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Chemical Structure| 2444-36-2
Chemical Structure| 2444-36-2
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Product Details of [ 2444-36-2 ]

CAS No. :2444-36-2 MDL No. :MFCD00004317
Formula : C8H7ClO2 Boiling Point : -
Linear Structure Formula :- InChI Key :IUJAAIZKRJJZGQ-UHFFFAOYSA-N
M.W : 170.59 Pubchem ID :17124
Synonyms :

Calculated chemistry of [ 2444-36-2 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 43.0
TPSA : 37.3 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) : -5.84 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.52
Log Po/w (XLOGP3) : 2.12
Log Po/w (WLOGP) : 1.97
Log Po/w (MLOGP) : 2.25
Log Po/w (SILICOS-IT) : 2.18
Consensus Log Po/w : 2.01

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.5
Solubility : 0.533 mg/ml ; 0.00313 mol/l
Class : Soluble
Log S (Ali) : -2.53
Solubility : 0.498 mg/ml ; 0.00292 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.79
Solubility : 0.279 mg/ml ; 0.00164 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.36

Safety of [ 2444-36-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 2444-36-2 ]

* 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 [ 2444-36-2 ]
  • Downstream synthetic route of [ 2444-36-2 ]

[ 2444-36-2 ] Synthesis Path-Upstream   1~20

  • 1
  • [ 2444-36-2 ]
  • [ 74-89-5 ]
  • [ 61-70-1 ]
Reference: [1] RSC Advances, 2017, vol. 7, # 71, p. 45227 - 45231
  • 2
  • [ 2444-36-2 ]
  • [ 64-17-5 ]
  • [ 40061-54-9 ]
YieldReaction ConditionsOperation in experiment
97% Reflux Intermediate AR(1)ethyl 2-(2-chlorophenyl)acetateA mixture of 2-(2-chlorophenyl)acetic acid (10 g, 58.6 mmol) in EtOH (Volume: 152 ml) was treated with H2S04 (1.719 ml, 32.2 mmol). The result mixture was refluxed overnight. The heat was removed, and the reaction mixture was concentrated. The resulting oil was dissolved in EtOAc and CAREFULLY treated with aqueous Na2C03 (3.47 g, 32.8 mmol) (CAUTION: Gas evolution) until the solution remained basic and no further gas evolution was seen. The EtOAc layer was then removed and the aqueous layer was again extracted two times with EtOAc. The combined organic layers were then washed with brine, dried over Na2S04 and concentrated in vacuo to obtain ethyl 2-(2- chlorophenyl)acetate (1 1.32 g, 57.0 mmol, 97 percent yield). LC-MS (M+H)+ = 199.1.3/4 NMR (500MHz, CD3OD) δ 7.41 (ddd, J=16.8, 5.6, 3.5 Hz, 1H), 7.35 (dd, J=5.5, 3.7 Hz, 1H), 7.28 (dd, J=5.8, 3.7 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 3.80 (s, 2H), 1.26 (t, J=7.2 Hz, 3H).
Reference: [1] Patent: WO2012/103297, 2012, A1, . Location in patent: Page/Page column 195-196
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
[3] Australian Journal of Chemistry, 2013, vol. 66, # 8, p. 864 - 873
[4] Journal of Medicinal Chemistry, 1993, vol. 36, # 26, p. 4239 - 4249
[5] Chinese Journal of Chemistry, 2010, vol. 28, # 4, p. 605 - 612
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1263 - 1266
[7] Synthesis (Germany), 2015, vol. 47, # 13, p. 1913 - 1921
  • 3
  • [ 2444-36-2 ]
  • [ 1643-28-3 ]
Reference: [1] Journal of Organic Chemistry, 1964, vol. 29, p. 3175 - 3179
  • 4
  • [ 2444-36-2 ]
  • [ 108-24-7 ]
  • [ 6305-95-9 ]
Reference: [1] Journal of the American Chemical Society, 1959, vol. 81, p. 3391,3392
[2] Journal of the American Chemical Society, 1961, vol. 83, p. 1691 - 1697
[3] Archiv der Pharmazie, 1992, vol. 325, # 12, p. 751 - 760
[4] Angewandte Chemie - International Edition, 2009, vol. 48, # 4, p. 800 - 802
[5] Angewandte Chemie - International Edition, 2016, vol. 55, # 17, p. 5309 - 5312[6] Angew. Chem., 2016, vol. 128, # 17, p. 5395 - 5398,4
  • 5
  • [ 110-86-1 ]
  • [ 2444-36-2 ]
  • [ 108-24-7 ]
  • [ 6305-95-9 ]
Reference: [1] Journal of the American Chemical Society, 1959, vol. 81, p. 3391,3392
  • 6
  • [ 2444-36-2 ]
  • [ 19819-95-5 ]
YieldReaction ConditionsOperation in experiment
18.3g With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 30℃; In the preparation of the starting material may exist during the adjacent S1 and S1, and isopropanolamine docking reactionAfter ring-closure reaction can be impurities B, C, D. The reaction is as follows:Specific operations are as follows: 20g of o-chlorophenylacetic acid (o-S1) was added to 200ml of tetrahydrofuran,Stirring was cooled to 0 ° C, 8.9g lithium aluminum hydride added in batches, plus Bi, warmed to 25 ~ 30 ° C reaction,After the reaction was added 300ml of water, dichloromethane 400ml, liquid separation,The organic phase was added to 20 g of anhydrous sodium sulfate, dried and concentrated under reduced pressure at 30-35 ° C.,Obtained light yellow oil (o-S1-1): 18.3g; under ice bath,To the adjacent S1-1 bottle dropping phosphorus tribromide, dropping temperature during the 0 ~ 10 , dropsInsulation Stir 10min after the completion of a white smoke generation, warming to 75 ~ 80 , stirring insulation 2h,After completion of the reaction was added 30ml saturated sodium bicarbonate solution, 200ml of ethyl acetate, stirred for 20min,Liquid separation, the organic phase was added 20g anhydrous sodium sulfate after drying 40 ~ 45Concentration under reduced pressure gave a yellow liquid (vicinal S2): 22.4 g Yield: 87.0percent
Reference: [1] Journal of Medicinal Chemistry, 1981, vol. 24, # 6, p. 678 - 683
[2] Patent: US6342501, 2002, B1, . Location in patent: Scheme 2
[3] Angewandte Chemie - International Edition, 2015, vol. 54, # 36, p. 10596 - 10599[4] Angew. Chem., 2015, vol. 127, p. 10742 - 10745,4
[5] Journal of Organic Chemistry, 1964, vol. 29, p. 3175 - 3179
[6] Tetrahedron Asymmetry, 1998, vol. 9, # 15, p. 2725 - 2737
[7] Journal of Organic Chemistry, 2007, vol. 72, # 3, p. 898 - 911
[8] Chemical Communications, 2005, # 35, p. 4453 - 4455
[9] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
[10] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3719 - 3735
[11] Patent: CN106478506, 2017, A, . Location in patent: Paragraph 0106; 0107
  • 7
  • [ 2444-36-2 ]
  • [ 74-88-4 ]
  • [ 2184-85-2 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With N,N,N,N,N,N-hexamethylphosphoric triamide; lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at 0 - 20℃; for 1 h;
Stage #2: at 0 - 20℃; for 0.5 h;
Stage #3: With hydrogenchloride In tetrahydrofuran; n-heptane; ethylbenzene; water
Example 308; 3-(4-Fluorophenyl)-5-[2-(2-chlorophenyl)propionylamino]-4-(4-pyrimidinyl)isoxazole; a: Synthesis of 2-(2-chlorophenyl)propionic acid; To 1 g of 2-chlorophenylacetic acid, 8.8 mL of 2M LDA heptane, THF, ethylbenzene solution was dropped under cooling with ice, and further 1.58 g of HMPA and 5 mL of THF were added followed by an hour's stirring at room temperature. Then 1.25 g of methyl iodide was added under cooling with ice and stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, rendered acidic with 10percent aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate and thereafter removed of the solvent by distillation under reduced pressure. The residue was purified on 30 g silica gel column chromatography (eluent, chloroform: methanol = 20:1) to provide 0.928 g (yield: 86percent) of the title compound as a pale yellow, oily substance. 1H-NMR(CDCl3)δ: 7.50-7.10(m, 4H), 4.27(q, J=7.2Hz, 1H), 1.52(d, J=7.2Hz, 3H). Mass, m/e: 184(M+), 139(base).
60%
Stage #1: With 1,2-disodiotetraphenylethane In tetrahydrofuran at 0℃; for 2 h; Inert atmosphere
Stage #2: at 0 - 20℃; Inert atmosphere
Stage #3: With hydrogenchloride In water
General procedure: To 5 mL of a 0.24 M solution of diorganometal 1b or 1c (1.2 mmol), chilled at 0 °C, was added a solution of the appropriate arylacetic acid 2 (1.1 mmol) dissolved in 5 mL of dry THF, and the resulting mixture was vigorously stirred for 2 h at 0 °C. To the resulting dark brown mixture, chilled at the same temperature, were added 1.7 mmol of the appropriate electrophile. The resulting mixture was vigorously stirred and allowed to reach rt overnight, after which time it was quenched by slow dropwise addition of H2O (15 mL). The organic solvent was evaporated in vacuo and the resulting mixture was extracted with CH2Cl2 (3.x.10 mL). The aqueous phase was acidified with 1 N HCl, extracted with CH2Cl2 (3.x.10 mL), and the organic phases were collected, washed with H2O (1.x.10 mL), brine (10 mL), dried (Na2SO4), and the solvent was evaporated. Crude reaction products were purified and characterized as reported below. The reaction mixture containing crude β-hydroxyacid 2df was quenched by adding it to 15 mL of 10percent HCl containing about 15 g of crushed ice,14 and worked up as described above. After evaporation of the solvent, the resulting crude material was purified and characterized as reported below. Quenching with D2O was realized as described in the above paragraph.
Reference: [1] Patent: EP1832584, 2007, A1, . Location in patent: Page/Page column 66
[2] Tetrahedron, 2011, vol. 67, # 19, p. 3470 - 3475
[3] Organic Letters, 2011, vol. 13, # 7, p. 1666 - 1669
[4] Journal of the American Chemical Society, 2017, vol. 139, # 44, p. 15632 - 15635
  • 8
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  • [ 2184-85-2 ]
Reference: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 11, p. 1704 - 1711
  • 9
  • [ 2444-36-2 ]
  • [ 29270-30-2 ]
YieldReaction ConditionsOperation in experiment
48% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; for 5 h; To a solution of 2.0 g of (2-chlorophenyl)acetic acid (11.76 mmole, Aldrich) and 2.1 g ofNBS (11.76 mmole, Aldrich) in 60 mL of CCI4 (carbon tetrachloride) in a dry flask under nitrogen were added 569 mg of benzoyl peroxide (2.35 mmole, Fluka). The solution was stirred at 8O0C for 5 h. The reaction mixture was filtered and the mother liquors were evaporated under reduced pressure. The resulting crude was purified by flash chromatography on 50 g silica gel cartridge using a gradient of DCM/AcOEt (DCM/Ethyl acetate) 10/0 to 5/5 as an eluent. Solvents were removed under reduced pressure to give the title compound (1.7 g, 48percent); 1H-NMR (400 MHz, CDCI3): δ 5.95 (1 H, s), 7.35 (3H, m), 7.80 (1 H, d).
Reference: [1] Patent: WO2008/148853, 2008, A1, . Location in patent: Page/Page column 51
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2008, vol. 47, # 1, p. 97 - 105
[3] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 2, p. 1355 - 1360
[4] Patent: CN103450005, 2016, B, . Location in patent: Paragraph 0051-0053
  • 10
  • [ 2444-36-2 ]
  • [ 29270-33-5 ]
  • [ 29270-30-2 ]
Reference: [1] Patent: US6358971, 2002, B1,
  • 11
  • [ 2444-36-2 ]
  • [ 106-48-9 ]
  • [ 25563-04-6 ]
YieldReaction ConditionsOperation in experiment
79% With potassium carbonate In toluene at 20 - 110℃; for 21 h; Inert atmosphere Potassium carbonate (109 gm) was charged into a clean and dry RBF at below 20°C under N2 atmosphere. To this toluene (400 ml) and 4-chloro phenol (56.5 gm) were added at the same temperature. To the resulting mixture 0.5 gm of CuCl was added at 20°C and the temperature of the reaction mixture was slowly raised to 100°C. To this 2-chloro phenyl acetic acid (50 gm) was added at 100°C and the obtained mixture was stirred for 1 hr at the same temperature. The reaction mixture was refluxed for 8 hrs at 110°C. K2C03 (80 gm) was added to the resulting mixture and stirred for 12 hrs at the same temperature. Then the reaction mixture was cooled to room temperature and water (250 ml) was added. The resulting mixture was acidified with HC1 and againvwater (100 ml) was added. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Both the organic layers were combined and washed with 10percent NaCl solution. The resulting organic layer was dried over Na2S04 and the solvent was completely distilled off under vacuum at below 60°C. n-Heptane (50 ml) was added to the obtained residue and stirred for 30-45 min at 25-35°C. The obtained solid was filtered, washed with n-heptane and then dried at 50-60°C to get the title compound. Yield: 79percent.
68.8%
Stage #1: With potassium carbonate In diethylene glycol dimethyl ether at 0 - 130℃; for 9 h;
Stage #2: With hydrogenchloride In diethylene glycol dimethyl ether; water
[Reference Example 2: Synthesis of 2-(2-(4-chlorophenoxy)phenyl)acetic acid] A mixture of 552.0 g (4.0 mol) of potassium carbonate and 1500 mL of diglyme was kept at 0-20°C while adding 283.1 g (2.2 mol) of 4-chlorophenol thereto and mixing, and then 5.74 g (0.04 mol) of copper(I) bromide was added. The obtained mixture was heated to 100°C, and 90.3 g (0.53 mol) of 2-chlorophenylacetic acid was added. This mixture was stirred at the same temperature for 1 hour, and then 159.4 g (0.93 mol) of 2-chlorophenylacetic acid was further added. After stirring the obtained mixture at 120-130°C for approximately 8 hours, completion of the reaction was confirmed by high-performance liquid chromatography. The reacted mixture was cooled to near room temperature, and then approximately 700 mL of water and approximately 650 mL of 35 wtpercent hydrochloric acid water were added in that order. The pH of the aqueous layer was below 1. After further adding about 500 mL of water to the obtained mixture, it was extracted once with 400 mL and once with 200 mL of toluene, in that order. The obtained organic layers were combined and washed 3 times with 500 mL of water and once with 500 mL of brine, in that order. The obtained organic layer was subjected to dehydration treatment with anhydrous magnesium sulfate, and 100 mL of heptane was added dropwise to approximately 400 g of the residue obtained by partially concentrating the treated organic layer. The internal temperature of the mixture after the dropwise addition was about 70°C, and crystals precipitated in the mixture. Upon completion of the dropwise addition, the mixture was cooled to 20-25°C and the crystals were separated off by filtration. The obtained crystals were washed with 100 mL of a heptane/toluene = 1/1 mixed solvent and dried under reduced pressure to obtain 245.6 g of 2-(2-(4-chlorophenoxy)phenyl)acetic acid as a white solid. The yield was 68.8percent.
Reference: [1] Patent: WO2012/38975, 2012, A2, . Location in patent: Page/Page column 35
[2] Patent: EP2166012, 2010, A1, . Location in patent: Page/Page column 13
[3] Patent: WO2011/159903, 2011, A2, . Location in patent: Page/Page column 36
  • 12
  • [ 67-56-1 ]
  • [ 2444-36-2 ]
  • [ 57486-68-7 ]
YieldReaction ConditionsOperation in experiment
97.5% for 16 h; Heating / reflux To 2-chlorophenylacetic acid (1.04 g, 6mmol) in MEOH (25 mL) was added sulfuric acid (6 drops) and the solution was refluxed for 16 hours. After concentration, the residue was taken up in ethyl acetate and washed with sat'd aq. NAHC03, H20 and brine. The organic layer was dried over NA2S04 and concentrated to give methyl (2-chlorophenyl) acetate 6a (1.08 g, 97.5 percent) as a yellowish oil. GCMS (EI) M/Z 184,186 (M+).
97.5% for 16 h; Heating / reflux To 2-CHLOROPHENYLACETIC acid (1.04 g, 6MMOL) in MEOH (25 mL) was added sulfuric acid (6 drops) and the solution was refluxed for 16 hours. After concentration, the residue was taken up in ethyl acetate and washed with sat'd aq. NAHC03, H20 and brine. The organic layer was dried over NA2S04 and concentrated to give methyl (2-chlorophenyl) acetate 2a (1.08 g, 97.5 percent) as a yellowish oil. GCMS (EI) M/Z 184,186 (M+).
97.8% at 0 - 20℃; for 3 h; Inert atmosphere; Schlenk technique General procedure: Thionyl chloride (1.06 mL, 14.63 mmol) was added to dropwise the solution of phenyl aceticacid derivatives (1 g, 4.877 mmol) in methanol (10 mL) at 0 . The reaction was allowed to room temperature for 3 h. The reaction mixture was evaporated under reduced pressure. The residue was dissolved ethyl acetate and water. The mixture was extracted with ethyl acetate and washed with sodium hydrogen carbonate aqueous solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6a-f.
97.2% at 0℃; Reflux 1. To a solution of Compound 1 (20 g, 117.6 mmol) in MeOH (100 mL) was added SOCl2 (10 mL) dropwise at 0 ° C The resulting solution was stirred at reflux overnight. TLC indicated reaction completion. The solvent was removed in vacuum, and the residue was treated with water and extracted with EA. The organic extracts were washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated to give Compound 2 (21 g, 97.2 percent).
79% Reflux General procedure: To an appropriately substituted phenylacetic acid (10 mmol) dissolved in dried methanol (50 mL), concentrated sulfuric acid (0.5 mL) was added dropwise.The mixture was refluxed from 7 to 9 h. Next, the solvent was evaporated, and residue was dissolved in 40 mL of ethyl acetate, washed with 0.5percent NaOH andbrine. Organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to give the products as colorless oils. 1.1.1. Methyl 2-(2-chlorophenyl)acetate (3e)CAS: 57486-68-7. Colorless oil, yield 79percent, 1H NMR [DMSO-d6] : 7.37-7.47 (m, 2H, Ph-4,6-H), 7.27-7.83 (m, 2H, Ph-3,5-H), 3.80 (s, 2H, Ph-CH2), 3.61 (s, 3H,CH3).

Reference: [1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 13, p. 2843 - 2866
[2] Tetrahedron Letters, 2003, vol. 44, # 2, p. 331 - 334
[3] Patent: WO2005/7165, 2005, A1, . Location in patent: Page 43
[4] Patent: WO2005/7633, 2005, A1, . Location in patent: Page 30-31
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 20, p. 5515 - 5518
[6] Patent: WO2016/77240, 2016, A2, . Location in patent: Page/Page column 31; 32; 49
[7] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 117 - 124
[8] Journal fuer Praktische Chemie (Leipzig), 1900, vol. <2>62, p. 562
[9] Journal of Medicinal Chemistry, 1993, vol. 36, # 23, p. 3738 - 3742
[10] Patent: WO2012/38975, 2012, A2, . Location in patent: Page/Page column 34
[11] Patent: WO2012/145234, 2012, A2, . Location in patent: Page/Page column 31
[12] Advanced Synthesis and Catalysis, 2015, vol. 357, # 11, p. 2479 - 2484
[13] Synlett, 2015, vol. 26, # 13, p. 1880 - 1884
[14] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3719 - 3735
[15] Chemical Communications, 2017, vol. 53, # 75, p. 10429 - 10432
[16] Journal of Chemistry, 2017, vol. 2017,
[17] Tetrahedron Letters, 2018, vol. 59, # 22, p. 2161 - 2166
[18] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 44, p. 11797 - 11805
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  • [ 149-73-5 ]
  • [ 57486-68-7 ]
YieldReaction ConditionsOperation in experiment
97% With sulfuric acid In methanol; water at 20℃; for 4 h; Example 19: Synthesis of N4- (4-aminomethyl-cyclohexylmethyl)-N2-[1-(2-chloro-phenyl)- 1-METHYL-ETHYL]-5-NITRO-PYRIMIDINE-2,4-DIAMINE To a solution of 10.0 g (59 MMOL) (2-chlorophenyl) acetic acid in MEOH (10 mL) was added 9.6 mL (88 mmol) OF TRIMETHYL ORTHOFORMATE and 0.32 mL (6.0 mmol) OF H2SO4. The reaction was stirred at room temperature for 4 h then diluted with EtOAc and washed with H2O followed by a saturated aqueous solution OF NAHCO3. The organic phase was dried over anhydrous NA2S04 and concentrated under reduced pressure to provide 10.6 g (97percent) of (2-chlorophenyl)-acetic acid methyl ester as a clear oil. The crude reaction product was not purified but used immediately.
Reference: [1] Patent: WO2004/67516, 2004, A1, . Location in patent: Page 85 - 86
  • 14
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  • [ 57486-68-7 ]
YieldReaction ConditionsOperation in experiment
97% With sulfuric acid; sodium hydrogencarbonate; trimethyl orthoformate In methanol Example 19
Synthesis of N4-(4-aminomethyl-cyclohexylmethyl)-N2-[1-(2-chloro-phenyl)-1-methyl-ethyl]-5-nitro-pyrimidine-2,4-diamine
To a solution of 10.0 g (59 mmol) (2-chlorophenyl)acetic acid in MeOH (10 mL) was added 9.6 mL (88 mmol) of trimethyl orthoformate and 0.32 mL (6.0 mmol) of H2SO4.
The reaction was stirred at room temperature for 4 h then diluted with EtOAc and washed with H2O followed by a saturated aqueous solution of NaHCO3.
The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 10.6 g (97percent) of (2-chlorophenyl)-acetic acid methyl ester as a clear oil.
Reference: [1] Patent: US2005/124640, 2005, A1,
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  • [ 2444-36-2 ]
  • [ 7664-93-9 ]
  • [ 57486-68-7 ]
Reference: [1] Patent: US6048893, 2000, A,
[2] Patent: US6124343, 2000, A,
  • 16
  • [ 2444-36-2 ]
  • [ 608-31-1 ]
  • [ 71-36-3 ]
  • [ 15307-79-6 ]
YieldReaction ConditionsOperation in experiment
42.9% With sodium hydroxide; potassium iodide; copper(I) iodide; potassium carbonate In N,N-dimethyl-formamide Example 1
A stirred mixture of 5.11 g of o-chlorophenylacetic acid, 24.30 g of 2,6-dichloroaniline, 8.28 g of potassium carbonate, 4.98 g of potassium iodide, 4.50 g of cuprous iodide and 60 ml of N,N-dimethylformamide was refluxed under a nitrogen atmosphere for 7 hours.
The reaction mixture was filtered and the filtration residue was thoroughly washed with warm water.
The washing solution was combined with the filtrate and n-butanol was added thereto.
The mixture was concentrated under a reduced pressure.
The concentration residue was thoroughly washed with chloroform and then diluted with icewater.
It was then acidified with 2 N hydrochloric acid and extracted with chloroform.
A 2 N aqueous sodium hydroxide solution was added to the chloroform layer and the whole was stirred at room temperature for 30 minutes and then cooled to precipitate crystals.
Thus, 4.09 g (yield: 42.9percent) of sodium o-(2,6-dichloroanilino)phenylacetate was obtained. 22percent of unreacted o-chlorophenylacetic acid was recovered.
m.p. 283°-285° C. (decomp.)
Reference: [1] Patent: US4410724, 1983, A,
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  • [ 608-31-1 ]
  • [ 15307-79-6 ]
Reference: [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 23, p. 6910 - 6914[2] Angew. Chem., 2018, vol. 130, # 23, p. 7026 - 7030,5
  • 18
  • [ 2444-36-2 ]
  • [ 85650-56-2 ]
Reference: [1] Patent: WO2011/159903, 2011, A2,
[2] Patent: WO2011/159903, 2011, A2,
[3] Patent: WO2011/159903, 2011, A2,
[4] Patent: WO2012/38975, 2012, A2,
[5] Patent: WO2012/38975, 2012, A2,
  • 19
  • [ 2444-36-2 ]
  • [ 85259-19-4 ]
YieldReaction ConditionsOperation in experiment
28% With thionyl chloride; bromine In methanol Step A
Preparation of methyl 2-bromo-2-(2-chlorophenyl)acetate
A mixture of 2-chlorophenylacetic acid (5.00 g, 29.3 mmol) and thionyl chloride (2.67 mL, 1.25 eq) were heated at reflux while bromine (1.51 mL, 1.0 eq) was added from a dropping funnel over 15 minutes.
The reaction mixture was heated at reflux 19.5 hours, and then cooled to room temperature.
Methanol (30 mL, 25 eq) was then added slowly, as an exotherm and violent bubbling resulted.
The reaction mixture was then concentrated in vacuo.
The residue was partitioned between water and ether and the aqueous phase was then extracted twice with ether.
The combined ether portions were washed with 5percent NaHSO3, dried (MgSO4), filtered, and concentrated in vacuo.
The residue was purified on a silica gel flash chromatography column (170*45 mm) eluted with 15percent ethyl acetate/hexane to yield 2.13 g(28percent) of the title compound.
1 H NMR (300 MHz, CDCl3, ppm): δ 3.8 (s, 3H), 5.95 (s, 1H), 7.25-7.45 (m, 3H), 7.7-7.8 (m, 1H).
Reference: [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 23, p. 3738 - 3742
[2] Chemical and Pharmaceutical Bulletin, 1982, vol. 30, # 10, p. 3601 - 3616
[3] Patent: US5177095, 1993, A,
[4] Patent: US5240938, 1993, A,
[5] Patent: US5264439, 1993, A,
[6] Advanced Synthesis and Catalysis, 2015, vol. 357, # 11, p. 2479 - 2484
[7] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 2, p. 1355 - 1360
[8] Patent: CN107383055, 2017, A,
  • 20
  • [ 67-56-1 ]
  • [ 2444-36-2 ]
  • [ 85259-19-4 ]
YieldReaction ConditionsOperation in experiment
28% With thionyl chloride; bromine In hexane Step A
Preparation of Methyl 2-bromo-2'-chlorophenylacetate
o-Chlorophenylacetic acid (5.00 g, 29.3 mmol) and thionyl chloride (2.67 ml, 36.6 mmol) are heated to reflux.
Bromine (1.51 ml, 29.3 mmol) was added dropwise over 10 minutes and continued to reflux for 17 hrs.
The reaction was cooled to room temperature and 30 ml of CH3 OH was added slowly.
The solvent was removed in vacuo and the residue chromatographed on silica gel eluding with 5percent ethyl acetate in hexane.
The product was isolated in a 28percent yield (2.13 g).
1 H NMR (300 MHz, CDCl3, ppm): 3.8 (s, 3H); 5.95 (s, 1H); 7.25-7.45 (m, 3H); 7.7-7.8 (m, 1H).
28% With thionyl chloride; bromine In hexane Step A:
Preparation of Methyl 2-bromo-2'-chlorophenylacetate
o-Chlorophenylacetic acid (5.00 g, 29.3 mmol) and thionyl chloride (2.67 ml, 36.6 mmol) are heated to reflux.
Bromine (1.51 ml, 29.3 mmol) was added dropwise over 10 minutes and continued to reflux for 17 hrs.
The reaction was cooled to room temperature and 30 ml of CH3 OH was added slowly.
The solvent was removed in vacuo and the residue chromatographed on silica gel eluding with 5percent ethyl acetate in hexane.
The product was isolated in a 28percent yield (2.13 g).
1 H NMR (300 MHz, CDCl3, ppm): 3.8 (s, 3H); 5.95 (s, 1H); 7.25-7.45 (m, 3H); 7.7-7.8 (m, 1H).
Reference: [1] Patent: US5183810, 1993, A,
[2] Patent: US5246944, 1993, A,
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