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CAS No. : | 1006037-03-1 | MDL No. : | MFCD11616340 |
Formula : | C11H13NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JUMQWXLIAYMPHT-UHFFFAOYSA-N |
M.W : | 191.23 | Pubchem ID : | 45140209 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.36 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 52.78 |
TPSA : | 52.32 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.37 cm/s |
Log Po/w (iLOGP) : | 2.27 |
Log Po/w (XLOGP3) : | 1.54 |
Log Po/w (WLOGP) : | 1.25 |
Log Po/w (MLOGP) : | 1.57 |
Log Po/w (SILICOS-IT) : | 2.0 |
Consensus Log Po/w : | 1.73 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.11 |
Solubility : | 1.47 mg/ml ; 0.00767 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.25 |
Solubility : | 1.08 mg/ml ; 0.00565 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.94 |
Solubility : | 0.222 mg/ml ; 0.00116 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.29 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride In diethyl ether; ethyl acetate | Step 2:To a solution of ER-886774-00 (1.63 g, 0.0085 mol) in ethyl acetate (10 mL) was added 2.0 M of hydrogen chloride in Ether (6.0 mL, 0.012 mol). After stirring for several minutes, the reaction mixture was concentrated to give the title compound (quantitative yield) as pale brown solid. |
68.7 g | With hydrogenchloride In ethyl acetate at 20℃; for 2 h; | To a cooled solution of methyl 4-(1-aminocyclopropyl)benzoate (D6) (100 g, 524 mmol) in ethyl acetate (500 ml) 4N HCl (g)/ethyl acetate solution (300 ml) was added and the resulting mixture was stirred at room temperature for 2 hours. Evaporated the solvent, the residue was recrystallized with petroleum ether/EtOAc to afford the title compound (D7) (68.7 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.2% | Stage #1: 4-cyanobenzoic acid methyl ester; ethylmagnesium bromide With titanium(IV) isopropylate In toluene at -25 - -13℃; for 2.58333h; Stage #2: With boron trifluoride diethyl etherate In toluene at -24 - -8℃; for 1.16667h; Stage #3: With hydrogenchloride; sodium hydroxide; water more than 3 stages; | 31.1 Example 31; 4-{l-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3- thienyl}carbonyl)amino]cyclopropyl} benzoic acid diethylamine salt; Step 1 - Cyclopropanation; Materials MW Amount Moles EflMethyl 4-cyanobenzoate 6 161.16 2.60 Kg 16.13 1.00Ti(OiPr)4 284.22 4.73 L 16.13 1.00EtMgBr [3.07M] 133.27 10.51 L 32.27 2.00BF3OEt2 141.93 4.09 L 32.27 2.00Toluene [ 15 mL/g ] 4O L2-Me-THF [ 30 mL/g 8O L3N HC1 [ 15 mL/g ] 4O L3N NaOH [ 10 mL/g ] 26 LA 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 nitrile-ester 6 (2.60 Kg, 1.00 eq) and toluene (40 L, 15 mL/g). The mixture was cooled to -25 0C using the cooling bath filled with 2-propanol and dry ice. The Ti(OiPr)4 (4.73 L, 1.00 eq) was added to the solution over 5 minutes. The ethylmagnesium bromide (10.5 L, 2.0eq) was added over a period of 2 hrs keeping the temperature of the reaction mixture between -25 0C and -13 0C. The mixture was aged at -20 0C for 30 minutes. The borontrifluoride diethyl ether (4.09 L) was added over 40 minutes keeping the reaction mixture between -24 0C and -8 0C. The mixture was aged at -20 0C for 30 minutes, then the conversion was measured by HPLC and showed to be 93%. The reaction was quenched by the addition of HCl. 20 L (7.5 mL/g) of 3N HCl was slowly added (over 30 minutes) to the reaction mixture causing an exotherm of 39 0C (exotherm -16 0C -> +23 0C). The organic layer was transferred to the extractor, then the rest of the HCl (20 L, 7.5 mL/g) was added to the flask to dissolve the amine salt. After stirring for 10 minutes, the aqueous layer was transferred to the extractor. The mixture was stirred 10 minutes, then the layers were separated. The aqueous layer was washed with toluene (13 L, 5 mL/g). The aqueous layer was extracted with 2-Me-THF 2 x 10 mL/g (2 x 26 L) and 2 x 5 mL/g (2 x 13 L). Combined Me-THF layers were washed with 3N NaOH (26 L, 10 mL/g) and the pH of the NaOH solution was adjusted to pH 9 using ION NaOH (1.6 L) prior to the layer separation. The organic layer was washed with brine (13 L, 5 mL/g). The assay yield of the cyclopropylamine 7 was determined on the Me-THF layer prior to its concentration and showed to be 43.2% (1.334 Kg). The losses to the aqueous layer were bellow 3.8%. |
43.2% | Stage #1: 4-cyanobenzoic acid methyl ester With titanium(IV) isopropylate In toluene at -25℃; for 0.0833333h; Stage #2: ethylmagnesium bromide In toluene at -25 - -13℃; for 2.5h; Stage #3: With hydrogenchloride; sodium hydroxide; boron trifluoride diethyl etherate; water more than 3 stages; | A.1 A visually clean 100 L 5-neck round-bottom flask equipped with a mechanical stirrer, a thermocouple, a nitrogen inlet was charged with the nitrile-ester 6 (2.60 Kg, 1.00 eq) and toluene (40 L, 15 mL/g). The mixture was cooled to -25 0C using a cooling bath filled with 2-propanol and dry ice. The Ti(OiPr)4 (4.73 L, 1.00 eq) was added to the solution over 5 minutes. The ethylmagnesium bromide (10.5 L, 2.0eq) was added over a period of 2 hrs keeping the temperature of the reaction mixture between -25 0C and -13 0C. The mixture was aged at -20 0C for 30 minutes. The borontrifluoride diethyl ether (4.09 L) was added over 40 minutes keeping the reaction mixture between -24 0C and -8 0C. The mixture was aged at -20 °C for 30 minutes, then the conversion was measured by HPLC and showed to be 93%. The reaction was quenched by the addition of HCl. 20 L (7.5 mL/g) of 3N HCl was slowly added (over 30 minutes) to the reaction mixture causing an exotherm of 39 0C (exotherm -16 0C -^ +23 °C). The organic layer was transferred to the extractor, then the rest of the HCl (20 L, 7.5 mL/g) was added to the flask to dissolve the amine salt. After stirring for 10 minutes, the aqueous layer was transferred to the extractor. The mixture was stirred 10 minutes, then the layers were separated. The aqueous layer was washed with toluene (13 L, 5 mL/g). The aqueous layer was extracted with 2-Me-THF 2 x 10 mL/g (2 x 26 L) and 2 x 5 mL/g (2 x 13 L). Combined Me-THF layers were washed with 3N NaOH (26 L, 10 mL/g) and the pH of the NaOH solution was adjusted to pH 9 using ION NaOH (1.6 L) prior to the layer separation. The organic layer was washed with brine (13 L, 5 mL/g). The assay yield of the cyclopropylamine 7 was determined on the Me-THF layer prior to its concentration and showed to be 43.2% (1.334 Kg). The losses to the aqueous layer were bellow 3.8%. |
43.2% | Stage #1: 4-cyanobenzoic acid methyl ester With titanium(IV) isopropylate In toluene at -25℃; for 0.0833333h; Inert atmosphere; Large scale reaction; Stage #2: ethylmagnesium bromide In toluene at -20℃; for 2.5h; Inert atmosphere; Large scale reaction; Stage #3: With boron trifluoride diethyl etherate In toluene at -20℃; for 1.16667h; Inert atmosphere; Large scale reaction; |
43% | Stage #1: 4-cyanobenzoic acid methyl ester; ethylmagnesium bromide In tetrahydrofuran; toluene at -25℃; for 2.5h; Stage #2: With boron trifluoride diethyl etherate In tetrahydrofuran; toluene at -25℃; for 1.33333h; Stage #3: With hydrogenchloride; water In tetrahydrofuran; toluene at -25℃; | 1.2 Step 2: Methyl 4-(l-aminocyclopropyl)benzoateMe5 Methyl 4-cyanobenzoate (2.6 kg, 16.1 mol) was dissolved in 40 L of toluene at -250C and Ti(Oi-Pr)4 (4.73 L, l.lmol) was added over 5 min, followed by EtMgBr (10.5 L of a 3.07M solution in THF, 32.3 mol) over 2 hr. After aging for 30 min, BF3OEt2 (4.1 L, 32 mol) was added over 40 min and the mixture was aged for another 40 min. The reaction was quenched by the addition of 40 L of 3N HCl. The layers were separated and the aqueous layer was washed>0 with 13 L toluene. The aqueous layer was then extracted with 2-MeTHF (2x26L and 2x13L). The combined 2-MeTHF layers were washed with 3N NaOH and the pH of the NaOH layer adjusted to 9 before separation of the layers. The organic layer was washed with 13 L of brine. Yield = 43%. 1H NMR (500 MHz, CDCI3): δ 8.00 (d, 2H), 7.35 (d, 2H), 3.95 (s, 3H), 1.25 (t,2H), 1.10 (t, 2H). |
41.3% | Stage #1: 4-cyanobenzoic acid methyl ester; ethylmagnesium bromide With titanium(IV) isopropylate In diethyl ether at -70 - 20℃; for 1.5h; Stage #2: With boron trifluoride diethyl etherate In diethyl ether for 2h; | Intermediate 1a: 4-|1-r(Pyridin-2-ylmethyl)-aminol-cvclopropyl|-benzoic acid methyl ester a) Ethylmagnesium bromide (22.75 ml; 68.26 mmol, 3 M in ether) was added at -70 0C to a solution of a nitrile (5 g; 31 .03 mmol) and Ti(Oi-Pr)4 (10.1 mL, 34.13 mmol) in Et2O (16O mL).The yellow solution was stirred for 30 min. After the solution was warmed to rt (1 h), BF3-OEt2 (7.8 mL, 62.05 mmol) was added. After the mixture was stirred for 2 h, 1 N HCI (1 10 mL) and ether (ca. 15 mL) were added. NaOH (10% aq, ca. 10 mL) was added to the resulting two clear phases and the mixture was extracted with ether. The combined ether layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (n-heptan/ EtOAc) to give 4-(1 -Amino-cyclopropyl)- benzoic acid methyl ester as a yellow oil (2.45 g; 41 .3% yield. (MS: m/z : 192) |
Stage #1: 4-cyanobenzoic acid methyl ester; ethylmagnesium bromide With titanium(IV) isopropylate In toluene at -25 - -13℃; Industry scale; Stage #2: With boron trifluoride diethyl etherate In toluene at -24 - -8℃; for 1.16667h; Industry scale; | A 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 0C 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 0C and -13 0C. The mixture was aged at -20 0C for 30 minutes and borontrifluoride diethyl ether (4.09 L) was added over 40 minutes keeping the reaction mixture between -24 0C and -8 0C. The mixture was aged at -20 0C 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% NH4OH / CH3CN 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 0C); tR = 9.6 min. | |
Stage #1: 4-cyanobenzoic acid methyl ester; ethylmagnesium bromide With titanium(IV)isopropoxide In diethyl ether at -70℃; for 1h; Stage #2: With boron trifluoride diethyl etherate In diethyl ether for 2h; | Description 6: methyl 4-(1-aminocyclopropyl)benzoate (D6)To the solution of methyl 4-cyanobenzoate (100 g, 620 mmol) in diethyl ether (3 L) was added titanium (IV) isospropoxide (194 g, 682 mmol), followed by dropwise addition of ethylmagnesium bromide 3M solution in diethylether (450ml, 1 .36 mol) at -70 °C. The mixture was stirred for 1 h, and then boron trifluoride etherate (157ml, 1 .24 mol) was added at once. After 2 hours, aqueous HCI (5%) was added until the pH showed acidy, then the mixture was filtered. The solid was washed with ethylacetate. The aqueous phase was separated and the organic layer was washed with water. All aqueous layers were collected together, basified with 1 M NaOH and extracted with ethylacetate. The organic layer was dried (Na2S04) and concentrated to afford the title compound (D6) (32.0 g).1 H NMR (400MHz ,CHLOROFORM-d) δ (ppm): 7.97-7.98 (2H, m), 7.31 -7.34 (2H, m), 3.90 (3H, s,), 1 .15-1 .18 (2H, m), 1 .04-1 .07 (2H, m). | |
32 g | Stage #1: 4-cyanobenzoic acid methyl ester; ethylmagnesium bromide With titanium(IV) isopropylate In diethyl ether at -70℃; for 1h; Stage #2: With boron trifluoride diethyl etherate In diethyl ether for 2h; | 6 Description 6: methyl 4-(1-aminocyclopropyl)benzoate (D6) To the solution of methyl 4-cyanobenzoate (100 g, 620 mmol) in diethyl ether (3 L) was added titanium (IV) isospropoxide (194 g, 682 mmol), followed by dropwise addition of ethylmagnesium bromide 3M solution in diethylether (450 ml, 1.36 mol) at -70° C. The mixture was stirred for 1 h, and then boron trifluoride etherate (157 ml, 1.24 mol) was added at once. After 2 hours, aqueous HCl (5%) was added until the pH showed acidy, then the mixture was filtered. The solid was washed with ethylacetate. The aqueous phase was separated and the organic layer was washed with water. All aqueous layers were collected together, basified with 1M NaOH and extracted with ethylacetate. The organic layer was dried (Na2SO4) and concentrated to afford the title compound (D6) (32.0 g). |
Stage #1: 4-cyanobenzoic acid methyl ester; ethylmagnesium bromide In tetrahydrofuran; diethyl ether at -78℃; Inert atmosphere; Stage #2: With boron trifluoride diethyl etherate In tetrahydrofuran; diethyl ether; water Inert atmosphere; Stage #3: With hydrogenchloride; sodium hydroxide In water | 22.1 Example 22(1R)-f4-(1 -amino-cvclopropyl))-ben2θylamιnol-(3-carboxy-2-hvdroxy)be nzyl- methylboronic acid formate Step 1. Synthesis of 4-(1 -amino-cyclopropylj-benzoic acid methyl ester. To 4-cyano-benzoιc acid methyl ester (12 g, 74.6 mmol) in diethyl ether (300 ml) at -78°C under argon titanium isopropoxide (23.3 g, 81.9 mmol) was added followed by slow addition of ethyl magnesium bromide (52.1 ml, 156.3 mmol, 3M solution in THF) After stirring the reaction mixture for 15 minutes, the cooling bath was removed. After stirring the mixture for 1 hour, BF3*Et2O was added slowly and mixture stirred for another 1 hour. The reaction was quenched with 1 N HCI (75 ml) and extracted with Et2O (3x100 ml) The aqueous layer was basified with 3N NaOH solution and extracted with Et2O (3x100 ml). The ether layer was combined and was dried over MgSO4, and concentrated in vacuo. The crude product which was obtained in 41 % was taken to next step without purification ESI-MS m/z 192 (MH)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.9% | In tetrahydrofuran at 20℃; for 17h; | 31.2 Step 2 - Cycloproylamine, Methanesulfonic Acid Salt Formation; Materials MW Amount Moles E3Cyclopropylamine 7 191 .23 2.63 Kg 13.75 1.00MsOH 96. 11 1.00 L 15.40 1.12THF [ 14 mL/g ] 37 LA 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 7 (2.63 Kg, 1.00 eq) and THF (32 L, 12 mL/g). To the solution was added the MsOH (1.00 L, 1.12 eq) as a THF (4.0 L, 1.5 mL/g) solution over a period of 2 hrs. After the first 10 minutes of addition, seeds (500 mg) were added to start the crystallization. The solution was stirred at RT for a period of 15 hrs. The suspension was filtered and rinse with a small portion of the mother liquors. The salt was washed twice with cold THF (2 x 8 L, 2 x 3 mL/g), then dried on the frit for 3 hrs. The salt was dried in the vacuum oven first at 30 0C for 20hrs, then at 50 0C for a period of 60 hrs. The yield of material obtained was 3.93 Kg, which was 94.4%wt (yield = 92.9%). The losses to the mother liquors were 8.2 g (0.3%). |
92.9% | In tetrahydrofuran at 20℃; for 17h; | A.2 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 7 (2.63 Kg, 1.00 eq) and THF (32 L, 12 mL/g). To the solution was added the MsOH (1.00 L, 1.12 eq) as a THF (4.0 L, 1.5 mL/g) solution over a period of 2 hrs. After the first 10 minutes of addition, seeds (500 mg) were added to start the crystallization. The solution was stirred at RT for a period of 15 hrs. The suspension was filtered and rinsed with a small portion of the mother liquors. The salt was washed twice with cold THF (2 x 8 L, 2 x 3 mL/g), then dried on the frit for 3 hrs. The salt was dried in the vacuum oven first at 30 0C for 20hrs, then at 50 0C for a period of 60 hrs. The yield of material obtained was 3.93 Kg, which was 94.4%wt (yield = 92.9%). The losses to the mother liquors were 8.2 g (0.3%). |
92.9% | In tetrahydrofuran at 20℃; Inert atmosphere; Large scale reaction; |
92.9% | In tetrahydrofuran at 20℃; for 17h; Industry scale; Inert atmosphere; Cooling; | A 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 0C for 20 hours and then at 50 0C 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; 1H NMR (400 MHz, DMSO-d6): δ 8.78 (s, 3 H); 7.96 (d, J= 8.24 Hz, 2 H); 7.50 (d, J= 8.24 Hz, 2H); 3.84 (s, 3 H); 2.35 (s, 3 H); 1.46-1.39 (m, 2 H); 1.33-1.22 (m, 2 H). 13C 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.8% | With potassium phosphate In Isopropyl acetate; water at 20℃; for 2h; | 31.3 Step 3 - Methanesulfonic Acid Salt Break Materials MW Amount Moles EaMsOH salt 14 (94.4%wt) 287.33 3.93 Kg 12.91 1.002M K3PO4 [ 5 mL/g ] 19 L iPAc [ lO mL/g ] 39 LA visually clean 160 L 5-neck extractor equipped with a mechanical stirrer, a thermocouple and a nitrogen inlet was charged with the MsOH salt 14 (3.85 Kg, 1.00 eq) and iPAc (39 L, 10 mL/g). To the solution was added the 2M K3PO4 (19 L, 5 mL/g). The solution was stirred at RT for a period of 2 hrs 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, 5 mL/g) and once with saturated NaCl solution (19 L, 5 mL/g). The assay yield of cyclopropylamine was checked on the iPAc solution and showed to be 2.445 Kg (98.8%). The losses to the aqueous layer were below 0.1%. The iPAc layer was concentrated on rotavap and swiched with 10 L THF. |
98.8% | With potassium phosphate In Isopropyl acetate at 20℃; for 2h; | A.3 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 14 (3.85 Kg, 1.00 eq) and iPAc (39 L, 10 mL/g). To the solution was added the 2M K3PO4 (19 L, 5 mL/g). The solution was stirred at RT for a period of 2 hrs 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, 5 mL/g) and once with saturated NaCl solution (19 L, 5 mL/g). The assay yield of cyclopropylamine was checked on the iPAc solution and showed to be 2.445 Kg (98.8%). The losses to the aqueous layer were below 0.1%. The iPAc layer was concentrated on a rotavap and flushed with 10 L THF. |
98.8% | With potassium phosphate In Isopropyl acetate at 20℃; for 2h; Inert atmosphere; Large scale reaction; |
98.8% | With potassium phosphate In Isopropyl acetate at 20℃; for 2h; Industry scale; Inert atmosphere; | A 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 K3PO4 (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; 1H NMR (400 MHz, CDCl3) 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); 13C NMR (100 MHz, CDCl3): 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 CnH13NO2 (M + H) 192.10191, found 192.10257 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 3 - 27℃; for 1h; | 31.8 Step 8 - Amidation / Hydrolysis; Materials MW Amount Moles EflThiophene acid 5 314.32 2.68 Kg 8.54 1.00Oxalyl chloride 126.93 897 mL 10.25 1.20DMF 73.09 6.64 mL 0.085 1%Cyclopropylamine 7 191.23 1.88 Kg 9.82 1.15N,N-diisopropylethylamine 129.25 2.24 L 12.81 1.50LiOH 4N 23.95 7.47 L 29.9 3.50THF [ 12 mL/g ] 32 LMeOH [ 4 mL/g ] 10.7 L2N HC1 [ 7 mL/g ] 19 L Me-THF [25 mL/g ] 67 LA visually clean 100 L 5 -neck round-bottom flask equipped with a mechanical stirrer, a thermocouple, a nitrogen inlet, a cooling bath and a NaOH scrubber was charged with the thiophene acid 5 (2.95 Kg at 91%wt = 2.68 Kg, 1.00 eq) and THF (16 L, 6 mL/g). The DMF (6.64 mL, l%mol) was added. The oxalyl chloride (897 rnL, 1.20 eq) was added to the solution over a period of 30 minutes at RT. An exotherm of 1O0C was noticed during the addition of the oxalyl chloride (temperature rose from 17 0C to 27 0C). The mixture was aged at RT for 2 hrs (conversion 99.9%), then the solvent and excess oxalyl chloride were removed using the batch concentrater. The residue was flushed with THF (20 L). The residue was dissolved in THF (27 L, 10 mL/g) and the solution was cooled to 3 0C. The Hunig's base (2.24 L, 1.50 eq) was added to the solution. The cyclopropylamine 7 (1.88 Kg, 1.15 eq) was added to the solution as a THF solution (5 L, 2 mL/g) over a period of 30 minutes. An exotherm of 20 0C was observed (temperature 7 0C -> 270C). The mixture was aged 30 minutes. The conversion to the amide-ester was 99.8%. To the solution was added MeOH (4mL/g, 10.7 L) and the 4N LiOH (7.47 L, 3.5 eq). An exotherm of 14 0C was observed (temperature 17 0C -> 31 0C). The mixture was heated to 55 0C and kept at this temperature for 1.5 hrs. The conversion to the amide-acid was 99.5%. The mixture was cooled to 22 0C and the reaction was quenched by the addition of 2N HCl (19 L, 7 mL/g). The organic solvents were removed using the batch concentrator and flushed with 20 L of Me-THF. The residue (as a suspension in HCl) was dissolved in Me-THF (54 L, 20 mL/g). The biphasic mixture was transferred to the extractor and the layers were separated. The aqueous layer was back extracted using Me-THF (13L, 5 mL/g). Combined organic layers were washed with water (13 L, 5 mL/g). The assay yield of the compound 9 was determined on the organic layer prior to its concentration and showed to be 88.0% (3.56 Kg). The losses to the aqueous layer were below 0.1%. | |
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 3 - 27℃; for 1h; | A.8 A visually clean 100 L 5-neck round-bottom flask equipped with a mechanical stirrer, a thermocouple, a nitrogen inlet, a cooling bath and a NaOH scrubber was charged with the thiophene acid 5 (2.95 Kg at 91%wt = 2.68 Kg, 1.00 eq) and THF (16 L, 6 mL/g). The DMF (6.64 mL, l%mol) was added. The oxalyl chloride (897 mL, 1.20 eq) was added to the solution over a period of 30 minutes at RT. An exotherm of 10 0C was noticed during the addition of the oxalyl chloride (temperature rose from 17 0C to 27 0C). The mixture was aged at RT for 2 hrs (conversion 99.9%), then the solvent and excess oxalyl chloride were removed using the batch concentrater. The residue was flushed with THF (20 L). The residue was dissolved in THF (27 L, 10 mL/g) and the solution was cooled to 3 0C. Diisopropylethylamine (2.24 L, 1.50 eq) was added to the solution. The cyclopropylamine 7 (1.88 Kg, 1.15 eq) was added to the solution as a THF solution (5 L, 2 mL/g) over a period of 30 minutes. An exotherm of 20 0C was observed (temperature 7 0C -> 270C). The mixture was aged 30 minutes. The conversion to the amide-ester was 99.8%. To the solution was added MeOH (4mL/g, 10.7 L) and the 4N LiOH (7.47 L, 3.5 eq). An exotherm of 14 0C was observed (temperature 17 0C -> 31 0C). The mixture was heated to 55 0C and kept at this temperature for 1.5 hrs. The conversion to the amide-acid was 99.5%. The mixture was cooled to 22 0C and the reaction was quenched by the addition of 2N HCl (19 L, 7 mL/g). The organic solvents were removed using the batch concentrator and flushed with 20 L of Me-THF. The residue (as a suspension in HCl) was dissolved in Me-THF (54 L, 20 mL/g). The biphasic mixture was transferred to the extractor and the layers were separated. The aqueous layer was back extracted using Me-THF (13L, 5 mL/g). The combined organic layers were washed with water (13 L, 5 mL/g). The assay yield of the compound 9 was determined in the organic layer prior to its concentration and shown to be 88.0% (3.56 Kg). The losses to the aqueous layer were below 0.1%. | |
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 3℃; for 1h; Inert atmosphere; Large scale reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 0 - 20℃; for 1.16667h; | 31.2 Step 2 - Isocyanate formation.; Materials MW Amount mmoles EflCyclopropyl amine 191.23 6.Og 31.4 1.00Triethylamine 101.19 6.98g 69.0 2.20Phosgene 98.92 16.29g 32.9 1.05Phosgene was diluted into DCM (40 niL) and cooled to 00C and a DCM (10 mL) solution of cyclopropyl amine and Et3N was added over 60min. The mixture was warmed to rt and aged lOmin. The mixture was washed with IN HCl and brine, then dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (10->30% EtOAc/hexanes) to afford 3.67g of isocyanate. | |
With triethylamine In 1,2-dichloro-ethane at 0 - 20℃; for 1.16667h; | A.2 Phosgene was diluted into DCM (40 mL) and cooled to 0°C and a DCM (10 mL) solution of cyclopropyl amine and Et3N was added over 60min. The mixture was warmed-to rt and aged lOmin. The mixture was washed with IN HCl and brine, then dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (10->30% EtOAc/hexanes) to afford 3.67g of isocyanate. | |
With triethylamine In dichloromethane; toluene at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 0 - 20℃; for 2h; | Step 3: Methyl 4-{ l-[(2,3-dihydro-lH-indol-7-ylcarbonyl)amino]cyclopropyl}benzoatel-(te^butoxycarbonyl)indoline-7-carboxylic acid (300 mg, 1.14 mmol), HATU (475 mg, 21.2 mmol) and methyl 4-(l-aminocyclopropyl)benzoate (262 mg, 1.37 mmol) were added to acetonitrile (7.6 ml). The solution was cooled in an ice bath and DIPEA (695 ul, 3.99 mmol) was added. After 2 hr at RT, the mixture was poured into a solution OfNaHCO3 (l/2sat.) and washed 3 times with EtOAc. The combined organic layers were washed with brine and dried with Na2SO4. The solvent was removed and the crude mixture purified by flash chromatography on silica gel. The Boc group was removed with 1:1 TFA/DCM using the standard procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; | 3.3 Step 3: Methyl 4-{l-[({l-[4-(trifluoromethyl)benzyl]-lH-indol-7- yl } carbonyl)amino]cyclopropyl } benzoateMethyl l-[4-(trifluoromethyl)benzyl]-lH-indole-7-carboxylate (30.8 g, 97 mmol), HATU (38.6 g, 101 mmol) and methyl 4-(l-aminocyclopropyl)benzoate (24.9 g, 130 mmol) were added to DMF (483 ml). The solution was cooled in an ice bath and DIPEA (50.6 ml, 290 mmol) was added. The mixture was aged overnight at RT and 500 ml of EtOAc was added. The mixture was then poured into 2 L OfNaHCO3 (l/2sat.). The layers were cut and the aqueous layer was washed 2 more times with DCM. The combined organic layers were washed with brine and dried with Na2SO4. The solvent was removed and the crude mixture purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): δ 9.18 (s, IH), 7.75 (m, 3H), 7.60 (d, 2H), 7.45 (d, IH), 7.40 (d, IH), 7.20 (d, 2H), 7.15 (t, IH), 6.90 (d, 2H), 6.65 (d, IH), 5.70 (s, 2H), 3.85 (s, 3H), 1.20 (m, 2H), 0.95 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.1% | Stage #1: pyridine-2-carbaldehyde; 4-(1-aminocyclopropyl)-benzoic acid methyl ester In methanol at 20℃; for 12h; Stage #2: With sodium tetrahydroborate In methanol at 0 - 20℃; for 1.5h; Stage #3: With water In methanol | b) A solution of 4-(1 -Amino-cyclopropyl)-benzoic acid methyl ester (2.45 g, 12.8 mmol) and Pyridine-2-carbaldehyde (1 .22 ml, 12.8 mmol) in methanol (50 ml) was stirred for 12 h atRT.) and then cooled to 0 QC. Then NaBH4 (291 mg; 7.7 mmol) was added and the reaction mixture was stirred at 0 QC for 30 min and 1 h at RT. The reaction mixture was poured into water (30 ml), concentrated and aqueous layer was extracted with ethyl acetate; the organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated and the residue was purified by flash chromatography on silica gel (n-heptan/ EtOAc) to give the title as a yellow oil (2.8 g; 77.1% yield. (MS: m/z : 283). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
226 mg | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-bis-(diphenylphosphino)ferrocene; bis(benzonitrile)palladium(II) dichloride; triethylamine In methoxybenzene at 140℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride; In diethyl ether; ethyl acetate; | Step 2:To a solution of ER-886774-00 (1.63 g, 0.0085 mol) in ethyl acetate (10 mL) was added 2.0 M of hydrogen chloride in Ether (6.0 mL, 0.012 mol). After stirring for several minutes, the reaction mixture was concentrated to give the title compound (quantitative yield) as pale brown solid. |
With hydrogenchloride; In ethyl acetate; at 20℃; for 2h; | . Procedure BTo a cooled solution of methyl 4-(1 -aminocyclopropyl)benzoate (D6) (100 g, 524 mmol) in ethyl acetate (500ml) 4N HCI(g)/ethyl acetate solution (300ml) was added and the resulting mixture was stirred at room temperature for 2 hours. Evaporated the solvent, the residue was recrystallized with petroleum ether/EtOAc to afford the title compound (D7) (68.7 g) as a white solid.LCMS: (ES/+) m/z: 192 [MH+] C1 1 H13N02 requires 191 .091 H NMR (400MHz ,CHLOROFORM-d) delta (ppm): 9.14 (3H, brs), 7.97 (2H, d, J= 8.4 Hz), 7.53 (2H, d, J= 8.4 Hz), 3.87 (3H, s), 1 .53 - 1 .49 (2H, m), 1 .28 - 1 .31 (2H, m). | |
68.7 g | With hydrogenchloride; In ethyl acetate; at 20℃; for 2h; | To a cooled solution of methyl 4-(1-aminocyclopropyl)benzoate (D6) (100 g, 524 mmol) in ethyl acetate (500 ml) 4N HCl (g)/ethyl acetate solution (300 ml) was added and the resulting mixture was stirred at room temperature for 2 hours. Evaporated the solvent, the residue was recrystallized with petroleum ether/EtOAc to afford the title compound (D7) (68.7 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; | A 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 0C 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 0C 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 0C. 1H NMR (500 MHz, Acetone-d6): 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). 13C NMR (125 MHz, Acetone-d6): 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. 19F NMR (375 MHz, Acetone-d6): δ -63.0. IR (neat): 3265, 3009, 2947, 2843, 1717, 1639, 1500, 1409, 1321, 1278, 11 17. HRMS (ES): m/z calcd for [C28H23F3N2O3 + 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 H3PO4 / CH3CN 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, 350C); indole ester /R = 6.22 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile at 20℃; for 6h; | 22.2 Step 2. Synthesis of 4-(1-tert-butoxycarbonylamino-cyclopropyl)- benzoic acid. The crude 4-(1 -amιno-cyclopropyl)-benzoιc acid methyl ester (4 0 g, 20.9 mmol) which was made in the previous step was dissolved in CH3CN (80 ml), boc?O (4.8 g, 21 9) was then added and the solution stirred at room temperature for 6 hours The reaction was quenched with water (100 ml) and extracted with EtOAc (3x100 ml) The organic layers were combined and were dried over MgSO4, and concentrated in vacuo to obtained crude 4-(1-tert- butoxycarbonylamino-cyclopropyO-benzoic acid methyl ester ESI-MS m/z 292 (MH)* To this crude product in H2O (60 ml) and MeOH (150 ml), NaOH (2 4 g. 60 mmol) was added and the mixture stirred 15 hours at room temperature. MeOH was evaporated, and more water (200 ml) was added 1 N HCI was added slowly which caused the precipitation of the product. The solid was filtered off to give yield. ESI-MS m/z 278 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In tetrahydrofuran; methanol; hexane at 20℃; for 12h; Cooling with ice; | procedure for methyl 4-(l-aminocyclopropyl)benzoateStep 1 :4-(l-aminocyclopropyl)benzoic acid (1.75 g, 0.00988 mol) was stirred in THF (20 mL) and Methanol (10 niL) over ice/water bath. 2.00 M of trimethylsilyldiazomethane in hexane (9.9 mL, 0.020 mol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated down to viscous oil which solidified upon standing to give a crystalline solid. Crude material was dried on high vacuum line for 12 hours to give methyl 4-(l- aminocyclopropyI)benzoate (1.65 g, 87%) as pale brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydrogenchloride / ethyl acetate; diethyl ether 2.1: diisopropyl-carbodiimide; HOBt-6-carboxamidomethyl polystyrene / dmap / dichloromethane; N,N-dimethyl-formamide / 12 h / 40 °C 2.2: 12 h / 40 °C 3.1: lithium hydroxide / 1,4-dioxane / 12.33 h / 60 - 140 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 0.67 h / 20 °C 2.2: 3 h / 20 °C 3.1: sodium hydroxide; water / 1,4-dioxane / 12 h / 60 °C 3.2: 0.17 h / 0 °C / pH 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 0.67 h / 20 °C 2.2: 0.67 h / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 0.25 h 4.1: sodium hydroxide; water / 1,4-dioxane / 60 °C 4.2: 20 °C / pH 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 3.2: 75 - 80 °C 4.1: water; lithium hydroxide monohydrate / 1,4-dioxane / 0.33 h / 70 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 3.2: 75 - 80 °C 4.1: water; lithium hydroxide monohydrate / 1,4-dioxane / 0.33 h / 70 °C / Microwave irradiation 5.1: pyridine / 60 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / dichloromethane / 0.17 h / 110 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: potassium carbonate; ethyl acetate / acetonitrile / 0.83 h / 200 °C / Microwave irradiation 2.2: 0.08 h / 150 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: triethylamine; sodium carbonate / tetrahydrofuran; methanol / 24 h / 75 °C 4.1: sodium hydroxide; water / 1,4-dioxane / 20 °C 4.2: pH 5 - 6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 0.17 h / 20 °C 2.2: 24 h / 20 °C 3.1: sodium hydroxide; water / 1,4-dioxane / 12 h / 60 °C 3.2: 0.17 h / 0 °C / pH 2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 0.67 h / 20 °C 2.2: 0.67 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 2.2: 20 °C 3.1: sodium hydroxide / tetrahydrofuran; methanol / 2 h / 40 °C 3.2: 0.17 h / 0 °C / pH 1 - 2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 2.2: 20 °C 3.1: water; lithium hydroxide monohydrate / 1,4-dioxane / 0.17 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 2.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 2.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 0.67 h / 20 °C 2.2: 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 0.67 h / 20 °C 2.2: 0.67 h / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 0.25 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 3.2: 75 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 1 h / 20 °C 3: triethylamine; sodium carbonate / tetrahydrofuran; methanol / 24 h / 75 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hydrogenchloride / ethyl acetate / 2 h / 20 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-1H-benzotriazol hydrate / N,N-dimethyl-formamide / 0.17 h / 20 °C 2.2: 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 1.5 h / 20 °C / Cooling with ice 2.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.25 h / Inert atmosphere; Cooling with ice 2.2: 20 °C / Cooling with ice 3.1: hydrogenchloride / methanol / 3.5 h / 20 °C / Cooling with ice 3.2: 6 h / 140 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.86 g | With triethylamine In dichloromethane at 20℃; for 1.5h; Cooling with ice; | 67 [0339] Preparation Example 67: Preparation of methyl 4-(1-ethoxycarbonylaminocyclopropyl)benzoate [0339] Preparation Example 67: Preparation of methyl 4-(1-ethoxycarbonylaminocyclopropyl)benzoate[0340][0341] Methyl 4-(1-aminocyclopropyl)benzoate (1.84 g) and triethylamine (2.82 mL) were dissolved in dichloromethane(40 mL), ethyl chlorocarbonate (1.01 mL) was added under ice-cooling, and the mixture was stirred at the same temperaturefor 30 min and at room temperature for 1 hr. After completion of the reaction, the solvent was evaporated, tothe residue was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography(hexane:ethyl acetate) to give the title compound (0.86 g).EP 2 565 182 A140510152025303540455055MS (ESI) m/z:264(M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 1.5 h / 20 °C / Cooling with ice 2.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.25 h / Inert atmosphere; Cooling with ice 2.2: 20 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; | 11.4 (4) To a solution of the foregoing compound (h-11) (0.21 g, 0.55 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (h-12) (0.12 g, 0.60 mmol) in DMF (3.2 mL), DIPEA (0.24 mL, 1.4 mmol) was added dropwise and, thereafter, HATU (0.23 g, 0.60 mmol) was added and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, water was added and extraction was conducted with ethyl acetate; the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvents in the organic layer were distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=70:300:100) to give methyl 4-(1-{2-chloro-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-5-carboxamido}cyclopropyl)benzoate (h-13) (amount, 0.26 g; yield, 84%). |
84% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; | 11.4 To a solution of the foregoing compound (h-11) (0.21 g, 0.55 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (h-12) (0.12 g, 0.60 mmol) in DMF (3.2 mL), DIPEA (0.24 mL, 1.4 mmol) was added dropwise and, thereafter, HATU (0.23 g, 0.60 mmol) was added and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, water was added and extraction was conducted with ethyl acetate; the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvents in the organic layer were distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=70:300:100) to give methyl 4-(1-{2-chloro-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-5-carboxamido}cyclopropyl)benzoate (h-13) (amount, 0.26 g; yield, 84%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; | 12.4 (4) To a solution of the foregoing compound (h-18) (3.0 g, 8.9 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (h-12) (2.0 g, 11 mmol) in DMF (22 mL), DIPEA (3.9 mL, 22 mmol) was added dropwise; thereafter, HATU (3.7 g, 9.8 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was added to water and thereafter the precipitating solids were recovered by filtration to give methyl 4-(1-{2-chloro-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-1-(4-methylbenzyl)-1H-imidazole-5-carboxamido}cyclopropyl)benzoate (h-19) (amount, 4.2 g; yield, 93%). |
93% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; | 12.4 To a solution of the foregoing compound (h-18) (3.0 g, 8.9 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (h-12) (2.0 g, 11 mmol) in DMF (22 mL), DIPEA (3.9 mL, 22 mmol) was added dropwise; thereafter, HATU (3.7 g, 9.8 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was added to water and thereafter the precipitating solids were recovered by filtration to give methyl 4-(1-{2-chloro-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-1-(4-methylbenzyl)-1H-imidazole-5-carboxamido}cyclopropyl)benzoate (h-19) (amount, 4.2 g; yield, 93%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 16h; | 3 4-(1-[2-Methyl-4-(4-trifluoromethyl-benzyl)-4H-thieno[3,2-b]pyrrole-3-carbonyl]-amino}-cyclopropyl)-benzoic acid A mixture of 0.3 g of 2-methyl-4-(4-trifluoromethyl-benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid, 0.25g of 4-(1-amino-cyclopropyl)-benzoic acid methyl ester, 0.5 g of HATU and 0.25 ml of Pr2NEt in 8 ml of DMF was stirred at room temperature for 16 h. The reaction was then diluted with 30 ml of water and extracted with 100 ml of EtOAc. The organic layer was washed with 50 ml of water and 50 ml of brine and dried over Na2SO4. The extract was filtered, and concentrated to give the crude methyl ester which was dissolved in 20 ml of 1:1 THF/MeOH and treated with 10 ml of 0.5 M aqueous LiOH solution. After stirring for 15 h at room temperature, 1 ml of AcOH was added and the reaction mixture was extracted with 75 ml of EtOAc. The organic layer was washed with 50 ml of brine, dried over Na2SO4. The extract was filtered and concentrated to give 0.25 g of the title compound | |
With dipropylethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 16h; | 4 4-(1-[4-(4-Trifhioromethyl-benzyl)-4H-thieno[3,2-b]pyrrole-3-carbonyl]-amino}-cyclopropyl)-benzoic acid A mixture of 0.33 g of 4-(4-Trifluoromethyl-benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid, 0.23g of 4-(1-amino-cyclopropyl)-benzoic acid methyl ester, 0.5 g of HATU and 0.25 ml of Pr2NEt in 8 ml of DMF was stirred at room temperature for 16 h. The reaction was then diluted with 30 ml of water and extracted with 100 ml of EtOAc. The organic layer was washed with 50 ml of water and 50 ml of brine and dried over Na2SO4. The extract was filtered, and concentrated to give the crude methyl ester which was dissolved in 20 ml of 1:1 THF/MeOH and treated with 10 ml of 0.5 N aqueous LiOH solution. After stirring for 15 h at room temperature, 1 ml of AcOH was added and the reaction mixture was extracted with 75 ml of EtOAc. The organic layer was washed with 50 ml of brine, dried over Na2SO4. The extract was filtered and concentrated to give 0.22 g of the title compound | |
With dipropylethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 16h; | 5.3 Step 3 4-(1-[2-Oxo-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indole-7-carbonyl]-amino}-cyclopropyl)-benzoic acid A mixture of 0.40 g of 2-oxo-1-(4-trifluoromethyl-benzyl)-2,3-dihydro-1H-indole-7-carboxylic acid, 0.29 g of (+-)4-(1-amino-ethyl)-benzoic acid methyl ester, 0.19 g of HOBT-hydrate, 0.30 g of ethyl-dimethylaminopropyl-carbodiimide hydrochloride (EDCI) and 0.150 ml of N-methylmorpholine in 7 ml of DMF was stirred at room temperature for 16 h. The reaction was then quenched with 10 ml of water and 5 ml of sat. NaHCO3 solution. The resulting mixture extracted with 25 ml of EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude methyl ester (0.3 g) which was dissolved in 5 ml THF, 5 mL MeOH and treated with 4 mL of 1N LiOH solution. After stirring at 50 °C for 12 h, the reaction mixture was concentrated under reduced pressure to remove THF and MeOH. The residue was diluted with 8 mL of water and treated with 1 mL of AcOH with vigorous stirring. After stirring for 2 h, the solid was collected by filtration and air-dried to give 0.25 g of the title compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In acetonitrile at 0 - 20℃; for 2h; | 12.5 Step 5: tert-Butyl 7-[[1-(4-methoxycarbonyJ.phenyl) cyclopropyl] carbamoyl] Spiro [indoline3,4’ -tetrahydropyran] -1-carboxylate Step 5: tert-Butyl 7-[[1-(4-methoxycarbonyJ.phenyl) cyclopropyl] carbamoyl] Spiro [indoline3,4’ -tetrahydropyran] -1-carboxylateTo a mixture of 1-tert-butoxycarbonylspiro[indoline-3,4’- tetrahydropyran]-7-carboxylic acid (0.3 g, 0.9 mmcl), methyl4-(1-aminocyclopropyl)benzoate (0.3 g; 1.35 mmol) and HATU (0.51 g, 1.35 mmcl) in acetonitrile (10 mL) at 0°C was added DIPEA (0.46 mL, 2.70 mmcl) . The resulting reaction mixture was stirred for 2 hours at room temperature. The product formation was confirmed by TLC, then the reaction mixture was quenchedwith water (20 mL) and extracted with ethyl acetate (3 x 20 mL) . The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated under vacuo. The crude mixture thus obtained was purified by cornbiflash column chromatography to give the titlecompound (0.4 g, 88%)MS(ESI)m/z: 407.2 [[M-t-Bu]+1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 2h; | 13.5 Step 5: tert-Butyl 7-[[1-(4-methoxycarbonyiphenyl) cyclopropyl] carbamoy].) Spiro [2H-pyrrolo [3 ,2-cJpyridine-3, 1’ -cyclopropane) -1-carboxylate Step 5: tert-Butyl 7-[[1-(4-methoxycarbonyiphenyl) cyclopropyl] carbamoy].) Spiro [2H-pyrrolo [3 ,2-cJpyridine-3, 1’ -cyclopropane) -1-carboxylateTo a mixture of 1-tert-butoxycarbonylspiro[2H-- pyrrolo[3,2-c]pyridine-3, 1’-cyclopropane]-7-carboxylic acid (0.3 g, 1.03 mmcl), methyl 4-(l-aminocyclopropyl)benzoate(0.28 g, 1.24 mmcl) and HATU (0.589 g, 1.55 mmcl) in DMF (10 mL) at 0°C was added DIPEA (0.36 mL, 2.06 mmcl), and the resulting reaction mixture was stirred for 2 hour at room temperature. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL) . The combinedorganic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated under vacuc. The crude mixlure thus obtained was carried further for the next reaction.MS(ESI)m/z: 464.1 [[M + 1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | for 1h; Heating; | 4.2 Step 2: Methyl 4- [1- [ (4-benzyloxy-3-nitro-2- pyridyl) amino] cyclopropyl]benzoate A round bottom flask was charged with a mixture of 4- benzyloxy-2-chloro-3-nitropyridine (13.0 g, 49 mmol) and methyl 4- ( 1-aminocyclopropyl ) benzoate (18.8 g, 98 mmol). The flask was immersed in preheated oil bath at 160°C, and the mixture was stirred for 1 hour. The reaction completion was confirmed by TLC, then the mixture was cooled to room temperature, and the residue was triturated with ethanol and filtered to give the title compound as an off-white solid (15 g, 73 %) . MS(ESI)m/z: 419.9 (M+l); XH NMR (400 MHz, DMSO-d6) ; δ 0.64 (dd, J= 4.8, 6.8 Hz, 2H) , 1.02 (dd, J= 6.0, 8.4 Hz, 2H) , 3.82 (s, 3H) , 5.33 (s, 2H), 6.07 (d, J = 7.2 Hz, 1H) , 7.04 (d, J = 7.6 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H) , 7.32-7.36 (m, 1H) , 7.42- 7.44 (m, 3H) , 7.70 (d, J = 7.6 Hz, 1H) , 7.79 (d, J = 8.4 Hz, 2H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; HATU / acetonitrile / 2 h / 0 - 20 °C 2: trifluoroacetic acid / dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; HATU / acetonitrile / 2 h / 0 - 20 °C 2: trifluoroacetic acid / dichloromethane 3: tetra-(n-butyl)ammonium iodide; N-ethyl-N,N-diisopropylamine / acetonitrile / 2 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0 - 20 °C 2.1: methanol; potassium hydroxide; water / tetrahydrofuran / 2 h / 50 °C 2.2: pH 1 - 1.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0 - 20 °C 2.1: methanol; potassium hydroxide; water / tetrahydrofuran / 2 h / 50 °C 2.2: pH 1 - 1.5 3.1: ethanol / 0.5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; HATU / acetonitrile / 2 h / 0 - 20 °C 2: trifluoroacetic acid / dichloromethane 3: tetra-(n-butyl)ammonium iodide; N-ethyl-N,N-diisopropylamine / acetonitrile / 2 h / 70 °C 4: potassium hydroxide; ethanol; water / 2 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: acetonitrile / 6 h / 20 °C 2: methanol; water; sodium hydroxide / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triethylamine / toluene / 1.5 h / 0 - 20 °C 2.1: n-butyllithium / tetrahydrofuran / 0.42 h / 0 - 20 °C 2.2: 0.08 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: triethylamine / toluene / 1.5 h / 0 - 20 °C 2.1: n-butyllithium / tetrahydrofuran / 0.42 h / 0 - 20 °C 2.2: 0.08 h / 20 °C 3.1: lithium hydroxide; water / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / toluene / 1.5 h / 0 - 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine / toluene / 1.5 h / 0 - 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: water; lithium hydroxide monohydrate / tetrahydrofuran; methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.04 g | With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20 - 60℃; | 5.4 Step 4: methyl 4-(l-(l-methyl-4-(4-(trifluoromethyl)phenoxy)-lH-indole-3- carboxamido)cyclopropyl)benzoate To a solution of l-methyl-4-(4-(trifluoromethyl)phenoxy)-lH-indole-3-carboxylic acid (0.032 g, 0.095 mmol), methyl 4-(l-aminocyclopropyl)benzoate (0.022 g, 0.114 mmol) and HATU (0.054 g, 0.143 mmol) in DMF(3 mL) was added NMM (0.019 g, 0.19 mmol) at room temperature. The resulting solution was stirred at room temperature for 3 h. The desired MS peak was detected by LCMS, but most of the starting material was remained. Another 10 eq. of B was added and stirred at 60 °C for 3 days. LCMS shows this reaction was completed. IN HCI solution was added to quench this reaction and adjust pH= 3-4. Then, the resulting solution was extracted with EtOAc (10 mL*3), washed by brine, dried over Na2S04 and concentrated. This crude product was separated via silica gel column (MeOH in DCM from 0 to 3%) to give 0.040 g of the title product as a pale yellow solid. MS (ES-API positive): 509 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.69 g | With triethylamine In toluene at 0 - 20℃; for 1.5h; | 1.1 Step 1: Methyl 4-(l-isocyanatocyclopropyl)benzoate To a solution of methyl 4-(l-aminocyclopropyl)benzoate (1.3 g, 6.87 mmol) and triphosgene (0.621g, 2.09 mmol) in toluene (30 mL) was added Et3N (1.45 mL, 10.46 mmol) dropwise at 0 °C. This reaction was stirred at 0 °C for 30 min Then, stirred at room temperature for lh. TLC check reaction, the starting material was consumed by TLC, and filtration this suspension and concentration to give a 0.69 g of the title product as a pale-yellow solid, which was used for next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.079 g | With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20 - 50℃; for 5h; | 6.3 Step 3: methyl 4-(l-(4-(4-(trifluoromethyl)phenoxy)-lH-indole-3- carboxamido)cyclopropyl)benzoate To a solution of l-methyl-4-(4-(trifluoromethyl)phenoxy)-lH-indole-3-carboxylic acid (0.073 g, 0.227 mmol), methyl 4-(l-aminocyclopropyl)benzoate (0.217 g, l.Mmmol) and HATU (0.173 g, 0.454 mmol) in DMF (3 mL) was added NMM (0.046 g, 0.454 mmol) at room temperature. The resulting solution was stirred at 50 °C for 5 h. LCMS shows this reaction was completed. IN HCI solution was added to quench this reaction and adjust pH= 3-4. Then, the resulting solution was extracted with EtOAc (10 mL*3), washed by brine, dried over Na2S04 and concentrated. This crude product was separated via silica gel column (MeOH in DCM from 0 to 3%) to give 0.079 g of the title product as a pale yellow solid. MS (ES-API positive): 495 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: ethanol / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: ethanol / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: ethanol / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: ethanol / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: sodium hydroxide / ethanol; water / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: magnesium hydroxide / ethanol / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: calcium hydroxide / ethanol / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: ammonium hydroxide / water / 22 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: water / 24 h / 20 - 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: water / 38 h / 20 - 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: acetone / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: acetone / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: ethanol / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: ethanol / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; dipropylethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: water; lithium hydroxide / tetrahydrofuran; methanol / 15 h / 20 °C 3: ethanol / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C / Inert atmosphere; Schlenk technique 1.2: 1 h / Inert atmosphere; Schlenk technique 2.1: acetonitrile / 20 °C / Inert atmosphere; Schlenk technique; UV-irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Stage #1: 4-(1-aminocyclopropyl)-benzoic acid methyl ester; p-toluenesulfonyl chloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; Inert atmosphere; Schlenk technique; Stage #2: With dmap In dichloromethane for 1h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: (R)-6-(tert-butoxycarbonyl)-6 azaspiro[2.5]octane-5-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: 4-(1-aminocyclopropyl)-benzoic acid methyl ester With triethylamine at 30℃; for 6h; | 1.1c (0111) Example 1c) synthesis of intermediate () tert-butyl (R)-5-((1-(4-(methoxycarbonvi) phen vDcvcloprop vDcarbamo vi)-6-azaspiro[2.51octane-6-carbox ylate With reference to scheme 1 the intermediate (I) was obtained. (0113) 10g (0.039mmol) of starting material 1 were dissolved in DCM (200ml), HOBt hydrate (1 .1 eq) and EDC-HCI (1 .1 eq) were added and the mixture was stirred at 20°C for 30 minutes. Starting material 2 (1 .02 eq) was added, then TEA (1 .2 eq.); the reaction was left stirring for 6 hours at 30°C, then was quenched with water (100ml). The organic phase was washed with 5% sodium bicarbonate solution (100ml), 1 M citric acid solution (200ml), water (200ml). DCM was evaporated, t-butylmethyl ether (200ml) was added then the solvent was evaporated again. 400ml of t-butylmethyl ether was added, the suspension was stirred at 20°C for 17 hours, then the white solid was filtrated and washed with cool t-butylmethyl ether. The product was dried under vacuum at 50°C. Yield 14.7g (88%) (0114) 1 H NMR (400MHz, CHLOROFORM-d) d = 8.01 - 7.93 (m, 2H), 7.28 (s, 2H), 6.74 (s, 1 H), 4.83 (br s, 1 H), 4.21 (br s, 1 H), 3.92 (s, 3H), 3.10 - 2.87 (m, 1 H), 2.10 - 1 .99 (m, 1 H), 1 .97 - 1.85 (m, 1 H), 1 .84 - 1.75 (m, 1 H), 1 .52 (s, 9H), 1 .40 (br s, 4H), 0.88 - 0.81 (m, 1 H), 0.63 - 0.45 (m, 1 H), 0.45 - 0.29 (m, 2H), 0.28 - 0.18 (m, 1 H). ESI + m/z 429 [M+H]+ |
88% | Stage #1: (R)-6-(tert-butoxycarbonyl)-6 azaspiro[2.5]octane-5-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: 4-(1-aminocyclopropyl)-benzoic acid methyl ester With triethylamine In dichloromethane at 30℃; for 6h; | 1c With reference to scheme 1 the intermediate (I) was obtained.10g (0.039mmol) of starting material 1 were dissolved in DCM (200ml), HOBt hydrate (1.1eq) and EDC-HCl(1.1eq) were added and the mixture was stirred at 20°C for 30 minutes. Starting material 2 (1.02 eq) was added, thenTEA (1.2 eq.); the reaction was left stirring for 6 hours at 30°C, then was quenched with water (100ml). The organicphase was washed with 5% sodium bicarbonate solution (100ml), 1M citric acid solution (200ml), water (200ml). DCMwas evaporated, t-butylmethyl ether (200ml) was added then the solvent was evaporated again. 400ml of t-butylmethylether was added, the suspension was stirred at 20°C for 17 hours, then the white solid was filtrated and washed withcool t-butylmethyl ether. The product was dried under vacuum at 50°C. Yield 14.7g (88%)1H NMR (400MHz, CHLOROFORM-d) δ = 8.01 - 7.93 (m, 2H), 7.28 (s, 2H), 6.74 (s, 1H), 4.83 (br s, 1H), 4.21 (br s,1H), 3.92 (s, 3H), 3.10 - 2.87 (m, 1H), 2.10 - 1.99 (m, 1H), 1.97 - 1.85 (m, 1H), 1.84 - 1.75 (m, 1H), 1.52 (s, 9H), 1.40(br s, 4H), 0.88 - 0.81 (m, 1H), 0.63 - 0.45 (m, 1H), 0.45 - 0.29 (m, 2H), 0.28 - 0.18 (m, 1H).ESI + m/z 429 [M+H]+ |
87% | Stage #1: (R)-6-(tert-butoxycarbonyl)-6 azaspiro[2.5]octane-5-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Large scale; Stage #2: 4-(1-aminocyclopropyl)-benzoic acid methyl ester With triethylamine In dichloromethane at 20℃; for 24h; Large scale; | 1.1c Example 1c) synthesis of compound (I) tert-butyl (R)-5-((1-(4-(methoxycarbonvi) phenyl)cvclopropyl)carbamoyl)-6-azaspirof2.5ioctane-6-carboxylate With reference to scheme 1 , the compound (I) was obtained. In a reactor, starting material 1 (SM1, 8 Kg) HOBt hydrate (5.8 Kg) and EDC-HCI (1.1 Kg) were dissolved in DCM (150 L) and stirred at RT; after 30 minutes, starting material 2 (SM2, 7.5 Kg) and TEA (3.4 L) were added and the reaction was left stirring for 24 hours at RT, then was quenched with water (70 L) and phases separated. The organic phase was washed with 5% sodium bicarbonate solution (2 x 70 L), 1 M citric acid solution (80 L), water (70 L), then DCM was evaporated t-butylmethyl ether (17 L) was added, the suspension obtained was stirred at RT for 17 hours, then the solid was filtrated and washed with cool t-butylmethyl ether (15 L). The title compound was dried under vacuum at 50°C for 8 hours. Yield 11 .65 Kg (87%; white solid). 1H NMR (400MHz, chloroform-d) d = 8.01 - 7.93 (m, 2H), 7.28 (s, 2H), 6.74 (s, 1 H), 4.83 (br s, 1 H), 4.21 (br s, 1 H), 3.92 (s, 3H), 3.10 - 2.87 (m, 1 H), 2.10 - 1.99 (m, 1 H), 1.97 - 1.85 (m, 1 H), 1 .84 - 1.75 (m, 1 H), 1 .52 (s, 9H), 1.40 (br s, 4H), 0.88 - 0.81 (m, 1H), 0.63 - 0.45 (m, 1 H), 0.45 - 0.29 (m, 2H), 0.28 - 0.18 (m, 1 H). ESI + m/z 429 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: N-BOC-D-pipecolic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.666667h; Stage #2: 4-(1-aminocyclopropyl)-benzoic acid methyl ester With triethylamine In dichloromethane at 20℃; for 15h; | 2.2a - Example 2a: synthesis of intermediate (V) tert-butyl (R)-2-((1-(4- (methox vcarbon yl ) phen vDcycloprop vDcarbamo yl) piperidine- 1 -carbox ylate (0173) Boc-D-pipecolic acid (500 mg, 2.181 mmol) was dissolved in DCM (13 ml). N- hydroxybenzotriazole hydrate (2.62 mmol) and EDCI (3.05 mmol) were added and the reaction mixture was left stirring for 40 min. SM2 (2.268 mmol) was added followed by TEA (2.94 mmol). The reaction mixture was left stirring at room temperature for 15h, then water (20ml) was added. Phases were separated and the aqueous layer was extracted with DCM (2 x 15ml_). The combined organic layers were evaporated and loaded on SNAP Ultra-HP Sphere-Si (10g) column eluting with cyclohexane/AcOEt 100% up to 70/30. Yield 810mg (92%), light yellow foam. 1H NMR (400MHz, CHLOROFORM-d) d = 8.00 - 7.93 (m, J= 8.3 Hz, 2H), 7.27 - 7.22 (m, J= 8.3 Hz, 2H), 6.76 (br s, 1 H), 4.85 - 4.67 (m, 1 H), 4.12 (br s, 1 H), 3.92 (s, 3H), 2.97 - 2.66 (m, 1 H), 2.29 (br s, 1 H), 1 .72 - 1 .59 (m, 3H), 1.54 - 1.22 (m, 15H). (0174) ESI + m/z 403 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58 g | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 27℃; | 2.iii Step(iii) In a flask was taken (R)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanoic acid (62 g, 1.0 eq.) in DMF (10 V) at 0 °C followed by the addition of HATU (1 .5 eq.), methyl 4-(1 - aminocyclopropyl)benzoate (1.0 eq.) and DIPEA (3.0 eq.) at same temperature. Then the reaction mixture was allowed warm to RT with continued stirring. After completion of the reaction, the reaction mixture was poured in water (10 V) The obtained solid was filtered, washed with cooled Water (2 V) and dried under vacuum to give 105 g of the crude product. The crude compound was purified by column chromatography using 60-120 mesh silica gel and the product was eluted in 10-15 % ethyl acetate and hexane system to afford methyl (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl) benzoate as a viscus liquid 58 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20 - 27℃; for 18h; | Step(i) To (2R)-2-hydroxy-3-methyl-butanoic acid (200 mg, 1.69 mmol) in DMF (8.5 mL) was added DIPEA (0.9 mL, 5.08 mmol) and HATU (775 mg, 2.03 mmol) followed by methyl 4-(1-aminocyclopropyl)benzoate (356 mg, 1.86 mmol). The reaction mixture was stirred for 18 hours at room temperature then partitioned between EtOAc and water. The organics were separated, washed with brine, dried (phase separator) and concentrated in vacuo. The crude material was purified by flash column chromatography (normal phase) [gradient 0-75% EtOAc in iso-hexane] to afford Intermediate 5, methyl (R)-4-(1-(2-hydroxy-3- methylbutanamido)cyclopropyl)benzoate (212 mg, 0.73 mmol, 43%) as a dark orange solid. Data available in Table 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 4-(1-aminocyclopropyl)-benzoic acid methyl ester; cyclobutyl-2-hydroxyacetic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20 - 27℃; for 0.166667h; Stage #2: With triethylamine In dichloromethane at 0 - 27℃; for 18h; | Step (i) Methyl 4-(1-aminocyclopropyl)benzoate (1.45 g, 7.61 mmol), 2-cyclobutyl-2- hydroxy-acetic acid (900 mg, 6.92 mmol), EDC (2.0 g, 10.37 mmol) and HOBt monohydrate (93 mg, 0.69 mmol) were dissolved in DCM (21.0 mL) after which the reaction mixture was stirred for 10 minutes at RT. Triethylamine (2.4 mL, 17.29 mmol) was added dropwise at 0 °C and the reaction mixture stirred for 18 hours at RT. The reaction mixture was partitioned between water and EtOAc and the organics separated, washed with 1 M HCI (aq.), saturated NaHCO3 (aq.) and brine. The organics were separated, dried via passage through a hydrophobic frit and concentrated to afford Intermediate 58, methyl 4-(1-(2-cyclobutyl-2- hydroxyacetamido)cyclopropyl)benzoate (1.5 g, 4.85 mmol, 70%) as a light brown solid. The material was used without any further purification. Data available in table 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 110℃; for 18h; | 2.1 Methyl 4-(1-morpholinocyclopropyl)benzoate (2b) Methyl 4-(1-aminocyclopropyl)benzoate 2a (191 mg, 1 mmol),1-Bromo-2-(2-bromoethoxy)ethane (696 mg, 3 mmol), DIPEA (645 mg, 5 mmol) and DMF (3 mL) were combined, heated to 110°C and stirred for 18 hours. After cooling to room temperature, water (10 mL) was added, followed by extraction with ethyl acetate (3 x 10 mL). The combined organic phases were washed with water (3 x 5 mL), then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100/1 to 19/1) to obtain the target product 2b (150 mg, 57%). |
Tags: 1006037-03-1 synthesis path| 1006037-03-1 SDS| 1006037-03-1 COA| 1006037-03-1 purity| 1006037-03-1 application| 1006037-03-1 NMR| 1006037-03-1 COA| 1006037-03-1 structure
[ 1295297-96-9 ]
Methyl 3-(1-aminocyclopropyl)benzoate
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