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[ CAS No. 877397-65-4 ] {[proInfo.proName]}

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Chemical Structure| 877397-65-4
Chemical Structure| 877397-65-4
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Product Details of [ 877397-65-4 ]

CAS No. :877397-65-4 MDL No. :MFCD09863793
Formula : C8H7Cl2FO Boiling Point : -
Linear Structure Formula :- InChI Key :JAOYKRSASYNDGH-BYPYZUCNSA-N
M.W : 209.05 Pubchem ID :11557536
Synonyms :

Calculated chemistry of [ 877397-65-4 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.25
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 47.35
TPSA : 20.23 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.59 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.16
Log Po/w (XLOGP3) : 2.79
Log Po/w (WLOGP) : 3.28
Log Po/w (MLOGP) : 3.44
Log Po/w (SILICOS-IT) : 3.53
Consensus Log Po/w : 3.04

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.2
Solubility : 0.133 mg/ml ; 0.000634 mol/l
Class : Soluble
Log S (Ali) : -2.87
Solubility : 0.281 mg/ml ; 0.00135 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.78
Solubility : 0.035 mg/ml ; 0.000167 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.14

Safety of [ 877397-65-4 ]

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 [ 877397-65-4 ]

* 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 [ 877397-65-4 ]
  • Downstream synthetic route of [ 877397-65-4 ]

[ 877397-65-4 ] Synthesis Path-Upstream   1~9

  • 1
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YieldReaction ConditionsOperation in experiment
94.9%
Stage #1: With sodium methylate In methanol at 0 - 20℃; for 4 h;
Stage #2: With sodium acetate; acetic acid In water
Sodium methoxide (19 mmol; 0.5 M in methanol) was added slowly to compound S-2 (4.64 g, 18.8 mmol) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for 4 hours. The solvent was evaporated and H2O (100 mL) was added. The cooled reaction mixture was neutralized with sodium acetate-acetic acid buffer solution to pH 7. Ethyl acetate (100 mL.x.2) was added to extract the aqueous solution. The combined organic layers were dried over Na2SO4, filtered, and evaporated to obtain S-1 as a white solid (4.36 g, 94.9percent yield); SFC-MS: 97percent ee. 1H NMR (400 MHz, chloroform-D) δ ppm 1.65 (d, J=6.8 Hz, 3 H) 5.58 (q, J=6.9 Hz, 1H) 6.96-7.10 (m, 1H) 7.22-7.36 (m, 1H).
94.4% With sodium methylate In methanol at 0 - 20℃; for 4 h; Sodium methoxide (19 mmol; 0.5 M in methanol) was added slowly to compound S-2 (4.64 g, 18.8 mmol) under a nitrogen atmosphere at 0 C. The resulting mixture was stirred at room temperature for 4 hours. The solvent was evaporated and H2O (100 mL) was added. The cooled reaction mixture was neutralized with sodium acetate-acetic acid buffer solution to pH 7. Ethyl acetate (100 mLx2) was added to extract the aqueous solution. The combined organic layers were dried over Na2SO4, filtered, and evaporated to obtain a white solid (4.36 g, 94.9percent yield); SFC-MS: 97percent ee. 1H NMR (400 MHz, chloroform-D) ? ppm 1.65 (d, J=6.8 Hz, 3H) 5.58 (q, J=6.9 Hz, 1H) 6.96-7.10 (m, 1H) 7.22-7.36 (m, 1H).
94.9% at 0 - 20℃; for 4 h; Sodium methoxide (19 mmol; 0.5 M in methanol) was added slowly to compound S-2 (4.64 g, 18.8 mmol) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature for 4 hours. The solvent was evaporated and H2O (100 mL) was added. The cooled reaction mixture was neutralized with sodium acetate-acetic acid buffer solution to pH 7. Ethyl acetate (100 mL x 2) was added to extract the aqueous solution. The combined organic layers were dried over Na2SO4, filtered, and evaporated to obtain a white solid (4.36 g, 94.9percent yield); SFC-MS: 97percent ee. 1H NMR (400 MHz, chloroform-D) 8 ppm 1.65 (d, J=6.8 Hz, 3 H) 5.58 (q, ^6.9 Hz, 1 H) 6.96 - 7.10 (m, 1 H) 7.22 - 7.36 (m, 1 H).
94.9%
Stage #1: With sodium methylate In methanol at 0 - 20℃; for 4 h;
Stage #2: With water In methanolsodium acetate-acetic acid buffer
Sodium methoxide (19 mmol; 0.5 M in methanol) was added slowly to compound S-2 (4.64 g, 18.8 mmol) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature for 4 hours. The solvent was evaporated and H20 (100 mL) was added. The cooled reaction mixture was neutralized with sodium acetate-acetic acid buffer solution to pH 7. Ethyl acetate (100 mL x 2) was added to extract the aqueous solution. The combined organic layers were dried over Na2S04, filtered, andevaporated to obtain a white solid (4.36 g, 94.9percent yield); SFC-MS: 97percent ee. 1H NMR (400 MHz, chloroform-D) D ppm 1.65 (d, J=6.8 Hz, 3 H) 5.58 (q, J=6.9 Hz, 1 H) 6.96 - 7.10 (m, 1 H) 7.22 - 7.36 (m, 1 H).
94.9% With sodium methylate In methanol at 0 - 20℃; for 4 h; Inert atmosphere Sodium methoxide (19 mmol; 0.5 M in methanol) was added slowly to compound S-2 (4.64 g, 18.8 mmol) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature for 4 hours. The solvent was evaporated and H20 (100 mL) was added. The cooled reaction mixture was neutralized with sodium acetate-acetic acid buffer solution to pH 7. Ethyl acetate (100 mL x 2) was added to extract the aqueous solution. The combined organic layers were dried over Na2504, filtered, and evaporated to obtain S-i as a white solid (4.36 g, 94.9percent yield); SFC-MS: 97percent ee. 1H NMR (400 MHz, chloroform-D) 6 ppm 1.65 (d, J=6.8 Hz, 3 H) 5.58 (q, J6.9 Hz, 1 H) 6.96 - 7.10 (m, 1 H) 7.22 - 7.36 (m, 1 H).
94.9% With sodium methylate In methanol at 0 - 20℃; for 4 h; Inert atmosphere Sodium methoxide (19 mmol; 0.5 M in methanol) was added slowly to compound S-2 (4.64 g, 18.8 mmol) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature for 4 hours. The solvent was evaporated and H2O (100 mL) was added. The cooled reaction mixture was neutralized with sodium acetate-acetic acid buffer solution to pH 7. Ethyl acetate (100 mL x 2) was added to extract the aqueous solution. The combined organic layers were dried over Na2SO4, filtered, and evaporated to obtain S-1 as a white solid (4.36 g, 94.9percent yield); SFC-MS: 97percent ee. 1H NMR (400 MHz, chloroform-D) δ ppm 1.65 (d, J=6.8 Hz, 3 H) 5.58 (q, J=6.9 Hz, 1 H) 6.96 - 7.10 (m, 1 H) 7.22 - 7.36 (m, 1 H).
94.9% With sodium methylate In methanol at 0 - 20℃; for 4 h; Inert atmosphere (0254) Sodium methoxide (19 mmol; 0.5 M in methanol) was added slowly to compound S-2 (4.64 g, 18.8 mmol) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for 4 hours. The solvent was evaporated and H2O (100 mL) was added. The cooled reaction mixture was neutralized with sodium acetate-acetic acid buffer solution to pH 7. Ethyl acetate (100 mL×2) was added to extract the aqueous solution. The combined organic layers were dried over Na2SO4, filtered, and evaporated to obtain S-1 as a white solid (4.36 g, 94.9percent yield); SFC-MS: 97percent ee. 1H NMR (400 MHz, chloroform-D) δ ppm 1.65 (d, J=6.8 Hz, 3H) 5.58 (q, J=6.9 Hz, 1H) 6.96-7.10 (m, 1H) 7.22-7.36 (m, 1H).

Reference: [1] Patent: US2008/293769, 2008, A1, . Location in patent: Page/Page column 4-5
[2] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 20
[3] Patent: WO2006/21881, 2006, A2, . Location in patent: Page/Page column 59
[4] Patent: WO2006/21886, 2006, A1, . Location in patent: Page/Page column 50-51
[5] Tetrahedron Asymmetry, 2010, vol. 21, # 19, p. 2408 - 2412
[6] Patent: WO2013/17989, 2013, A1, . Location in patent: Page/Page column 64
[7] Patent: EP2764866, 2014, A1, . Location in patent: Paragraph 0047
[8] Patent: US2016/206608, 2016, A1, . Location in patent: Paragraph 0254
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YieldReaction ConditionsOperation in experiment
66.7% at 40℃; for 5.25 h; Inert atmosphere (1) primary crystals(2,6-dichloro-3-fluorophenyl into an (S) -1-; 30g Compound (2) was added 105mL of petroleum ether obtained in Preparation Example 1 embodiment taken, heated and stirred under argon for 40 , dissolve yl) ethanol seed, after 45min, a seed crystal was smaller; after 1 hour, the disappearance of seed; 3.5h, the precipitated white solid (precipitated to the bottom); 10H, no further solid separated; dry filtration dry, weighing 20g, yield 66.7percent; chiral phase detection ee: 60.5percent (test conditions AD-H; n-hexane (0.1percent acetic acid): isopropanol = 80: 20; 0.3ml / L; 254nm ; 30 ).(2) secondary crystalsTake a crystalline compound obtained 30g, was added 105mL of petroleum ether, heated and stirred under argon for 40 , dissolved; into an (S) -1- (2,6- dichloro-3-fluorophenyl) ethanol seed , after 45min, a seed crystal was smaller; after 1 hour, the disappearance of seed; 3.5h, the precipitated white solid (precipitated to the bottom); 10H, no further solid separated; dry suction filtration, weighed 20g a yield of 66.7percent; according to the aforementioned chromatographic conditions, chiral phase detection ee: 95.5percent.(3) three times crystallizedTaking a second resultant crystalline compound 30g, was added 105mL of petroleum ether, heated and stirred under argon for 40 , dissolved; into an (S) -1- (2,6- dichloro-3-fluorophenyl) ethanol crystal species, after 45min, a seed crystal was smaller; after 1 hour, the disappearance of seed; 3.5h, the precipitated white solid (precipitated to the bottom); 10H, no further solid separated; dry suction filtration, weighed 20g, yield 66.7percent; according to the aforementioned chromatographic conditions, chiral phase detection ee: 99.5percent.
65.6% With dmap; 1-(tert-butoxycarbonyl)-L-proline; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,2-dichloro-ethane at 0 - 20℃; To a solution of A5 (41.8g, 200mmol) in 1,2-dichloroethane (800mL) was added Boc-L-Pro (26.9g, 125mmol) followed by EDCI (31. lg, 163mmol) and DMAP (4.12g, 33.8mmol) at 0°C. The resulting mixture was stirred at r.t. overnight and then water (350mL) was added and separated, the water phase was extracted with DCM(150mLx3), dried over MgS04, concentrated and purified by columnchromatography to (PE:EA=30:1) to give CI (13.72g, yield: 65.6percent).
65.6% With dmap; 1-(tert-butoxycarbonyl)-L-proline; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,2-dichloro-ethane at 0 - 20℃; To a solution of A5 (41.8g, 200mmol) in 1,2-dichloroethane (800mL) was added Boc-L-Pro (26.9g, 125mmol) followed by EDCI (31. lg, 163mmol) and DMAP (4.12g, 33.8mmol) at 0°C. The resulting mixture was stirred at r.t. overnight and then water (350mL) was added and separated, the water phase was extracted with DCM(150mLx3), dried over MgS04, concentrated and purified by columnchromatography to (PE:EA=30:1) to give CI (13.72g, yield: 65.6percent).
58% With dmap; 1-(tert-butoxycarbonyl)-L-proline; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,2-dichloro-ethane at -5℃; 1-(2,6-Dichloro-3-fluorophenyl)ethan-1-ol 37 (24.00 g, 114.81 mmol) was dissolved in 300 mL of CH2ClCH2Cl. The solution was cooled to -5 °C. To the solution was successively added Boc-L-proline (16.06 g, 74.63 mmol), EDCI (17.61 g, 91.85 mmol) and DMAP (1.68 g, 13.78 mmol). The resulting mixture was continued to stir overnight and diluted with 100 mL of water. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE/EA 100:1-50:1, v/v) to afford (1S)-1-(2,6-dichloro-3-fluorophenyl)ethan-1-ol. (7.00 g, 58percent yield). 1H NMR (400 MHz, CDCl3) δ 7.26 (dd, J = 4.8, 8.8 Hz, 1H), 7.02 (dd, J = 8.0, 8.8 Hz, 1H), 5.57 (q, J = 6.8 Hz, 1H), 2.86 (s, 1H), 1.64 (d, J = 6.8 Hz, 3H).
140 g
Stage #1: With 1-(tert-butoxycarbonyl)-L-proline; toluene-4-sulfonic acid; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 2 h;
Stage #2: With sodium hydroxide In methanol; water at 25℃; for 1.5 h;
500 g of TM1, 322 g of Boc-L-proline was dissolved in 1.5 L of anhydrous dichloromethane, and 375 g of EDCI and 118 g of p-toluenesulfonic acid in methylene chloride solution were added dropwise at 0 ° C, After reaction at room temperature for 2 hours, the reaction was monitored by TLC (PE / EA = 5: 1).The reaction solution was washed with water, dried and evaporated to dryness. The crude oil was collected by vacuum distillation under a vacuum of 10 mm Hg and collected at 100-110 ° C. The crude product was dissolved in 250 mL of n-hexane at room temperature and the temperature was lowered to -20 ° C. Filtration at low temperature gave 150 g of a white solid in 60percent yield in a single configuration, with a yield of 30percent (eepercent> 98percent). A mixture of 406 g of the by-product (containing BP1, BP2 and BP3) was dissolved in 1.21 L of methanol, and 120 g of a saturated aqueous solution of sodium hydroxide was added dropwise at a controlled temperature of 25C, and stirring was continued for 1.5 hours.The reaction was complete by TLC (PE / EA = 10: 1).The pH of the system was adjusted to pH = 7 with hydrochloric acid, the solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium hydrogencarbonate solution and brine, dried to give 205 g of a mixture of BP2 and TM2 , Yield 98percent.2. 299 g of a mixture of BP2 and TM2 (mass ratio of about 7: 3) was combined with 258 g of Boc-D-proline and 367 g of triphenylphosphine in 2.15 L of THF at 0 ° C. (PE / EA = 10: 1), 1 L of water was added, THF was removed by rotary evaporation, extracted with ethyl acetate 0.5 L x 3, and ethyl acetate (2: 1) was added to the reaction mixture and the mixture was stirred for 2 hours at 20 ° C. The layers were washed with saturated aqueous sodium bicarbonate, dried over ethyl acetate and concentrated to give a large amount of solid. The solid was washed with ether and the solids removed by filtration. The filtrate was concentrated to dryness to give a mixture of BP4 and TM2 dissolved in 1.21 L of methanol at 25 ° C A saturated aqueous solution of 120 g of sodium hydroxide was added dropwise, and stirring was continued for 1.5 hours.The reaction was complete by TLC (PE / EA = 10: 1).The pH of the system was adjusted to pH = 7 with hydrochloric acid, the solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium hydrogencarbonate solution and then brine, dried and dried to obtain crude product which was recrystallized from n-hexane to give 140 g TM2, yield 67percent (eepercent: > 98percent).

Reference: [1] Patent: CN105237346, 2016, A, . Location in patent: Paragraph 0050; 0051; 0052; 0053; 0054; 0055; 0056-0061
[2] Patent: WO2012/48259, 2012, A2, . Location in patent: Page/Page column 38-39
[3] Patent: WO2012/48258, 2012, A2, . Location in patent: Page/Page column 31-32
[4] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6804 - 6820
[5] Patent: WO2013/17989, 2013, A1,
[6] Patent: WO2013/17989, 2013, A1,
[7] Patent: EP2764866, 2014, A1,
[8] Patent: EP2764866, 2014, A1,
[9] Patent: EP2764866, 2014, A1,
[10] Patent: CN103664896, 2016, B, . Location in patent: Paragraph 0097; 0098
[11] Patent: US2016/206608, 2016, A1,
[12] Patent: US2016/206608, 2016, A1,
[13] Patent: US2016/206608, 2016, A1,
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Reference: [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 7, p. 1333 - 1337
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Reference: [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 7, p. 1333 - 1337
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Reference: [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 7, p. 1333 - 1337
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Reference: [1] Patent: WO2013/17989, 2013, A1,
[2] Patent: WO2013/17989, 2013, A1,
[3] Patent: EP2764866, 2014, A1,
[4] Patent: EP2764866, 2014, A1,
[5] Patent: EP2764866, 2014, A1,
[6] Patent: US2016/206608, 2016, A1,
[7] Patent: US2016/206608, 2016, A1,
  • 7
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Reference: [1] Patent: WO2013/17989, 2013, A1,
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  • [ 877399-98-9 ]
  • [ 877397-65-4 ]
Reference: [1] Patent: WO2013/17989, 2013, A1,
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  • [ 15128-82-2 ]
  • [ 877397-65-4 ]
  • [ 877397-70-1 ]
YieldReaction ConditionsOperation in experiment
88.3% With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 13 h; 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-nitropyridine
3-Hydroxy-2-nitropyridine (175 mg, 1.21 mmol) and triphenylphosphine (440 mg, 1.65 mmol) were added sequentially to a stirred solution of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (229.8 mg, 1.1 mmol) in THF (10 mL) under a nitrogen atmosphere.
The reaction mixture was maintained at room temperature for 1 h and then diisopropyl azo-dicarboxylate (0.34 mL, 1.65 mmol) was added at 0° C.
The mixture was stirred for an additional 12 h.
The reaction mixture was evaporated under vacuum to give an oil.
The residue was purified by flash chromatography (eluding with 20-->25percent EtOAc in hexanes) to give the title compound as a white solid (321.5 mg; 0.97 mmol; 88.3percent yield); MS (APCI) (M+H)+ 331; SFC-MS: 99.5percent ee. 1H NMR (400 MHz, chloroform-D) δ ppm 1.85 (d, J=6.6 Hz, 3H) 6.10 (q, J=6.6 Hz, 1H) 7.04-7.13 (m, 1H) 7.21 (dd, J=8.5, 1.14 Hz, 1H) 7.30 (dd, J=9.0, 4.9 Hz, 1H) 7.37 (dd, J=8.6, 4.6 Hz, 1H) 8.04 (dd, J=4.6, 1.3 Hz, 1H).
88.3% With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 13 h; 3-Hydroxy-2-nitropyridine (175 mg, 1.21 mmol) and triphenylphosphine (440 mg, 1.65 mmol) were added sequentially to a stirred solution of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (229.8 mg, 1.1 mmol) in THF (10 mL) under a nitrogen atmosphere. The reaction mixture was maintained at room temperature for 1 h and then diisopropyl azo-dicarboxylate (0.34 mL, i.65 mmol) was added at 0°C. The mixture was stirred for an additional 12 h. The reaction mixture was evaporated under vacuum to give an oil. The residue was purified by flash chromatography (eluting with 20->25percent EtOAc in hexanes) to give the title compound as a white solid (321.5 mg; 0.97 mmol; 88.3percent yield); MS (APCI) (M+H)+ 331; SFC-MS: 99.5percent ee. 1H NMR (400 MHz, chloroform-D) 8 ppm 1.85 (d, J=6.6 Hz, 3 H) 6.10 (q, J=6.6 Hz, 1 H) 7.04 -7.13 (m, 1 H) 7.21 (dd, J=8.5, 1.14 Hz, 1 H) 7.30 (dd, ^=9.0, 4.9 Hz, 1 H) 7.37 (dd, J=Q.6, 4.6 Hz, 1 H) 8.04 (dd, Jt4.6, 1.3 Hz, 1 H).
80.4% With triphenylphosphine; diisopropyl azodicarboxylate In toluene at -20 - 20℃; for 1 h; Inert atmosphere The (S) - 1 - (2,6-dichloro-3-fluoro phenyl) ethanol (42.80g, 204 . 7mmol), 3-hydroxy-2-nitro-pyridine (28.97g, 206 . 8mmol), triphenylphosphine (61.22g, 233 . 4mmol) in 300 ml toluene in, N2protection, using ethanol does the ice-bath lower the temperature to -20 °C. Dropwise DIAD (48.44g, 239 . 6mmol) toluene (50 ml) solution. Is omitted, to eliminate outside bath, the natural reaction system rose to room temperature, stirring 1 hour. TLC confirmed the completion of reaction, adding 3.7 ml water, stirring overnight. The salt bath is then used to lower the temperature to -10 °C reaction system, separating solid. Filtering, the filter cake is washed with the toluene washes, concentrating the filtrate to the stem, by adding 150 ml ethanol, concentrated again, two times repeatedly, shall be II-1 crude product (110g). Ethanol is added to the crude 3.4L, beating 4 °C 1 hour. Filtering, with 4 °C ethanol washing, the filter cake reduced-pressure drying, be II-1 (54.48g, 80.4percent), white solid.
80% With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 2 h; 300 g of TM2, 205 g of SM2 and 540 g of triphenylphosphine were dissolved in 2 L of THF and 361 g of DEAD was added dropwise at 0 ° C. After completion of the dropwise addition, the mixture was stirred at room temperature for two hours, and the reaction was complete by TLC (PE / EA = 3: 1).The ethyl acetate layer was dried and concentrated to 2 ° C to 0 ° C to precipitate a large amount of solid which was collected by filtration and the filtrate was concentrated to a final concentration of ethyl acetate. 1L. After cooling, the solid was separated. The solids were collected by filtration twice, washed with PE / EA = 5: 1 and filtered to remove solids (about 500 g), and the filtrate was evaporated to remove the solvent.Column chromatography gave 400 g of TM3 (pale yellow solid, eluent PE / EA = 7: 1) in 80percent yield.
61%
Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere
Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 0℃; for 12 h;
Step 1:
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethyoxyl)-2-nitropyridine
(S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethanol (20.9 g, 0.10 mol) was dissolved in anhydrous tetrahydrofuran (200 mL), and then 3-hydroxy-2-nitropyridine (16.0 g, 0.11 mol) and triphenylphosphine (40.0 g, 0.15 mol) were subsequently added under a nitrogen atmosphere.
The reaction liquid was stirred at room temperature for 1 hour.
After the reaction was cooled to 0°C, DIAD (40 mL, 0.15 mol) was added and the resultant was stirred for 12 hours.
The solvent was evaporated, and the crude oil product was purified by silica gel column chromatography to give (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethyoxyl)-2-nitropyridine (20.2 g, 61percent yield).
61%
Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere
Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 0℃; for 12 h;
(S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (20.9 g, 0.10 mol) was dissolved in anhydrous tetrahydrofuran (200 mL), and then 3-hydroxy-2-nitropyridine (16.0 g, 0.11 mol) and triphenylphosphine (40.0 g, 0.15 mol) were subsequently added under a nitrogen atmosphere.
The reaction mixture was stirred at room temperature for 1 hour, cooled to 0°C, diisopropyl azodicarboxylate (40 mL, 0.15 mol) was added and the mixture was stirred for 12 hours at 0°C.
After evaporating the solvent, the resulting oil product was purified by silica gel column chromatography to give (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxyl)-2-nitropyridine (20.2 g, 61percent yield).
61%
Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere
Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 0℃; for 12 h;
(S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (20.9 g, 0.10 mol) was dissolved in 200 mL anhydrous tetrahydofuran, to which 3-hydroxy-2-nitropyridine (16.0 g, 0.11 mol) and triphenylphosphine (40.0 g, 0.15 mol) were sequentially added under a nitrogen atmosphere, and the reaction solution was stirred at room temperature for 1 hour, cooled to 0° C. and diisopropyl azodicarboxylate (40 mL, 0.15 mol) was added dropwise.
After the addition was complete, stirring was continued at 0° C. for 12 hours.
The solvent was distilled off to obtain an oily material, which was separated by silica gel column chromatography, to give (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (20.2 g). Yield: 61percent.
2.5 kg
Stage #1: With triphenylphosphine In toluene at -20℃; for 3 h; Inert atmosphere; Large scale
Stage #2: With di-isopropyl azodicarboxylate In toluene at -20 - 25℃; for 2 h; Large scale
1.82 kg of compound (CZT-2),1.23 kg 3-hydroxy-2-nitropyridinewith2.60 kg of triphenylphosphine dissolvedIn 15.0 liters of dry toluene,Nitrogen protection,Cool to -20 degrees.In 3 hours slowly joined2.04 kg DIAD 2.62 litersToluene solution,Keep the system temperature between -20 degrees and -10 degrees,After the addition was complete, the temperature was raised to 25 ° C for 2 hours.Add 0.16 liters of water to quench the reaction,Cooled to -5 degrees,filter,The filtrate was concentrated under reduced pressure.Recrystallization from 7.5 liters of absolute ethanol,To obtain 2.50 kg of compound (CZT-3) in a yield of 85percent

Reference: [1] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 20
[2] Patent: WO2006/21886, 2006, A1, . Location in patent: Page/Page column 51
[3] Organic Process Research and Development, 2011, vol. 15, # 5, p. 1018 - 1026
[4] Patent: CN105348265, 2016, A, . Location in patent: Paragraph 0056; 0057; 0058
[5] Patent: CN103664896, 2016, B, . Location in patent: Paragraph 0108; 0109
[6] Patent: EP2952510, 2015, A1, . Location in patent: Paragraph 0112; 0113
[7] Patent: EP3176160, 2017, A1, . Location in patent: Paragraph 0041
[8] Patent: US2018/244649, 2018, A1, . Location in patent: Paragraph 0152; 0153; 0154
[9] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
[10] Patent: CN106317024, 2017, A, . Location in patent: Paragraph 0049; 0050
[11] Patent: CN107417603, 2017, A, . Location in patent: Paragraph 0021
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