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CAS No. : | 59878-57-8 | MDL No. : | MFCD06369645 |
Formula : | C8H14N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KIALFUYSJAAJSU-UHFFFAOYSA-N |
M.W : | 154.21 | Pubchem ID : | 2064235 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.88 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 50.07 |
TPSA : | 32.34 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.58 cm/s |
Log Po/w (iLOGP) : | 1.79 |
Log Po/w (XLOGP3) : | -0.48 |
Log Po/w (WLOGP) : | -1.0 |
Log Po/w (MLOGP) : | 0.28 |
Log Po/w (SILICOS-IT) : | 0.91 |
Consensus Log Po/w : | 0.3 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.36 |
Solubility : | 67.1 mg/ml ; 0.435 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.27 |
Solubility : | 286.0 mg/ml ; 1.85 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.91 |
Solubility : | 19.0 mg/ml ; 0.123 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.25 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P261-P264-P270-P272-P273-P280-P301+P312+P330-P302+P352-P305+P351+P338+P310-P333+P313-P391-P501 | UN#: | 3082 |
Hazard Statements: | H302-H317-H318-H410 | Packing Group: | Ⅲ |
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 |
---|---|---|
97% | With trifluoroacetic acid In dichloromethane at 20 - 30℃; Inert atmosphere | 1-Tertbutoxycarbonyl-4-(cyclopropanecarbonyl) piperazine (190 mg, 0.75 mmol) was dissolved in dichloromethane, and then trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature until complete reaction, and then washed with saturated sodium bicarbonate solution for three times. The organic phases were concentrated to give 112 mg (yield 97percent) pale yellow solid of N-(cyclopropanecarbonyl) piperazine for use. |
97% | With trifluoroacetic acid In dichloromethane at 20℃; | 1 -Tertbutoxycarbonyl-4-(cyclopropanecarbonyl)piperazine (190 mg, 0.75 mmol) was dissolved in dichloromethane, and then trifluoroacetic acid (1 mE) was added. The reaction mixture was stirred at room temperature until complete reaction, and then washed with saturated sodium bicarbonate solution for three times. The organic phases were concentrated to give 112mg (yield 97percent) pale yellow solid of N-(cyclopropanecarbonyl) piperazine for use. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.3% | With hydrogen In ethanol at 20℃; | In 100 mL of ethanol was dissolved benzyl 4-(cyclopropylcarbonyl)piperazine-1-carboxylate (3.00 g,10.4 mmol), and 1.5 g of 10percent palladium-carbon was added thereto, followed by stirring at room temperature under hydrogen atmosphere overnight. The palladium-carbon was removed by filtration, and the filtrate was evaporated to give the title compound (1.50 g, 97.3percent) as a colorless oil.1H-NMR Spectrum (CDCl3,400MHz) δ(ppm): 0.73-0.80(2H,m), 0.96-1.03(2H,m),1.67-1.77(1H,m),2.82-2.97(4H,m),3.60-3.71 (4H,m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With hydrogen In ethanol | 10percent Palladium on carbon (175 mg, 10percent by wt.) was placed under an inert atmosphere and suspended in EtOH (5 mL). A solution of (4-benzyl-piperazin-1-yl)-cyclopropyl- methanone (1.75 g, 7.16 mmol) dissolved in EtOH (25 mL) was added. The reaction mixture was placed under H2 atmosphere (1 atmosphere pressure) and stirred overnight.The resulting mixture was filtered through a pad of Celite.(R). and the solvent was concentrated in vacuo to give 1.07 g (97percent) of the title compound as a clear oil. 1H-NMR(300 MHz, CD3OD) δ 3.74 (broad s, 2H), 3.57 (broad s, 2H), 2.87 (broad s, 2H), 2.80 (broad s, 2H), 1.97 to 1.91 (m, 1 H), 0.89 to 0.78 (m, 4H); ES-MS m/z 154.9 [M+H]+, RT(min) 1.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; borane pyridine; acetic acid; In ethanol; 1,2-dichloro-ethane; | Examples 35-92; General Procedure for Examples 35-92; A solution of 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde (intermediate 2) (0.037 g, 0.1 mmol) in DCE (0.5 ml) was added to the appropriate amine (0.1 mmol) followed by a freshly prepared solution of pyridine-borane complex (25 ul, 8M in pyridine, 0.2 mmol) and acetic acid (25 ul) in EtOH (0.5 ml). The reaction was then shaken overnight, concentrated and the residue purified by preparative HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium aluminium tetrahydride; In tetrahydrofuran; for 0.5h;Heating / reflux; | Lithium aluminium hydride (770 mg, 20.3 mmol) was suspended in tetrahydrofuran (150 mL), <strong>[59878-57-8]1-(cyclopropylcarbonyl)piperazine</strong> (1.56 g, 10.1 mmol) was gradually added thereto, and the reaction mixture was heated under reflux for 30 minutes. The reaction mixture was cooled to room temperature, and 0.8 mL of water, 0.8 mL of a 15% aqueous solution of sodium hydroxide and 2.3 mL of water were sequentially gradually added thereto. The precipitated insoluble matter was removed by filtration through Celite, and the filtrate was evaporated to give the title compound (1.40g) as a colorless oil. The product was used for the synthesis of (8E,12E,14E)-7-((4-cyclopropylmethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (the compound of Example 27) without further purification.1H-NMR Spectrum (CDCl3,400MHz) delta(ppm): 0.09-0.15(2H,m), 0.48-0.56(2H,m),0.82-0.93(1H,m),2.25(2H,d,J=7.2Hz) 2.48-2.65(4H,m),2.90-2.99(4H,m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.3% | With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; | In 100 mL of ethanol was dissolved benzyl 4-(cyclopropylcarbonyl)piperazine-1-carboxylate (3.00 g,10.4 mmol), and 1.5 g of 10% palladium-carbon was added thereto, followed by stirring at room temperature under hydrogen atmosphere overnight. The palladium-carbon was removed by filtration, and the filtrate was evaporated to give the title compound (1.50 g, 97.3%) as a colorless oil.1H-NMR Spectrum (CDCl3,400MHz) delta(ppm): 0.73-0.80(2H,m), 0.96-1.03(2H,m),1.67-1.77(1H,m),2.82-2.97(4H,m),3.60-3.71 (4H,m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of intermediate 4a (100 mg) and intermediate 12 (31 mg) in dry 1,2-dichloroethane (5 mL) and acetonitrile (1 mL) was stirred at r.t. for 30 minutes under a nitrogen atmosphere. Then, sodium triacetoxyborohydride (42 mg) was added and the mixture was stirred at 23 C. for 24 hours. The solution was diluted with AcOEt and washed with water. The organic layer was dried and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt/MeOH 9:1) to give: [0379] example 11a (2 mg-T.I.c.: AcOEt/MeOH 8:2 Rf=0.33), [0380] example 11b (7 mg-T.I.c.: AcOEt/MeOH 8:2 Rf=0.16). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With trifluoroacetic acid; In dichloromethane; at 20 - 30℃;Inert atmosphere; | 1-Tertbutoxycarbonyl-4-(cyclopropanecarbonyl) piperazine (190 mg, 0.75 mmol) was dissolved in dichloromethane, and then trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature until complete reaction, and then washed with saturated sodium bicarbonate solution for three times. The organic phases were concentrated to give 112 mg (yield 97%) pale yellow solid of N-(cyclopropanecarbonyl) piperazine for use. |
97% | With trifluoroacetic acid; In dichloromethane; at 20℃; | 1 -Tertbutoxycarbonyl-4-(cyclopropanecarbonyl)piperazine (190 mg, 0.75 mmol) was dissolved in dichloromethane, and then trifluoroacetic acid (1 mE) was added. The reaction mixture was stirred at room temperature until complete reaction, and then washed with saturated sodium bicarbonate solution for three times. The organic phases were concentrated to give 112mg (yield 97%) pale yellow solid of N-(cyclopropanecarbonyl) piperazine for use. |
With trifluoroacetic acid; In dichloromethane; at 20℃; for 2.0h; | TFA (965 muL) was added to a solution of intermediate 11 (210 mg) in anhydrous DCM (1 mL). The solution was stirred at r.t. for 2 hours, then it was concentrated in vacuo. The residue was diluted in a saturated potassium carbonate solution (10 mL) and extracted with AcOEt (2×20 mL). The combined organic extracts were dried and concentrated in vacuo to give the title compound (110 mg) as an oil. [0244] T.I.c.: AcOEt, Rf=0.14. [0245] IR (CDCl3, cm-1): 1626 (CO). [0246] NMR (CDCl3): delta (ppm) 3.7 (bs, 1H); 3.63 (bd, 4H); 2.88 (bd, 4H); 1.72 (m, 1H); 0.99 (m, 2H); 0.75 (m, 2H). [0247] MS (ES/+): m/z=155 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sodium borohydrid;titanium(IV) isopropylate; In ethanol; | Example 15 1-Cyclopropylcarbonyl-4-(6-methoxy-indan-1-yl)piperazine An intimate mixture of 6-methoxy-1-indanone (1.6 g, 10 mmol), 1-cyclopropanecarbonylpiperazine (1.5 g, 10 mmol) and titanium(IV) isopropoxide (4 mL, 12 mmol) was heated on the steam bath for 10 minutes. Additional titanium isopropoxide (1 mL, 3 mmol) was added and the mixture stirred for 20 hr. The material was dissolved in ethanol and sodium borohydride added (0.9 g, 22 mmol). After stirring for 1 hr the solution was heated to reflux and more sodium borohydride (0.9 g, 22 mmol) added. When solution had occurred 15% NaOH solution (50 mL) was added. The insoluble material was removed and discarded. The solution was concentrated in vacuo and the residue mixed with ether. The mixture was washed with water and 1N HCl solution. The acid washes were made basic and the mixture was extracted with ether to give the product as an oil which was converted to the fumarate salt and crystallized from acetone to give the salt (1.8 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 2 4-Amino-2-[4-(cyclopropylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline <strong>[59878-57-8]N-(Cyclopropylcarbonyl)piperazine</strong> (3.08 g., 0.02 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (4.74 g., 0.02 mole) are reacted according to the procedure of Example 1(a). The crude product crystallized from ethanol affords analytically pure 4-amino-2-[4-(cyclopropylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 283.5-285.5 C. (corr.). Analysis. Calcd. for C18 H23 N5 O3 (percent): C, 60.49; H, 6.49; N, 19.59. Found (percent): C, 60.56; H, 6.46; N, 19.41. | ||
Example 128 4-Amino-2-[4-(cyclopropylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline <strong>[59878-57-8]N-(Cyclopropylcarbonyl)piperazine</strong> (3.08 g., 0.02 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (4.74 g., 0.02 mole) are reacted according to the procedure of Example 127(a). The crude product crystallized from ethanol affords analytically pure 4-amino-2-[4-(cyclopropylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 283.5 C. (corr.). Analysis, Calcd. for C18H23N5O3 (percent): C, 60.49; H, 6.49; N, 19.59. Found (percent): C, 60.56; H, 6.46; N, 19.41. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With hydrogen;palladium 10% on activated carbon; In ethanol; under 760.051 Torr; | 10% Palladium on carbon (175 mg, 10% by wt.) was placed under an inert atmosphere and suspended in EtOH (5 mL). A solution of (4-benzyl-piperazin-1-yl)-cyclopropyl- methanone (1.75 g, 7.16 mmol) dissolved in EtOH (25 mL) was added. The reaction mixture was placed under H2 atmosphere (1 atmosphere pressure) and stirred overnight.The resulting mixture was filtered through a pad of Celite and the solvent was concentrated in vacuo to give 1.07 g (97%) of the title compound as a clear oil. 1H-NMR(300 MHz, CD3OD) delta 3.74 (broad s, 2H), 3.57 (broad s, 2H), 2.87 (broad s, 2H), 2.80 (broad s, 2H), 1.97 to 1.91 (m, 1 H), 0.89 to 0.78 (m, 4H); ES-MS m/z 154.9 [M+H]+, RT(min) 1.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | To the reaction flask was added compound 6 (prepared in Example 3-2, 256.5g,0.86mol), CDI (139.45g, 0.86mol), 1.6LTHF, after stirring for 0.5h Compound 7 (138.8g,0.90mol) at room temperature The reaction 3h, after completion of the reaction, water was added to quench the reaction, of THF was distilled off under reduced pressure, theresidue was dissolved in ethyl acetate was added, the organic phase was separated,washed with water three times, the organic phase was dried over anhydrous Na 2SO 4Dried,filtered and concentrated to give Ola Trapani (356.3g, 0.82mol), yield 95%, HPLC purity 99.8%. | |
91.5% | With pivaloyl chloride; triethylamine; In ethanol; dichloromethane; at 20℃; for 4h; | (4) The product of the previous step (0.3 g, 1 mmol) was weighed, dissolved in 5 mL of dichloromethane, and trimethylacetyl chloride (121 yL, 1 mmol) and triethylamine (208 mL, 1.5 mmol) were stirred at room temperature. The reaction was clarified until the solution was clarified. 1 - (cyclopropylcarbonyl)-pyridazine (0.3 g, 2 mmol) was dissolved in 5 mL of ethanol, added dropwise to the above clear solution, reacted at room temperature for 4 h, and extracted with dichloromethane (15 mL). The organic phase was washed with water, and the organic layer was dried over anhydrous sodium sulfate, and then evaporated to dryness to afford ololani (0.4 g, 0.9 mmol), yield 91.5%, purity 99.8%. |
81.9% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 30 - 50℃; | In a 500 mL reaction flask, 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (Formula II, 15.0 g, 50.3 mmol) and DMF ( 100ml),After the addition, the system was stirred for 0.5 h to dissolve the system, and then 1-cyclopropyl-formylpiperazine (8.55 g, 55.4 mmol) and HBTU (21.0 g, 55.4 mmol) were added.DIPEA (8.5 g, 65.8 mmol) was then added dropwise to the system.The dropping process controls the reaction temperature not to be higher than 50 C, and the system is kept at 30 ± 5 C overnight after the addition.After the reaction was completed, the mixture was filtered, and the filter cake was washed with 1 L of purified water, and then the filter cake was transferred to a 1 L reaction flask.Purified water (500 mL) was added, kept at 30 ± 5 C, and stirred for 1 h.After suction filtration, the filter cake was washed with purified water (100 mL) and blast dried for about 24 h.The crude product (19.7 g) was obtained, and the crude material was recrystallized from DMF (75 ml)17.9g, 81.9%). |
34% | To a solution of 2-Fluoro-5-((4-oxo3,4-dihydrophthalazin-l-yl)methyl)benzoic acid (50 mg, 0.168 mmol) in DMA (1 mL) was added DIPEA (56 L, 0.336 mmol) and HBTU (64 mg, 0.170 mmol). The reaction mixture was stirred for 1 hour before addition of cyclopropylpiperazine-l-ylmethanone (0.170 mmol) was carried out. The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was then extracted with DCM (3 x 5 mL) and washed with water (3 x 20 mL). The organic layers were collected, dried with MgS04 and the excess solvent removed in vacuo. Purification via reverse phase HLPC was carried out affording 4-(3-(4 (cyclopropanecarbonyl) piperazine- l-carbonyl)-4- fluorobenzy phthalazin- 1 (2//)-one (olaparib) (25 mg, 34%) as a white solid. *H NMR (400 MHz, CDCh) d = 10.65 (s, 1H), 8.44 - 8.37 (m, 1H), 7.75 - 7.61 (m, 3H), 7.34 - 7.22 (m, 2H), 6.97 (t, J = 8.9 Hz, 1H), 4.22 (s, 2H), 3.90 - 3.09 (m, 8H), 1.79 - 1.52 (s, 3H), 0.99 - 0.88 (m, 2H), 0.81 - 0.63 (s, 2H); {}1^ NMR (376 MHz, CDCb) d = - 117.6; Mp: 69 - 7lC. Data is in accordance with known literature (Menear, K.A., et al., ibid.). | |
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 3 - 20℃; for 3.5h;Product distribution / selectivity; | Example 2: Alternative synthesis of Compound A using i-fcyclopropylcarbonyl) piperazineMethods (also for Examples 3 & 4)NMR1H NMR spectra were recorded using Bruker DPX 400 spectrometer at 400 MHz. Chemical shifts were reported in parts per million (ppm) on the delta scale relative to tetramethylsilane internal standard. Unless stated otherwise all samples were dissolved in DMSOd6.Mass SpectraMass spectra were recorded on an Agilent XCT ion trap mass spectrometer using tandem mass spectrometry (MS/MS) for structural confirmation. The instrument was operated in a positive ion elctrospray mode.(a) 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (Compound A)2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(15.23g, 51.07 mmol) was suspended with stirring under nitrogen in acetonitrile (96 ml). Diisopropylethylamine (19.6 ml, 112.3 mmol) was added followed by 1-cyclopropylcarbonylpiperazine (l)(9.45g, 61.28 mmol) and acetonitrile (1 ml). The reaction mixture was cooled to 18C. O-Benzotriazol-1-yl- tetramethyluronium hexafluorophosphate (25.18g, 66.39 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to 3C and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3C) acetonitrile (20 ml) before being dried in vacuo at up to 4O0C to give the title compound as a pale yellow solid (20.21 g).Mass Spectrum: MH+ 4351H NMR (400MHz. DMSO-d6) delta: 0.70 (m, 4H), 1.88 (br s, 1 H), 3.20 (br s, 2H), 3.56 (m, 6H), 4.31 (s, 2H), 7.17 (t, 1 H), 7.34 (dd, 1 H), 7.41 (m, 1 H), 7.77 (dt, 1 H), 7.83 (dt, 1 H), 7.92 (d, 1 H), 8.25 (dd, 1 H), 12.53 (s, 1 H). | |
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 3 - 20℃; for 3.5h; | (a) 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (Compound A)2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(15.23g, 51.07 mmol) was suspended with stirring under nitrogen in acetonitrile (96 ml). Diisopropylethylamine (19.6 ml, 112.3 mmol) was added followed by 1-cyclopropylcarbonylpiperazine (l)(9.45g, 61.28 mmol) and acetonitrile (1ml). The reaction mixture was cooled to 18C. O-Benzotriazol-1-yl- tetramethyluronium hexafluorophosphate (25.18g, 66.39 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to 3C and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3C) acetonitrile (20 ml) before being dried in vacuo at up to 400C to give the title compound as a pale yellow solid (20.21 g).Mass Spectrum: MH+ 4351H NMR (400MHz, DMSO-d6) delta: 0.70 (m, 4H), 1.88 (br s, 1H), 3.20 (br s, 2H), 3.56 (m, 6H), 4.31 (s, 2H), 7.17 (t, 1H), 7.34 (dd, 1 H), 7.41 (m, 1H), 7.77 (dt, 1H), 7.83 (dt, 1H), 7.92 (d, 1H), 8.25 (dd, 1 H)1 12.53 (S1 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In ISOPROPYLAMIDE; at 20℃; for 18h; | (e) Library Synthesis (10a-m)To a solution of 2-fluoro-5-(4-oxo-3,4,5,6,7,8-hexahydro-phthalazin-1-ylmethyl)-benzoic acid (22 mg, 0.07 mmol), in DMA (1 ml) was added HBTU (53 mg, 0.140 mmol), triethylamine (20 muL, 0.140 mol) and amine (0.140 mmol). The crude reaction mixture was stirred for 18 hours at room temperature and then submitted for preparative HPLC purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 18h; | (d) Library Synthesis (5a-h)To a solution of 3-(4-oxo-3,4,5,6,7,8-hexahydro-phthalazin-1-ylmethyl)-benzoic acid (4) (20 mg, 0.07 mmol), in DCM (1 ml) was added HBTU (53 mg, 0.140 mmol), triethylamine (20 muL, 0.140 mol) and amine (0.140 mmol). The reaction mixture was stirred for 18 hours at room temperature and concentrated in vacuo. The crude samples were submitted for preparative HPLC purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Example 169 Amethyl 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoate; To a solution of 3-(methoxycarbonyl)benzoic acid (0.9 g, 5 mmol) in dichloromethane (20 mL), 1-hydroxybenzotriazole (0.75 g, 5.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.06 g, 5.5 mmol) and triethyl amine (2 mL) were added. The mixture was stirred at room temperature for 30 min, and then <strong>[59878-57-8]cyclopropyl(piperazin-1-yl)methanone</strong> (1.0 g, 5 mmol) was added and the mixture was stirred at room temperature for 16 h. The resulting mixture was added water (50 mL) and extracted with dichloromethane (100 mL×3), the organic phase was washed with sodium bicarbonate, brine and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 20:1 to 2:1), 0.95 g of methyl 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoate as an oil was obtained, Yield 60%. 1H-NMR (400 MHz, CDCl3) 0.80-0.82 (m, 2H), 1.00-1.04 (m, 2H), 1.24-1.27 (m, 1H), 3.25-3.78 (m, 8H), 3.94 (s, 3H), 7.52-7.55 (t, J=7.6 Hz, 1H), 7.63-7.65 (d, J=7.6 Hz, 1H), 8.09-8.14 (m, 2H); LC-MS (ESI) m/z: 317(M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 36h;Sealed tube; | INTERMEDIATE 48(S)-tert~BvLtyl 1 - { 8-chloro-2- F4-C cvclopropanecarbonvDpiperazin- 1 -yl] quinolin-3- vDethylcarbamateIntermediate 11 (150 mg, 0.44 mmol), cyclopropyl(piperazin-l-yl)methanone (0.16 mL, 1.1 mmol), NMP (2 mL) and DIPEA (0.38 mL, 2.2 mmol) were combined in a sealed tube and heated to 14O0C for 36 h. After cooling, Et2O was added to the reaction mixture. The organic layer was washed with water and brine. The organic layer was dried (MgSO4), filtered and the solvent was removed in vacuo. Purification by column chromatography on silica, eluting with 0-5% MeOH in EtOAc, gave the title compound (175 mg, 86%) as a yellow gum. deltaH (CDCl3) 8.00 (IH, s), 7.71 (IH, dd, J7.5, 1.3 Hz), 7.62 (IH, dd, J8.1, 1.3 Hz), 7.34-7.28 (IH, m), 5.15 (IH, br s), 4.95 (IH, br s), 3.86 (4H, br s), 3.60 (2H, br s), 3.34 (2H, br s), 1.85-1.77 (IH, m), 1.46 (3H, s), 1.44 (9H, s), 1.05- 1.00 (2H, m), 0.80 (2H, dd, J 7.8, 3.5 Hz). LCMS (ES+) 459 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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60% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 96h;Sealed tube; | INTERMEDIATE 46(S)-N-(I - (2- r4-(Cyclopropanecarbony?piperazin- 1 -yl] -8-methylquinolin-3 -yl) ethvD- 2,2,2-trifluoroacetamideIntermediate 45 (100 mg, 0.32 mmol), cyclopropyl(piperazin-l-yl)methanone (0.09 mL, 0.63 mmol), NMP (2 mL) and DIPEA (0.10 mL, 0.80 mmol) were combined in a sealed tube and heated to 1400C for 4 days. After cooling, Et2O (50 mL) was added to the reaction mixture. The organic layer was washed with water (5 x 50 mL) and brine. The organic layer was dried (MgSO4), filtered and the solvent was removed in vacuo. Purification by column chromatography on silica, eluting with 0-30% EtOAc in isohexane, gave the title compound (82 mg, 60%) as a pale yellow gum. delta? (CDCl3) 8.01 (IH, s), 7.75-7.65 (IH, m), 7.59 (IH, d, J 8.1 Hz), 7.55-7.48 (IH, m), 7.40-7.31 (IH, m), 5.58-5.47 (IH, m), 4.00-3.86 (3H, s), 3.85-3.72 (IH, s), 3.54-3.30 (2H, m), 3.18 (2H, m), 2.71 (3H, s), 1.84-1.76 (IH, m), 1.64 (3H, d, J6.8 Hz), 1.09-0.97 (2H, m), 0.84-0.75 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 16h; | To a solution of Intermediate 9 (500 mg, 1.48 mmol) in NMP (6 mL) were added (cyclopropyl)(piperazin-l-yl)methanone (455 mg, 2.95 mmol) and DIPEA (1.3 mL), and the mixture was heated at 140C for 16 h. The reaction mixture was taken up in EtOAc^ (150 mL) and water (50 mL) and the organic layer was washed with water (2 x 50 mL) and brine (50 mL). The organic layer was separated and dried (phase separation cartridge), and the solvent was removed in vacuo. Purification by columnchromatography (Si02, 10-20% EtOAc in isohexane) gave a beige solid (390 mg, 57%). To a solution of this material (390 mg, 0.85 mmol) in DCM (6 mL) was added TFA (3 mL) and the resulting solution was stirred at r.t. for 15 minutes. The solvents were30removed in vacuo. The residue was dissolved in MeOH (5 mL), then placed on an SCX cartridge, washed (MeOH), eluted (7M ammonia in MeOH) and concentrated in vacuo to afford a white solid (304 mg, 100%). To a portion of this material (60 mg, 0.17 mmol) in NMP (1.2 mL) were added DIPEA (0.14 mL) and 4-chloropyrido[3,2-c/]pyrimidine (33 - - mg, 0.2 mmol). The resulting solution was heated under microwave irradiation at 150C for 1 h. Purification by preparative HPLC afforded the title compound (51 mg, 61%) as a beige solid. deltaEta (DMSO-ifc) 8.93-8.88 (2H, m), 8.54 (2H, d, J 11.51 Hz), 8.17 (IH, dd, J 8.46, 1.58 Hz), 7.90 (IH, dd, J 8.46, 4.25 Hz), 7.74 (IH, dd, J 8.94, 6.26 Hz), 7.33 (IH, t, J9.12 Hz), 5.91 (IH, m), 4.05-3.13 (8H, s), 2.58 (3H, m), 2.12-2.07 (IH, m), 1.67 (3H, d, J 6.71 Hz), 0.90-0.73 (4H, m). LCMS (ES+) 486 (M+H)+, RT 2.78 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | In methanol; at 20℃; for 24h; | General procedure: A solution of 5-bromo-5-(4-phenoxyphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione (1.0 mmol) in methanol (5 ml) was treated with the substituted piperazines or homopiperazines (2 mmol) and stirred for 24 h at ambient temperature. Compounds 8a, 8b, 8c, 8f, and 8g precipitated. The precipitates were collected by filtration and dried in vacuo to afford the solids. In the case of compounds 8d, 8e, 8h, 8i and 9a-d, the solvents of reactions were removed and the residues purified by flash column chromatography and dried to yield the pure solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | General procedure: To a solution of compound 19 (100 mg, 0.33 mmol) in anhydrous DMF (3 mL) was added appropriate amine (0.43 mmol), EDC (82 mg, 0.43 mmol), 1-hydroxybenzotriazole monohydrate (66 mg, 0.43 mmol), and triethylamine (43 mg, 0.43 mmol). The reaction mixture was stirred at rt overnight, and partitioned between methylene chloride and brine. The organic phase was washed with brine, water, and concentrated. The residue was separated by HPLC to provide compounds 20. For compounds 20f, 20g, and 20h whose syntheses involved the use of BOC-protected amine, the coupling product was then treated with TFA (0.5 ml) in CH2Cl2 (2 mL) at rt for 1 h. Removal of the volatiles provided the crude 20 that can be further purified by HPLC to give the title products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 20℃; for 2h; | To a solution of 1 i (28 mg, 0.089 mmol) in acetonitrile (2 mL) were added DIPEA (48 muIota_, 0.267 mmol), 1j (15 muIota_, 0.107 mmol) and HATU (41 mg, 0.107 mmol). The resulting mixture was stirred at room temperature for 2 h and purified by reversed phase prep HPLC to give title compound 1 as white solid (36 mg, 90% yield). The mass of the compound was obtained by Shimadzu LCMS-2020, MS(ESI) : m/z = 451 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With dmap; tetrakis(triphenylphosphine) palladium(0); potassium bromide; In N,N-dimethyl-formamide; at 120℃; | c. In the round bottom flask, the compound V29.14g was sequentially added.1-cyclopropionylpiperazine 13.34g, pd(PPh3)4 4.99g,0.173 mol of 4-dimethylaminopyridine, 10.29 g of potassium bromide, 500 ml of N,N-dimethylformamide, and then placed on a condenser, which was evacuated and flushed into CO.Repeatedly, then a balloon filled with carbon monoxide is placed on the upper end of the condenser.The temperature was controlled at 120 C, the reaction was continuously stirred, and the reaction was monitored by TLC.After the reaction is over, the temperature is lowered to room temperature and mixed.The extract was extracted with ethyl acetate, washed with purified water and dried over anhydrous sodium sulfate.Vacuum drying to obtain Olaparib (I) 36.48g, yield 97%The purity is 99.93%. |
96% | With dmap; tetrakis(triphenylphosphine) palladium(0); potassium bromide; In N,N-dimethyl-formamide; at 120℃; | The round bottom flask is sequentially added in the compound V 26.99 g, 1 - cyclopropanecarboxylic formyl piperazine 12.49 g, 4.7 gpd (PPh3)4, 4 - Dimethylamino pyridine (0.162 muM), potassium bromide 9.64 g, N, N - dimethyl formamide 500 ml, then covering with the condenser tube, will be its evacuation and into the CO, repeatedly, in the condenser and then the upper end of the sleeve is a balloon filled with carbon monoxide. The temperature control in the 120 C, continuously stirring reaction, for monitoring the reaction TLC, to be after the reaction temperature to the room temperature, the mixture of ethyl acetate extraction, purified water washing, anhydrous sodium sulfate drying, vacuum drying to obtain aurar handkerchief nepal (I) 33.81 g, yield 96%, purity 99.93%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With N-ethyl-N,N-diisopropylamine; potassium iodide; In acetonitrile; at 80℃; for 12h; | General procedure: 74 (250 mg, 0.71 mmol) was mixed with acetonitrile (5 mL), diisopropylethylamine (3 mL) and KI (250 mg) and 2,2-dimethyl-1-(piperazin-1-yl)propan-1-one (600 mg) and heated at 80 C for 12 h. On cooling, the mixture was poured into a saturated solution of ammonium chloride (40 mL) and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with brine (40 mL), dried (magnesium sulfate), filtered and concentrated. The crude residue was purified by Flashmaster II (eluting with 0-50 % ethyl acetate in dichloromethane) to give 1-(4-[2-fluoro-4-(trifluoromethyl)phenyl](pyridin-3-yl)methyl}piperazin-1-yl)-2,2-dimethylpropan-1-one (14) (52 mg, 17 %) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | In toluene; at 120℃; for 1.5h;Microwave irradiation; | Step 1. Synthesis of methyl 4-((3-((4-(cyclopropancarbonyl)piperazin-l-yl)methyl)-4-oxo-1 ,2,3,4-tetrahydrocarbazol-9- l)methyl)benzoate [formula 2-5]To a microwave vial were added methyl 4-((3 -methyl en-4-oxo- 1,2,3,4- tetrahydrocarbazol-9-yl)methyl)benzoate [formula 2-4] (0.10 g, 0.290 mmol), 1- (cyclopropylcarbonyl)piperazine (0.134 g, 0.869 mmol) and toluene (3.0 mL), and a reaction was carried out in a microwave reactor at 120C for 90 minutes. Then, the reaction mixture was extracted with ethyl acetate and saturated NH4C1 aqueous solution, the organic layer was washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. Residue was purified by column chromatography (Si02; dichloromethane/methanol, 10/1) to yield the title compound (0.056 g, 39 %). |
39% | In toluene; at 120℃; for 1.5h;Microwave irradiation; | To a microwave vial were added methyl 4-((3-methylen-4-oxo-1,2,3,4-tetrahydrocarbazol-9-yl)methyl)benzoate [formula 2-4] (0.10 g, 0.290 mmol), <strong>[59878-57-8]1-(cyclopropylcarbonyl)piperazine</strong> (0.134 g, 0.869 mmol) and toluene (3.0 mL), and a reaction was carried out in a microwave reactor at 120 C. for 90 minutes. Then, the reaction mixture was extracted with ethyl acetate and saturated NH4Cl aqueous solution, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Residue was purified by column chromatography (SiO2; dichloromethane/methanol, 10/1) to yield the title compound (0.056 g, 39%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27 mg | With chloro-(2-dicyclohexylphosphino-2?,6?-diisopropoxy-1,1?-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butyl ether adduct; sodium t-butanolate; ruphos; In 1,4-dioxane; at 20℃; for 16h;Inert atmosphere; | Step 2: N-[4-(4-Cyclopropanecarbonyl-piperazin-l-yl)-benzyl]-N-isobutyl-C-phenyl- methanesulfonamide In a vial, N-[(4-bromophenyl)methyl]-N-isobutyl-l-phenyl-methanesulfonamide (53 mg, 0.13 mmol), 2-dicyclohexylphosphino-2',6'-di-i-propoxy-l, r-biphenyl (3.2 mg, 0.0067 mmol) , chloro(2-dicyclohexylphosphino-2',6'-di-i-propoxy- 1 , 1 '-biphenyl)[2-(2 aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (6 mg, 0.0067 mmol) and sodium teri-butoxide (20 mg, 0.20 mmol) were combined and the vial was purged with nitrogen. 1,4-Dioxane (1 mL) and cyclopropyl(piperazin-l-yl)methanone (31 mg, 0.20 mmol) were then added and the reaction was stirred at ambient temperature for 16 hours. The reaction was then partitioned between water and dichloromethane and the dichloromethane layer was isolated with a phase separator cartridge, concentrated and purified by preparative reverse phase HPLC to yield 27 mg of N-[4-(4- cyclopropanecarbonyl-piperazin-l-yl)-benzyl]-N-isobutyl-C-phenyl- methanesulfonamide. 1H NMR (400 MHz, DMSO) delta 7.38 - 7.34 (m, 5H), 7.21 (d, J = 8.5 Hz, 2H), 6.94 (d, J= 6.8 Hz, 2H), 4.40 (s, 2H), 4.16 (s, 2H), 3.82 - 3.78 (m, 2H), 3.62 - 3.58 (m, 2H), 3.20-3.05 (m, 4H), 2.80 (d, J= 7.5, 2H), 2.12 - 1.92 (m, 1H), 1.60- 1.45 (m, 1H), 0.83 - 0.69 (m, 4H), 0.67 (d, J= 7.1 Hz, 6H); LCMS (m/z) ES+470.2 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Piperazine derivatives 1-3 are known.10 Piperazine derivatives 4-14 were synthesized from the commercially available appropriate monoalkylated piperazines (1.44 mmol) and 2-nitro-1H-imidazolyl-propylbromide or 3-nitro-1H-1,2,4-triazolylpropylbromide (1.485 mmol)30 in the presence of potassium carbonate (13.24 mmol) in dry acetonitrile (25 mL) as described before.10 The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 48 h, then filtered to remove the inorganic salts. The organic filtrate was evaporated and the residue extracted from water-chloroform. The organic layer was separated and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated and the residue purified by preparative TLC on alumina plates with ethyl acetate:petroleum ether mixture. The desired product was dissolved in ethyl acetate and converted to its HCl salt by treating with HCl gas in dry ether (1 M solution) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a solution of the above compound (68mg, 0.27mmol) in anhydrous DMF (2mL) under N2 at 0C were added WSC (61mg, 0.32mmol) and HOBt (43mg, 0.32mmol). The resulting mixture was stirred for 30min, then it was added with DIPEA (141mul, 0.81mmol) and <strong>[59878-57-8]1-(cyclopropylcarbonyl)piperazine</strong> (115mul, 0.81mmol). Stirring was continued at room temperature for 20h. The residue was partitioned between water and ethyl acetate and the phases were separated. The organic layer was washed with brine, dried, filtered and evaporated. Purification by flash chromatography (CH2Cl2:MeOH 95:5) afforded 85mg (80%) of the title compound. 1H NMR (CDCl3) delta 10.88 (1H, br s); 8.18-7.95 (3H, m); 7.47 (1H, d, J=8.4Hz); 7.34-7.18 (2H, m); 6.50 (1H, m); 3.97-3.73 (4H, m); 3.88-3.72 (2H, m); 3.54-3.34 (2H, m); 1.75 (1H, m); 1.09-0.94 (2H, m); 0.90-0.64 (2H, m). Anal. Calcd for C22H21FN4O2: C, 67.33; H, 5.39; N, 14.28. Found: C, 69.86; H, 5.34; N, 13.88. | |
80% | EDC (61 mg, 0.32 mmol) and HOBt (43 mg, 0.32 mmol) were added to a 0C solution of 2-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-6-yl)benzoic acid (68 mg, 0.27 mmol) in anhydrous DMF (2 ml). The resulting solution was stirred at 0C for 30 mmbefore adding DIPEA (141 il, 0.31 mmol) and <strong>[59878-57-8]1-(cyclopropylcarbonyl)piperazine</strong>(115 jil mg, 0.81 mmol). The reaction mixture was then stirred at RT for 20 h.Standard extraction with AcOEt and washing with H20 afforded the desiredadduct.Purification: DCM/MeOH: 95/5 to get a white sticky solid.Yield: 80%.iff NMR (300 MHz CDC13), oe: 10.88 (1H, bs); 8.18-7.95 (3H, m); 7.47 (1H, d, J = 8.4Hz); 7.34-7.18 (2H, m); 6.50 (1H, m); 3.97-3.73 (4H, m); 3.88-3.72 (2H, m); 3.54-3.34(2H, m); 1.75 (1H, m); 1.09-0.94 (2H, m); 0.90-0.64 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | 3-((4-Oxo-3,4-dihydro-phthalazin-1-yl-oxyl)methyl) benzoic acid (148 mg, 0.5 mmol) was dissolved in N, N-dimethylformamide, and then 1-(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (115 mg, 0.63 mmol), triethylamine (83.6 muL, 0.63 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (81.6 mg, 0.63 mmol) were added successively. The mixture was stirred at room temperature for half an hour, and then N-(cyclopropanecarbonyl) piperazine was added and reacted at room temperature overnight, and then the reaction was quenched with water. The mixture was extracted with ethyl acetate, and washed with water for two times. The organic phases were combined and washed with saturated saline, dried with anhydrous sodium sulfate, concentrated and then purified by column chromatography (dichloromethane:methanol=20:1) to give a white solid 173 mg (yield 88%). 1H NMR (600 MHz, DMSO-d6):delta 11.94 (s, 1H), 8.21 (d, 1H, J = 7.68 Hz), 7.99 (d, 1H, J = 7.86 Hz), 7.94-7.92 (m, 1H), 7.90-7.88 (m, 1H), 7.61 (d, 1H, J = 7.62 Hz), 7.55 (s, 1H), 7.49 (t, 1H, J = 7.62 Hz), 7.39 (d, 1H, J = 7.62 Hz), 5.38 (s, 2H), 3.87-3.47 (m, 8H), 1.95 (brs, 1H), 0.69-0.72 (m, 4H); ESI-MS m/z: calculated for 432.1, found 455.1 [M+Na]+. | |
88% | 3-((4-oxo-3,4-dihydrophthalazin-1-yl-oxyl)methyl)benzoic acid (148 mg, 0.5 mmol) was dissolved in N,Ndimethylformamide, and then 1 -(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) (115 mg, 0.63 mmol), triethylamine (83.6 pL, 0.63 mmol) and 1-hydroxy- 7-azabenzotriazole (HOAt) (81.6 mg, 0.63 mmol) were added successively. The mixture was stirred at room temperature for half an hour, and then N-(cyclopropanecarbonyl) piperazine was added and reacted at room temperature over-night, and then the reaction was quenched with water. The mixture was extracted with ethyl acetate, and washed with water for two times. The organic phases were combined and washed with saturated saline, dried with anhydrous sodium sulfate, concentrated and then purified by column chromatography (dichloromethane:methanol=20: 1) to give a white solid 173mg (yield 8 8%). ?H NMR (600 MHz, DMSO-d5): oe 11.94 (s, 1H), 8.21 (d, 1H, J=7.68 Hz), 7.99 (d, 1H, J=7.86 Hz), 7.94-7.92 (m, 1H), 7.90-7.88 (m, 1H), 7.61 (d, 1H, J=7.62 Hz), 7.55 (s, 1H), 7.49 (t, 1H, J=7.62 Hz), 7.39 (d, 1H, J=7.62 Hz), 5.38 (s, 2H), 3.87-3.47 (m, 8H), 1.95 (brs, 1H), 0.69-0.72 (m, 4H); ESI-MS mlz: calculated for 432.1. found455.1 [M+Na]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3-((4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl) benzoic acid (54 mg, 0.3 mmol) was dissolved in N, N-dimethylformamide, and then 1-(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (220 mg, 1.2 mmol), triethylamine(150 muL, 1.2 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt)(165 mg, 1.2 mmol) were added successively. The mixture was stirred at room temperature for half an hour, and then N-(cyclopropanecarbonyl) piperazine was added and reacted at room temperature overnight, and then the reaction was quenched with water, extracted with ethyl acetate, and washed with water for three times. The organic phases were combined and washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated for column chromatography isolation (dichloromethane:methanol=20:1) to give Compound 7. A white solid was obtained. 1H NMR (600 MHz, DMSO-d6): delta 11.98 (s, 1H), 8.27 (d, 1H, J = 7.38 Hz), 8.10 (d, 1H, J = 7.74 Hz), 7.99-8.01 (m, 1H), 7.94-7.96 (m, 1H), 7.52 (t, 1H, J= 7.86 Hz), 7.39-7.38 (m, 2H), 7.28 (d, 1H, J = 7.62 Hz), 3.33-3.81 (m, 8H), 1.96 (brs, 1H), 0.69-0.74 (m, 4H); ESI-MSm/z: calculated for 418.16, found 417.89 [M-H]+. | ||
3-(4-oxo-3,4-dihydro-phthalazin- 1 -yl-oxyl)benzoic acid (54 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide, and then 1-(3-dimethylaminopropyl)-3-ethylcar- bodiimide hydrochloride (EDCI) (220 mg, 1.2 mmol), triethylamine (150 pL, 1.2 mmol) and 1 -hydroxy-7-azaben- zotriazole (HOAt) (165 mg, 1.2 mmol) were added successively. The mixture was stirred at room temperature for half an hour, and then N-(cyclopropanecarbonyl) piperazine was added and reacted at room temperature overnight, and then the reaction was quenched with water, extracted with ethyl acetate, and washed with water for three times. The organic phases were combined and washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated for colunm chromatography isolation (dichloromethane:methanol=20: 1) to give Compound 7. A white solid was obtained. ?H NMR (600 MHz, DMSO-d5): oe 11.98 (s, 1H), 8.27 (d, 1H, J=7.38 Hz), 8.10 (d, 1H, J=7.74 Hz), 7.99-8.01 (m, 1H), 7.94-7.96 (m, 1H), 7.52 (t, 1H, J=7.86 Hz), 7.39-7.38 (m, 2H), 7.28 (d, 1H, J=7.62 Hz), 3.33-3.81 (m, 8H), 1.96 (brs, 1H), 0.69-0.74 (m, 4H); ESI-MSm/z: calculated for4l8.16. found 417.89 [M-H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h; | (Formula 5-4: methyl 4-((N-(3-(benzo[d][1,3]dioxol-5-yl)phenyl)-4-(cyclopropanecarbonyl)piperazine-1-carboxamido)methyl)benzoate)[1167][1168]Compound ofFormula 5-3(methyl 4-(((3-(benzo[d][1,3]dioxol-5-yl)phenyl)((4-nitrophenoxy)carbonyl)amino)methyl)benzoate; 0.180 g, 0.342 mmol) was dissolved in dimethylformamide (2 mL), and then <strong>[59878-57-8]cyclopropyl(piperazin-1-yl)methanone</strong>(0.158 g, 1.03 mmol) and potassium carbonate (0.142 g, 1.03 mmol) were added and stirred at 50 C for 16 hours. After completion of the reaction, the organic layer was extracted with ethyl acetate and saturated ammonium chloride aqueous solution, dehydrated with anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then the residue was purified and concentrated by column chromatography (silica; ethyl acetate/hexane= 30%) to give the desired compound ofFormula 5-4(0.096 g, 52%) in the form of a yellow liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In N,N-dimethyl-formamide; at 60℃; for 48h; | (Formula 7-6: methyl 4-((4-(cyclopropanecarbonyl)-N-(pyridin-2-yl)piperazine-1-carboxamido)methyl)benzoate)[1011][1012]Compound ofFormula 7-5(methyl 4-((((4-nitrophenoxy)carbonyl)(pyridin-2-yl)amino)methyl)benzoate; 0.40 g, 0.982 mmol) was dissolved in dimethylformamide (10 mL), and then <strong>[59878-57-8]cyclopropyl(piperazin-1-yl)methanone</strong> (0.167 mL, 1.17 mmol) was added, and the mixture was heated and stirred at 60 for 2 days. Then, the dimethylformamide was removed under reduced pressure, water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dehydrated with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified and concentrated by column chromatography (silica; methanol/dichloromethane=5%) to give the desired compound ofFormula 7-6(0.4 g, 96%) in the form of a white oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | General procedure: To a solution of acid (0.33mmol) in DMF (2mL), diisopropylethylamine (0.33mmol) and HATU (0.33mmol) were added. The mixture was left 33h stirring at room temperature and then the appropriate amine (0.45mmol) was added. After 16h at room temperature the solvent was removed under reduced pressure; the residue was dissolved in 2mL of DCM and washed with 2mL of 0.4N Na2CO3 solution. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
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67% | With triethylamine; In dichloromethane; at 20℃;Inert atmosphere; | General procedure: Compounds 1a-l and compounds 15-19 were synthesized in the same reaction: In a dichloromethane solution (2-3 mL) of chloroacetylchloride(1.1 eq), a dichloromethane solution (8-10 mL) of the appropriate piperazine (1 eq) and triethylamine (2.5 eq) was added dropwise and the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was evaporated and the residue was extracted with ethylacetate-brine. The organic layer was dried over Na2SO4 and chromatographed on silica preparative TLC to give the desired products.When the reaction was run for 2 h, compounds 1a-l were the mainproducts (>90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.1 g | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In water; N,N-dimethyl-formamide; at 20℃; for 5h; | 0.62g to 1.0g of Intermediate VI and cyclopropylmethyl - piperazin-1-yl - methyl ketone was added to a 100mL one-neck flask was added10mLDMF clear solution was stirred, then add 2.05gHBTU, 0.82g triethylamine, room temperature for 5h. After completion of the reaction the reactionIt was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate spin column chromatography to give 1.1g solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.4% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; water; N,N-dimethyl-formamide; at 20℃; | At room temperature will 4-carboxyphenyl boronic acid pinacol ester (3g, 12.10mmol) was dissolved in dichloromethane (27ml, 0.422mol) And N,N-dimethylformamide (9ml, 0.116mol) was added 1-cyclopropyl-methylpiperazine (2.3g, 14.9mmol), And successively added 1-ethyl - (3-dimethylaminopropyl)carbodiimide hydrochloride (2.79g, 14.4mmol), N- hydroxybenzotriazole (1.98g, 12.9mmol), triethylamine (2.5ml, 17.99mmol), The reaction was stirred at room temperature until TLC monitoring Completion of the reaction starting material, the reaction solution was added 30ml of water, stirred for 30 minutes, (100ml * 3) and extracted with dichloromethane, and then With a saturated sodium chloride solution (100ml * 2) washing the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, to give: (4- Cyclopropylcarbonyl - piperazin-1-yl) - [4- (4,4,5,5-tetramethyl - [1,3,2] dioxaborolan-2-yl) - phenyl ] - methanone (3.5g, White solid), 61.4% yield, used in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.4% | At room temperature 1-cyclopropane carboxylic acid piperazine (2.37g, 15.37mmol) and p-formyl benzene boronic acid (1.92g, 12.81mmol) Was dissolved in dichloromethane (40ml), stirred for 1 hour at room temperature, again was added sodium cyanoborohydride (1.77g, 28.18mmol), Was stirred at room temperature until the reaction is complete as monitored by TLC, water was added 20ml, extracted with dichloromethane, washed with saturated brine twice, The organic phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, to give: (4-benzyl-acid - piperazin-1-yl) - cyclopropyl - methanone, (1.6 g of, White solid), yield: 43.4%, was used directly in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | A mixture of (S) - 4 - (2-hydroxy-1-phenyl-ethylamine) - 5-methyl-pyrrolo [2,1-f] [1, 2, 4] triazine-6-carboxylic acid (100 mg, 0 . 32mmol) and 1-cyclopropanecarboxylic formyl piperazine (74 mg, 0 . 48mmol) dissolved in N, N-dimethyl formamide (8 ml) in, then add 1-hydroxy benzotriazole (52 mg, 0 . 39mmol), 1-ethyl-3 - (3-dimethylamino-propyl) carbodiimide hydrochloride (74 mg, 0 . 39mmol) and triethylamine (98 mg, 0 . 96mmol), stirring the mixture at room temperature until the TLC reaction monitoring raw material the reaction is complete, to be added in to the reaction solution (100 ml), ethyl acetate (50 ml × 3) extraction, then by saturated sodium chloride solution (100 ml × 2) washing, the organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, the resulting residue is purified with silica gel column chromatography, to obtain (S) - (4-cyclopropyl carbonyl-piperazine-1-yl) - [4 - (2-hydroxy-1-phenyl-ethylamine) - 5-methyl-pyrrolo [2,1-f] [1, 2, 4] triazin-6-yl]-methyl ketone (99 mg, white solid), yield: 69.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | In N,N-dimethyl-formamide; at 20℃; for 20h; | A mixture of 2- [6- (6-fluoro - pyridin-3-yl) - thieno [3,2-d] pyrimidin-4-yl-amine] -2-phenyl - ethanol (110mg, 0.3mmol) and N - cyclopropylcarbonyl piperazine (138mg, 0.9mmol) was dissolved in N, N- dimethylformamide (5ml), and stirred for 20 hours at room temperature, the reaction mixture was added to 200ml of water, with ethyl acetate (100ml * 3 ) was extracted, washed with saturated sodium chloride solution (100ml * 3) washing the organic phase was dried over anhydrous magnesium sulfate filtered, and concentrated under reduced pressure was purified by silica gel column chromatography the residue to give cyclopropyl - (4 - {5- [4- (2-hydroxy-1-phenyl - ethylamine) - thieno [3,2-d] pyrimidin-6-yl] - pyridin-2-yl} - piperazin-1-yl) - methanone (15mg, pale yellow solid), yield: 10%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In dichloromethane; at 0 - 10℃; for 1.5h;Industrial scale; | The active amide intermediate prepared in step 1 was dissolved in 10 ml of methylene chloride,The solution was cooled to 0 to 10 C and then added dropwise to a solution of 1-cyclopropylcarbamoylpiperazine (2.62 g, 17 mmol) and triethylamine (7.1 ml, 51 mmol) in 20 ml of dichloromethane for 1.5 hours at 0 to 10 C , Washed with 30 ml of water 3 times, the organic layer concentrated dry, add ethanol - water mixture (1: 2, v / v) 50 ml,And the filtrate was stirred at 0-5 C for 10 hours. The filtrate was filtered and dried to obtain 6.8 g of orapani. The yield was 92.0% and the purity was 99.87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In methanol; at 0℃; | [0138] To a solution of 37% aq. formaldehyde (15 uL) in MeCH (1 mL) was added 5-chlorobenzoisothiazol-3-one (25 mg, 0.13 mmol) and cyclopropyl(piperazin1-yl)methanone (20 mg, 0.13 mmol). The resulting suspension was stirred for several days, cooled to 0C and resulting precipitate was filtered to give the title compound as a white powder (35.6 mg, 78% yield). 1H NMR (400 MHz, CDCI3) O 8.00 (d, 1 H), 7.59 (dd, 1 H), 7.48 (d, 2H), 4.72 (5, 2H), 3.68 (bds, 4H), 2.73 (bds, 4H), 1.68(m, 1H), 0.96(m, 1H), 0.74(m, 1H). |
Tags: 59878-57-8 synthesis path| 59878-57-8 SDS| 59878-57-8 COA| 59878-57-8 purity| 59878-57-8 application| 59878-57-8 NMR| 59878-57-8 COA| 59878-57-8 structure
[ 1956325-48-6 ]
(3-Aminoazetidin-1-yl)(cyclopropyl)methanone hydrochloride
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[ 27561-62-2 ]
Cyclohexyl(piperazin-1-yl)methanone
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[ 1286207-68-8 ]
(R)-(3-Aminopyrrolidin-1-yl)(cyclopropyl)methanone hydrochloride
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[ 27561-62-2 ]
Cyclohexyl(piperazin-1-yl)methanone
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[ 909409-91-2 ]
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[ 143673-66-9 ]
(R)-3-Isopropylpiperazine-2,5-dione
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3-Isopropylpiperazine-2,5-dione
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[ 1638137-85-5 ]
(S)-1-(3-Methylpiperazin-1-yl)ethanone hydrochloride
Similarity: 0.68
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