Structure of 184177-81-9
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CAS No. : | 184177-81-9 |
Formula : | C23H23N3O3 |
M.W : | 389.45 |
SMILES Code : | O=C(OC1=CC=CC=C1)NC2=CC=C(N3CCN(C4=CC=C(O)C=C4)CC3)C=C2 |
MDL No. : | MFCD03784249 |
InChI Key : | IKRKMYDCUZYKHX-UHFFFAOYSA-N |
Pubchem ID : | 1317528 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 29 |
Num. arom. heavy atoms | 18 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 6 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 120.87 |
TPSA ? Topological Polar Surface Area: Calculated from |
65.04 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
3.09 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
4.66 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.38 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.0 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.25 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.28 |
Log S (ESOL):? ESOL: Topological method implemented from |
-5.25 |
Solubility | 0.00217 mg/ml ; 0.00000558 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-5.75 |
Solubility | 0.000688 mg/ml ; 0.00000177 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-6.31 |
Solubility | 0.000191 mg/ml ; 0.00000049 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.37 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
1.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.92 |
* 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 |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 4 - 5h; | To a solution of 4-[4-(4-hydroxy-phenyl)-piperazin-l-yl]-phenyl-carbamic acid phenyl ester (40g) and triethylamine (4Ig) in lambdazetaiV-dimethylformamide (400ml), acetylchloride (24.2g) was added at 0 C-10 0C. The resulting mixture was warmed to ambient temperature and stirred for 4-5 hours. After completion of reaction (monitored by TLC)5 the reaction mixture was quenched with ice water (1200ml) and filtered to obtain 42.Og of the title compound having purity of 98.0% by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine; In 1,4-dioxane; at 90 - 100℃; for 24h; | mixture of N?-((2S,3S)-2-(benzyloxy)pentan-3-yl)formohydrazide compound of formula-17 (45.5 g) obtained in example-13, dioxane (500 ml) added <strong>[184177-81-9]phenyl 4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenylcarbamate</strong> compound of formula-19 (50 g) was heated to 90-100 C. Triethylamine (26 g) was added to the reaction mixture at 90-100 C. over a period of 1 hour and stirred for 24 hours at 90-100 C. After completion of the reaction, the reaction mixture was cooled to 25-30 C. and dichloromethane was added to the reaction mixture. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Water was added to the filtrate. Both organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both organic layers were combined and washed with 2% sodium hydroxide solution followed by water, and then with 5% hydrochloric acid solution followed by water and 5% NaHCO3 solution washing. Distilled off the solvent from organic layer under reduced pressure to get the title compound. Isopropyl alcohol (75 ml) was added to the obtained compound and the reaction mixture was cooled to 25-30 C. The reaction mixture was stirred for 6 hours at 25-30 C. Filtered the solid, washed with isopropyl alcohol and then dried to get the title compound. Yield: 28 g; Purity by HPLC: 97.67%; Impurity-A: 0.37%b) Purification of Compound of Formula-20 The obtained compound of formula-20 (30 g) was dissolved in methanol (960 ml) by heating at 60-65 C. The reaction mixture was cooled to 25-30 C. and stirred for 30 minutes at the same temperature. Filtered the precipitated solid and dried to get the pure compound of formula-20. Yield: 70%; Purity by HPLC: 99.15%; Impurity-A: 0.09% |
0.89 kg | With triethylamine; In 1,4-dioxane; at 90 - 95℃;Large scale; | N'-[(l S,2S)-2-(Benzyloxy)-l-ethylpropyl]formic hydrazide (1 kg) and 1,4- Dioxane (5 lit) were added to the flask at room temperature along with Phenyl 4- (4-(4-hydroxyphenyl)piperazin-l-yl)phenylcarbamate (1.4 kg). The reaction mass was heated to 90-95C and Triethylamine (0.89 lit) was slowly added and stirred for 1 hr and maintained for 12-18 hrs. TLC was checked for intermediate and cooled to Room temperature and Dichloromethane (20 lit) was charged and filter through the Hyflow bed and washed with Dichloromethane (5 lit). Water (4 lit) was added and stirred for 10 min. Aqueous layer and Organic layer were separated and organic layer was washed with brine solution. Organic layer was separated and dried with Sodium sulphate and distilled completely under vacuum at below 50C and co- distilled with Toluene (1 lit) and Isopropyl alcohol (1 lit). Isopropyl alcohol (2.5 lit) was added to the crude and maintained at 65-70C for 1 hr, then cooled to Room temperature, stirred for 30 min and cooled to 10-15C, and then filtered and washed with Isopropyl alcohol (0.5 lit).Out Put: 0.89 kg; HPLC: 97%. |
With triethylamine; In 1,4-dioxane; at 90 - 100℃; for 24h; | A mixture of compounds 4 (18.0 g, 0.046 mol), 5 (16.38 g, 0.069 mol), and dioxane (180 mL) was heated to 90-100 C. Triethylamine (9.36 g, 0.092 mol) was added to the reaction mixture and then stirred for 24 h at 90-100 C. After the completion of the reaction, the reaction mixture was cooled to 25-30 C and dichloromethane (25 mL) was added to the reaction mixture. Compound 1 was obtained by filtration and concentration under vacuo and stirred in isopropyl alcohol (27 mL) at 25-30 C for 6 h. Pure compound 1 was got by recrystallization with methanol. 1H NMR (DMSO-d6, 400 MHz): delta 0.793 (t, 3H, CH3), 1.242 (d, 3H, CH3), 1.765 (q, 2H, CH2), 3.122 (t, 4H, piperazine-CH2), 3.327 (t, 4H, piperazine-CH2), 3.745 (m, 1H, N-CH), 3.990 (m, 1H, O-CH), 4.275-4.544 (d, 2H, Ar-CH2), 6.691 (d, 2H, Ar-H), 6.869 (d, 2H, Ar-H), 7.119 (d, 2H, Ar-H), 7.172 (q, 2H, Ar-H), 7.232 (m, 3H, Ar-H), 7.476 (d, 2H, Ar-H), 8.323 (s, 1H, N2C-H), 8.787 (s, 1H, Ar-OH). HRMS (ESI+): m/z: calcd for C30H35N5O3: 536.2638 [M+Na+]; found: 536.2619. IR (KBr, lambda, cm-1): 3468.1 (s), 1678.2 (s), 1605.1 (m), 1485.07 (s), 1231.9 (s), 1115.4 (s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.6% | In tetrahydrofuran; at 0 - 25℃;Large scale; | Will be 4.00kg1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine (VII) and 35.57 kg of tetrahydrofuran100L glass reactor, open the stirring, cooling to 0 ~ 10 .Maintain the temperature below 25 drop 2.56kgPhenyl chloroformate (VIII),0.5 to 1 hour drop finished, temperature control 20 ~ 25 to continue the reaction of 0.5 to 1.0 hours. TLC monitoring reaction, the reaction finishedAfter the completion of the cooling to 0 ~ 10 ,Add saturated aqueous sodium bicarbonate solution (sodium bicarbonate 2.00kg dissolved in purified water 38kg), then add purified water 20kg,Stirring for 10 ~ 20min. Centrifuge the filter to the basic solvent-free effluent, and then rinse with 8kg of purified water, centrifugal rejection to the basic solvent-free effluent.The whole batch of wet goods in the vacuum -0.06MPa ~ -0.1MPa, the control temperature of 40-50 conditions,Dry under reduced pressure 12 to 16 hours. 5.47 kg of a gray solid,Phenyl (4- (4- (4-hydroxy) -1-piperazinyl) phenyl) carbamate(V);HPLC purity: 98.5% yield: 94.6% |
215 g | In N,N-dimethyl-formamide; at 0 - 30℃; for 3h; | Example-8 Preparation of Phenyl-4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl carbamate (Formula-19) Phenyl chloroformate (139.5 g) was added to a pre-cooled solution of 4-(4-(4-aminophenyl)piperazin-1-yl)phenol compound of formula-18 (200 g) in dimethyl formamide (1400 ml) at 0-10 C. Temperature of the reaction mixture was raised to 25-30 C. and then stirred for 3 hours at 25-30 C. After completion of the reaction, the reaction mixture was quenched with water. Filtered the precipitated solid and washed with water. |
In N,N-dimethyl-formamide; at 0 - 10℃; | Phenyl chloroformate (13.95 g, 0.089 mol) was added to a pre-cooled solution of compound 2 (20 g, 0.074 mol) in dimethylformamide (140 mL) at 0-10 C. After the completion of the reaction, the reaction mixture was quenched with water. Ispropyl alcohol (IPA, 60 mL) was added to the solid and the mixture was heated to 60-65 C and stirred for 1 h at the same temperature. Compound 4 was filtered off, washed with IPA, and dried. 1H NMR (DMSO-d6, 400 MHz): delta 3.155 (t, 8H, piperazine-CH2), 6.685 (d, 2H, p-aminophenol-3-CH), 6.859 (d, 2H, p-aminophenol-2-CH), 6.981 (d, 2H, aniline-3-CH), 7.237 (m, 2H, aniline-2-CH), 7.406 (t, 2H, phenol-CH), 7.447 (d, 2H, phenol-CH), 8.871 (s, 1H, p-aminophenol-OH), 9.989 (s, 1H, CO2NH). IR (KBr, lambda, cm-1) 3460 (s), 3368 (m), 1662 (s), 1568 (s), 1340 (s), 1160(s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.4% | Will be 4.36kgN '- ((2S, 3S) -2-benzyloxy) pentyl-3-formylhydrazide oxalate(VI)And 45.36 kgDioxane into the 100L glass reactor,Stir, add 3.45kgN, N-diisopropylethylamine. Stirring for 1 to 1.5 hours,Add another 5.47kgPhenyl (4- (4- (4-hydroxy) -1-piperazinyl) phenyl) carbamate(V).After the addition is complete, the temperature is raised to 80 ± 5 C for 24 to 30 hours. TLC monitoring.After the reaction is completed, the system is cooled to 15 ~ 25 ,57.79 kg of dichloromethane and 21.81 kg of pure water were added and stirred for 10 to 20 minutes.Collect the lower organic phase and discard the aqueous phase.The organic phase was transferred to a 100 L glass reactor, and 21.81 kg of purified water was added to the autoclave,Stirring for 10 to 20 minutes, standing and stratifying, collecting the lower organic phase and discarding the aqueous phase. The organic phase was transferred to a 100 L glass reactor. Saturated aqueous sodium chloride solution (6.54 kg of sodium chloride was dissolved in purified water 21.81 kg) was added and stirred for 10 to 20 minutes. The layers were allowed to stand and the organic phase was collected and the aqueous phase was discarded.The organic phase was transferred to a 20 L rotary vial, and at a vacuum of -0.08 to -0.1 MPa,Control the temperature of 30 ~ 40 , concentrated to remove the dichloromethane, to the solvent-free distillation. A brown solid was obtained.The solid was transferred to a 100 L glass autoclave, 32.27 kg of methyl t-butyl ether was added, and the mixture was heated to 50 to 60 C for 0.5 to 1 hour, cooled to 20 ± 5, and stirred for 2 to 3 hours. Centrifuge the filter to the basicSolvent-free, filter cake with 12.91kg methyl tert-butyl ether leaching, centrifugal rejection to the basic solvent-free effluent. Will be all wet goodsAt a vacuum of -0.08 to -0.1 MPa,Control temperature 40 ~ 50 Drying under reduced pressure 6 to 10 hours. A gray solid5.31kg, that is2 - ((2S, 3S) -2- (benzyl) -3-pentyl) -4- (4- (4-(4-hydroxy) -1-piperazine) phenyl)-2,4-dihydro-3-dihydro-1,2,4-triazol-3-one (III), HPLC purity: 98.8%, yield: 77.4% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.5% | With N-ethyl-N,N-diisopropylamine; In toluene; for 19h; | To a 250 ml four-necked flask equipped with a thermometer and a condenser was added <strong>[184177-81-9]phenyl (4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)carbamate</strong> (12 g, 30.78 mmol, 1 eq. ), toluene (150ml),N'-((2R,3R)-2-(benzyloxy)pentan-3-yl)hydrazide (8 g, 33.85 mmol, 1.1 eq.) and DIPEA (4.38 g, 33.85 mmol, 1.1 eq.), Warming back. TLC showed complete reaction after 19 h.After cooling to room temperature, the solvent was evaporated under reduced pressure.The residue obtained was chromatographed to give 7.2 g of off white solid.The yield was 45.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.07 g | With N-ethyl-N,N-diisopropylamine; In toluene; for 39h;Reflux; | Add to a 250ml single-mouth bottle with a water separator(4-(4-(4-Hydroxyphenyl)piperazin-1-yl)phenyl)carbamic acid phenyl ester(8g, 20.54mmol),N'-((2S,3R)-2-(Benzyloxy)pentan-3-yl)hydrazide (5.1 g, 21.57 mmol, 1.05 eq.), DIPEA (2.92 g, 22.6 mmol, 1.2 eq.) Toluene (80 ml), refluxed for 39 h.TLC showed the reaction was complete.Evaporate solvent and volatiles under reduced pressure.The residue obtained was purified by column chromatography to yield 4.07 g of white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.5 g | With N-ethyl-N,N-diisopropylamine; In toluene; for 36h; | Add <strong>[184177-81-9]phenyl (4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)carbamate</strong> (10 g, 25.68) to a 250 ml four-necked flask with a condenser, water separator and thermometer. Mm),N'-((2R,3S)-2-(benzyloxy)pent-3-yl)formylhydrazide(6.37 g, 26.97 mmol, 1.05 eq.), DIPEA (3.65 g, 28.45 mmol, 1.1 eq.), toluene (100 ml).TLC showed complete reaction after 36 h.Cool to room temperature and distill off the solvent and volatiles under reduced pressure.The residue obtained was purified by column chromatography to yield 3.5 g white. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.7% | With triethylamine; In tetrahydrofuran; at 60 - 65℃; for 24h;Large scale; | Add 163 kg of tetrahydrofuran, 12.58 kg of POP, 10.32 kg of triethylamine to a clean four-neck glass jar.15.88kgPOK,Turn on the stirring and gradually increase the temperature to 60-65 C.The reaction was incubated for 24 h, the reaction solution was filtered while hot, and the filter cake was rinsed with dichloromethane.The mother liquor was concentrated under reduced pressure and concentrated under reduced pressure to dryness.85kg of methyl tert-butyl ether was recrystallized, filtered through a 12kg silica gel pad, and the filtrate was cooled to 0-10 C and stirred for 12 hours, filtered.The filter cake was dried to give a yield of 19.63 kg of a white solid, 79.7%. |
79.7% | With triethylamine; In tetrahydrofuran; at 60 - 65℃; for 24h;Large scale; | Add 163 kg of tetrahydrofuran to a clean four-neck glass jar. 12.58kg POP, 10.32kg triethylamine, 15.88kg POK, when the stirring is turned on, the system is gradually heated to 60-65 C, and the reaction is kept for 24 hours. The reaction solution was filtered while hot, and the filter cake was rinsed with dichloromethane. The mother liquor was concentrated under reduced pressure and concentrated under reduced pressure to dryness. 85kg methyl tert-butyl ether recrystallized, Filtered by pre-laying 12kg of silica gel pad. The filtrate was cooled to 0-10 C and stirred for 12 h, filtered. The filter cake was dried to give a yield of 19.63 kg of a white solid, 79.7%. |
79.7% | With triethylamine; In tetrahydrofuran; at 60 - 65℃; for 24h;Large scale; | Add 163kg of tetrahydrofuran to the clean four-neck glass bottle, 12.58kg POP,10.32kg of triethylamine, 15.88kg POK,After stirring, the system was gradually heated to 60-65 C, and the reaction was kept for 24 hours. The reaction solution was filtered while hot, and the filter cake was rinsed with dichloromethane.The mother liquor was concentrated under reduced pressure and concentrated under reduced pressure to dryness.Add 17kg of dichloromethane, 85kg of methyl tert-butyl ether, recrystallize, filter through 12kg of silica gel pad, pre-package 12kg of silica gel, the filtrate is cooled to 0~10 C and stirred for 12h, filtered, and the filter cake is dried to obtain 19.63kg of gray solid. The rate is 79.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.7% | In tetrahydrofuran; at 60 - 65℃; for 24h; | 3 L of tetrahydrofuran, 233 g of M5, 200 g of triethylamine, 293 g of POK were added to a clean four-necked glass vial, and the system was gradually heated to 60-65 C.The reaction was incubated for 24 h, and the reaction solution was filtered while hot.The filter cake was rinsed with dichloromethane, and the mother liquid was concentrated under reduced pressure and concentrated to dryness.Add 300g of dichloromethane and recrystallize 1500g of methyl tert-butyl etherFiltered by pre-packaging 200g of silica gel pad.The filtrate was cooled to 0-10 C and stirred for 12 h.filter,The filter cake was dried to obtain a yield of 361 g of gray solids of 79.7%. |
79.7% | In tetrahydrofuran; at 60 - 65℃; for 24h; | Add 3L of tetrahydrofuran to a clean four-neck glass jar. 233g M5, 200g triethylamine, 293g POK, open to stir, The system gradually warmed to 60-65 C, and the heat preservation reaction was 24 h. The reaction solution was filtered while hot, and the filter cake was rinsed with dichloromethane. The mother liquor was concentrated under reduced pressure and concentrated under reduced pressure to dryness. Recrystallization from 1500 g of methyl tert-butyl ether, Filtered by pre-packaging 200g of silica gel pad. The filtrate was cooled to 0-10 C and stirred for 12 h, filtered. The filter cake was dried to give 361 g of a white solid with a yield of 79.7%. |
79.7% | With triethylamine; In tetrahydrofuran; at 60 - 65℃; for 24h; | Add 3 L of tetrahydrofuran, 233 g of M5, 200 g of triethylamine, 293 g of POK to a clean four-neck glass jar.When the stirring is turned on, the system is gradually heated to 60-65 C, and the reaction is kept for 24 hours, and the reaction liquid is filtered while hot.The filter cake was rinsed with dichloromethane.The mother liquor was concentrated under reduced pressure and concentrated under reduced pressure to dryness.Add 300g of dichloromethane,Recrystallization from 1500 g of methyl tert-butyl ether,Filtered by pre-packaging 200g of silica gel pad.The filtrate was cooled to 0-10 C and stirred for 12 h.filter,The filter cake is dried to obtain 361gGray solid yield 79.7% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.1% | With N-ethyl-N,N-diisopropylamine; In 5,5-dimethyl-1,3-cyclohexadiene; at 140℃; for 20h; | 20.0 g of Compound 3 (0.051 mol) (R = phenyl) and 5.9 g of Compound 4 (0.051 mol) were sequentially added to a 500 ml three-necked flask.7.8 g of N,N-diisopropylethylamine (0.06 mol), 200 ml of xylene,Warm to 140 C. The reaction was detected by TLC and the reaction was complete at 20 h. Heat off and cool to room temperature. After suction filtration, the cake was recrystallized from 180 ml of a mixed solvent (toluene: isopropyl alcohol = 1:1) to give 12.3 g of pale yellow solid.Purity >99.5%. |
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