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Example 9 Procedure for preparation of (R)-l-amino-N-(l-cyano-2-(4'-((4-propylpiperazin-l-yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide (PZ1047)Reaction schemeThe preparation of PZ1047-1: A mixture of piperazine (19.4 g, 100 mmol), Et3N (5.05 g, 50 mmol) and 1-bromopropane (6.15 g, 50 mmol) in EtOH (100 ml) was heated to reflux overnight. TLC showed the reaction was almost complete. EtOH was removed under reduced pressure. The residue was dissolved in H20 and extracted with DCM. The combined organic phase was dried over Na2S04 and concentrated in vacuo to give PZ1047-1 (10 g, 100%) as yellow oil.
Specific examples of the compounds of the formula (6) are given below. 1-Methylpiperazine, 1-ethylpiperazine, 1-propylpiperazine, 1-isopropylpiperazine, 1-butylpiperazine, 1-isobutylpiperazine, 1-sec-butylpiperazine.
By the procedure of Example 3, using in place of morpholine, the following compounds: ... N-methylpiperazine N-ethylpiperazine N-propylpiperazine N-butylpiperazine
Example 17 4-Amino-2-(4-n-propyl-1-piperazinyl)-5-(2,3,5-trichloro phenyl)pyrimidine dimesylate N-propylpiperazine dihydrobromide (Lancaster 5g) in water (15ml) was passed into an ion exchange column (IR410 OH form) (BDH) and eluted with water. The secondary amine positive element was concentrated, dissolved in diethylether, dried (MgSO4) and evaporated to dryness to give N-propylpiperazine as a colourless oil (0.6g).
By the procedure of Example 1, using in place of morpholine the following 1-lower alkylpiperazines: 1-ethylpiperazine 1-propylpiperazine 1-butylpiperazine
By the procedure of Example 2, using the following 1-lower alkylpiperazines in place of dimethylamine: 1-methylpiperazine 1-ethylpiperazine 1-propylpiperazine 1-butylpiperazine
Similarly, using in place of N-methylpiperazine the following lower alkylpiperazines: N-ethylpiperazine N-propylpiperazine N-butylpiperazine
32
1-<4-chloro-benzyl>-4-propyl-piperazine dihydrobromide[ No CAS ]
5-oxo-2-[2-oxo-3-(2-oxo-4-phenyl-oxazolidin-3-yl)-4-styryl-azetidin-1-yl]-5-(4-propyl-piperazin-1-yl)-pentanoic acid 3-trifluoromethyl-benzylamide[ No CAS ]
2-(1H-indol-4-yl)-4-morpholin-4-yl-6-(4-propyl-piperazin-1-ylmethyl)-thieno[3,2-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In N,N-dimethyl-formamide; at 20℃;Product distribution / selectivity;
Methanesulfonic acid 2-(lH-indol-4-yl)-4~morpholin~4-yl-thieno[3,2- d]pyrimidin-6-ylmethyl ester, amine and triethylamine were mixed together in DMF and stirred at room temperature. When the reaction was judged to be complete, the solvent was removed under reduced pressure, the residue dissolved in DMSO and purified by preparative HPLC. The chromatographic solvents were removed under reduced pressure to afford the product > 85% purity.
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; diethyl ether;
EXAMPLE 1 1-(4-Chloro-3-trifluoromethyl-phenyl)-4-propyl-piperazine A mixture o f <strong>[445-01-2]5-bromo-2-chlorobenzotrifluoride</strong> (0.2 g, 0.85 mmol), n-propyl piperazine (0.15 g, 1.17 mmol), sodium tert-butoxide (0.134 g) dppf (14 mg) and [Pd2(dba)3 (10 mg) in dioxane (5 ml) was heated under argon at 100 C. for 24 h. After cooling to roomtemperature, the reaction mixture was taken up in Et2O (40-50 ml) and washed with brine (15-20 ml). The organic fraction was dried (MgSO4), filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel using CH2Cl2:MeOH (9:1 (v/v)). The amine was converted into the HCl-salt and recrystallized from ethanol/diethylether; m.p. 268 C. (HCl); MS m/z (rel. intensity, 70 eV)) 307 (M+, 6), 279 (33), 277 (98), 70 (bp), 56 (40). Rf=0.35 (EtOAc)
5-Oxo-5-(4-propylpiperazin-1-yl)pentanoic acid may be obtained in the following manner: 1.5 g of glutaric anhydride and then 1.66 g of N-propylpiperazine in solution in 5 cm3of dioxane are added to 10 cm3 of dioxane in a round-bottomed flask kept under an argon atmosphere. After stirring for 2.5 hours at room temperature, the solvent is evaporated under reduced pressure and then the resulting oil is supplemented with 100 cm3 of diethyl ether. After stirring for one hour, the solid obtained is filtered, dried at 20 C. (90 Pa) to give 2.47 g of 5-oxo-5-(4-propylpiperazin-1-yl)pentanoic acid in the form of a white solid which is used as it is.
6-Chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(4-propyl-1-piperazinyl)imidazo[1,5-a]quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6-Chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(4-propyl-1-piperazinyl)imidazo[1,5-a]quinazoline (Compound 56), m.p. 186-188 C., from 5,6-dichloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a]quinazoline and <strong>[21867-64-1]1-propylpiperazine</strong>;
4-hydroxy-5-(4-propylpiperazinylmethyl)-1,3-benzodioxole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With formaldehyd; In acetonitrile;
a) 4-hydroxy-5-(4-propylpiperazinylmethyl)-1,3-benzodioxole Aqueous formaldehyde (37%; 3.67 g, 45.3 mmol) was added dropwise to a stirred solution of 4-hydroxy-1,3-benzodioxole (5.2 g, 37.8 mmol) and N-propylpiperazine (5.8 g, 45.3 mmol) in acetonitrile (25 ml). The reaction mixture was stirred at room temperature for one hour and evaporated in vacuo. The remaining oil (13.0 g) was purified chromatographically (with ethylacetate/methanol=9/1 (v/v) as an eluent to give 4-hydroxy-5-(4-propylpiperazinylmethyl)-1,3-benzodioxole (5.9 g, 56% yield; compound No. 25), m.p. 115-117 C.
EXAMPLE 16 8-chloro-10,11-dihydro-10-[(4-propyl-1-piperazinyl)carbonyl]dibenz[b,f][1,4]oxazepine STR23 By the methods of Example 14, ethyl 1-piperazinecarboxylate was reacted with the methanesulfonate of n-propanol and the product, ethyl 4-propyl-1-piperazinecarboxylate, was converted to 1-propylpiperazine.
Example 16 8-chloro-10,11-dihydro-10-[(4-propyl-1-piperazinyl)carbonyl]dibenz[b,f][1,4]oxazepine STR23 By the methods of Example 14, ethyl 1-piperazinecarboxylate was reacted with the methanesulfonate of n-propanol and the product, ethyl 4-propyl-1-piperazinecarboxylate, was converted to 1-propylpiperazine.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 100℃; for 16h;
2. 4-[6-(3-Chloro-4-fluoro-phenyl)-2-(4-propyl-piperazin-l-yl)-pyrimidin-4-yl]-piperazine-l-carboxylic acid tert-butyl ester; Fi.CIHeat a solution of 4-[2-chloro-6-(3-chloro-4-fluoro-phenyl)-pyrimidin-4-yl]-piperazine-l-carboxylic acid tert-butyl ester (2.5 g, 5.9 mmol), N-propylpiperazine (5.9 mmol) and DIEA (11.7 mmol) in DMA at 100C for 16 h. Cool, partition between 10% NaOH and EtOAc and wash the organic layer with additional NaOH solution (3x). Dry the organic layer (Na2SO4) and concentrate under reduced pressure to afford the title compound.
9-Bromo-6-(4-n-propyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.20 g (30%)
With sodium hydroxide;titanium tetrachloride; In ethyl acetate; toluene;
EXAMPLE 18 9-Bromo-6-(4-n-propyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine A stirred mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1200 ml of toluene was heated until a solution resulted. Then there was added 32.1 g (0.25 mole) of N-propylpiperazine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was refluxed for 3 hours, and then cooled to room temperature. The mixture was stirred with 500 ml of 2N sodium hydroxide solution for 15 minutes and the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, filtered, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated to an oily solid. The oily solid was dissolved in 25 ml of hot ethyl acetate, filtered, and allowed to crystallize first at room temperature, then at 0 C. to yield 3.20 g (30%) of product, mp 134-136 C. ANALYSIS: Calculated for C22 H25 BrN4: 62.12%C 5.92%H 13.17%N. Found: 61.84%C 5.81%H 12.82%N.
1-chloro-2-[(2-hydroxyethoxy)-(4-fluorophenyl)-methyl]benzene methanesulfonate[ No CAS ]
1-[2-[(2-Chlorophenyl)-(4-fluorophenyl)-methoxy]ethyl]-4-propylpiperazine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(a) 1-[2-[(2-Chlorophenyl)-(4-fluorophenyl)-methoxy]ethyl]-4-propylpiperazine dihydrochloride, m.p.; 213-214 C., is prepared by reacting 1-chloro-2-[(2-hydroxyethoxy)-(4-fluorophenyl)-methyl]benzene methanesulfonate with 1-propyl-piperazine. Analysis: Calculated for C22 H28 ClFN2 O (base): C 67.59; H 7.22; Cl 9.07; F 4.86; N 7.17%; found: C 67.66; H 7.38; Cl 9.24; F 5.03; N 7.40%.
b. p-(4-Propyl-1-piperazinyl)acetophenone. A mixture of 33.2 g. of p-fluoroacetophenone, 48.3 g. of N-propylpiperazine and 99.5 g. of potassium carbonate in 100 ml. of dimethyl sulfoxide is stirred and heated at 95 for 4.5 hours, then cooled and poured into ice water. The precipitate of p-(4-propyl-1-piperazinyl)-acetophenone is collected by filtration, washed with water and dried; m.p. 68-70 after crystallization from hexane.
With potassium carbonate; In dimethyl sulfoxide;
b. p-(4-Propyl-1-piperazinyl)acetophenone. A mixture of 33.2 g. of p-fluoroacetophenone, 48.3 g. of N-propylpiperazine and 99.5 g. of potassium carbonate in 100 ml. of dimethyl sulfoxide is stirred and heated at 95 for 4.5 hours, then cooled and poured into ice water. The precipitate of p-(4-propyl-1-piperazinyl)acetophenone is collected by filtration, washed with water and dried; m.p. 68-70 after crystallization from hexane.
EXAMPLE 3 Preparation of the hydrobromic acid salt of 3-dimethylamino-5-(4-propylpiperazin-1-yl)-1,2,4-dithiazolium bromide 12 Parts of N-propylpiperazin in 50 parts of acetone was added dropwise to a solution of 14.2 parts of dimethylthiocarbamoyl isothiocyanate in 100 parts of acetone at 10-15 C. The solution was allowed to warm to room temperature, stirred for 2 hours, filtered, and evaporated under reduced pressure to remove the acetone therefrom. The resulting crude dithiobiuret intermediate was added to 50 parts of a 10% sodium hydroxide solution. The resulting solution was washed twice with 50 parts of chloroform and neutralized with glacial acetic acid. The solution was then extracted twice with 50 parts of methylene chloride. The organic extracts were dried, filterd, and evaporated under reduced pressure to afford the intermediate dithiobiuret as a viscous oil.
EXAMPLE XIII 2-(4'-Propyl-piperazino)-5-oxo-8 -ethyl-5,8-dihydro-pyrido-(2,3-d)pyrimidine-6-carboxylic acid. SPC20 As described in Example XII, the condensation of 2.8 g of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine with 2.2 g of 1-propyl-piperazine, in chloroform (40 cm3) gives, after the treatments described in Example XII. 3.14 g of 2-(4'-propyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido-(2,3-d)pyrimidine (yield 84%); melting point 149C, after recrystallisation from ethyl acetate. Analysis for C19 H27 N5 O3 (molecular weight 373.45): Calculated %: C, 61.10; H, 7.29; N, 18.75. Found %; C, 61.50; H, 7.22; N, 18.91.
EXAMPLE 14 4-(4-n-Propylpiperazine-1-yl)-3-sulfamoylbenzoic acid The reaction was carried out in a manner analogous to that of Example 1, using 150 ml of N-n-propylpiperazine instead of the N-methylpiperazine. The crystalline crude product was purified by boiling with a 2:1 mixture of ethanol and dimethylformamide, in which the final product was only difficultly soluble in the hot state. Yield: 75 g (40% of the theory), degradation point: 305 C.
Example 113 (4S)-1-[4-(1H-indol-5-yl)-3-[3-(4-propyl-1-piperazinyl)propoxy]benzoyl]-4-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was obtained by the same procedure as in Example 57 using the compound in Reference Example 191 and N-propylpiperazine (yield: 67.4%).
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