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Chemical Structure| 4023-34-1
Chemical Structure| 4023-34-1
Structure of 4023-34-1 * Storage: {[proInfo.prStorage]}
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Product Details of [ 4023-34-1 ]

CAS No. :4023-34-1 MDL No. :MFCD00001277
Formula : C4H5ClO Boiling Point : -
Linear Structure Formula :- InChI Key :ZOOSILUVXHVRJE-UHFFFAOYSA-N
M.W : 104.53 Pubchem ID :77637
Synonyms :

Calculated chemistry of [ 4023-34-1 ]

Physicochemical Properties

Num. heavy atoms : 6
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.75
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 24.22
TPSA : 17.07 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) : -6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.5
Log Po/w (XLOGP3) : 1.23
Log Po/w (WLOGP) : 1.1
Log Po/w (MLOGP) : 0.62
Log Po/w (SILICOS-IT) : 1.6
Consensus Log Po/w : 1.21

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 3.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.2
Solubility : 6.64 mg/ml ; 0.0635 mol/l
Class : Very soluble
Log S (Ali) : -1.19
Solubility : 6.81 mg/ml ; 0.0652 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.97
Solubility : 11.1 mg/ml ; 0.107 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.28

Safety of [ 4023-34-1 ]

Signal Word:Danger Class:8,3
Precautionary Statements:P210-P233-P240-P241-P242-P243-P264-P270-P280-P301+P310+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P370+P378-P403+P235-P405-P501 UN#:2920
Hazard Statements:H301-H314-H226 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 4023-34-1 ]

* 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 [ 4023-34-1 ]
  • Downstream synthetic route of [ 4023-34-1 ]

[ 4023-34-1 ] Synthesis Path-Upstream   1~26

  • 1
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YieldReaction ConditionsOperation in experiment
93%
Stage #1: With triethylamine; magnesium chloride In ethyl acetate at 0 - 40℃; for 20 h;
Stage #2: at 0 - 20℃; for 20 h;
To ethyl acetate (100 ml) suspension of potassium ethyl malonate (17.0 g, 0.10 mol) were added triethylamine (34.7 ml, 0.25 mol) and magnesium chloride (14.3 g, 0.15 mol) with cooling with ice, and then the resulting mixture was stirred at 40°C for 20 hours. To tetrahydrofuran (50 ml) solution of cyclopropanecarboxylicacid (4.30 g, 50.0 mmol) were added oxalyl chloride (4.36 ml, 50.0 mmol) and a catalytic amount of N,N-dimethylformamide with cooling with ice, and the resulting mixture was stirred as such for 1 hour and then at room temperature for 1 hour. The above-mentioned malonic acid solution was added to this acid chloride solution with cooling with ice, and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into 300 ml of aqueous 10 percent citric acid solution, and the mixture was extracted with ethyl acetate (300 ml .x. 3). The organic layer was successively washed with 500 ml of aqueous saturated sodium bicarbonate solution and 300 ml of brine, and dried over sodium sulfate. The solvent was evaporated, and7.26g (93percent) of the entitled compound was obtained as a colorless oil (this was directly used in the next reaction).1H-NMR(400MHz, CDCl3)δ: 0.94-0.99(2H, m), 1.10-1.15(2H, m), 1.28(3H, t, J=7.08Hz), 2.01-2.06(1H, m), 3.57 (2H, s), 4.21(2H, q, J=7.08Hz).
60%
Stage #1: With magnesium chloride In acetonitrile at 25℃; for 0.0833333 h;
Stage #2: With triethylamine In acetonitrile at 25℃; for 16 h;
To a solution of ethyl potassium malonate (6.5 g, 38.26 mmol) in acetonitrile was added MgCl2 (4.55 g, 47.8 mmol) and the mixture stirred for 5 min at 25° C. TEA (10.7 mL, 76.54 mmol) was then added, followed by dropwise addition of cyclopropanecarbonyl chloride (2 g, 19.13 mmol) and stirring was continued at 25° C. for 16 h, after which, the mixture was diluted with water, acidified to pH 3 with 6N HCl, extracted with diethylether (3*40 mL), dried over Na2SO4, and concentrated to give 3-Cyclopropyl-3-oxo-propionic acid ethyl ester (1.8 g, 60percent).
Reference: [1] Patent: EP1479681, 2004, A1, . Location in patent: Page 59
[2] Patent: US2011/71150, 2011, A1, . Location in patent: Page/Page column 31
  • 2
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  • [ 24922-02-9 ]
YieldReaction ConditionsOperation in experiment
63% With n-butyllithium In tetrahydrofuran; hydrogenchloride; water a
Ethyl 3-cyclopropyl-3-oxopropanoate
To a cooled (-70° C.) solution of monoethyl malonate (33.97 g, 257.10 mmol) in THF (639 mL) was added n-BuLi (1.6M in hexanes, 319 mL, 514.19 mmol) and the mixture was stirred under an argon atmosphere for 15 min.
The resulting solution was cooled to -65° C. and cyclopropanecarbonyl chloride (15.55 g, 148.77 mmol) was added.
The reaction mixture was stirred for 1 h and then allowed to warm up to room temperature.
Some drops of water were added and THF was removed.
The residue was taken up in 1N HCl/Et2 O and extracted with Et2 O.
The organic phase was washed with saturated NaHCO3, dried and concentrated to a residue.
This was purified by chromatography on silica gel (hexane-EtOAc mixtures of increasing polarity) to afford the title compound as a yellow oil (14.7 g, 63percent).
1 H-NMR-(CDCl3) δ (TMS): 1.1 (m, 4H), 1.28 (t, J=7.2 Hz, 3H), 2.04 (m, 1H), 3.55 (s, 2H), 4.21 (q, J=7.2 Hz, 2H).
Reference: [1] Patent: US5827863, 1998, A,
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 4, p. 547 - 558
[3] Patent: US5157040, 1992, A,
  • 3
  • [ 2033-24-1 ]
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  • [ 24922-02-9 ]
Reference: [1] Patent: WO2016/102347, 2016, A1, . Location in patent: Paragraph 0355
[2] Patent: WO2017/211666, 2017, A1, . Location in patent: Paragraph 0269
  • 4
  • [ 18457-03-9 ]
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  • [ 24922-02-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 6, p. 803 - 807
  • 5
  • [ 2033-24-1 ]
  • [ 64-17-5 ]
  • [ 4023-34-1 ]
  • [ 24922-02-9 ]
Reference: [1] MedChemComm, 2013, vol. 4, # 9, p. 1297 - 1304
  • 6
  • [ 4023-34-1 ]
  • [ 6952-93-8 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 5, p. 1184 - 1187
[2] Organic Syntheses, 2005, vol. 81, p. 254 - 261
  • 7
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  • [ 2516-33-8 ]
Reference: [1] Journal of Organic Chemistry, 1984, vol. 49, # 3, p. 431 - 435
  • 8
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  • [ 345-35-7 ]
  • [ 150322-73-9 ]
  • [ 95-52-3 ]
  • [ 446-51-5 ]
  • [ 1759-53-1 ]
Reference: [1] Patent: WO2009/68923, 2009, A2, . Location in patent: Page/Page column 13-14
  • 9
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  • [ 6228-73-5 ]
YieldReaction ConditionsOperation in experiment
100% With ammonia In dichloromethane at 20℃; for 2 h; Intermediate 3: Synthesis of cvclopropanecarboxamide Ammonia was purged through a well-stirred solution of cyclopropane carbonyl chloride (1 g, 9.61 mmol) in dichloromethane (10 mL) for 2 hours at room temperature. Solvent was removed under vacuum, the residue was taken up in ethyl acetate and filtered The filtrate was concentrated to afford pure cyclopropanecarboxamide as a crystalline solid (0.81 g, 100percent).1H NMR (400 MHz, CHCI3-cf): δ 5.63 - 5.91 (br. s, 2H), 1 .43 (m, 1 H), 0.98 (dd, J=4.42, 2.98 Hz, 2H), 0.79 (dd, J=7.91 , 2.95 Hz, 2H). MS: 85.91 (M+1 ).
100% With ammonia In dichloromethane; water at 20℃; for 2 h; Synthesis of cyclopropanecarboxamide Ammonia was purged through a well-stirred solution of cyclopropane carbonyl chloride (1 g, 9.61 mmol) in dichloromethane (10 mL) for 2 hours at room temperature. Solvent was removed under vacuum, the residue was taken up in ethyl acetate and filtered. The filtrate was concentrated to afford pure cyclopropanecarboxamide as a crystalline solid (0.81 g, 100percent). 1H NMR (400 MHz, CHCl3-d): δ 5.63-5.91 (br. s, 2H), 1.43 (m, 1H), 0.98 (dd, J=4.42, 2.98 Hz, 2H), 0.79 (dd, J=7.91, 2.95 Hz, 2H). MS: 85.91 (M+1).
Reference: [1] Patent: WO2012/160464, 2012, A1, . Location in patent: Page/Page column 59-60
[2] Patent: US2014/155398, 2014, A1, . Location in patent: Paragraph 0365
[3] Chemische Berichte, 1923, vol. 56, p. 2201
[4] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1901, vol. 33, p. 377[5] Chem. Zentralbl., 1901, vol. 72, # II, p. 579
[6] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1905, vol. 37, p. 308[7] Chem. Zentralbl., 1905, vol. 76, # I, p. 1704
[8] Chem. Zentralbl., 1902, vol. 73, # I, p. 913
  • 10
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  • [ 6228-73-5 ]
Reference: [1] Patent: US4673674, 1987, A,
  • 11
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  • [ 6952-89-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6629 - 6635
  • 12
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  • [ 56-40-6 ]
  • [ 64513-70-8 ]
Reference: [1] Patent: WO2011/49150, 2011, A1, . Location in patent: Page/Page column 282-283
  • 13
  • [ 67-56-1 ]
  • [ 2033-24-1 ]
  • [ 4023-34-1 ]
  • [ 32249-35-7 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: With pyridine In chloroform at 10 - 20℃; for 2 h;
Stage #2: for 3 h; Heating / reflux
Reference Example 1
Production of methyl 3-cyclopropyl-3-oxopropionate
Merdramic acid (50 g; 347 mmols) was dissolved in chloroform (550 ml), and pyridine (56 g; 700 mmols) was added thereto.
Subsequently, a solution of cyclopropanecarboxylic acid chloride (40 g; 383 mmols) in chloroform (50 ml) was added dropwise thereto at a temperature of 10°C or lower while cooling in an ice-bath.
After completion of the dropwise addition, the mixture was stirred for further 1 hour under cooling in the ice-bath, then at room temperature for 1 hour.
Subsequently, after cooling again using the ice-bath, 1N-HCL aqueous solution (500 ml) was added thereto.
The reaction product was extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate, followed by concentrating under reduced pressure.
Then, methanol (500 ml) was added thereto to dissolve the residue, and the solution was heated for 3 hours under reflux.
After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was distilled to obtain 40 g of methyl 3-cyclopropyl-3-oxopropionate.
Yield: 80percent
Physical properties: bp. 80°C (10mmHg)
Reference: [1] Patent: EP1852428, 2007, A1, . Location in patent: Page/Page column 31
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6836 - 6840
  • 14
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YieldReaction ConditionsOperation in experiment
71.1% With pyridine In dichloromethane at 0 - 20℃; a.2 2-te/t-Butvl-4-f4-(3-chloro-propvl)-piperazin-1-vll-6-cvclopropvl-pyrimidine; a.2.1: Methyl-2-cvclopropanovl-acetate; 48.6 g of meldrum's acid (337.4 mmol) were dissolved in 200 ml of dichloromethane at room temperature and the solution was cooled to 0°C. 40 g of pyridine (506.1 mmol) were added to said solution. 35.3 g of cyclopropyl carbonic acid chloride (337.4 mmol) were then added at 0°C within 1 h. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCI and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and stirred under reflux for 2h. The reaction mixture was concentrated to dryness and the oily residue was purified by destination at 90 °C bath temperature to yield 42.7 g (71,1 percent) of the title compound.MS (ESI) m/z: 143.1 [M+H]+1H-NMR (CDCI3): 5 [ppm] 3.75 (s, 3H), 3.6 (s, 2H), 2.0 (m, 1H), 1.15 (m, 2H),0.95 (m, 2H)
Reference: [1] Patent: WO2006/15842, 2006, A1, . Location in patent: Page/Page column 36
  • 15
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  • [ 87661-20-9 ]
YieldReaction ConditionsOperation in experiment
91% at 0 - 5℃; for 1.5 h; 219.1 g (1913 mmol, 1 equiv.) potassium tert-butylate were suspended in 2.5 L tert-butyl methyl ether and cooled to 0-5° C. 200 g (1 equiv.) cyclopropanecarbonyl chloride were added over 60 min, maintaining the temperature between 0-5° C. (ice-ethanol bath cooling).
In-line FTIR reaction monitoring indicates a feed controlled reaction.
The reaction mixture was stirred 30 min at 0-5° C. and 1 L of 5percent aqueous sodium hydrogencarbonate solution was added.
The aqueous phase was separated and extracted with 500 ml tert-butyl methyl ether.
The organic phases were washed with 500 ml half saturated aq. sodium chloride solution, combined and concentrated under reduced pressure (30° C./150 mbar) to provide 271 g of the title compound (91percent yield corrected for 8percent residual tert-butyl methyl ether).
91% at 0 - 5℃; for 1.5 h; Alternative Preparation of (S)-6-Aza-spiro[2.5]octan-4-ol; hydrochloridei) Cyclopropanecarboxylic Acid tert-butyl ester; 219.1 g (1913 mmol, 1 eq.) potassium tert-butylate were suspended in 2.5 L TBME and cooled to 0-5° C. 200 g (1 eq.) cyclopropanecarbonyl chloride were added over 60 min, maintaining the temperature between 0-5° C. (ice-EtOH bath cooling). In-line FTIR reaction monitoring indicates a feed controlled reaction. The reaction mixture was stirred 30 min at 0-5° C. and 1 L of 5percent aq. NaHCO3 solution was added. The aqueous phase was separated and extracted with 500 ml TBME. The organic phases were washed with 500 ml half sat. aq. NaCl solution, combined and concentrated under reduced pressure (30° C./150 mbar) to provide 271 g of the title compound (91percent yield corrected for 8percent residual TBME).
91% at 0 - 5℃; for 1.5 h; i) Cyclopropanecarboxylic acid tert-butyl ester; 219.1 g (1.91 mol, 1 eq.) potassium tert-butylate were suspended in 2.5 L tert-butyl methyl ether and cooled to 0-5° C. 200 g (1 eq.) cyclopropanecarbonyl chloride were added over 60 min, maintaining the temperature between 0-5° C. (ice-ethanol bath cooling). In-line FTIR reaction monitoring indicates a feed controlled reaction. The reaction mixture was stirred 30 min at 0-5° C. and 1 L of 5percent aq. sodium hydrogencarbonate solution was added. The aqueous phase was separated and extracted with 500 ml tert-butyl methyl ether. The organic phases were washed with 500 ml half saturated aq. sodium chloride solution, combined and concentrated under reduced pressure (30° C./150 mbar) to provide 271 g of the title compound (91percent yield corrected for 8percent residual tert-butyl methyl ether).
91% at 0 - 5℃; for 1 h; i)
Cyclopropanecarboxylic acid tert-butyl ester
219.1 g (1.91 mol, 1 eq.) potassium tert-butylate were suspended in 2.5 L tert-butyl methyl ether and cooled to 0-5° C. 200 g (1 eq.) cyclopropanecarbonyl chloride were added over 60 min, maintaining the temperature between 0-5° C. (ice-ethanol bath cooling).
In-line FTIR reaction monitoring indicates a feed controlled reaction.
The reaction mixture was stirred 30 min at 0-5° C. and 1 L of 5percent aq. sodium hydrogencarbonate solution was added.
The aqueous phase was separated and extracted with 500 ml tert-butyl methyl ether.
The organic phases were washed with 500 ml half saturated aq. sodium chloride solution, combined and concentrated under reduced pressure (30° C./150 mbar) to provide 271 g of the titled compound (91percent yield corrected for 8percent residual tert-butyl methyl ether).
63.2% at 0 - 50℃; for 0.5 h; Example 1Atert-Butyl Cyclopropanecarboxylate 50.99 g (454.4 mmol) of potassium tert-butoxide were dissolved in 454 ml of abs. THF and cooled to 0° C. The solution was stirred vigorously, and 50 g (478.3 mmol) of cyclopropanecarbonyl chloride were added dropwise such that the reaction temperature did not exceed 50° C. (cooling required). After the addition has ended, the resultant suspension was stirred for another 30 min. After cooling, the reaction mixture was, under reduced pressure, concentrated to about one third of the original volume and then added to 2 liters of saturated aqueous ammonium chloride solution. The pH was adjusted to 8 by addition of saturated sodium bicarbonate solution and the mixture was then extracted three times with diethyl ether. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure without heating (cold water bath). The residue was distilled at a bath temperature of about 85° C. and 42 mbar. This gave 43.1 g (63.2percent of theory) of the target compound as a clear liquid.GC-MS (Method 1): Rt=1.8 min1H-NMR (400 MHz, DMSO-d6): δ=1.52-1.48 (m, 1H), 1.41 (s, 9H), 0.82-0.72 (m, 4H).

Reference: [1] Patent: US2009/23713, 2009, A1, . Location in patent: Page/Page column 20
[2] Patent: US2010/22518, 2010, A1, . Location in patent: Page/Page column 20
[3] Patent: US2010/16282, 2010, A1, . Location in patent: Page/Page column 19
[4] Patent: US2011/92698, 2011, A1, . Location in patent: Page/Page column 22
[5] Journal of Organic Chemistry, 2009, vol. 74, # 22, p. 8726 - 8732
[6] Patent: US2012/28971, 2012, A1, . Location in patent: Page/Page column 14
[7] Angewandte Chemie - International Edition, 2018, vol. 57, # 2, p. 574 - 578[8] Angew. Chem., 2018, vol. 130, p. 583 - 587,5
[9] Patent: WO2011/48032, 2011, A1, . Location in patent: Page/Page column 51
[10] Patent: WO2017/223020, 2017, A1, . Location in patent: Page/Page column 36
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  • [ 75-65-0 ]
  • [ 87661-20-9 ]
Reference: [1] Monatshefte fuer Chemie, 1937, vol. 70, p. 392,393[2] Zeitschrift fuer Elektrochemie und Angewandte Physikalische Chemie, 1937, vol. 43, p. 283
[3] Patent: WO2011/46771, 2011, A1, . Location in patent: Page/Page column 196
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Reference: [1] Patent: WO2005/51911, 2005, A1, . Location in patent: Page/Page column 73
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  • [ 372-09-8 ]
  • [ 118431-88-2 ]
YieldReaction ConditionsOperation in experiment
54% With n-butyllithium In tetrahydrofuran; water; ethyl acetate EXAMPLE 1
3-Cyclopropyl-3-oxopropanenitrile
To a mechanically stirred solution of 15.0 g (176 mmol) 2-cyanoacetic acid and 100 mg 1,10-phenanthroline in 500 mL THF at -78° C. was added 141 mL (352 mmol) 2.5M n-butyllithium in hexanes.
The solution was warmed in a water bath to 0° C.
After 15 minutes at 0° C. most of the brown color had faded.
The mixture was cooled to -78° C. and to it was added a solution of 8.0 mL (88 mmol) cyclopropanecarbonyl chloride in 8 mL THF.
The mixture was warmed to RT and stirred 15 minutes, was poured into 300 mL 5percent HCl solution in water, and was extracted three times with ether.
The combined organic material was washed with saturated aqueous sodium bicarbonate then with brine, was dried over magnesium sulfate, was stripped of solvent in vacuo, and was chromatographed on silica gel under medium pressure using 30percent ethyl acetate in hexanes to give 6.5 g (54percent yield) of the title compound.
The title compound was stored with 1percent w/w BHT in 40 mL CH2 Cl2 at -5° C. Rf 0.12 in 20percent EtOAc/hexane, visualized by ninhydrin stain (green tint); 1 H-NMR (300 MHz, CDCl3): δ3.63 (s, 2H), 2.10 (m, 1H), 1.20 (m, 2H), 1.10 (m, 2H).
54% With n-butyllithium In tetrahydrofuran; water; ethyl acetate EXAMPLE 1
3-Cyclopropyl-3-oxopropanenitrile
To a mechanically stirred solution of 15.0 g (176 mmol) 2-cyanoacetic acid and 100 mg 1,10-phenanthroline in 500 mL THF at -78° C. was added 141 mL (352 mmol) 2.5M n-butyllithium in hexanes.
The solution was warmed in a water bath to 0° C.
After 15 minutes at 0° C. most of the brown color had faded.
The mixture was cooled to -78° C. and to it was added a solution of 8.0 mL (88 mmol) cyclopropanecarbonyl chloride in 8 mL THF.
The mixture was warmed to RT and stirred 15 minutes, was poured into 300 mL 5percent HCl solution in water, and was extracted three times with ether.
The combined organic material was washed with saturated aqueous sodium bicarbonate then with brine, was dried over magnesium sulfate, was stripped of solvent in vacuo, and was chromatographed on silica gel under medium pressure using 30percent ethyl acetate in hexanes to give 6.5 g (54percent yield) of the title compound.
The title compound was stored with 1percent w/w BHT in 40 mL CH2 Cl2 at -5° C. Rf 0.12 in 20percent EtOAc/hexane visualized by ninhydrin stain (green tint); 1 H-NMR (300 MHz, CDCl3): δ3.63 (s, 2H), 2.10 (m, 1H), 1.20 (m, 2H), 1.10 (m, 2H).
Reference: [1] Patent: US5250521, 1993, A,
[2] Patent: US5260285, 1993, A,
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  • [ 118431-88-2 ]
Reference: [1] Patent: WO2015/97122, 2015, A1, . Location in patent: Page/Page column 74
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  • [ 4023-34-1 ]
  • [ 372-09-8 ]
  • [ 118431-88-2 ]
Reference: [1] Patent: US5804532, 1998, A,
[2] Patent: US5804532, 1998, A,
  • 21
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  • [ 372-09-8 ]
  • [ 118431-88-2 ]
Reference: [1] Patent: EP496631, 1992, A1,
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  • [ 147356-78-3 ]
YieldReaction ConditionsOperation in experiment
72.9% With triethylamine In dichloromethane at 0 - 20℃; Example 96. Synthesis of 3-fluoro-2-(4-(3-(5-hydroxy-2-methylpiperidin-l-yl)- -pyrazol-l-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile, 1-96 Synthesis of compound 96.2. To a solution of Ν,Ο-dimethylhydroxylamine HCl (10.0g, 95.69 mmol, 1.0 eq) and Et3N (19.36 g, 191.6 mmol, 2.0 eq) in CH2C12 (60 mL) reaction mixture was stirred at 0 °C for 30 min. Compound 96.1 was added at 0 °C. Reaction mixture was stirred at room temperature for 15 h. Upon completion of the reaction, organic layer was washed with water, brine, sat NaHCC solution and 1.0 N HCl, dried over Na2S04 and concentrated under reduced pressure to pressure to obtain crude. Crude was purified by column chromatography to provide 96.2 (9.0 g, 72.9percent).
61% With triethylamine In dichloromethane at 0℃; for 1 h; Cooling with ice N,O-dimethyl-hydroxylamine HCl (40 g, 410 mmol) was suspended under nitrogen in DCM (400 mL) and cooled in ice. Triethylamine (63 mL, 451 mmol) was added slowly, then cyclopropanecarbonyl chloride (41 mL, 451 mmol) was added slowly. Stirring without cooling was continued for 1 h. Extraction: 2.x.DCM, 1.x.1N HCl, 1.x.NaCl. Distillation: 75° C./20 mbar. One obtained 32.5 g (61percent) of a colorless oil.
61% With triethylamine In dichloromethane at 0℃; for 1 h; Cyclopropanecarboxylic acid methoxy-methyl-amide N, O-dimethyl-hydroxylamine HC1 (40 g, 410 mmol) was suspended under nitrogen in DCM (400 mL) and cooled in ice. Triethylamine (63 mL, 451 mmol) was added slowly, then cyclopropanecarbonyl chloride (41 mL, 451 mmol) was added slowly. Stirring without cooling was continued for 1 h. Extraction: 2 x DCM, 1 x 1 N HC1, 1 x NaCl. Distillation: 75 °C/20 mbar. One obtained 32.5 g (61 percent) of a colorless oil.
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 4840 - 4860
[2] Patent: WO2017/40757, 2017, A1, . Location in patent: Paragraph 00466-00467
[3] Patent: US2005/197337, 2005, A1, . Location in patent: Page/Page column 10
[4] Patent: WO2005/94828, 2005, A1, . Location in patent: Page/Page column 19
[5] Patent: WO2008/34860, 2008, A1, . Location in patent: Page/Page column 139
[6] Patent: WO2010/30727, 2010, A1, . Location in patent: Page/Page column 100-101
[7] Patent: WO2014/116593, 2014, A1, . Location in patent: Page/Page column 40
[8] Patent: WO2015/24905, 2015, A1, . Location in patent: Paragraph 00295
[9] Patent: US2015/80391, 2015, A1, . Location in patent: Paragraph 0573; 0574
[10] Patent: US2016/60197, 2016, A1, . Location in patent: Paragraph 0234; 0235; 0236
[11] Synthesis (Germany), 2018, vol. 50, # 3, p. 539 - 547
  • 23
  • [ 4023-34-1 ]
  • [ 57260-71-6 ]
  • [ 414910-15-9 ]
YieldReaction ConditionsOperation in experiment
98% With triethylamine In dichloromethane at 0 - 20℃; for 3 h; Large scale S1: N-Boc-piperazine (1.82 kg, 9.77 mol) was added to a 20 L four-necked flask with mechanical stirring and a thermometer.Triethylamine (1.48 kg, 14.66 mol), dichloromethane 5.46 Kg, cooled to 0 ° C,Cyclopropylcarbonyl chloride (1.12 kg, 10.75 mol) was slowly added dropwise, and the temperature was controlled from 0 ° C to 10 ° C.After the completion of the dropwise addition, the reaction was carried out for 3 hours at 10 ° C to 20 ° C.Add 5kg of water, add sodium carbonate to adjust pH=8-9, separate the liquid, collect the organic phase, add 1.50Kg of water phase, and extract once with dichloromethane.The methylene chloride phases were combined, washed once with 2 kg of 0.05 M diluted hydrochloric acid, and once with 2 kg of water.The dichloromethane was concentrated to remove 2.43 kg of 4-(cyclopropanecarbonyl)piperazine-1-carboxylic acid tert-butyl ester, yield 98percent.The nuclear magnetic warp alignment is consistent with the standard map.
73% With potassium carbonate In dichloromethane at 0 - 20℃; A mixture of compound tert-butyl piperazine-1 carboxylate (3.725 g, 20 mmol) and potassium carbonate (5.53 g, 40 mmol) in anhydrous dichloromethane (30 mL) was cooled to 0° C., cyclopropanecarbonyl chloride (2.30 g, 22 mmol) was then added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with 10percent citric acid (50 mL), followed by saturated sodium bicarbonate (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate (3.7 g, yield 73percent) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 0.76-0.81 (m, 2H), 0.98-1.03 (m, 2H), 1.49 (s, 9H), 1.69-1.75 (m, 1H), 3.46-3.48 (m, 4H), 3.63-3.65 (m, 4H); LC-MS (ESI) m/z: 255(M+1)+.
73% With potassium carbonate In dichloromethane at 0 - 20℃; Example 17Atert- Butyl 4-(cyclopropanecarbonyl)piperazine- 1 -carboxylate[00523] A mixture of compound tert-butyl piperazine-1 carboxylate (3.725 g, 20 mmol) and potassium carbonate (5.53 g, 40 mmol) in anhydrous dichloromethane (30 mL) was cooled to 0 °C,cyclopropanecarbonyl chloride (2.30 g, 22 mmol) was then added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with 10percent citric acid (50 mL), followed by saturated sodium bicarbonate (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4- (cyclopropanecarbonyl)piperazine- 1 -carboxylate (3.7 g, yield 73percent) as a white solid. ^-NMR (400 MHz, CDCI3) δ (ppm): 0.76-0.81 (m, 2H), 0.98-1.03 (m, 2H), 1.49 (s, 9H), 1.69-1.75 (m, 1H), 3.46-3.48 (m, 4H), 3.63-3.65 (m, 4H); LC-MS (ESI) m/z: 255(M+1)+.
Reference: [1] Patent: CN108341792, 2018, A, . Location in patent: Paragraph 0028; 0033
[2] Patent: US2010/35883, 2010, A1, . Location in patent: Page/Page column 56
[3] Patent: WO2011/130661, 2011, A1, . Location in patent: Page/Page column 102
[4] Patent: US2004/14770, 2004, A1, . Location in patent: Page/Page column 11
  • 24
  • [ 110-85-0 ]
  • [ 4023-34-1 ]
  • [ 1021298-67-8 ]
Reference: [1] Patent: WO2008/47082, 2008, A2, . Location in patent: Page/Page column 25
  • 25
  • [ 1257705-09-1 ]
  • [ 4023-34-1 ]
  • [ 1206161-97-8 ]
YieldReaction ConditionsOperation in experiment
91.2% With 4-methyl-morpholine In 1,4-dioxane at 50℃; for 4 h; Green chemistry The intermediate (III) obtained in step E)With cyclopropanyl chloride in an amidated reaction in a system consisting of N-methylmorpholine and 1,4-dioxane,The amidation reaction time was 4 h,The amidation reaction temperature was 50 ° C,The molar ratio of the intermediate (III), cyclopropanyl chloride, N-methylmorpholine and 1,4-dioxane was 1: 2.8: 2.5:TLC plate to determine the reaction is completed, cooled to room temperature,Adding methylene chloride and water, separating the organic phase with water,Then washed with brine, dried over magnesium sulfate,Evaporated to dryness and the residue was purified over a silica gel column [elution solvent: ethyl acetate / n-hexane (3: 7 v / v)To obtain a solid yellowish solid,That is, Filgotinib, yield 91.2percentThe reaction of this step is the same as in Example 1.
Reference: [1] Patent: CN104987333, 2017, B, . Location in patent: Paragraph 0039; 0040; 0047; 0054; 0061
  • 26
  • [ 1121057-75-7 ]
  • [ 4023-34-1 ]
  • [ 1616388-38-5 ]
Reference: [1] Patent: WO2014/100620, 2014, A2, . Location in patent: Paragraph 0319
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