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[ CAS No. 1316215-12-9 ] {[proInfo.proName]}

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Chemical Structure| 1316215-12-9
Chemical Structure| 1316215-12-9
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Quality Control of [ 1316215-12-9 ]

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Product Details of [ 1316215-12-9 ]

CAS No. :1316215-12-9 MDL No. :MFCD28023593
Formula : C24H26ClN5O3 Boiling Point : -
Linear Structure Formula :- InChI Key :VLIUIBXPEDFJRF-UHFFFAOYSA-N
M.W : 467.95 Pubchem ID :53340426
Synonyms :
ACY241;HDAC-IN-2
Chemical Name :2-((2-Chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide

Calculated chemistry of [ 1316215-12-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 33
Num. arom. heavy atoms : 18
Fraction Csp3 : 0.25
Num. rotatable bonds : 13
Num. H-bond acceptors : 5.0
Num. H-bond donors : 3.0
Molar Refractivity : 127.29
TPSA : 107.45 ?2

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.28 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.62
Log Po/w (XLOGP3) : 4.05
Log Po/w (WLOGP) : 4.79
Log Po/w (MLOGP) : 2.98
Log Po/w (SILICOS-IT) : 3.38
Consensus Log Po/w : 3.76

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 1.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -4.84
Solubility : 0.00679 mg/ml ; 0.0000145 mol/l
Class : Moderately soluble
Log S (Ali) : -6.01
Solubility : 0.000457 mg/ml ; 0.000000976 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -8.35
Solubility : 0.00000209 mg/ml ; 0.0000000045 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 3.27

Safety of [ 1316215-12-9 ]

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:

Application In Synthesis of [ 1316215-12-9 ]

* 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.

  • Downstream synthetic route of [ 1316215-12-9 ]

[ 1316215-12-9 ] Synthesis Path-Downstream   1~11

  • 1
  • [ 615-41-8 ]
  • [ 1316215-12-9 ]
YieldReaction ConditionsOperation in experiment
93% In dimethyl sulfoxide; Example 2 Synthesis of 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide (Compound B) Synthesis of Intermediate 2: See synthesis of intermediate 2 in Example 1. Synthesis of Intermediate 3: A mixture of compound 2 (69.2 g, 1 equiv.), 1-chloro-2-iodobenzene (135.7 g, 2 equiv.), Li2CO3 (42.04 g, 2 equiv.), K2CO3 (39.32 g, 1 equiv.), Cu (1 equiv. 45 mum) in DMSO (690 ml) was degassed and purged with nitrogen. The resulting mixture was stirred at 140° C. Work-up of the reaction gave compound 3 at 93percent yield. Synthesis of Intermediate 4: See synthesis of intermediate 4 in Example 1. Synthesis of Intermediate 6: See synthesis of intermediate 6 in Example 1.
With nitrogen; potassium carbonate; aniline; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; Example 1 Synthesis of 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide (Compound A) Reaction Scheme: Experimental Procedure Synthesis of Intermediate 2: A mixture of aniline (3.7 g, 40 mmol), compound 1 (7.5 g, 40 mmol), and K2CO3 (11 g, 80 mmol) in DMF (100 ml) was degassed and stirred at 120° C. under N2 overnight. The reaction mixture was cooled to r.t. and diluted with EtOAc (200 ml), then washed with saturated brine (200 ml*3). The organic layers were separated and dried over Na2SO4, evaporated to dryness and purified by silica gel chromatography (petroleum ethers/EtOAc=10/1) to give the desired product as a white solid (6.2 g, 64percent). Synthesis of Intermediate 3: A mixture of compound 2 (69.2 g, 1 equiv.), 1-chloro-2-iodobenzene (135.7 g, 2 equiv.), Li2CO3 (42.04 g, 2 equiv.), K2CO3 (39.32 g, 1 equiv.), Cu (1 equiv. 45 mum) in DMSO (690 ml) was degassed and purged with nitrogen. The resulting mixture was stirred at 140° C. Work-up of the reaction gave compound 3 at 93percent yield. Synthesis of Intermediate 4: 2N NaOH (200 ml) was added to a solution of compound 3 (3.0 g, 9.4 mmol) in EtOH (200 ml). The mixture was stirred at 60° C. for 30 min After evaporation of the solvent, the solution was neutralized with 2N HCl to give a white precipitate. The suspension was extracted with EtOAc (2*200 ml), and the organic layers were separated, washed with water (2*100 ml), brine (2*100 ml), and dried over Na2SO4. Removal of the solvent gave a brown solid (2.5 g, 92percent). Synthesis of Intermediate 6: A mixture of compound 4 (2.5 g, 8.58 mmol), compound 5 (2.52 g, 12.87 mmol), HATU (3.91 g, 10.30 mmol), and DIPEA (4.43 g, 34.32 mmol) was stirred at r.t. overnight. After the reaction mixture was filtered, the filtrate was evaporated to dryness and the residue was purified by silica gel chromatography (petroleum ethers/EtOAc=2/1) to give a brown solid (2 g, 54percent). Synthesis of 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide (Compound A):
YieldReaction ConditionsOperation in experiment
General procedure: [0237] A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0° C. for 10 min. Hydroxylamine (50percent) (10 ml) was cooled to 0° C. and added to the mixture. The resulting mixture was stirred at r.t. for 20 min. After removal of the solvent, the mixture was neutralized with 1M HCl to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent).
General procedure: 10406] A mixture of the compound 6 (2.0 g, 4.6 mmol),sodium hydroxide (2N, 20 mE) in MeOR (50 ml) and DCM(25 ml) was stirred at 00 C. for 10 mi Hydroxylamine (5 0percent)(10 ml) was cooled to 00 C. and added to the mixture. Theresulting mixture was stirred at tt. for 20 mi Afier removalof the solvent, the mixture was neutralized with 1 M HC1 togive a white precipitate. The crude product was filtered andpurified by pre-HPLC to give a white solid (950 mg, 48percent).
General procedure: Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0° C. for 10 min. Hydroxylamine (50percent) (10 ml) was cooled to 0° C. and added to the mixture. The resulting mixture was stirred at rt for 20 min. After removal of the solvent, the mixture was neutralized with 1M HCl to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent).
General procedure: Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide [0160] sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0° C. for 10 min. Hydroxylamine (50percent) (10 ml) was cooled to 0° C. and added to the mixture. The resulting mixture was stirred at r.t. for 20 min. After removal of the solvent, the mixture was neutralized with 1M HCl to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent).
General procedure: A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0° C. for 10 min. Hydroxylamine (50percent) (10 ml) was cooled to 0° C. and added to the mixture. The resulting mixture was stirred at r.t. for 20 min. After removal of the solvent, the mixture was neutralized with 1M HCl to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent).
General procedure: A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0° C. for 10 min. Hydroxylamine (50percent) (10 ml) was cooled to 0° C. and added to the mixture. The resulting mixture was stirred at r.t. for 20 min. After removal of the solvent, the mixture was neutralized with 1M HCl to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent).
General procedure: Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0° C. for 10 min. Hydroxylamine (50percent) (10 ml) was cooled to 0° C. and added to the mixture. The resulting mixture was stirred at rt for 20 min. After removal of the solvent, the mixture was neutralized with 1M HCl to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent).
With hydroxylamine; sodium hydroxide; In methanol; dichloromethane; at 0 - 20℃; for 0.333333h; General procedure: Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5 - carboxamide (Compound A): A mixture of the compound 6 (2.0 g, 4.6 mmol), sodiumhydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0°C for 10 mm. Hydroxylamine (50percent) (10 ml) was cooled to 0°C and added to the mixture. The resulting mixture was stirred at r.t. for 20 mm. After removal of the solvent, the mixture wasneutralized with 1M HC1 to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent).
General procedure: A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0°C for 10mm. Hydroxylamine (50percent) (10 ml) was cooled to 0°C and added to the mixture. Theresulting mixture was stirred at rt for 20mm. After removal of the solvent, the mixture was neutralized with 1 M HC1 to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent).
General procedure: A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0 °C for lOmin. Hydroxylamine (50percent) (10 ml) was cooled to 0 °C and added to the mixture. The resulting mixture was stirred at rt for 20min. After removal of the solvent, the mixture was neutralized with 1M HC1 to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent).
General procedure: A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0 °C for 10 min. Hydroxylamine (50percent) (10 ml) was cooled to 0 °C and added to the mixture. The resulting mixture was stirred at r.t. for 20 min. After removal of the solvent, the mixture was neutralized with 1M HC1 to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent).
General procedure: Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)- 7-oxoheptyl)pyrimidine-5- carboxamide: A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeCH (50 ml) and DCM (25 ml) was stirred at 0°C for 10 mi Hydroxylamine (50percent) (10 ml) was cooled to 0°C and added to the mixture. The resulting mixture was stirred at r.t. for 20 mm. After removal of the solvent, the mixture was neutralized with 1M HClto give a whiteprecipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent).
General procedure: A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 ml_) in MeOH (50 ml) and DCM (25 ml) was stirred at 0 °C for 10 min. Hydroxylamine (50percent) (10 ml) was cooled to 0 °C and added to the mixture. The resulting mixture was stirred at r.t. for 20 min. After removal of the solvent, the mixture was neutralized with 1 M HCI to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent).
General procedure: A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 ml_) in MeOH (50 ml) and DCM (25 ml) was stirred at 0 °C for 10 min. Hydroxylamine (50percent) (10 ml) was cooled to 0 °C and added to the mixture. The resulting mixture was stirred at r.t. for 20 min. After removal of the solvent, the mixture was neutralized with 1 M HCI to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48percent)

  • 3
  • [ 89793-12-4 ]
  • [ 1316215-12-9 ]
  • 10
  • C25H27ClN4O3 [ No CAS ]
  • [ 1316215-12-9 ]
YieldReaction ConditionsOperation in experiment
85% With hydroxylamine hydrochloride; sodium methylate; In methanol; at 0℃;Large scale; Hydroxylamine hydrochloride (3.3 Kgs, 10 eq) and methanol (9.6 Kgs) were charged to a reactor. The resulting solution was cooled to 0-5 Cand 25% sodium methoxide (11.2 Kgs, 11 eq) was charged slowly, maintaining the temperature at 0-10 C. Once the addition was complete, the reaction was mixed at 20 C for 1-3 hours and filtered, and the filter cake was washed with methanol (2 x 2.1 Kgs). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±5C.Compound 5 (2.2 Kgs) was added. The reaction was stirred until the reaction was complete (method TM-113.964, compound 5 2%). The mixture was filtered and water (28 Kgs) and ethyl acetate (8.9 Kgs) were added to the filtrate. The pH was adjusted to 8 - 9 using 6N HC1 then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (25.7 Kgs), then dried under reduced pressure to constant weight. The crude solid compound(I) was determined to be Form IV Pattern D.The crude solid (1.87 Kgs) was suspended in isopropyl alcohol (IPA, 27.1 Kg). The slurry was heated to 75±5 C to dissolve the solids. The solution was seeded with crystals of Compound (I) (Form JlPattern A), and was allowed to cool to ambient temperature. The resulting precipitate was stirred for 1-2 hours before filtering. The filter cake was rinsed withIPA (2 x 9.5 Kgs), then dried at 45-55C to constant weight under reduced pressure to result in 1.86 kg crystalline white solid Compound (I) (Form JlPattern A) in 85% yield and 99.5% purity (AUC%, HPLC method TM-i 13.94 1).
85% With hydroxylamine hydrochloride; sodium methylate; In methanol; at 0℃;Large scale; Step (5): Synthesis of Compound (I): Hydroxylamine hydrochloride (3.3 Kgs, 10 eq) and methanol (9.6 Kgs) were charged to a reactor. The resulting solution was cooled to 0-5 C and 25% sodium methoxide (1 1 .2 Kgs, 1 1 eq) was charged slowly, maintaining the temperature at 0-10 C. Once the addition was complete, the reaction was mixed at 20 C for 1 -3 hours and filtered, and the filter cake was washed with methanol (2 x 2.1 Kgs). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±5C. Compound 5 (2.2 Kgs) was added. The reaction was stirred until the reaction was complete (method TM-1 13.964, compound 5 < 2%). The mixture was filtered and water (28 Kgs) and ethyl acetate (8.9 Kgs) were added to the filtrate. The pH was adjusted to 8 - 9 using 6N HCI then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (25.7 Kgs), then dried under reduced pressure to constant weight. The crude solid compound (I) was determined to be Form IV/ Pattern D. The crude solid (1 .87 Kgs) was suspended in isopropyl alcohol (IPA, 27.1 Kg). The slurry was heated to 75±5 C to dissolve the solids. The solution was seeded with crystals of Compound (I) (Form I/Pattern A), and was allowed to cool to ambient temperature. The resulting precipitate was stirred for 1 -2 hours before filtering. The filter cake was rinsed with IPA (2 x 9.5 Kgs), then dried at 45-55C to constant weight under reduced pressure to result in 1 .86 kg crystalline white solid Compound (I) in 85% yield and 99.5% purity (AUC%, HPLC method of Table 3).
85% With hydroxylamine; sodium methylate; In methanol; at 0℃;Large scale; Hydroxylamine hydrochloride (3.3 Kgs, 10 eq) and methanol (9.6 Kgs) were charged to a reactor. The resulting solution was cooled to 0-5 C and 25% sodium methoxide (1 1.2 Kgs, 11 eq) was charged slowly, maintaining the temperature at 0-10 C. Once the addition was complete, the reaction was mixed at 20 C for 1-3 hours and filtered, and the filter cake was washed with methanol (2 x 2.1 Kgs). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±5C. Compound 5 (2.2 Kgs) was added. The reaction was stirred until the reaction was complete (compound 5? 2%). The mixture was filtered and water (28 Kgs) and ethyl acetate (8.9 Kgs) were added to the filtrate. The pH was adjusted to 8 - 9 using 6N HCI then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (25.7 Kgs), then dried under reduced pressure to constant weight. The crude solid compound (I) was determined to be Form IV/ Pattern D. The crude solid (1.87 Kgs) was suspended in isopropyl alcohol (IPA, 27.1 Kg). The slurry was heated to 75±5 C to dissolve the solids. The solution was seeded with crystals of Compound (I) (Form I/Pattern A), and was allowed to cool to ambient temperature. The resulting precipitate was stirred for 1-2 hours before filtering. The filter cake was rinsed with IPA (2 x 9.5 Kgs), then dried at 45-55C to constant weight under reduced pressure to result in 1.86 kg crystalline white solid Compound (I) in 85% yield and 99.5% purity
85% With hydroxylamine hydrochloride; sodium methylate; In methanol;Large scale; Hydroxylamine hydrochloride (3.3 Kgs, 10 eq) and methanol (9.6 Kgs) were charged to a reactor. The resulting solution was cooled to 0-5 C and 25% sodium methoxide (1 1.2 Kgs, 11 eq) was charged slowly, maintaining the temperature at 0-10 C. Once the addition was complete, the reaction was mixed at 20 C for 1-3 hours and filtered, and the filter cake was washed with methanol (2 x 2.1 Kgs). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±5C. Compound 5 (2.2 Kgs) was added. The reaction was stirred until the reaction was complete (method TM-1 13.964, compound 5? 2%). The mixture was filtered and water (28 Kgs) and ethyl acetate (8.9 Kgs) were added to the filtrate. The pH was adjusted to 8 - 9 using 6N HCI then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (25.7 Kgs), then dried under reduced pressure to constant weight. The crude solid compound (I) was determined to be Form IV/ Pattern D. (0303) The crude solid (1.87 Kgs) was suspended in isopropyl alcohol (IPA, 27.1 Kg). The slurry was heated to 75±5 C to dissolve the solids. The solution was seeded with crystals of Compound (I) (Form I/Pattern A), and was allowed to cool to ambient temperature. The resulting precipitate was stirred for 1-2 hours before filtering. The filter cake was rinsed with IPA (2 x 9.5 Kgs), then dried at 45-55C to constant weight under reduced pressure to result in 1.86 kg crystalline white solid Compound (I) in 85% yield and 99.5% purity (AUC%, HPLC method of Table 2). (0304) Table 2: HPLC Method (0305) Column Zorbax Eclipse XDB-C18, 4.6 mm x 150 mm, 3.5 muetaiota (0306) Column Temperature 40C (0307) UV Detection Wavelength Bandwidth 4 nm, Reference off, 272 nm (0308) Flow rate 1.0 mL/min (0309) Injection Volume 10 muIota_ with needle wash (0310) Mobile Phase A 0.05% trifluoroacetic acid (TFA) in purified water (0311) Mobile Phase B 0.04% TFA in acetonitrile (0312) Data Collection 40.0 min (0313) Run Time 46.0 min (0314) Gradient Time (min) Mobile Phase A Mobile Phase B (0315) 0.0 98% 2% (0316) 36.0 0% 100% (0317) 40.0 0% 100% (0318) 40.1 98% 2% (0319) 46.0 98% 2%
85% With hydroxylamine hydrochloride; sodium methylate; In methanol; at 0 - 20℃;Large scale; Synthesis of Compound (I): Hydroxylamine hydrochloride (3.3 Kgs, 10 eq) and methanol (9.6 Kgs) were charged to a reactor. The resulting solution was cooled to 0-500 and 25% sodium methoxide (11 .2 Kgs, 11 eq) was charged slowly, maintaining the temperature at 0-10 00. Once the addition was complete, the reaction was mixed at 20 00 for 1-3 hours and filtered, and the filter cake was washed with methanol (2 x 2.1 Kgs). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±500. Compound 5 (2.2 Kgs) was added. The reaction was stirred until the reaction was complete(compound 5 2%). The mixture was filtered and water (28 Kgs) and ethyl acetate (8.9 Kgs) were added to the filtrate. The pH was adjusted to 8 - 9 using 6N HCI then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (25.7 Kgs), then dried under reduced pressure to constant weight. The crude solid compound (I) was determined to be Form IV Pattern D.The crude solid (1.87 Kgs) was suspended in isopropyl alcohol (IPA, 27.1 Kg). The slurry was heated to 75±5 00 to dissolve the solids. The solution was seeded with crystalsCompound (I) (Form I/Pattern A), and was allowed to cool to ambient temperature. The resulting precipitate was stirred for 1-2 hours before filtering. The filter cake was rinsed with IPA (2 x 9.5 Kgs), then dried at45-5500to constant weight under reduced pressure to result1 .86 kg crystalline white solid Compound (I) in 85% yield and 99.5% purity (AUC%, e.g., by the HPLC method of Table 3)
48% 10276] A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mE) in MeOH (50 ml) and DCM (25 ml) was stirred at 0 C. for 10 mi Hydroxylamine (50%) (10 ml) was cooled to 0 C. and added to the mixture. The resulting mixture was stirred at r.t. for 20 mm. After removal of the solvent, the mixture was neutralized with 1M HC1 to give a white precipitate. The crude product was filtered and purified by pre-HPEC to give a white solid (950 mg, 48%).
48% mixture of the compound 6 (2.Q g, (0217) 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 mi) and DCM (25 ml) was stirred at 0 G for 10 min. Hydroxylamine (50%) (10 mi) was cooled to 0 C and added to the mixture. The resulting mixture was stirred at r.t. for 20 min. After removal of the solvent, the mixture was neutralized with 1 M HCI to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48%).
With hydroxylamine hydrochloride; sodium methylate; In methanol; at 0 - 20℃;Large scale; Hydroxylamine hydrochloride (3.3 Kgs, 10 eq) and methanol (9.6 Kgs) were charged to a reactot The resulting solution was cooled to 0-5 C. and 25% sodium methoxide (11.2 Kgs, 11 eq) was charged slowly, maintaining the temperature at 0-10 C. Once the addition was complete, the reaction was mixed at 20 C. for 1-3 hours and filtered, and the filter cake was washed with methanol (2x2.1 Kgs). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±5 C. Compound 5 (2.2 Kgs) was added. The reaction was stirred until the reaction was complete (method TM-113.964, compound 52%). The mixture was filtered and water (28 Kgs) and ethyl acetate (8.9 Kgs) were added to the filtrate. The pH was adjusted to 8-9 using 6N HC1 then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (25.7 Kgs), then dried under reduced pressure to constant weight. The crude solid compound (I) was determined to be Form IV/Pattern D. The crude solid (1.87 Kgs) was suspended in isopropyl alcohol (IPA, 27.1 Kg). The slurry was heated to 75±5 C. to dissolve the solids. The solution was seeded with crystals of Compound (I) (Form I/Pattern A), and was allowed to cool to ambient temperature. The resulting precipitate was stirred for 1-2 hours before filtering. The filter cake was rinsed with IPA (2x9.5 Kgs), then dried at 45-55 C. to constant weight under reduced pressure to result in 1.86 kg crystalline white solid Compound (I) (Form I/Pattern A) in 85% yield and 99.5% purity. See ?HNMR data in FIG. 6.

  • 11
  • C17H11Cl2N3O [ No CAS ]
  • [ 1316215-12-9 ]
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