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Chemical Structure| 62965-35-9
Chemical Structure| 62965-35-9
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Product Details of [ 62965-35-9 ]

CAS No. :62965-35-9 MDL No. :MFCD00065574
Formula : C11H21NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :LRFZIPCTFBPFLX-SSDOTTSWSA-N
M.W : 231.29 Pubchem ID :2734668
Synonyms :

Calculated chemistry of [ 62965-35-9 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.82
Num. rotatable bonds : 6
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 61.02
TPSA : 75.63 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) : -6.09 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.25
Log Po/w (XLOGP3) : 2.28
Log Po/w (WLOGP) : 2.01
Log Po/w (MLOGP) : 1.42
Log Po/w (SILICOS-IT) : 0.75
Consensus Log Po/w : 1.74

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.31
Solubility : 1.12 mg/ml ; 0.00485 mol/l
Class : Soluble
Log S (Ali) : -3.51
Solubility : 0.0722 mg/ml ; 0.000312 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.47
Solubility : 7.8 mg/ml ; 0.0337 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.81

Safety of [ 62965-35-9 ]

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 [ 62965-35-9 ]

* 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 [ 62965-35-9 ]
  • Downstream synthetic route of [ 62965-35-9 ]

[ 62965-35-9 ] Synthesis Path-Upstream   1~23

  • 1
  • [ 62965-35-9 ]
  • [ 20859-02-3 ]
YieldReaction ConditionsOperation in experiment
75%
Stage #1: With methanesulfonic acid In dichloromethane at 25℃; for 3 h;
Stage #2: With triethylamine In dichloromethane at 25℃; for 1 h;
Example 9
Production of (S)-tert-leucine
Methanesulfonic acid (576 mg, 6 mmol) was added to a solution of (S)-N-(tert-butoxycarbonyl)-tert-leucine (1155 mg, 5 mmol) and methylene chloride (5 mL), and the mixture was stirred at 25° C. for 3 hours.
When triethylamine (708 mg, 7 mmol) was added thereto, a solid was precipitated.
The solid was sufficiently precipitated, and then the solution was stirred at 25° C. for 30 minutes and further stirred at 25° C. for 30 minutes.
Thereafter, the solid was separated by filtration under reduced pressure.
The solid was washed with methylene chloride (5 mL), and then was subjected to vacuum drying.
Thereby, the titled compound was produced as a white solid (514 mg, yield of 75percent).
Titled Compound:
1H-NMR (D2O): δ (ppm) 0.87 (s, 9H), 3.40 (s, 1H)
Reference: [1] Tetrahedron Asymmetry, 2006, vol. 17, # 13, p. 1995 - 1999
[2] Patent: US2014/343289, 2014, A1, . Location in patent: Paragraph 0067-0069
[3] Patent: EP2423187, 2012, A1, . Location in patent: Page/Page column 15
  • 2
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  • [ 62965-35-9 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In methanol at 0 - 5℃; STEP A: 2(S)-tert-Butoxycarbonylamino-3,3-dimethyl-butyric Acid
To a suspension of L-tert-leucine (26.1 g, 0.2 mol) in methanol (150 ML) was added triethylamine (56 ML, 0.4 mol) and the mixture cooled to 0° C.
To the mixture was added slowly a solution of di-tert-butyldicarbamate (48 g, 0.22 mol) in methanol (40 ML) such that an internal temperature of between 0 and 5° C. was maintained..
The reaction was allowed to stir overnight and the solvents were removed in vacuo..
The residue was dissolved in ethyl acetate (200 ML) and washed with 10percent w/v aqueous citric acid solution (3*100 ML)..
The organic layer was dried over MgSO4, filtered and the solvents removed in vacuo to give the title product as a pale yellow oil (48.9 g, >100percent, residual solvent).
1H NMR (CDCl3): δ/ppm 9.20 (1H, bs), 5.10 (1H, m), 4.15 (1H, m), 1.45 (9H, s), 1.00 (9H, s).
100% With triethylamine In methanol at 0 - 5℃; To a suspension of L-tert-leucine (26.1 g, 0.2 mol) in methanol (150 mL) was added triethylamine (56 mL, 0.4 mol) and the mixture cooled to 0 C. To the mixture was added slowly a solution: of di-tert-butyldicarbamate (48 g, 0.22 mol) in methanol (40 mL) such that an internal temperature of between 0 and 5 C. was maintained. The reaction was allowed to stir overnight and the solvents were removed in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with 10percent w/v aqueous citric acid solution (3100 mL). The organic layer was dried over MgSO4, filtered and the solvents removed in vacuo to give the title product as a pale yellow oil (48.9 g, >100percent, residual solvent). 1H NMR (CDCl3): ?/ppm 9.20 (1H, bs), 5.10 (1H, m), 4.15 (1H, m), 1.45 (9H, s), 1.00 (9H, s).
100% With sodium hydroxide In 1,4-dioxane at 20℃; for 12 h; (1) adding sodium hydroxide, L-tert-leucine and water according to a molar ratio of 1: 1: 10 into a reactor,Then, an equimolar amount of (Boc) 2O and L-tert-leucine were dissolved in 10 times of 1,4-dioxane,Slowly dripped into the reactor, stirred at room temperature for 12 hours after dripping finished, after the solvent was concentrated to half and the same volume of ethyl acetate was added and the reaction solution was concentrated, then added 4mol / L hydrochloric acid half of the volume of ethyl acetate, liquid separation , The organic phase was washed once with an equal volume of water, dried over anhydrous sodium sulfate and evaporated to give the compound 5, the structure is shown in Formula 8;
99% With triethylamine In 1,4-dioxane; water Triethylamine (890 uL, 6.40 mmol) was added dropwise to a stirred solution of L-tert- leucine (300 mg, 2.29 mmol) and di-tert-butyl dicarbonate (599 mg, 2.74 mmol) in dioxane/water 1: 1 (8 mL) and the solution was stirred overnight. The mixture was extracted with petroleum ether (2x) and the aqueous phase was cooled to 0 °C and carefully acidified to pH 3 by slow addition of 4M NaHS04 H20. The acidified water phase was extracted with EtOAc (3x) and the combined organic phases were washed with brine (2x) and was then dried, filtered and concentrated to give compound 36 (522 mg, 99 percent) as a colorless powder. No further purification was needed. 1H-NMR (300 MHz, CD30D) 8 0.99 (s, 9H), 1.44 (s, 9H), 3.96 (s, 1H); 13C-NMR (75.5 MHz, CD30D) 5 27.1, 28.7, 34.9, 68.0, 80.5, 157.8, 174.7.
99% With sodium hydroxide In water; isopropyl alcohol at 25℃; for 3 h; Example 20 An aqueous solution (1150 g) containing L-tert-leucine (100 g, 762 mmol) was stirred, and the pH of the solution was adjusted to 9 using a 30percent by weight of sodium hydroxide aqueous solution. Then, isopropanol (160 g) was added thereto. Further, di-tert-butyl dicarbonate (174.7 g, 800 mmol) was added thereto at 25°C with maintaining the pH between 8.5 and 9.5 using a 30percent by weight of sodium hydroxide aqueous solution. The mixture was stirred for about 3 hours, and the resultant was analyzed; as a result, 175 g of N-tert-butoxycarbonyl-L-tert-leucine was produced (yield: 99percent).
96% With sodium hydroxide In water at 7 - 20℃; for 14 h; Example 17 An aqueous solution (250.5 g) containing L-tert-leucine (20.5 g, 0.16 mol) was cooled to 7°C, and a 48percent by weight of sodium hydroxide aqueous solution (16.5 g) was added thereto. Then, di-tert-butyl dicarbonate (34.92 g, 0.16 mol, 1.00 equivalent) was slowly added with maintaining the pH in 9.4-10.8. After the addition, the mixture was stirred at not more than 20°C for 14 hours. Then, the yield and the amount of the generated impurity were analyzed by HPLC. Yield: 96percent, Reaction selectivity: 98percentExample 18 The reaction was carried out in the same condition
92%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 16 h;
Stage #2: With hydrogenchloride In water; ethyl acetate
Step 6: Preparation of N-(tert-Butoxycarbonyl)-L-tert-leucine; To a suspension of L-tert-leucine (5.0 g, 38 mmol) in dioxane (50 mL) and H2O (35 mL) at 0° C. was added 1M NaOH (38 mL, 1 equiv.) followed by Boc2O (9.3 g, 42 mmol, 1.1 equiv.). The reaction mixture was stirred at 0° C. to room temperature over 16 h then concentrated to approx half volume under reduced pressure. The aqueous residue was treated with EtOAc (75 mL) and 1 M HCl (50 mL), the aqueous phase separated and further extracted with EtOAc (50 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give the product as a colourless glassy solid (7.99 g, 92percent).
89%
Stage #1: With sodium hydroxide In 1,2-dioxacyclohexane; water at 0 - 20℃; for 4 h;
Stage #2: With potassium hydrogensulfate In water
Preparation of N-(tert-Butoxycarbonyl)-L-tert-leucine (MD009)
L-tert-Leucine (2.63 g, 20 mmol) was dissolved in a mixture of water (50 ml), 1,2-dioxan (20 ml), and 0.8 g sodium hydroxide, cooled in an ice bath. Di-tert-butylcarbonate (4.8 g, 22 mmol) in 1,2-dioxan (20 ml) was added dropwise to the cooled solution.
The reaction mixture was stirred at room temperature for 4 h and the pH was adjusted between 8 and 9.
Dioxane was then evaporated in vacuo and the resulting solution was acidified with 10percent aqueous potassium hydrogen sulfate to pH 3 and extracted with ethyl acetate (4*50 ml).
The combined organic layers were washed with 10percent aqueous potassium hydrogen sulfate (3*30 ml), brine (3*30 ml), and water (3*30 ml).
The organic phase was dried with anhydrous magnesium sulfate and concentrated in vacuo to give a white solid.
This resulted in a 89percent yield (4.133 g, 17.87 mmol).
1H-NMR (CDCl3, 400 MHz), doubling of peaks caused by rotamers around the N-Boc group, 5.81 (bs, 0.2H, NH), 5.09 (d, 0.8H, J=8.8 Hz, NH), 4.13 (d, 0.8H, J=9.6 Hz, H-2), 3.91 (bs, 0.2H, H-2), 1.45 (s, 9H, H-9, H-10, H-11), 1.02 (s, 9H, H-4, H-5, H-6). TLC (MeOH:CH2Cl2 5:20) Rf=0.91, (MeOH:H2O:CH2Cl2 45:5:200) Rf0.86.

Reference: [1] Patent: US6716878, 2004, B1, . Location in patent: Page column 14
[2] Patent: US6716878, 2004, B1, . Location in patent: Page column 62
[3] Patent: CN107325025, 2017, A, . Location in patent: Paragraph 0086; 0087
[4] Patent: WO2005/73195, 2005, A2, . Location in patent: Page/Page column 96-97
[5] Tetrahedron, 2008, vol. 64, # 18, p. 3980 - 3997
[6] Patent: EP2423187, 2012, A1, . Location in patent: Page/Page column 14
[7] Patent: EP2423187, 2012, A1, . Location in patent: Page/Page column 13
[8] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4815 - 4830
[9] RSC Advances, 2014, vol. 4, # 24, p. 12257 - 12265
[10] Patent: US2008/161254, 2008, A1, . Location in patent: Page/Page column 21
[11] Patent: US2005/171014, 2005, A1, . Location in patent: Page/Page column 7-8
[12] ACS Catalysis, 2017, vol. 7, # 2, p. 1383 - 1391
[13] Organic Letters, 2016, vol. 18, # 18, p. 4518 - 4521
[14] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 2, p. 827 - 838
[15] Journal of Medicinal Chemistry, 1998, vol. 41, # 2, p. 199 - 223
[16] Angewandte Chemie - International Edition, 2000, vol. 39, # 15, p. 2752 - 2754
[17] Bioorganic and medicinal chemistry letters, 2004, vol. 14, # 1, p. 275 - 278
[18] Chemistry - A European Journal, 2003, vol. 9, # 17, p. 4031 - 4045
[19] Chemistry - A European Journal, 2001, vol. 7, # 5, p. 1014 - 1027
[20] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4620 - 4631
[21] Nature, 2009, vol. 461, # 7266, p. 968 - 970
[22] Chemistry - A European Journal, 2010, vol. 16, # 44, p. 13068 - 13071
[23] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1832 - 1837
[24] Tetrahedron Asymmetry, 2011, vol. 22, # 3, p. 300 - 308
[25] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 8, p. 2425 - 2429
[26] Chinese Chemical Letters, 2012, vol. 23, # 3, p. 297 - 300
[27] Chemical Communications, 2012, vol. 48, # 42, p. 5193 - 5195
[28] Chemistry - A European Journal, 2014, vol. 20, # 21, p. 6526 - 6531
[29] Journal of the American Chemical Society, 2014, vol. 136, # 51, p. 17869 - 17881
[30] Journal of Organic Chemistry, 2015, vol. 80, # 15, p. 7770 - 7778
[31] Tetrahedron, 2018, vol. 74, # 52, p. 7485 - 7494
  • 3
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YieldReaction ConditionsOperation in experiment
99% With triethylamine In 1,4-dioxane; water Example 8
Boc-L-tert-leucine-OH (8)
Triethylamine (890 uL, 6.40 mmol) was added dropwise to a stirred solution of L-tert-leucine (300 mg, 2.29 mmol) and di-tert-butyl dicarbonate (599 mg, 2.74 mmol) in dioxane/ water 1:1 (8 mL) and the solution was stirred overnight.
The mixture was extracted with petroleum ether (2*) and the aqueous phase was cooled to 0°C and carefully acidified to pH 3 by slow addition of 4M NaHSO4*H2O.
The acidified water phase was extracted with EtOAc (3*) and the combined organic phases were washed with brine (2*) and was then dried, filtered and concentrated to give the title compound 8 (522 mg, 99 percent) as a colorless powder.
No further purification was needed.
1H-NMR (300 MHz, CD3OD) δ 0.99 (s, 9H), 1.44 (s, 9H), 3.96 (s, 1H); 13C-NMR (75.5 MHz, CD3OD) δ 27.1, 28.7, 34.9, 68.0, 80.5, 157.8, 174.7.
99% With triethylamine In 1,4-dioxane; water Example 2
Boc-L-tert-leucine-OH (2).
Triethylamine (890 μL, 6.40 mmol) was added dropwise to a stirred solution of L-tert-leucine (300 mg, 2.29 mmol) and di-tert-butyl dicarbonate (599 mg, 2.74 mmol) in dioxane/ water 1:1 (8 ml) and the solution was stirred overnight.
The mixture was extracted with petroleum ether (2*) and the aqueous phase was cooled to 0°C and carefully acidified to pH 3 by slow addition of 4M NaHSO4*H2O.
The acidified water phase was extracted with EtOAc (3*) and the combined organic phases were washed with brine (2*) and were then dried, filtered and concentrated to give the title compound 2 (522 mg, 99 percent) as a colorless powder.
No further purification was needed. 1H-NMR (300 MHz, CD3OD)δ 0.99 (s, 9H), 1.44 (s, 9H), 3.96 (s, 1H); 13C-NMR (75.5 MHz, CD3OD) δ 27.1, 28.7, 34.9, 68.0, 80.5, 157.8, 174.7.
Reference: [1] Patent: EP1881001, 2008, A1,
[2] Patent: EP1881002, 2008, A1,
  • 4
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YieldReaction ConditionsOperation in experiment
73% at 0 - 25℃; In a four-neck flask, 10.0 g (1.0 eq) of N-Boc-t-butyl ethylamine alcohol compound was added. Isopropyl acetate 100ml, sodium bromide 2.0eq, sodium bicarbonate 2.0eq, TMEPO 0.05eq, Cool to 0-5 °C. Temperature control 0 ~ 5 °C, sodium hypochlorite drops 1.2eq, about 1.0 ~ 1.5h drops, heat 2h, Warm up to 20 ~ 25 °C, heat 1.0 ~ 2.0h. Sodium thiosulfate solid 0.6 eq was added and incubated for 0.5 h. The aqueous layer was further extracted with 20 ml isopropyl acetate and the phases separated. Add 20 ml of isopropyl acetate to the aqueous layer, add citric acid, adjust the pH to 2 to 3, separate the phases, extract the aqueous layer with 20 ml of x 2 isopropyl acetate, combine the organic layers, add 50 ml of water to wash, separate the phases, and then apply the organic layer. Dry with 0.5g anhydrous magnesium sulfate 0.5h, suction filtration, the filtrate was evaporated to dryness at 40 ~ 50 °C, 40 ~ 50 °C insulation, 5ml of isopropyl acetate was added, 25ml of heptane was added dropwise, slowly cooling and crystallization, 20 ~ 30 °C heat 0.5h, suction filtration, washing, 7.8g boutique, yield 73percent. Optical purity 100percent.
Reference: [1] Patent: CN107778192, 2018, A, . Location in patent: Paragraph 0060-0062
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Reference: [1] Patent: EP618221, 1994, A2,
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  • [ 58482-93-2 ]
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Reference: [1] Patent: US5338726, 1994, A,
  • 7
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Reference: [1] Organic letters, 2001, vol. 3, # 6, p. 897 - 899
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Reference: [1] Organic letters, 2001, vol. 3, # 6, p. 897 - 899
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  • [ 58632-95-4 ]
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Reference: [1] Tetrahedron, 1991, vol. 47, # 29, p. 5453 - 5462
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  • [ 1203546-60-4 ]
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Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 22, p. 11229 - 11237
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Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 22, p. 11229 - 11237
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Reference: [1] Patent: CN107778192, 2018, A,
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  • [ 1070-19-5 ]
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Reference: [1] Collection of Czechoslovak Chemical Communications, 1977, vol. 42, p. 1069 - 1076
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Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 22, p. 11229 - 11237
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  • [ 18107-18-1 ]
  • [ 176504-88-4 ]
Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 2, p. 296 - 301
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  • [ 74-88-4 ]
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Reference: [1] Tetrahedron Asymmetry, 1996, vol. 7, # 7, p. 2145 - 2150
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Reference: [1] Organic letters, 2001, vol. 3, # 6, p. 897 - 899
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  • [ 162537-11-3 ]
Reference: [1] Patent: EP2423187, 2012, A1,
  • 19
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  • [ 630420-16-5 ]
YieldReaction ConditionsOperation in experiment
94% With O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; To a solution of the product from step 3 (6.07 g, 10 mmol) in 100 mL of CH2Cl2, maintained at 0° C., was added 8.7 mL of iPr2EtN (50 mmol) followed by Boc-L-tert-leucine (2.772 g, 12 mmol) and HATU (5.7 g, 15 mmol). The reaction mixture was warmed to RT and stirred for 16 h before being concentrated in vacuo and the residue dissolved in EtOAc (300 mL). The EtOAc solution was washed sequentially with 1N HCl (3.x.50 mL), H2O (2.x.30 mL), and brine (2.x.50 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo and the crude product obtained after purification by flash column chromatography (SiO2, eluted with 33percent acetone in hexanes) to provide a white solid product (7 g, 94percent yield). 1H NMR (400 MHz, CD3OD) δ ppm 1.00-1.06 (m, 11H), 1.16 (s,9H), 1.14-1.24 (m, 2H), 1.44 (dd, J=9.32, 5.29 Hz, 1H), 1.88 (dd, J=8.06, 5.54 Hz, 1H), 2.17-2.39 (m, 2H), 2.59 (dd, J=13.85, 6.80 Hz, 1H), 2.87-3.02 (m, 1H), 4.00 (s, 3H), 4.01-4.14 (m, 1H), 4.17-4.24 (m, 1H), 4.43 (d, J=12.09 Hz, 1H), 4.52-4.65 (m, 1H), 5.12 (d, J=10.07 Hz, 1H), 5.30 (d, J=16.87 Hz, 1H), 5.65-5.91 (m, 2H), 7.56 (s, 1H), 7.68 (d, J=9.06 Hz, 1H), 8.05 (s, 1H), 8.09 (d, J=9.06 Hz, 1H). LC-MS, MS m/z 748 (M++H). Anal. Calcd for C35H46ClN5O9S: C 55.84, H 6.32, N 9.10, S. 4.16. Found: C 56.02, H 6.31, N 9.04.
Reference: [1] Patent: US2009/274652, 2009, A1, . Location in patent: Page/Page column 38; 40
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YieldReaction ConditionsOperation in experiment
69.5% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; To a solution of 3 (278 mg, 0.52 mmol) and Boc-L-tert-leucine, 120 mg, 0.52 mmol) in DCM (38 mL) were added HATU (395.2 mg, 1.04 mmol) and diisopropylethylamine 0.364 mL). The reaction mixture was stirred at room temperature overnight. Solvents were evaporated and the crude mixture was purified by reverse phase HPLC (CH3CN/H2O, 0.1percent formic acid, 0-90percent) to afford the Boc-protected compound (270 mg, 69.5percent) as a white solid. LC-MS (ESI) m/z 748.5 [M+1]+, (calcd MS 747.3). 1H NMR (400 MHz, CDCl3) δ 10.00-10.12 (m, 1H), 8.04-8.12 (m, 1H), 7.95-8.04 (m, 1H), 7.60-7.70 (m, 1H), 7.47 (s, 1H), 6.93-7.03 (m, 1H), 5.70-5.93 (m, 2H), 5.21-5.32 (m, 1H), 5.08-5.19 (m, 2H), 4.47-4.61 (m, 1H), 4.29-4.45 (m, 1H), 4.14-4.24 (m, 1H), 4.02-4.11 (m, 1H), 3.99 (s, 3H), 2.85-2.95 (m, 1H), 2.47-2.64 (m, 2H), 2.04-2.16 (m, 1H), 1.93-2.01 (m, 1H), 1.45-1.51(m, 2H), 1.33-1.38 (m, 2H), 1.20 (br. s, 9H), 1.01 (s, 9H). The above intermediate (270 mg, 0.36 mmol) was treated with excess of HCl (4 N in dioxane). The resulting mixture was stirred at room temperature for 2 h. After evaporation of solvents, the hydrochloride salt of compound 4 was obtained as a white solid.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2048 - 2054
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  • [ 630420-16-5 ]
YieldReaction ConditionsOperation in experiment
94% With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 0 - 20℃; for 16 h; Step 9To a solution of the product of Step 8, Example 1001, (2S,4R)-4-(7-chloro-4- methoxyisoquinolin- 1 -yloxy)-N-(( 1 R,2S)- 1 -(cyclopropylsulfonylcarbamoyl)-2- vinylcyclopropyl)pyrrolidine-2-carboxamide as HC1 salt (6.07 g, 10 mmol) in 100 mL of CH2CI2, maintained at 0°C, was added 8.7 mL of iP^EtN (50 mmol) followed by Boc-L-tert-leucine (2.772 g, 12 mmol) and HATU (5.7 g, 15 mmol). The reaction mixture was warmed to RT and stirred for 16h before being concentrated in vacuo and the residue dissolved in EtOAc (300 mL). The EtOAc solution was washed sequentially with IN HC1 (50 mL x 3), H20 (30 mL x 2), and brine (50 ml x 2). The organic phase was dried over MgS04 and concentrated in vacuo and the crude product obtained after purification using a Biotage (33percent acetone in hexanes) to provide 7 g (94percent) of the desired product. XH NMR (400 MHz, CD3OD) δ ppm 1.00- 1.06 (m, 1 1 H), 1.16 (s, 9 H), 1.14-1.24 (m, 2 H), 1.44 (dd, J=9.32, 5.29 Hz, 1 H), 1.88 (dd, J=8.06, 5.54 Hz, 1 H), 2.17 - 2.39 (m, 2 H), 2.59 (dd, J=13.85, 6.80 Hz, 1 H), 2.87 - 3.02 (m, 1 H), 4.00 (s, 3 H), 4.01 - 4.14 (m, 1 H), 4.17 - 4.24 (m, 1 H), 4.43 (d, J=12.09 Hz, 1 H), 4.52 - 4.65 (m, 1 H), 5.12 (d, J=10.07 Hz, 1 H), 5.30 (d, J=16.87 Hz, 1 H), 5.65 - 5.91 (m, 2 H), 7.56 (s, 1H), 7.68 (d, J=9.06 Hz, 1 H), 8.05 (s, 1 H), 8.09 (d, J=9.06 Hz, 1 H);MS: (M+H)+ 748.
Reference: [1] Patent: WO2012/166459, 2012, A1, . Location in patent: Page/Page column 29
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  • [ 62965-35-9 ]
  • [ 630420-16-5 ]
YieldReaction ConditionsOperation in experiment
80.7% With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 0.2 - 23℃; for 17.5 h; Inert atmosphere Preparation of Compound (I) DIPEA (9.824 ml) followed by HATU (7.99 g) were added to a stirred mixture of Compound F (IO g, 99.2percent potency, 99.6 AP) and Compound G (4.41 g) in CH2Cl2 (100 ml) at 2.7-5 0C under nitrogen. The resulting light brown solution was stirred at 0.2-3 0C for 1.5 h, at 3-20 0C in 0.5 h and at 20-23 0C for 15.5 h for a reaction completion. It was quenched with 2N HCl (50 ml) at 23 0C and stirred for 20 min at 23-24 0C. The biphasic mixture was polish filtered through diatomaceous earth (Celite.(R).) (10 g) to remove insoluble solids of HOAT and HATU. The filter cake was washed with 20 ml Of CH2Cl2. After separating the organic phase from the <n="29"/>filtrates, it was washed with 2N HCl (5x 50 ml) and water (2x 50 ml). The organic phase (115 ml) was concentrated to -50 ml, which was diluted with absolute EtOH (200 proof, 100 ml) and concentrated again to -50 ml. Absolute EtOH (50 ml) was added to bring the final volume to 100 ml. It was then warmed to 500C to form a clear solution and held at 500C for 35 min. The ethanolic solution was cooled from 50 to 23 0C over 15 min to form the crystal slurry. The slurry was stirred at 23 0C for 18 h, cooled to 0.3 0C over 30 min and kept at 0.2-0.3 0C for 2 h. After the filtration, the cake was washed with cold EtOH (2.70C, 2x 6 ml) and dried at 53 °C/72 mm/67 h to give Compound (I) in Form TlF-1/2 as an off white solid (10.49 g, 80.7percent yield, 99.6 AP).
Reference: [1] Patent: WO2009/85659, 2009, A1, . Location in patent: Page/Page column 25; 26-27
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Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 5, p. 1730 - 1752
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