Garigipati脒合成反应

三甲基铝和氯化铵反应得到MeAlClNH2，其和腈反应得到脒。

Adamantane amidine hydrochloride (5). Cold Me3Al 1 (25 mL, 50 mmol) in PhMe was added gradually with stirring to a suspension of NH4Cl 2 (2.9 g, 54 mmol) in dry PhMe (20 mL) at 5 C under N2. The mixture was warmed to r.t. and stirred for 2 h until CH4 evolution stopped, the cyano adamantane 4 (4.83 g, 30 mmol) was added in 10 mL PhMe and the mixture was heated to 80 C under Ar for 18 h (TLC). The mixture was poured into a slurry of SiO2 (15 g) and CHCl3 (50 mL) and after 5 min silica was filtered and washed with MeOH and the combined solvents were concentrated to 15 mL. NH4Cl was filtered off and MeOH/HCl (10 mL, conc 2 g, 54 mmol) followed by Et2O (400 mL)

was added. After 10 h of stirring, filtration provided 5.8 g of crude 5. Recrystallization (4:1 iPrOH: Me2CO) afforded 4.1 g of 5 (64%), mp 257–259 C.

【Moss RA, Tet Lett., 1995, 36, 8761】

14.5 mL (29 mmol) of trimethyl aluminum (2.0 M toluene solution) was dropwise added to a 20 mL of toluene containing 1.55 g (28.9 mmol) of ammonium chloride at room temperature. After stirring for 1.5 hours, 2 g (28.9mmol) of isobutironitrile was added thereto and the resulting mixture was heated to 85°C for 9 hours. After completion of a reaction, the reaction solution was poured into 200 mL of chloroform containing 500 g of silicagel and filtered. The residue was washed with 200 mL of methanol and distillation was conducted to give 2.3 g (26.7 mmol) of the title compound in a yield of 92percent. Mass(EI) 87(M++.)

【Patent： LG LIFE SCIENCES, LTD.; WO2006/104356; (2006); (A1) English】

相关文献

1 Neinreb SM Syn Comm 1982 12 989

2 Garigipati RS Tet Lett 1990 31 1969

3 Moss RA Tet Lett 1995 36 8761

4 Dabak H Turk J Chem 2002 26 547

5 Gielen H Tet Lett 2002 43 419

编译自：Organic Syntheses Based On Name Reactions, 3RdEd, A. Hassner, Page 175.

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由腈制备脒

脒类化合物，是重要的药物中间体，甚至本身就是常见的药物，如三氮脒，头孢硫脒等。由脒合成嘧啶环是合成嘧啶最重要的方法。

由腈合成脒，主要分为碱性条件和酸性条件。碱性条件常见的有醇钠，LiHMDS。酸性条件有盐酸气，三甲基铝，N-乙酰基半胱氨酸，酰氯等等。常见的氨源有，氯化铵，碳酸铵，碳酸氢铵，醋酸铵，氨气，LiHMDS等等。

反应实例

1、LiHMDS条件实例【Patent; MERCK PATENT GMBH; WO2006/94604; (2006); (A1) English】

to a 50 mL dry reaction flask charged with 1 M LiHMDS in THF (22 mmol), p- chlorobenzonitrile (2.76 g, 20.0mmol) in 2 mL of THF is added, and the reaction mixture is kept stirring at RT for 4 h, at which point 5-6 N HCI (in/PrOH, 15 mL) is added. The crude reaction mixture is kept at 0oC overnight.The precipitated product is filtered, washed with diethyl ether to yield 3.5 g (93percent) of the compound of formula 2b as a white solid, m.p. 238 oC (litm.p. 243-245oC) (E. Ragona, D. L. Nelson, M. Mares-Guis, J. Amer. Chem. Soc. EPO 1975, 97, 6844-6848). - IR (KBr): nu(tilde) = 3239 crrf1, 3054, 1678, 1460, 1401 , 1036, 715. - 1H NMR (250 MHz, [D6]DMSO): δ = 7.60-7.77 (m, 2 H), 7.85-7.97 (m, 2 H), 8.4 (br. s, 3 H, NH). - 13C NMR (62.9 MHz, [D6]DMSO), δ = 126.79

(Cquat), 129.36 (+), 130.57 (+), 139.1 (Cquat), 165.1 (NCN).

2、甲醇钠条件下反应【Patent; NEUROCRINE BIOSCIENCES, INC.; LABORATORIOS ALMIRALL, S. A.; WO2008/70661; (2008); (A1)English】

To a solution of sodium methoxide (5.55 mmol) in methanol (50 mL) was added 2- furonitrile (5.0 g, 53.2 mmol, leq.). The mixture was stirred at room temperature for 3 hours. To the resulting solution was slowly added ammonium chloride (3.14 g, 58.7 mmol, l.leq.) and the mixture was stirred at room temperature for 68 hours. The resulting suspension was filtered and the solvent removed under reduced pressure. The solid obtained was washed with ethyl ether (3x25 mL) to give 7.5 g (96percent yield) of 2- furancarboxamidine (HCl). δ (200 MHz, DMSO-d6):6.88-6.86 (m, IH); 7.89 (d, J=3.8 Hz, IH); 8.19 (s, IH); 9.22 (s, 3H).

3、盐酸气条件下反应【Patent; MEGAFINE PHARMA (P) LTD.; MATHAD, Vijayavitthal Thippannachar; SOLANKI, Pavankumar Vrajlal; UPPELLI, Sekhar Babu; SARODE, Ganesh Gitaram; WO2015/128875; (2015); (A2) English】

100 gm(0.207 mol) Ethyl3 - { [(2- { [(4-cyanophenyl)amino]methyl } - i-methyl-i Hbenzimidazol-5 -yl)carbonylj(pyridin-2-yl)amino} propanoate was added to 500 ml ethanolic hydrochloride solution having HCl content between 34 to 36 at temperature not more than 35°C. Upon domplete addition reaction mixture was stirred for 10-15 mm. and temperature of reaction was raised to 38-42°C. Completion of reaction was monitored by HPLC. Reaction mixture was

then cooled to 25-30oC and diluted with 1500 ml ethanol. reaction mixture was then cooled to 0-5°C and was purged with ammonia gas till to achieve neutral pH. To the reaction mixture was added 75 gm ammonium carbonate and reaction mixture was warmed to 28-32°C and stirred for 10-12 hr. completion of reaction was monitored by HPLC. Reaction mixture was filtered and the residue was washed with ethanol 500 ml. combined filtrate was concentrated under vacuum to obtain residue. To the obtained residue was added 500 ml ethanol and 1000 ml ethyl acetate. Mixture was refluxed for 30 mm. and then cooled to 25-30°C. precipitated product was stirred for 60 mm. at 25-30°C and then filtered and dried at 40-45°C to obtain crude Ethyl3-{[(2-{[(4- {carbamimidoyl } phenyl)amino]methyl} -1-methyl-i H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino } propanoate.Yield: l00g (96.61percent); Purity by HPLC: 95.3 percent.

4、N-乙酰基半胱氨酸条件【Patent; Shandong Luoxin Pharmaceutical Co., Ltd.; Zhao, Jinlong; Yu, Defeng; Zhang, Guijie; (15 pag.);CN105669651; (2016); (A) Chinese】

In four flask equipped with a mechanical stirrer, thermometer, reflux condenser. take For bromoxynil 36.4g (0.2mol) was poured into a beaker, add 100ml of absolute ethanol, stirring to dissolve completely; then weighed 32.4g N- acetylcysteine (0.2mol), into another beaker was then added 150ml of absolute ethanol, stirring the mixture to complete dissolution, then a solution of ethanol will bromoxynil and N- acetylcysteine ethanol solution was poured into four flask, stirred and heated to 45 The reaction 20h . Weigh 8.6g ammonium carbamate (0.11 mol), was slowly added portionwise to a 4-neck flask, 20h, after complete dissolution the reaction, the reactionAfter completion of standing 48h, suction filtered, the filter cake was washed with ethanol, and drying, a white solid product was obtained 38g of bromobenzene formamidine (Compound ), yield 95.4percent, HPLC purity was 99.6percent.

【Patent; CIPLA LIMITED; KING, Lawrence; RAO, Dharmaraj Ramachandra; MALHOTRA, Geena; PULLELA, Venkata Srinivas; ACHARYA, Vinod Parameshwaran; SINARE, Sudam Nanabhau; (43 pag.); WO2016/27077；(2016); (A1) English】

Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N- (pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (ll)using N-acetyl cysteine 10 g (0.020 mol) of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH- benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) was dissolved in 600 ml EtOH.NH3 (15-18percentw/w) and stirred at 25°C. Added 3.38 g (0.020 mol) of N-acetyl

cysteine to the reaction mass and stirred for 24 hours at 70-75°C under 2.0-2.3 kg of pressure. The ethanol was distilled under vacuum and residue was purified by column. Yield: 5.5 g Efficiency: 53percent

【Patent; Inghardt, Tord; Johansson, Anders; Svensson, Arne; US2004/19033; (2004); (A1) English】

A solution of Boc-Aze-NH-CH2-((5-cyano)-2-pyrimidinyl) (0.83 g, 2.6 mmol; see step (iv) above), N-acetylcysteine (0.43 g, 2.6 mmol) and ammonium acetate (0.60 g, 7.8 mmol) in 10 mL of methanol was heated at 60° C. under nitrogen for 2 days. The solvent was evaporated and the crude material was purified by preparative RPLC using a gradient of CH3CN: 0.1M NH4OAc (5:95 to 100:0).

The fractions of interest were freeze dried to give 1.0 g (93percent) of the desired material.

1H NMR (300 MHz, D2O, signals obscured by the HDO signal) δ9. 17 (s, 2H), 4.1-3.9 (m, 2H), 2.60 (m, 1H), 2.29 (m,1H), 1.93 (s, 3H), 1.44 (s, 9H)

5、三甲基铝条件下反应【Patent： LG LIFE SCIENCES, LTD.; WO2006/104356; (2006); (A1) English】

14.5 mL (29 mmol) of trimethyl aluminum (2.0 M toluene solution) was dropwise added to a 20 mL of toluene containing 1.55 g (28.9 mmol) of ammonium chloride at room temperature. After stirring for 1.5 hours, 2 g (28.9mmol) of isobutironitrile was added thereto and the resulting mixture was heated to 85°C for 9 hours. After completion of a reaction, the reaction solution was poured into 200 mL of chloroform containing 500 g of silicagel and filtered. The residue was washed with 200 mL of methanol and distillation was conducted to give 2.3 g (26.7 mmol) of the title compound in a yield of 92percent. Mass(EI) 87(M++.)

6、乙酰氯条件【Patent; GLAXO GROUP LIMITED; JIN, Yun; WAN, Zehong; ZHANG, Qing; WO2012/76435; (2012); (A1) English】

To a solution of 3-(3-bromo-4-fluorophenyl)propanenitrile (5.0 g, 21.05 mmol) in toluene (20 mL) and methanol (6.32 mL, 156 mmol) at 0°C was added acetyl chloride (7.51 mL, 105 mmol) dropwise over 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was cooled to 0°C by an ice bath, to which ammonia (30.1 mL, 210 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated to give a crude product. Recrystallization from toluene/methanol (1: 1) then afforded the title compound

as a white solid (5.2 g, 93 percent yield). [M+H+] =245