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Henderson, Ian M. ; Zeng, Fanxun ; Bhuiyan, Nazmul H. , et al. Biochem. Pharmacol.,2022,195,114868.
Abstract: Interest in development of potent, selective inhibitors of the phosphatase from the receptor type protein tyrosine phosphatase PTPRD as antiaddiction agents is supported by human genetics, mouse models and studies of our lead compound PTPRD phosphatase inhibitor, 7-butoxy illudalic acid analog 1 (7-BIA). We now report structure-activity relationships for almost 70 7-BIA-related compounds and results that nominate a 7- cyclopentyl methoxy analog as a candidate for further development. While efforts to design 7-BIA analogs with substitutions for other parts failed to yield potent inhibitors of PTPRDs phosphatase, ten 7-position substituted analogs displayed greater potency at PTPRD than 7-BIA. Several were more selective for PTPRD vs the receptor type protein tyrosine phosphatases S, F and J or the nonreceptor type protein tyrosine phosphatase N1 (PTPRS, PTPRF, PTPRJ or PTPN1/PTP1B), phosphatases at which 7-BIA displays activity. In silico studies aided design of novel analogs. A 7-position cyclopentyl methoxy substituted 7-BIA analog termed NHB1109 displayed 600-700 nM potencies in inhibiting PTPRD and PTPRS, improved selectivity vs PTPRS, PTPRF, PTPRJ or PTPN1/PTP1B phosphatases, no substantial potency at other protein tyrosine phosphatases screened, no significant potency at any of the targets of clin.-useful drugs identified in EUROFINS screens and significant oral bioavailability. Oral doses up to 200 mg/kg were well tolerated by mice, though higher doses resulted in reduced weight and apparent ileus without clear organ histopathol. NHB1109 provides a good candidate to advance to in vivo studies in addiction paradigms and toward human use to reduce reward from addictive substances.
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Keywords: Receptor type protein tyrosine phosphatase ; Cell adhesion molecule ; Addiction ; Drug reward ; Opiates ; Stimulants
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Purchased from AmBeed: 37595-74-7 ; 637-59-2 ; 103-63-9 ; 64473-35-4 ; 20443-99-6 ; 939-26-4 ; 3814-32-2 ; 3814-30-0 ; 36881-42-2 ; 17247-58-4 ; 589-15-1 ; 2550-36-9 ; 7051-34-5 ; 161043-38-5 ; 161395-96-6 ; 59311-24-9 ; 78358-86-8 ; 83642-03-9
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Janssens, Liesl K ; Ametovski, Adam ; Sparkes, Eric , et al. ACS Chem. Neurosci.,2023,14(1):35-52.
Abstract: Over 200 synthetic cannabinoid receptor agonists (SCRAs) have been identified as newpsychoactive substances. EffectivemonitoringandcharacterizationofSCRAsarehindered by the rapid pace of structural evolution. Ahead of possible appearanceontheillicitdrugmarket,newSCRAsweresynthesized tocompletea systematic libraryof cumyl-indole-(e.g.,CUMYL CPrMICA,CUMYL-CPMICA)andcumyl-indazole-carboxamides (e.g.,CUMYL-CPrMINACA,CUMYL-CPMINACA), encompass ing butyl, pentyl, cyclopropylmethyl, cyclobutylmethyl, cyclo pentylmethyl, andcyclohexylmethyl tails.Comprehensivepharma cologicalcharacterizationwasperformedwiththreeassayformats, monitoring the recruitment of either wild-type or C-terminally truncated(βarr2d366)β-arrestin2totheactivatedcannabinoid1 receptor(CB1)ormonitoringGβγ-mediatedmembranehyperpolarization.Alteredcompoundcharacterizationwasobservedwhen comparingderivedpotency(EC50)andefficacy(Emax)values frombothassaysmonitoringthesameoradifferentsignalingevent, whereasrangesandrankingordersweresimilar.Structure−activityrelationships(SAR)wereassessedinthreefold, resultinginthe identificationof thependant tailasacriticalpharmacophore,withtheoptimalchainlengthforCB1activationapproximatingann pentyl (e.g., cyclopentylmethyl or cyclohexylmethyl tail). The activityof the SCRAs encompassing cyclic tails decreasedwith decreasingnumberofcarbonsformingthecyclicmoiety,withCUMYL-CPrMICAshowingtheleastCB1activityinallassayformats. The SARs were rationalized viamolecular docking, demonstrating the importance of the optimal steric contributionof the hydrophobictail.WhileSARconclusionsremainedlargelyunchanged, thedifferential compoundcharacterizationbybothsimilar anddifferentassaydesignsemphasizestheimportanceofdetailingspecificassaycharacteristicstoallowadequateinterpretationof potenciesandefficacies.
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Keywords: structure−activity relationship ; functional assays ; membrane potential ; βarrestin2 recruitment ; new psychoactive substances ; molecular docking
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Purchased from AmBeed: 43120-28-1 ; 585-32-0 ; 3814-30-0 ; 120-72-9 ; 17247-58-4 ; 2550-36-9 ; 7051-34-5 ; 173600-10-7
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CAS No. : | 7051-34-5 |
Formula : | C4H7Br |
M.W : | 135.00 |
SMILES Code : | BrCC1CC1 |
MDL No. : | MFCD00001306 |
InChI Key : | AEILLAXRDHDKDY-UHFFFAOYSA-N |
Pubchem ID : | 81503 |
GHS Pictogram: | ![]() |
Signal Word: | Danger |
Hazard Statements: | H225 |
Precautionary Statements: | P210-P403+P235 |
Class: | 3 |
UN#: | 1993 |
Packing Group: | Ⅲ |
* 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 potassium hydroxide; In water; dimethyl sulfoxide; | a 3-Cyclopropylmethyloxy-2-hydroxymethyl Pyridine Potassium hydroxide (5.2 g, 0.093 mol) was ground to a powder under nitrogen, added to DMSO (30 ml) and stirred for 20 min under nitrogen at room temperature. The mixture was cooled to 0 C. and 3-hydroxy-2-hydroxymethyl pyridine hydrochloride (5.0 g, 0.031 mol) was added. The slurry was stirred at 0 C. for 1 h before the addition of cyclopropylmethyl bromide (3.01 ml, 4.2 g, 0.031 mol). The mixture was allowed to warm to room temperature and stirred under nitrogen overnight. Water (100 ml) was added, and the resultant solution was acidified to pH 1 with hydrochloric acid (5 N). The solution was washed with dichloromethane (3*100 ml), basified to pH 14 with sodium hydroxide solution (4 N), and washed again with dichloromethane (3*100 ml). The organic layers from the second extraction were combined, washed with water (1*100 ml) and saturated sodium chloride solution (1*100 ml), dried over magnesium sulfate and concentrated in vacuo to give 3-cyclopropylmethyloxy-2-hydroxymethyl pyridine as a dark brown solid (2.40 g). 1H NMR (250 MHz, CDCl3) δ 0.35 (2H, m), 0.65 (2H, m), 1.26 (1H, m), 3.85 (2H, d, J=6.8 Hz), 4.33 (1H, br s), 4.77 (2H, s), 7.13 (2H, m), 8.13 (2H, m); MS (ES+) m/e 180 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | B) 5-Amino-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.200 g, 1.07 mmol) was dissolved in 10 mL dry DMF. Potassium carbonate (0.45 g, 3.26 mmol) and cyclopropyl methylbromide (0.166 g, 1.23 mmol) were added and the reaction mixture was stirred at 80 C. overnight. The reaction mixture was diluted with 100 mL water and extracted three times with ethyl acetate (50 mL each). The organic phases were pooled, dried with sodium sulfate and evaporated. The crude product was flash-chromatographed on silica gel with heptane/ethyl acetate 100:0?0:100 gradient to yield 5-(cyclopropylmethoxycarbonyl-(cyclopropylmethyl)-amino)-2-methyl-thiazole-4-carboxylic acid ethyl ester (140 mg, 39%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; di-isopropyl ether; Petroleum ether; | 200 ml of tetrahydrofurane are introduced into a 2 liter reactor equipped with a mechanical stirrer, a dropping funnel, a reflux condenser and a thermometer and are cooled before adding 6.6 g of lithium aluminum hydride under a nitrogen atmosphere. This suspension is cooled to -5° and 80 g (0.296 mol) of ethyl p-benzoxyacetate are added dropwise thereto in such a way that the temperature does not exceed 0°. The whole is then kept at ambient temperature for 3 hours. The reaction mixture is then cooled and the excess AlLiH4 is destroyed with an excess of sodium potassium double tartrate, the mixture is filtered and the residue is evaporated. The 2-(p-benzoxyphenyl)-ethanol is caused to crystallise by trituration in isopropyl ether. 58.4 g (yield=86percent) of this product are obtained; M.p.: 86°-88°. 2.6 g (0.055 mol) of sodium hydride are suspended in 20 ml of dimethylformamide in a 250 ml flask equipped with a magnetic stirrer, a dropping funnel and a reflux condenser. 11.4 g (0.05 mol) of 2-(p-benzoxyphenyl)-ethanol dissolved in 30 ml of the same solvent are then added. The mixture is gently heated to 30° and a further 70 ml of dimethylformamide are then added. A precipitate is observed. 7.42 g (0.055 mol) of cyclopropylmethyl bromide dissolved in 20 ml of dimethylformamide are then added and the mixture is heated for 8 hours to a temperature of 60°. Progressive disappearance of the solid product is observed. The reaction mixture is poured into water and extracted with ether, and the ether solution is washed with water, dried over sodium sulphate and evaporated to dryness. The solid residue is stirred for 30 minutes in petroleum ether; the insoluble 2(p-benzoxyphenyl)-ethanol which has not reacted is then filtered off, the solvent is evaporated and the residue is rectified. 5.9 (yield=74percent) of 4-[2-(cyclopropylmethoxy)-ethyl]-1-benzoxy-benzene are thus obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; di-isopropyl ether; Petroleum ether; | 200 ml of tetrahydrofurane are introduced into a 2 liter reactor equipped with a mechanical stirrer, a dropping funnel, a reflux condenser and a thermometer and are cooled before adding 6.6 g of lithium aluminium hydride under a nitrogen atmosphere. This suspension is cooled to -5° and 80 g (0.296 mol) of ethyl p-benzoxy-acetate are added dropwise thereto in such a way that the temperature does not exceed 0°. The whole is then kept at ambient temperature for 3 hours. The reaction mixture is then cooled and the excess AlLiH4 is destroyed with an excess of sodium potassium double tartrate, the mixture is filtered and the residue is evaporated. The 2-(p-benzoxyphenyl)-ethanol is caused to crystallise by trituration in isopropyl ether. 58.4 g (yield=86percent) of this product are obtained; M.p.: 86°-88°. 2.6 g (0.055 mol) of sodium hydride are suspended in 20 ml of dimethylformamide in a 250 ml flask equipped with a magnetic stirrer, a dropping funnel and a reflux condenser. 11.4 g (0.05 mol) of 2-(p-benzoxyphenyl)-ethanol dissolved in 30 ml of the same solvent are then added. The mixture is gently heated to 30° and a further 70 ml of dimethylformamide are then added. A precipitate is observed. 7.42 g (0.055 mol) of cyclopropylmethyl bromide dissolved in 20 ml of dimethylformamide are then added and the mixture is heated for 8 hours to a temperature of 60°. Progressive disappearance of the solid product is observed. The reaction mixture is poured into water and extracted with ether, and the ether solution is washed with water, dried over sodium sulphate and evaporated to dryness. The solid residue is stirred for 30 minutes in petroleum ether; the insoluble 2-(p-benzoxyphenyl)-ethanol which has not reacted is then filtered off, the solvent is evaporated and the residue is rectified. 5.9 g (yield=74percent) of 4-[2-(cyclopropyl-methoxy)-ethyl]-1-benzoxy-benzene are thus obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 278 8-Cyclopropyl-<strong>[211244-81-4]2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one</strong> The title compound was prepared from <strong>[211244-81-4]2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one</strong> (3 g, 15.5 mmol) and bromomethyl cyclopropane (1.6 mL, 16 mmol) by using the procedure described in Example 272. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | b) 4-Cyclopropylmethoxy-3-fluoro-ben?oic acid methyl ester 3-Fluoro-4-hydroxy-benzoic acid methyl ester (1.02 g, 6.0 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.45 g, 3.0 mmol, 0.5 eq) and K2CO3 (1.66 g, 12.0 mmol, 2.0 eq) were added ad the mixture was stirred at room temperature for 20 min. (Bromomethyl)cyclopropane (0,53 mL, 5.4 mmol, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and it was extracted with DCM and dried.0.91 g of title product (yield 69%) were recovered and used without further purification.C12H13FO31H-NMR (dmso-d6): 0.34-0.37 (2PI5 m); 0.57-0.62 (2H. m); 1.22-1.26 (IH, m); 3.82 (3H, s); 3.99 (2H, d, J=6.8 Hz); 7.26 (IH, t, J=8.4 Hz); 7.67-7.77 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Preparation 53: 1 -Cyclopropylmethyl- 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> <n="62"/>--61-Add lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.200 g, 2.08 mmol) to a suspension of sodium hydride (0.092 g, 2.29 mmol) in DMF (3 mL) at 0 0C. Stir for 20 min. at 0 0C. Add a solution of l-(bromomethyl)cyclopropane (0.295 g, 2.18 mmol) in DMF (4 mL) dropwise to the reaction mixture. Stir reaction to ambient temperature for 18 hr. Quench with aqueous saturated sodium bicarbonate solution and add ethyl acetate. Separate organic layer. Extract aqueous layer twice with ethyl acetate, dry combined organics (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0: 100 to 60:40 ethyl acetate:hexanes) to give the title preparation (175 mg, 56percent). GC-MS: m/z = 150 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 19h; | A 0.1 M solution of 5-Bromo-1H-benzo[d]imidazol-2-yl)methanol (630 mg, 2.8 mmol) in dimethylformamide was stirred with 2.4 equiv of cesium carbonate and (0.3 mL, 1.2 equiv) of cyclopropylmethyl bromide at 50 C. for 19 h. At the end dimethylformamide was evaporated in vacuo. The residue was partitioned between ethyl acetate (70 mL) and water (30 mL). Organic layer was dried (sodium sulfate) and evaporated in vacuo to give 800 mg of crude product which by LC-MS was 75% pure. LC/MS (HPLC method 1): tR=2.1 min, 281(MH)+. Silica gel TLC (ethyl acetate:hexane=4: 1) revealed two major products with Rf=0.29 and 0.20, which without separation were used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In dimethyl sulfoxide; at 10 - 30℃; | Example - 1: Preparation of 1 - [(Benzyloxy) - 4 - (2 - cyclopropyl methoxy) ethyl] benzene:In a 1.0 lit flask charged 4-benzyloxy-2-phenyl ethanol (100 gms, 0.44 moles) in dimethyl sulfoxide (300 ml). Stirred and charged powdered potassium hydroxide (61.4 gms, 1.1 moles). Stirred and cooled to 10 - 150C. Charged cyclopropyl methyl bromide (71.1 gms, 0.53 moles). Raised the temperature to 25 - 300C and maintained. After 3 hours, the reaction mass was quenched in chilled water (600 ml) maintaining temperature below 5°C. The pH of the reaction solution was adjusted with dilute (1 :4) hydrochloric acid, extracted the solution with 3 x 200 ml of toluene and distilled out toluene under vacuum below 550C. Charged petroleum ether (250 ml) to the residual mass and cooled to 00C and maintained under stirring for 2 hours. Filtered the separated solid and washed with petroleum ether. Charcoalised the filtrate for 30 minutes and filtered through hyflow bed and distilled out solvent to get the product. Wt of the product = 90 - 92 gms. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Sodium hydride (280 mmol) was added in portions to a cold (0 C.) solution of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidine-1-carboxylate</strong> (76.9 mmol) in N,N-dimethylformamide (100 mL). The mixture was maintained for 60 min and was then treated with a solution of (bromomethyl)cyclopropane (231 mmol) in N,N-dimethylformamide (100 mL) and potassium iodide (0.66 mmol). The reaction mixture was allowed to warm to rt where it was maintained for 30 min. The reaction mixture was subjected to microwave irradiation for 2 h at 90 C. The reaction mixture was concentrated and the residue was diluted with ethyl acetate (200 mL) and water (200 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3*200 mL) and the combined organic layers were washed with brine (2*200 mL) and dried (magnesium sulfate). The residue was purified by chromatography (20/1 petroleum ether/ethyl acetate) to provide the product in 81% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium hydroxide; In dichloromethane; water; at 20℃; for 16h; | To a stirred solution of <strong>[39903-01-0]2-amino-5-bromopyridine-3-ol</strong> (25 g, 132.9 mmol) in dichloromethane (150 mL) was added (bromomethyl)cyclopropane (35.88 g, 265.8 mmol), aliquat (7.5 g) and 40percent aqueous sodium hydroxide (150 mL) at RT, followed by stirring for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (2 x 500 mL). The combined organic layers were concentrated to dryness in vacuo and the resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 25percent ethyl acetate in hexane) affording 5-bromo-3-(cyclopropylmethoxy)pyridin-2-amine as and off white solid ( 15 g, 47percent): |
47% | With sodium hydroxide; In dichloromethane; water; at 20℃; for 16h; | Preparative Example 1 Step 1: 5-bromo-3-(cyclopropylmethoxy)pyridin-2-amine To a stirred solution of <strong>[39903-01-0]2-amino-5-bromopyridine-3-ol</strong> (25 g, 132.9 mmol) in dichloromethane (150 mL) was added (bromomethyl)cyclopropane (35.88 g, 265.8 mmol), aliquat (7.5 g) and 40percent aqueous sodium hydroxide (150 mL) at RT, followed by stirring for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (2 x 500 mL). The combined organic layers were concentrated to dryness in vacuo and the resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 25percent ethyl acetate in hexane) affording 5-bromo-3- (cyclopropylmethoxy)pyridin-2-amine as and off white solid ( 15 g, 47percent): H NMR (300 MHz, DMSO-d6) delta 7.61 (s, 1H), 7.19 (s, 1H), 5.81 (s, 2H), 4 - 3.8 (m, 2H), 1.35 - 1.1 (m, 1H), 0.65 - 0.55 (m, 2H), 0.2 - 0.4 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h; | Step 1 Preparation of Compound 26 (0564) Potassium carbonate (4.78 g, 34.6 mmol) and (bromomethyl)cyclopropane (2.03 mL, 20.8 mmol) were added to the DMF solution (10 ml) of Compound 25 (2.0 g, 13.8 mmol), and the mixture was stirred at 80 C. for 8 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate. The solvent was condensed under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate) to afford Compound 26 (470 mg, yield 17%). (0565) 1H-NMR (CDCl3) delta: 6.89 (d, J=3.0 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.66 (dd, J=8.8, 2.9 Hz, 1H), 4.56 (s, 1H), 3.81 (d, J=6.7 Hz, 2H), 1.34-1.21 (m, 1H), 0.65-0.59 (m, 2H), 0.37-0.32 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; | (Step 1) (0757) To a solution of the compound obtained in Step 1 of Example 1 (2.00 g, 9.66 mmol) and (bromomethyl)cyclopropane (2.341 mL, 24.14 mmol) in DMF (20 mL) was added potassium carbonate (2.50 g, 18.10 mmol), and the mixture was stirred overnight at 70C. The reaction mixture was allowed to be cooled to room temperature, and filtered through silica gel. The filtrate was concentrated under reduced pressure to give 1,3-bis(cyclopropylmethyl)-<strong>[32618-85-2]6-nitroquinazoline-2,4(1H,3H)-dione</strong> as a pale brown oil (quantitative). 1H-NMR(300MHz,DMSO-d6):delta0.21-0.57(6H,m),0.96-1.36(2H,m),2.69-2.78(1H,m),2.80-3.19(1H,m),3.75-3.99(2H,m),4.13(2H,d,J=7.2Hz),7.84(1H,d,J=9.4Hz),8.52(1H,dd,J=9 .3,2.8Hz),8.74(1H,d,J=2.6Hz). |
79% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; | A mixture of 15a (333 mg, 1.61 mmol), (bromomethyl)cyclopropane (0.624 mL, 6.43 mmol) and K2CO3 (489mg, 3.54 mmol) in DMF (10 mL) was stirred at rt for 16 h. The mixture was quenched with brine at rt and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5-30% EtOAc in hexane) to give 1,3-bis(cyclopropylmethyl)-<strong>[32618-85-2]6-nitroquinazoline-2,4(1H,3H)-dione</strong> (402 mg, 1.28 mmol, 79%) as a colorless solid. 1H NMR (300 MHz, CDCl3): d 0.32-0.76 (8H, m), 1.11-1.44 (2H, m),4.00 (2H, d, J = 7.2 Hz), 4.12-4.16 (2H, m), 7.45 (1H, d, J = 9.4 Hz),8.50 (1H, dd, J = 9.3, 2.8 Hz), 9.11 (1H, d, J = 2.6 Hz). |
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; | Potassium carbonate (2.502 g, 18.10 mmol) was added to a mixture of <strong>[32618-85-2]6-nitroquinazoline-2,4(1H,3H)-dione</strong> (2.00 g, 9.66 mmol) and (bromomethyl)cyclopropane (2.341 mL, 24.14 mmol) in DMF (20 mL), and the mixture was stirred at 70C overnight. The reaction mixture was cooled and insoluble materials were filtered off. The filtrate was concentrated under reduced pressure to give crude 1,3-bis(cyclopropylmethyl)-<strong>[32618-85-2]6-nitroquinazoline-2,4(1H,3H)-dione</strong> (3.28 g, 10.40 mmol, 108%) as a pale-brown oil. The resultant product was used for the next step without purification. 1H NMR (300 MHz, DMSO-d6): delta 0.21-0.57(6H,m), 0.96-1.36(2H,m), 2.69-2.78(1H,m), 2.80-3.19(1H,m), 3.75-3.99(2H,m), 4.13(2H,d,J=7.2 Hz), 7.84(1H,d,J=9.4 Hz), 8.52(1H,dd,J=9.3,2.8 Hz), 8.74(1H,d,J=2.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
131 mg | With potassium carbonate; In acetone;Reflux; | To a solution of ethyl 5-hydroxy-1 H-indole-2-carboxylate (0.25g, 1 .22 mmol) in acetone (3ml_) was added K2C03 (0.51 g, 3.66 mmol) and cyclopropylmethyl bromide (.24ml_, 2.44 mmol). The mixture was heated to reflux overnight. After cooling, the mixture wasfiltered through celite and concentrated under reduced pressure. The crude product was purified using flash chromatography on silica gel with 8:2 hexanes/ethyl acetate as eluent to give 131 mg of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | To a solution of NaH (6.89 g, 172.22 mmol, 60percent in mineral oil) in DMF (150 mL) was added <strong>[42726-73-8]tert-butyl methyl malonate</strong> (30 g, 172.22 mmol, 29.13 mL) and the reaction mixture was stirred at 25 °C for 2 h. Bromomethylcyclopropane (27.9 g, 206.67 mmol, 19.79 mL) was added dropwise slowly and stirred for 16 h. The reaction mixture was quenched by the addition of aq. NH4CI (300 mL) at 0 °C, extracted with EtOAc (3 chi 300 mL), washed with brine (3 chi 300 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:MTBE = 100: 1 to 4: 1) to provide the title compound (29.5 g, 75percent) as a white oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; triethylamine; In acetonitrile; at 20 - 90℃; | To a solution of 1 H-pyrazol-4-amine (1 g, 95% purity, 11 .4 mmol) in acetonitrile (57 mL) were added (bromomethyl)cyclopropane (1.65 ml, 17.1 mmol, GAS-RN 7051-34-5),powdered potassium carbonate (3.95 g, 28.6 mmol), and triethylamine (2.39 mL,17.1 mmol). The mixture was heated to 900 for 4h and stirred at room temperatureovernight. For work-up, it was filtered, and the solid was rinsed with ethyl acetate.Goncentration of the filtrate in vacuo followed by flash chromatography led to N(cyclopropylmethyl)-1 H-pyrazol-4-amine (416 mg, 24% yield, 90% purity).LG-MS (Method B): Rt = 0.54 mm; MS (ESIpos): m/z = 138 (M÷H)1HNMR (400MHz, DMSO-d6) oe [ppm]: 0.16 (m, 2H), 0.42 (m, 2H), 0.99 (m, 1H), 2.68 (m,2H), 4.23 (m, 1H), 7.03 (5, 2H), 12.01 (5, 1H).As additional fraction, N, N-bis(cyclopropylmethyl)- 1 H-pyrazol-4-am me was isolated(657 mg, 27% yield, 90% purity).LG-MS (Method B): Rt = 0.97 mm; MS (ESIpos): m/z = 192 (M÷H)1HNMR (400MHz, DMSO-d6) oe [ppm]: 0.06 (m, 4H), 0.33 (m, 4H), 0.84 (m, 2H), 2.82 (d,4H), 7.07 (5, 2H), 12.07 (5, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.2% | To a stirred solution of 6-bromo-W-methylpyridin-3-amine (1200 mg, 6.44mmol) in DMF, 60% NaH (1030 mg, 25.76mmol) was added at 0C and stirred at rt for 15 minutes. It was cooled at 0C, and (bromomethyl)cyclopropane (1738 mg, 12.88 mmol) was added. It was allowed to stir at rt for 1 h. The reaction mixture was cooled to 0C, quenched with water and extracted with EtOAc. The separated organic layer was washed with water and brine solution and dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography and eluted at 15% EtOAc in pet ether to afford the title compound (1.0 g, 64.2 %) as a yellow gummy;LC-MS (method 5): Rt = 1.20 min; m/z = 240.97 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h; | To a stirred suspension of methyl 5-hydroxy-2-methyl-pyrazole-3-carboxylate (3.00 g, 19.0 mmol) and K2CO3 (2.90 g, 21.0 mmol) in DMF (19 mL) at room temperature was added cyclopropylmethyl bromide (2.0 mL, 21.0 mmol) and the reaction mixture stirred at 50 C for 16 h. The reaction mixture was diluted with water (190 mL) and the aqueous layer extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), passed through a phase separator, and concentrated in vacuo. The crude material was purified by flash chromatography using a gradient of 0-50% EtOAc in isohexanes to afford the title compound (3.14 g, 78% Yield) as a colourless oil. 6H (300 MHz, d-Chloroform) 6.18 (s, 1H), 4.02 (s, 3H), 3.94 (d, J = 7.1 Hz, 2H), 3.85 (s, 3H), 1.33-1.20 (m, 1H), 0.64-0.57 (m, 2H), 0.36-0.31 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With silver(I) oxide; at 80℃; for 16h;Darkness; | <strong>[99337-98-1]2-((1R,4R)-4-hydroxycyclohexyl)isoindoline-1,3-dione</strong> (L040-1, 2g, 8.2mmol) was dissolved in (bromomethyl)cyclopropane (20mL) To this, silver oxide (3.8 g, 16.4 mmol) was added. The reaction was stirred at 80C in the dark for 16h.The concentrated residue was separated by column chromatography (PE/EA=5/2) to obtain compound L043-1. |
Tags: 7051-34-5 synthesis path| 7051-34-5 SDS| 7051-34-5 COA| 7051-34-5 purity| 7051-34-5 application| 7051-34-5 NMR| 7051-34-5 COA| 7051-34-5 structure
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