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CAS No. :765-43-5 MDL No. :MFCD00001297
Formula : C5H8O Boiling Point : -
Linear Structure Formula :- InChI Key :HVCFCNAITDHQFX-UHFFFAOYSA-N
M.W :84.12 Pubchem ID :13004
Synonyms :

Safety of [ 765-43-5 ]

Signal Word:Danger Class:3
Precautionary Statements:P210 UN#:1224
Hazard Statements:H225 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 765-43-5 ]

* 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 [ 765-43-5 ]
  • Downstream synthetic route of [ 765-43-5 ]

[ 765-43-5 ] Synthesis Path-Upstream   1~36

  • 1
  • [ 765-43-5 ]
  • [ 100-63-0 ]
  • [ 2731-06-8 ]
  • [ 74204-92-5 ]
YieldReaction ConditionsOperation in experiment
34% With ammonium iodide In acetonitrile for 16 h; Reflux General procedure: A mixture of phenylhydrazine (10mmol), ketone (12 mmol) and NH4I (10 mmol) in acetonitrile (20 mL)was heated to reflux for the time indicated below. The mixture was treated witha 5percent NaOH solution and extracted with EtOAc. The organic layer was dried overanhydrous MgSO4, filtered and evaporated. The residue was subjectedto column chromatography, tetrahydropyridazines being eluted with chloroform,tryptamine being eluted with ethanol.
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 43, p. 5936 - 5939
  • 2
  • [ 765-43-5 ]
  • [ 89830-98-8 ]
Reference: [1] Patent: WO2018/151830, 2018, A1,
  • 3
  • [ 765-43-5 ]
  • [ 450-95-3 ]
  • [ 24922-02-9 ]
YieldReaction ConditionsOperation in experiment
55% With NaH In hydrogenchloride; diethyl ether; ethanol; hexane; ethyl acetate; mineral oil; Diethyl carbonate A.
3-Cyclopropyl-3-oxopropanoic acid, ethyl ester
To a slurry of NaH (60percent in mineral oil, 19.200 gm, 0.48 mol) in dry diethyl carbonate (80 ml) was added a solution of methyl cyclopropyl ketone (23.5 ml, 20.00 gm, 0.238 mol) in Et2 O (30 ml).
After the addition of approximately 10percent of the ketone solution, EtOH (0.25 ml) was added and addition of the ketone continued.
Soon after the addition was complete, the reaction became quite exothermic with vigorous H2 evolution.
Periodic cooling with an ice bath was required.
After one hour, H2 evolution had ceased and the mixture was diluted with Et2 O (200 ml) and hexane (185 ml).
The solution was cooled in an ice bath and carefully treated with 5percent HCl (10 ml), at which time a thick slurry developed.
The solid was collected by filtration and washed with hexane.
The solid was then partitioned between Et2 O and 5percent HCl until all of the solid had dissolved and the aqueous layer remained acidic.
The organic layer was separated and washed with H2 O, saturated NaHCO3, and brine, then dried (MgSO4), filtered and stripped.
The liquid residue was subjected to flash chromatography (Merck SiO2, 20percent EtOAc in hexane) to provide compound A (20.357 gm, 55percent) as a yellow liquid.
TLC Rf 0.24 (20percent EtOAc in hexane)
55% With NaH In hydrogenchloride; diethyl ether; ethanol; hexane; ethyl acetate; mineral oil; Diethyl carbonate A.
3-Cyclopropyl-3-oxopropanoic acid, ethyl ester
To a slurry of NaH (60percent in mineral oil, 19.200 g, 0.48 mol) in dry diethyl carbonate (80 ml) was added a solution of methyl cyclopropyl ketone (23.5 ml, 20.00 g, 0.238 mol) in Et2 O (30 ml).
After the addition of approximately 10percent of the ketone solution, EtOH (0.25 ml) was added and the addition of the ketone continued.
Soon after the addition was complete, the reaction became quite exothermic with vigorous H2 evolution.
Periodic cooling with an ice bath was required.
After one hour, H2 evolution had ceased and the mixture was diluted with Et2 O (200 ml) and hexane (185 ml).
The solution was cooled in an ice bath and carefully treated with 5percent HCl (10 ml), at which time a thick slurry developed.
The solid was collected by filtration and washed with hexane.
The solid was then partitioned between Et2 O and 5percent HCl until all of the solid had dissolved and the aqueous layer remained acidic.
The organic layer was separated and washed with H2 O, saturated NaHCO3, and brine, then dried (MgSO4), filtered and stripped.
The liquid residue was subjected to flash chromatography (Merck SiO2, 20percent EtOAc in hexane) to provide compound A (20.357 g, 55percent) as a yellow liquid.
TLC: Rf =0.24 (20percent EtOAc in hexane).
Reference: [1] Patent: US5506219, 1996, A,
[2] Patent: US5506219, 1996, A,
  • 4
  • [ 765-43-5 ]
  • [ 616-38-6 ]
  • [ 24922-02-9 ]
YieldReaction ConditionsOperation in experiment
60% With sodium t-butanolate In toluene at 15 - 75℃; 48g of sodium tert-butoxide was added to 500mL of toluene, cooled to 10°C and 225g of dimethyl carbonate was added dropwise. After stirring for 30 min, 75.7g cyclopropyl methyl ketone was added dropwise and the reaction temperature was controlled not higher than 15°C. Stirring was continued for 30 min, and the reaction temperature was raised to 75°C overnight. The reaction was cooled to room temperature, the solution was poured into 500mL of ice water, adjusted pH1-2 with hydrochloric acid. The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated to give 83g og an orange oil (A-3-2), yield: 60percent, purity: 98.28percent.
Reference: [1] Patent: CN105218449, 2016, A, . Location in patent: Paragraph 0072; 0073
  • 5
  • [ 765-43-5 ]
  • [ 105-58-8 ]
  • [ 24922-02-9 ]
Reference: [1] Tetrahedron Letters, 1993, vol. 34, # 51, p. 8267 - 8270
[2] Bulletin de la Societe Chimique de France, 1973, p. 1711 - 1717
[3] Tetrahedron Letters, 1979, p. 2339 - 2342
[4] Patent: US2004/147561, 2004, A1, . Location in patent: Page 60
[5] Chemical Communications, 2017, vol. 53, # 58, p. 8136 - 8139
  • 6
  • [ 765-43-5 ]
  • [ 141-52-6 ]
  • [ 105-58-8 ]
  • [ 24922-02-9 ]
Reference: [1] Journal of the American Chemical Society, 1947, vol. 69, p. 2073
  • 7
  • [ 765-43-5 ]
  • [ 60-29-7 ]
  • [ 105-58-8 ]
  • [ 24922-02-9 ]
Reference: [1] Journal of the American Chemical Society, 1948, vol. 70, p. 497,499
  • 8
  • [ 765-43-5 ]
  • [ 100114-57-6 ]
Reference: [1] Patent: WO2017/117708, 2017, A1,
  • 9
  • [ 765-43-5 ]
  • [ 75-16-1 ]
  • [ 2270-59-9 ]
YieldReaction ConditionsOperation in experiment
77%
Stage #1: at 30 - 35℃; for 1 h;
Stage #2: With sulfuric acid In tetrahydrofuran; water at 0 - 30℃; for 0.25 h;
105 kg of 12percent methyl magnesium bromide in THF corresponding to 12.6 kg of the same with 100percent concentration are charged into a stainless reactor.Keeping the reaction temperature between 30 and 35° C. by cooling with a brine bath 6.7 kg of cyclopropylmethylketone (II) are poured. Once pouring is complete, the reaction mixture is stirred at 30-35° C. for at least 1 hour, then cooled to 5-10° C. and the reaction mixture is poured into another enameled reactor containing 60 kg of 35percent sulphuric acid, cooled to 0-10° C.The reaction mixture is brought to a temperature between 25 and 30° C. and kept at that temperature for at least 15 minutes, then the phases are left to superate, the lower aqueous phase is removed.The organic phase is washed with 6.7 kg of demineralised water. It is stirred at 25-30° C. and left to decant to allow the separation of the two phases. The lower aqueous phase is removed.The solvent is removed from the organic phase by vacuum distillation until an oily residue is obtained, to which 10.1 kg of THF are added and the mixture is stirred until it is completely dissolved. Then the solution is poured into a container with suitable capacity and sent to the next stage.10 kg of product at 100percent are obtained.Yield: 77percent referring to the kg of cyclopropylmethylketone (II).
77%
Stage #1: at 30 - 35℃; for 1 h;
Stage #2: With sulfuric acid In tetrahydrofuran; water at 0 - 30℃; for 0.25 h;
105 kg of 12percent methyl magnesium bromide in THF corresponding to 12,6 kg of the same with 100percent concentration are charged into a stainless reactor. Keeping the reaction temperature between 30 and 35°C by cooling with a brine bath 6.7 kg of cyclopropylmethylketone (II) are poured. Once pouring is complete, the reaction mixture is stirred at 30-350C for at least 1 hour, then cooled to 5-100C and the reaction mixture is poured into another enamelled reactor containing 60 kg of 35percent sulphuric acid, cooled to 0-10°C. The reaction mixture is brought to a temperature between 25 and 3O0C and kept at that temperature for at least 15 minutes, then the phases are left to superate, the lower aqueous phase is removed.The organic phase is washed with 6.7kg of demineralised water. It is stirred at 25- 30°C and left to decant to allow the separation of the two phases. The lower aqueous phase is removed.The solvent is removed from the organic phase by vacuum distillation until an oily residue is obtained, to which 10.1kg of THF are added and the mixture is stirred until it is completely dissolved. Then the solution is poured into a container with suitable capacity and sent to the next stage. 10kg of product at 100percent are obtained.Yield: 77percent referring to the kg of cyclopropylmethylketone (II) .
71%
Stage #1: for 0.333333 h; Reflux; Inert atmosphere
Stage #2: With sulfuric acid In water at 10℃; for 0.5 h; Inert atmosphere
To a solution of methylmagnesium bromide (3M in Et2O, 60 mmol, 1.2 eq.) in THF (20 mL) was added dropwise a solution of cyclopropylmethyl ketone (4.21 g, 50 mmol, 1.0 eq.) in THF (7 mL). The mixture was then heated to reflux for 20 minutes. On cooling to room temperature, the reaction mixture was slowly added to a cooled solution of conc. sulphuric acid in water (1:2) at a rate that the temperature does not raise above 10°C. After addition, stirring was continued for 30 minutes. The organic layer was then separated and the aqueous phase extracted with Et2O. The combined organic extracts were washed with sat.NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was distilled under vacuum (37 mmHg, 77°C) to give compound 10 as colorless oil (5.788 g, 71percent yield).
70%
Stage #1: at 0℃; Reflux
Stage #2: With sulfuric acid In tetrahydrofuran; diethyl ether; water at 0 - 20℃;
To a solution of methylmagnesium bromide (3.0 M in Et2O, 31 mL, 97 mmol) in THF (30 mL) at 0 °C was added dropwise a solution of cyclopropyl methyl ketone (6.87 g, 80 mmol) in THF (12 mL). The mixture was heated under reflux for 20 min, cooled to room temperature then slowly added to a cooled solution of concentrated H2SO4 in water (60 mL, 1:2) at a steady rate so that the temperature did not rise above 10 °C. The resulting mixture was stirred for 30 min at 0 °C then the organic layer was separated. The aqueous phase was extracted with Et2O (3 × 50 mL) and the organic phases combined, washed with sat. NaHCO3 (100 mL) and brine (100 mL) and dried (MgSO4). The solvent was removed in vacuo to give the product as a yellow liquid (9.115 g, 55.89 mmol, 70percent).

Reference: [1] Chemistry - A European Journal, 2009, vol. 15, # 40, p. 10473 - 10485
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 47, p. 9707 - 9715
[3] Organic Letters, 2006, vol. 8, # 24, p. 5421 - 5424
[4] European Journal of Organic Chemistry, 2006, # 14, p. 3181 - 3192
[5] Patent: US2009/43093, 2009, A1, . Location in patent: Page/Page column 3
[6] Patent: WO2007/9953, 2007, A1, . Location in patent: Page/Page column 7
[7] European Journal of Organic Chemistry, 2016, vol. 2016, # 3, p. 434 - 437
[8] Synthesis (Germany), 2016, vol. 48, # 19, p. 3301 - 3308
[9] Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 2680 - 2688
[10] Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11595 - 11600
[11] Synthesis, 1979, p. 37 - 38
[12] Advanced Synthesis and Catalysis, 2017, vol. 359, # 8, p. 1331 - 1338
  • 10
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  • [ 6746-94-7 ]
YieldReaction ConditionsOperation in experiment
55.6% With potassium hydroxide; phosphorus pentachloride In quinoline; dodecane; dimethyl sulfoxide; toluene EXAMPLE 1
Preparation of Cyclopropylacetylene
A 4-neck 500 mL jacketed reactor with provision for heating and cooling, equipped with N2-inlet, thermocouple, air stirrer and addition funnel was flushed with nitrogen for 15 minutes and nitrogen atmosphere was maintained throughout the reaction.
Dodecane (156 mL) was charged to the reactor and stirred.
The reactor was cooled to 1° C.
Finely ground PCl5 (156 gm, 0.75 mol, 1.5 equivalent, 98percent) was charged to the reactor between 1 to 5° C. (3 minutes) with constant stirring.
Quinoline (156 g, 1.25 mol, 2.5 equivalent) was charged to the stirring slurry between 0 to 5° C.
The mixture was aged at 0° C. for 0.5 h and cooled to -5° C. Neat cyclopropylmethylketone (2, 50 mL, 1 equivalent, 0.5 mol) was charged to the reactor between -5 to -3° C.
The reaction mixture was stirred at -3° C. for 15 h and 20° C. for 4 h. GC analysis of the reaction mixture shows a 95percent complete reaction.
The reaction mixture was filtered through a pressure filter, the solids were washed with 3*50 mL dodecane (9243 gm filtrate and 264.8 gm solids).
The filtrate was quenched with 300 mL of 15N KOH solution (by slowly adding the filtrate to KOH) between 0 to 15° C. (1 h).
The aqueous layer was extracted with 50 mL of dodecane.
The combined organics were dried over 19.4 g Na2SO4.
Organic layer 200 g. (8.8 g CPA 3, 14.8 g CPVC 4, 55.6percent solution yield).
The organic layer was vacuum distilled at pot temp 97° C., 24-33° C. head temp, 650 mm Hg (1 h).
Distillate collected 22 g.
The distillate was charged into 28 g of potassium t-butoxide (90.5 equivalent with respect to CPMK)/35 mL DMSO (1.2 mL/g K-t-BuO) at 40 to 45° C. (controlled by icebath cooling) and heated to 70° C. for 2 h.
Distilled at pot temperature of 90-115° C. 90.8percent pure CPA (5.7 gm).
Cooled the pot to 60° C., charged 50 mL of toluene and distilled at 116-118° C. to obtain a CPA solution of 26.3percent in toluene (9 g).
Reference: [1] Patent: US6235957, 2001, B1,
[2] Patent: US6235957, 2001, B1,
[3] Patent: US6235957, 2001, B1,
[4] Patent: CN107698417, 2018, A,
  • 11
  • [ 24154-06-1 ]
  • [ 765-43-5 ]
  • [ 6746-94-7 ]
Reference: [1] Journal of the American Chemical Society, 1969, vol. 91, p. 2117 - 2118
  • 12
  • [ 765-43-5 ]
  • [ 6228-73-5 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1972, p. 4643 - 4649
  • 13
  • [ 765-43-5 ]
  • [ 141-78-6 ]
  • [ 21573-10-4 ]
YieldReaction ConditionsOperation in experiment
47%
Stage #1: With ethanol; sodium hydride In tetrahydrofuran at 20℃; Inert atmosphere; Cooling with ice
Stage #2: at 40℃; for 4 h;
PREPARATION 176 1 -Cyclopropylbutane-1 ,3-dione Sodium hydride (60percent dispersion in oil, 0.95 g, 23.8 mmol) was washed several times with pentane and then suspended in 18 ml tetrahydrofuran under nitrogen. Ethyl acetate (2.3 ml, 23.5 mmol) and 2 drops of ethanol were added. A solution of cyclopropyl methyl ketone (1 .0 g, 1 1 .9 mmol) dissolved in 5 ml tetrahydrofuran was added drop-wise with stirring, maintaining the reaction temperature below 20 °C with an ice-bath. 18-Crown-6 (63 mg, 0.25 mmol) was added and the mixture was stirred at 40 °C for 4 h. The mixture was evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous phase was washed with ether. The aqueous was then acidified to pH 2 with 2N hydrochloric acid. The aqueous was extracted three times with ether and the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 0.7 g (5.5 mmol, 47percent) of the title compound. Purity 100percent. 1 H NMR (400 MHz, CHLOROFORM-c/) mixture of keto and enol tautomers Keto form δ ppm 0.83 - 0.99 (m, 2 H), 1 .07 - 1 .17 (m, 2 H), 1 .55 - 1 .71 (m, 1 H), 2.25 (s, 3 H), 3.69 (s, 2 H). Enol form δ ppm 0.83 - 0.99 (m, 2 H), 1 .07 - 1 .17 (m, 2 H), 1 .55 - 1 .71 (m, 1 H), 2.02 (s, 3 H), 5.61 (s, 1 H). UPLC/MS (3 min) retention time 0.69, 1 .33 min. LRMS: m/z 127 (M+1 ).
Reference: [1] Journal of Labelled Compounds and Radiopharmaceuticals, 2009, vol. 52, # 10, p. 435 - 442
[2] Patent: CN108840791, 2018, A, . Location in patent: Paragraph 0030-0031; 0033-0038; 0040-0044; 0046-0050; 0052
[3] Patent: WO2013/10880, 2013, A1, . Location in patent: Page/Page column 166-167
[4] Journal of Organic Chemistry, 1952, vol. 17, p. 685,688
[5] Patent: EP2548863, 2013, A1, . Location in patent: Paragraph 0179
[6] Patent: WO2013/10881, 2013, A1, . Location in patent: Page/Page column 64-65
[7] Patent: WO2013/39988, 2013, A1, . Location in patent: Page/Page column 56
[8] Patent: WO2013/173441, 2013, A2, . Location in patent: Page/Page column 49
[9] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 6, p. 1581 - 1588
[10] Patent: US2014/256739, 2014, A1, . Location in patent: Paragraph 0745
  • 14
  • [ 765-43-5 ]
  • [ 108-24-7 ]
  • [ 21573-10-4 ]
Reference: [1] Journal of Organic Chemistry, 1952, vol. 17, p. 685,688
  • 15
  • [ 108-86-1 ]
  • [ 765-43-5 ]
  • [ 5558-04-3 ]
Reference: [1] Organic Letters, 2011, vol. 13, # 24, p. 6504 - 6507
[2] Journal of Organic Chemistry, 2006, vol. 71, # 24, p. 9057 - 9061
[3] Journal of Organic Chemistry USSR (English Translation), 1983, vol. 19, p. 1291 - 1297[4] Zhurnal Organicheskoi Khimii, 1983, vol. 19, # 7, p. 1437 - 1444
[5] Chemische Berichte, 1994, vol. 127, # 4, p. 691 - 696
  • 16
  • [ 765-43-5 ]
  • [ 100-58-3 ]
  • [ 5558-04-3 ]
Reference: [1] Chemistry - A European Journal, 2014, vol. 20, # 9, p. 2440 - 2444
  • 17
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  • [ 5558-04-3 ]
Reference: [1] Zhurnal Obshchei Khimii, 1950, vol. 20, p. 581,587; engl. Ausg. S. 613, 618
[2] Journal of the American Chemical Society, 1977, vol. 99, # 2, p. 505 - 509
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1977, vol. 26, p. 113 - 116[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1977, vol. 26, p. 132 - 136
  • 18
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  • [ 3469-26-9 ]
Reference: [1] Journal of the American Chemical Society, 2002, vol. 124, # 16, p. 4271 - 4281
  • 19
  • [ 765-43-5 ]
  • [ 69267-75-0 ]
YieldReaction ConditionsOperation in experiment
99% With bromine In methanol at -5℃; for 2 h; A solution of cyclopropyl methyl ketone (20.7 mL, 220 mmol) in MeOH (100 mL) was treated with bromine (11.3 mL, 220 mmol) at -5° C. for 2 hours. 50 mL water was added and the reaction was warmed up to room temperature overnight. The mixture was diluted with water (150 mL) and extracted with ethyl ether. The organic phases were separated and washed with NaHCO3, dried (Na2SO4), and concentrated to dryness, affording a light yellow oil (35 g, 99percent).1H NMR (CDCl3) δ 0.91-1.02 (m, 2H), 1.03-1.16 (m, 2H), 2.08-2.20 (m, 1H), 4.02 (s, 2H).
99% With bromine In methanol at 0 - 20℃; for 1.5 h; Example 21 : (2R,75R)-2-[(l-Aminoisoquinolin-6-yl)amino]-7-[(25)-2-cyclopropyl-2- hydroxyethoxy]-8-fluoro-4,15,20-trimethyl-13-oxa-4,l l- diazatricyclo[14.2.2.16,10]henicosa-l(18),6,8,10(21),16,19-hexaene-3,12-dione; trifluoroacetic acid -Bromo- 1 -cyclopropylethanone [00300] To a solution of 1 -cyclopropylethanone (18.85 mL, 201 mmol) in MeOH (120 mL) at 0 °C was added bromine (10.40 mL, 202 mmol) dropwise. The reaction mixture was stirred at 0 °C for 1 h, rt for 30 min, and quenched by addition of water. The mixture was extracted with ether (3x100 mL). The organic layer was washed with sat. sodium bicarbonate and brine, dried over MgS04 and concentrated to give 21A (32.5 g, 199 mmol, 99percent yield) as a light brown oil. -Butyl 2-(2-cyclopropyl-2-oxoethoxy)-3-fluoro-5-nitrobenzyl(methyl)carbamate [00301] To a solution of 17D (1.15 g, 3.83 mmol) in DMF (10 mL) was added 21A (1.486 g, 3.69 mmol), K2C03 (2.65 g, 19.15 mmol). The mixture was stirred 60 °C for 2 h, quenched with water, extracted with EtOAc (2x). The extract was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography to give 21B (1.486 g, 3.69 mmol, 96percent yield). MS (ESI) m/z: 383.2 (M+H)+. 21C: tert-Butyl 2-(2-cyclopropyl-2-hydroxyethoxy)-3-fluoro-5- nitrobenzyl(methyl)carbamate [00302] 2 IB (1.47 g, 3.84 mmol) was dissolved in MeOH (15 mL) at 0 °C. NaBH4 (0.175 g, 4.61 mmol) was added. The reaction mixture was stirred rt for 1 h. quenched with water, extracted with EtOAc (2x). The extract was dried over sodium sulfate and concentrated. The crude was purified by prep HPLC. To give 21C (830 mg, 2.159 mmol, 56.2percent yield). MS (ESI) m/z: 385.4 (M+H)+. NMR (400 MHz, chloroform-d) δ ppm 7.95 (dd, J=11.86, 2.20 Hz, 1 H) 7.88 (s, 1 H) 4.70 (d, J=11.86 Hz, 1 H) 4.51 (s, 3 H) 4.35 (d, J=13.62 Hz, 1 H) 4.20 (t, J=7.91 Hz, 1 H) 3.21 (t, J=7.47 Hz, 1 H) 2.75 (s, 3 H) 1.45 (s, 9 H) 0.90 (dd, J=8.13, 4.17 Hz, 1 H) 0.49 - 0.61 (m, 2 H) 0.41 (td, J=9.23, 4.83 Hz, 1 H) 0.22 - 0.29 (m, 1 H). 21D: (5)-tert-Butyl 2-(2-cyclopropyl-2-hydroxyethoxy)-3-fluoro-5- nitrobenzyl(methyl)carbamate [00303] 21C (200 mg, 0.520 mmol) was separated by a prep chiral HPLC. The 2nd peak was concentrated to give 21D (82 mg, 0.213 mmol, 41.0percent yield). The absolute stereochemistry is undetermined. 21E: (5)-Benzyl 2-(2-cyclopropyl-2-hydroxyethoxy)-3-fluoro-5- nitrobenzyl(methyl)carbamate [00304] To 21D (88 mg, 0.229 mmol) in EtOAc (2 mL) was added 4.0 M HC1 in dioxane (1.5 mL, 6.00 mmol). The mixture was stirred rt for lh, concentrated. The residue was dissolved in DMF (10 ml). N-(benzyloxycarbonyloxy) succinimide (62.8 mg, 0.252 mmol) was added, followed by N,N-diisopropylethylamine (0.120 mL, 0.687 mmol).The mixture was stirred rt for 16 h, then was quenched with water, extracted with EtOAc (3x30 ml). The organic layer was washed with brine, dried ( a2S04) and concentrated. The crude product was purified by flash chromatography (0-60percent EtOAc in hexane) to give 21E (99 mg, 103percent yield). MS (ESI) m/z 419.3 (M+H)+. 2 IF: (5)-Benzyl 2-(2-((tert-butyldimethylsilyl)oxy)-2-cyclopropylethoxy)-3-fluoro-5- nitrobenzyl(methyl)carbamate [00305] To a solution of 21E (99 mg, 0.237 mmol) in DMF (3 mL), was added tert- butyldimethylsilyl chloride (178 mg, 1.183 mmol) and imidazole (81 mg, 1.183 mmol). The reaction mixture was stirred at rt for 60 h., then was quenched with water, extracted with EtOAc (2x). The organic layer was washed with brine, dried ( a2S04) and concentrated. The crude product was purified by flash chromatography to give 2 IF mg, 0.173 mmol, 73.0percent yield). MS (ESI) m/z: 533.4 (M+H)+. 21G: (5)-4-(2-((tert-Butyldimethylsilyl)oxy)-2-cyclopropylethoxy)-3-fluoro-5- ((methylamino)methyl)aniline [00306] To a solution of 21F (92 mg, 0.173 mmol) in MeOH (5 mL) was added 10percent Pd-C (50 mg, 0.047 mmol). The mixture was evacuated and flushed with H2 (3X), then was stirred under a balloon of for 5 h. The mixture was filtered and concentrated to give 21G (62 mg, 0.168 mmol, 97percent yield). MS (ESI) m/z: 369.4 (M+H)+. 21H: tert-Butyl -[6-([({5-amino-2-[(25)-2-[(tert-butyldimethylsilyl)oxy]-2- cyclopropylethoxy] -3 -fluorophenyl }methyl)(methy l)carbamoyl]( {4- [(2R)-1- hydroxypropan-2-yl]-3-methylphenyl})methyl}amino)isoquinolin-l-yl]-N-[(?ert- butoxy)carbonyl]carbamate [00307] Intermediate 5 (33 mg, 0.170 mmol), glyoxylic acid monohydrate (15.66 mg, 0.170 mmol) and Intermediate 1 (61.1 mg, 0.170 mmol) were dissolved in DMF (1 mL) and acetonitrile. The solution was stirred at 80 °C for 2 h. The mixture was cooled to rt. To this mixture were added sequentially TEA (0.1 19 mL, 0.850 mmol), 21G (62.7 mg, 0.170 mmol) and BOP (90 mg, 0.204 mmol). The mixture was stirred at rt for 30 min. The reaction mixture was concentrated, purified by prep HPLC to give 21H (62 mg, 0.068 mmol, 39.8percent yield) as light yellow solid. MS (ESI) m/z: 916.8 (M+H)+. 211: tert-Butyl N-[(tert-butoxy)carbonyl]-N-(6- [(2RJ5R)-7-[(25)-2-cyclopropyl-2- hydroxyethoxy]-8-fluoro-4, 15,20-trimethyl-3, 12-dioxo-13-oxa-4,l 1- diazatricyclo[ 14.2.2.16>10]henicosa- 1 (18),6,8, 10(21), 16, 19-hexaen-2- yl] amino }isoquinolin-l-yl)carbamate [00308] A solution of 21H (62 mg, 0.069 mmol) in acetonitrile (2 mL) and dichloromethane (2 mL) was cooled to 0 °C. To this solution was added phosgene (20percent in toluene, 0.038 mL, 0.076 mmol). The mixture was stirred at 0 °C for 5 min, and rt for 20 min. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.096 mL, 0.690 mmol) in ΟΗ2( (60 mL) at rt. The solution was stirred at rt for 16 h. The solvent was removed under reduced pressure, and the residue was mixed with THF (3 mL) and TBAF (2 mL, 1M), the solution was stirred rt for 1 h. The mixture was concentrated and purified by flash chromatography (0-90percent EtOAc in Hex) to give s mixture of diastereoisomers (38 mg, 0.046 mmol, 66.5percent yield). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-0 column 21.1 x 250 mm) to give 211 (16 mg, 0.019 mmol, 42.1percent yield). MS (ESI) m/z: 828.7 (M+H)+. Example 21 [00309] To a solution of 211 (16 mg, 0.019 mmol) in EtOAc (2 mL) was added 4.0 M HCl in dioxane (2 mL, 8.00 mmol). The mixture was stirred rt for 4h, then concentrated and purified by prep HPLC to give Example 21 (8.2 mg, 10.83 μιηο, 56.1percent yield). MS (ESI) m/z: 628.5 (M+H)+. NMR (400 MHz, methanol-d4) δ ppm 8.04 (d, J=9.34 Hz, 1 H) 7.63 (d, J=8.24 Hz, 1 H) 7.43 (d, J=8.25 Hz, 1 H) 7.30 (d, J=7.15 Hz, 1 H) 7.16 - 7.24 (m, 2 H) 6.90 (d, J=7.15 Hz, 1 H) 6.83 (d, J=2.20 Hz, 1 H) 6.52 (dd, J=12.37, 2.47 Hz, 1 H) 5.73 (s, 1 H) 5.66 (s, 1 H) 5.43 (d, J=17.04 Hz, 1 H) 4.65 (t, J=l 1.27 Hz, 1 H) 4.09 - 4.18 (m, 1 H) 3.99 - 4.08 (m, 2 H) 3.96 (dd, J=10.44, 4.40 Hz, 1 H) 3.48 (ddd, J=1 1.13, 7.01, 4.40 Hz, 1 H) 3.28 (s, 3 H) 3.15 (ddd, J=l 1.27, 7.70, 3.57 Hz, 1 H) 2.32 (s, 3 H) 1.29 (d, J=7.15 Hz, 3 H) 0.91 - 1.02 (m, 1 H) 0.48 - 0.57 (m, 2 H) 0.33 - 0.41 (m, 1 H) 0.23 - 0.33 (m, 1 H). Analytical HPLC (low H, 254 nM): Sunfire, RT = 6.49 min, 97.6percent purity; XB ridge, RT = 5.53 min, 100percent purity.
98.8% With bromine In methanol at 0 - 20℃; Cooling with ice-water bath To a cooled (ice-water bath) solution of 1 -cyclopropylethanone (4.20 g, 50.0 mmol) in methanol (35 mL) was added dropwise bromine (7.99 g, 2.58 mL, 50 mmoL). The mixture was stirred at 00C for 2 h, and at r.t. for 30 min. Water (10 mL) was added. The mixture was stirred at r.t. for an additional 15 min., and was diluted with water (50 mL). The mixture was extracted with ether (3x60 mL), washed with sat. NaHCO3 and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated to afford the crude product 8.05 g (98.8percent) which was directly used in next step reaction without further purification.
98% With bromine In methanol at 0 - 20℃; for 1 h; Step 1. To a solution of cyclopropyl methyl ketone (10.0 g, 0.12 mol) in methanol (80 mL) was added bromine (19.0 g, 0.12 mol) dropwise at 0 °C. The resulting mixture was allowed to cool below 10 °C for 30 minutes, followed by continued stirring at room temperature for 30 minutes. The reaction was quenched with water (150 mL) and extracted with ethyl ether (3 x 150 mL). The extract was sequentially washed with Na2CC>3 (10percent, 100 mL), water (100 mL) and brine (100 mL), then dried over MgS04, filtered and evaporated to afford 2-bromo-l-cyclopropylethanone (19.0 g, 98percent) as a clear oil.
88% With bromine In methanol at 0 - 10℃; for 0.75 h; Reference Example 256: 2-Bromo-l-cyclopropyI-ethanone. Bromine (6.2 mL, 119 mmol) was added slowly to a solution of 1-cyclopropyl- ethanone (10.0 g, 119 mmol) in methanol (50 mL) at 0 °C. The reaction mixture was warmed to 10 °C and stirred for 45 min, during which time the colour was discharged. The mixture was diluted with water (50 mL) and stirred overnight. The mixture was further diluted with water (200 mL) and whole extracted with ether. The organic phase was washed successively with 10percent sodium carbonate solution, water and brine, dried over anhydrous calcium chloride and concentrated to afford 2-bromo-l-cyclopropyl- ethanone (17.0 g, 88 percent).
61% With bromine In methanol at 0 - 20℃; for 21 h; To a stirred solution of 1-cyclopropylethanone (50 g, 595 mmol) in MeOH (350 mL) at 0 °C (ice bath) was added bromine (32 mL, 595 mmol) dropwise over a period of 1hour (the initial red colour of the reaction mixture became colourless by the end of the addition of bromine). The resulting solution was then stirred below 5 °C for 4 hours, then water (175 mL) was added and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture was then poured into water (1000 mL) and extracted with CH2C12 (2 x 1000 mL). The combined organic layers was washed withsaturated aqueous NaHCO3 solution (500 mL), water (500 mL) and finally with brine (500 mL). The organic layer was dried over Na2504, filtered and concentrated in vacuo to give a light-brown oil. Pure 2-bromo-l-cyclopropyl-ethanone was obtained by vacuum distillation of this crude oil at 100 °C (59 g, 6 1percent).‘H NMR (400 MHz, CDCI3) 6 = 4.01 (s, 2H), 2.22-2.17 (m, 1H), 1.14-1.11 (m, 2H), 1.03-0.99 (m,2H).
61% With bromine In methanol; water at 0 - 20℃; for 21 h; To a stirred solution of 1-cyclopropylethanone (50 g, 595 mmol) in MeOH (350 mL) at 0 °C (ice bath)was added bromine (32 mL, 595 mmol) dropwise over a period of 1 hour (the initial red colour of thereaction mixture became colourless by the end of the addition of bromine). The resulting solution was then stirred below 5 °C for 4 hours, then water (175 mL) was added and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture was then poured into water (1000 mL) and extracted with CH2CI2 (2 x 1000 mL). The combined organic layers was washed with saturated aqueousNaHCO3 solution (500 mL), water (500 mL) and finally with brine (500 mL). The organic layer was dried over Na2504, filtered and concentrated in vacuo to give a light-brown oil. Pure 2-bromo-1-cyclopropyl- ethanone was obtained by vacuum distillation of this crude oil at 100 °C (59 g, 61percent).1H NMR (400 MHz, CDCI3) ö = 4.01 (s, 2H), 2.22-2.17 (m, 1 H), 1.14-1.11 (m, 2H), 1.03-0.99 (m, 2H).
52% With bromine In methanol; water Step A:
Preparation of 2-bromo-1-cyclopropylethanone 264a.
To a stirred ice-cooled solution of cyclopropyl methyl ketone (21 g, 1 eq.) in methanol (150 mL) was added dropwise bromine (12.9 ml, 1 eq.).
The reaction was allowed to proceed (decolorization) below 10° C.
Stirring was continued at room temperature for 1 hr before adding water (75 mL).
After an additional 15 min, the mixture was diluted with water (225 mL) and extracted with ethyl ether (two times).
Ether layers were washed with 10percent Na2CO3 solution and brine.
Dried organic layers were evaporated in vacuo to yield a crude orange oil, purified by distillation to yield compound 264a as a colorless oil in 52percent yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 0.98-1.02 (m, 2H), 1.09-1.13 (m, 2H), 2.15-2.22 (m, 1H), 4 (s, 2H).
2-Bromo-1-cyclobutylylethanone 264b was synthesised from cyclobutyl methyl ketone (22 g, 1 eq.) and bromine (11.5 mL, 1 eq.) as a yellow oil in 60percent yield, following the procedure as described for compound 264a. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.75-1.84 (m, 1H), 1.89-2 (m, 1H), 2.10-2.27 (m, 4H), 3.49-3.57 (m, 1H), 3.82 (s, 2H).
52% With bromine In methanol at 10 - 20℃; for 1.41667 h; To a stirred ice-cooled solution of cyclopropyl methyl ketone (21 g, 1 eq.) in methanol (150 mL) was added dropwise bromine (12.9 ml, 1 eq.). The reaction was allowed to proceed(decolorization) below 10 0C. Stirring was continued at room temperature for 1 hr before adding water (75 mL). After an additional 15 min, the mixture was diluted with water (225 mL) and extracted with ethyl ether (two times). Ether layers were washed with 10percent Na2CO3 - 165 -SDI-18153v2 solution and brine. Dried organic layers were evaporated in vacuo to yield a crude orange oil, purified by distillation to yield compound 264a as a colorless oil in 52percent yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 0.98-1.02 (m, 2H), 1.09-1.13 (m, 2H), 2.15-2.22 (m, IH), 4 (s, 2H).
41.4 g With bromine In methanol at 0 - 32℃; for 1 h; PREPARATION EXAMPLE 3: N-rri -(4-cvclopropylthiazol-2-yl)cvclopropyllmethyll-2- (trifluoromethyl)benzamide (Compound A10)Step 1 : 2-bromo-1 -cvclopropyl-ethanone 1-Cyclopropylethanone (20 g, 237.8 mmol) was dissolved in Methanol (1 18.9 mL). At 0°C was Bromine (38.00 g, 237.8 mmol) added drop wise in 30 minutes. The brown solution was stirred at 0°C. After 5 minutes the reaction mixture was exothermic and the temperature raised to 32°C. Afterwards the solution was colorless. The reaction mixture was stirred for 30 minutes. Then 250ml water were added carefully. The emulsion was extracted 3 times with 100ml Diethyl ether. The combined organic phases were washed with 70ml 10percent IS^COg, 75ml water and 75ml brine. The organic phase was dried withNa2SC>4 , filtrated and evaporated at 300mbar/40°C. The desired product was obtained as a brownish liquid (41.4g).1H-NMR (CDCIs): 4.05 (s, 2H), 2.32 (m, 1 H), 1.22 (m, 2H), 1.13 (m, 2H)
40 g
Stage #1: With bromine In methanol at 0℃; for 2 h; Inert atmosphere
Stage #2: With water In methanol at 20℃; for 16 h; Inert atmosphere
To a stirred solution of 18 cyclopropyl methyl ketone (25 g, 297.6 mmol) in 19 methanol (125 mL) was added 20 bromine (47.5 g, 297.2 mmol) drop wise at 0° C. under inert atmosphere and stirred at same temperature for 2 h. To this, 21 water (125 mL) was added and stirred at room temperature for 16 h. After completion of reaction (monitored by TLC; 0.4 Rf, 10percent 13 EtOAc in 14 petroleum ether), the reaction mixture was diluted with water (75 mL) and extracted with diethyl ether (2×250 mL). The combined organic layer was washed with saturated NaHCO3 solution (2×100 mL), brine (100 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford 22 2-bromo-1-cyclopropylethanone (40 g) as a colorless oil, which was directly taken for next reaction without further purification.1HNMR (400 MHz, CDCl3): δ 4.01 (s, 2H), 2.25-2.21 (m, 1H), 1.16-1.12 (m, 2H), 1.05-0.98 (m, 2H); GCMS: m/z 162 [M+]; RT=5.09 min (ZB-5MS column; 100° C./1 min, 20° C./min/310° C./5 min)
35 g With bromine In methanol at -5 - 20℃; [0302] A solution of cyclopropyl methyl ketone (20.7 mL, 220 mmol) in MeOH (100 mL) was treated with bromine (11.3 mL, 220 mmol) at -5°C for 2 h. 50 mL of water was added and the reaction was warmed up to room temperature overnight. The mixture was diluted with water (150 mL) and extracted with ethyl ether. The organic phases were separated and washed with NaHC03, dried (Na2S04), and concentrated to dryness, affording light yellow oil (35 g).
3.48 g With bromine In methanol; water at 20℃; for 3.16667 h; Cooling with ice To a methanol solution (12.0 mL) of cyclopropyl methyl ketone (1.80 g) was added under ice-cooling bromine (1.10 mL), and the reaction mixture was stirred at the same temperature for 10 min.
Water (6.00 mL) was added, and the reaction mixture was stirred at room temperature for 3 h
The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted 3 times with diethyl ethe
The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give bromomethyl cyclopropyl ketone (3.48 g).

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YieldReaction ConditionsOperation in experiment
74% With potassium permanganate; sodium carbonate In water at 50℃; for 10 h; Preparation of 2-cyclopropyl-2-oxoacetic acidThe mixture of 1 -cyclopropylethanone (lOg, U 8.9mmol), and sodium carbonate ( 145mg, 1.36mmol) in water (66ml) was heated at 50°C, then the solution of KMn04 (19.8g, 125.2mmol) in water (594ml) was slowly added over lOh at this temperature, followed by adding methanol(90ml). The mixture was filtered and the filtrate was concentrated to yield a white solid. The solid was added to acetone (80ml) and heated for 30min at 65 °C, then cooled to room temperature, the white solid was precipitated and collected by filtration, dried to give the desired product (lOg, 74percent) as a white solid. m/z [M-l]~ 113.0'HNMR(CD3OD): δ 2.49-2.43(1Η, m), 1.06-0.98(4H, m)
74% at 50℃; Preparation of 2-cyclopropyl-2-oxoacetic acid
The mixture of 1-cyclopropylethanone (10 g, 118.9 mmol), and sodium carbonate (145 mg, 1.36 mmol) in water (66 ml) was heated at 50, then the solution of KMnO4 (19.8 g, 125.2 mmol) in water (594 ml) was slowly added over 10 h at this temperature, followed by adding methanol (90 ml).
The mixture was filtered and the filtrate was concentrated to yield a white solid.
The solid was added to acetone (80 ml) and heated for 30 min at 65, then cooled to room temperature, the white solid was precipitated and collected by filtration, dried to give the desired product (10 g, 74percent) as a white solid.
m/z [M-1]- 113.0
1HNMR (CD3OD): δ 2.49-2.43 (1H, m), 1.06-0.98 (4H, m)
6.0 g at -3 - 20℃; for 16 h; To a mixture of 1-cyclopropylethanone (5.0 g, 59.4 mmol), NaOH (4.99 g, 125 mmol) in water (120 mL) at -4 °C was added potassium permanganate (18.79 g,119 mmol) portion wise with vigorous stirring. The inner temperature wasmaintained between -3 to 1 °C during the addition process. The reaction mixture was warmed to RT and stirred for 16 h. To the reaction mixture was added EtOH (20 mL) and the mixture was stirred for 15 mm. It was then filtered to remove the solid and washed with water. The filtration was acidified with 12 N HC1 at 0 °C, extracted with EtOAc (2x). The combined extract was washed with brine, dried (Na2SO4) andconcentrated to afford acid 4a (6.0 g). ‘H NMR (400 MHz, CDC13) 7.69 - 7.40 (m,1H), 2.95 (if, J= 7.6, 4.8 Hz, 1H), 1.42 - 1.22 (m, 4H).
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YieldReaction ConditionsOperation in experiment
93% With sodium In ethanol at 0 - 80℃; Inert atmosphere Sodium metal was dissolved into a solution of EtOH (150ml) at RT under nitrogen atmosphere to form NaOEt (16.19 gm). This mixture was cooled to 0 0C. Diethyl oxalate (34.76gm) and isopropyl methyl ketone (20gm) was added drop wise for about 15 min and warmed to RT. Now EtOH (100 ml) was added and stirred at RT for about 1 hour. Heat this reaction mixture to 80 0C for about 45 minuets and cooled to RT and concentrated under reduced pressure. To this resulting solid, add EtOAC. Wash with EtOH and filtered on cloth to get fine smooth powder.. This solid is dissolved in water and acidified with dilute Sulphuric acid (pH-2). This compound is extracted with diethyl ether and dried over sodium sulphate and was concentrated under reduced pressure to obtain the brown colored liquid compound (4Og, 93percent yield ).
93% With sodium ethanolate In ethanol at 0 - 80℃; for 2 h; Inert atmosphere Synthesis of (1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methanamine (Employed for the Synthesis of Example Compound no. 12)Step a: Sodium metal was dissolved into a solution of EtOH (150 ml) at RT under nitrogen atmosphere to form NaOEt (16.19 gm). This mixture was cooled to 0° C. Diethyl oxalate (34.76 gm) and isopropyl methyl ketone (20 gm) was added drop wise for about 15 min and warmed to RT. Now EtOH (100 ml) was added and stirred at RT for about 1 hour. Heat this reaction mixture to 80° C. for about 45 minutes and cooled to RT and concentrated under reduced pressure. To this resulting solid, add EtOAC. Wash with EtOH and filtered on cloth to get fine smooth powder. This solid is dissolved in water and acidified with dilute Sulphuric acid (pH-2). This compound is extracted with diethyl ether and dried over sodium sulphate and was concentrated under reduced pressure to obtain the brown colored liquid compound (40 g, 93percent yield).
93%
Stage #1: at 0 - 20℃; for 1.25 h; Inert atmosphere
Stage #2: With sulfuric acid In water
Synthesis of (1-(3-chloroDhenyl)-3-cyclODroDyl-1H-pyrazol-5-yl)methanamine (employed for the synthesis of example compound no. 12); Step a; Sodium metal was dissolved into a solution of EtOH (150ml) at RT under nitrogen atmosphere to form NaOEt (16.19 gm). This mixture was cooled to 0 °C. Diethyl oxalate (34.76gm) and isopropyl methyl ketone (20gm) was added drop wise for about 15 min and warmed to RT. Now EtOH (100 ml) was added and stirred at RT for about 1 hour. Heat this reaction mixture to 80 °C for about 45 minuets and cooled to RT and concentrated under reduced pressure. To this resulting solid, add EtOAC. Wash with EtOH and filtered on cloth to get fine smooth powder.. This solid is dissolved in water and acidified with dilute Sulphuric acid (pH-2). This compound is extracted with diethyl ether and dried over sodium sulphate and was concentrated under reduced pressure to obtain the brown colored liquid compound (40g, 93percent yield ).
74% With sodium In ethanol for 2.5 h; Reflux Intermediate 29ethyl 4-cyclopropyl-2,4-dioxobutanoateSodium metal (2.411 g, 105 mmol) was dissolved in ethanol (50 mL). The solution was heated to reflux followed by addition of a mixture of 1-cyclopropylethanone (8.4 g, 100 mmol) and diethyl oxalate (14.59 g, 100 mmol) dropwise over 30 minutes. The reaction mixture was heated at reflux for an additional 2h, and then allowed to cool to room temperature over a 2 d period. The contents were diluted with water (200 mL) and acidified by dropwise addition of 6N HC1. The contents were extracted with EtOAc (3 x 75 mL), washed with water, brine, dried over MgS04, filtered, and concentrated in vacuo. The final product was collected as 14.3g (74percent). LCMS E-S (M+H) =184.8 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.03 (d, J=7.83 Hz, 2 H) 1.13 - 1.19 (m, 2 H) 1.31 (t, J=7.07 Hz, 3 H) 1.81 - 1.90 (m, 1 H) 4.29 (q, J=7.16 Hz, 2 H) 6.43 (s, 1 H).
66% With sodium ethanolate In ethanol at 0 - 80℃; Sodium ethoxide (10 g, 147 mmol) is combined with absolute EtOH (60 mL) in an oven-dried flask, under nitrogen and heated to 70° C. to aid dissolution. The mixture is cooled to 0° C., treated drop-wise with a mixture of cyclopropyl methyl ketone (14.56 mL, 147 mmol) and diethyl oxylate (19.96 mL, 147 mmol) and warmed to RT. Stirring was difficult, so additional EtOH (60 mL) is added and the mixture is stirred for 1 h, then heated to 80° C. for 45 min. The mixture is cooled to RT and concentrated to dryness. The resulting solid is triturated with EtOAc, filtered, and rinsed with EtOAc and Et2O to remove the reddish color. The solid is dissolved in water (300 mL), acidified to pH 2 with dilute H2SO4, extracted with Et2O (400 mL total), dried (Na2SO4) and concentrated to afford 18.0 g (66percent yield) of ethyl 4-cyclopropyl-2,4-dioxobutanoate as an amber oil. HRMS (ESI) calcd for C9H12O4 +H: 185.0814, found 185.0821 (M+H)+. Ethyl 4-cyclopropyl-2,4-dioxobutanoate (12.92 g, 70.1 mmol) is combined with hydroxylamine hydrochloride (14.62 g, 210.4 mmol) in EtOH (250 mL), heated to reflux for 1 h, cooled, and concentrated to dryness. The residue is partitioned between H2O (250 mL) and EtOAc (2.x.250 mL) and the combined organics are dried (MgSO4) and concentrated to an amber oil (13.89 g). The crude material is chromatographed over 500 g silica gel, eluting with 25percent EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 10.71 g (84percent yield) of ethyl 5-cyclopropylisoxazole-3-carboxylate as a yellow oil. MS (CI) m/z: 182 (M+H)+. Sodium hydroxide (1.76 g, 44.0 mmol) in H2O (5 mL) is added to a solution of ethyl 5-cyclopropylisoxazole-3-carboxylate (1.97 g, 10.9 mmol) in MeOH (10 mL). The mixture is stirred at RT for 3 h, concentrated to remove the MeOH, and acidified to pH 2 with 5percent HCl. The acid is extracted with CH2Cl2 (6.x.20 mL), dried (MgSO4) and concentrated to afford 1.56 g (93percent yield) of 5-cyclopropylisoxazole-3-carboxylic acid as a white solid. MS (Cl) m/z: 154 (M+H)+. 5-Cyclopropylisoxazole-3-carboxylic acid (1.53 g, 10 mmol) is dissolved in benzene (30 mL), treated with oxalyl chloride (3.46 mL, 40 mmol) and heated to reflux for 2 h. The mixture is cooled, concentrated to dryness and the residual benzene is azeotroped off with CH2Cl2. The resulting acid chloride is dissolved in Me2CO (15 mL) and treated with a solution of NaN3 (1.95 g, 30 mmol) in H2O (7 mL). The mixture is vigorously stirred for 1 h, concentrated to remove the Me2CO, triturated with H2O, filtered, rinsed with water and dried under vacuum to afford 1.76 g (99percent yield) of 5-cyclopropylisoxazole-3-carbonyl azide as an off-white solid. 1H NMR (CDCl3, 400 MHz): δ 1.02, 1.14, 2.10, 6.35 ppm. 5-Cyclopropylisoxazole-3-carbonyl azide (447 mg, 2.5 mmol) is combined with 5-chloro-2,4-dimethoxyaniline (471 mg, 2.5 mmol) in anhydrous MeCN (30 mL) and heated to reflux for 18 h. The mixture is cooled and the resulting solid is filtered, rinsed with Et2O and dried in a vacuum oven to afford 619 mg (73percent yield) of Example 621 as a very light purple solid. HRMS (ESI) calcd for C15H16N3O4Cl +H: 338.0907, found 338.0896 (M+H)+.
48%
Stage #1: for 0.5 h; Cooling with ice; Inert atmosphere
Stage #2: at 0 - 20℃;
Metal Na (6 g, 0.26 mol) was added to ethanol (1 .5 L) in portions and stirred until it dissolved. The above solution was cooled in an ice-water bath, and compound 5 (20 g, 0.24 mol) was added dropwise under N2 atmosphere. 0.5 h later, oxalic acid diethyl ester (31 .6 g, 0.22 mol) was added dropwise at 0°C with strong stirring. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and concentrated to remove ethanol on a rotary evaporator (water bath be- low 40 °C), and the residue was acidified to pH 2 by 6N aq. HCI and extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated on a rotary evaporator (water bath below 30 °C) to give compound 6 (21 g, yield: 48percent). H-NMR (CDCI3): δ= 6.47 (s, 1 H), 4.37-4.32 (m, 2H), 1.92-1.86 (m, 1 H), 1 .37 (t, 3H, J= 7.2 Hz), 1 .24-1 .04 (m, 4H).
31% With sodium ethanolate In ethanol at 0 - 20℃; To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1.2 eq) in EtOH (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 eq) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1.1 eq) dropwise at 00C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and EtOH was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCI (15mL) and extracted with diethyl ether (2 * 25 mL). The organic layer was washed with brine solution and dried (Na2SO4), filtered and concentrated to give a pale brown liquid (400 mg, 31percent).
31% With sodium methylate In ethanol at 0 - 20℃; for 3 h; Diethyl oxalate (0.92 mL, 6.85 mmol, 1 equiv.) was added at RT to a freshly prepared sodium methanolate solution (prepared by dissolving sodium (1 g, 8.2 mmol, 1.2 equiv.) in EtOH (30 mL)), and cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1.1 equiv.) was then added dropwise at 0° C. The reaction mixture was slowly heated to RT and stirred for a further 3 h. Ice-cold water (10 mL) was added and the EtOH was distilled off under reduced pressure. The remaining aqueous phase was diluted with 2N hydrochloric acid (15 mL) and extracted with diethyl ether (2.x.25 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over Na2SO and concentrated under reduced pressure. A pale brown liquid was obtained as product (400 mg, 31percent yield).
31% at 0 - 23℃; for 3 h; To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1.2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1.1 equivalents) dropwise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCI (15mL) and extracted with diethyl ether (2 * 25 mL). The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated to give a pale brown liquid (400 mg, 31 percent).
31% at 0 - 20℃; for 3 h; Step a: To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1.2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1.1 equivalents) dropwise at 0В° C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCl (15 mL) and extracted with diethyl ether (2Г—25 mL). The organic layer was washed with brine solution and dried over sodium sulfate, filtered and concentrated to give a pale brown liquid (400 mg, 31percent).
31% With sodium ethanolate In ethanol at 0 - 20℃; for 3 h; To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1 .2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1 .1 equivalents) dropwise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCI (15mL) and extracted with diethyl ether (2 ? 25 mL). The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated to give a pale brown liquid (400 mg, 31 percent).
31% at 0 - 23℃; for 3 h; Step a: To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1 .2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1 .1 equivalents) dropwise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCI (15mL) and extracted with diethyl ether (2 χ 25 mL). The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated to give a pale brown liquid (400 mg, 31 percent).
31% With sodium ethanolate In ethanol at 0 - 23℃; for 3 h; To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1 .2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1 .1 equivalents) dropwise at 0 'Ό. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCI (15mL) and extracted with diethyl ether (2 χ 25 mL). The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated to give a pale brown liquid (400 mg, 31 percent).
31% at 0 - 23℃; for 3 h; Step a: To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1 .2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1 .1 equivalents) dropwise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCL (15mL) and extracted with diethyl ether (2 χ 25 mL). The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated to give a pale brown liquid (400 mg, 31 percent)
820 g With sodium In ethanol at 20 - 80℃; for 2 h; Inert atmosphere Into a 10-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen Na (164 g, 1.20 equiv) was added in portions to ethanol (5 L). A solution of (C02Et)2 (869 g, 1.00 equiv) and 1-cyclopropylethan-l-one (500 g, 5.94 mol, 1.00 equiv) was added dropwise with stirring at 0-20°C. The resulting solution was stirred for 1 h at 20-30°C and then for an additional 1 h at 80°C. The resulting solution was diluted with 15 L of H20. The pH was adjusted to 2 with hydrochloric acid (12N). The resulting solution was extracted with ethyl acetate and the organic layers combined and washed with NaHC03 (sat. aq.). The extract was concentrated under vacuum yielding 820 g (crude) of ethyl 4-cyclopropyl-2,4-dioxobutanoate as yellow oil. TLC (ethyl acetate/petroleum ether =1/5): Rf = 0.5.

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