BACKGROUND OF THE INVENTION This invention relates to a process for making indoline cyclopropyl amide derivatives, which are EP4 antagonists useful for treating prostaglandin E mediated diseases, such as acute and chronic pain, osteoarthritis and rheumatoid arthritis. The compounds are antagonists of the pain and inflammatory effects of E-type prostaglandins and are structurally different from NSAIDs and opiates. Three review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists: Eicosanoids: From Biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf, and VeIo eds, Plenum Press, New York, 1996, chap. 14, 137-154; Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87; and Prostaglandins and Other Lipid Mediators, 2002, 69, 557-573.

Thus, selective prostaglandin ligands, agonists or antagonists, depending on which prostaglandin E receptor subtype is being considered, have anti-inflammatory, antipyretic and analgesic properties similar to a conventional non-steroidal anti-inflammatory drug, and in addition, have effects on vascular homeostasis, reproduction, gastrointestinal functions and bone metabolism. These compounds may have a diminished ability to induce some of the mechanism- based side effects of NSAIDs which are indiscriminate cyclooxygenase inhibitors. In particular, the compounds are believed to have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin- sensitive asthmatic subjects. In The Journal of Clinical Investigation (2002, 110, 651-658), studies suggest that chronic inflammation induced by collagen antibody injection in mice is mediated primarily through the EP4 subtype of PGE2 receptors. Patent application publications WO 96/06822 (March 7, 1996), WO 96/11902 (April 25, 1996), WO 2008/01164 (February 14, 2008) and EP 752421 -Al (January 08, 1997) disclose compounds as being useful in the treatment of prostaglandin mediated diseases.

Indoline cyclopropyl derivatives are useful as EP4 antagonists and processes for making such compounds are disclosed in PCT/CA08/000351, filed on February 22, 2008. Although the synthetic method disclosed in the above reference suffices to prepare small quantities of material, they suffer from a variety of safety issues, low yields or lengthy processes that are not amenable to large scale synthesis. The present invention describes an efficient and economical process for the preparation of derivatives that is useful for the production of kilogram quantities of material for preclinical, clinical and commercial use. SUMMARY OF THE INVENTION

The invention encompasses a process for making indoline cyclopropyl amide derivatives, which are EP4 antagonists useful for treating pain and inflammation.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses a process for making a compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the step of:

(al) reacting a compound of Formula 4 or 4a

4a

with a compound of Formula 6 or 6a

6 6a in the presence of a activating agent, a peptide coupling agent, and a first amine base in N ,N- dialkylformamide solvent to yield a compound of Formula 7, and

(bl) hydrolyzing the compound of Formula 7 in an alkanol solvent with a first base of formula χl-0H, wherein χl is selected from the group consisting of: potassium, cesium, lithium, sodium and rubidium, followed by acidification to yield the compound of Formula I; and

(cl) optionally reacting the compound of Formula I with a second base to yield a pharmaceutically acceptable salt of the compound of Formula I.

For the above steps (al) to (cl), the following amounts of the reagents may be used relative to compound 4a, l-(4-trifluoromethyl-benzyl)-lH-indole-7-carboxylic acid diisopropylamine salt: 0.8 to 1.6 equivalents of compound 6, 0.7 to 1.3 equivalents of the activating agent, 1 to 1.6 equivalents of the peptide coupling agent, 1 to 5 equivalents of the first amine base, 5 to 2OL of N,N-dialkylformamide per kg of compound 4a, 5 to 2OL of alkanol, per kg of compound 4a, 1 to 10 equivalents of the first base, 1 to 10 equivalents of the acid used in the acidification step, and 1 to 1.5 equivalents of the second base used to form the pharmaceutically acceptable salt. For purposes of this specification, alkanol my be a linear or branched Cj.galkanol, preferably ethanol.

For purposes of this specification, the N,N-dialkylformamide is defined to include N,N-diethylformamide and N,N-dimethylformamide. N,N-dimethylformamide is preferred.

For purposes of this specification, the term "activating agent" is defined to include triazolols, such as 1 -hydroxy-benzotriazole (HOBt) or 1 -hydroxy-7-azabenzotriazole (HOAt). An embodiment of the invention encompasses the process of the invention wherein the activating agent is 1 -hydroxy-benzotriazole (HOBT).

For purposes of this specification, the term "peptide coupling agent" is defined to include carbodiimide activating groups leading to the formation of amide bonds, such as diisopropylcarbodiimide, dicyclohexylcarbodiimide, and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide. An embodiment of the invention encompasses the process of the invention wherein the peptide coupling agent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC-HCl).

For purposes of this specification, the term "first amine base" is defined to include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, for example, N-methylmorpholine, diethylamine, triethylamine and dipropylamine. An embodiment of the invention encompasses the process of the invention wherein the first amine base is N-methylmorpholine.

For purposes of this specification, the term "first base" is defined to include any appropriate strong base such as lithium hydroxide or sodium hydroxide. In an embodiment of the invention, the first base is lithium hydroxide.

For purposes of this specification, the term "acidification" is defined to include the addition of an appropriate acid, such as HCl.

For purposes of this specification, the term "second base" is defined to include an appropriate base which forms a pharmaceutically acceptable salt with the compound of Formula I. An embodiment of the invention encompasses the process of the invention wherein the base is diethylamine.

For purposes of this specification, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, N-methylmorpholine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganese, potassium, sodium, zinc, and the like. Preferred salts derived from inorganic bases include sodium, potassium and calcium.

The invention also encompasses the process described in steps (al) to (cl) above further comprising making the compound of Formula 4a by

4a

(dl) reacting a compound of Formula 4

with a second amine base in alkanoate solvent to yield a compound of Formula 4a.

For the above step (dl), the following amounts of the reagents may be used relative to compound 4, 1 -(4-trifluoromethyl -benzyl)- lH-indole-7-carboxylic acid: 1 to 1.5 equivalents of the second amine base, 1 to 15L of alkanoate per kg of compound 4. For purposes of the specicifcation the alkanoate solvent is defined to include isopropylacetate, ethylacetate and methylacetate. Isopropylacetate is preferred.

For purposes of this specification, the term "second amine base" is defined to include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, for example, N-methylmorpholine, diethylamine, triethylamine and dipropylamine, diisopropylamine. An embodiment of the invention encompasses the process of the invention wherein the second amine base is diisopropylamine.

The invention also encompasses the process described in steps (al) to (dl) above further comprising making the compound of Formula 4 by

(el) reacting a compound of Formula 1

with a compound of Formula 2

in the presence of a third base and N,N-dialkylformamide to yield a compound of Formula 3, and

(fl) hydro lyzing the compound of Formula 3 in a solvent of alkanol with a fourth base of formula χl-OH, wherein χl is selected from the group consisting of: potassium, cesium, lithium, sodium and rubidium, followed by acidification to yield the compound of Formula 4.

For the above step (el) to (fl), the following amounts of the reagents may be used relative to compound 1, lH-indole-7-carboxylic acid methyl ester: 1 to 1.5 equivalent of compound 2, 1 to 1.5 equivalents of the third base, 5 to 2OL of N,N-dialkylformamide per kg of compound 1, 1 to 10 equivalents of the of the acid used in the acidification step, and 2 to 15L of methanol per kg of compound 1.

For purposes of this specification, the alkanol is defined as C^alkanol. Methanol is preferred.

For purposes of this specification, the N,N-dialkylformamide is defined to include N,N-diethylformamide and N,N-dimethylformamide. For purposes of this specification, the term "third base" is defined to include any appropriate strong base such as potassium tert-butoxide or sodium hydride. In an embodiment of the invention, the third base is potassium tert-butoxide. For purposes of this specification, the term "fourth base" is defined to include any appropriate strong base such as lithium hydroxide or sodium hydroxide. In an embodiment of the invention, the fourth base is lithium hydroxide.

For purposes of this specification, the term "acidification" is defined to include the addition of an appropriate acid, such as HCl.

The invention also encompasses the process described in steps (al) to (fl) above further comprising making the compound of Formula 6

by (g 1 ) reacting a compound of Formula 5

with an ethyl Grignard reagent of the formula EtMgX, wherein X is a halide, in the presence of Lewis acid to yield a compound of Formula 6.

For purposes of this specification the Lewis acid is defined to include organotitanium, such as titaniumisopropoxide, chlorotriisopropoxytitanium, and triisopropoxymethyltitaniummethane, as well as boron trihalide and titanium tetrachloride.

For purposes of this specification, the term "boron trihalide" is defined to include BX3, wherein X is F, Cl or Br, or an adduct thereof such as with an ether. In an embodiment of the invention the boron trihalide is boron trifluoride diethyl ether. Titaniumisopropoxide, followed by the addition of boron trihalide is preferred.

For the above step (gl), the following amounts of the reagents may be used relative to compound 5, methyl 4-cyanobenzoate: 2 to 4 equivalents of the ethyl Grignard reagent, and 2 to 6 equivalents Lewis acid (for example, 1 to 2 equivalents of titaniumisopropoxide, and 1 to 4 equivalents of boron trihalide).

For the purposes of this specification, the term "ethyl Grignard reagent" is defined to include ethyl magnesium bromide and ethyl magnesium chloride. In an embodiment of the invention the Grignard reagent is EtMgBr. For purposes of this specification, the term "boron trihalide" is defined to include BX3, wherein X is F, Cl or Br, or an adduct thereof such as with an ether. In an embodiment of the invention the boron trihalide is boron trifluoride diethyl ether.

Unless specified, all reactions may be conducted in an appropriate solvent which can be readily selected by one having ordinary skill in the art in view of the examples that follow.

The invention also encompasses the diethylamine salt of the compound of Formula I

I.

The following abbreviations have the indicated meanings:

DIPEA N,N'-dπsopropylethylamine

Et ethyl

EDC-HCl N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

DMF dimethylformamide

HOBT 1 -hydroxy-benzotriazole

HOAT 1 -hydroxy-azabenzotriazole

Me methyl

Ms mesyl

MTBE methyl t-butyl ether

NMM N-methlymorpholine

TFA trifluoroacetic acid

THF tetrahydrofuran Examples:

EXAMPLE A

4-( 1 - { [ 1 -(4-Trifluoromethyl -benzyl)- 1 H-indole-7-carbonyl] -amino } -cyclopropy^-benzoic acid diethylamine salt

1) KOtBu (1 2 eq), DMF, 2 hours

Example A

Indole-Ester Alkylation

1) KOtBu (1.2 eq), DMF, 2 hours

Materials MW Amount Moles Ea

Indole-ester 1 175.18 209.8 g 1.20 1.00

Potassium tert-butoxide 112.21 161.6 g 1.44 1.20

Trifluoromethyl benzene 239.03 343.7 g 1.44 1.20

Bromide 2

DMF 9 mL/g 1 .9 L

H ₂ O 9 mL/g 1 .9 L

H ₂ O rinse 4 x 4.8 mL/g 4 X I L

To a stirred solution of lH-Indole-7-carboxylic acid methyl ester 1 (209.8 g, 1.20 mole) in DMF (1.4 L) at 9 ⁰ C was added KOtBu (161.6 g, 1.44 mole) portion wise (temperature rose to 15 ⁰ C). The cold bath was removed and the reaction mixture was stirred at r.t. for 2 hours. The reaction mixture was cooled to 10 ⁰ C and a solution of l-bromomethyl-4-trifluoromethyl-benzene 2 (343.7g, 1.44 mole) in DMF (400 mL) was added over 2.5 hours and the flask was rinsed with DMF (100 mL). H ₂ O (1.9 L) was added at 15 ⁰ C in order to precipitate the product. The slurry was filtered and rinsed with H ₂ O (4 X IL) and the product dried under a flow of N ₂ under vacuum. 411.1 g of material was obtained at 82 A%. A sample was purified by chromatography : ¹ H NMR (500 MHz, Acetone-*/*) δ 7.88 (dd, J = 7.8, 1.1 Hz, IH), 7.60 (d, J = 8.2 Hz, IH), 7.58 (d, J = 3.2 Hz, IH), 7.53 (dd, J= 7.5, 1.1 Hz, IH), 7.13 (X, J = 7.6 Hz, IH), 7.07 (d, J = 8.0 Hz, IH), 6.74 (d, J = 3.2 Hz, IH), 5.83 (s, 2H), 3.72 (s, 3H); ¹⁹ F NMR (377 MHz, Acetone-afe) δ - 62.4; ¹³ C NMR (100 MHz, Acetone-tf ₆ ) δ 167.7, 143.8, 132.8, 132.7, 132.2, 128.9 (q, J= 32 Hz), 127.3, 126.0, 125.5 (m), 124.9, 123.3, 119.0, 117.4, 102.8, 52.2, 51.8; IR (CDCl ₃ ) 3112, 3076, 3038, 2987, 2949, 2844, 1925, 1716, 1619, 1524, 1448, 1421, 1321, 1275, 1161, 1134, 1113, 1067, 1017, 844, 749, 731cm ^"1 ; HRMS-ESI (m / z): [M+H] ⁺ calcd for Ci ₈ H ₁₄ F ₃ NO ₂ , 334.10494; found 334.10548. Hydrolysis of Alkylated Indole-Ester

Materials MW Amount Moles Efl

Alkylated indole-ester 3 333.30 406 g 1.21 1.00

4N LiOH 1.5 L 6.0 5.00

MeOH 6.2 niL/g 2 .5 L

4N HC1 3.7 niL/g 1 .5 L

MeOH : H ₂ O (I : 1) 2 x 0.8 niL/g 2 X 32O mL

MeOH 9.9 niL/g 4 L

H ₂ O 9.9 mL/g 4 L

MeOH : H ₂ O (I : 1) 2 x 1.6 mL/g 2 X 64O mL

A stirred suspension of 1 -(4-trifluoromethyl -benzyl)- lH-indole-7-carboxylic acid methyl ester 3 (406 g, 1.21 mole) in MeOH (2.5 L) was heated to 70 ⁰ C. An aqueous solution of 4N LiOH (1.5 L) was then added and the reaction mixture was stirred at that temperature for 2 hours. The mixture was cooled to 10 ⁰ C and an aqueous solution of 4 N HCl (1.5 L) was slowly added at such a rate that keeped the temperature below 25 ⁰ C. The slurry was filtered and rinsed with MeOH : H ₂ O (1 : 1) (2 X 320 mL). The product was crystallized from MeOH (4L) and H ₂ O (4L). The slurry was filtered and rinsed with MeOH : H ₂ O (1 : 1) (2 X 640 mL) and dried under a flow of N ₂ /vacuum to provide 350 g (86 A%, 79 wt%) : ¹ H NMR (500 MHz, Acetone-t/ ₆ ) δ 11.7 (s, IH), 7.88 (dd, J= 7.8, 0.9 Hz, IH), 7.71 (d, J= 8.0 Hz, IH), 7.57 (d, J= 8.2 Hz, IH), 7.56 (d, J = 3.2 Hz, IH), 7.14 (t, J= 7.7 Hz, IH), 7.09 (d, J= 8.1 Hz, IH), 6.73 (d, J= 3.2 Hz, IH), 5.93 (s, 2H); ¹⁹ F NMR (377 MHz, Acetone-^) δ -62.7; ¹³ C NMR (100 MHz, Acetone-^) δ 168.1, 144.1, 133.2, 132., 132.2, 128.9 (q, J= 32 Hz), 127.3, 127.3, 125.7, 125.4, 1 18.9, 1 17.4, 102.8, 52.2; IR (CDCl ₃ ) 1684, 1526, 1417, 1322, 1269, 2258, 1124, 1064, 725 cm ^'1 HRMS-ESI (m I z): [M+H] ⁺ calcd for C ₁₇ H ₁₃ F ₃ NO ₂ , 320.08929; found 320.08958. Indole-Acid Diisopropylamine Salt Formation

Materials MW Amount Moles Ea

Alkylated indole-acid 4 319.28 35O g 1.09 1.00

Diisopropylamine 188 niL 0.71 1.33

iPrOAc 5 mL/g 1.75 L heptane 5 mL/g 1.75 L iPrOAc .- Heptane (1 : 1) 2 x 2.5 mL/g 2 x 860 niL

To a stirred solution of l-(4-Trifluoromethyl -benzyl)- lH-indole-7-carboxylic acid 4 (350 g, 1.09 mole) in iPrOAc (1.75 L) was added 1Pr ₂ NH (100 mL, 0.71 mole) dropwise and seeded. The slurry was stirred for 30 min and the rest of the iPr ₂ NH (88 mL, 0.62 mole) was added over a period of 30 min. The slurry was aged for another 30 min, heptane (1.75 L) was added and the solid filtered over a frit and rinsed twice with (1 : 1) iPrOAc : heptane (2 x 860 mL), dried under vacuum with a N ₂ flow to give 352.8g of white solid (78 % yield) : ¹ H NMR (500 MHz, Acetone-^) δ 7.59(dd, J = 7.8, 0.9 Hz, IH), 7.54 (d, J 8.1= Hz, IH), 7.51 (d, J = 7.2 Hz, IH), 7.28 (d, J = 3.2 Hz, IH), 7.14 (t, J= 8.0 Hz, IH), 7.01 (t, J = 7.5 Hz, IH), 6.57 (d, J= 3.2 Hz, IH), 6.12 (s, 2H), 3.17 (quint, J = 6.4 Hz, 2H), 1.15 (d, J = 6.5 Hz, 12H); ¹⁹ F NMR (377 MHz, Acetone-^) δ -62.3; ¹³ C NMR (100 MHz, Acetone-^) δ 173.8, 146.1, 133.8, 131.6, 131.2, 132.2, 129.1 (q, J = 32 Hz), 127.8, 127.5, 126.0, 125.97, 125.93, 125.89, 125.3 (q, J = 271 Hz), 124.4, 122.3, 119.5, 103.2, 51.8, 46.7, 19.3. Cyclopropanation Reaction

Materials MW Amount M] oles t ifl

Methyl 4-cyanobenzoate 5 161.16 2.60 Kg 16 .13 1 .00

Ti(OiPr) ₄ 284.22 4.73 L 16 .13 1 .00

3.1 M EtMgBr 133.27 10.5 L 32 .27 2 .00

BF ₃ OEt ₂ 141.93 4.09 L 32 .27 2 .00

Toluene 15 mL/g 4O L

2-Me-THF 30 mL/g 8O L

3N HC1 15 mL/g 4O L

3N NaOH 10 mL/g 26 L

Brine 5 mL/g 13 L

A visually clean 100 L 5 -neck round-bottom flask equipped with a mechanical stirrer, a thermocouple, a nitrogen inlet and a cooling bath was charged with the methyl 4-cyanobenzoate 5 (2.60 Kg, 16.13 moles) and toluene (40 L). The mixture was cooled to -25 ⁰ C and Ti(OiPr) ₄ (4.73 L, 16.13 moles) was added to the solution over 5 minutes. Then, 3.1M ethylmagnesium bromide (10.5 L, 32.27 moles) was added over a period of 2 hours keeping the temperature of the reaction mixture between -25 ⁰ C and -13 ⁰ C. The mixture was aged at -20 ⁰ C for 30 minutes and borontrifluoride diethyl ether (4.09 L) was added over 40 minutes keeping the reaction mixture between -24 ⁰ C and -8 ⁰ C. The mixture was aged at -20 ⁰ C for 30 minutes and the reaction was quenched by the slow addition of 3N HCl (40 L) over 30 minutes. The mixture was transferred into an extractor and the layers were separated. The aqueous layer was washed with toluene (13 L) and extracted with 2-Me-THF (2 x 26 L) and (2 x 13 L). The combined Me-THF layers were washed with 4N NaOH (26 L) and with brine (13 L). The assay yield of the cyclopropylamine was 43% (1.334 Kg). Conversion and purity were determined by HPLC with a 4.6 mm * 250 mm Zorbax Extend C18 column (0.1% NH ₄ OH / CH ₃ CN 95:5 to 60:40 over 8 min, then hold 2.5 min, to 10:90 over 4.5min, hold 5.5min, 1.0 mL/min, 210 nm, 40 ⁰ C); t _R = 9.6 min. Cyclopropylamine, Methanesulfonic Acid Salt Formation

Materials MW Amount Moles Efl

Cyclopropylamine 6 191.23 2.63 Kg 13.75 1.00 MsOH 96.11 1.00 L 15.40 1.12

THF 14 mL/g 37 L

A visually clean 100 L 5 -neck round-bottom flask equipped with a mechanical stirrer, a thermocouple, a nitrogen inlet and a cooling bath was charged with the cyclopropylamine 6 (2.63 Kg, 13.75 moles) and THF (32 L). A solution of MsOH (1.00 L, 15.40 moles) in THF (4.0 L) was added drop wise over a period of 2 hours (after the first 10 minutes of addition, seeds (500 mg) were added to start the crystallization). The suspension was stirred at r.t. for a period of 15 hours, filtered and rinsed with a small portion of the mother liquors. The salt was washed twice with cold THF (2 x 8 L), then dried on the frit for 3 hours, in the vacuum oven, first at 30 ⁰ C for 20 hours and then at 50 ⁰ C for a period of 60 hours to give 3.93 Kg at 94.4%wt (92.9% yield, 96.2A%). The losses to the mother liquors were 8.2 g (0.3%). Melting point : 229.2-230.7 °C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.78 (s, 3 H); 7.96 (d, J= 8.24 Hz, 2 H); 7.50 (d, J= 8.24 Hz, 2

H); 3.84 (s, 3 H); 2.35 (s, 3 H); 1.46-1.39 (m, 2 H); 1.33-1.22 (m, 2 H). ¹³ C NMR (100 MHz, DMSO-de): δ 165.8, 143.3, 129.3, 128.8, 126.4, 52.3, 35.6, 13.9; IR (neat) 3017, 2959, 2722,

1710, 1613, 1436, 1291, 1018, 768; HRMS (ESI) m/z calcd for C1 1H13NO2 (M + H) 192.10191, found 192.10424.

Cyclopropylamine, Methanesulfonic Salt Break

Materials MW Amount Moles

MsOH salt 6a 287.33 3.93 Kg 12.91 1.00

2M K ₃ PO ₄ 5 mL/g 19L iPAc lO mL/g 39L

A visually clean 160 L 5 -neck extractor equipped with a mechanical stirrer, a thermocouple and a nitrogen inlet was charged with the MsOH salt 6a (3.85 Kg, 12.91 moles) and iPAc (39 L). To the solution was added 2M K ₃ PO ₄ (19 L). The solution was stirred at r.t. for a period of 2 hours to completely break the salt so that no solid remained in suspension. The layers were separated. The organic layer was washed once with water (19 L) and once with brine (19 L). The assay yield of cyclopropylamine was checked on the iPAc solution and showed to be 2.445 Kg (98.8% yield, 95.5A%). The losses to the aqueous layer were below 0.1%. The iPAc layer was concentrated on rotavap and swiched with 10 L THF. Melting point : 49.6-50.4°C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (d, J = 8.28 Hz, 2 H), 7.29 (d, J = 8.28 Hz, 2 H), 3.86 (s, 3 H), 2.26 (s, 2 H), 1.20-1.07 (m, 2 H), 1.08-0.98 (m, 2 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 166.9, 152.2, 129.6, 127.6, 124.7, 51.9, 36.4, 19.2; IR (neat) 3393, 3369, 3325, 2955, 1710, 1610, 1282, 1108, 1015, 830 cm-1. HRMS (ESI) m/z calcd for C _n H ₁₃ NO ₂ (M + H) 192.10191, found 192.10257. Amidation Reaction

4a

Materials MW Amount Moles Efl

Indole-acid 420.47 20O g 0.476 1.00 diisopropylamine salt 4a

Cyclopropylamine 6 191.23 109.2 g 0.571 1.20

1 -Hydroxybenzotriazole 153.14 72.8 g 0.476 1.00

Hydrate

N-(3-Dimethylaminopropyl)- 191.70 H9 g 0.618 1.30 N'-ethylcarbodiimide hydrochloride N-Methylmorpholine 101.15 157 mL 1.43 3.00

DMF 7.6 mL/g 1.52 L

DMF 12.4 mL/g 2.48 L

Water 10 mL/g 2.00 L

DMF : water (2 : 1) 10 mL/g 2.00 L

IN HCL 10 mL/g 2.00 L

IN NaOH 10 mL/g 2.00 L

Water 10 mL/g 2.00 L

To a cooled solution of 1 -(4-Trifluoromethyl -benzyl)- lH-indole-7-carboxylic acid diisopropylamine salt 4a (200.0 g, 476 mmol), methyl 4-(l-aminocyclopropyl)benzoate 6 (118 g at 92.5 wt%, 109.2 g, 571 mmol) and 1 -hydroxybenzotriazole (72.8 g, 476 mmol) in DMF (1.52 L) at 0-5 ⁰ C was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (119 g, 618 mmol) and N-methylmorpholine (157 mL, 1.43 mol). The reaction mixture was stirred for 30 min at 0-5 ⁰ C and then warmed to room temperature. After 16 hours at room temperature DMF (2.48 L) was added. Water (2.00 L) was added over 1 hour and the resulting slurry was stirred at room temperature for 1 hour. The slurry was then filtered and rinsed with 2: 1 DMF / water (2.00 L). The filter cake was resuspendended in IN HCl (2.00 L), filtered, resuspended in IN NaOH (2.00 L), filtered, resuspended in water (2.00 L), filtered and dried on filter for 16 hours. HPLC assay of the filter cake showed 570.8 g at 39.37 wt% (224.7 g, 96% yield) 97.5 A%. Mp: 189-191 ⁰ C. ¹ H NMR (500 MHz, Acetone-d ₆ ): δ 8.31 (s, 1 H), 7.83 (d, J = 8.1 Hz, 2 H), 7.76 (d, J= 7.9 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.42 (d, J= 7.3 Hz, 1 H), 7.37 (d, J= 3.2 Hz, 1 H), 7.34 (d, J= 8.1 Hz, 2 H), 7.10 (t, J= 7.6 Hz, 1 H), 6.96 (d, J= 8.0 Hz, 2 H), 6.66 (d, J - 3.2 Hz, 1 H), 5.76 (s, 2 H), 3.85 (s, 3 H), 1.25-1.21 (m, 2 H), 1.10-1.05 (m, 2 H). ¹³ C NMR (125 MHz, Acetone-d ₆ ): δ 169.8, 167.0, 150.0, 145.1, 133.1, 132.1, 131.9, 130.1, 129.9 (q, J = 32.6 Hz), 128.6, 127.3, 126.2, 126.1, 125.3 (q, J = 271.1 Hz), 124.2, 123.3, 123.1, 119.5, 103.4, 52.1, 51.8, 35.5, 18.8. ¹⁹ F NMR (375 MHz, Acetone-d ₆ ): δ -63.0. IR (neat): 3265, 3009, 2947, 2843, 1717, 1639, 1500, 1409, 1321, 1278, 11 17. HRMS (ES): m/z calcd for [C ₂₈ H ₂₃ F ₃ N ₂ O ₃ + H] ⁺ : 493.1734; found: 493.1746. Conversion and purity were determined by HPLC with a 4.6 mm x 5 cm Zorbax SB-C 18 column (0.1% aq H ₃ PO ₄ / CH ₃ CN 90:10 to 5:95 over 6 min, hold 2 min, to 90:10 over 0.1 min, hold 2 min, 1 mL/min, 220 nm, 35 ⁰ C); indole ester / _R = 6.22 min.

In the alternative, the intermediate 7 can be obtained using a combination of the following coupling partners : the indole-acid diisopropylamine salt 4a with the cyclopropylamine mesylate salt 6a, or the indole-acid 4 with either the cyclopropylamine 6 or cyclopropylamine mesylate salt 6a following the same experimental procedure.

Benzylic Ester Hydrolysis

Materials MW Amount Moles Efl

Benzylic ester 7 492.49 222.5 g 0.452 1.00 4N LiOH 565 mL 2.259 5.00 4N HC1 565 mL 2.259 5.00 IN HCl 111.3 mL 0.10 0.22

EtOH lO mL/g 2.23L

EtOH : IN HCl (1.78: 1) lO mL/g 2.23 L water lO mL/g 2.23 L

To a heated slurry of methyl 4-(l-[({ l-[4-(trifluoromethyl)benzyl]-lH-indol-7-yl} carbonyl)amino] cyclopropyl) benzoate 7 (565.2 g at 39.37 wt%, 222.5 g, 452 mmol) in EtOH (2.23 L) at 65 ⁰ C was added 4N LiOH (565 mL, 2.26 mol) over 10 minutes. The slurry was stirred at this temperature for 1.5 hours during which time it turned into a clear solution and it was then cooled to room temperature. 4N HCl (565 mL, 2.26 mol) was added over 1 hour then IN HCl (111.3 mL, 0.1 mol) was added over 10 min. The resulting slurry was filtered, washed with 1.78: 1 EtOH / IN HCl (2.23 L). The filter cake was resuspended in water (2.23 L), filtered and dried on filter for 3h. The solid was dried in a vacuum oven at 30 ⁰ C for 60 hours with nitrogen sweep. The desired acid (195.7 g, 90% yield) was isolated as a white powder (98.8 A%). Mp: 247-248 ⁰ C. ¹ H NMR (400 MHz, Acetone-d ₆ ): δ 11.2-11.0 (m, 1 H), 8.29 (s, 1 H), 7.89 (d, J = 8.2 Hz, 2 H), 7.76 (d, J= 7.9 Hz, 1 H), 7.53 (d, J = 8.1 Hz, 2 H), 7.43 (d, J= 7.3 Hz, 1 H), 7.38 (d, J- 2.7 Hz, 1 H), 7.37 (d, J = 8.3 Hz, 2 H), 7.10 (t, J = 7.6 Hz, 1 H), 6.97 (d, J= 8.0 Hz, 2 H), 6.66 (d, J = 3.2 Hz, 1 H), 5.78 (s, 2 H), 1.27-1.21 (m, 2 H), 1.1 1-1.05 (m, 2 H). ¹³ C NMR (125 MHz, Acetone-dό): δ 169.8, 167.5, 149.8, 145.1, 133.1, 132.1, 131.9, 130.4, 129.3 (q, J = 32.4 Hz), 128.9, 127.3, 126.1, 126.1, 125.3 (q, J= 269.2 Hz), 124.2, 123.3, 123.1, 119.5, 103.4, 51.8, 35.5, 18.8. . ¹⁹ F NMR (375 MHz, Acetone-d ₆ ): δ -63.0. IR (neat): 3274, 3013, 2887, 1696, 1678, 1630, 1517, 1413, 1317, 1283, 1122. HRMS (ES): m/z calcd for [C ₂₇ H ₂ IF ₃ N ₂ O ₃ + H] ⁺ : 479.1577; found: 479.1591. Conversion was determined by HPLC with a 4.6 mm x 5 cm Zorbax SB-C18 column (0.1% aq H ₃ PO ₄ / CH ₃ CN 90:10 to 5:95 over 6 min, hold 2 min, to 90:10 over 0.1 min, hold 2 min, 1 mL/min, 220 nm, 35 ⁰ C); t _R = 5.49 min.

Diethylamine Salt Formation

Example A

Materials MW Amount Moles Efl

Benzoic acid 8 478.46 192.4 g 0.40 1.00 Diethylamine 73.14 5O mL 0.48 1.20

EtOH 9.9 mL/g 1.9 L MTBE 9.9 mL/g 1.9 L

MTBE 2 x 5 mL/g 2 x 950 mL

A suspension of 4-(l-{[l-(4-Trifluoromethyl-benzyl)-lH-indole-7-carbonyl] -amino }- cyclopropyl)-benzoic acid 8 (192.4g, 0.40 mole) in ethanol (1.9 L) was heated to 60 ⁰ C and Et ₂ NH (50 mL, 0.48 mole) was added. The solution was seeded and stirred at 60 ⁰ C for an additional 30 min before being slowly cooled to r.t. MTBE (1.9 L) was then slowly added over 2 hours. The slurry was filtered and rinsed with MTBE (2 X 950 mL) and dried under vacuum with a flow OfN ₂ to give 205.6g of white solid (93 % yield, 99.3 A%). ¹ H NMR (500 MHz, DMF-d ₆ + D ₂ O): δ 9.0 (s, 1 H), 7.92 (d, J = 8.3 Hz, 2 H), 7.80 (d, J = 7.8 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 2 H), 7.51 (d, J= 3.2 Hz, 1 H), 7.45 (d, J= 7.2 Hz, 1 H), 7.27 (d, J= 8.3 Hz, 2 H), 7.16 (t, J= 7.5 Hz, 1 H), 7.08 (d, J = 8.0 Hz, 2 H), 6.71 (d, J = 3.2 Hz, 1 H), 5.78 (s, 2 H), 3.05 (q, J= 7.2 Hz, 4H), 1.27 (t, J = 7.2 Hz, 6H), 1.20-1.17 (m, 2 H), 0.97-.096 (m, 2 H). ¹³ C NMR (125 MHz, DMF-d ₆ ): δ 169.3, 169.2, 146.6, 144.5, 133.7, 132.3, 131.4, 130.9, 129.3, 126.8, 125.4, 124.6, 123.0, 122.7, 122.5, 118.7, 102.6, 50.8, 42.5, 17.8, 12.6.