WO2010011584A2

WO2010011584A2 - Process for making a renin inhibitor

Info

Publication number: WO2010011584A2
Application number: PCT/US2009/051101
Authority: WO
Inventors: Remy Angelaud; Ian Davies; Courtney Maguire; Stephen Lau; Paul O'shea; Scott Shultz
Original assignee: Merck & Co., Inc.; Merck Frosst Canada Ltd.
Priority date: 2008-07-25
Filing date: 2009-07-20
Publication date: 2010-01-28
Also published as: WO2010011584A3

Abstract

A salt of the compound (3'R,4'S)-6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid [2-chloro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amide selected from the group consisting of monoacetate salt and bis-D-tartrate salt. In one embodiment of the invention, the salt is (3',4'S)-6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid [2-chloro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amide monoacetate. In one embodiment of the invention, the salt is (3'R, 4'S)-6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid [2-chloro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amide bis-D-tartrate. The invention also describes a asymmetric synthesis of (3'R, 4'S)-6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid [2-chloro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amide as a monoacetate salt or as a bis-D-tartrate salt.

Description

TITLE OF THE INVENTION

PROCESS FOR MAKING A RENIN INHIBITOR

BACKGROUND OF THE INVENTION WO2006/129237 describes a procedure for preparing racemic compound 6-[2-

(2_?6-DichIoro-4-methyl-phenoxy>ethoxy]"r,2^t,3^> _J4'₅5',6'-hexahydro-[3,4']bipyridinyl-3^l- carboxylic acid [2-chloro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyI-amide and chiral separation to form the active diastereoisomer (3% ^'5)-6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]- 1 ^■ ₅2'_s3'_s4',5'.6^l-hexahydro-[3_:,4']bipyridinyl-3^l-carboxylic acid [2-chloro-5-(2-methoxy-ethyl> benzyl] -cyclopropyl-amide.

The present invention describes an asymmetric synthesis to (3% 4'5)-6-[2~(2,6- Dichloro^-methyl-phenoxyJ-ethoxyJ-r^'^'^'^'^'-hexahydro-β^'Jbipyridinyl-S'-carboxylic acid t2-chloro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amide via a catalytic asymmetric hydrogenation of an ene-ester intermediate. The invention also describes a synthesis of a cyclopropylamine intermediate, and acetate and bis-D-tartrate salts of (3% ¥'5)-6-[2-(2,6- Dichloro-4-methyl-ρhenoxy)-ethoxy]-r,2',3^l,4^r ₅5',6'-hexahydro-[3_}4']bipyridiiiyl-3^r-carboxylic acid [2-chloro-5-(2-methoxy-ethyl)-ben2yl]-cyclopropyl-amide.

SUMMARY OF THE INVENTION The invention describes a salt of the compound (3% ¥'5)-6-[2-(2,6-Dichloro-4- methyl-ρhenoxy)-ethoxy]-r,2^l _s3'₎4',5'_s6^I-hexahydro-[3,4^t]bipyridinyl-3'-carboxylic acid [2-chloro- 5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amide selected from the group consisting of monoacetate salt and bis-D-tartrate salt hi one embodiment of the invention, the salt is (3% 4'5)-6-[2-(2_s6-Dichloro-4- methyI-ρhenoxy)-ethoxy]-r,2^r _J3',4',5',6^I-hexahydro-t3,4']bipyridinyl-3'-carboxylic acid [2-chlorθ" 5-(2-methoxy-ethyl)-benzyl] -cyclopropyl-amide monoacetate. hi one embodiment of the invention, the salt is (3% 4'5)-6-[2-(2,6-DichIoro-4- methyl-phenoxy^ethoxyJ-r^'^'^'jS'jό'-hexahydro-tS^'Jbipyridinyl-S'-carboxylic acid [2-chloro- 5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amide bis-D-tartrate. The invention also describes asymmetric synthesis of (3% 4'5)-6-[2-(2,6-

Dichloro-4-methyl-phenoxy)-ethoxy]-r,2^l _s3',4^l,5^t,6'-hexahydro-[3_s4']bipyridinyl-3^l-carboxylic acid [2-chloro-5-(2-methoxy-ethyl)-beri2yl] -cyclopropyl-amide as a monoacetate salt or as a bis- D-tartrate salt.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

_ \ _ The salt (3% ^'₍S)-6-[2-(2_?6-Dichloro-4-methyl-phenoxy)-ethoxy]-l¹,2¹,3¹.4^l,5',6^<" hexahydro43,4']bipyricu^"nyl-3'-carboxylic acid [2-chloro-5-(2~methoxy-ethyl)^»benzyl]- cyclopropyl-amide monoacetate is

monoacetate sait

The salt (3% 4'5)-6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-l'_!2',3^r _;4¹,5',6¹- hexahydro-[3,4']bipyridinyl-3^r-carboxyHc acid [2-chloro-5-(2-methoxy-ethyl)-benzyl]- cyclopropyl-amide bis-D-tartrate is

bis-D-tartrate salt

The invention also includes a compound which, is

where R is Br or B(OH)2-

The invention also includes a compound which is

The invention also includes a compound which is

The invention al

The invention also includes a process for preparing boronic acid J

which comprises a) adding BuMgCl to 2

and cooling to a temperature of between 0°C and -5O⁰C, b) adding B(OCH3)3 to the bromopyridine to form a mixture, and c) warming the mixture formed in step b) to a temperature of between 10°C and -15OC, to form the boronic acid 3\

In one embodiment of the process for preparing compound 31, the temperature in step a) is between about -25°C and -45OC.

In another embodiment of the process for preparing compound 3', the temperature in step a) is about -35⁰C. hi another embodiment of the process for preparing compound 3', the temperature in step c) is between about O⁰C and -10°C. in another embodiment of the process for preparing compound 3', the temperature in step a) is about -5⁰C.

The invention also includes a process for preparing cis ester S

which comprises a) combining a ferrocene containing bisphosphine ligand and a ruthenium catalyst to form a catalyst solution, and b) hydrogenating ene-ester 5

in the presence of the catalyst solution, to form chiral ester 8.

In one embodiment of the process for preparing chiral ester 8, the ferrocene containing bisphosphine Iigand is (if)-l-[(^)-2-(Di-2-furylphosphino)-ferrocenyl]ethyldi-fe?-f.' bulyl-phosphine and the ruthenium catalyst is Ru(l,5-η5-cyclooctadϊenyl)(methylallyl)2.

The invention also includes a process for preparing trans acid 9

Boc which comprises a) adding Boc2θ to cis ester 8

at a temperature between 15°C and 30°C to form a mixture; and b) heating the mixture formed in step a) to a temperature between about 60°C and about 80OC for a period of time between about 1 hour and 3 hours, to form trans acid 9.

In one embodiment of the process for preparing trans acid 9, the temperature in step a) is between about 20OC and 25°C.

In another embodiment of the process for preparing trans acid 9, the temperature in step a) is about 22°C.

In another embodiment of the process for preparing trans acid 9, the temperature in step b) is between about 68<>C and 72oC.

Li another embodiment of the process for preparing trans acid 9, the temperature in step b) is about 70°C.

The invention also includes a process for preparing

which comprises adding phosphoric acid to

to form compound 12.

Catalysts

The catalyst (if)-l -[(^-2-(Di-2-furylphosphino)-ferrocenyl]ethyldi-tert.-butyl- phosphine (also referred to as (i?)-(5)-2-Fur2PF-PtBu2, and also as SL-J212-1), available from

Solvias AG (Basel, Switzerland), is shown as

(COD)Ru(Me-allyl)₂ (also referred to as " Ru(l,5-η5- cyclooctadienyl)(methylallyl)2^tl) is available from Arran Chemicals.

The process for preparing salts of the invention, and for preparing intermediate compounds of the process, is outlined in Scheme L

Scheme 1

Scheme 1 (continued)

rtrate salt

The process for preparing intermediate compound JjO of the process, is outlined in

Scheme 2.

Scheme 2

Step 1 ; 2,6-Dichloro-4-methylphenol 1

To a 400L vessel was charged p-cresol (8.0 kg, 74 moles) and acetonitrile (31 kg).

The solution was cooled to 0⁰C and 10% aqueous sodium hypochlorite solution (127 kg, 169 moles) was added over 2 hours keeping the temperature <5°C. On complete addition the batch was allowed to warm to 18 ⁰C and agitated overnight when HPLC showed complete reaction. The batch was cooled to 10 ⁰C and MTBE (49 kg) was charged followed by solid sodium bisulfite (3.85 kg, 37 moles) in portions ensuring the temperature does not exceed 18 ⁰C. The batch was aged for 1 hour when starch iodide paper indicated no oxidant present. Concentrated hydrochloric acid (12.4 kg, 126 moles) was then added while keeping the temperature <10°C (pH of aq phase = 5 ~~ 5.5). The batch was warmed to 15 ⁰C and the aqueous phase separated. The MTBE solution of 2,6-dichloro-4-methylphenol 1 was carried forward into the next step. Assay yield = 11.6 kg, 89%.

Step 2. Bromopyridine 2

KOH

To a 400 L glass lined vessel was charged the MTBE solution of 2,6- dichlorocresol from the previous steρ(l 1.6 kg, 65.5 moles). The solution was concentrated under reduced pressure at <40 ⁰C to a volume of 15-20 L. MTBE (49 kg) was charged to the vessel and concentration under reduced pressure at <40 ⁰C continued to a volume of 15-20 L. Dimethylacetamide 83 kg) was then charged and distillation continued to remove the remaining MTBE. To the DMAc solution was then charged ethylene carbonate (6.4 kg, 72 moles) and N- methyl imidazole (0.53 kg, 6.5 moles). The solution was heated to 120 ⁰C and aged for 20 hours when HPLC showed complete reaction. The solution was cooled to 10 ⁰C and potassium hydroxide (5.18 kg, 92 moles) was added keeping the temperature <20 ⁰C. The batch was stirred for 30 minutes at ambient temp.

The dibromopyridϊne (15.8 kg, 66.7 moles) was added and the mixture was heated to 80-90° C and aged for 2 hrs. HPLC then showed 60 LCAP product 2 and 34 LCAP intermediate hydroxyethyl ether remaining. The mixture was cooled to 10 ⁰C and additional powdered potassium hydroxide (2.0 kg, 35.6 moles) was charged. The mixture was stirred at 20 ⁰C for 30 minutes and then heated to 90 °C for a further 2 hours when HPLC analysis showed 85 LCAP product 2 and<5 LCAP hydroxyethyl ether remaining. The batch was cooled to 80 ⁰C and water (230 kg) charged over 1 hour with vigorous stirring.

The slurry was cooled to 20 °C and aged for 1 hour. The batch was filtered and the cake was washed with water (2 x 55 kg) and then with isopropanol (2 x 55 kg). The cake was dried under a nitrogen stream then dried in vacuo at 40 ⁰C to afford a pale beige solid. Yield = 18.91 kg, 77%, 97.9 LCAP.

Step 3: pinacol borate ester 3

Aryl bromide 2 (12.37 kg, 32.8 moles), pinacolatodiboron (10.0 kg, 39.4 moles), potassium acetate (9.66 kg, 98.4 moles) and DMAc (92.7 kg) were charged to a 400L glass lined vessel and degassed three times with nitrogen/vacuum purges. The mixture was then inerted with sub-surface nitrogen sparging for 15 minutes. PdCl₂(OpPf)-CH₂Cl₂ (804 g, 0.984 moles) was added and sub- surface nitrogen sparging continued for a further 15 minutes. The batch was heated to 80-85⁰C and aged for 20 hours when HPLC showed complete reaction. The reaction mixture was then allowed to cool to 20° - 25° C and water (99 kg) and isopropyl acetate (87 kg) were added. The mixture was stirred for 30 minutes and allowed to settle overnight The aqueous layer was cut and then the organic layer was washed with water (50 kg). The organic layer was then concentrated under reduced pressure at <40 ⁰C to a volume of 25-30 L. The concentrated iPAc solution was diluted with n-heptane (20.5 kg) and the solution passed through a pad of silica gel (10 kg). The silica pad was washed through with 1:1 iPAc/n-heptane (120 L). The filtrate and washes were concentrated under reduced pressure at <40°C to ca 25-30L. Isopropanol (50 kg) was added and the solution concentrated again by distillation at <40 ⁰C to a volume of ca 30 L. Isopropanol (50 kg) was added and the resulting slurry stirred at 20 ⁰C over the weekend. The solid was collected by filtration, the cake washed with isopropanol (20 kg) and dried in vacuo at 4O⁰C to afford pinacol borate ester 3 as an off white solid. Yield = 9.943 kg, 71%, HPLC 96.5 LCAP.

Alternate synthesis (to boronic acid 3')

BuIi (2.5M in hexanes, 5 niL, 0.95 eq.) was added to a solution of THF (20 mL) at

-1OC, followed by addition of BuMgCl (2M in THF, 3 mL, 0.45 eq.) and the mixture was stirred at -1OC for 30 rain. The solution was then cooled down to -45C and a solution of bromopyridine 2 (5g) in THF (30 mL) was added dropwise over 20 min (-35 max temp). The resulting mixture was stirred at -35C for 30 min (no more SM by HPLC, des-chloro imp < ILCAP) and B(OMe)3 (3 mL, 2 eq.) was added. The mixture was warmed up to -5C for 20 min then 2N aqueous HCl (60 mL) was added and the slurry was stirred at 2OC for 30 min. The white solid was filtered off, washed with water (50 mL) and then with hexanes (2x50mL). The solid was dried in vacuo with N2 stream to give 4g of boronic acid 3' as a white powder.

Step 4: TFA protection

The suspension of compound 6 in 48 L of Me-THF was cooled to 3 ⁰C under nitrogen. Triethylamine (10.1 L) was charged, followed by the addition of trifluoroacetic anhydride (4.2 L) over 60 min at 4-5 ⁰C. Resulting slurry was aged at < 5 ⁰C for another 10 min and sample was taken to confirm <0.8% 6 by HPLC. 2N HCl (6 L) was poured and the mixture was transferred to IOOL extractor. Reaction flask was rinsed with 30 L of 2N HCl and the solution was also transferred to the extractor. Aqueous layer was cut and organic layer was washed with 36 L of water, then 36 L of 10% KHCO3. After washes, 38.7 kg of organic solution were obtained. 90.42 G of the solution were concentrated and 17.87 g of oily product 7 was obtained. By NMR it was pure enough for next reaction. Based on these data, the yield of 7 would be 7.64 kg or 99% without purity correction. The bulky organic solution was batch concentrated to get the product 7 as yellow oil and it was used for next reaction without further purification.

Step 5: triflation

Compound 7 was dissolved in 40 L of DCM and triethylamine (6.0 L) was charged. After the mixture was cooled to -28 ⁰C under nitrogen, triflic anhydride (5.27 L) was added over 60 min at <-10 ⁰C. Resulting solution was aged at <-10 ⁰C for another 10 min and sample was taken to confirm <0.6% 7 by HPLC. GMP water (11 L) was poured into the flask and the mixture was transferred to a IOOL extractor with 11 L of water. Aqueous layer was cut and organic layer was washed with 22 L of 2N HCl, 22 L of water, 22 L of 10% KHCO3, and 22 L of water in order. The organic solution was concentrated by batch concentration to about 30 L and 30 L of heptane were charged. The mixture was further concentrated to about 40 L (slurry was generated suddenly and agitation failed). Because agitation failed the heavy slurry was filtered at 37 ⁰C. The cake was rinsed with 11 L of heptane. After drying under N2 stream, 10.353 kg of product 4 was obtained as light brown color solid. HPLC showed it's >99% pure and NMR showed it's pure. Yield of this step was 91%.

Into a 100 L round bottom flask charge borane 3, triflate 4, Pd(dppf)Cl₂, KHCO₃, 2-methyl-THF and water. Degas with N₂/vacuum purges. Heat the mixture to 6O⁰C and age for 1 hour. Assay for completion. If complete, let cool to 20-25⁰C. Pump into the 180 L extractor containing 48 L 5% NaH₂PO. Agitate 10 minutes, let settle. Collect aqueous layer and then add 50 L hexanes to the organic layer. The organic layer was then treated with 30 L water and 3.0 kg NaCl, agitated for 15 minutes and allowed to settle.

The remaining organic layer was then diluted with an additional 38 L hexanes. This knocked out some tarry material which collected on the walls of the vessel. The organic layer was collected and passed through a 10 kg silica gel plug in an 18" filter pot. The cake was washed with 12 L 1:1 2-methyl-THF / hexanes.

The filtrate was concentrated to a volume of ca 28 L and then diluted back to 48 L with 2-methyl THF. The solution was then treated to the slow addition of 4N HCl in Dioxane (10 L) and allowed to stir overnight. The solids are then collected, washed with 1:1 2-MTHF / hexanes, and sucked dry under a nitrogen tent to give 11.2 kg (90% yield) of 5 HCl salt.

Step 7: Asymmetric Hydrogenation

Catalyst Preparation

In a nitrogen filled glovebox, (O₂ < 10 ppm) (R)-(S)-SL-J212-1 ((R)-(S)-Fur2PF- PtBu2 (obtained from) (2.63 mol%, 52239 g/mol, 230.4 g, 0.441 mol) was combined with (COD)Ru(Me-allyl)₂ (2.5 mol%, 319.5 g/mol, 134.2 g, 0.42 mol) in a 1 gallon blow can followed by CH₂Cl₂ (2.5 L, N₂ degassed, anhydrous).

Hydrogenation

Ene-ester 5 (32.4 kg, 28.4 wt% in 2-Me-THF) was drawn into autoclave under partial vacuum followed by 2-Me-THF (KF < or = 200 ppm, 30 volumes) rinse bringing the batch volume to 300 L. HBF₄*OEt₂ (3.40 kg, 1.25 equiv.) added slowly while monitoring batch temperature (maintained < 40 ⁰C).

The autoclave was sealed and purged with N₂ (3 x 40 psig), The catalyst solution was introduced into the autoclave. The reactor was sealed and then pressure tested to 1000 psig N₂. The reactor was then vented and pressurized with H₂ to 1000 psig. Agitation was began and the reaction temperature maintained at 23 ⁰C for 43 h.

The reaction was vented and HPLC confirmed <0.1 LCAP ene-ester with an ee of > 99%.

Quench Materials NaHCO₃ (100.0 kg, 7.5 wt%) was added slowly to the hydrogenation batch while maintaining a batch temperature <30 ⁰C. The aqueous layer was confirmed to have pH ~ 8. The aqueous layer was cut away and the organic layer was washed with water (150 L).

The organic layer (282.6 kg) was assayed and the concentration of chiral ester 8 was determined to be 3.0 wt% (8.48 kg chiral ester). The batch was then distilled to a final weight of 71.0 kg. 12.0 kg Me-THF was used to rinse the distillation vessel.

Step 8: Protected group switch, epimerization /saponification

Cis ester 8 (8.48 kg, 15.44 mol) solution in 85 L 2-MeTHF treated with 4.25 kg of Darco KB-G for 1 h. Filtered over 4 kg silica gel pad on a pad of solkafloc, eluting with 2 x 20 L 2-MeTHF. Batch concentrated and flushed with 20 L EtOH to give 99% recovery. Water level should be at or below 6000 ppm.

Cis ester (4.4 kg, 8.01 mol) dissolved in 20 L EtOH. Cooled in ice bath to 5 ⁰C and NaOEt (3.59 L, 9.61 mol) added over 15 min. Allowed to warm to -15 ⁰C over 4 h. water (0.173 kg, 9.61 mol) added and stirred 10 h. Cooled to 5 ⁰C. Boc₂O (2.098 kg, 9.61 mol) added as a neat melt in -200 g portions (GAS EVOLUTION). Stirred 30 min while allowing to warm to rt.

NaOH (20.0 L, 40.0 mol) added over 15-20 min, heated to 70 ⁰C for 2 h. Cooled to rt. Extractor filled with 20 L IPAC and HCl (24.03 L₅ 48.1 mol). Cooled to <10 ⁰C. Product solution in EtOH added to the extractor, rbf rinsed with mixture of 2L 2M HCl and 2L IPAC. Mixed 5 min. and layers cut. Aq layer (should be acidic, pH < 4) extracted with 20 L IPAC. Combined organic layers washed with 2 x 10 L 'A-sat'd brine. Batch concentrated and flushed with 20 L IPAC. Concentrate to -16 L volume. Warm to 70 ⁰C while 40 L heptane added. Allowed to cool to -50 ⁰C and additional 40 L heptane added, cooled to rt overnight. Product filtered, washing with 20 L 5: 1 heptane:IPAC and flushed with N₂ for 20 h.

Product can be dried under vacuum/N₂ flush at 70 ⁰C to bring water level at or below 3000 ppm. 3.9 kg trans acid 9 isolated as a beige powder (88%, 95 wt%, 7.05 mol).

Step 9: amide coupling

2.62 kg solution of amine 10 in MTBE (88.5 wt%, 2.3 kg total) flushed with 20 L of 2-MeTHF and concentrated. Water level in amine should be at or below 3000 ppm.

Trans acid 9 (3.84 kg, 6.94 mol) suspended in 2-MeTHF (8.00 L) and 2-MeTHF (8.00 L). Tosyl chloride (1.747 kg, 9.16 mol) was added as a solid and the slurry was cooled to - 20 ⁰C in dry ice/IP A bath. 1-raethylimidazole (1.942 L, 2436 mol) was added over 15 min, dissolving the slurry and warming the mixture to -10 ⁰C. Mixture stirred for 3 h while internal temperature was kept between -10 and -5 ⁰C. Amine (2.031 kg, 8.47 mol) in MeCN (2 L) and 2-MeTHF (2 L) added over 5 min and the reaction was allowed to warm to room temp and stirred 16 h under N₂.

An extractor was charged with 20 L of 3:1 2-MeTHF :MTBE, cooled to 15 ⁰C and the reaction mixture was added. The reaction was quenched with 20 L water and the reaction flask rinsed with 2 L MTBE. Layers were separated and the aqueous layer was extracted with 20 L of 3:1 2-MeTHF:MTBE. The combined organics were washed with 20 L 0.5N NaOH (made from diluting IM NaOH solution), 20 L 0.5N HCl (made from diluting IM HCl solution) and 20 L water. The organic layer was then treated with 2.5 kg Darco KB-G for 1 hr and filtered over solkafloc, washing with 20 L of 3:1 2-MeTHF:MTBE to give 4.87 kg of coupled product 11 (94%, 6.52 mol).

Step 10: BOC deprotection

10 L MTBE added to 11 (4.8 kg, 6.42 mol) solution in -10 L 2-MeTHF. Phosphoric acid (5 L of 85wt% solution, 74 mol) added over 10 min and heated to 60 ⁰C for 16 h. Diluted with 10 L MTBE, cooled to 0 ⁰C and quenched with 5 N NaOH (-18 L) to reach pH >12. Layers cut and organics extracted with 10 L MTBE. Combined organic layers washed with 5 L water, then extracted with 3 x 10 L 40% v/v aq MsOH (12 L MsOH). Aq MsOH layer washed with 5 L MTBE and then diluted with 20 L MTBE, cooled to 0 ⁰C and basified with 10 N NaOH (-19 L) to pH >12. Layers cut and aq layer back extracted with 2 x 5 L MTBE. Combined organic layers washed with 2 x 10 L 1/2 satd brine. Dried over Na₂SO₄. Batch concentrated to give free base 12 (3.95 kg, 6.10 mol, 95 % yield). Flushed with 20 L THF.

Step 11 : Bis-D-tartrate salt

Free base 12 (3.9 kg, 6.03 mol) dissolved in 30 L THF. D-taxtaric acid (1.809 kg, 12.06 mol) added neat and stirred at rt for 20 h. Tartaric acid slowly goes into solution and then salt slowly comes out. 45 L MTBE added over 1 h and stirred 1 h. Filtered, washing with 35 L 1.5:1 MTBE:THF. Dried under N₂ flush to give 5.1 kg of bis-tartrate salt 14 (90%, 5.42 mol).

Step 12: Mono acetate salt

Bis-D-tartrate salt 14 (5 kg, 5.28 mol) suspended in 25 L MTBE and 25 L of 1 M

NaOH added over 5 L portions over 2 h. Stirred 2 h or until solid completely dissolved. Layers cut and aq layer extracted with 10 L MTBE. Combined organic layers washed with 2 x 10 L ¹A sat'd brine and dried over Na₂SO₄.

A visually clean IOOL RBF equipped with an overhead stirrer, a vacuum inlet, a nitrogen inlet, an addition funnel and a temperature probe containing a solution of 12 (3141 g) in

MTBE was charged with MTBE (20 L) (filtered through an inline filter (Polycap™ 36 HD,

1 μrn, Whatman Inc).

A solution of AcOH (600 mL) in heptane (4 L) was filtered through an inline filter

(Polycap™ 36 HD, Iμm, Whatman Inc) into the addition funnel and rinsed with heptane (200 mL).

AcOH/heptane (500 mL) was added before seeding (22.28g). The slurry was aged at room temperature for 30 min and the rest of AcOH/heptane (4.3 L) was added over 35 min.

The slurry was aged at room temperature for 3 hours and at 0⁰C for 30 min.

Supernatant assay showed 1.8 g/L. The slurry was filtered through a filter pot, and the solid obtained was washed three times with cold heptane : MTBE (1 : 9) (0 ⁰C, 3 X 3 L) and once with cold heptane : MTBE

(1 : 1) (0 ⁰C, 10 L). The solid was dried over week end under vacuum and nitrogen sweep and filtered over a sieve to give the AcOH salt 13 as a white powder: 2941.6 g (82.7% AY, 97.55 A%).

Amine side chain 10

Step 13 : aldehyde formation

A visually clean 100-L round-bottom flask equipped with a mechanical stirrer, a dropping runnel, a thermocouple and a N₂ Met was charged with 12 L of degassed THF followed by 5-bromo-2-chlorobenzoic acid (5.03 kg, 21.35 mol)and 3 L of degassed THF. The brown solution was degassed for 10 minutes at rt then cooled to -45°C. iPrMgCI was added via the addition runnel. For the first equivalent of iPrMgCI (10.7 L)₅ the temperature went up to -1°C and the addition took 75 minutes. The addition was stopped to allow the reaction to cool to - 20⁰C. The remaining iPrMgCI (17.1 L) was added over 75 minutes. Final temperature = -28⁰C. The reaction mixture was slowly warmed to rt for a total aging time of 15 hours. The orange slurry was cooled to 0⁰C and a degassed solution of DMF (4.15 L,

53.4 mol) in THF (16 L) was slowly added, with vigorous stirring, over 80 minutes. The rate of addition was controlled in order to keep the temperature below 20⁰C. 4 L of fresh THF was added at this point to facilitate the stirring. The thick slurry was stirred at rt for 30 minutes at which point 4N HCl (23.5 L₅ 92.14 mol) was slowly added over 50 minutes (T_max - 37°C). The reaction mixture was aged at 30⁰C fro 45 minutes until all solids dissolved.

The batch was transferred to the extractor (4 L of MTBE was used to rinsed the reaction flask) and the 2 layers were cut. The organic layer was successively washed with 10% wt/wt aqueous LiCl (15 L, 3 mL/g) followed by 2 x IM Na₂CO₃ (30 L and 20 L, 1.5 eq. and 1.0 eq.). The combined Na₂CO₃ layer was washed with MTBE (25 L, 5 mL/g), transferred to a visually clean 100-L round-bottom flask equipped with a mechanical stirrer, a thermocouple, a dropping funnel and N₂ inlet and cooled to 0⁰C. 6N HCl (16 L, 4.5 eq.) was added over 1 hour and the white slurry was aged at 1-2°C for 20 minutes. The white slurry was filtered on a filter pot and the white solid was rinsed with water (32 L, 6.5 mL/g) and heptane (40 L) and then dried on the filter pot for 64 hours (vacuum + N₂ sweep). The solid was dried in the vacuum oven (47°C, house vacuum, slight N₂ sweep) for 40 hours. KF analysis was performed (3500 ppm) and was found acceptable, i.e. <5500 ppm. The white solid was transferred in a plastic double bag and assayed: 3410 g x 92 wt% = 3137 g (80% yield)

Step 14: Wittig reaction

A visually clean 100-L round-bottom flask equipped with a mechanical stirrer, a dropping funnel, a thermocouple, a reflux condenser and a N₂ inlet was charged with THF (20 L) and NaH (745 g, 1.1 eq.). The suspension was cooled to -20⁰C. A solution of aldehyde (3.137 kg, 16.93 mol) in THF (7 L) was slowly added to the NaH suspension. The addition took place over 1 hour from -18⁰C to 3⁰C. 4 L of fresh THF was used to rinse the plastic container holding the aldehyde solution and the dropping funnel.

The suspension was warmed to 15°C and the (methoxymethyl)triphenylphosphonium chloride reagent (solid) (7.55 kg, 22.01 mol) was added in one portion.

The reaction mixture was heated to 45⁰C and NaH (945 g) was added in 9 portions of ~105 g each over 60 minutes. A small exotherm was observed at 5O⁰C without gas evolution. The funnel and the walls of the reaction flask were rinsed with 2 L of fresh THF. The slurry was slowly warmed to 55°C at which point a stronger gas evolution was observed as well as an exotherm to 60⁰C.

The internal temperature stabilized to 56-57°C and was maintained for 30 minutes. The slurry was dark orange at this point. HPLC analysis revealed that the reaction was complete. The batch was cooled to rt and aged O/N. The next morning, IN NaOH (25.5 L, 1.5 eq.) and MTBE (17 L) were charged to the extractor and cooled to 1O⁰C. The batch was transferred by vacuum to the extractor and it was vigorously stirred at 18-19⁰C for 15 minutes.

The layers were cut and the organic layer was washed 2 x IN NaOH (17 L and 8.5

L, 1.0 eq. and 0.5 eq.). The 3 aqueous layers were combined and washed 3 times with iPAc (3 x 15 L, 3 x 5 mL/g). The aqueous layer was in-line filtered and transferred to a visually clean 100-

L round-bottom flask equipped with a mechanical stirrer, a thermocouple, a dropping funnel and a N₂ inlet and it was cooled to O⁰C. 6N HCl (13 L, 4.4 eq.) was slowly added at 0⁰C over 90 minutes (pH 1 at this point) and the yellow slurry was aged at 0⁰C for 20 minutes. The slurry was filtered on a filter pot and rinse with water (52 L, 17 mL/g). Water was added in 3 portions of 17 L and a slurry was made in the filter-pot each time.

The yellow solid was dried on the filter pot for 66 hours. It was then dried in the vacuum oven for 48 hours (50⁰C₅ house vacuum, slight N₂ sweep) yielding 3099 g (86 %) of a 1:1 mixture of E/Z isomers.

Step 15: hydrogenatϊon

The 10 gallon reactor was first prepared by making a conditioning run using only a small charge of 20 wt% Pd(OH)₂/C in EtOAc at total batch volume. Run conditions were 45 psig pressure of hydrogen, room temperature and ran for 2 hours. The solvent was removed from the reactor and discarded.

A 5-gallon carboy container was charged with 3.08 kg of starting material JJ (14.49 mol) and it was dissolved in 10 liters of EtOAc. The resulting solution was sucked into the 10 gallon reactor and the carboy was then rinsed with 2 L of EtOAc. The rinsate was then added to the vessel as well. This was repeated a second time. 308 grams of 20 wt% Pd(OH)₂ZC was added to a flask containing 2 L of EtOAc and this solution was next sucked into the reactor. The flask was rinsed twice as well. The balance of EtOAc solvent was added to the vessel for a total of 24.7 L yielding a concentration of ~8 L/kg. The batch was pre-cooled to 15°C and the agitation rate was set to 800 RPM at the start of reaction. The hydrogen pressure was 45 psig and the run time was set for 18 hours. The initial reaction rate was extremely fast and the heat generated from the reaction increased the batch temperature to a high of 32 degrees; this was quickly quenched back down to 25 C and the run was stopped after 2 hours. The resulting batch was dropped and the reactor was rinsed with 15 L of fresh

EtOAc. The batch was filtered on a pad of solka floe using an 18" filter pot and 15 L of EtOAc was used to rinse the pad. The desired compound was kept as an EtOAc solution and it was assayed: 2.98 kg (96% yield).

Step 16: amide coupling

The carboxylic acid 18 (5.78 kg, 26.93 mol) in solution in EtOAc (from the hydrogenation vessel) was in-line filtered with an activated carbon cartridge and concentrated with the batch-concentrator to a final volume of 48 L. The batch was cooled to 10⁰C and CDI (solid)(5.24 kg, 32.31 mol) was added in

10 portions over 30 minutes.

The reaction mixture was aged at rt for 1.5 hrs. Cyclopropylamine (2.83 L, 40.40 mol) was added via the dropping funnel fitted with a piece of Nalgene tubing immersed in the reaction mixture. The rate of addition was controlled such that the temperature did not exceed 33.5°C. The addition took 30 minutes. The batch was aged at 30⁰C for 1.5 hours then it was cooled to rt. The batch was transferred by vacuum to the extractor and cooled to 15°C. 3N HCI (36 L, 4.0 eq.) was added with stirring.

Fresh EtOAc was added (23.5 L, 4 niL/g) with more stirring. The 2 layers were cut and the organic layer was successively washed with IM Na₂CO₃ (36 L), followed by ¹A- saturated brine (36 L). Assay of the EtOAc layer: 5.88 kg (86%).

The crude batch was in-line filtered in a visually clean 100-L round-bottom flask and was subsequently batch-concentrated and solvent-switched to IPAc.

8 L of fresh BPAc was added to the batch to make a solution of final volume - 23.2 L. The batch was heated to 7O⁰C until a clear solution was obtained, then it was cooled to 65⁰C at which point hexanes (12 L) was slowly added over 1 hour between 62.5°C and 65°C. The batch was further cooled to 60⁰C, seeded with 17.5 g of seeds. The batch was slowly cooled to 55⁰C over 45 minutes then to rt and aged for 10 hours at rt. The next morning, the mother liquors were analyzed by HPLC and showed 808 g of amide lost to the mother liquors (14%). The batch was filtered, rinsed with 10% iPAc/hexanes (24 L, 4 mL/g) followed by hexanes (20 L, 3.5 mL/g). The batch was dried on the filter pot (vacuum and N₂ sweep) for 24 hrs and yielded 4.82 kg (83% yield, 100 wt%) of a white solid.

Step 17: borane reduction

99 A visually clean 100-L round bottom flask equipped with a mechanical stirrer, a thermocouple, a reflux condenser and a N₂ inlet was charged with 20 L of THF followed by the amide 19 (4.799 kg, 18.20 mol). 3 L of fresh THF was added to rinse the walls of the flask.

To the amide in solution in THF at rt was added NaBH₄ (solid)(2.862 kg, 75.66 mol) in one portion. No exotherm or gas evolution was observed. BF₃-THF (9.4 L, 85.12 mol) was slowly added via the dropping funnel over 75 minutes such that the temperature never exceeded 36°C. The slurry was aged at 37°C for 18 hours. HPLC analysis showed ~93 % conversion. The batch was cooled to 1O⁰C and slowly transferred via the pump to the extractor containing cool (6-12⁰C) 3N HCl (28.4 L.4.5 eq.). The reaction mixture was warmed to 4O⁰C for 1 hour then cooled to 21⁰C. The white precipitate was filtered on a filter pot and rinsed with MTBE (24 L, 5 mL/g). The filtrate was transferred to the clean extractor and more MTBE was added (24 L, 5 rnL/g). The layers were cut and the organic layer was washed 4 times with 2N HCl (3 x 24 L, and 1 x 12 L, 3 x 5 mL/g and 1 x 2.5 mL/g). The acidic layer was transferred to the extractor and washed with MTBE (14 L. 3 mL/g). The MTBE layer was back-extracted with 2N HCI (4 L). The combined aqueous acidic layer was cooled to 10°C and basified with 50% wt/wt aqueous NaOH (10L) until pH>10.

The cloudy mixture was cooled to 21⁰C and extracted with MTBE (48 L, 10 mL/g). The organic layer was washed with water (20 L, 4 mL/g) and transferred to 20-L plastic containers. The batch was dried with Na₂SO₄ (8 kg), in-line filtered to a visually clean 100-L round-bottom flask equipped with a mechanical stirrer and a thermocouple and batch- concentrated to yield 4.22 kg of a pale yellow oil 70 wt% in MTBE/THF (93 % assay yield) which was stored in a glass bottle covered with foil under a positive pressure of N₂.

Claims

WHAT IS CLAIMED IS:

1. A salt of the compound (3% 4'iS)-6-[2-(2,6-Dichloro-4-merayl-phenoxy)-- ethoxy]-l ^3\4^6'-hexahy(ho-[3,4']bipyridinyl-3'-carboxylic acid [2-chloro-5-(2-methoxy- ethyl)-benzyl]~cyclopropyl-amide selected from the group consisting of monoacetate salt and bis- D-tartrate salt.

2. A salt of claim 1 which is (3% 4'₁S)-6-[2-(2,6-Dichloro-4-methyl-phenoxy)- ethoxy]-r,2',3^l _;4'_f5',6^t~hexahydro-[3_>4']bipyridinyl-3^l-carboxylic acid [2-chloro-5-(2-methoxy- ethyl)-benzyl] -cyclopropyl-amide monoacetate.

3. A salt of claim 1 which is (3% ^'5)-6-[2-(2,6-Dichloro-4-methyl-phenoxy)- ethoxy]-r,2',3^t _J4'_;5'_?6'-hexahydro-[3,4']bipyridinyl-3¹-carboxylic acid [2-chloro-5-(2-methoxy- ethyl)-benzyl] -cyclopropyl-amide bis-D-tartrate.

4. A compound which is

where R is Br or B(OH)2-

5. A compound which is

6. A compound which is

7. A compound which is

8. A process for preparing boronic acid y_

which comprises a) adding BuMgCl to 2

and cooling to a temperature of between 0°C and -50OC, b) adding B(OCH3)3 to the bromopyridine to form a mixture, and c) warming the mixture formed in step b) to a temperature of between 10°C and -15°C₅ to form the boronic acid 3'.

9. The process of Claim 8, wherein the temperature in step a) is between about -25^OC and -45OQ

10. The process of Claim 9, wherein the temperature in step a) is about

1 1. The process of Claim 8, wherein the temperature in step c) is between about OoC and -lOoC.

12. The process of Claim 11, wherein the temperature in step a) is about -5OC.

13. A process for preparing cis ester 8

in the presence of the catalyst solution, to form chiral ester 8.

14. The process of Claim 13, wherein the ferrocene containing bisphosphine ligand is (R)- 1 - [(S)-2-(Di-2-furylphosphino)-ferrocenyl]ethyldi-fer/.-butyl-phosphine and the ruthenium catalyst is Ru(l_;5-η5-cyclooctadienyl)(methylallyl)2-

15. A process for preparing trans acid 9

Boc which comprises a) adding Boc2θ to cis ester 8

at a temperature between 15OC and 3O⁰C to form a mixture; and b) heating the mixture formed in step a) to a temperature between about 60°C and about 80°C for a period of time between about 1 hour and 3 hours, to form trans acid 9.

16. The process of Claim 15, wherein the temperature in step a) is between about 20OC and 25<>C.

17. The process of Claim 16, wherein the temperature in step a) is about 22OC.

18. The process of Claim 15, wherein the temperature in step b) is between about

68OC and 72<>C.

19. The process of Claim 18, wherein the temperature in step b) is about 700C.

20. A process for preparing

which comprises adding phosphoric acid to

to form compound 12.