Cyclopenta[c]pyrrole-1-carboxylic acid, octahydro-, 1,1-dimethylethyl ester, (1S,3aR,6aS)-, ethanedioate (1:1)

6.2 Example 29:; Preparation of (1 S, 3aR, 6aS)-octahydrocyclopenta[c]pyrrole- 1 - carboxylic acid t-butyl ester oxalic acid 1 : 1 salt from (lS, 3aR, 6aS)- octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride.; [0419] Step 1 : To a 1650 mL thick- walled glass pressure bottle (Ace Glass, Inc., 8648-157) equipped with a magnetic stirring bar was charged 75 g (306.9 mmol) of the (lS, 3aR, 6aS)- octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride / ammonium chloride admixture prepared in Example 28, 375 mL dichloromethane, and 497 mL t-butyl acetate. The resulting mixture was stirred vigorously at ambient temperature (about 21[Isolation of Hydrogenoxalate] [0155] To 250 mg of the mixture of the hydrochloride of amino acid (i) and ammonium chloride prepared in Example 29 were added 4 mL of chloroform and 1.7 mL of tert-butyl acetate. The resulting suspension was cooled to 0° C. and then 0.25 mL of methanesulfonic acid was added. The mixture was warmed slowly to 25° C. and then stirred at this temperature for 18 hours. The resulting white suspension was cooled to 0° C., and then 1.3 mL of a 50percent aqueous sodium hydroxide solution was added carefully with the temperature kept at 20° C. or lower. Water (15 mL) and chloroform (15 mL) were added and then stirred for 15 minutes. The layers were separated and the aqueous layer was subjected to extraction with 15 mL of chloroform three times. The organic layers were combined, dried over magnesium sulfate, and filtered. The solvent was then evaporated under reduced pressure. To the pale green residue was added a solution of 2.5 mL of tert-butyl acetate and 146.7 mg of oxalic acid in 2-propanol (2.5 mL). The resulting mixture was heated to 75 to 80° C., stirred for 30 minutes, allowed to cool to ambient temperature (about 20° C.), stirred for 18 hours, and then filtered. The resulting cake was washed with 5 mL of 2-propanol and with 5 mL of methyl tert-butyl ether respectively and then dried, affording 0.08 g (0.27 mmol: overall yield from nitrile (h): 25percent) of hydrogenoxalate of tert-butyl (j) as a white solid.A mixture of the (S)-1, 2, 3, 4-tetrahydro-1-naphthylammonium salt prepared as in Example 3, Method 1 (81.7 g, 0.203 mol), t-butyl methyl ether (400 mL) and 5percent NaHSO6.2 Example 29:; Preparation of (1 S, 3aR, 6aS)-octahydrocyclopenta[c]pyrrole- 1 - carboxylic acid t-butyl ester oxalic acid 1 : 1 salt from (lS, 3aR, 6aS)- octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride.; [0419] Step 1 : To a 1650 mL thick- walled glass pressure bottle (Ace Glass, Inc., 8648-157) equipped with a magnetic stirring bar was charged 75 g (306.9 mmol) of the (lS, 3aR, 6aS)- octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride / ammonium chloride admixture prepared in Example 28, 375 mL dichloromethane, and 497 mL t-butyl acetate. The resulting mixture was stirred vigorously at ambient temperature (about 21[Isolation of Hydrogenoxalate] [0155] To 250 mg of the mixture of the hydrochloride of amino acid (i) and ammonium chloride prepared in Example 29 were added 4 mL of chloroform and 1.7 mL of tert-butyl acetate. The resulting suspension was cooled to 0° C. and then 0.25 mL of methanesulfonic acid was added. The mixture was warmed slowly to 25° C. and then stirred at this temperature for 18 hours. The resulting white suspension was cooled to 0° C., and then 1.3 mL of a 50percent aqueous sodium hydroxide solution was added carefully with the temperature kept at 20° C. or lower. Water (15 mL) and chloroform (15 mL) were added and then stirred for 15 minutes. The layers were separated and the aqueous layer was subjected to extraction with 15 mL of chloroform three times. The organic layers were combined, dried over magnesium sulfate, and filtered. The solvent was then evaporated under reduced pressure. To the pale green residue was added a solution of 2.5 mL of tert-butyl acetate and 146.7 mg of oxalic acid in 2-propanol (2.5 mL). The resulting mixture was heated to 75 to 80° C., stirred for 30 minutes, allowed to cool to ambient temperature (about 20° C.), stirred for 18 hours, and then filtered. The resulting cake was washed with 5 mL of 2-propanol and with 5 mL of methyl tert-butyl ether respectively and then dried, affording 0.08 g (0.27 mmol: overall yield from nitrile (h): 25percent) of hydrogenoxalate of tert-butyl (j) as a white solid.A mixture of the (S)-1, 2, 3, 4-tetrahydro-1-naphthylammonium salt prepared as in Example 3, Method 1 (81.7 g, 0.203 mol), t-butyl methyl ether (400 mL) and 5percent NaHSO[Isolation of Hydrogenoxalate] [0155] To 250 mg of the mixture of the hydrochloride of amino acid (i) and ammonium chloride prepared in Example 29 were added 4 mL of chloroform and 1.7 mL of tert-butyl acetate. The resulting suspension was cooled to 0 C. and then 0.25 mL of methanesulfonic acid was added. The mixture was warmed slowly to 25 C. and then stirred at this temperature for 18 hours. The resulting white suspension was cooled to 0 C., and then 1.3 mL of a 50% aqueous sodium hydroxide solution was added carefully with the temperature kept at 20 C. or lower. Water (15 mL) and chloroform (15 mL) were added and then stirred for 15 minutes. The layers were separated and the aqueous layer was subjected to extraction with 15 mL of chloroform three times. The organic layers were combined, dried over magnesium sulfate, and filtered. The solvent was then evaporated under reduced pressure. To the pale green residue was added a solution of 2.5 mL of tert-butyl acetate and 146.7 mg of oxalic acid in 2-propanol (2.5 mL). The resulting mixture was heated to 75 to 80 C., stirred for 30 minutes, allowed to cool to ambient temperature (about 20 C.), stirred for 18 hours, and then filtered. The resulting cake was washed with 5 mL of 2-propanol and with 5 mL of methyl tert-butyl ether respectively and then dried, affording 0.08 g (0.27 mmol: overall yield from nitrile (h): 25%) of hydrogenoxalate of tert-butyl (j) as a white solid.A mixture of the (S)-1, 2, 3, 4-tetrahydro-1-naphthylammonium salt prepared as in Example 3, Method 1 (81.7 g, 0.203 mol), t-butyl methyl ether (400 mL) and 5% NaHSO4-H2O (867 mL, 0.304 mol) was stirred for 30 minutes until all solids were dissolved. The organic phase was washed with water (334 mL) then concentrated to 259 mL. t-Butyl methyl ether (334 mL) was added and the solution was concentrated again to 259 mL. The addition-concentration process was repeated twice more. After the final concentration, t-BuOH (158 mL) and dimethylaminopyridine (5.04 g, 41.3 mmol) were added. A solution of Boc2O (67.6 g, 0.31 mol) in t-butylmethyl ether (52.0 mL) was added. After stirring for 5 hours at ambient temperature, t-butyl methyl ether (158 mL) and 5% aqueous NaHSO4-H2O (260 mL) were added and the resultant mixture was stirred. The organic phase was washed with 5% aqueous NaCl (twice, 260 mL each). The organic phase was concentrated to 320 mL, and tetrahydrofuran (320 mL) was added. The organic phase was concentrated again to 320 mL, and tetrahydrofuran (320 mL) was added. After concentrating to 320 mL once more, methane sulfonic acid (80.1 g, 0.62 mol) was added and the solution was stirred at ambient temperature for 4.5 hours. The reaction mixture was added to a 30% aqueous solution of K2CO3 (571 mL) and stirred. The aqueous phase was extracted with isopropyl acetate (320 mL). The combined organic phases were concentrated to 320 mL, and isopropyl acetate (320 mL) was added. The organic solution was concentrated again to 320 mL. The organic phase was washed with water (320 mL). Isopropyl acetate (320 mL) was added to the organic phase and the solution was concentrated to 192 mL. Isopropyl acetate (320 mL) was added a second time, and the organic solution was concentrated to 192 mL. A solution of oxalic acid (24.1 g, 267 mmol) in isopropyl acetate (448 mL) was added to the organic solution over 2 hours. The mixture was stirred for 2-4 hours, and the slurry was filtered. The white solids were rinsed with isopropyl acetate (100 mL) and dried at 35-40 C. under vacuum to yield 52.6 g of the title compound (85% yield); A mixture of (S)-1, 2, 3, 4-tetrahydro-1-naphthylammonium salt as prepared by the method of Example 3, Method 2 (148 g, 0.609 mol), t-butyl methyl ether (726 mL) and 5% NaHSO4-H2O (1.58 L, 0.913 mol) was stirred until all of the solids had dissolved. The phases were separated and the organic phase washed with water (726 mL). The organic phase was concentrated to about 400 mL. t-Butyl methyl ether (726 mL) was added and the mixture concentrated to 590 mL. The addition of t-butyl methyl ether and concentration was repeated to give a final volume of 350 mL. Dimethylaminopyridine (8.42 g, 68.9 mmol) and t-butyl alcohol (260 mL) were added, followed by addition of a solution of Boc2O (112 g, 0.52 mol) in MTBE (88 mL) over 0.5 hour. The mixture was stirred for 5 hours at 22-25 C. A solution of 5% sodium bisulfate in water was added and the mixture stirred for 0.5 hour. The organic phase was washed with 5% sodium chloride (twice, 440 mL each) and concentrated to 270 mL. Tetrahydrofuran (540 mL) was added and the mixture concentrated to 270 mL; this procedure was repeated twice more to give a final volume of 270 mL. Methane sulfonic acid (67 mL) was added over 0.5 hour while maintaining a temperature of lower than 30 C. and the mixture stirred at 22-25 C. for 12 hours. The mixture was added to a 30% aqueous solution of potassium carbonate (478 mL) while maintaining a temperature of 22-25 C. The mixture was filtered, the phases separated and the aqueous phase extracted with isopropyl acetate (twice, 540 mL each). The organic phase was concentrated to 270 mL, then twice evaporated with isopropyl acetate (540 ml) to give a final volume of 540 mL. The organic phase was washed with water (twice, 540 mL), then twice evaporated with isopropyl acetate (320 mL) to give a final volume of 320 mL. Additional isopropyl acetate (429 mL) was added followed by addition of a solution of oxalic acid (40.4 g, 0.448 mol) in t-butylmethyl ether (321 mL) over 2 hours maintaining a temperature of 22-25 C. The mixture was stirred for 3 hours at 22-25 C. then filtered. The filter cake was washed with isopropyl acetate (100 mL) and the product dried at 35-40 C. under vacuum to give the title compound as a white solid (88.4 g, 81%).6.2 Example 29:; Preparation of (1 S, 3aR, 6aS)-octahydrocyclopenta[c]pyrrole- 1 - carboxylic acid t-butyl ester oxalic acid 1 : 1 salt from (lS, 3aR, 6aS)- octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride.; [0419] Step 1 : To a 1650 mL thick- walled glass pressure bottle (Ace Glass, Inc., 8648-157) equipped with a magnetic stirring bar was charged 75 g (306.9 mmol) of the (lS, 3aR, 6aS)- octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride / ammonium chloride admixture prepared in Example 28, 375 mL dichloromethane, and 497 mL t-butyl acetate. The resulting mixture was stirred vigorously at ambient temperature (about 210C) to break large aggregates to provide a free-stirring suspension. This suspension was cooled to an internal temperature of 00C using a brine - ice bath and 75.4 mL (1162 mmol) methanesulfonic acid was added dropwise over 15 minutes, during which the internal temperature rose to 5C. The pressure bottle was sealed and the reaction mixture was allowed to warm to ambient temperature (about 210C) with vigorous stirring over 18 hours, during which the reaction mixture became a suspension of white inorganic salts in an amber solution. The mixture was cooled in an ice bath and the pressure bottle carefully vented and uncapped. The mixture was transferred to a 3 L flask and cooled in an ice bath with stirring. 400 mL of 50% (wt:wt) NaOH in water was added to the mixture over 35 minutes while maintaining its temperature below 200C. The stirring was halted and the phases were allowed to separate. The organic phase (-850 mL) was removed to a separate vessel. The remaining aqueous phase and rag layer (pH 13, -800 mL) were extracted with 375 mL dichloromethane. The organic phases were combined (-1250 mL) and washed with water (2 x 225 mL). The resulting organic phase was filtered to remove a rag layer and any insoluble material, and the solvent was removed by rotary vacuum evaporation to give 48.3 g dark-amber oil. The 1H NMR spectrum of the oil showed (lS, 3aR, 6aS)- octahydrocyclopenta[c]pyrrole-l-carboxylic acid ?-butyl ester.[0420] A second preparation following the same procedure yielded was 50.6 g of the trans- (lS, 3aR, 6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid t-butyl ester oil.[0421] Step 2: 97.9 g (463.3 mmol) of (lS, 3aR, 6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid t-butyl ester from the two preparations according to Step 1 were dissolved in 750 mL t-butyl acetate and charged to a 3 L four-neck flask equipped with overhead mechanical stirring, a thermometer, addition funnel, and reflux condenser. With stirring at ambient temperature (-210C), a solution of 44.0 g (488.6 mmol) of oxalic acid in 750 mL 2-propanol was added dropwise over 37 minutes, increasing the mixture's temperature to 31C. Solids began to precipitate after addition of -50 mL of the oxalic acid solution, and resulted in a thick suspension after the addition of 450 mL. After addition of 500 mL of the oxalate solution, the precipitated solids redissolved to provide a dark yellow solution. Solids precipitated again rapidly after the addition of 600 mL of the oxalic solution and persisted through the end of the oxalic acid addition. This suspension was then heated 78C to provide a thin suspension which was allowed to cool passively with stirring to ambient temperature (-210C). After 16 hours since the cooling began, the precipitated solids were collected by filtration and washed successively with isopropanol (450 mL), isopropyl acetate (450 mL), and methyl t-butyl methyl ether (450 mL). The solids were dried in a vacuum oven (300C, 25' vacuum, N2 stream) to provide 118.1 g (lS, 3aR, 6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid t-butyl ester oxalic acid 1 : 1 salt (64% yield from (lS, 3aR, 6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid hydrochloride) as a dense, tan free flowing powder (99.7% purity by GC analysis), which exhibited the expected 1H-NMR spectrum for (lS, 3aR, 6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid ?-butyl ester oxalic acid (1 : 1) salt.[0422] Recrystallization of (1 S, 3aR, 6aS)- octahydrocyclopenta[c]pyrrole- 1 -carboxylic acid t-butyl ester oxalic acid (1 :1) salt: The tan powder from Step 2 above (118. I g, 391.9 mmol) and isopropanol (1950 mL) were charged to a 3 L four neck flask equipped with a mechanical stirring, a thermometer, and a reflux condenser. The suspension was stirred and heated to 74C to completely dissolve the salt, resulting in a yellow solution. The stirring was slowed and the solution was allowed to cool passively to ambient temperature (-210C). After 20 hours since the cooling began, the precipitated solids collected by filtration and washed successively with isopropanol (1 L), isopropyl acetate (1 L), and methyl ?-butyl methyl ether (1 L). The solids were dried in a vacuum oven (400C, 28' vacuum, N2 stream) to provide 110.45 g (lS, 3aR, 6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid t-butyl ester oxalic acid 1 :1 salt (59.7% yield from ...A solution of potassium carbonate (73.3 g) in water (220 mL) was added to a suspension of (1S, 2S, 5R) 3-azabicyclo[3.3.0]octane-2-carboxylic, t-butylester, oxalate (80.0 g) in isopropyl acetate (400 mL) while maintaining a temperature of about 20 C. The mixture was stirred for 0.5 hour, tha phases separated and the organic phase washed with 25% w/w aqueous potassium carbonate (80 mL) to give a solution of the free base; 1S, 2S, 5R) 3-azabicyclo[3.3.0]octane-2-carboxylic, t-butylester, oxalate (1.0 eq.) was suspended in isopropyl acetate (6 vol.) and a solution of potassium carbonate (3.0 eq.) in water (3.5 vol.) was added at 20-25 C. The mixture was stirred for 3 hours then the phases separated. The organic phase was washed with water (2 vol.).Method 3000Pi81 8/2USD, 5Epsilon) 3-^^was suspended in Lsopropyj. acetate (6 vol ). arid a . -solution of potassium carbonate (3.0 eq.) in water (3.5 vol.) was added at 20 to 25C. The mixture was stirred for 3 hours, then the phases wer separated. The organic phase was washed with water (2 vol).£080179 j Cbz~to- -.leucme dlcyeloh xyiainin salt (1 .05 eq.) was suspended in isopropy. acetate (6 vol), and sulfuric acid (1 .3 eq.) in water (5 vol.) was added at 2 to 25C. The mixture was stirred for 30 minutes* the phases were separated, and. the organic phase wa washed with water (2 times, 2.5 vol.).J 000181 ] The two solutions from above were combined and then cooled to 0 to 5'C. MQBt hydrate (1.1 eq.) and BDC ( IJ eq, ) were suspended in the mixture, and the mixture was stirred for 6 hours. The mixture was washed with water (5 vol.), nd the resulting organic phase was treated with L-iysifte ( 1 eq.) and N-methylnrorp.holine (2 eq.) a 20 to 25BC to destroy excess activated ester. The mixture was then washed with 5 percent potassium carbonate (5 vol.), 1 hydrochloric acid (5 vol.), 5 percent potassium, carbonate (5 vol), and water (twice, 5 vol.) to give a solution of the title compound in isopropyl acetate.Method 3[000174] (I S, 2S, 5R) 3-azabicyclo[3.3.0]octane-2-carboxylic-tert-butylester-oxalate (1.0 eq.) was suspended in isopropyl acetate (6 vol.), and a solution of potassium carbonate (3.0 eq.) in water (3.5 vol.) was added at 20 to 25C. The mixture was stirred for 3 hours, then the phases were separated. The organic phase was washed with water (2 vol.).[000175] Cbz-tert-leucine dicyclohexylamine salt (1.05 eq.) was suspended in isopropyl acetate (6 vol.), and sulfuric acid (1.3 eq.) in water (5 vol.) was added at 20 to 25C. The mixture was stirred for 30 minutes, the phases were separated, and the organic phase was washed with water (2 times, 2.5 vol.).[000176] The two solutions from above were combined and then cooled to 0 to 5C. HOBt hydrate (1.1 eq.) and EDC (1.1 eq.) were suspended in the mixture, and the mixture was stirred for 6 hours. The mixture was washed with water (5 vol.), and the resulting organic phase was treated with L-lysine (1 eq.) and N-methylmorpholine (2 eq.) at 20 to 25C to destroy excess activated ester. The mixture was then washed with 5 percent potassium carbonate (5 vol.), 1 N hydrochloric acid (5 vol.), 5 percent potassium carbonate (5 vol.), and water (twice, 5 vol.) to give a solution of the title compound in isopropyl acetate

Molecular Weight:301.34
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:4
Exact Mass:301.15253745
Monoisotopic Mass:301.15253745
Topological Polar Surface Area:113
Heavy Atom Count:21
Complexity:328
Defined Atom Stereocenter Count:3
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes