxylic acid methyl ester (42d) (80 mg, 140.72 μmol) in methanol (5 mL) was added 5 N NaOH (562.88 μL), the reaction mixture was heated to 60 °C for 5 h, and the solvent was removed under reduced pressure. The residue was taken up in water (10 mL), and aqueous HCl (5 M) was added to pH 7. The slurry was extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of dichloromethane, acetonitrile, and methanol (90/5/5 v/v/v) to give 60 mg (77%) of 6- (2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]- oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d). 1 H NMR (400 MHz, DMSO-d6): 1.68 (m, 1H), 1.79 (dm, J = 25.3 Hz, 2 H), 2.07 to 2.23 (m, 5H), 2.38 (m, 1H), 2.46 (t, J = 7.2 Hz, 2H), 2.52 (m, 1H), 2.62 (m, 1H), 2.55 to 2.89 (m, 3H), 4.47 (td, J = 6.2 and 47.6 Hz, 2H), 4.72 (m, 1H), 6.63 (d, J = 8.9 Hz, 2H), 6.71 (m, 3H), 7.18 (d, J = 8.4 Hz, 1H), 8.26 (dd, J = 2.0 and 8.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 12.3 (m, 1H). LCMS: 554 (M + H)+ . 

PATENT

Amcenestrant can be prepared according to methods known from the literature, for example U.S. Patent No. 9,714,221.

Example 1: Preparation of amorphous Amcenestrant

[00164] Amcenestrant (20 mg, prepared according to U.S. Patent No. 9,714,221) was dissolved in ethyl acetate (0.2 mL) at room temperature (25°C). Solution was left in opened flask at RT for 16 days, until all the solvent evaporated. Obtained solid was analyzed by XRPD.

PATENT

U.S. Patent No. 9,714,221

https://patents.google.com/patent/US9714221B1/en

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017140669

Example 51. 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

Methode B:

Step 1 : 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.

To a solution of methyl 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (D5) (150 mg, 298.56 μιηοΙ), in dioxane (12 ml) and water (2 ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 μηηοΙ), Cs2C03 (204.48 mg, 626.97 μηιοΙ), and Pd(dppf)CI2 (14.63 mg, 17.91 μιηοΙ). The reaction mixture was heated at 90°C for 3 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg (47%) of 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.

LC/MS (m/z, MH+): 568

Step 2 : 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

To a solution of 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (80 mg, 140.72μιηο!) in MeOH (5 ml) was added a solution of NaOH (562.88 μΙ, 5 M) and the reaction mixture was heated at 60°C for 5 hours and the solvent removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous HCI (5 M) added to pH

7. The slurry was extracted with DCM, dried over MgS04 and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) to give 60 mg (77%) of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019020559

Intermediate (c). Tert-butyl (3S)-3-[4-(4,4!5!5-tetramethyl-1 !3,2-dioxaborolan-2yl)phenoxy]pyrrolidine-1 -carboxylate

To a solution of commercially available 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (a) (82.7 g, 364.51 mmol) in THF (2 L) was added under argon (R)-1 -N-Boc-3-hydroxypyrrolidine (b) (84.43 g, 437.41 mmol) followed by Ν,Ν,Ν’,Ν’-tetramethylazodicarboxamide (99.1 g, 546.77 mmol). The clear reaction mixture turned orange and triphenylphosphine (143.41 g, 546.77 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, meanwhile a precipitate of triphenylphosphine oxide formed (Ph3P=0). The reaction mixture was poured in water (1 .5 L) and extracted with ethyl acetate (AcOEt) (3×1 .5 L). Gathered organic phases were dried over magnesium sulfate (MgS04), filtered and concentrated under reduced pressure. The residue was taken up into diisopropylether (1 .5 L) and the solid formed (Ph3P=0) was filtered. The solvent was concentrated under reduced pressure and the residue purified by column chromatography eluting with a mixture of heptane with AcOEt (90/10; v/v) to give 145 g (100%) of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1 -carboxylate (c) as a colorless oil.

1H NMR (400 MHz, DMSO-d6, δ ppm): 1 .27 (s : 12H); 1 .39 (s : 9H); 2.05 (m : 1 H); 2.14 (m : 1 H); 3.37 (3H); 3.55 (m : 1 H); 5.05 (s : 1 H); 6.94 (d, J = 8.4 Hz : 2H); 7.61 (d, J = 8.4 Hz : 2H)

Intermediate (d). (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride

To a solution of (S)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1 -carboxylate (c) (80 g, 195.23 mmol) in MeOH (450 ml) was added slowly HCI 4N in dioxane (250 ml).

After 1 .5 hours, the reaction mixture was concentrated under reduced pressure and the residue was taken up into Et20 with stirring to give a solid which then was filtered and dried under vacuum to give 61.8 g (95%) of (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride (d) as a white powder.

1H NMR (400 MHz, DMSO-d6, δ ppm): 1.28 (s : 12H); 2.10 (m : 1 H); 2.21 (m : 1 H); 3.31 (3H); 3.48 (m : 1 H); 5.19 (m : 1 H); 6.97 (d, J = 8.4 Hz : 2H); 7.63 (d, J = 8.4 Hz : 2H); 9.48 (s : 1 H); 9.71 (s : 1 H).

LC/MS (m/z, MH+): 290

Intermediate (e). (3S)-1 -(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine

To a suspension of (S)-3-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine hydrochloride (d) (20 g, 61.42 mmol) in acetonitrile (100 ml), was added K2C03 (21 .22 g, 153.54 mmol) and 1 -iodo-3-fluoropropane (12.15 g, 61.42 mmol), under argon. The reaction

mixture was stirred at 40°C for 24 hours. After cooling to room temperature, the reaction mixture was filtered and washed with acetonitrile. The filtrate was concentrated under reduced pressure and the residue was taken up in DCM and the solid formed was filtered and washed with DCM. The filtrate was concentrated to give 21.5 g (100%) of (3S)-1 -(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) as a yellow foam.

1H NMR (400 MHz, DMSO-d6, δ ppm): 1.27 (s : 12H); 1 .77 (m : 2H); 1 .84 (m : 1 H); 2.27 (m : 1 H); 2.41 (m : 1 H); 2.49 (2H); 2.62 (dd, J = 2.6 and 10.4Hz : 1 H); 2.69 (m : 1 H); 2.83 (dd, J = 6.2 and 10.4Hz : 1 H); 4.47 (td, J = 6.2 and 47Hz : 2H) ; 4.99 (m : 1 H); 6.77 (d , J = 8.4 Hz : 2H); 7.58 (d, J = 8.4 Hz : 2H).

LC/MS (m/z, MH+): 350

Intermediate (B). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate

To a solution of 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A) (1 .52 g, 8.63 mmol), in acetone (60 ml), was added K2C03 (1 .19 g, 8.63 mmol) and pivaloyl chloride (1.06 ml, 8.63 mmol). The reaction mixture was stirred at room temperature for 16 hours, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane in AcOEt (100/0 to 85/15, v/v) to give 1.55 g (69%) of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate (B) as a colorless oil.

1H NMR (400 MHz, DMSO-d6, δ ppm): 7.65 (d, 1 H); 7.10-7.04 (m, 2H); 2.95 (t, 2H); 2.68 (t, 2H); 1 .85-1 .65 (m, 4H).

LC/MS (m/z, MH+): 261

Intermediate (C). 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate

To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate (B) (15 g, 57.62 mmol) in DCM (500 ml) was added dropwise under argon pyridine (7.28 ml, 86.43 mmol) and trifluoromethanesulfonic anhydride (19.58 ml, 1 15.24 mmol). The reaction mixture was stirred at room temperature for 2 hours and ice (200 g) was added. The phases were separated, the aqueous phase was washed with DCM and the gathered organic phases were dried over MgS04, filtered and evaporated under reduced pressure to give 22 g (97%) of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate (C) as a white solid.

LC/MS (m/z, MH-): 391

Intermediate (D). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimeth lpropanoate

To a solution of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (C) (22 g, 56.07 mmol) and (3S)-1 -(3-fluoropropyl)-3-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) (20.56 g, 58.87 mmol) in dioxane (420 ml) and water (120 ml) was added under argon Pd(dppf)CI2 (2.75 g, 3.36 mmol) and Cs2C03 (36.57 g, 1 12.13 mmol). The reaction mixture was stirred for 1 hour at room temperature and was partitioned between water and DCM. The aqueous phase was washed with DCM and the gathered organic phases dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0 to 5%; V/V) to give 31 g (100 %) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D).

LC/MS (m/z, MH+): 466

Intermediate (E). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol

To a solution under argon of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D) (24.8 g, 53.26 mmol) in MeOH (300 ml), was added NaOH 5M (23 ml, 1 15.00 mmol). The reaction mixture was stirred for 2 hours at room temperature. pH was then adjusted to 7 by addition of 6N aqueous HCI solution. The MeOH was concentrated under reduced pressure, then DCM was added. The organic phase was dried over MgS04, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/ MeOH from 100/0 to 95/05 to give 18.8 g (93%) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (E) as a beige solid.

LC/MS (m/z, MH+): 382

Intermediate (F). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate

To a solution of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (E) (20.6 g, 54.00 mmol) in DCM (200 ml) and pyridine (6.55 ml, 81 .00 mmol), cooled to 5°C (ice bath), was added dropwise trifluoromethanesulfonic anhydride (18.93 ml, 108.00 mmol) under argon, and the reaction temperature was maintained <15°C. The ice bath was removed, and the brown suspension was stirred at room temperature for 2 hours. Ice (200 g) and DCM (200 ml) were added and the phases separated. The organic phase was dried over MgS04, and concentrated under reduced pressure. The residue was

purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 24.7 g (89.1 %) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (F) as a brown oil.

LC/MS (m/z, MH+): 514

Intermediate (G). Methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (F) (10.1 g, 19.67 mmol) in DMF (66 ml) and MeOH (33 ml), were added Pd(dppf)CI2 (909 mg, 1.18 mmol) and diisopropylethylamine (7.21 ml). The black suspension was carbonylated in an autoclave at 70°C under 5 bars of CO for 5 hours. The reaction mixture was filtered, then the filtrate was partially concentrated under reduced pressure. The residue was partitioned between AcOEt and water. The organic phase was washed with water (2x 100 ml), dried over MgS04, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCIW MeOH from 100/0 to 95/05 to give 7.13 g (86%) of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) as a brown gum.

LC/MS (m/z, MH+): 424

Intermediate (A1 ). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethanesulfonate

To a solution of commercially available 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A) (18.5 g, 105 mmol) in DCM (185 ml) and lutidine (13.35 ml, 1 13.505 mmol), cooled at 5°C under argon, was added dropwise trifluoromethanesulfonic anhydride (20.22 ml,

123.29 mmol) while keeping temperature between 10 and 20°C. The reaction mixture was stirred for 1 hour at 5°C then at room temperature for 1 hour.

Then, ice (200 g) was added and the slurry partitioned between water and DCM. The organic phase was washed with aqueous NaHC03 solution, dried over MgS04, filtered off and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/AcOEt from 100 to 90/10 to give 28.2 g (87%) of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (A1 ) as an orange oil. LC/MS (m/z, MH+): 309

Intermediate (B1 ). Methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate

To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (A1 ) (5.03 g, 16.32 mmol) in DMF (24 ml) and MeOH (12 ml), were added Pd(dppf)CI2 (754 mg, 0.98 mmol) and diisopropylethylamine (6 ml). The black suspension was carbonylated in an autoclave at 70°C under 5 bars of CO for 2.5 hours. The reaction mixture was filtered, then the filtrate was partially concentrated under reduced pressure, and the residue, was partitioned between AcOEt and water. The organic phase was washed with water (2x 75 ml) and aqueous HCI 0.5 N, dried over MgS04 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/AcOEt from 100/0 to 90/10 to give 3.4 g (95%) of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (B1 ) as a colorless oil.

LC/MS (m/z, MH+): 219

Intermediate (C1 ). Methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (B1 ) (18,19 g, 83,34 mmol) in DCM (500 ml) and anhydrous pyridine (1 1 ml, 130,56 mmol), cooled at 5°C under argon, was added dropwise trifluoromethanesulfonic anhydride (30 ml, 176,54 mmol). The reaction mixture, a thick suspension, was stirred at room temperature for 24 hours, then ice was added and partitioned between water and DCM. The organic phase was dried over MgS04, filtered off and concentrated under reduced pressure to give 29 g (100%) of methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (C1 ) as a yellow gum.

LC/MS (m/z, MH+): 351

Intermediate (G). Methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (C1 ) (29 g, 82.9 mmol), (3S)-1 -(3-fluoropropyl)-3-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) (28.9 g, 82.9 mmol), in dioxane (225 ml) were added Pd(dppf)CI2 under argon, complex with DCM (3.73 g, 4.57 mmol) and Cs2C03 1 .5 M aqueous solution (1 1 1.12 ml, 166.68 mmol). The reaction mixture was stirred at 60°C for 1 hour.

After cooling to room temperature, the reaction mixture was poured into a mixture of water (500 ml) and AcOEt (400ml). The organic phase was washed with brine, dried over MgS04, filtered on celite and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 23 g (65%) of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) as a brown gum.

LC/MS (m/z, MH+): 424

Intermediate (H). Methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide

To a solution of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3-carboxylate (G) (13.93 g, 32.89 mmol), in DCM (150 ml) was added under argon pyridinium tribromide (15.78 g, 44.41 mmol). The reaction mixture was stirred for 1 hour at room temperature. Water (200 ml) was added, organic phase was then dried over MgS04, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 16.4 g (85%) of methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3-carboxylate hydrobromide (H) as a yellow meringue.

LC/MS (m/z, MH+): 502

Intermediate (I). 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}- -dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.

To a solution of methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (H) (150 mg, 298.56 μηηοΙ), in dioxane (12 ml) and water (2 ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 μηιοΙ), Cs2C03 (204.48 mg, 626.97 μπιοΙ), and Pd(dppf)CI2 (14.63 mg, 17.91 mol). The reaction mixture was heated at 90°C for 3 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by column

chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg (47%) of 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (I).

LC/MS (m/z, MH+): 568

Compound (1 ). 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen -2-carboxylic acid

To a solution of 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (I) (80 mg, 140.72 μηηοΙ) in MeOH (5 ml) was added a solution of NaOH (562.88 μΙ, 5 M) and the reaction mixture was heated at 60°C for 5 hours and the solvent removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous HCI (5 M) added to pH 7. The slurry was extracted with DCM, dried over MgS04 and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) to give 60 mg (77%) of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid. 1H NMR (400 MHz, DMSO-d6, δ ppm): 1 .68 (m, 1 H); 1 ,79 (dm, J=25.3 Hz, 2 H); 2.07 to 2.23 (m, 5 H); 2.38 (m, 1 H); 2.46 (t, J=7.2 Hz, 2 H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.55 to 2.89 (m, 3 H); 4.47 (td, J=6.2 and 47.6 Hz, 2 H); 4.72 (m, 1 H); 6.63 (d, J=8.9 Hz, 2 H); 6.71 (m, 3 H); 7.18 (d, J=8.4 Hz, 1 H); 8.26 (dd, J=2.0 and 8.4 Hz, 1 H); 7.58 (d, J=2,0 Hz, 1 H); 7.63 (d, J=8.4 Hz, 1 H); 7.79 (s, 1 H); 12.3 (m, 1 H)

LC/MS (m/z, MH+): 554

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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