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Product Details of [ 1722-12-9 ]

CAS No. :1722-12-9 MDL No. :MFCD00006060
Formula : C4H3ClN2 Boiling Point : -
Linear Structure Formula :- InChI Key :UNCQVRBWJWWJBF-UHFFFAOYSA-N
M.W : 114.53 Pubchem ID :74404
Synonyms :

Calculated chemistry of [ 1722-12-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 27.04
TPSA : 25.78 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.74 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.41
Log Po/w (XLOGP3) : 0.36
Log Po/w (WLOGP) : 1.13
Log Po/w (MLOGP) : 0.16
Log Po/w (SILICOS-IT) : 1.74
Consensus Log Po/w : 0.96

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.41
Solubility : 4.44 mg/ml ; 0.0388 mol/l
Class : Very soluble
Log S (Ali) : -0.47
Solubility : 39.2 mg/ml ; 0.342 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.21
Solubility : 0.705 mg/ml ; 0.00615 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.19

Safety of [ 1722-12-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P270-P271-P264-P280-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330-P302+P352+P312-P304+P340+P312-P501 UN#:N/A
Hazard Statements:H302+H312+H332-H315-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1722-12-9 ]

* 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.

  • Upstream synthesis route of [ 1722-12-9 ]
  • Downstream synthetic route of [ 1722-12-9 ]

[ 1722-12-9 ] Synthesis Path-Upstream   1~69

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Reference: [1] Tetrahedron Letters, 2006, vol. 47, # 25, p. 4249 - 4251
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  • [ 1450-85-7 ]
Reference: [1] Journal of the Chemical Society, 1951, p. 1218,1221
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  • [ 917-54-4 ]
  • [ 13036-57-2 ]
YieldReaction ConditionsOperation in experiment
67%
Stage #1: at -30 - 0℃; for 1 h;
Stage #2: With water; acetic acid In tetrahydrofuran; diethyl ether at 0℃; for 0.166667 h;
Stage #3: With 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran; diethyl ether at 20℃; for 0.5 h;
To a finely dispersed suspension of 2-chloropyrimidine (8.01 g, 69.9 mmol) in a 10: 1 mixture of [ET2O-THF] (500 mL) [AT-30°C] was added dropwise MeLi (46 mL, 1.6M in [ET20,] 73.6 mmol). The reaction mixture was stirred [AT-30°C] for 30 min, and was then warmed to [0°C] and stirred for 30 min. To the reaction mixture was then added a 1: 1: 20 mixture of H2O- [HOAC-THF] (100 mL), and the mixture was stirred at [0°C] for 10 min. To the mixture was then added a solution of DDQ (16.7 g, 73.6 mmol) in THF (100 [ML),] and the mixture was stirred and warmed to room temperature for 30 min. The mixture was then diluted with [ET2O] (300 mL) and washed with IN aq. [NAOH] [(3X100] [ML)] followed by brine (300 mL). The organic phase was then dried over anhydrous [MGSO4,] filtered, concentrated in vacuo, and purified by flash chromatography using EtOAc-hexanes (1: 2) as eluent to afford 6.06 g of 2-chloro-4- methylpyrimidine (67percent) as white crystalline plates. To a solution of 2-chloro-4-methylpyrimidine (6.06 g, 47.1 mmol) in [MEOH] (40 [ML)] was added hydrazine monohydrate (10 mL, 206 [MMOL).] The solution was stirred for 16 h at room temperature and then purified by reverse phase HPLC to provide 4.43 g of the title compound [(76percent)] as a white solid. MH+ 125.
Reference: [1] Journal of Organic Chemistry, 1988, vol. 53, # 17, p. 4137 - 4140
[2] Patent: WO2003/101442, 2003, A1, . Location in patent: Page 53
[3] Patent: US6342503, 2002, B1, . Location in patent: Example 8
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  • [ 84-58-2 ]
  • [ 13036-57-2 ]
Reference: [1] Patent: US6107301, 2000, A,
  • 5
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  • [ 5188-07-8 ]
  • [ 823-09-6 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 5, p. 887 - 890
  • 6
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  • [ 74-88-4 ]
  • [ 289-95-2 ]
  • [ 823-09-6 ]
Reference: [1] Organic Letters, 2003, vol. 5, # 22, p. 4133 - 4136
  • 7
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  • [ 14080-23-0 ]
YieldReaction ConditionsOperation in experiment
71% With 3-quinuclidinol In dimethyl sulfoxide at 70℃; for 2.5 h; General procedure: A mixture of 2-chloropyrimidines(10 mmol), potassium cyanide (13–15 mmol), water (20 mmol), and DMSO(20 mL) was heated to 60 C. A solution of 3-quinuclidinol (0.1–0.2 mmol) inDMSO(5 mL) was added to the reaction mixture over 0.5 h. The reaction mixturewas stirred at 50–70 C for additional hours as specified in Table 1. Uponcompletion, the mixture was cooled to room temperature and water (50 mL) wasadded. The resulting mixture was extracted with isopropyl acetate (3 40 mL)(product 7a precipitated out after water addition and was collected by filtration).The combined organic layers were washed with water (2 30 mL), dried overMgSO4, filtered, and concentrated under vacuum to give crude 2-cyanopyrimidines, which were purified by column chromatography (SiO2) to afford pureproducts.
65% With 1,4-diaza-bicyclo[2.2.2]octane In water; dimethyl sulfoxide at 20℃; for 48 h; Synthesis of Pyrimidine-2-carbonitrile [0504] To a stirred solution of 2-chloropyrimidine (20.0 g, 174.6 mmol) in DMSO (40 mL) were added DABCO (3.72 g, 33.17 mmol), KCN (12.48 g, 192 mmol) and drop-wise addition of H20 (15 mL) at RT. The resulting solution was stirred at RT for 48 h. After consumption of starting material by TLC, the reaction mixture was diluted with water and extracted with EtO Ac. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was triturated with Hexane to afford pyrimidine-2-carbonitrile (12 g, 65percent) as dark brown solid. 1H-NMR (DMSO-d6, 400 MHz): δ 9.04 (s, 2H), 8.92 (d, 1H); LC-MS: 99.41percent; 107.6 (M+2); (column; X-bridge C-18, (50x3.0 mm, 3.5μ); RT 1.14 min. 0.1percent Aq TFA: ACN; 0.8 ml/min); TLC: 30percent EtOAc/Hexane (Rf: 0.2)
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 36, p. 5055 - 5057
[2] Patent: WO2013/142269, 2013, A1, . Location in patent: Paragraph 0503
[3] Patent: WO2012/40230, 2012, A1, . Location in patent: Page/Page column 79-80
  • 8
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  • [ 14080-23-0 ]
Reference: [1] Organic Letters, 2007, vol. 9, # 9, p. 1711 - 1714
  • 9
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  • [ 151-50-8 ]
  • [ 14080-23-0 ]
Reference: [1] Chemical Communications, 2006, # 3, p. 341 - 343
[2] Organic Preparations and Procedures International, 1994, vol. 26, # 6, p. 684 - 687
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Reference: [1] Pharmaceutical Bulletin, 1955, vol. 3, p. 175,176
[2] Annales de Chimie (Cachan, France), 1960, vol. <13>5, p. 351,399,402
[3] Patent: US5883254, 1999, A,
[4] Patent: US5883254, 1999, A,
  • 11
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Reference: [1] Chimia, 1996, vol. 50, # 11, p. 538 - 543
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 26, p. 4420 - 4425
[3] Chimia, 1996, vol. 50, # 11, p. 538 - 543
  • 12
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Reference: [1] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699
  • 13
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Reference: [1] Journal of the American Chemical Society, 1959, vol. 81, p. 905
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YieldReaction ConditionsOperation in experiment
30% With potassium carbonate In methanol at 80℃; Sealed tube Intermediate AT: l-methyl-5-phenyl-1H-imidazol-2-amineStep 1: Synthesis of N-methylpyrimidin-2-amineTo a solution of 2-chloropyrimidine (1 g, 8.7 mmol) in methanol (10 mL) is added a 2M solution of methylamine (13.2 mL, 26.2 mmol) in methanol, followed by K2C03 (2.5 g, 18 mmol). The reaction flask is sealed and heated to 80 °C overnight. The reaction is then cooled to room temperature and concentrated to remove volatiles. The residue is partitioned between water and CH2C12. The organic layer is dried (Na2S04) and concentrated to afford the title compound (290 mg, 30percent) as a brown oil.
Reference: [1] Bulletin of the Chemical Society of Japan, 1998, vol. 71, # 8, p. 1973 - 1991
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 6626 - 6637
[3] Molecules, 2004, vol. 9, # 7, p. 520 - 526
[4] Patent: WO2011/71716, 2011, A1, . Location in patent: Page/Page column 99
[5] Journal of the American Chemical Society, 1954, vol. 76, p. 1065,1067
[6] Journal of the Chemical Society, 1953, p. 331,336
[7] Journal of Medicinal Chemistry, 2011, vol. 54, # 2, p. 472 - 484
[8] Patent: US2012/172374, 2012, A1, . Location in patent: Page/Page column 37-38
[9] Organic Letters, 2017, vol. 19, # 17, p. 4656 - 4659
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YieldReaction ConditionsOperation in experiment
99.8% at 100℃; for 0.5 h; [1484] a mixture of 2-chloropyrimidine (15 g, 131 mmol), NH2NH2.H2O (30 ml), K2CO3 (15 g, 109 mmol) was stirred at 100 °C for 30 min. The mixture was ice cooled and the resulting crude crystals were collected by filtration. The crystals were washed with cold water, air dried, and recrystallized from petroleum ether (150 ml) to give compound 350a (14.4 g, 131 mmol, yield: 99.8percent) as a yellow solid. 1H NMR (400mhz, DMSO-d6) δ 8.30 (d, = 4.8 hz, 2h), 8.12 (br s, ih), 6.59 (t, j = 4.7 hz, ih), 4.13 (s, 2h).
80% With hydrazine hydrate In ethanol for 2 h; H2mphp was synthesized by the following procedure. 2-Chloropyrimidine (1.145 g, 20 mmol) was dissolvedin ethanol (30 mL). Then, excess hydrazine hydrate (85percent, 6 mL) was added to the above solutionunder stirring. A bright yellow solution formed, from which white needle crystals appeared after 2 h. The crystals were collected by filtration and recrystallized in ethanol (yield 80percent). 3-Methylsalicylaldehyde(1.36 g, 10 mmol) was added to an ethanolic solution (30 mL) of 2-hydrazinopyrimidine (1.10 g, 10 mmol)and light yellow precipitate formed immediately. After reflux for 3 h, the reaction mixture was filteredand the precipitate washed with ethanol to yield light yellow powder of H2mphp. Yield 95percent.
40% With hydrazine In ethanol at 20℃; for 1.33333 h; [Referential Example 34] 2-Hydrazinopyrimidine; [Show Image] Hydrazine monohydrate (20 ml) was added to a suspension of 2-chloropyrimidine (6.00 g) in ethanol (60 ml) at room temperature, and the mixture was stirred for 80 minutes. The solvent was evaporated under reduced pressure, and water (34 ml) was added to the residue. The solid precipitate was collected by filtration to give the title compound (2.30 g, 40percent). 1H-NMR (400 MHz, DMSO-d6)δ: 4.12 (2H, s), 6.57-6.60 (1H, m), 8.12 (1H, s), 8.30 (2H, d, J = 4.9 Hz). EI-MSm/z: 110 (M+).
40% With hydrazine In ethanol at 20℃; for 1.33333 h; [Referential Example 3] 2-Hydrazinopyrimidine [Show Image] Hydrazine monohydrate (20 mL) was added to a suspension of 2-chloropyrimidine (6.00 g) in ethanol (60 mL) at room temperature, followed by stirring for 80 minutes. The solvent of reaction mixture was evaporated under reduced pressure, and then water (34 mL) was added to the residue. The solid that precipitated was collected through filtration, to thereby give the title compound (2.30 g, 40percent). 1H-NMR(400MHz,DMSO-d6)δ:4.12(2H,s), 6.57-6.60 (1H,m), 8.12(1H,s), 8.30(2H,d,J=4.9Hz). EI-MS m/z:110(M+).
25% at 20℃; for 1.6 h; PREPARATION 9Preparation of 2-hydrazinylpyrimidine; A solution of 2-chloropyrimidine (0.70 g, 6.11 mmol) in pyridine (15 mL) and anhydrous hydrazine (2.5 mL) was stirred for 5 minutes at ambient temperature, and further pyridine (8 mL) was added. The reaction mixture was stirred at ambient temperature for 1.5 h and concentrated in vacuo. The residue was suspended in water (4 mL) and the resultant solid was collected by suction filtration and air-dried to afford 2-hydrazinylpyrimidine as a colorless solid in 25percent yield (0.171 g): 1H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J = 4.8 Hz, 2H), 8.13 (br s, 1 H), 6.59 (t, J = 4.8 Hz, 1 H), 4.12 (br s, 2H).

Reference: [1] Patent: WO2018/64119, 2018, A1, . Location in patent: Paragraph 1484
[2] Journal of Organic Chemistry, 1999, vol. 64, # 15, p. 5644 - 5649
[3] Patent: US2003/187014, 2003, A1,
[4] Journal of Coordination Chemistry, 2016, vol. 69, # 7, p. 1218 - 1225
[5] Journal of Physical Organic Chemistry, 2015, vol. 28, # 2, p. 108 - 115
[6] Patent: EP1698626, 2006, A1, . Location in patent: Page/Page column 47-48
[7] Patent: EP1762568, 2007, A1, . Location in patent: Page/Page column 22-23
[8] Patent: WO2008/121861, 2008, A2, . Location in patent: Page/Page column 65
[9] Yakugaku Zasshi, 1953, vol. 73, p. 598,600[10] Chem.Abstr., 1954, p. 9362
[11] Bulletin des Societes Chimiques Belges, 1959, vol. 68, p. 30,55
[12] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 21, p. 3191 - 3193
[13] Patent: EP967212, 1999, A1,
[14] Patent: EP2264105, 2010, A1, . Location in patent: Page/Page column 164
[15] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2887 - 2889
[16] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5266 - 5269
[17] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1071 - 1074
[18] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2284 - 2288
[19] Molecules, 2018, vol. 23, # 9,
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YieldReaction ConditionsOperation in experiment
83% at 20℃; for 3 h; Dissolve 2-chloropyrimidine (10.04 g, 87.7 mmol) in pyridine (200 mL) and add hydrazine (35.8 mL, 1.14 mol) to the mixture followed by pyridine (100 mL). Stir the mixture for 3 hr. at room temperature then concentrate. Suspend the residue in water and filter. Wash the cake with cold methanol. Collect the powder and dry under vacuum to give pyrimidin-2-ylhydrazine as a white powder (8.05 g, 83percent).
Reference: [1] Patent: WO2008/141020, 2008, A1, . Location in patent: Page/Page column 58
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YieldReaction ConditionsOperation in experiment
65% With sodium carbonate In ethanol; water; toluene at 100℃; for 20 h; 2-Phenylpyrimidine
To a dried flask was added the 2-chloropyrimidine (0.50 g, 4.37 mmol), phenyl-boronic acid (0.69 g, 5.68 mmol), Na2CO3 (0.92 g, 8.70 mmol), PdCl2 (38.7 mg, 0.22 mmol) and dppb (92.9 mg, 0.22 mmol).
The mixture was then purged under nitrogen for 10 minutes, followed by the addition of a degassed mixture of toluene (12 mL), water (6 mL), ethanol (2 mL).
The reaction mixture was allowed to stir at 100° C.
After 20 h, the mixture was filtered on a celite pad, then the volatiles were removed under reduced pressure.
Purification via silica gel column chromatography using a mixture of 10percent Et2O/DCM gave a white solid (65percent).
Spectral data is identical to previous reports.26
32 %Chromat. With [Ni(9,10-phenanthrenequinonethiosemicarbazone)2]; potassium carbonate In N,N-dimethyl acetamide at 90℃; for 7 h; General procedure: To a mixture of aryl halide (1 mmol), phenylboronic acid (1.5 mmol) and K2CO3 (1 mmol) in dimethylacetamide (4 mL) was added the catalyst (1 molpercent) as a dimethylacetamide solution (1 mL). The resultant mixture was then heated at 90C for 7 h. Then, the mixture was cooled, water was added and the product was extracted with ethylacetate. The organic layer was washed with brine, dried over Na2SO4, filtered, passed through celite, and analyzed by GC. GC yields were obtained based on corresponding aryl halide. The isolated yield was characterized by 1H NMR.
85 %Chromat. With [Pd2(μ-1,1′-bis(diphenylphosphino)ferrocene)(4-methoxy-N′-(mesitylidene)benzohydrazide)2]; tetrabutylammomium bromide; potassium carbonate In water; N,N-dimethyl-formamide at 90℃; for 12 h; An oven-dried round bottom flask (10 ml) was charged with 0.1ml dimethylformamide solution of complex IV (0.1 mol percent for aryl bromides and 0.2 mol percent for aryl chlorides), aryl boronic acid (1.2 mmol), aryl halide (1.0 mmol), K2CO3 (1.5 mmol), TBAB (1.0 mmol) and 2 ml water. The reaction mixture was then heated (to 70 °C for aryl bromides and 90 °C for aryl chlorides) with stirring under aerobic conditions for the required time. At the end of the reaction, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (2×5 ml). The combined extract was washed with water (2×10 ml), dried over anhydrous sodium sulfate and then subjected to GC-MS analysis for identification and yield determination (from the areas under the peaks) of the products. In the case of reactions with 2-naphthylboronic acid, the combined extract was evaporated to dryness under reduced pressure and the residue was purified by column chromatography (silica gel, ethyl acetate/n-hexane) to afford the coupling products. The products were identified by 1H and 13C NMR and HR-MS analysis.
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YieldReaction ConditionsOperation in experiment
91% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In tetrahydrofuran at 80℃; for 4 h; Inert atmosphere To a solution of 2-chloropyrimidine (1.21 g, 10.0 mmol) and Pd(dppf)Cl2(408 mg, 0.5 mmol) in THF (50 mL), triphenylindium (4.0 mmol, ~0.3 M en THF) was added. Themixture was stirred at 80 °C for 4 h and the reaction quenched by addition of drops of MeOH. Thesolvent was evaporated and EtOAc (25 mL) was added. The organic phase was washed with HCl(5percent, 15 mL), satd. NH4Cl (15 mL) and brine (15 mL), dried, filtered, and concentrated. The crudewas purified by flash chromatography (20percent EtOAc/hexane) affording, after concentration and drying,12 (1.42 g, 9.09 mmol, 91percent) as a white solid. M.p. 36–38 °C (lit. [38], 36–38 °C). 1H NMR (CDCl3, 300 MHz) δ 6.95 (t, J = 4.9 Hz, 1 H), 7.42–7.49 (m, 3 H), 8.47–8.50 (m, 2 H), 8.66 (d, J = 4.9 Hz, 2 H) ppm;13C NMR (CDCl3, 75 MHz) δ 119.0 (CH), 128.2 (2 x CH), 128.6 (2 x CH), 130.8 (CH), 137.5 (C), 157.1(2 x CH), 164.5 (C) ppm; IR (ATR) 3087, 3066, 3039 cm-1; MS (EI) m/z (percent) 156 (M+, 92), 103 (100);HRMS (EI) m/z calcd for C10H8N2 156.0682, found 156.0683.
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  • 25
  • [ 10199-67-4 ]
  • [ 67-66-3 ]
  • [ 1722-12-9 ]
  • [ 7431-45-0 ]
  • [ 244-76-8 ]
Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 24, p. 3581 - 3585
  • 26
  • [ 930-36-9 ]
  • [ 67-66-3 ]
  • [ 4513-94-4 ]
  • [ 1722-12-9 ]
  • [ 51269-82-0 ]
Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 24, p. 3581 - 3585
[2] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 24, p. 3581 - 3585
  • 27
  • [ 60-35-5 ]
  • [ 1722-12-9 ]
  • [ 13053-88-8 ]
YieldReaction ConditionsOperation in experiment
91% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In 1,4-dioxane at 100℃; for 16 h; Inert atmosphere A screw-cap vial was charged with benzamide (121 mg, 1.00 mmol), Cs2CO3 (456 mg, 1.40 mmol), Xantphos (87 mg, 0.15 mmol), Pd2(dba)3 (46 mg, 0.050 mmol), 2-chloropyrimidine (137 mg, 1.20 mmol), and 1,4-dioxane (2 mL). The mixture was sparged with nitrogen for 3 min, stirred for 16 h at 100 °C, and cooled to room temperature. The residue was diluted with dichloromethane, filtered through celite, and concentrated. The crude product was purified by silica gel flash chromatography (40-100percent ethylacetate/hexanes) to provide N-(pyrimidin-2-yl)benzamide (188 mg, 0.85 mmol, 94percent yield) as an amorphous solid (Table 1, entry 8).
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 9, p. 1020 - 1022
  • 28
  • [ 1722-12-9 ]
  • [ 2949-92-0 ]
  • [ 49844-93-1 ]
Reference: [1] Angewandte Chemie - International Edition, 2006, vol. 45, # 18, p. 2958 - 2961
  • 29
  • [ 1722-12-9 ]
  • [ 591-51-5 ]
  • [ 13036-50-5 ]
Reference: [1] Patent: US2006/69110, 2006, A1, . Location in patent: Page/Page column 69
  • 30
  • [ 1722-12-9 ]
  • [ 98-80-6 ]
  • [ 13036-50-5 ]
Reference: [1] Synthesis, 2010, # 7, p. 1166 - 1170
  • 31
  • [ 1722-12-9 ]
  • [ 100-59-4 ]
  • [ 13036-50-5 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 22, p. 4429 - 4438
  • 32
  • [ 1722-12-9 ]
  • [ 13036-50-5 ]
  • [ 5188-07-8 ]
  • [ 56734-10-2 ]
Reference: [1] Patent: US2003/60626, 2003, A1,
  • 33
  • [ 110-85-0 ]
  • [ 1722-12-9 ]
  • [ 20980-22-7 ]
YieldReaction ConditionsOperation in experiment
88% With potassium carbonate In water at 35 - 65℃; General procedure: 2-Chloro-4,6-disubstituted-pyrimidines 17 were prepared bythe reaction of the diazoniumsalts of 4,6-disubstituted-pyrimidin-2-amines (16) with concentrated hydrochloric acid and ZnCl2 [35].Compound 18 was prepared according to literature [32], and themethod was improved. To a stirred solution of piperazine(45 mmol) and K2CO3 (16.5 mmol) in water (20 mL) was addedchloropyrimidine 17 (18 mmol) in small portions at 50e65 C. Themixture was stirred for 1 h at 60e65 C and cooled to 35 C. Theyellowsolid, 1,4-bispyrimidylpiperazine byproduct, was filtered off,and the filtrate was then extracted three times with chloroform,dried over Na2SO4, and evaporated in vacuum to give compound 18,which was used for the following reactions without further purification. 18a: yellow oil, yield 88percent.
83.8% With ammonia In water at 98℃; for 3 h; The 24 g anhydrous piperazine, 100 ml water and 8 ml ammonia water into the 250 ml three port into reaction, stirring and heating to 98 °C, dropwise 10 g of 2 - chloro pyrimidine and 90 ml water mixed solution, in 3 hours paused, 98 °C lower heat insulating 0.5 hours. To turns on lathe the distillation, removing about 120 ml water of, cooling to room temperature, dichloromethane is used for extraction 3 times, each time the 30 ml. The combined dichloromethane, adding 4 g anhydrous calcium chloride drying 1 hour, filtering, in the 40 °C lower steaming and removing dichloromethane, shall be 15.6 g product, liquid phase purity 90.04percent, disubstituted by-product (the second piperazine pyrimidine) 11percent. GC analysis of the residual piperazine 0.21percent, yield 83.8percent.
80.7%
Stage #1: With ammonium hydroxide In water at 95 - 100℃;
Stage #2: at 95 - 100℃; for 4 h;
100 g of anhydrous piperazine, 360 ml of water and 32 ml of aqueous ammonia were poured into a 1000 ml three-necked reaction flask and heated to 95 ° C to 100 ° C with stirring. A mixed solution of 44 g of dichloropyrimidine and 360 ml of water was added dropwise, and the mixture was dropped at about 3 hours and incubated at 95 ° C to 100 ° C for 1 hour. Spin distillation, remove about 480ml of water, cooling to room temperature, extracted with dichloromethane 3 times, each 120m. The combined methylene chloride was added with 16 g of anhydrous calcium chloride for 1 hour, filtered and the dichloromethane was removed by steaming at 40 ° C to give 57 g of product, liquid purity of 89.74percent, disubstituted by-product (dipyrimidinyl piperazine) 10percent. GC analysis of piperazine residue 0.19percent, the yield of 80.7percent.
Reference: [1] Chinese Journal of Chemistry, 2015, vol. 33, # 10, p. 1124 - 1134
[2] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 167 - 178
[3] Organic Letters, 2016, vol. 18, # 20, p. 5272 - 5275
[4] Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11357 - 11360
[5] Patent: CN107216318, 2017, A, . Location in patent: Paragraph 0021; 0024; 0027
[6] Patent: CN106432212, 2017, A, . Location in patent: Paragraph 0010; 0018
[7] Journal of Organic Chemistry, 1953, vol. 18, p. 1484,1487
[8] Farmaco, 2005, vol. 60, # 5, p. 439 - 443
[9] Journal of Chemical Research, 2006, # 12, p. 809 - 811
[10] Patent: US35053, 1995, E1,
[11] Patent: US5099019, 1992, A,
[12] Patent: US4598078, 1986, A,
[13] Patent: US4668687, 1987, A,
[14] Patent: US4355031, 1982, A,
[15] Patent: EP263213, 1988, A1,
[16] Molecules, 2008, vol. 13, # 10, p. 2426 - 2441
[17] Patent: US2005/234046, 2005, A1, . Location in patent: Page/Page column 57
[18] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 16, p. 3886 - 3890
[19] Patent: CN107266429, 2017, A, . Location in patent: Paragraph 0021; 0024; 0027
  • 34
  • [ 110-85-0 ]
  • [ 1722-12-9 ]
  • [ 20980-22-7 ]
  • [ 84746-24-7 ]
Reference: [1] Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 9, p. 5515 - 5522
  • 35
  • [ 110-91-8 ]
  • [ 1722-12-9 ]
  • [ 57356-66-8 ]
YieldReaction ConditionsOperation in experiment
79% With 1-methyl-3-(2-pyridinyl)-3,4,5,6-tetrahydropyrimidin-3-ium hexafluorophosphate; potassium <i>tert</i>-butylate; palladium diacetate In 1,2-dimethoxyethane at 100℃; for 0.666667 h; Microwave irradiation General procedure: The Buchwald–Hartwig amination reaction under microwave irradiation was conducted in a CEM Discover apparatus. A 10-mL Teflon vessel was charged with 1.0 mmol of hetero-aryl halide, 3.0 mmol of amine, 2.0 of mmol base, 0.05 mmol of Pd(OAc)2 , 0.10 mmol of LHX, and 2.0 mL of solvent. The mixture was irradiated at 150 W at 100 °C for the specified time and then allowed to cool. The reaction mixture was extracted 3 times with diethyl ether, and the combined organic extracts were washed with water, dried (MgSO4) , and evaporated to dryness. Purification of the residue by flash chromatography on silica gel afforded the pure products.
79% With potassium carbonate In N,N-dimethyl-formamide for 24 h; To a solution of morpholine 5a (3.63 mL, 42 mmol) in DMF (50 mL), K2CO3 (5.8 g, 42 mmol) was added; after 20 min stirring, 2-chloropyrimidine (4.0 g,35 mmol) was added. The reaction mixture was stirred for 24 h, the solvent was removed in vacuo, the residue was purified by column chromatography (elution with ethyl acetate—hexane, 1 : 1).
12% With (2-mesityl-1H-inden-3-yl)dicyclohexyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In 1,2-dimethoxyethane at 120℃; for 24 h; Inert atmosphere General procedure: Pd(dba)2/1-catalyzed amination of aryl halides: An oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Pd(dba)2 (5.8 mg, 0.010 mmol), ligand 1 (8.6 mg, 0.020 mmol) and tBuONa (134 mg, 1.4 mmol). The flask was capped with a rubber septum, evacuated, and then flushed with argon. This cycle was repeated three times. Amine (1.2 mmol), aryl halide (1.0 mmol) and DME (4 mL) were then successively added by syringe. The tube was stirred at room temperature for several minutes and then placed into a preheated oil bath (120 °C) for the time period as indicated in tables. After completion of reaction as judged by GC analysis, the reaction tube was allowed to cool to room temperature and the reaction mixture was adsorbed onto silica gel, and then purified by column chromatography (hexane/ethyl acetate as eluent) to afford the desired product.
Reference: [1] European Journal of Organic Chemistry, 2016, vol. 2016, # 36, p. 5957 - 5963
[2] ChemSusChem, 2013, vol. 6, # 8, p. 1455 - 1460
[3] Journal of Organic Chemistry, 2017, vol. 82, # 7, p. 3741 - 3750
[4] Turkish Journal of Chemistry, 2015, vol. 39, # 1, p. 121 - 129
[5] Russian Chemical Bulletin, 2014, vol. 63, # 6, p. 1350 - 1358[6] Izv. Akad. Nauk, Ser. Khim., 2014, # 6, p. 1350 - 1358
[7] Journal of Organometallic Chemistry, 2012, vol. 706-707, p. 99 - 105
[8] Journal of the Chemical Society, 1954, p. 1190,1192
[9] European Journal of Medicinal Chemistry, 2017, vol. 136, p. 270 - 282
  • 36
  • [ 110-91-8 ]
  • [ 1722-12-9 ]
  • [ 64-17-5 ]
  • [ 57356-66-8 ]
Reference: [1] Journal of the Chemical Society, 1954, p. 1190,1192
  • 37
  • [ 1722-12-9 ]
  • [ 63-74-1 ]
  • [ 68-35-9 ]
Reference: [1] Yakugaku Zasshi, 1950, vol. 70, p. 283,284[2] Chem.Abstr., 1951, p. 2894
  • 38
  • [ 1722-12-9 ]
  • [ 31462-54-1 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogen iodide In water at -10 - -5℃; for 1 - 2 h; Under N2, 2-chloropyrimidine (200 g, 1.75 mol) was added in 5 portions to aqueous HI (850 ml, 57percent in water) at -10 to -5° C. The mixture was stirred at -10 to -5° C. and the reaction was followed by HPLC. After complete reaction (60 to 120 min), the pH was set to 7.25+/-0.25 with NaOH (30percent) and the temperature was increased to 18-23° C. To decolorize the mixture, 16 g Na2SO3 was added, decreasing the pH to 3+/-1. TBME (600 ml) was added to the mixture and the mixture was saturated with NaCl (300 g). The phases were separated and the aqueous phase was extracted with TBME (4.x.400 ml). The combined organic layers were washed with aqueous Na2SO3 (50 ml) (1percent) and water (100 ml). The organic layer was evaporated to dryness and co-evaporated with TBME (100 ml) under vacuum at 45 to 50° C. Yield: 330 g (90percent). Assay (HPLC): 98percent pure vs. standard.
55% With hydrogen iodide In water at 0℃; for 0.25 h; Cooling with ice Ice cooled hydriodic acid (Wako Pure Chemical Industries, Ltd.) (14.7 ml, 57percent) was added gradually to 3.68 g (32.0 mmoles) of 2-chloropyrimidine (Sigma-Aldrich Corporation), and the reaction mixture was agitated for fifty minutes at 0°C. Ice cooled aqueous sodium carbonate solution was added to the reaction solution until the solution was neutral, and aqueous sodium sulfite solution was subsequently added. The product was extracted using diethyl ether, and the organic layer was dried using anhydrous sodium sulfate after it was washed once using a saturated aqueous sodium chloride solution. The solvent was removed, and the pale yellow oil remaining was dissolved in boiling hexane. The solution was left standing to cool, and 3.62 g (17.6 mmoles, 55percent) of colorless needle-like crystals (Compound 2) was obtained. The analytical results for Compound 2 obtained (2-iodopyrimidene) are shown below. 1H-NMR (400 MHz, CDCl3, TMS, rt) δ 8.47 (2H, d, J = 4.8 Hz), 7.32 (1H, t, J = 4.9 Hz)
Reference: [1] Patent: US2006/58343, 2006, A1, . Location in patent: Page/Page column 7
[2] Journal of Organic Chemistry, 2002, vol. 67, # 18, p. 6550 - 6552
[3] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1990, # 7, p. 1269 - 1274
[4] Patent: EP2395055, 2011, A1, . Location in patent: Page/Page column 8
[5] Journal of the American Chemical Society, 2012, vol. 134, # 12, p. 5528 - 5531
  • 39
  • [ 1722-12-9 ]
  • [ 32779-36-5 ]
YieldReaction ConditionsOperation in experiment
14.1 g With N-Bromosuccinimide; boron trifluoride diethyl etherate In acetonitrile at 20℃; Reflux In a reaction flask was added 11.5 g (0.1 mol) of 2-chloropyrimidine, bromination reagent NBS 21.3 g (0.12 mol) and acetonitrile 80 mL. A catalytic amount of 2.8 g (0.02 mol) of BF3-Et2O was added at room temperature. After the addition was complete, heating to reflux for 5-8 hours. Completion of the reaction was detected by TLC. Cooling. After insoluble solids were filtered off, after distilling the solvent under reduced pressure, ethyl acetate was added to dissolve followed by dropwise addition of 45 mL of saturated Na2CO3 solution. The organic layer was separated. The aqueous layer was further mixed with 60 mL of ethyl acetate and stratified again. After combining the organic layers, washed with a saturated saline solution. Dried to give 14.1 g of pale yellow 2-chloro-5-bromopyrimidine as a solid. It was used directly in the next reaction.
29 g Reflux 24g 2-chloropyrimidine was added to 200ml acetic acid, 50g bromine was added dropwise, heated to reflux overnight, cooled,Water and ethyl acetate were added, the extracts were separated, the organic phase was collected, dried and concentrated to give 29 g of 5-bromo-2-chloropyrimidine.
29 g Reflux 24 g of 2-chloropyrimidine was added to 200 ml of acetic acid, and 50 g of bromine was added dropwise. The mixture was heated under reflux and stirred overnight. After cooling, water and ethyl acetate were added and the mixture was extracted and collected. The organic phase was collected, dried, and concentrated to give 29 g of 5-bromo-. 2-chloropyrimidine.
Reference: [1] Patent: CN104788482, 2016, B, . Location in patent: Paragraph 0017
[2] Patent: CN107400113, 2017, A, . Location in patent: Paragraph 0021; 0022
[3] Patent: CN107698556, 2018, A, . Location in patent: Paragraph 0020; 0021; 0022
  • 40
  • [ 1722-12-9 ]
  • [ 4595-60-2 ]
Reference: [1] European Journal of Organic Chemistry, 2002, # 24, p. 4181 - 4184
[2] Tetrahedron Letters, 2000, vol. 41, # 10, p. 1653 - 1656
  • 41
  • [ 1722-12-9 ]
  • [ 34671-83-5 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2005, vol. 42, # 7, p. 1423 - 1428
[2] Journal of Organic Chemistry, 2002, vol. 67, # 2, p. 443 - 449
[3] Synthetic Communications, 1991, vol. 21, # 7, p. 901 - 906
[4] Tetrahedron, 1994, vol. 50, # 41, p. 11893 - 11902
[5] Patent: EP2172470, 2010, A1, . Location in patent: Page/Page column 43
  • 42
  • [ 1722-12-9 ]
  • [ 31575-35-6 ]
Reference: [1] Chemistry Letters, 1993, # 3, p. 509 - 512
[2] Chemistry Letters, 1993, # 3, p. 509 - 512
  • 43
  • [ 1722-12-9 ]
  • [ 105-53-3 ]
  • [ 63155-11-3 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at -78℃; for 0.166667 h;
Stage #2: at 20 - 120℃; for 90 h;
To a solution of diethylmalonate (6.65 mL, 43.65 mmol) in DMF (30 mL) at -78 °C,was added NaH (1.76 g, 52.38 mmol, 60percent dispersion in mineral oil). The reaction was stirredfor 10 min at -78 °C, warmed to room temperature and 2-chloropyrimidine (1.0 g, 8.73 mmol)in DMF (3 mL) was added. The reaction mixture was heated to 80 °C for 72 hours, then to120 °C for 18 hours, and upon completion was cooled to room temperature. The solution was15 quenched by addition of IN HCl, neutralized with saturated aqueous NaHC03 and extractedwith EtOAc (3X). The combined organics were dried over Na2S04, filtered, concentrated andpurified by flash chromatography on silica gel (0-1 00percent EtOAc in hexanes) to give the titlecompound as a yellow-orange oil (1.34 g, 92percent). MS 167 (MH+).
Reference: [1] Patent: WO2014/25706, 2014, A1, . Location in patent: Page/Page column 87
  • 44
  • [ 1722-12-9 ]
  • [ 594-19-4 ]
  • [ 66522-06-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 10, p. 2800 - 2803
[2] Patent: US2006/69110, 2006, A1, . Location in patent: Page/Page column 70
  • 45
  • [ 1722-12-9 ]
  • [ 75-98-9 ]
  • [ 66522-06-3 ]
Reference: [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 9, p. 2750 - 2755
[2] Dalton Transactions, 2018, vol. 47, # 34, p. 11942 - 11952
  • 46
  • [ 1722-12-9 ]
  • [ 815-17-8 ]
  • [ 66522-06-3 ]
Reference: [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 9, p. 2750 - 2755
  • 47
  • [ 1722-12-9 ]
  • [ 75-61-6 ]
  • [ 133391-65-8 ]
  • [ 133391-64-7 ]
  • [ 116470-67-8 ]
Reference: [1] Journal of Fluorine Chemistry, 1990, vol. 50, # 3, p. 411 - 426
  • 48
  • [ 1722-12-9 ]
  • [ 75-61-6 ]
  • [ 116470-67-8 ]
Reference: [1] Journal of the Chemical Society, Chemical Communications, 1988, # 10, p. 638 - 639
  • 49
  • [ 1722-12-9 ]
  • [ 3605-01-4 ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine In ethanol at 95 - 100℃; for 1 h; The intermediate intermediate piperonyl piperazine, 360 ml of absolute ethanol and 120 ml of triethylamine were placed in a 1000 ml three-necked reaction flask and heated to 95 ° C to 100 ° C with stirring. A mixed solution of 70 g of dichloropyrimidine and 360 ml of absolute ethanol was added dropwise, and the mixture was incubated at 95 ° C to 100 ° C for 1 hour, distilled under reduced pressure, and about 400 ml of ethanol and triethylamine solution were removed, cool to room temperature and filter. Atmospheric distillation, remove the ethanol and triethylamine about 250ml, cooled to room temperature, filter the solid, add water, beating, pumping filter, to get piribedil crude 160g, content 92percent, the total yield of 80percent.
Reference: [1] Patent: CN106432212, 2017, A, . Location in patent: Paragraph 0010; 0020
  • 50
  • [ 1722-12-9 ]
  • [ 32231-06-4 ]
  • [ 3605-01-4 ]
YieldReaction ConditionsOperation in experiment
44% With potassium carbonate In tetrahydrofuran for 2 h; Reflux 250 ml of a three-necked flask was added 50 g of piperonyl piperazine, 26 g of dichloropyrimidine, 330 ml of tetrahydrofuran and 65 g of potassium carbonate, and the mixture was heated under reflux for 2 hours. The mixture was cooled and cooled, and 1600 ml of distilled water was added thereto, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a dark red viscous liquid (56.3 g). Add 40ml of anhydrous ethanol, dissolve, slightly cold, add activated carbon 40g, reflux 30 minutes, hot filter, cooling, precipitation of white solid, filtration, 40 °C vacuum drying to get 30.2 g of white crystalline powder, yield 44percent.
Reference: [1] Journal of Organic Chemistry, 2018, vol. 83, # 16, p. 9144 - 9155
[2] Patent: CN106432212, 2017, A, . Location in patent: Paragraph 0015
  • 51
  • [ 1722-12-9 ]
  • [ 57260-73-8 ]
  • [ 584-08-7 ]
  • [ 137583-05-2 ]
Reference: [1] Patent: US6159964, 2000, A,
  • 52
  • [ 1722-12-9 ]
  • [ 107-15-3 ]
  • [ 137583-05-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 1, p. 360 - 371
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 4, p. 705 - 716
  • 53
  • [ 1722-12-9 ]
  • [ 1126-09-6 ]
  • [ 111247-60-0 ]
YieldReaction ConditionsOperation in experiment
81% for 18 h; Reflux; Inert atmosphere Method ACompound 1: l-Pyrimidin-2-yl-piperidine-4-carboxylic acid ethyl esterA mixture of 2-chloropyrimidine (2.28g, 20mmol) and ethyl isonipecotate (4.72g, 30mmol) in toluene (10ml) was heated at reflux for 18 h. then cooled to RT. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. The organics were separated, dried, and the solvents removed in vacuo. The residue was purified by flash chromatography on silica (eluant: EtOAc/pet. ether 40/60 v/v) to yield the title compound as a colourless oil.Yield = 4.0Og, 81percent. (ESI+): [M+H]+ = 236.0
Reference: [1] Farmaco, 1993, vol. 48, # 10, p. 1439 - 1445
[2] Patent: WO2010/97576, 2010, A1, . Location in patent: Page/Page column 39
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8696 - 8711
  • 54
  • [ 1722-12-9 ]
  • [ 688-73-3 ]
  • [ 153435-63-3 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 12 h; Inert atmosphere
After replacing the nitrogen in the round bottom flask, dissolve HSn (Bu) 3 (12.5 g) in 20 ml of anhydrous THF, add 2M LDA (18.75 g) while stirring at 0 ° C and stir for 30 minutes. Then, 2-chloropyrimidine (4 g, 35 mmole) dissolved in 20 mL of anhydrous THF at -18 ° C was slowly added dropwise. Subsequently, the reaction temperature was lowered to room temperature, and the mixture was stirred for 12 hours. After completion of the reaction, 30 ml of water was added and extracted with EA. Removal of the solvent followed by column purification hex to yield 11.68 g (90percent yield).
56%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at 0℃; for 0.25 h;
Stage #2: at -78 - 20℃;
A 2.0 M lithium diisopropylamide/heptane, tetrahydrofuran, an ethylbenzene solution (26.2 ml), and tri-n-butyltin hydride (14.1 ml) were added in that order to anhydrous tetrahydrofuran (100 ml) under an argon atmosphere at 0°C, and the mixture was stirred at 0°C for 15 min.
The reaction mixture was cooled to -78°C, and 2-chloropyrimidine (5.0 g) dissolved in anhydrous tetrahydrofuran (20 ml) was added dropwise to the cooled mixture.
The mixture was slowly brought to room temperature and was stirred overnight.
Water was added to the reaction mixture to stop the reaction.
The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate.
The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate.
The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a hexane-ethyl acetate system to give 2-tri-n-butylstannylpyrimidine (9.1 g, yield 56percent).
To anhydrous tetrahydrofuran (100 ml) were added a 2.0 M lithium diisopropylamide/heptane, tetrahydrofuran, an ethylbenzene solution (26.2 ml), and tri-n-butyltin hydride (14.1 ml) in that order under an argon atmosphere at 0°C. The mixture was stirred at 0°C for 15 min. The reaction mixture was cooled to -78°C. 2-Chloropyrimidine (5.0 g) dissolved in anhydrous tetrahydrofuran (20 ml) was added dropwise to the cooled reaction mixture. The mixture was slowy brought to room temperature and was stirred overnight. Water was added to the reaction mixture to stop the reaction. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a hexane-ethyl acetate system to give 2-tri-n-butylstannylpyrimidine (9.1 g, yield 56percent). 2-Tri-n-butylstannylpyrimidine (5.0 g) was dissolved in tetrahydrofuran (130 ml) under an argon atmosphere. A 1.6 M n-butyllithium/hexane solution (8.6 ml) was added dropwise to the solution at -78°C, and the mixture was stirred at -78°C for 30 min. 4,5-Dimethylfurfural (1.85 g) dissolved in tetrahydrofuran (20 ml) was added dropwise to the solution, and the mixture was brourgh to room temperature with stirring. Water was added to the reaction mixture to stop the reaction. The solvent was removed by distillation under the reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a hexane-ethyl acetate system to give (5-ethylfuran-2-yl)-pyrimidin-2-yl-methanol (888 mg, yield 32percent). (5-Ethylfuran-2-yl)-pyrimidin-2-yl-methanol (880 mg) was dissolved in chloroform (15 ml), manganese dioxide (3.8 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite, and the solvent was removed from the filtrate by distillation under the reduced pressure. The residue was used in the next reaction without purification. The residue, methanol (7 ml), and a 28percent aqueous ammonia solution (8 ml) were placed in a sealed tube, and the mixture was stirred at 160°C overnight. The reaction mixture was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography with a hexane-acetone system to give 6-ethyl-2-pyrimidin-2-yl-pyridin-3-ol (305 mg, yield 35percent).
Reference: [1] Patent: KR2018/75381, 2018, A, . Location in patent: Paragraph 0071; 0072-0074
[2] Patent: EP1724268, 2006, A1, . Location in patent: Page/Page column 58; 77; 95
  • 55
  • [ 123-75-1 ]
  • [ 1722-12-9 ]
  • [ 192197-34-5 ]
YieldReaction ConditionsOperation in experiment
87% With 1-methyl-3-(2-pyridinyl)-3,4,5,6-tetrahydropyrimidin-3-ium hexafluorophosphate; potassium <i>tert</i>-butylate; palladium diacetate In 1,2-dimethoxyethane at 100℃; for 0.666667 h; Microwave irradiation General procedure: The Buchwald–Hartwig amination reaction under microwave irradiation was conducted in a CEM Discover apparatus. A 10-mL Teflon vessel was charged with 1.0 mmol of hetero-aryl halide, 3.0 mmol of amine, 2.0 of mmol base, 0.05 mmol of Pd(OAc)2 , 0.10 mmol of LHX, and 2.0 mL of solvent. The mixture was irradiated at 150 W at 100 °C for the specified time and then allowed to cool. The reaction mixture was extracted 3 times with diethyl ether, and the combined organic extracts were washed with water, dried (MgSO4) , and evaporated to dryness. Purification of the residue by flash chromatography on silica gel afforded the pure products.
76%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil for 0.5 h; Reflux
Stage #2: for 48 h; Reflux
Example 5
Synthesis of HK-9, HK-11, HK-13 and HK-15
The following describes the general synthesis of 2-(pyrrolidine-1-yl)pyrimidine (HK-9), 4,6-dimethoxy-2-(pyrrolidine-1-yl)pyrimidine, HK-11, 2-(piperidine-1-yl)pyrimidine (HK-13), 4,6-dimethoxy-2-(piperidine-1-yl)pyrimidine (HK-15), 5-benzyloxy-2-(pyrrolidine-1-yl)pyrimidine (Compound 35), 5-benzyloxy-2-(piperidine-1-yl)pyrimidine (Compound 36), 5-benzyloxy-4,6-dimethoxy-2-(pyrrolidine-1-yl)pyrimidine (Compound 37), and 5-benzyloxy-4,6-dimethoxy-2-(piperidine-1-yl)pyrimidine (Compound 38).
Referring to the reaction scheme of , to 9.53 mL (116 mmol) pyrrolidine (29) in 400 mL of anhydrous THF was added 2.78 g of sodium hydride (116 mmol) and the mixture was refluxed for 0.5 hr.
After cooling to r.t., 12 g (105 mmol) of 2-chloropyrimidine (33) was added dropwise and the mixture was refluxed for 2 days and then cooled in an ice bath.
Water (200 mL) was then added to the cooled reaction mixture and the THF was removed in vacuo.
The aqueous residue was extracted with CHCl3 and the combined CHCl3 extracts were washed with brine, dried over magnesium sulfate, and filtered.
After removal of solvent in vacuo, the residue was purified by silica gel column chromatography using 20:1 hexanes:EtOAc as eluent.
The product was then recrystallized from diethyl ether (Et2O) to give a 12.0 g (76percent) of HK-9 as a yellow solid, mp 39.0-39.6° C. 1H NMR (CDCl3) δ 8.31 (d, J=4.88 Hz, 2H), 6.45 (t, J=4.88 Hz, 1H), 3.57 (t, J=4.4 Hz, 4H), 2.01-1.98 (m, 4H). Anal. Calcd for C8H11N3; C, 64.40; H, 7.43; N, 28.16. Found: C, 64.42; H, 7.53; N, 27.97.
Reference: [1] Turkish Journal of Chemistry, 2015, vol. 39, # 1, p. 121 - 129
[2] European Journal of Organic Chemistry, 2016, vol. 2016, # 36, p. 5957 - 5963
[3] Tetrahedron Letters, 2004, vol. 45, # 4, p. 757 - 759
[4] ChemSusChem, 2013, vol. 6, # 8, p. 1455 - 1460
[5] Patent: US2014/235858, 2014, A1, . Location in patent: Paragraph 0077
[6] Journal of Medicinal Chemistry, 2015, vol. 58, # 22, p. 8796 - 8805
[7] Pesticide Science, 1997, vol. 50, # 3, p. 258 - 274
[8] Journal of Heterocyclic Chemistry, 2004, vol. 41, # 3, p. 343 - 348
  • 56
  • [ 1722-12-9 ]
  • [ 269409-73-6 ]
  • [ 579476-26-9 ]
YieldReaction ConditionsOperation in experiment
79% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In water; N,N-dimethyl-formamide at 110℃; Inert atmosphere To a degassed souton of DMF:H20 (10:1 raUo) (0.3 M), under an atmosphere of nitrogen, was added the pnaco ester (1 mmo), 2-bromopyrdne or 2-choropyrmdne (1 .5 eq.), and Cs2CO3 (4.4 eq.). The whoe mxture was degassed once agan and then Pd(PPh3)4 (5mopercent) was added. The resutng souton was heated to 110°C overnght. The sovent was removed in vacuo to give a dark gummy residue, which was taken up nto EtOAc and H20, then acdfied with 2 M HC to pH 2. The organic ayer was separated and the aqueous ayer was further extracted with EtOAc (2x). The combined organic ayers were dried over MgSO4 and concentrated in vacuo to gve a back ofly residue. The residue was dry oaded ontosWca ge in vacuo then purfied by flash coumn chromatography, eutng with 10-30percent EtOAc/petroeum benzne and 1percent acetic acid to afford the tWe compound.The foHowng compounds were made by Suzuk CoupUng F:CO2HP7BiOff-whte scUd (79percent) yed). 1H NMR (400 MHz,DM80) 6 8.99 (t, J = 1.5 Hz, 1 H), 8.95 (d, J = 4.9Hz, 2H), 8.61 (d, J= 7.9 Hz, 1H), 8.09 (d, J 7.7 Hz,1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.50 (t, J = 4.9 Hz, 1 H).LCMS B rt2.96 mn, m/z201.1 [M + H].
Reference: [1] Patent: WO2016/198507, 2016, A1, . Location in patent: Page/Page column 40; 51
  • 57
  • [ 626-55-1 ]
  • [ 1722-12-9 ]
  • [ 483324-01-2 ]
YieldReaction ConditionsOperation in experiment
53%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 1 h; Inert atmosphere
Stage #2: at -30 - 0℃; for 1.66667 h;
Stage #3: With 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran; diethyl ether; hexane; water at 0 - 20℃; for 0.25 h;
Preparation of 2-chloro-4-pyridin-3-yl-pyrimidine lll-a To a solution of n-butyllithium (2.5 molar in hexane, 13.5 mL, 34 mmol) in anhydrous diethylether (50 mL) under argon at -78 ' was added 3-bromo pyridine (3 mL, 31 mmol). The mixture was stirred for 1 h, then a suspension of 2-chloro pyrimidine (3.6 g, 31 mmol) in anhydrous diethylether (30 mL) was added portionwise over 10 min. The resulting mixture was stirred at -30 °C for 30 min, and then allowed to warm to 0 °C for 1 h, at which point the reaction was successively quenched by addition of water (1 mL) in THF (10 mL) and DDQ (7.6 g, 34 mmol) in THF (25 mL). The resulting brown suspension was stirred at room temperature for 15 min, then cooled to 0 ', and treated with hexane (25 mL) and aqueous NaOH (3N, 25 mL). The mixture was stirred at 0 ' for 5 min, diluted with water (100 mL) and then extracted with ethyl acetate. The combined organic layers were washed with water, dried on MgS04, and concentrated to a minimum volume to afford after filtration lll-a as a pale brown solid (3.14 g, 53 percent). H NMR (400 MHz, DMSO- de) δ 9.35 (dd, J = 2.3, 0.8 Hz, 1 H), 8.90 (d, J = 5.3 Hz, 1 H), 8.79 (dd, J = 4.8, 1 .6 Hz, 1 H), 8.54 (ddd, J = 8.0, 2.3, 1 .7 Hz, 1 H), 8.26 (d, J = 5.3 Hz, 1 H), 7.62 (ddd, J = 8.0, 4.8, 0.8 Hz, 1 H).
Reference: [1] Organic Letters, 2005, vol. 7, # 19, p. 4113 - 4116
[2] Patent: WO2014/202763, 2014, A1, . Location in patent: Page/Page column 48-49
  • 58
  • [ 60573-68-4 ]
  • [ 1722-12-9 ]
  • [ 483324-01-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 1, p. 366 - 370
[2] Molecules, 2016, vol. 21, # 4,
  • 59
  • [ 1722-12-9 ]
  • [ 483324-01-2 ]
Reference: [1] Patent: WO2008/11110, 2008, A2, . Location in patent: Page/Page column 34-35
  • 60
  • [ 110-85-0 ]
  • [ 1722-12-9 ]
  • [ 219599-99-2 ]
Reference: [1] Patent: US2001/20022, 2001, A1,
[2] Patent: US2002/143179, 2002, A1,
[3] Patent: US6486162, 2002, B2,
  • 61
  • [ 5382-16-1 ]
  • [ 1722-12-9 ]
  • [ 893755-98-1 ]
YieldReaction ConditionsOperation in experiment
81% With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 18 h; Step 1 : 1-(2-Pyrimidinyl)-4-piperidinol (180) <n="157"/>4-Hydroxypiperidine (1.5 g, 14.7 mmol) was combined with 2-chloropyrimidine (1.5 g, 13.4 mmol) and diisopropylethylamine (6 ml_, 33.5 mmol) into 50 ml. acetonitrile. The mixture was heated at 80 0C for 18 hours. The reaction mixture was then concentrated to dryness and the crude residue was then purified on via flash column chromatography using a gradient of 0-60percent ethylacetate/hexane to give 2.1 g (81percent) of the desired compound 180 as a white solid. 1H NMR (400 MHz, CDCI3): δ 8.28 (d, J = 4.6 Hz 2 H), 6.49 (t, J = 4.8 Hz, 1 H), 4.49 - 4.33 (m, 2 H), 4.01 - 3.88 (m, 1 H), 3.37 - 3.21 (m, 2 H), 2.02 - 1.90 (m, 2 H), 1.60 - 1.45 (m, 2 H); LCMS (ESI): m/z 180 (M + H)+.
Reference: [1] Patent: WO2008/8895, 2008, A1, . Location in patent: Page/Page column 155; 156
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 24, p. 10972 - 10994
  • 62
  • [ 1722-12-9 ]
  • [ 395082-55-0 ]
YieldReaction ConditionsOperation in experiment
18%
Stage #1: With N,N,N,N,-tetramethylethylenediamine; zinc(II) chloride In tetrahydrofuran at 0℃; for 2 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuranInert atmosphere
To a stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine (0.50 mL, 3.0 mmol) in THF (6 mL) were successively added BuLi(about 1.6 M hexanes solution, 3.0 mmol) and, 5 min later, ZnCl2·TMEDA7 (0.26 g, 1.0mmol). The mixture was stirred for 15 min at 0 °C before introduction of 2-chloropyrimidine(2, 0.11 g, 1.0 mmol). After 2 h at this temperature, a solution of I2 (0.76 g, 3.0 mmol) in THF(10 mL) was added. The mixture was stirred overnight before addition of an aqueoussaturated solution of Na2S2O3 (10 mL) and extraction with AcOEt (3 x 20 mL). The combinedorganic layers were dried over MgSO4, filtered and concentrated under reduced pressure.Purification was performed by chromatography on silica gel (eluent: heptane/AcOEt 95/5) toafford 4a in 18percent yield as a beige powder
Reference: [1] Chemistry - A European Journal, 2009, vol. 15, # 6, p. 1468 - 1477
[2] Synlett, 2015, vol. 26, # 20, p. 2811 - 2816
  • 63
  • [ 1722-12-9 ]
  • [ 109384-19-2 ]
  • [ 412293-91-5 ]
YieldReaction ConditionsOperation in experiment
68%
Stage #1: With sodium hydride In tetrahydrofuran at 5℃; for 0.5 h;
Stage #2: at 20℃; for 18 h;
Preparation 28; tert-Butyl 4-(pyrimidin-2-yloxy)piperidine-1-carboxylate; 1-tert-Butoxycarbonyl-4-hydroxypiperidine (10g, 50mmol) was dissolved in tetrahydrofuran (200mL) and cooled to 5°C. Sodium hydride (60percent dispersion in mineral oil, 2.5g, 65mmol) was added portionwise and the resulting mixture was stirred for 30 minutes at 5°C. 1-Chloropyrimidine (11.4g, 99mmol) was added and the mixture was stirred for 18 hours at room temperature. The mixture was then filtered, concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Re- crystallisation of the residue for diisopropyl ether (50mL) afforded the title compound in 68percent yield, 9.5g.
Reference: [1] Patent: WO2005/105779, 2005, A1, . Location in patent: Page/Page column 46
  • 64
  • [ 1722-12-9 ]
  • [ 41979-39-9 ]
  • [ 116247-92-8 ]
YieldReaction ConditionsOperation in experiment
66% With triethylamine In ethanolHeating / reflux 5.1. Preparation of N-(3 '-chloro-3-methylbiphenyl-4-yl)-l-(pyrimidin-2- yl)piperidin-4-amineThe title compound was prepared stepwise, as described below. A. 1 -Pyrimidin-2-yl-piperidin-4-one : A mixture of 4-piperidone monohydrate hydrochloride (4.84 g, 31.5 mmol), 2-chloropyrimidine (3.44 g, 30 mmol) and TEA (10.04 ml, 72 mmol) in EtOH (150 ml) was heated at reflux for overnight. The mixture was concentrated to almost dry and diluted with EtOAc (400 ml). The EtOAc layer was washed with water (2 x 50 ml) and brine (2x50 ml). The aq layer was back extracted with EtOAc (4 x 100 ml). The combined EtOAc was dried (Na2SO4) and the solvent was removed. The residue was subjected to ISCO (12Og column, hexane 5 min., 0-80percent EtOAc in hexane over 70 min., then EtOAc for 15 min) to give the titled compound (3.5 g, 66percent). HPLC: column, Luna Phenyl-Hexyl 5 μm 4.6x50 mm, 10-90percent solvent B (acetonitrile) in solvent A (10 mM ammonium acetate aq.) over 3 min., flow rate 3 ml/min, retention time, 0.97 and 1.08 min.; MS (MH+: 178).1H NMR (300 MHz, chloroform- d), δ ppm 2.52 (t, J=6.29 Hz, 4 H), 4.15 (t, J=6.20 Hz, 4 H), 6.60 (t, J=4.67 Hz, 1 H), 8.38 (d, J=4.77 Hz, 2 H).
53%
Stage #1: at 20 - 80℃;
Stage #2: With water; sodium hydrogencarbonate In ethyl acetate
A. 1 -Pyrimidin-2-yl-piperidin-4-one : To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with ethyl acetate (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40percent ethyl acetate/hexanes) to give l-pyrimidin-2-yl-piperidin-4-one (320 mg, 53percent) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J= 6.4 Hz, 2 H), 6.61 (t, J= 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H).
53%
Stage #1: at 20 - 80℃;
Stage #2: With sodium hydrogencarbonate In water; ethyl acetate
A. 1 -Pyrimidin-2-yl-piperidin-4-one:; To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with ethyl acetate (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40percent ethyl acetate/hexanes) to give l-pyrimidin-2-yl-piperidin-4-one (320 mg, 53percent) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J= 6.4 Hz, 2 H), 6.61 (t, J= 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H).
53% at 20 - 80℃; 6.8. Preparation of Biphenyl-4-yl-fl-pyrimidin-2-yl-l,2,3i6-tetrahydro- pyridin-4-vl)-methanone; To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with EtOAc (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40percent EtOAc/hexanes) to give l-pyrimidin-2-yl- piperidin-4-one (320 mg, 53percent) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J = 6.4 Hz, 2 H), 6.61 (t, J = 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H).
53% at 80℃; To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 80° C. overnight and concentrated under reduced pressure. The residue was treated with EtOAc (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2.x.10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40percent EtOAc/hexanes) to give 1-pyrimidin-2-yl-piperidin-4-one (320 mg, 53percent) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J=6.4 Hz, 2 H), 6.61 (t, J=6.4 Hz, 9 H), 4.16 (t, J=5.6 Hz, 2 H), 2.53 (t, J=5.6 Hz, 2 H).

Reference: [1] Patent: WO2008/58064, 2008, A1, . Location in patent: Page/Page column 17
[2] Patent: WO2008/58068, 2008, A1, . Location in patent: Page/Page column 23
[3] Patent: WO2008/67120, 2008, A2, . Location in patent: Page/Page column 23
[4] Patent: WO2008/67121, 2008, A2, . Location in patent: Page/Page column 52
[5] Patent: US2006/258672, 2006, A1, . Location in patent: Page/Page column 17
  • 65
  • [ 41661-47-6 ]
  • [ 1722-12-9 ]
  • [ 116247-92-8 ]
YieldReaction ConditionsOperation in experiment
21.54% With triethylamine In 1,4-dioxane at 90℃; for 12 h; To a mixture of 2-chloropyrimidine (300.00 mg, 2.62 mmol, 1.00 eq) and piperidin-4-one (311.59 mg, 3.14 mmol, 1.20 eq) in dioxane (5.00 mL) was added triethylamine (795.35 mg, 7.86 mmol, 3.00 eq) and the mixture was stirred at 90 °C for 12 h. The mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (Si02, PE/EA=10/1 to 1/1) to afford l-pyrimidin-2-ylpiperidin-4- one (100.00 mg, 564.33 umol, 21.54percent yield) as a yellow solid. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.37 (d, J=4.9 Hz, 2H), 6.59 (t, J=4.6 Hz, 1H), 4.21 - 4.11 (m, 4H), 2.51 (t, J=6.2 Hz, 4H).
Reference: [1] Patent: WO2016/172496, 2016, A1, . Location in patent: Paragraph 00638-00639
  • 66
  • [ 1722-12-9 ]
  • [ 40064-34-4 ]
  • [ 116247-92-8 ]
Reference: [1] Patent: WO2008/58064, 2008, A1, . Location in patent: Page/Page column 20
  • 67
  • [ 1722-12-9 ]
  • [ 1032452-86-0 ]
Reference: [1] Molecules, 2016, vol. 21, # 4,
  • 68
  • [ 1722-12-9 ]
  • [ 127-17-3 ]
  • [ 1312535-78-6 ]
Reference: [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 9, p. 2750 - 2755
  • 69
  • [ 1722-12-9 ]
  • [ 541-41-3 ]
  • [ 1196152-00-7 ]
Reference: [1] Patent: US9953768, 2018, B2, . Location in patent: Page/Page column 79-80
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