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[ CAS No. 50-01-1 ]

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CAS No. :50-01-1 MDL No. :MFCD00013026
Formula : CH6ClN3 Boiling Point : -
Linear Structure Formula :- InChI Key :N/A
M.W :95.53 g/mol Pubchem ID :5742
Synonyms :

Safety of [ 50-01-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319 Packing Group:N/A
GHS Pictogram:

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  • Downstream synthetic route of [ 50-01-1 ]

[ 50-01-1 ] Synthesis Path-Upstream   1~52

  • 1
  • [ 156667-51-5 ]
  • [ 58243-08-6 ]
  • [ 50-01-1 ]
  • [ 156-81-0 ]
Reference: [1] Patent: US5521192, 1996, A,
  • 2
  • [ 2032-34-0 ]
  • [ 50-01-1 ]
  • [ 156-81-0 ]
Reference: [1] Journal of the American Chemical Society, 1950, vol. 72, p. 2587,2593
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 1, p. 240 - 253
  • 3
  • [ 50-01-1 ]
  • [ 1679-40-9 ]
  • [ 1193-74-4 ]
Reference: [1] European Journal of Organic Chemistry, 2017, vol. 2017, # 29, p. 4247 - 4254
  • 4
  • [ 1118-61-2 ]
  • [ 50-01-1 ]
  • [ 1791-73-7 ]
YieldReaction ConditionsOperation in experiment
10.5 g
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: at 110℃; for 10 h; Inert atmosphere
2,4-Diamino-6-methylpyrimidine was synthesized in accordance with the process described in Aust. J. Chem., 1984, vol. 37, pp. 1195-1201. (0362) Guanidine hydrochloride (23.8 g) was added to methanol (50 mL) and a solution of sodium methoxide in 28percent methanol (51 mL), followed by stirring at room temperature for 30 minutes. Subsequently, the precipitated salt was removed by filtration, followed by concentration under reduced pressure to give a guanidine-free product solution. Then, 3-amino crotononitrile (16.4 g) and 1-butanol (60 mL) were added to the solution. The reaction solution was stirred with heating at 110° C. for 10 hours under a nitrogen gas flow. After completion of the reaction, the precipitated salt was removed by hot filtration, and 100 mL of acetone was added to the remaining solution, followed by stirring under ice cooling for 30 minutes to give a crude product. The crude product was recrystallized from acetone to yield 10.5 g of 2,4-diamino-6-methylpyrimidine. (0363) Methyl benzoate (23 g: 169 mmol) and sodium methoxide (22 g: 407 mmol) were added to a solution of 2,4-diamino-6-methylpyrimidine (10 g: 81 mmol) in N-ethylpyrrolidone (100 mL), followed by stirring with heating at 40° C. for 2 hours. The temperature of the reaction system was decreased to room temperature. The reaction solution was poured into a 1N aqueous hydrochloric acid solution, and the solid component was collected by filtration. The crude product was recrystallized from 2-propanol to yield compound (1-2). (0364) The NMR spectrum of produced compound (1-2) is as follows. (0365) 1H-NMR (solvent: d6-DMSO, standard: tetramethylsilane) δ (ppm) 2.50 (3H, s) 7.45-7.70 (6H, m) 7.90 (1H, s) 7.95-8.05 (4H, m) 10.88 (1H, s) 11.10 (1H, s)
Reference: [1] Australian Journal of Chemistry, 1984, vol. 37, # 6, p. 1195 - 1201
[2] Patent: US2016/159750, 2016, A1, . Location in patent: Paragraph 0361-0365
  • 5
  • [ 50-01-1 ]
  • [ 70807-22-6 ]
  • [ 1791-73-7 ]
Reference: [1] Organic Process Research and Development, 2013, vol. 17, # 3, p. 427 - 431
  • 6
  • [ 3959-05-5 ]
  • [ 50-01-1 ]
  • [ 1687-51-0 ]
YieldReaction ConditionsOperation in experiment
68%
Stage #1: With potassium carbonate; copper(I) bromide In dimethyl sulfoxide at 120℃; for 24 h; Inert atmosphere; Schlenk technique
Stage #2: at 120℃; for 0.5 h; Schlenk technique
General procedure: A 25 mL Schlenk tube wascharged with a magnetic stirrer and DMSO (2.0 mL). Substituted(2-bromophenyl)methylamine (1) (0.5 mmol), amidine hydrochloride (2) (1.0 mmol),CuBr (0.1 mmol, 14.2 mg), and K2CO3 (1.5 mmol, 207 mg) were added to the tube.The mixture was stirred at 80-120 oC under nitrogen atmosphere for 24 h, and thenunder air for 0.5 h. The resulting mixture was cooled to room temperature and filtered,and the solid was washed with ethyl acetate for two times (3 × 3 mL). The combinedfiltrate was concentrated by the rotary evaporator, and the residue was purified bycolumn chromatography on silica gel using petroleum ether/ ethyl acetate as eluent togive the desired target product.
Reference: [1] Synlett, 2013, vol. 24, # 16, p. 2089 - 2094
  • 7
  • [ 50-01-1 ]
  • [ 6630-33-7 ]
  • [ 1687-51-0 ]
Reference: [1] Synthesis, 2009, # 16, p. 2679 - 2688
  • 8
  • [ 50-01-1 ]
  • [ 109-77-3 ]
  • [ 1004-38-2 ]
Reference: [1] Australian Journal of Chemistry, 2007, vol. 60, # 2, p. 120 - 123
  • 9
  • [ 7424-91-1 ]
  • [ 107-31-3 ]
  • [ 50-01-1 ]
  • [ 3167-50-8 ]
YieldReaction ConditionsOperation in experiment
65%
Stage #1: With sodium methylate In 1,4-dioxane; methanolReflux; Large scale
Stage #2: Large scale
Stage #3: Large scale
1 kg of methyl 3,3-dimethoxypropanoate was dissolved in 7 L of 1 ,4-dioxane. 1 .58 kg of sodium methoxide solution (30 wpercent in methanol) were added. The mixture was heated to reflux, and ap. 4.9 kg of distillate were removed. The resulting suspension was cooled to r.t., and 0.5 kg of methyl formate was added. The reaction mixture was stirred overnight, then 0.71 kg of guanidine hydrochloride was added, and the reaction mixture was stirred at r.t. for 2 h. The reaction mixture was then heated to reflux, and stirred for 2 h. 13.5 L of water were added, followed by 0.72 kg of aqueous sodium hydroxide solution (45 wpercent). The reaction mixture was heated at reflux for additional 0.5 h, and then cooled to 50°C. 0.92 kg of aqueous hydrochloric acid (25 wpercent) were added until pH 6 was reached. Seeding crystals were added, and additional 0.84 kg of aqueous hydrochloric acid (25 wpercent) were added at 50 until pH 2 was reached. The mixture was cooled to 20 and stirred overnight. The suspension was filtered, the collected solids washed twice with water, then twice with methanol, yielding 0.61 kg (65percent).
Reference: [1] Patent: WO2016/71426, 2016, A1, . Location in patent: Page/Page column 36; 37
  • 10
  • [ 50-01-1 ]
  • [ 105-56-6 ]
  • [ 100643-27-4 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 1, p. 318 - 324
[2] Australian Journal of Chemistry, 2007, vol. 60, # 2, p. 120 - 123
  • 11
  • [ 2042-37-7 ]
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  • [ 1899-48-5 ]
Reference: [1] Synlett, 2010, # 1, p. 101 - 106
  • 12
  • [ 50-01-1 ]
  • [ 123-06-8 ]
  • [ 16462-27-4 ]
YieldReaction ConditionsOperation in experiment
79%
Stage #1: for 0.166667 - 0.25 h; Reflux
Stage #2: at 20℃; for 8 h;
To the freshly prepared sodium ethoxide [sodium (0.83 g, 36 mmol) in 20 ml absolute ethanol] solution; guanidine hydrochloride (3.1 g, 32.8 mmol) was added and the reaction mixture was heated to reflux for 10-15 min, the clear solution immediately turned turbid white. The solution was filtered and washed with 10 mL absolute ethanol and the filtrate with combined washings was used further. To the filtrate, ethoxymethylene malononitrile (4 g, 32.8 mmol) was added in portions and the reaction mixture stirred for 8 h at room temperature, after which it was concentrated to dryness and the obtained residue was dissolved in glacial acetic acid at reflux temperature. On cooling yellow crystals started precipitating out. The product was filtered, washed with diethyl ether (2x20mL) and then dried to yield of 2, 4-diaminopyrimidine-5-carbonitrile (3.5 g, 79percent) as yellow solid.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 7, p. 2428 - 2433
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 1, p. 240 - 253
[3] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5652 - 5661
  • 13
  • [ 502164-18-3 ]
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  • [ 2164-66-1 ]
YieldReaction ConditionsOperation in experiment
60% With triethylamine In propiononitrile at 100℃; for 4 h; Triethylamine (29mL, 210mmol) was added to a suspension of methyl 4-butoxy-2-oxo-3-butenate (37g, 200mmol,) and guanidine hydrochloride (23 g, 240 mmol) in propionitrile (50mL), and the mixture was stirred for 4 hours at 100°C.
The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 18g as the mixture of the title Reference Compound and the butyl ester form of the title Reference compound as a gray-white solid (Yield: 60percent).
1H-NMR (500MHz, DMSO-d6)
δ 3.85(s,3H),6.99-7.06(m,3H),8.48(d,J = 4.8 Hz,1H)
Reference: [1] Patent: EP1864977, 2007, A1, . Location in patent: Page/Page column 16
  • 14
  • [ 50-01-1 ]
  • [ 1683-85-8 ]
Reference: [1] Tetrahedron Letters, 1995, vol. 36, # l, p. 1527 - 1530
  • 15
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  • [ 1683-85-8 ]
Reference: [1] Chemistry Letters, 1995, # 3, p. 239 - 240
  • 16
  • [ 128229-03-8 ]
  • [ 50-01-1 ]
  • [ 109-89-7 ]
  • [ 1683-85-8 ]
Reference: [1] Tetrahedron Letters, 1995, vol. 36, # l, p. 1527 - 1530
  • 17
  • [ 3510-99-4 ]
  • [ 50-01-1 ]
  • [ 3977-29-5 ]
YieldReaction ConditionsOperation in experiment
62.1% at 100℃; for 3 h; Added to the mixture obtained in step a)Amount of anhydrous methanol dissolved,Into guanidine hydrochloride 95.5g (1mol)Heated to 100 reflux 3h,The mixture of solvents evaporated to dryness,Add the right amount of distilled water to just dissolve,Let cool to room temperature,With 1mol / L dilute hydrochloric acid to adjust the PH value to 6.5,A solid precipitation, suction filtration,Rinse with deionized water,The resulting wet finished product is at a temperature of 60 ° CVacuum drying oven available 12h availableAbout 77.7 g of 2-amino-4-hydroxy-6-methylpyrimidine.The product is 2-amino-4-hydroxy-6-methylpyrimidine,Purity of 99percentYield 62.1percent
Reference: [1] Patent: CN107188856, 2017, A, . Location in patent: Paragraph 0025; 0026; 0027; 0028; 0029; 0034-0039
  • 18
  • [ 50-01-1 ]
  • [ 141-97-9 ]
  • [ 3977-29-5 ]
Reference: [1] Bioorganic Chemistry, 2018, vol. 78, p. 258 - 268
  • 19
  • [ 50-01-1 ]
  • [ 105-45-3 ]
  • [ 3977-29-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2429 - 2439
  • 20
  • [ 50-01-1 ]
  • [ 133-13-1 ]
  • [ 30201-72-0 ]
YieldReaction ConditionsOperation in experiment
88%
Stage #1: With sodium In ethanol at 20℃; for 4 h; Inert atmosphere
Stage #2: for 1 h; Inert atmosphere; Reflux
General procedure: Metallic sodium (12.9 g, 0.56 mol) was dissolved in absolute ethanol (300 mL) under argon while being intensively stirred with a mechanical stirrer. The reaction flask was equipped with a reflux condenser with a chlorocalcium tube. After all the sodium was dissolved and the reaction mixture was cooled to room temperature; guanidine hydrochloride(21.02 g, 0.22 mol) was added under intensive stirring, followed by the corresponding monosubstituted malonic acid diester (0.2 mol). The reaction mixture was further intensively stirred due to the production of the solid product,which is so massive that after 2 h it already practically precludes stirring. After another 2 h, absolute ethanol (200 mL) was added and the reaction mixture was refluxed for 1 h while being stirred. Afterward, ethanol (ca200–300 mL) was evaporated on a vacuum rotary evaporatorand water (500 mL) was added to the reaction mixture. After stirring, the product (in the form of sodium salt) was almost dissolved. The obtained mixture was subsequently neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the desired product in the form of a fine solid. This mixture was subsequently heated under reflux for 10 min and then cooled to laboratory temperature. This heating and cooling was repeated twice to get a well-filterable solid product. The solid product was filtered off, washed with water (2 x 50 mL),ethanol (2 x 50 mL), and acetone (2 x 50 mL). The product was dried under high vacuum at 60 °C for 2 days. The obtained purity of the product prepared in this manner is sufficient for the following reaction and based on analyses contains only crystalline water.
88% With sodium In ethanolInert atmosphere General procedure: Metallic sodium (12.9 g, 0.56 mol) was dissolved in absolute ethanol (300 mL) under argon while being intensively stirred with a mechanical stirrer. The reaction flask was equipped with a reflux condenser with a chlorocalcium tube. After all the sodium was dissolved and the reaction mixture was cooled to room temperature; guanidine hydrochloride (21.02 g, 0.22 mol) was added under intensive stirring, followed by the corresponding monosubstituted malonicacid diester (0.2 mol). The reaction mixture was further intensively stirred due to the production of the solid product, which is so massive that after 2 h it already practically precludes stirring. After another 2 h, absolute ethanol (200 mL) was added and the reaction mixture was refluxed for 1 h while being stirred. Afterward, ethanol (ca 200–300 mL) was evaporated on a vacuum rotary evaporator and water (500 mL) was added to the reaction mixture. After stirring, the product (in the form of sodium salt) was almost dissolved. The obtained mixture was subsequently neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the desired product in the form of a fine solid. This mixture was subsequently heated under reflux for 10 min and then cooled to laboratory temperature. This heating and cooling was repeated twice to get a well-filterable solid product. The solid product was filtered off, washed with water (2 9 50 mL), ethanol (2 9 50 mL), and acetone (2 9 50 mL). The product was dried under high vacuum at 60 °C for 2 days. The obtained purity of the product prepared in this manner is sufficient for the following reaction and based on analyses contains only crystalline water.
Reference: [1] Medicinal Chemistry Research, 2014, vol. 23, # 10, p. 4482 - 4490
[2] Medicinal Chemistry Research, 2014, vol. 23, # 10, p. 4482 - 4490
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  • [ 16075-42-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 1, p. 35 - 38
[2] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 2, p. 509 - 513
  • 22
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  • [ 50-01-1 ]
  • [ 16075-42-6 ]
Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1991, vol. 27, # 4, p. 398 - 406[2] Khimiya Geterotsiklicheskikh Soedinenii, 1991, # 4, p. 502 - 511
  • 23
  • [ 56-23-5 ]
  • [ 127099-85-8 ]
  • [ 67-72-1 ]
  • [ 50-01-1 ]
Reference: [1] Journal of the American Chemical Society, 1965, vol. 87, p. 3088
[2] , Gmelin Handbook: C: MVol.D2, 4.1.2.7.4.2, page 222 - 225,
[3] Diss. Univ. of Florida 1966, 103 S., [4] Diss. Abstr. B, 1967, vol. 28, p. 1444
  • 24
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  • [ 50-01-1 ]
Reference: [1] Patent: US9874568, 2018, B2,
  • 25
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  • [ 50-01-1 ]
Reference: [1] Journal of the American Chemical Society, [2] Journal of the American Chemical Society, 1922, vol. 44, p. 2342 - 2352
[3] J. Soc. Chem. Ind. (London), 1929, vol. 40, p. T109 - T112
[4] , Gmelin Handbook: C: MVol.D1, 24.9.4.1, page 289 - 290,
  • 26
  • [ 57-13-6 ]
  • [ 50-01-1 ]
Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 18, p. 358
  • 27
  • [ 57-13-6 ]
  • [ 50-01-1 ]
Reference: [1] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1961, vol. 34, p. 1973 - 1977[2] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1961, vol. 34, p. 2079 - 2084
[3] , Gmelin Handbook: C: MVol.D1, 45.8.4.3.1, page 418 - 418,
  • 28
  • [ 56-23-5 ]
  • [ 7664-41-7 ]
  • [ 50-01-1 ]
Reference: [1] Ber. Dtsch. Chem. Ges., 1914, vol. 47, p. 903 - 913
[2] , Gmelin Handbook: C: MVol.D1, 49.1.7, page 469 - 470,
  • 29
  • [ 593-85-1 ]
  • [ 50-01-1 ]
Reference: [1] Zeitschrift fur Anorganische und Allgemeine Chemie, 2018, vol. 644, # 5, p. 280 - 287
  • 30
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  • [ 7664-41-7 ]
  • [ 57-13-6 ]
  • [ 50-01-1 ]
Reference: [1] , Gmelin Handbook: C: MVol.D1, 49.1.2, page 466 - 467,
[2] Patent: DE527237, 1931, ,
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 18, p. 358
  • 31
  • [ 64-17-5 ]
  • [ 420-04-2 ]
  • [ 50-01-1 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1868, vol. 146, p. 259
  • 32
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  • [ 31407-74-6 ]
  • [ 50-01-1 ]
Reference: [1] Chemische Berichte, 1917, vol. 50, p. 234
  • 33
  • [ 1674-62-0 ]
  • [ 420-04-2 ]
  • [ 471-29-4 ]
  • [ 50-01-1 ]
  • [ 4674-68-4 ]
Reference: [1] Nippon Kagaku Kaishi, 1944, vol. 65, p. 271,279[2] Chem.Abstr., 1947, p. 3763
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  • [ 120747-84-4 ]
YieldReaction ConditionsOperation in experiment
41% With sodium ethanolate In ethanol at 90℃; for 12 h; Preparation 3: Step 1: To a mixture of dialdehyde 19 (900 mg, 7.1 [MMOL)] and guanidine hydrochloride (678 mg, 7.1 [MMOL)] in absolute EtOH (20 ml) was added sodium ethoxide (483 mg, 7.1 [MMOL).] The reaction mixture was heated at 90 °C for 12 h, cooled to RT, concentrated-dry loaded on silica gel and flash chromatographed [(0-] 10percent [CH30H/20-30percent ACETONE/CH2CI2)] to produce 20 (355 mg, 2.9 mmol ; 41 percent) as a yellowish solid. Alternatively, 20 can be prepared according to the procedure described in JP Patent 63227573.
41% With sodium ethanolate In ethanol at 90℃; for 12 h; To a mixture of 900 mg (7.1 mmol) of dialdehyde 66 and 678 mg (7.1 mmol) of guanidine hydrochloride in 20 mL of absolute ethanol was added 483 mg (7.1 mmol) of sodium ethoxide. Reaction mixture was heated at 900C for 12 h, cooled to room temperature, concentrated-dry loaded on silica gel and flash chromatographed (0-10percent MeOH/ 20-30percent acetone/ CH2Cl2) to produce 355 mg (2.9 mmol; 41percent) of 67 as a yellowish solid.
Reference: [1] Patent: WO2004/831, 2003, A1, . Location in patent: Page 20
[2] Patent: WO2008/108957, 2008, A2, . Location in patent: Page/Page column 53
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YieldReaction ConditionsOperation in experiment
34% With sodium In ethanol for 21 h; Reflux Sodium (1.2 g, 52 mmol) was dissolved in anhydrous ethanol (45 mL). To this freshly prepared solution was added methanetricarbaldehyde (14, 4.8 g, 47.96 mmol) and guanidine hydrochloride (5.5 g, 57.55 mmol). The resulting solution was stirred at room temperature for 1 hour and then refluxed for 20 hours. The solvent was evaporated and the residue was taken up in water (100 mL) and acidified to pH 1 by slow addition of 2N HCI. The acidic aqueous solution was neutralized by drop-wise addition of saturated aqueous sodium bicarbonate and was extracted by ethyl acetate (3 x 50 mL) Combined organic layers were washed with water, brine, dried over sodium sulfate andconcentrated under vacuo to afford 2-aminopyrimidine-5-carbaldehyde (15) as ayellowish solid. Yield: 2 g (34percent). 1H NMR (400 MHz, DMSO-d6) O 9.71 (5, 1H), 8.69 (5,2H), 7.77 (br s, 2H). GCMS [mlz]: 123.0
Reference: [1] Heterocycles, 1990, vol. 31, # 6, p. 1105 - 1109
[2] Bulletin de la Societe Chimique de France, 1990, # 5, p. 660 - 666
[3] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 973 - 976
[4] Patent: WO2016/193844, 2016, A1, . Location in patent: Page/Page column 103; 104
  • 36
  • [ 54551-83-6 ]
  • [ 50-01-1 ]
  • [ 29110-48-3 ]
YieldReaction ConditionsOperation in experiment
15% at 20℃; for 30 h; A solution of methyl 2-(2,6-dichlorophenyl)acetate (75 mg, 0.26 mmol) in ethanol (3 mL) was added to a solution of guanidine hydrochloride (25 mg, 0.26 mmol) and sodium ethoxide (6.0 mg of sodium in 2 mL methanol).
The resulting solution was stirred at room temp for 30 h.
The reaction mixture was evaporated and extracted with chloroform/water.
The organic layer was mixed with ethanolic solution to get product as hydrochloric salt.
White Solid (15 mg, 15percent).
1H NMR (dmso-d6, 600 MHz) δ 12.18 (s, 1H), 8.40 (br s, 2H), 8.18 (br s, 2H), 7.51 (d, 2H, J=8.2 Hz), 7.38 (t, 1H, J=7.6 Hz), 4.13 (s, 2H).
13C NMR (150 MHz, dmso-d6) δ 170.91, 154.88, 135.92, 130.67, 130.58, 128.74, 39.34. ESI-HRMS Calc m/z for C9H10Cl2N3O 246.0195 (M+H)+, found 246.0200. HPLC 96.56percent purity tR=19.17 min.
Reference: [1] Patent: US2018/230105, 2018, A1, . Location in patent: Paragraph 0538; 0539
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  • [ 50-01-1 ]
  • [ 17168-45-5 ]
  • [ 206564-00-3 ]
YieldReaction ConditionsOperation in experiment
86% With potassium carbonate In DMF (N,N-dimethyl-formamide) at 100℃; for 21 h; A suspension of 3-(dimethylamino)-1-(2-furyl)-2-propen-1-one (5.0 g, 30.3 mmol), guanidine hydrochloride (5.8 g, 60.7 mmol) and potassium carbonate (8.4 g, 60.9 mmol) in N, N-dimethylformamide (50 ml) was stirred at 100°C for 21 hours. After cooling as it was, the reaction mixture was diluted with ice water (250 ml). The resulting solid was collected by filtration and washed with water, to give the title compound (4.19 g, 86percent) as a pale brown solid.1H NMR (400 MHz, DMSO-d6) δ ppm; 6.66 (2H, br s), 6.68 (1H, dd, J = 2.0, 3.2 Hz), 6.88 (1H, d, J = 5.2 Hz), 7.17 (1H, dd, J = 0.8, 3.2 Hz), 7.88 (1H, dd, J = 0.8, 2.0 Hz), 8.28 (1H, d, J = 5.2 Hz); MS m/e (ESI) 162 (MH+).
Reference: [1] Patent: EP1439175, 2004, A1, . Location in patent: Page 46
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  • [ 206564-00-3 ]
Reference: [1] Green Chemistry, 2011, vol. 13, # 11, p. 3238 - 3247
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  • [ 219511-71-4 ]
YieldReaction ConditionsOperation in experiment
91%
Stage #1: With sodium hydroxide In water at 0℃; for 0.166667 h;
Stage #2: at 0 - 27℃; for 15 h;
a) BOC-guanidine BOC-guanidine was synthesised in accordance with Ando et al., Tetrahedron (2010), 66(32), 6224-6237: 22.93 g (0.24 mol) of guanidinium chloride are added to the solution of 19.2 g (0.48 mol) of sodium hydroxide pellets in 50 ml of water at 0° C. The solution is left to stir for 10 min., a solution of 13.1 g (60 mmol) of di-tert-butyl dicarbonate in 150 ml of acetone is then added in one portion at 0° C., and the reaction mixture is then left to stir at room temperature for 15 hours. The acetone is subsequently stripped off in vacuo, and the aqueous mixture is extracted twice with 50 ml of ethyl acetate. The combined organic phases are washed with 50 ml of saturated sodium chloride solution and dried over sodium sulfate. After the solvent has been stripped off, the residue is recrystallised from ethyl acetate/n-heptane, giving 8.7 g (91percent) of BOC-guanidine as white crystals. EI−MS (M+): 159
Reference: [1] European Journal of Organic Chemistry, 2008, # 2, p. 324 - 329
[2] Patent: US2015/361037, 2015, A1, . Location in patent: Paragraph 0232; 0233
[3] Tetrahedron Letters, 2007, vol. 48, # 39, p. 6996 - 6999
[4] Organic and Biomolecular Chemistry, 2012, vol. 10, # 25, p. 4899 - 4906
[5] Chemical Communications, 2008, # 3, p. 344 - 346
[6] Angewandte Chemie, International Edition, 2009, vol. 48, # 36, p. 6722 - 6725[7] Angewandte Chemie, 2009, vol. 121, # 36, p. 6850 - 6853
[8] Chemistry - A European Journal, 2011, vol. 17, # 51, p. 14508 - 14517
[9] Supramolecular Chemistry, 2011, vol. 23, # 6, p. 470 - 479
[10] Patent: WO2009/141386, 2009, A1, . Location in patent: Page/Page column 176
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  • [ 50-01-1 ]
  • [ 219511-71-4 ]
YieldReaction ConditionsOperation in experiment
59% With sodium hydroxide In water Example 6
N-,N'-Di-Boc-Guanidine
1,4-Dioxane (50 ml) is added to a solution of guanidine hydrochloride (2.39 g, 25 mmol) and sodium hydroxide (4.0 g, 0.1 mol) in water (25 ml) and the resulting mixture is cooled to 0° C. Di-tert-butyl-pyrocarbonate(12.0 g, 55 mmol) is added in one portion while stirring.
The reaction mixture is allowed to warm to room temperature within 2 h.
After stirring for 20 h the mixture is concentrated in vacuo to one third of its original volume.
The resulting suspension is diluted with water (50 ml) and extracted three times with ethyl acetate (50 ml each).
The combined extracts are washed with 10percent citric acid, water and brine and dried with magnesium sulfate.
After filtering and removal of the solvent under reduced pressure the crude product is purified by flash chromatography on silica gel (eluent: dichloromethane-methanol 97:3). N-,N'-di-Boc-guanidine (3.84 g, 59percent) is obtained as a colorless powder: mp: 144° C.; 1 H NMR (360 MHz, DMSO-d6) δ 10.42 (br s, 1H), 8.47 (br s, 2H), 1.39 (s, 18H); FAB-MS m/e (relative intensity) 260 (50; M+H+), 204 (48), 148 (100); Anal. Calc. for: C, 50.95percent; H, 8.16percent;.N, 16.21percent; Found: C, 50.83percent; H, 8.04percent;.N, 16.26percent.
Reference: [1] Patent: US6072075, 2000, A,
  • 41
  • [ 24424-99-5 ]
  • [ 50-01-1 ]
  • [ 332882-82-3 ]
  • [ 219511-71-4 ]
Reference: [1] Patent: US2010/4450, 2010, A1, . Location in patent: Page/Page column 16
  • 42
  • [ 24424-99-5 ]
  • [ 50-01-1 ]
  • [ 332882-82-3 ]
  • [ 219511-71-4 ]
  • [ 216584-22-4 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8432 - 8439
[2] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8432 - 8439
  • 43
  • [ 6342-56-9 ]
  • [ 50-01-1 ]
  • [ 4637-24-5 ]
  • [ 165807-05-6 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: at 110℃; for 15 h;
Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide at 110℃; for 36 h;
Pyruvic aldehyde dimethyl acetal (10 g, 84 mmol) and N, N’-dimethyl formamide dimethyl diacetal (10 g, 84 mmol) in DMF (30 ml) were heated in a round bottom flask at 110 °C for 15 h. Guanidine hydrochloride (12 g, 127 mmol) and NaOH (6.7 g, 169 mmol) in water were then added to the reaction mixture. The mixture was refluxed for further 36 h. The reaction mass was then cooled and filtered. The product was recrystallized from hot ethyl acetate to yield white crystalline solid 2 (10 g, 70percent).
36%
Stage #1: at 100℃; for 16 h;
Stage #2: With sodium hydroxide In water at 20℃; for 48 h;
Procedure H: Intermediate 8 (1-8) - 2-Aminopyrimidine-4-carboxaldehyde dimethylacetal.; [0093] A solution of 5.5 mL (41 mmol, 1.0 eq.) of dimethylformamide dimethyl acetal and 5.0 mL (41 mmol, 1.0 eq.) pyruvric aldehyde dimethyl acetal was heated at 100 0C for 16 h. Methanol was removed in vacuo to afford a brown oil. A solution of 1.8 g (45 mmol, 1.1 eq.) of sodium hydroxide in 5 mL of water was added to a solution of 4.3 g (45 mmol, 1.1 eq.) of guanidine HCl in 10 mL of water. The resulting solution was added to the above described oil. The resulting mixture was stirred at room temperature for 48 h. The mixture was filtered to provide 2.5 g (15 <n="38"/>mmol, 36percent) of 2-aminopyrimidine-4-carboxaldehyde dimethyl acetal (1-8).
50% With sodium hydroxide In water a)
2-Aminopyrimidine-4-carboxaldehyde dimethyl acetal
Dimethylformamide dimethyl acetal (55 mL, 0.41 mol), and pyruvic aldehyde dimethyl acetal (50 mL, 0.41 mol) were combined and heated to 100° for 18 h.
Methanol was removed in vacuo to afford an oil.
A solution of NaOH (18 g, 0.45 mol) in H2 O (50 mL) was added to guanidine HCl (43 g, 0.45 mol) in H2 O (100 mL), and the resulting solution was added to the above described oil.
The resulting mixture was stirred at 23° for 48 h.
Filtration afforded 25 g (50percent) of the title compound.
Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 28, p. 3715 - 3717
[2] Patent: EP1227092, 2002, A2, . Location in patent: Page 25
[3] Patent: EP1229035, 2002, A1, . Location in patent: Page 25
[4] Patent: EP1227091, 2002, A2, . Location in patent: Page 25
[5] Patent: WO2007/104053, 2007, A2, . Location in patent: Page/Page column 36-37
[6] Patent: US5593992, 1997, A,
[7] Patent: US5670527, 1997, A,
  • 44
  • [ 67751-23-9 ]
  • [ 50-01-1 ]
  • [ 165807-05-6 ]
Reference: [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 15, p. 4310 - 4313[2] Angew. Chem., 2017, vol. 129, p. 4374 - 4377,4
[3] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 22, p. 3111 - 3116
[4] Patent: US2008/85898, 2008, A1, . Location in patent: Page/Page column 17
[5] Patent: WO2015/97123, 2015, A1, . Location in patent: Page/Page column 141
  • 45
  • [ 50-01-1 ]
  • [ 4637-24-5 ]
  • [ 165807-05-6 ]
YieldReaction ConditionsOperation in experiment
50% With sodium hydroxide In water a
2-Aminopyrimidine-4-carboxaldehyde dimethyl acetal
Dimethylformamide dimethyl acetal (55 mL, 0.41 mol), and pyrrhic aldehyde dimethyl acetal (50 mL, 0.41 mol) were combined and heated to 100° for 18 h.
Methanol was removed in vacuo to afford an oil.
A solution of NaOH (18 g, 0.45 mol) in H2 O (50 mL) was added to guanidine HCl(43 g, 0.45 mol) in H2 O (100 mL), and the resulting solution was added to the above described oil.
The resulting mixture was stirred at 23° for 48 h.
Filtration afforded 25 g (50percent) of the title compound.
Reference: [1] Patent: US5593991, 1997, A,
  • 46
  • [ 67751-23-9 ]
  • [ 50-01-1 ]
  • [ 165807-05-6 ]
Reference: [1] Patent: US6288062, 2001, B1,
  • 47
  • [ 167764-63-8 ]
  • [ 50-01-1 ]
  • [ 159138-80-4 ]
Reference: [1] Patent: WO2005/79803, 2005, A1, . Location in patent: Page/Page column 41
[2] Patent: WO2005/79803, 2005, A1, . Location in patent: Page/Page column 41
  • 48
  • [ 50-01-1 ]
  • [ 308348-93-8 ]
YieldReaction ConditionsOperation in experiment
61.5% at 100℃; for 1 h; Step f:
2-Amino-pyrimidine-5-carboxylic acid methyl ester (Compound 207)
To a mixture of guanidine hydrochloride (42.2 g, 0.44 mol) in DMF (300 mL) was added compound 206 (80 g, 0.40 mol).
The resulting mixture was heated at 100° C. for 1 h.
The reaction mixture was filtered before cooled.
The filter cake was washed with 50 mL of DMF and the combined filtrate was concentrated to leave a residue which was suspended in cold EtOH and washed with cold EtOH (50 mL) to afford the compound 207 (38 g, 61.5percent) as a yellow solid. LCMS (m/z): 154.2 [M+1]+, 195.1[M+42]+. 1H NMR (400 MHz, CD3OD): δ 3.88 (s, 3H), 8.77 (s, 2H).
61.5% at 100℃; for 1 h; To a mixture of guanidine hydrochloride (42.2 g, 0.44 mol) in DMF (300 mL) was added compound 206 (80 g, 0.40 mol). The resulting mixture was heated at 100 °C for 1 h.The reaction mixture was filtered before cooled. The filter cake was washed with 50 mLof DMF and the combined filtrate was concentrated to leave a residue which wassuspended in cold EtOH and washed with cold EtOH (50 mL) to afford the compound 207(38 g, 61.5percent) as a yellow solid. LCMS (m/z): 154.2 [M+if, i95.i[M+42f. ‘HNMR(400 MHz, CD3OD): ö 3.88 (s, 3H), 8.77 (s, 2H).
50% at 100℃; for 1 h; Sodium (1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (1.37 g, 7.8 mmol) was diluted in DMF (12 mL), and guanidine hydrochloride (640 mg, 6.7 mmol) was added. The mixture was stirred at 100 0C for 1 h, then was cooled to rt and diluted with water. Methyl 2-aminopyrimidine-5-carboxylate precipitated as a light yellow solid, which was isolated by vacuum filtration (510 mg, 50percent): 1H NMR (DMSO-Gf6) δ: 8.67 (s, 2H), 7.56 (br s, 2H), 3.79 (s, 3H).
50% at 100℃; for 1 h; Sodium (1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (1.37 g, 7.8 mmol) was diluted in DM F (12 mL), and guanidine hydrochloride (640 mg, 6.7 mmol) was added. The mixture was stirred at 100 °C for 1 h, then was cooled to rt and diluted with water. Methyl 2-aminopyrimidine-5-carboxylate precipitated as a light yellow solid, which was isolated by vacuum filtration (510 mg, 50percent): 1 H NMR (DMSO-cfe) δ: 8.67 (s, 2H), 7.56 (br s, 2H), 3.79 (s, 3H
50% at 100℃; for 1 h; Preparation of 2-aminopyrimidine-5-carboxylicSodium (1 Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1 -en-1 -olate was prepared as described by Zhichkin (Zhichkin et a/., 2002).Sodium (1 Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1 -en-1 -olate (1.37 g, 7.8 mmol) was diluted in DMF (12 mL), and guanidine hydrochloride (640 mg, 6.7 mmol) was added. The mixture was stirred at 100 °C for 1 h, then was cooled to rt and diluted with water. Methyl 2- aminopyrimidine-5-carboxylate precipitated as a light yellow solid, which was isolated by vacuum filtration (510 mg, 50percent): 1H NM (DMSO-cfe) δ: 8.67 (s, 2H), 7.56 (br s, 2H), 3.79 (s, 3H).
50% at 100℃; for 1 h; Intermediate APreparation of 2-aminopyrimidine-5-carboxylic acidSodium (1 Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1 -en-1-olate was prepared as described by Zhichkin (Zhichkin et al., 2002).Sodium (1 Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1 -en-1 -olate (1.37 g, 7.8 mmol) was diluted in DMF (12 mL), and guanidine hydrochloride (640 mg, 6.7 mmol) was added. The mixture was stirred at 100 °C for 1 h, then was cooled to rt and diluted with water. Methyl 2- aminopyrimidine-5-carboxylate precipitated as a light yellow solid, which was isolated by vacuum filtration (510 mg, 50percent): 1H NMR (DMSO-cfe) δ: 8.67 (s, 2H), 7.56 (br s, 2H), 3.79 (s, 3H).Methyl 2-aminopyrimidine-5-carboxylate (300 mg, 2.0 mmol) was diluted in methanol (5 mL) containing a few drops of water. Lithium hydroxide (122 mg, 5.1 mmol) was added, and the reaction mixture was stirred at 60 °C overnight. The mixture was concentrated under reduced pressure, then diluted in water and adjusted to pH 4 with 1 M HCI. 2-Aminopyrimidine-5- carboxylic acid precipitated as a white solid, which was isolated by vacuum filtration (244 mg, 90percent): 1 H NMR (DMSO-d6) δ: 12.73 (1 H, br s), 8.63 (2H, s), 7.44 (2H, br s).
63 g at 100℃; for 3 h; Inert atmosphere The crude enolate from step 1 was dissolved in DMF (200 mL), and guanidine hydrochloride (64 g, 670 mmol) was added. The mixture was heated at 1 00 °C under N2 for 3 h. After cooling to rt, water was added and the mixture was cooled with an ice-water bath. The resulting precipitate was collected by vacuum filtration and dried under vacuum to give the desired product (63 g, 61 percent yield for 2 steps).

Reference: [1] Patent: US9249156, 2016, B2, . Location in patent: Page/Page column 35
[2] Patent: WO2018/85342, 2018, A1, . Location in patent: Page/Page column 26; 28
[3] Patent: WO2008/70150, 2008, A1, . Location in patent: Page/Page column 59
[4] Patent: WO2012/62748, 2012, A1, . Location in patent: Page/Page column 53
[5] Patent: WO2012/62743, 2012, A1, . Location in patent: Page/Page column 57
[6] Patent: WO2012/62745, 2012, A1, . Location in patent: Page/Page column 58
[7] ChemMedChem, 2016, p. 1517 - 1530
[8] Patent: WO2013/127266, 2013, A1, . Location in patent: Page/Page column 131
[9] Patent: WO2013/130943, 2013, A1, . Location in patent: Paragraph 0183
  • 49
  • [ 7424-91-1 ]
  • [ 107-31-3 ]
  • [ 50-01-1 ]
  • [ 308348-93-8 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 50℃; for 4 h;
Stage #2: at 100℃; for 3 h; Inert atmosphere
Methyl 3,3-dimethoxypropanoate ( 1 00 g, 675 mmol) and methyl formate (8 1 g, 1 350 mmol) were dissolved in anhydrous THF (450 mL). Sodium hydride (60percent dispersion; 32.4 g, 8 1 0 mmol, 1 .2 eq.) was then added slowly in portions at 0 °C. The reaction mixture was stirred at rt for 1 h, then was heated at 50 °C for 3 h. During this period, H2 evolution was observed. After cooling to rt, the solvent was then removed under reduced pressure to give the crude product which was directly used in the next step without further purification. The crude enolate from step 1 was dissolved in DMF (200 mL), and guanidine hydrochloride (64 g, 670 mmol) was added. The mixture was heated at 1 00 °C under Ni for 3 h. After cooling to rt, water was added and the mixture was cooled with an ice-water bath. The resulting precipitate was collected by vacuum filtration and dried under vacuum to give the desired product (63 g, 61 percent yield for 2 steps).
61%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 50℃; for 4 h;
Stage #2: at 100℃; for 3 h; Inert atmosphere
Methyl 3,3-dimethoxypropanoate ( 1 00 g, 675 mmol) and methyl formate (8 1 g, 1 350 mmol) were dissolved in anhydrous THF (450 mL). Sodium hydride (60percent dispersion; 32.4 g, 8 1 0 mmol, 1 .2 eq.) was then added slowly in portions at 0 °C. The reaction mixture was stirred at rt for 1 h, then was heated at 50 °C for 3 h. During this period, H2 evolution was observed. After cooling to rt, the solvent was then removed under reduced pressure to give the crude product which was directly used in the next step without further purification. The crude enolate from step 1 was dissolved in DMF (200 mL), and guanidine hydrochloride (64 g, 670 mmol) was added. The mixture was heated at 1 00 °C under N2 for 3 h. After cooling to rt, water was added and the mixture was cooled with an ice-water bath. The resulting precipitate was collected by vacuum filtration and dried under vacuum to give the desired product (63 g, 61 percent yield for 2 steps).
Reference: [1] Patent: WO2013/127267, 2013, A1, . Location in patent: Page/Page column 82
[2] Patent: WO2013/127268, 2013, A1, . Location in patent: Page/Page column 60
  • 50
  • [ 50-01-1 ]
  • [ 308348-93-8 ]
YieldReaction ConditionsOperation in experiment
30% at 100℃; for 1 h; Synthesized by the method described in Synthesis, 2002,6,720; 3,3-dimethoxy-2-methoxy-carbonyl-propen-1-ol sodium salt (3.0g) and guanidine hydrochloride was dissolved in DMF (24mL). The mixture was stirred for 1 hour at 100°C. After cooling to room temperature,Was filtered off and water was added to the precipitated solid,After drying under reduced pressure,To give the title compound 720mg (30percent).
Reference: [1] Patent: JP5851663, 2016, B1, . Location in patent: Paragraph 0171
  • 51
  • [ 1221153-81-6 ]
  • [ 50-01-1 ]
  • [ 1221153-82-7 ]
Reference: [1] Patent: WO2010/42337, 2010, A1, . Location in patent: Page/Page column 42; 44; 45
  • 52
  • [ 1383716-87-7 ]
  • [ 50-01-1 ]
  • [ 1383716-40-2 ]
YieldReaction ConditionsOperation in experiment
31.3% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4 h; Examples 10a- lOv General method for synthesis of 4'-(cyclopropylmethyl)-N -pyridin-4-yl-4 ,5'- bipyrimidine-2, 2 '-diamines lOa-v.Preparation of 4 '-Cyclopropylmethyl-N2-pyridin-4-yl- [4,5 ' ] bipyrimidinyl-2,2 '- diamine (10a):(10a)To a solution of (3Z)-l-cyclopropyl-4-(dimethylamino)-3-[2-(pyridin-4- ylamino)pyrimidin-4-yl]but-3-en-2-one (9) (80 mg, 0.247 mmol) in DMF (2061 μ), Guanidine HC1 (35.3 mg, 0.371 mmol) and potassium carbonate (103 mg, 0.742 mmol) were added and the reaction was heated at 60°C for 4 hours. The crude product was purified by reverse-phase HPLC [30-90percent organic phase over 15 minutes] followed by Biotage.(TM). silica gel chromatography [10 g SNAP column, 100percent DCM to 12percentMeOH/DCM] to obtain the desired product as a white solid (24.72 mg, 31.3percent yield). 1H NMR (400 MHz, MeOD) δ ppm 0.01 - 0.14 (m, 2 H) 0.39 (q, J=6.06 Hz, 2 H) 0.94 - 1.10 (m, 1 H) 2.87 (d, J=7.07 Hz, 2 H) 7.10 (d, J=5.05 Hz, 1 H) 7.83 (d, J=6.57 Hz, 2 H) 8.30 (d, J=6.57 Hz, 2 H) 8.41 (s, 1 H) 8.57 (d, J=5.05 Hz, 1 H). HRMS (ES+) forC17H17N7 H+ [MH+]: calcd, 320.1624; found, 320.1636. UV-LC: 100percent UV purity at 254/214 nm; /R = 4.67 minute over 7.75 minutes.
Reference: [1] Patent: WO2012/85815, 2012, A1, . Location in patent: Page/Page column 61
[2] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 1, p. 72 - 76
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