Heterocyclic Building Blocks-piperazine

With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.74879-18-8,(S)-(+)-2-Methylpiperazine,as a common compound, the synthetic route is as follows.

In a sealed tube, 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-pyrido[1,2-a]pyrimidin-4-one (Intermediate 2; 33 mg, 0.107 mmol), and (S)-2-methylpiperazine (43 mg, 0.427 mmol, 4.0 eq.) were stirred in DMSO (2 mL) at 120 C. overnight. The solvent was removed under high vacuum. The residue was taken up in CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The organic layer was separated and dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography (SiO2, CH2Cl2/MeOH=95/5 to 90/10) to afford the title product (18 mg, 43%) as a light yellow solid. MS m/z 390.3 [M+H+]., 74879-18-8

The synthetic route of 74879-18-8 has been constantly updated, and we look forward to future research findings.

Reference：
Patent; Hoffmann-La Roche Inc.; PTC Therapeutics, Inc.; Ratni, Hasane; Green, Luke; Weetall, Maria L.; Naryshkin, Nikolai A.; (33 pag.)US2019/315773; (2019); A1;,
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848482-93-9,848482-93-9, (S)-4-(tert-Butoxycarbonyl)piperazine-2-carboxylic acid is a piperazines compound, ?involved in a variety of chemical synthesis. Rlated chemical reaction is continuously updated

To a solution of (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (500 mg, 2.171 mmol) in 1,4-dioxane (5 mL) and water (20 mL) was added potassium carbonate (1200 mg, 8.69 mmol) followed by (9Hfluoren-9-yl)methyl carbonochloridate (562 mg, 2.171 mmol) at 0° C. The mixture was stirred at RT for 18hrs and then treated with water (10 ml). The resulting mixture was extracted with diethyl ether (2×15 ml).The aqueous phase was acidified with aq. HCl (1M) to pH 2-3, and extracted with DCM (3×20 ml). Thecombined organic layers were dried over MgSO4 and concentrated to give the crude product. The crudeproduct was purified via prep HPLC (10-100percent CH3CN:Water with 0.1percent TFA buffer) to afford the product(S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (294 mg,30percent yield) as a white solid. 1H NMR (500 MHz, methanol-d4) d 7.83 (t, J=6.6 Hz, 2H), 7.68-7.58 (m,2H), 7.45-7.38 (m, 2H), 7.38-7.30 (m, 2H), 4.65 (br. s., 1H), 4.58 (d, J=13.7 Hz, 1H), 4.55-4.39 (m, 3H),4.33-4.18 (m, 1H), 2.91-2.85 (m, 4H), 1.47 (s, 9H). ESI-MS(+) m/z=475 (M+Na).

848482-93-9 (S)-4-(tert-Butoxycarbonyl)piperazine-2-carboxylic acid 1501850, apiperazines compound, is more and more widely used in various fields.

Reference：
Patent; Bristol-Myers Squibb Company; Miller, Michael Matthew; Mapelli, Claudio; Allen, Martin Patrick; Bowsher, Michael S.; Boy, Kenneth M.; Gillis, Eric P.; Langley, David R.; Mull, Eric; Poirier, Maude A.; Sanghvi, Nishith; Sun, Li-Qiang; Tenney, Daniel J.; Yeung, Kap-Sun; Zhu, Juliang; Reid, Patrick C.; Scola, Paul Michael; (892 pag.)US9308236; (2016); B2;,
Piperazine – Wikipedia
Piperazines – an overview | ScienceDirect Topics

With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.129799-08-2,1-tert-Butyl 3-methyl piperazine-1,3-dicarboxylate,as a common compound, the synthetic route is as follows.,129799-08-2

To a solution of I-a?ert-butyl 3-methyl piperazine-1,3-dicarboxylate (10.0 g, 70 mmol) in THF(200 mL) was added triethyl amine and benzyl bromide. The mixture was then stined at roomtemperature for 12 hours and concentrated in vacuo. The residue was then diluted with ethylacetate and water. The aqueous layer was discarded and the organic layer was washed once with water, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by silica-gel chromatography (0 – 10 % MeOH in DCM) to afford the desired product.

The synthetic route of 129799-08-2 has been constantly updated, and we look forward to future research findings.

Reference：
Patent; GENENTECH, INC.; CONSTELLATION PHARMACEUTICALS, INC.; ALBRECHT, Brian, K.; COTE, Alexandre; GEHLING, Victor; HSIAO-WEI TSUI, Vickie; KIEFER, James, Richard, Jr.; LIANG, Jun; MAGNUSON, Steven; NASVESCHUK, Christopher, G.; PASTOR, Richard; ROMERO, F. Anthony; TAYLOR, Alexander, M.; ZHANG, Birong; (287 pag.)WO2016/112284; (2016); A1;,
Piperazine – Wikipedia
Piperazines – an overview | ScienceDirect Topics

With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.169447-70-5,(S)-tert-Butyl 2-methylpiperazine-1-carboxylate,as a common compound, the synthetic route is as follows.

[00225] Step 1 : To a solution of 4-fluoronitrobenzene (0.5g, 3.54 mmol) in AcN (30 mL), (S)-tert-butyl 2-methylpiperazine-l-carboxylate (0.71 g, 3.54 mmol) and DIEA (0.74 mL, 4.25 mmol) were added. The mixture was refluxed for 15 h (in a sealed tube). After cooling, the resulting mixture was poured to water (300 ml). The mixture was stirred at room temperature for 30 min. The resulting reaction mixture was extracted with EtOAc (3×30 mL) and anhydrous Na2S04 and concentrated in vacuum. The resulting crude product was purified by Teledyne-Isco flash system by using EtO Ac/Hex, 0 to 30% of ethylacetate in hexane to provide compound tert-butyl (S)-4-(4-nitrophenyl)-2-methylpiperazine-l-carboxylate as light yellow solids (710 mg, 62%) as off white solids. 1H MR (400 MHz, DMSO-d6) delta 8.01 (d, J=9.6Hz, 2H), 6.97 (d, J =9.2Hz, 2H), 3.84 (m, 2H), 2.95-2.50 (m, 4H), 2.40 (m, 1H), 2.30 (br, 1H), 1.00 (d, J=6.0Hz, 3H); ESI-MS: calcd for (C11H15N302) 221, found 222 (MH+)., 169447-70-5

The synthetic route of 169447-70-5 has been constantly updated, and we look forward to future research findings.

Reference：
Patent; NANTBIOSCIENCE, INC.; TAO, Chunlin; POLAT,, Tulay; WEINGARTEN, Paul; NALLAN, Laxman; ARP, Forrest; WANG, Qinwei; HO, David; (129 pag.)WO2016/138527; (2016); A1;,
Piperazine – Wikipedia
Piperazines – an overview | ScienceDirect Topics

122833-04-9, 2-Methoxy-4-(4-methylpiperazin-1-yl)aniline is a piperazines compound, ?involved in a variety of chemical synthesis. Rlated chemical reaction is continuously updated

To a solution of 2-Chloro-4-(3-nitrophenoxy)quinazoline (3, 500 mg , 1.66 mmol) in isopropanol (IPA) (20 mL) was added p-TSA (315 mg, 1.66 mmol) and compound 4 (367 mg, 1.66 mmol). The solution was then stirred at 100 C for 30 min. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated to dryness, diluted with water, and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resultant crude product was purified by columnchromatography using 2-5% CH3OH-DCM to afford N-(2-methoxy-4-(4-methylpiperazin-l -yl) phenyl)-4-(3-nitrophenoxy) quinazolin-2-amine as yellow solid (5, 0.28 g, 34.6 %). NMR (CDClj): delta 8.30-8.10 (m, 3H), 7.80-7.60 (m, 4H), 7.40-7.20 (m, 2H), 6.50 (s, 1 H), 6.40 (bs, 1 H), 3.80 (s, 3H), 3.20-3.00 (m, 4H), 2.70-2.60 (m, 4H), 2.40 (s, 3H).

122833-04-9, The synthetic route of 122833-04-9 has been constantly updated, and we look forward to future research findings.

Reference：
Patent; GATEKEEPER PHARMACEUTICAL, INC.; GRAY, Nathanael, S.; ZHOU, Wenjun; WO2011/79231; (2011); A1;,
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Piperazines – an overview | ScienceDirect Topics

57260-71-6, tert-Butyl piperazine-1-carboxylate is a piperazines compound, ?involved in a variety of chemical synthesis. Rlated chemical reaction is continuously updated

57260-71-6, General procedure: 1-Boc-piperazine (150 mg, 0.81 mmoles) was dissolved in anhydrous DMF (2 mL) and, under stirring, DIPEA (303 mL, 1.78 mmoles), PyBOP (461 mg, 0.89 mmoles) and 2-thiophenecarboxylic acid (114 mg, 0.89 mmoles) were added at room temperature. After complete conversion of 1-Boc-piperazine monitored by TLC analysis, the solution was diluted with DCM and washed with NaOH 0.5M, brine, HCl 0.1M and brine. Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatographic column (eluent DCM/MeOH = 96/4) to obtain 10e (188 mg, 79% yield).

As the paragraph descriping shows that 57260-71-6 is playing an increasingly important role.

Reference：
Article; Giannini, Giuseppe; Battistuzzi, Gianfranco; Vesci, Loredana; Milazzo, Ferdinando M.; De Paolis, Francesca; Barbarino, Marcella; Guglielmi, Mario Berardino; Carollo, Valeria; Gallo, Grazia; Artali, Roberto; Dallavalle, Sabrina; Bioorganic and Medicinal Chemistry Letters; vol. 24; 2; (2014); p. 462 – 466;,
Piperazine – Wikipedia
Piperazines – an overview | ScienceDirect Topics

259808-67-8, 1-Boc-3,3-Dimethylpiperazine is a piperazines compound, ?involved in a variety of chemical synthesis. Rlated chemical reaction is continuously updated

Scheme 6 Step I: tert-Butyl 4-[5-(4-fluorophenyl)-7-isopropyl-furo[3,2-b]pyridine-2-carbonyl]- 3,3-dimethyl-piperazine-1-carboxylate The product was prepared according to General Procedure 1 using Intermediate D (750 mg, 2.51 mmol), HATU (1.24 g, 3.26 mmol), DMF (12 mL), Huenig’s base (1.31 mL, 7.52 mmol) and tert-butyl 3,3-dimethylpiperazine- 1-carboxylate (591 mg, 2.76 mmol) affording the title compound. tert-Butyl 4-[5-(4- fluorophenyl)-7-isopropyl-furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethyl-piperazine-1- carboxylate (1.24 g, 100% yield). An aliquot of the crude product was purified by mass- directed reverse phase HPLC affording the title compound, the remaining product was used in the subsequent step without further purification.1H NMR (400 MHz, DMSO-d6) 8.23 – 8.14 (m, 2H), 7.88 (s, 1H), 7.50 (s, 1H), 7.33 (t, J = 8.9 Hz, 2H), 3.86 (s, 2H), 3.58 – 3.39 (m, 5H), 1.49 (s, 6H), 1.42 (d, J = 7.7 Hz, 15H). ESI-MS m/z calc.495.25333, found 496.79 (M+1)+; Retention time: 2.02 minutes using method C General Procedure 1: Amide Formation The appropriate carboxylic acid (1.0 equiv) is dissolved in DMF or NMP (0.03 to 0.4M) before HATU (1.1 to 1.5 equiv), or T3P (1 to 5 equiv) the corresponding amine (1.0 to 1.5 equiv) and Huenig?s base (3.0 to 5.0 equiv) are added (the addition order of the reagents may vary) The mixture is stirred at room temperature for 45 min. to 72h. Either one of these 3 work-up procedures can be employed: 1. Water or aq. ammonium chloride is added and the aq. phase is extracted with EtOAc. The combined organic phase is washed with brine, dried over MgSO4, filtered and the filtrate evaporated under reduced pressure affording the title compound which is used in the subsequent step without further purification. 2. Water or aq. ammonium chloride is added and the aq. phase is extracted with EtOAc. The combined organic phase is washed with 1N HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered and the filtrate evaporated under reduced pressure affording the title compound which is used in the subsequent step without further purification. 3. The volatiles are removed under reduced pressure and the residue is purified by flash chromatography on silica gel or by mass-directed reverse phase HPLC, affording the title compound, 259808-67-8

The synthetic route of 259808-67-8 has been constantly updated, and we look forward to future research findings.

Reference：
Patent; VERTEX PHARMACEUTICALS INCORPORATED; SAYEGH, Camil Elie; STURINO, Claudio; FOURNIER, Pierre-Andre; LACOSTE, Jean-Eric; DIETRICH, Evelyne; MARTEL, Julien; VALLEE, Frederic; (494 pag.)WO2016/154075; (2016); A1;,
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Piperazines – an overview | ScienceDirect Topics

109-07-9, 2-Methylpiperazine is a piperazines compound, ?involved in a variety of chemical synthesis. Rlated chemical reaction is continuously updated

Thermometer, vacuum stirrer, four-necked flask 2L equipped with acooling tube, L- tartaric acid 270g (1.8 mol), acetic acid 108 g (1.8 mol), water 270g was added,was completely dissolved. Then, (±) -2- methylpiperazine 300g (3.0 mol), water 300g wasadded, and the reaction was heated 85 ° C or more, were completely dissolved. Then cooled to6874 ° C, (R) -2- methylpiperazine and L- diastereomers tartaric was added to precipitatecrystals, allowed to 1 hour aged at that temperature. Then, over a period of 5 hours and cooled to1218 ° C, and the precipitated crystals were filtered, diastereomeric salt 440g of wet biomass,liquid content 22.7wtpercent, optical purity of 92.3percent e. e. , R KaradaOsamuritsu Retrieving salt to theR-isomer of charge (±) in the 2-methyl piperazine, was 88percent. Then, charged 644g of water four-necked flask 2L, the resulting crystals 440g ((R) -2-methylpiperazine pure content = 132 g) were added. Furthermore, the addition of calciumhydroxide 162g (2.2mol), then heated to 80 ° C, and aged at that temperature for 5 hours.Cooled over a period of 2 hours up to 25 ° C, was filtered off precipitated crystals to remove thewet material crystal of 586g (mainly L- tartaric acid calcium). Get the filtrate 660 g, liberated with L- tartaric acid in the filtrate (R) -2- methylpiperazine were present 130 g. Thermometer, vacuum stirrer, four-necked flask 1L with a cooling tube equippedfiltrate 330g obtained in Reference Example 1 (in the filtrate of (R)-2-methyl-piperazine 65 g)was concentrated under reduced pressure, (R ) concentration of 2-methyl piperazine was distilledoff the water until the 30 percent. Then, toluene 356g was added to the concentrate, a mixedsolution was heated under normal pressure and azeotroped with water and toluene in arms 84 to87 ° C, excluding the water. Then, toluene was distilled off 212g under reduced pressure. Theconcentrate was cooled to 47 ° C, (R) -2- methylpiperazine 0.01g was added as a seed crystal toprecipitate crystals, followed by aging for 1 hour at 47 ° C. Was cooled over 5 hours 05 ° C,and aged for 2 hours at 06 ° C. The precipitated crystals were taken out by filtration underreduced pressure, vacuum drying, the crystalline body (R) -2- methylpiperazine was 45gacquired. The resulting quality of (R) -2- methylpiperazine of the crystal body, chemical purity of100percent, an optical purity of 99.5percent e. e. In and, R KaradaOsamuritsu acquisition crystals for (R) -2-methylpiperazine in charge filtrate was 69percent. 1, illustrating the steps from Reference Example 1 to Example 1. Was the first crystallizationfrom ( “1 crystallization” was described as) (described as “crystallization”) last crystallization upto six steps. Compared to the Comparative Example 2 step, short process, was able to get a goodoptically active 2-methylpiperazine of easy nature of handling. Thermometer, vacuum stirrer, four-necked flask 1L with a cooling tube equippedfiltrate 330g obtained in Reference Example 1 (in the filtrate of (R)-2-methyl-piperazine 65 g)was concentrated under reduced pressure, (R ) concentration of 2-methyl piperazine was distilledoff the water until the 30 percent. Then, cyclopentyl methyl ether 356g added to theconcentrated solution, mixed solution was heated to normal pressure and azeotroped water andcyclopentyl methyl ether at 8487 ° C, except for the water. It was then distilled off cyclopentylmethyl ether 205g under reduced pressure. The concentrate was cooled to 47 ° C, (R) -2-methylpiperazine 0.01g was added as a seed crystal to precipitate crystals, followed by aging for1 hour at 47 ° C. Was cooled over 5 hours 05 ° C, and aged for 2 hours at 06 ° C. Theprecipitated crystals were taken out by filtration under reduced pressure, vacuum drying, thecrystalline body (R) -2- methylpiperazine was 44g acquired. The resulting quality of (R) -2-methylpiperazine of the crystal body, chemical purity of 100percent, an optical purity of 99.6percent e. e. Inand, R KaradaOsamuritsu acquisition crystals for (R) -2- methylpiperazine in charge filtrate was 68percent. Thermometer, vacuum stirrer, four-necked flask 1L equipped with a Dean-Starkapparatus, 33percent (S) -2- methylpiperazine solution 300.0g ((S) -2- methylpiperazine 100.0 g,Quality: Chemistry purity 99.9percent, optical purity of 80.0percent e.e. ) Were charged. Then stirred withtoluene 586.0g (5.86wt times / (S) -2- methylpiperazine). The solution was heated under normalpressure, arms 84 to 87 ° was azeotroped with water and toluene in C, except for water only.Then, toluene was distilled off 286g under reduced pressure. The concentrate was cooled to4350 ° C, (S) -2-methylpiperazine 0.01g was added as a seed crystal to precipitate crystals,followed by aging for 1 hour at 4350 ° C. Then it cooled over 2 hours to 0 to 5 ° C, and agedfor 2 hours at 05 ° C. The precipitated crystals were taken out by filtration under reducedpressure, vacuum drying, the crystalline body (S)-2-methylpiperazine 66.8g was obtained (…, 109-07-9

109-07-9 2-Methylpiperazine 66057, apiperazines compound, is more and more widely used in various fields.

Reference：
Patent; TORAY FINE CHEMICALS COMPANY LIMITED; MORII, SEIJI; NISHIKAWA, TAKESHI; (12 pag.)JP2016/37495; (2016); A;,
Piperazine – Wikipedia
Piperazines – an overview | ScienceDirect Topics

With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.112257-12-2,tert-Butyl 4-(2-bromoacetyl)piperazine-1-carboxylate,as a common compound, the synthetic route is as follows.

Commercially available 4-nitroimidazole (0.55 g, 4.9 mmol) was dissolved in 2 mL of freshly distilled DMF, under N2, and cooled to 0 C. Sodium hydride (0.14 g, 5.9 mmol) was added to the reaction and stirred for 30 min before a dropwise addition of tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (1.50 g, 4.9 mmol) dissolvedin 2 mL of DMF. The mixture was slowly warmed to room temperature and stirred overnight. Addition of 10 mL of water caused a white precipitate to form. The solid was filtered and dried under reduced pressure overnight to afford tert-butyl 4-(2-(4-nitro-1H-imidazol-1-yl)acetyl)piperazine-1-carboxylate 8b (1.26 g, 3.7 mmol,76%); mp: 197-199 C. 1H NMR (400 MHz, CDCl3) delta 7.82-7.81 (d,J 1.5 Hz, 1H), 7.45-7.44 (d, J 1.4 Hz, 1H), 4.86 (s, 2H), 3.65-3.63(m, 2H), 3.56-3.54 (m, 2H), 3.50-3.47 (m, 4H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) delta 163.1, 154.6, 148.2, 137.1, 120.9, 81.1, 48.8, 45.0,42.5, 28.5; HRMS (ESI-TOF): [M+H]+ Calc’d for C14H22N5O5 m/z 340.1621. Found, m/z 340.1607.

112257-12-2, 112257-12-2 tert-Butyl 4-(2-bromoacetyl)piperazine-1-carboxylate 15829155, apiperazines compound, is more and more widely used in various fields.

Reference：
Article; Abuteen, Akram; Zhou, Feifei; Dietz, Christopher; Mohammad, Innus; Smith, Michael B.; Zhu, Quing; Dyes and Pigments; vol. 126; (2016); p. 251 – 260;,
Piperazine – Wikipedia
Piperazines – an overview | ScienceDirect Topics

414910-15-9, tert-Butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate is a piperazines compound, ?involved in a variety of chemical synthesis. Rlated chemical reaction is continuously updated

Example 17BCyclopropyl(piperazin- 1 -yl)methanone hydrochloride[00524] To a stirred mixture of compound ter/-butyl 4-(cyclopropanecarbonyl)piperazine- 1 -carboxylate (3.7 g, 14.5 mmol) in methanol (15 mL) was added hydrochloride/methanol (15 mL, 3M)) at 0 C. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was concentrated to give cyclopropyl(piperazin- 1 -yl)methanone hydrochloride (2.74 g, yield 100%) as an off- white solid. ^-NMR (400 MHz, DMSO-i/6) delta (ppm): 0.71-0.76 (m, 4H), 1.96-2.03 (m, 1H), 3.04-3.16 (m, 4H), 3.69-4.08 (m, 4H), 9.58 (s, 2H); LC-MS (ESI) m/z: 155(M+1)+., 414910-15-9

The synthetic route of 414910-15-9 has been constantly updated, and we look forward to future research findings.

Reference：
Patent; BIOMARIN PHARMACEUTICAL INC.; WANG, Bing; CHU, Daniel; WO2011/130661; (2011); A1;,
Piperazine – Wikipedia
Piperazines – an overview | ScienceDirect Topics