* 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.
Reference：
[1] Journal of the Chemical Society, 1909, vol. 95, p. 705
2
[ 1558-81-2 ]
[ 598-10-7 ]
Reference：
[1] Journal of the Chemical Society, 1929, p. 1478
[2] Journal of the Chemical Society, 1899, vol. 75, p. 928
3
[ 1558-81-2 ]
[ 598-10-7 ]
[ 6914-75-6 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1939, vol. 9, p. 356[2] Chem. Zentralbl., 1939, vol. 110, # II, p. 2913
4
[ 1558-81-2 ]
[ 1559-02-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1906, vol. <3> 35, p. 41
5
[ 7647-01-0 ]
[ 64-17-5 ]
[ 1558-81-2 ]
[ 1559-02-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1906, vol. <3> 35, p. 41
6
[ 7647-01-0 ]
[ 64-17-5 ]
[ 1558-81-2 ]
[ 18719-42-1 ]
[ 1559-02-0 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1939, vol. 9, p. 356[2] Chem. Zentralbl., 1939, vol. 110, # II, p. 2913
7
[ 106-93-4 ]
[ 105-56-6 ]
[ 1558-81-2 ]
Yield
Reaction Conditions
Operation in experiment
72%
With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 80℃;
A suspension of cyano-acetic acid ethyl ester (11.3 g, 0.1 mol), 1,2-Dibromo-ethane, Na4(n-Bu)4Br and K2CO3 in DMF (100 mL) was heated to 80° C. overnight. The mixture was poured into water (600 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether: EtOAc=10:15:1) to give 1-cyano-cyclopropanecarboxylic acid ethyl ester (10 g, yield: 72percent). 1H NMR (CDCl3 400 MHz): δ4.21 (q, J=7.2 Hz, 2H), 1.65-1.61 (m, 2H), 1.58-1.55 (m, 2H), 1.28 (t, J=7.2 Hz, 3H)
14.2 g
With potassium carbonate In acetone for 12 h; Reflux
(1) Synthesis of ethyl 1-cyanocyclopropanecarboxylate To a solution of ethyl cyanoacetate (11.8 g) in acetone (83.0 mL), potassium carbonate (43.1 g) and 1,2-dibromoethane (39.2 g) were added and the mixture was refluxed for 12 hours. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure and further dried under reduced pressure with heating to give ethyl 1-cyanocyclopropanecarboxylate as a red oil (14.2 g). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.1 Hz, 3 H) 1.57 - 1.62 (m, 2 H) 1.73 - 1.79 (m, 2 H) 4.19 (q, J=7.1 Hz, 2 H).
5 g
With potassium carbonate In acetoneReflux
Description 85Ethyl 1-cyanocyclopropanecarboxylate (P85)NTo the mixture of ethyl 2-cyanoacetate (5 g) and potassium carbonate (18.33 g) in acetone (20 mL)was added 1 ,2-dibromoethane (9.96 g) over a period of 10 mm. The reaction mixture was heated toreflux overnight. More 1 ,2-dibromoethane (9.96 g) was added and the reaction mixture was refluxed for another 2 hours. The reaction mixture was filtered through a pad of Celite and the cake was rinsed with aetone (20 mL). The combined filtrate was concentrated under reduced pressure to give the title compound (5 g) as orange oil. MS (ESI): C7H9N02 requires 139; found 140 [M+H].
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1983, vol. 19, p. 474 - 480[2] Zhurnal Organicheskoi Khimii, 1983, vol. 19, # 3, p. 541 - 548
[3] Synthetic Communications, 1996, vol. 26, # 3, p. 525 - 530
[4] Tetrahedron Letters, 2005, vol. 46, # 4, p. 635 - 638
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 2, p. 420 - 422
[6] Tetrahedron, 1995, vol. 51, # 3, p. 865 - 870
[7] Patent: US2014/107340, 2014, A1, . Location in patent: Paragraph 0100
[8] Beilstein Journal of Organic Chemistry, 2010, vol. 6,
[9] Macromolecules, 2005, vol. 38, # 11, p. 4588 - 4594
[10] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1988, vol. 27, p. 530 - 536
[11] Journal of the Chemical Society, 1899, vol. 75, p. 928
[12] Bulletin de la Societe Chimique de France, 1906, vol. <3> 35, p. 41
[13] Journal of the American Chemical Society, 1922, vol. 44, p. 415
[14] Journal of the Chemical Society, 1910, vol. 97, p. 1002
[15] Journal of the Chemical Society, 1899, vol. 75, p. 928
[16] Journal of the American Chemical Society, 1984, vol. 106, # 18, p. 5335 - 5348
[17] Russian Chemical Bulletin, 1994, vol. 43, # 1, p. 84 - 88[18] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1994, # 1, p. 89 - 93
[19] Patent: WO2006/28545, 2006, A2, . Location in patent: Page/Page column 162
[20] Patent: US2007/219196, 2007, A1, . Location in patent: Page/Page column 73
[21] Patent: WO2011/17561, 2011, A1, . Location in patent: Page/Page column 64
[22] Russian Chemical Bulletin, 2014, vol. 63, # 2, p. 409 - 415[23] Izvestiya Akademii Nauk. Seriya Khimicheskaya, 2014, vol. 2, p. 409 - 415,7
[24] Patent: EP2881384, 2015, A1, . Location in patent: Paragraph 0289; 0290
[25] Patent: WO2015/180612, 2015, A1, . Location in patent: Page/Page column 66
8
[ 107-04-0 ]
[ 105-56-6 ]
[ 1558-81-2 ]
Yield
Reaction Conditions
Operation in experiment
59.6%
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
To a stirred mixture of compound CXI-5 (30 g, 0.265 mol), l-bromo-2- chloroethane (75 g, 0.528 mol) in DMF (200 mL) was added K2C03 (110 g, 0.8 mol). The reaction mixture was heated to 80°C overnight. The mixture was diluted with ice water, extracted with hexane, washed with water and brine, dried over Na2S04, filtered and concentrated. The residue was main compound CXI-6 (22 g, yield 59.6percent) and used directly.
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 3.2, p. 631 - 633[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 3, p. 710 - 712
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 3.2, p. 631 - 633[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 3, p. 710 - 712
[5] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3784 - 3788
[6] Synthesis, 1987, # 8, p. 738 - 739
[7] Russian Chemical Bulletin, 1994, vol. 43, # 1, p. 84 - 88[8] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1994, # 1, p. 89 - 93
[9] Asian Journal of Chemistry, 2012, vol. 24, # 7, p. 3016 - 3018
[10] Asian Journal of Chemistry, 2012, vol. 24, # 4, p. 1571 - 1574
[11] Asian Journal of Chemistry, 2012, vol. 24, # 11, p. 5087 - 5089
10
[ 64648-13-1 ]
[ 105-56-6 ]
[ 1558-81-2 ]
Reference：
[1] Organic Preparations and Procedures International, 1992, vol. 24, # 5, p. 548 - 552
Reference：
[1] Journal of Fluorine Chemistry, 2000, vol. 104, # 2, p. 297 - 301
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3784 - 3788
[3] Asian Journal of Chemistry, 2012, vol. 24, # 4, p. 1571 - 1574
[4] Asian Journal of Chemistry, 2012, vol. 24, # 11, p. 5087 - 5089
[5] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1988, vol. 27, p. 530 - 536
[6] Journal of the Chemical Society, 1899, vol. 75, p. 928
[7] Bulletin de la Societe Chimique de France, 1906, vol. <3> 35, p. 41
[8] Asian Journal of Chemistry, 2012, vol. 24, # 7, p. 3016 - 3018
14
[ 1558-81-2 ]
[ 98730-77-9 ]
Yield
Reaction Conditions
Operation in experiment
65%
With lithium borohydride In tetrahydrofuran at 50℃; for 18 h;
LiBH4 (573 mg, 26.3 mmol, 2 eq) was added to ethyl-1 -cyanocyclopropane carboxylate (1 .7 ml_, 13.15 mmol, 1 eq.) in THF (18 ml_) and the mixture was heated to 50 °C for 18 h. The reaction was cooled to 0 °C and NaHC03 (sat'd aq) was added until gas evolution ceased. The mixture was diluted with brine (20 mL) and extracted with EtOAc (1 x 60 ml_), DCM (3 x 60 mL) and 10percent MeOH/DCM (2 x 60 ml_). The organic extracts were combined, dried (MgS04) and the solvent removed in vacuo to give the title compound as a clear oil (820 mg, 65percent); H NMR (500 MHz; CDCI3): 0.96-1 .01 (2H, m), 1 .27-1 .31 (2H, m), 3.64 (2H, s).
1.3 g
With methanol; sodium tetrahydroborate In 1,2-dimethoxyethane at 20℃; for 18 h;
Description 861-(Ilydroxymethyl)cyclopropanecarbonitrile (P86)To a mixture of ethyl 1 -cyanocyclopropanecarboxylate (D85, 4 g) in dimethoxyethane (80 mL) and methanol (8 mL) was added sodium borohydride (115 mrnol). The mixture was stirred at RT for 18hours. The solution was diluted with saturated NaHCO3 aqueous solution (100 mL) and then extracted with 10percent MeOH / DCM (3 xl 00 mE). The combined organic layer was dried over anhydrous sodium sulfate, seperated and concentrated under vacuum to afford the title compound (1.3 g) as pale brown oil. 111 NMR (400 MHz, DMSO-d6): 5.30 (t, J= 6.0 Hz, 1H), 3.39 (d, J= 5.8 Hz, 2H), 1.17-1.12 (m, 2H), 0.94-0.90 (m, 2H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 6, p. 1797 - 1801
[2] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 19, p. 8922 - 8931
[3] Patent: WO2017/55860, 2017, A1, . Location in patent: Page/Page column 183; 184
[4] Patent: WO2005/63247, 2005, A1, . Location in patent: Page/Page column 78
[5] Patent: WO2010/25179, 2010, A1, . Location in patent: Page/Page column 22
[6] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 151-152
[7] Patent: WO2015/180612, 2015, A1, . Location in patent: Page/Page column 66
[8] Patent: WO2016/97918, 2016, A1, . Location in patent: Page/Page column 94
[9] Journal of the American Chemical Society, 2017, vol. 139, # 36, p. 12398 - 12401
[10] Patent: US2009/264416, 2009, A1, . Location in patent: Page/Page column 17
[11] Patent: WO2009/24550, 2009, A1, . Location in patent: Page/Page column 30
poly(ethyl 1-cyanocyclopropanecarboxylate), degree of polymerization 41; monomer(s): ethyl 1-cyanocyclopropanecarboxylate; sodium thiophenolate[ No CAS ]
poly(ethyl 1-cyanocyclopropanecarboxylate), degree of polymerization 41; monomer(s): ethyl 1-cyanocyclopropanecarboxylate; sodium thiophenolate[ No CAS ]
[ 1558-81-2 ]
poly(ethyl 1-cyanocyclopropanecarboxylate), degree of polymerization 102; monomer(s): ethyl 1-cyanocyclopropanecarboxylate; sodium thiophenolate[ No CAS ]
With pyridine; sodium hypophosphite hydrate; acetic acid; In water; at 0℃;Inert atmosphere;
To a stirred mixture of 70 mL of pyridine/acetic acid/water (1/1/1) was added compound CXI-6 (crude from above procedure) and NaH2P02 (10 eq.) at 0C. The reaction mixture was flushed with N2 and to it was added Raney Ni (5 g). The reaction was stirred at room temperature for lh. The mixture was diluted with ice-water, extracted with hexane, washed with water and brine, dried over Na2S04, filtered and concentrated. The residue was main compound CXI-7 and used directly.
With hydrogen;platinum(IV) oxide; In methanol; under 2585.81 Torr; for 2h;
A solution of <strong>[1558-81-2]1-cyano-cyclopropanecarboxylic acid ethyl ester</strong> (1.0 g, 7.18 mmol), concentrated hydrochloric acid (1.5 mL), and platinum oxide (0.20 g) in methanol (50 mL) was pressurized with 50 psi of hydrogen for 2 hr. The heterogeneous mixture was filtered through Celite and concentrated to give the desired amine as a hydrochloride salt (1.26 g, 97%). MS found: (M+H)+=144
With hydrogenchloride; hydrogen;platinum(IV) oxide; In ethanol; under 2068.65 Torr; for 20h;
Concentrated hydrochloric acid (25 mL) and platinum oxide (0.98 g) were added to a solution of the material from Part A in ethanol (225 mL). The mixture was placed under hydrogen pressure (40 psi, 2.8 X lO5 Pa) on a Parr apparatus for 20 hours. The reaction mixture was filtered through a layer of CELITE filter aid. The filter cake was rinsed with methanol (200 mL). The filtrate was concentrated under reduced pressure. The residue was reconcentrated under reduced pressure three times from methanol and twice from toluene to provide 31.7 g of ethyl 1-aminomethylcyclopropionate hydrochloride
With hydrogenchloride; hydrogen;platinum(IV) oxide; In ethanol; water; under 2068.65 Torr; for 20h;
Platinum (IV) oxide (0.98 g) and concentrated hydrochloric acid (25 mL) were added to a solution of the material from Part A in ethanol (225 mL), and the mixture was placed under hydrogen pressure (40 psi, 2.8*105 Pa) on a Parr apparatus and shaken for 20 hours and then filtered through a layer of CELITE filter agent. The filter cake was washed with methanol (200 mL), and the combined filtrates were concentrated under reduced pressure. The residue was three times dissolved in methanol and concentrated and then twice dissolved in toluene and concentrated to afford ethyl 1-(aminomethyl)cyclopropanecarboxylate hydrochloride as a thick, pale yellow oil.
(2) Synthesis of the titled compound To a solution in ethanol (127mL) of the compound (14.0 g) obtained in step (1) above, a Raney nickel catalyst (about 2.8 g) was added. In a hydrogen atmosphere, the mixture was stirred at room temperature for 12 hours and further stirred at 40C for 12 hours. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. The resulting precipitate was recovered by filtration and washed with ethanol. The filtrate was concentrated to give the titled compound as a red oil (13.4 g). 1H NMR (300 MHz, DMSO-d6) delta ppm 0.82 - 0.88 (m, 2 H) 0.98 - 1.04 (m, 2 H) 1.13 - 1.21 (m, 3 H) 2.63 - 2.72 (m, 2 H) 4.00 - 4.10 (m, 2 H).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;
To a stirred mixture of compound CXI-5 (30 g, 0.265 mol), l-bromo-2- chloroethane (75 g, 0.528 mol) in DMF (200 mL) was added K2C03 (110 g, 0.8 mol). The reaction mixture was heated to 80C overnight. The mixture was diluted with ice water, extracted with hexane, washed with water and brine, dried over Na2S04, filtered and concentrated. The residue was main compound CXI-6 (22 g, yield 59.6%) and used directly.
With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; at 20 - 50℃;
[0536] (Z)-ethyl 1-(N?-hydroxycarbamimidoyl)cyclopropanecarboxylate (72a): Sodium hydroxide (0.33 g, 8.26 mmol) and hydroxylamine hydrochloride (0.55 g, 7.91 mmol) were stirred in EtOH (7.19 mL, 1 M) at r.t. for 2 h. The mixture was filtered through a fine frit and ethyl 1-cyano-1-cyclorpropanecarboxylate (1.0 g, 7.19 mmol) was added and the reaction heated to 50 C overnight. The mixture was then cooled to r.t., evaporated to a white solid, and immediately purified by flash chromatography. 46%. White solid. Rf = 0.37 (75% EtOAc in hexanes). 1H NMR (300 MHz, CDCI3) 6 5.01 (s, 2H), 4.11 (q, 7.1, 2H), 1.37 (dd, J = 4.2, 7.2, 2H), 1.29 (dd, J = 4.0, 7.1, 2H), 1.20 (t, J = 7.1, 3H). 13C NMR (75 MHz, CDCI3) 6 172.40, 152.34, 61.41, 25.02, 15.65, 14.11.
1-(1-methyl-1H-pyrazol-3-yl)-2-oxopyrrolidine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
237 mg
at 120℃; for 30h;
A) To a solution of 1-methyl-1H-pyrazol-3-amine (223 mg) in cyclopentyl methyl ether (5.0 mL) was added ethyl 1-cyanocyclopropanecarboxylate (0.90 ml). The reaction mixture was stirred at 120 C. for 30 hr, and diluted with ethyl acetate. The diluted solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (237 mg). MS (ESI+): [M+H]+190.8.
(S)-N-(5-chloro-3-((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)-2-methylphenyl)-2-((1-cyanocyclopropyl)methoxy)acetamide trifluoroacetate[ No CAS ]
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