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CAS No. : | 1380087-89-7 | MDL No. : | MFCD28144505 |
Formula : | C20H16ClN3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GCWIQUVXWZWCLE-INIZCTEOSA-N |
M.W : | 365.81 | Pubchem ID : | 57389999 |
Synonyms : |
CPI-0610
|
Num. heavy atoms : | 26 |
Num. arom. heavy atoms : | 17 |
Fraction Csp3 : | 0.15 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 103.75 |
TPSA : | 81.48 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.39 cm/s |
Log Po/w (iLOGP) : | 2.9 |
Log Po/w (XLOGP3) : | 3.02 |
Log Po/w (WLOGP) : | 3.37 |
Log Po/w (MLOGP) : | 2.27 |
Log Po/w (SILICOS-IT) : | 4.77 |
Consensus Log Po/w : | 3.27 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.3 |
Solubility : | 0.0185 mg/ml ; 0.0000505 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.4 |
Solubility : | 0.0147 mg/ml ; 0.0000402 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -7.57 |
Solubility : | 0.00000976 mg/ml ; 0.0000000267 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 4.22 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | 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 |
---|---|---|
Multi-step reaction with 7 steps 1: hydrogenchloride / methanol; 1,4-dioxane / 1 h / 20 °C 2: isopropylmagnesium bromide / tetrahydrofuran / 0.5 h / -30 - -5 °C 3: dmap / tetrahydrofuran / 0.5 h / 20 °C 4: tetrahydrofuran / -30 - 20 °C 5: trifluoroacetic acid / chloroform / 24 h / Reflux 6: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C 7: ammonia / dichloromethane; tetrahydrofuran / 1 h / -30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: isopropylmagnesium bromide / tetrahydrofuran / 0.5 h / -30 - -5 °C 2: dmap / tetrahydrofuran / 0.5 h / 20 °C 3: tetrahydrofuran / -30 - 20 °C 4: trifluoroacetic acid / chloroform / 24 h / Reflux 5: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C 6: ammonia / dichloromethane; tetrahydrofuran / 1 h / -30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: dmap / tetrahydrofuran / 0.5 h / 20 °C 2: tetrahydrofuran / -30 - 20 °C 3: trifluoroacetic acid / chloroform / 24 h / Reflux 4: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C 5: ammonia / dichloromethane; tetrahydrofuran / 1 h / -30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: tetrahydrofuran / -30 - 20 °C 2: trifluoroacetic acid / chloroform / 24 h / Reflux 3: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C 4: ammonia / dichloromethane; tetrahydrofuran / 1 h / -30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: trifluoroacetic acid / chloroform / 24 h / Reflux 2: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C 3: ammonia / dichloromethane; tetrahydrofuran / 1 h / -30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 2-[(7S)-9-(4-chlorophenyl)-3-methyl-5-oxa-4,8-diazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),3,8,11,13-hexaen-7-yl]acetic acid With 1,1'-carbonyldiimidazole In dichloromethane at 15 - 25℃; Stage #2: With ammonium hydroxide In dichloromethane at 0 - 5℃; for 1.33333h; | To produce crystalline material, a reactor was charged with 700 g of carboxylic acid (1) with 65.8 wt 1H NMR potency (460 g, 1.3 mol) in DCM (4.6 L). The batch was charged with carbonyldiimidazole (CDI, 264 g, 1.6 mol, 1.3 equiv) in four portions with the solids addition system. Over the course of the addition, the batch temperature was 15-18 °C. The batch was stirred for 1-2 hours at 20-25 °C when HPLC analysis indicated the starting material was <2%. The batch was cooled to 0-5 °C. The batch was charged with 28% aqueous ammonium hydroxide solution (432 mL, 6.5 mol, 5 equiv) by an addition funnel over 20 minutes while maintaining the temperature at 0-5 °C. The batch was stirred at 0-5 °C for 1 hour when HPLC analysis indicated the intermediate acyl-imidazole was <2%. The batch was warmed to 20-25 °C and DI water (2.3 L) was added. The batch was stirred vigorously for 15 minutes. The stirring was stopped and the phases were separated. The organic phase was washed with brine (2.3 L), dried (MgS04), treated with activated carbon (46 g, Darco G-60), filtered, and washed with DCM (1.5 L). The combined filtrates and washes were concentrated to dryness by rotary evaporation. The residue was redissolved in absolute alcohol (2.3 L) and heated to 50-55 °C. The batch was charged with DI water (2.3 L) by addition funnel over 1 hour while maintaining the temperature 50-55 °C. The batch was cooled over a period of 2 hours and an oil, instead of solids, was observed to form. The batch was reheated to 50-55 °C and gradually cooled to 15-25 °C over a period of 12-16 hours. The batch was cooled to 0-5 °C and stirred for 1-2 hours. The batch was filtered and washed with a 1: 1 mixture of DI water to absolute ethanol (230 mL). [0068] The solids were dried under high vacuum at 40-45 °C overnight to afford monohydrate crystalline Form A of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide [320 g, 70% yield, 95.1% (AUC) by HPLC]. Robertson Microlit analyzed the palladium level to be 84 ppm. XRPD, NMR, TGA, DSC, and an optical micrograph are depicted in Figures 1-3 and 5. Karl Fisher analysis confirmed an average water content of 4.5 wt%. The listing of XRPD peaks shown in Figure 1 are provided in Table 1 below. |
Multi-step reaction with 2 steps 1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C 2: ammonia / dichloromethane; tetrahydrofuran / 1 h / -30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.2 g | With ammonia In tetrahydrofuran; dichloromethane at -30℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
320 g | With water In ethanol at 50 - 55℃; for 1h; | Preparation of monohydrate 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide The residue was redissolved in absolute alcohol (2.3 L) and heated to 50- 55 °C. The batch was charged with DI water (2.3 L) by addition funnel over 1 hour while maintaining the temperature 50-55 °C. The batch was cooled over a period of 2 hours and an oil, instead of solids, was observed to form. The batch was reheated to 50-55 °C and gradually cooled to 15-25 °C over a period of 12-16 hours. The batch was cooled to 0-5 °C and stirred for 1-2 hours. The batch was filtered and washed with a 1 : 1 mixture of DI water to absolute ethanol (230 mL). The solids were dried under high vacuum at 40-45 °C overnight to afford monohydrate 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4- yl)acetamide [320 g, 70% yield, 95.1% (AUC) by HPLC, m/z 366 [M+H]+]. Karl Fisher analysis confirmed an average water content of 4.5 wt%. As shown by Figure 6, optical microscopy confirmed the monohydrate to be crystalline. |