* 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.
With piperidine; piperdinium acetate In tetrahydrofuran at 68℃; for 8 h; Green chemistry
A solution of compound 3R1 (4 mmol) in anhydrous THF (10 mL)was heated with piperidinium acetate (14.8 mmol), piperidine (9.9mmol) and paraformaldehyde (39.6 mmol). The reaction mixture wasrefluxed for 8 h at 68 °C. The solution was extracted with ethyl acetate(3 × 15 mL) and washed with 1 M HCl (40 mL) and brine (40 mL) andthen dried over anhydrous Na2SO4. The solvent was evaporated and thecrude product was purified by flash column chromatography with ethylacetate and petroleum (V/V = 1:10) to give 4R1.Colourless liquid; yield 92percent; 1H NMR (400 MHz, CDCl3): δ 0.89(–CH3, d, J = 6.6 Hz, 3H), 0.99 (–CH3, d, J = 6.6 Hz, 3H), 1.32 (–CH,ddd, J = 14.4, 9.6, 4.8 Hz, 1H), 1.42 (–CH3, s, 9H), 1.50–1.44 (–CH,m, 1H), 1.76–1.71 (–CH, m, 1H), 1.89 (–CH3, s, 3H), 5.05 (–CH, dd,J = 9.6, 3.6 Hz, 1H), 5.14 (–CH, d, J = 8.4 Hz, 1H), 5.87 (–CH, s, 1H),6.07 (–CONH, s, 1H); MS (ESI) m/z: 256.3 [M + H]+, 278.3 [M + Na]+;HRMS calcd for C14H25NO3Na [M + Na]+: 278.1726; found: 278.1734.
78.7%
With piperidine; piperidinyl acetate In tetrahydrofuran for 3 h; Reflux
0.4 mol of (S) -4-tert-butoxycarbonylamino-6-methyl-3-heptanone (2) was weighed and dissolved in 400 ml of tetrahydrofuran, Add 1.5 mol piperidine acetate and 1.0mol Piperidine and 2.0 moles of formaldehyde, Reflux 3h, then add 2.0mol formaldehyde, TLC check Test to complete, add appropriate amount of water after extraction with ethyl acetate, were washed with 1N dilute hydrochloric acid, saturated brine 1 times, organic phase Dried to give 0.31 mol of product (3) in a yield of 78.7percent.
59.1%
With sodium hydroxide In water at 65 - 70℃; for 3.08 h;
In a thermometer,A constant-pressure dropping funnel and a glass stopper in a 50 mL three-necked flask,Compound II (0.5 g, 0.002 mol) was added sequentially, Sodium hydroxide (0.16 g, 0.004 mol),Formaldehyde aqueous solution (0.012 mol),And methanol was added:Purified water = 1: 1 mixed solvent 15mL,Stirring vigorously for 5 min, So that the material dissolved completely.Water bath temperature control 65 ~ 70 ° C conditions,Reaction 3h,TLC detection of raw materials complete reaction is completed. The system was cooled to room temperature,And quenched by the addition of 50 mL of purified water,The product was extracted by addition of 50 mL of ethyl acetate, The ethyl acetate phase was washed twice with 50 mL of saturated brine,Then dried with Na2S04,The solvent was distilled off under reduced pressure,Crude product with PE: ΕΑ = 20: 1 eluent column chromatography,To give a colorless oil, 31 g, yield 59.1percent
Reference：
[1] Journal of Chemical Research, 2016, vol. 40, # 2, p. 82 - 86
[2] Patent: CN105017181, 2017, B, . Location in patent: Paragraph 0073; 0074; 0075
[3] Patent: CN105294501, 2016, A, . Location in patent: Paragraph 0064-0066
2
[ 6386-71-6 ]
[ 87694-50-6 ]
[ 247068-81-1 ]
Yield
Reaction Conditions
Operation in experiment
92%
at -78℃; for 2.5 h;
The second (right hand) molecular fragment can be made in parallel or in sequence. This procedure involves alkenylating a Weinreb amide of an amino terminal protected amino acid. For example, an amino terminal protected amino acid can be reacted with a reagent (for example, MeNHOMeHCl, EDCl, NMM, HoBt, DMF, 0, 12 h, 80percent) to make a Weinreb amide of the carboxyl terminus of the amino acid. Alkenylation is carried out by exposing the Weinreb amide to an alkenylating agent (for example, propen-2-yl lithium) to give an ?','-unsaturated ketone. For example, for an epoxomicin synthesis, Boc-Leu Weinreb amide can be reacted with propen-2-yl lithium to give the corresponding ?','-unsaturated ketone. Propen-2-yl lithium can be generated by reaction of 2-bromopropene with t-butyl lithium in a non-protic solvent (for example, diethyl ether) at low temperature (for example -78 C.), for at least 30 minutes (for example 2.5 hours) to give the ?','-unsaturated ketone in excellent yield (for example, 92percent).
To a 0 °C solution of (I) (10.0 g, 36.4 mmol,) in 100 mL of dry THF, under an atmosphere of argon was added isopropenyl magnesium bromide (364 mL, 182 mmol, 5.0 eq, 0.5 M solution in THF) dropwise using an addition funnel. The rate of addition was adjusted such that the internal reaction temperature was maintained below 5 °C. After six hoursthe reaction mixture was poured into 250 mL of sat. NH4Cl and 500 mL wet ice. After stirring for 30 minutes the mixture became clear and the volatiles were removed under reduced pressure and the crude material was diluted with EtOAc (200mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 150 mL), the organic layers were combined, washed with water (2 x 150 mL), brine (2 x 150 mL) and dried over MgSO4. The MgSO4 was removed by filtration and the volatiles were removed under reduced pressure. Purification by flash chromatography (15:1 hexanes/ EtOAc) gave (J) as a solid (7.5 g, 29.37 mmol).
72 g
at 25 - 40℃; for 2.75 h;
EXAMPLE 11: Preparation of te -butyl ((4S)-2,6-dimethyl -3-oxo hept-l-en-4- yl))carbamate of Formula XVIII A mixture of compound of Formula XVII (100 g) and toluene (1500 ml) was heated to 75- 80°C and was distilled completely under vacuum at same temperature to obtain residue. The obtained residue was dissolved in tetrahydrofuran (100 ml) at 25-30°C. In another reaction flask isopropenyl magnesium bromide (2.19 lit) was charged at 25-30°C and slowly added the above tetrahydrofuran solution over 2 hr at 25-40°C and stirred for 45 min at same temperature. After completion of the reaction, quenched the reaction mass in to 15percent ammonium chloride (1.5 lit) at 0-5 °C and organic layer was separated and concentrated under vacuum at below 40°C to obtain residue. The obtained residue was purified by silicycle silica by using ethyl acetate and cyclohexane solvent system. Product containing solvent fractions were combined and concentrated under vacuum at below 40°C to obtain residue. The obtained residue was dissolved in acetone (100 ml) at 25-30°C and allowed to cool to -5 to 0°C. To the clear solution water (1.5 lit) was added slowly at -5 to 0°C. Precipitated solid was filtered, washed with water (100 ml) and dried to get the title compound as a crystalline solid. Yield: 72 g; PXRD: Fig. 9; Chemical purity by HPCL: 99.44percent; Chiral purity by HPLC: 99.73percent.
Reference：
[1] ChemBioChem, 2012, vol. 13, # 6, p. 810 - 817
[2] Patent: WO2013/9923, 2013, A1, . Location in patent: Sheet 4
[3] Chemistry and Biology, 2014, vol. 21, # 6, p. 782 - 791
[4] Bioorganic and Medicinal Chemistry, 2018,
[5] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 11, p. 2955 - 2965
[6] Patent: KR2015/131405, 2015, A, . Location in patent: Paragraph 0526-0528
[7] Patent: WO2016/185450, 2016, A1, . Location in patent: Page/Page column 66
[8] European Journal of Medicinal Chemistry, 2019, vol. 161, p. 416 - 432
4
[ 557-93-7 ]
[ 87694-50-6 ]
[ 247068-81-1 ]
Yield
Reaction Conditions
Operation in experiment
38.5 g
Stage #1: With iodine; magnesium In tetrahydrofuran at 50 - 55℃; for 2.5 h; Inert atmosphere Stage #2: at 0 - 30℃; for 8.25 h;
A mixture of magnesium (24 gm), iodine (0.5 gm) and tetrahydrofuran (1000 ml) was heated to 50-55°C under nitrogen atmosphere. A solution of 2-bromo propene (123.5 gm) in tetrahydrofuran (250 ml) was slowly added lot wise to the reaction mixture at 50-55°C and stirred the reaction mixture for 2 hrs 30 min at the same temperature. Cooled the reaction mixture to 25-30°C and the resulting reaction mixture was added to a pre-cooled mixture of (S)-tert-butyl l-(methoxy(methyl)amino)-4-methyl-l-oxopentan-2-ylcarbamate (50 gm) and tetrahydrofuran at 0-5°C and stirred the reaction mixture for 15 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 8 hrs at the same temperature. The obtained reaction mixture was slowly added to a pre-cooled mixture of water and ammonium chloride at 0-5°C and stirred for 30 min at the same temperature. Neutralized the reaction mixture using aqueous hydrochloric acid solution and stirred the reaction mixture for 15 min. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and distilled off the solvent completely under reduced pressure. Dichloromethane was added to the obtained compound at 25-30°C and stirred for 5 min. Silica gel was added to the reaction mixture and distilled off the solvent completely from the reaction mixture. Cooled the obtained compound to 25-30°C, cyclohexane (247.5 ml) and ethyl acetate (2.5 ml) were added and stirred the reaction mixture for 45 min at the same temperature. Filter the reaction mixture and distill off the solvent completely from the filtrate under reduced pressure to get the title compound. Yield: 38.5 gm.
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5710 - 5718
[2] Patent: WO2016/170544, 2016, A1, . Location in patent: Page/Page column 35; 36
With isopropylmagnesium chloride; magnesium In tetrahydrofuran; n-heptane at -10 - 42℃; for 3 h; Inert atmosphere
(S)-tert-butyl (4-methyl-i -morpholino-oxopentan-2-yl)carbamate (1.0 eq)dissolved in THF (3 mL per gm) and heptane (1 mL per gm) was charged to a reaction vessel that was flushed with nitrogen gas. THF (3 mL per gm) and heptanes (1 mL per gm) were added to bring the solution to a total of 8 mL per gm morpholino starting material. Magnesium powder (2.2 eqs; Sigma Aldrich or Alfa Aesar) was added and the solution was cooled -10°C to -5°C. i-PrMgC1 (2.OM solution in THF; 1.0 eq) was added tothe reaction while maintaining the temperature between - 10°C and 0°C. The solution was then warmed to 35°C and 2-bromopropene (0.15 eq) was added. The temperature was monitored to observe initiation of the Grignard reaction which results in about a 5-10°c exotherm. Once the termperature dropped to 99percent conversion was observed by HPLC. The solution was cooled to ambient temperature, then added to a reaction vessel containing citric acid (8 mL per gm of morpholino starting material, 30percent w/w in H20) and heptane (2 mL per gm) cooled to-10°C to -5°C, while maintaining the temperature between -10°C to -5°C. During thequench it was important to keep the unquenched reaction solution stirring, as the stagnantsolution could solidify and cause clogging of the pump. The quenched solution was warmed to ambient temperature and stirred for 15-30 minutes and the aqueous layer was removed. Water (5 mL per gm) was added over 5-30 minutes while maintaining the temperature at 15-30°C. The mixture was stirred for 15-30 minutes and the aqueous layerwas removed. 5i02 (2 gm/gm, 6Oum 70-23 0 mesh) was added to the solution and the slurry was stirred for 15-30 minutes. The slurry was then filtered through a wet pad of5i02 (2 gm 5i02/gm of morpholino starting material), washed with 2percent IPAc in heptanes(10 mL per gm). The solution was concentrated to afford Intermediate 1, which was eitherstored for later use or immediately used in the next step. Yield: 83percent (based on HPLC assay). This method of generating the morpholino intermediate above is efficient as it reduced the volume of previous methods from 50 V to 25 V and tedious and time consuming column chromatography for purification was replaced with a silica gel plug filtration. The product of example 1 was isolated from Boc-L-Leu•monohydrate with anassay yield of 75percent over two steps.
With (R)-La-BINOL; triphenylphosphine; <i>tert</i>-butyl alcohol In toluene at 20℃; for 0.5 h;
Compound III (102 g, 0.4 mol), asymmetric chiral catalyst (R) -La-BINOL (3.24 g, 2 molpercent) was added to a 1 L reaction flask,Triphenylphosphine (14.8 g, 20 molpercent), 500 mL of toluene, and stirred at room temperature.Then, tert-butanol (108 g, 1.2 mol) was slowly added dropwise. After 0.5 h of reaction, TLC was monitored and the reaction was complete. The reaction solution was filtered and the filtrate was collected.The filtrate was quenched with 300 mL of saturated sodium sulfite solution. The tetrahydrofuran was evaporated under reduced pressure and then extracted with 400 mL of ethyl acetate. The organic phase was washed successively with 100 mL of water, 100 ml of saturated brine, dried over anhydrous sodium sulfate and dried under reduced pressure. 92 g of a pale yellow oil, which was Compound I, yield 85.0percent and ee was 93percent.
40%
With tetramethyl ammoniumhydroxide; urea hydrogen peroxide adduct In methanol; benzonitrile at -10℃; for 20 h; Inert atmosphere
To a solution of tert-butyl (S)-(2,6-dimethyl-3-oxohept-1-en-4 yl)carbamate (10 g, 37.2 mmol) in MeOH (80 ml) cooled to -10 °C, benzonitrile (8.4 ml, 82 mmol), hydrogen peroxide-urea adduct (14 g, 149 mmol) and tetramethylammonium hydroxide (6.9 g, 37.2 mmol) were added dropwise. The reaction mixture was stirred at -10 °C under N2 atmosphere for 20 h. After dilution with a saturated Na2S20 3 solution (120 ml) and 1 M HCI (7 ml), MeOH was evaporated under reduced pressure and the aqueous phase was extracted with EtOAc (50 ml x 3). The combined organic phases were dried over MgS04 and concentrated in vacuo affording a crude which was suspended in toluene (40 ml), stirred at 0-5 °C for 1 h, and filtered. The resulting solution was concentrated in vacuo affording a crude oil (7.45 g) containing tert-butyi((S)-4-methyi-1-((R)-2-methyloxiran-2-yl)1-oxopentan-2-yl)carbamate (diastereomeric ratio (dr)>10:1 by 1H-NMR) as the main product. This crude was purified by flash chromatography (cyclohexane/ethyl acetate) affording tert-butyl (( S)-4-methyi-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate (4.04 g, 40percent yield) as an oil 1H-NMR (400 MHz, CDCb) d 4.84 (d, J =8Hz, 1 H), 4.32 (ddd, J = 12, 10.4 and 3.2 Hz, 1 H), 3.29 (d, J = 4.8 Hz, 1 H), 2.88 (d, J = 4.8 Hz, 1 H), 1.72 (m, 1 H), 1.49 (s, 3 H), 1.45 (m, 1 H), 1.17 (ddd, J= 14.4, 10.4 and 4.2 Hz, 1 H), 0.97 (d, J= 6.8 Hz, 3 H), 0.93 (d, J= 6.8 Hz, 3 H). Analysis GC (optical purity) 96percent ee
20.8 g
With calcium hypochlorite In 1-methyl-pyrrolidin-2-one; water at -15 - 0℃; for 0.333333 h;
Water (214 mL) was added to a three neck flask equipped with a mechanical stirrer, an addition funnel, and a thermocouplewith display and cooled to an internal temperature of -5 to 0 °C. Solid calcium hypochlorite (107 g, 748 mmol) was thenadded over approximately 5 minutes, while the temperature of the mixture is maintained at approximately -5°C to 0°C.The mixture was then further cooled to -10°C to -5°C and stirred for 10 minutes followed by addition of NMP (1000 mL)via addition funnel at a rate to maintain internal temperature between -10 °C to -5 °C. The reaction slurry was then stirredat -10 °C for 15 minutes. (R) (47.8 g, 187 mmol) was dissolved in NMP (40 0mL) and added dropwise to the reactionmixture while maintaining the internal temperature between -15 °C and -10 °C. The reaction mixture was then stirred at-5 °C to 0 °C until the reaction was complete by TLC. Upon reaction completion, the mixture was quenched by slowaddition of 1.0 M sodium thiosulfate solution (500 mL), maintaining an internal temperature of -10 °C to -5 °C. Ethyl Acetate (1000 mL) was then added, the layers were separated and the aqueous layer was extracted twice more. Thecombined organic layers were washed with water (500 mL) and brine (500 mL), dried over magnesium sulfate, filteredand concentrated under reduced pressure to a to yellow oil which was dissolved in hexanes (600 mL) and filtered througha plug of silica to provide (H) as a pale yellow oil (20.8 g).
16.5 g
With dihydrogen peroxide; potassium carbonate; benzonitrile In methanol at 25 - 30℃; for 6 h;
A mixture of (S)-tert-butyl 2,6-dimethyl-3-o ohept-l-en-4-ylcarbamate (50 gm), methanol (1250 ml) and potassium carbonate (13.5 gm) was stirred for 15 min at 25-30°C. Benzonitrile (10.1 gm) was added to the reaction mixture and cooled to 0-5°C. 50percent hydrogen peroxide (1.6 gm) was slowly added to the reaction mixture at 0-5°C and raised the temperature of the reaction mixture to 25-30°C. Second lot of 50percent hydrogen peroxide (25 gm) was slowly added to the reaction mixture at 25-30°C and stirred for 6 hrs at the same temperature. The obtained reaction mixture was slowly added to a pre-cooled solution of sodium thiosulfate and water at 0-5°C and stirred the reaction mixture for 20 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C, dichloromethane was added and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous sodium thiosulfate solution. Distilled off the solvent completely from the organic layer under reduced pressure and the obtained compound was purified by column chromatography using ethyl acetate: cyclohexane as eluent. Yield: 16.5 gm
Reference：
[1] Patent: CN104672179, 2017, B, . Location in patent: Paragraph 0009; 0024; 0025; 0027-0043
[2] Patent: WO2018/100050, 2018, A1, . Location in patent: Page/Page column 15; 16; 17; 18
[3] ChemBioChem, 2012, vol. 13, # 6, p. 810 - 817
[4] Patent: WO2013/9923, 2013, A1, . Location in patent: Sheet 4; 5
[5] Bioorganic and Medicinal Chemistry, 2018,
[6] Patent: WO2014/18807, 2014, A1, . Location in patent: Paragraph 00112; 00115
[7] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 11, p. 2955 - 2965
[8] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5710 - 5718
[9] Chemistry and Biology, 2014, vol. 21, # 6, p. 782 - 791
[10] Journal of Chemical Research, 2016, vol. 40, # 2, p. 82 - 86
[11] Patent: KR2015/131405, 2015, A, . Location in patent: Paragraph 0554-0557
[12] Patent: WO2016/170544, 2016, A1, . Location in patent: Page/Page column 36
[13] Patent: WO2016/185450, 2016, A1,
[14] Patent: CN105017181, 2017, B,
[15] European Journal of Medicinal Chemistry, 2019, vol. 161, p. 416 - 432
14
[ 247068-81-1 ]
[ 247068-82-2 ]
Yield
Reaction Conditions
Operation in experiment
48%
at 0 - 4℃; for 43 h; Alkaline aqueous solution
For example, for an epoxomicin synthesis, a typical epoxidizing reagent (for example, alkaline hydrogen peroxide) can be reacted with the ?','-unsaturated ketone described above, in polar solvent (for example, aqueous solution or methanol in water) in the presence of a compound which gives a reactive intermediate, which reacts with the unsaturated ketone to give an epoxide product (for example, benzonitrile), and a moderately hindered base (for example, i-Pr2Net) at moderately low temperature (for example, 0 to 4 C.), for at least about 10 hours (for example, 43 hours) to give the ?','-epoxy ketone in good yield (for example, 76percent). For example, in the above synthesis of epoxomicin using Boc-protected Leu, the ratio of compound having the (R) ?' carbon to the compound having the (S) ?' carbon was 1.7:1. The same synthesis using Z-protected Leu gave a 4.0:1 (R):(S) ratio. These compounds were readily separated, for example by flash chromatography, in common solvent systems, for example hexanes:EtOAc 10:1).
0.059 g
With pyridine; sodium hypochlorite In water at -5 - 0℃; for 2 h;
To a -5 °C solution of (R) (0.200 g, 0.78 mmol) in pyridine (3 mL) was added 10percent aqueous NaOCl (1.5 mL)dropwise at a rate such that the internal reaction temperature remained below -4 °C. After the addition of NaOCl wascomplete, the reaction flask was placed in a 0 °C bath and stirred for two hours. The mixture was then diluted with EtOAc(10 mL), washed with water (2 x 10 mL), brine (2 x 10 mL) and dried over Na2SO4. The Na2SO4 was removed by filtrationand the volatiles removed under reduced pressure to give the crude mixture of (H) and (Q). Purification by flash chro-matography (20:1 hexanes/ EtOAc) gave (H) as an oil (0.059 g, 0.216 mmol) and (Q) as a solid (0.023 g, 0.085 mmol).
86 % ee
With (R)-La-BINOL; triphenylphosphine; <i>tert</i>-butyl alcohol In toluene at 20℃; for 0.5 h;
Compound III (102 g, 0.4 mol), asymmetric chiral catalyst (R) -La-BINOL (3.24 g, 2 molpercent) was added to a 1 L reaction flask,Triphenylphosphine (14.8 g, 20 molpercent), 500 mL of toluene, and stirred at room temperature.Then, tert-butanol (108 g, 1.2 mol) was slowly added dropwise. After 0.5 h of reaction, TLC was monitored and the reaction was complete. The reaction solution was filtered and the filtrate was collected.The filtrate was quenched with 300 mL of saturated sodium sulfite solution. The tetrahydrofuran was evaporated under reduced pressure and then extracted with 400 mL of ethyl acetate. The organic phase was washed successively with 100 mL of water, 100 ml of saturated brine, dried over anhydrous sodium sulfate and dried under reduced pressure. 92 g of a pale yellow oil, which was Compound I, yield 85.0percent and ee was 93percent.
51.22 % de
With C28H34F6MnN6O6S2; dihydrogen peroxide; acetic acid In acetonitrile at -20℃; for 1 h;
A 10 mL reaction tube was provided, to which was added compound Boc-1 (0.5 mmol, 127.5 mg), acetic acid (2.5 mmoia 43yL), 1 mL of acetonitrile solution, catalyst C2-3 (0.0025 mmol), and stirred at -20 °C. .30percent hydrogen peroxide (1.0 mmol, 100 μL) was dissolved in 1 ml of acetonitrile, and slowly added dropwise to the reaction system, and the addition was completed in one hour. Stirring was continued for one hour and the reaction was completed. The reaction was quenched by adding an appropriate amount of sodium thiosulfate, dried over anhydrous sodium sulfate, filtered, and then evaporated(ethyl acetate: petroleum ether = 1:100), an oily liquid,The yield of the two configuration mixtures was 97percent.The ratio of the target epoxide Boc-2 (R configuration) and its isomer compound Boc-3 (S configuration) R: S = 1:3.1.
35.484 % de
With C28H34F6MnN6O6S2; dihydrogen peroxide; acetic acid In acetonitrile at -20℃; for 2 h;
General procedure: General procedure for the catalytic epoxidation of the vinyl ketone 1.To a 10 mL tube was first charged with tert-butyl (S)-(2,6-dimethyl-3-oxohept-1-en-4-yl)carbamate (0.5 mmol, 128mg), Mn catalysts (0.5 molpercent), HOAc (5 equiv, 143 μL) and CH3CN (1.0 mL). Then the mixture was cooled to -20C and H2O2 (2 equiv, 30percent diluted with 0.5 mL of CH3CN) was added dropwise through a syringe pump over 60min, followed by an additional 60 min of stirring. When the reaction was completed, the resulting mixture wasquenched with Na2S2O3 and dried over anhydrous Na2SO4, after that, the solvent was removed under reducedpressure. The residue was purified by column chromatography on silica gel with petroleum ether and ethyl acetate(1:100-1:80) to give the corresponding product.1.Analytical data for the epoxyketone 2 and the newly synthesized ligands.tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate colorless transparent oily liquid. 1H NMR (400 MHz, Chloroform-d) δ: 4.90 (d, J = 8.5 Hz, 1H), 4.26 (t, J = 9.5 Hz,1H), 3.24 (d, J = 4.8 Hz, 1H), 2.83 (d, J = 5.0 Hz, 1H), 1.69-1.64 (m, 1H), 1.46-1.40 (m, 4H), 1.35 (s, 9H), 1.17-1.09(m, 1H), 0.91 (d, J = 8.0 Hz, 3H), 0.88 (d, J = 8.0 Hz, 3H). 13C NMR (400 MHz, Chloroform-d) δ: 207.9,155.3,79.8,58.7, 52.8, 41.0, 29.7, 28.3, 24.9, 23.4, 21.5, 17.6. tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate light yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 4.89 (s, 1H), 4.54 (s, 1H), 3.01 (s, 1H), 2.84 (s, 1H),1.68-1.65 (m, 1H), 1.53 (s, 3H), 1.33-1.24 (m, 2H), 0.95 (d, J = 4 Hz, 3H), 0.90 (d, J = 8.0 Hz, 3H). 13C NMR (400MHz, Chloroform-d) δ: 209.7, 155.7, 79.8, 59.1, 52.4, 51.5, 40.4, 29.8, 28.4, 25.2, 23.5, 21.4, 16.9.
Reference：
[1] Patent: US6831099, 2004, B1, . Location in patent: Page column 14, 16
[2] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 15, p. 2283 - 2288
[3] Chemistry - A European Journal, 2012, vol. 18, # 22, p. 6750 - 6753
[4] Patent: KR2015/131405, 2015, A, . Location in patent: Paragraph 0535-0539
[5] Patent: CN104672179, 2017, B, . Location in patent: Paragraph 0024; 0025; 0027-0043
[6] Patent: WO2018/27021, 2018, A1, . Location in patent: Page/Page column 37
[7] Patent: WO2018/100050, 2018, A1, . Location in patent: Page/Page column 18; 19
[8] Patent: CN108373456, 2018, A, . Location in patent: Page/Page column 6-9; 10; 11; 12; 13
[9] Chinese Chemical Letters, 2018,
tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate[ No CAS ]
[ 247068-82-2 ]
Yield
Reaction Conditions
Operation in experiment
28%; 48%
With dihydrogen peroxide; benzonitrile; N-ethyl-N,N-diisopropylamine; at 0 - 4℃; for 43h;Alkaline aqueous solution;
For example, for an epoxomicin synthesis, a typical epoxidizing reagent (for example, alkaline hydrogen peroxide) can be reacted with the ?','-unsaturated ketone described above, in polar solvent (for example, aqueous solution or methanol in water) in the presence of a compound which gives a reactive intermediate, which reacts with the unsaturated ketone to give an epoxide product (for example, benzonitrile), and a moderately hindered base (for example, i-Pr2Net) at moderately low temperature (for example, 0 to 4 C.), for at least about 10 hours (for example, 43 hours) to give the ?','-epoxy ketone in good yield (for example, 76%). For example, in the above synthesis of epoxomicin using Boc-protected Leu, the ratio of compound having the (R) ?' carbon to the compound having the (S) ?' carbon was 1.7:1. The same synthesis using Z-protected Leu gave a 4.0:1 (R):(S) ratio. These compounds were readily separated, for example by flash chromatography, in common solvent systems, for example hexanes:EtOAc 10:1).
0.023 g; 0.059 g
With pyridine; sodium hypochlorite; In water; at -5 - 0℃; for 2h;
To a -5 C solution of (R) (0.200 g, 0.78 mmol) in pyridine (3 mL) was added 10% aqueous NaOCl (1.5 mL)dropwise at a rate such that the internal reaction temperature remained below -4 C. After the addition of NaOCl wascomplete, the reaction flask was placed in a 0 C bath and stirred for two hours. The mixture was then diluted with EtOAc(10 mL), washed with water (2 x 10 mL), brine (2 x 10 mL) and dried over Na2SO4. The Na2SO4 was removed by filtrationand the volatiles removed under reduced pressure to give the crude mixture of (H) and (Q). Purification by flash chro-matography (20:1 hexanes/ EtOAc) gave (H) as an oil (0.059 g, 0.216 mmol) and (Q) as a solid (0.023 g, 0.085 mmol).
With (R)-La-BINOL; triphenylphosphine; tert-butyl alcohol; In toluene; at 20℃; for 0.5h;
Compound III (102 g, 0.4 mol), asymmetric chiral catalyst (R) -La-BINOL (3.24 g, 2 mol%) was added to a 1 L reaction flask,Triphenylphosphine (14.8 g, 20 mol%), 500 mL of toluene, and stirred at room temperature.Then, tert-butanol (108 g, 1.2 mol) was slowly added dropwise. After 0.5 h of reaction, TLC was monitored and the reaction was complete. The reaction solution was filtered and the filtrate was collected.The filtrate was quenched with 300 mL of saturated sodium sulfite solution. The tetrahydrofuran was evaporated under reduced pressure and then extracted with 400 mL of ethyl acetate. The organic phase was washed successively with 100 mL of water, 100 ml of saturated brine, dried over anhydrous sodium sulfate and dried under reduced pressure. 92 g of a pale yellow oil, which was Compound I, yield 85.0% and ee was 93%.
With calcium hypochlorite; In water; at 0 - 5℃; for 4h;
Ca(OCI)2 (0.75 g, 5.24 mmol) was slowly added to H20 (1.5 ml) at 0 C. The mixture was cooled to -5 to -10 oc and was stirred for 10 min. N-methyl-2-pyrrolidone (7 ml) was added and the mixture was stirred for 15 min. tert-Butyl (S)-(2,6-dimethyl-3-oxohept-1-en4-yl)carbamate (0.33 g, 1.3 mmol) dissolved in N-methyl-2-pyrrolidone (2.8 ml) was added dropwise and the reaction mixture was stirred for 4 h at 0-5 C. After this time, 1 M aqueous Na2S03 (3.5 ml) was added and the mixture was extracted with AcOEt. The combined organic phases were washed with H20 and with saturated aqueous NaCI solution, dried over MgS04 and concentrated under reduced pressure to give the crude product (0.26 g) as an orange oil. This residue was filtered through Si02 eluting with cyclohexane/AcOEt (from 100/0 to 95/5 cyclohexane/AcOEt) to give tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate (0.19 g, diastereomeric ratio 2.4:1 (S,R:S,S) by GC) as a yellow oil
With C28H34F6MnN6O6S2; dihydrogen peroxide; acetic acid; In acetonitrile; at -20℃; for 1h;
A 10 mL reaction tube was provided, to which was added compound Boc-1 (0.5 mmol, 127.5 mg), acetic acid (2.5 mmoia 43yL), 1 mL of acetonitrile solution, catalyst C2-3 (0.0025 mmol), and stirred at -20 C. .30% hydrogen peroxide (1.0 mmol, 100 muL) was dissolved in 1 ml of acetonitrile, and slowly added dropwise to the reaction system, and the addition was completed in one hour. Stirring was continued for one hour and the reaction was completed. The reaction was quenched by adding an appropriate amount of sodium thiosulfate, dried over anhydrous sodium sulfate, filtered, and then evaporated(ethyl acetate: petroleum ether = 1:100), an oily liquid,The yield of the two configuration mixtures was 97%.The ratio of the target epoxide Boc-2 (R configuration) and its isomer compound Boc-3 (S configuration) R: S = 1:3.1.
With C28H34F6MnN6O6S2; dihydrogen peroxide; acetic acid; In acetonitrile; at -20℃; for 2h;
General procedure: General procedure for the catalytic epoxidation of the vinyl ketone 1.To a 10 mL tube was first charged with tert-butyl (S)-(2,6-dimethyl-3-oxohept-1-en-4-yl)carbamate (0.5 mmol, 128mg), Mn catalysts (0.5 mol%), HOAc (5 equiv, 143 muL) and CH3CN (1.0 mL). Then the mixture was cooled to -20C and H2O2 (2 equiv, 30% diluted with 0.5 mL of CH3CN) was added dropwise through a syringe pump over 60min, followed by an additional 60 min of stirring. When the reaction was completed, the resulting mixture wasquenched with Na2S2O3 and dried over anhydrous Na2SO4, after that, the solvent was removed under reducedpressure. The residue was purified by column chromatography on silica gel with petroleum ether and ethyl acetate(1:100-1:80) to give the corresponding product.1.Analytical data for the epoxyketone 2 and the newly synthesized ligands.tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate colorless transparent oily liquid. 1H NMR (400 MHz, Chloroform-d) delta: 4.90 (d, J = 8.5 Hz, 1H), 4.26 (t, J = 9.5 Hz,1H), 3.24 (d, J = 4.8 Hz, 1H), 2.83 (d, J = 5.0 Hz, 1H), 1.69-1.64 (m, 1H), 1.46-1.40 (m, 4H), 1.35 (s, 9H), 1.17-1.09(m, 1H), 0.91 (d, J = 8.0 Hz, 3H), 0.88 (d, J = 8.0 Hz, 3H). 13C NMR (400 MHz, Chloroform-d) delta: 207.9,155.3,79.8,58.7, 52.8, 41.0, 29.7, 28.3, 24.9, 23.4, 21.5, 17.6. tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate light yellow solid. 1H NMR (400 MHz, Chloroform-d) delta 4.89 (s, 1H), 4.54 (s, 1H), 3.01 (s, 1H), 2.84 (s, 1H),1.68-1.65 (m, 1H), 1.53 (s, 3H), 1.33-1.24 (m, 2H), 0.95 (d, J = 4 Hz, 3H), 0.90 (d, J = 8.0 Hz, 3H). 13C NMR (400MHz, Chloroform-d) delta: 209.7, 155.7, 79.8, 59.1, 52.4, 51.5, 40.4, 29.8, 28.4, 25.2, 23.5, 21.4, 16.9.
The second (right hand) molecular fragment can be made in parallel or in sequence. This procedure involves alkenylating a Weinreb amide of an amino terminal protected amino acid. For example, an amino terminal protected amino acid can be reacted with a reagent (for example, MeNHOMeHCl, EDCl, NMM, HoBt, DMF, 0, 12 h, 80%) to make a Weinreb amide of the carboxyl terminus of the amino acid. Alkenylation is carried out by exposing the Weinreb amide to an alkenylating agent (for example, propen-2-yl lithium) to give an ?','-unsaturated ketone. For example, for an epoxomicin synthesis, Boc-Leu Weinreb amide can be reacted with propen-2-yl lithium to give the corresponding ?','-unsaturated ketone. Propen-2-yl lithium can be generated by reaction of 2-bromopropene with t-butyl lithium in a non-protic solvent (for example, diethyl ether) at low temperature (for example -78 C.), for at least 30 minutes (for example 2.5 hours) to give the ?','-unsaturated ketone in excellent yield (for example, 92%).
In tetrahydrofuran at 0℃; for 6h; Inert atmosphere;
82%
In tetrahydrofuran at 0 - 25℃; for 6h;
82%
In tetrahydrofuran at 0℃; for 6h; Inert atmosphere;
80%
In tetrahydrofuran at 0℃; for 6h;
70%
In tetrahydrofuran at 0℃; for 6h; Inert atmosphere;
Tert-butyl(S)-(2,6-dimethyl-3-oxohept-1-en-4-yl)carbamate(S-3)
To a solution of compound1-2 (1.7 g, 6 mmol) in THF (25 mL) was addedisopropenylmagnesium bromide dissolved in THF (0.5 N, 9 mmol) slowly at 0under nitrogen atmosphere. The reaction mixture was stirred at 0 for 6 h andquenched with saturated NH4Cl. Then the mixture was extracted withethyl acetate (20 mL×3). The combined organic layer was washed with brine,dried over anhydrous Na2SO4, and concentrated. Theresidue was purified by silica gel chromatography to afford 1.1 g colorlessliquid. Yield: 70%; 1H NMR (500MHz, CDCl3): δ =6.07 (s, 1H, =CH2), 5.87 (s, 1H, =CH2), 5.14 (d, 1H, J=8.0Hz, NH), 5.05 (m, 1H, CH), 1.89 (s,3H, CH3), 1.72 (m, 1H, CH), 1.46 (m, 1H, CH2), 1.42 (s,9H, CH3), 1.32 (m, 1H, CH2), 0.98 (d, 3H, J= 6.5Hz, CH3), 0.90 (d, 3H, J= 6.5Hz, CH3); ESI-MS: m/z =256[M+H]+.
64%
In tetrahydrofuran at -78℃; for 12h;
64%
Stage #1: isopropenylmagnesium bromide; N-(tert-butoxycarbonyl)-L-leucine-N'-methoxy-N'-methylamide In tetrahydrofuran at -78℃; Inert atmosphere;
Stage #2: With ammonium chloride at 20℃; Inert atmosphere;
In tetrahydrofuran at 0℃; Inert atmosphere;
2 General procedure for the synthesis of α,β-unsaturated ketone (3)
General procedure: To a suspension of Boc-protected amino acid 1 (10.0 mmol) in DCM (45.0 mL), HOBt (10.0 mmol) and EDCI (15.0 mmol) were added at 0 °C. The reaction mixture was kept at the same temperature and stirred for 30 min. Then N,O-dimethylhydroxylamine hydrochloride (10.0 mmol) and diisopropylethylamine (25.0 mmol) were added. After stirring at 0 °C for 3 h, the resulting mixture was washed with aqueous NaHCO3 solution (2 × 20 mL), brine (1 × 20 mL), and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue obtained was used in the next step without further purification. (0015) To a solution of isopropenylmagnesium bromide (15 mmol, 0.5 M in THF) was added a solution of Weinreb amide 2 (10 mmol) in dry THF (50 mL) dropwise at 0 °C under an atmosphere of nitrogen. The reaction mixture was stirred at the same temperature overnight and then poured into 100 mL of saturated NH4Cl solution. The solution was acidified to pH 2.0 with 6 N HCl, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with aqueous NaHCO3 (1 × 30 mL), brine (1 × 30 mL), and dried over Na2SO4. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (ethyl acetate-petroleum ether = 1:20) to give compound 3.
7.5 g
In tetrahydrofuran at 0 - 5℃; for 6h; Inert atmosphere;
18 Synthesis of (J)
To a 0 °C solution of (I) (10.0 g, 36.4 mmol,) in 100 mL of dry THF, under an atmosphere of argon was added isopropenyl magnesium bromide (364 mL, 182 mmol, 5.0 eq, 0.5 M solution in THF) dropwise using an addition funnel. The rate of addition was adjusted such that the internal reaction temperature was maintained below 5 °C. After six hoursthe reaction mixture was poured into 250 mL of sat. NH4Cl and 500 mL wet ice. After stirring for 30 minutes the mixture became clear and the volatiles were removed under reduced pressure and the crude material was diluted with EtOAc (200mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 150 mL), the organic layers were combined, washed with water (2 x 150 mL), brine (2 x 150 mL) and dried over MgSO4. The MgSO4 was removed by filtration and the volatiles were removed under reduced pressure. Purification by flash chromatography (15:1 hexanes/ EtOAc) gave (J) as a solid (7.5 g, 29.37 mmol).
72 g
In tetrahydrofuran at 25 - 40℃; for 2.75h;
11 EXAMPLE 11: Preparation of te -butyl ((4S)-2,6-dimethyl -3-oxo hept-l-en-4- yl))carbamate of Formula XVIII
EXAMPLE 11: Preparation of te -butyl ((4S)-2,6-dimethyl -3-oxo hept-l-en-4- yl))carbamate of Formula XVIII A mixture of compound of Formula XVII (100 g) and toluene (1500 ml) was heated to 75- 80°C and was distilled completely under vacuum at same temperature to obtain residue. The obtained residue was dissolved in tetrahydrofuran (100 ml) at 25-30°C. In another reaction flask isopropenyl magnesium bromide (2.19 lit) was charged at 25-30°C and slowly added the above tetrahydrofuran solution over 2 hr at 25-40°C and stirred for 45 min at same temperature. After completion of the reaction, quenched the reaction mass in to 15% ammonium chloride (1.5 lit) at 0-5 °C and organic layer was separated and concentrated under vacuum at below 40°C to obtain residue. The obtained residue was purified by silicycle silica by using ethyl acetate and cyclohexane solvent system. Product containing solvent fractions were combined and concentrated under vacuum at below 40°C to obtain residue. The obtained residue was dissolved in acetone (100 ml) at 25-30°C and allowed to cool to -5 to 0°C. To the clear solution water (1.5 lit) was added slowly at -5 to 0°C. Precipitated solid was filtered, washed with water (100 ml) and dried to get the title compound as a crystalline solid. Yield: 72 g; PXRD: Fig. 9; Chemical purity by HPCL: 99.44%; Chiral purity by HPLC: 99.73%.
In tetrahydrofuran at 0℃;
General procedure: To a solution of enone 27 (1 equiv.) in methanol (0.17M) at 0°C was added CeCl3·7H2O (1.5 eq.) and NaBH4 (1.4 eq., 6.0mmol, 227mg) portion wise. The mixture was stirred for 25min after which glacial acetic acid was added and the mixture was concentrated under reduced pressure. The resulting crude mixture was re-dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Compound 28 was obtained as a yellow oil (quantitative yield) and used for the next step without further purification.
1.09 kg
In tetrahydrofuran at -10 - 25℃; for 19h; Inert atmosphere; Large scale;
With (R)-La-BINOL; triphenylphosphine; tert-butyl alcohol; In toluene; at 20℃; for 0.5h;
Compound III (102 g, 0.4 mol), asymmetric chiral catalyst (R) -La-BINOL (3.24 g, 2 mol%) was added to a 1 L reaction flask,Triphenylphosphine (14.8 g, 20 mol%), 500 mL of toluene, and stirred at room temperature.Then, tert-butanol (108 g, 1.2 mol) was slowly added dropwise. After 0.5 h of reaction, TLC was monitored and the reaction was complete. The reaction solution was filtered and the filtrate was collected.The filtrate was quenched with 300 mL of saturated sodium sulfite solution. The tetrahydrofuran was evaporated under reduced pressure and then extracted with 400 mL of ethyl acetate. The organic phase was washed successively with 100 mL of water, 100 ml of saturated brine, dried over anhydrous sodium sulfate and dried under reduced pressure. 92 g of a pale yellow oil, which was Compound I, yield 85.0% and ee was 93%.
40%
With tetramethyl ammoniumhydroxide; urea hydrogen peroxide adduct; In methanol; benzonitrile; at -10℃; for 20h;Inert atmosphere;
To a solution of tert-butyl (S)-(2,6-dimethyl-3-oxohept-1-en-4 yl)carbamate (10 g, 37.2 mmol) in MeOH (80 ml) cooled to -10 C, benzonitrile (8.4 ml, 82 mmol), hydrogen peroxide-urea adduct (14 g, 149 mmol) and tetramethylammonium hydroxide (6.9 g, 37.2 mmol) were added dropwise. The reaction mixture was stirred at -10 C under N2 atmosphere for 20 h. After dilution with a saturated Na2S20 3 solution (120 ml) and 1 M HCI (7 ml), MeOH was evaporated under reduced pressure and the aqueous phase was extracted with EtOAc (50 ml x 3). The combined organic phases were dried over MgS04 and concentrated in vacuo affording a crude which was suspended in toluene (40 ml), stirred at 0-5 C for 1 h, and filtered. The resulting solution was concentrated in vacuo affording a crude oil (7.45 g) containing tert-butyi((S)-4-methyi-1-((R)-2-methyloxiran-2-yl)1-oxopentan-2-yl)carbamate (diastereomeric ratio (dr)>10:1 by 1H-NMR) as the main product. This crude was purified by flash chromatography (cyclohexane/ethyl acetate) affording tert-butyl (( S)-4-methyi-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate (4.04 g, 40% yield) as an oil 1H-NMR (400 MHz, CDCb) d 4.84 (d, J =8Hz, 1 H), 4.32 (ddd, J = 12, 10.4 and 3.2 Hz, 1 H), 3.29 (d, J = 4.8 Hz, 1 H), 2.88 (d, J = 4.8 Hz, 1 H), 1.72 (m, 1 H), 1.49 (s, 3 H), 1.45 (m, 1 H), 1.17 (ddd, J= 14.4, 10.4 and 4.2 Hz, 1 H), 0.97 (d, J= 6.8 Hz, 3 H), 0.93 (d, J= 6.8 Hz, 3 H). Analysis GC (optical purity) 96% ee
With dihydrogen peroxide; N-ethyl-N,N-diisopropylamine; In methanol; for 2h;
To a solution of compound 1003 (5.1 g, 20 mmol) in MeOH (50 mL) was added DIEA and a solution of H202 (4.6 mL 30%, 8Ommol). After the solution was stirred for 2 hours, it was poured into an aqueous NaHSO3 solution (100 mL). The mixture was extracted with EtOAc. The combined organic layers were then washed with brine. The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography gave desired stereoisomer compound 1004.
20.8 g
With calcium hypochlorite; In 1-methyl-pyrrolidin-2-one; water; at -15 - 0℃; for 0.333333h;
Water (214 mL) was added to a three neck flask equipped with a mechanical stirrer, an addition funnel, and a thermocouplewith display and cooled to an internal temperature of -5 to 0 C. Solid calcium hypochlorite (107 g, 748 mmol) was thenadded over approximately 5 minutes, while the temperature of the mixture is maintained at approximately -5C to 0C.The mixture was then further cooled to -10C to -5C and stirred for 10 minutes followed by addition of NMP (1000 mL)via addition funnel at a rate to maintain internal temperature between -10 C to -5 C. The reaction slurry was then stirredat -10 C for 15 minutes. (R) (47.8 g, 187 mmol) was dissolved in NMP (40 0mL) and added dropwise to the reactionmixture while maintaining the internal temperature between -15 C and -10 C. The reaction mixture was then stirred at-5 C to 0 C until the reaction was complete by TLC. Upon reaction completion, the mixture was quenched by slowaddition of 1.0 M sodium thiosulfate solution (500 mL), maintaining an internal temperature of -10 C to -5 C. Ethyl Acetate (1000 mL) was then added, the layers were separated and the aqueous layer was extracted twice more. Thecombined organic layers were washed with water (500 mL) and brine (500 mL), dried over magnesium sulfate, filteredand concentrated under reduced pressure to a to yellow oil which was dissolved in hexanes (600 mL) and filtered througha plug of silica to provide (H) as a pale yellow oil (20.8 g).
16.5 g
With dihydrogen peroxide; potassium carbonate; benzonitrile; In methanol; at 25 - 30℃; for 6h;
A mixture of (S)-tert-butyl 2,6-dimethyl-3-o ohept-l-en-4-ylcarbamate (50 gm), methanol (1250 ml) and potassium carbonate (13.5 gm) was stirred for 15 min at 25-30C. Benzonitrile (10.1 gm) was added to the reaction mixture and cooled to 0-5C. 50% hydrogen peroxide (1.6 gm) was slowly added to the reaction mixture at 0-5C and raised the temperature of the reaction mixture to 25-30C. Second lot of 50% hydrogen peroxide (25 gm) was slowly added to the reaction mixture at 25-30C and stirred for 6 hrs at the same temperature. The obtained reaction mixture was slowly added to a pre-cooled solution of sodium thiosulfate and water at 0-5C and stirred the reaction mixture for 20 min at the same temperature. Raised the temperature of the reaction mixture to 25-30C, dichloromethane was added and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous sodium thiosulfate solution. Distilled off the solvent completely from the organic layer under reduced pressure and the obtained compound was purified by column chromatography using ethyl acetate: cyclohexane as eluent. Yield: 16.5 gm
Stage #1: N-(tert-butoxycarbonyl)-L-leucine-N'-methoxy-N'-methylamide; allyl bromide With tert.-butyl lithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere;
Stage #2: With water; ammonium chloride In tetrahydrofuran; hexane Inert atmosphere;
4
Under argon atmosphere, to a -78°C solution of compound 1002 (8.2 g, 30 mmol) in THF (100 mL) was added a solution of t-BuLi (46 mL of 1 .3M in Hexane, 60 mmol). After the solution was stirred at -78°C, Isopropenyl bromide (3.63g, 30 mmol) was added. The reaction was stirred at -78°C for 1 hour, after which it was poured into a saturated aqueous ammonium chloride solution (100 mL). The mixture was extracted with EtOAc. The combined organic layers were then washed with brine. The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography gave compound 1003.
Stage #1: 2-bromoprop-1-ene With iodine; magnesium In tetrahydrofuran at 30 - 60℃; for 1h; Inert atmosphere; Large scale;
Stage #2: N-(tert-butoxycarbonyl)-L-leucine-N'-methoxy-N'-methylamide In tetrahydrofuran at 0℃; Inert atmosphere; Large scale;
2.1-2.3; 3.1-3.3 Example 3 Preparation of Compound C
Step 1: Preparation of format reagent: Add a mixture of magnesium powder and magnesium chips (mixed by mass ratio 1:1, 1.5kg), I2 (15 grains) into a 50L reactor, protected by nitrogen, and a small amount of THF is added to cover the magnesium powder. Warm up to 50°C, dissolve 2-bromopropene (5.0kg) in THF (38.2L), drop a small amount of dibromopropene THF solution into the reactor, the temperature rises rapidly, a lot of bubbles are generated, and the iodine color disappears. The reaction starts. Successfully maintain 60°C, slowly drip the THF solution of dibromopropene into the reaction kettle in batches. After the dripping is completed, the reaction is kept at 60°C for 1 hour, and then the temperature is reduced to about 30°C to obtain the Grignard reagent for use. Step 2: Dissolve compound B (3.9kg) in THF (4L) and add it to a 100L reactor, turn on the stirring, cool to below 0°C, add the Grignard reagent obtained in step 1 dropwise below 0°C, after dripping , Keep warm overnight. Step 3: Add saturated ammonium chloride solution (40L) into a 100L reactor, cool to below 0, drop the reaction solution in step 2 into saturated ammonium chloride solution, the temperature does not exceed 5, and then use dilute Adjust the PH value to 1-2 with HCl (1mol/L), add ethyl acetate (8L, 7L, 5L) for extraction three times, combine the organic phases, dry overnight with anhydrous sodium sulfate, concentrate to remove the solvent to obtain the crude product, which is passed through the column. Compound C was obtained, 2.3 kg, with a yield of 65% and a purity of 92.7%.
57%
Stage #1: 2-bromoprop-1-ene With tert.-butyl lithium In diethyl ether; pentane at -78℃; for 0.5h; Inert atmosphere;
Stage #2: N-(tert-butoxycarbonyl)-L-leucine-N'-methoxy-N'-methylamide In diethyl ether; pentane at -78 - 20℃; for 2.5h; Inert atmosphere;
38.5 g
Stage #1: 2-bromoprop-1-ene With iodine; magnesium In tetrahydrofuran at 50 - 55℃; for 2.5h; Inert atmosphere;
Stage #2: N-(tert-butoxycarbonyl)-L-leucine-N'-methoxy-N'-methylamide In tetrahydrofuran at 0 - 30℃; for 8.25h;
25 Example-25: Preparation of (S)-tert-butyl 2,6-dimethyI-3-oxohept-l-en-4-ylcarbamate
A mixture of magnesium (24 gm), iodine (0.5 gm) and tetrahydrofuran (1000 ml) was heated to 50-55°C under nitrogen atmosphere. A solution of 2-bromo propene (123.5 gm) in tetrahydrofuran (250 ml) was slowly added lot wise to the reaction mixture at 50-55°C and stirred the reaction mixture for 2 hrs 30 min at the same temperature. Cooled the reaction mixture to 25-30°C and the resulting reaction mixture was added to a pre-cooled mixture of (S)-tert-butyl l-(methoxy(methyl)amino)-4-methyl-l-oxopentan-2-ylcarbamate (50 gm) and tetrahydrofuran at 0-5°C and stirred the reaction mixture for 15 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 8 hrs at the same temperature. The obtained reaction mixture was slowly added to a pre-cooled mixture of water and ammonium chloride at 0-5°C and stirred for 30 min at the same temperature. Neutralized the reaction mixture using aqueous hydrochloric acid solution and stirred the reaction mixture for 15 min. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and distilled off the solvent completely under reduced pressure. Dichloromethane was added to the obtained compound at 25-30°C and stirred for 5 min. Silica gel was added to the reaction mixture and distilled off the solvent completely from the reaction mixture. Cooled the obtained compound to 25-30°C, cyclohexane (247.5 ml) and ethyl acetate (2.5 ml) were added and stirred the reaction mixture for 45 min at the same temperature. Filter the reaction mixture and distill off the solvent completely from the filtrate under reduced pressure to get the title compound. Yield: 38.5 gm.
Multi-step reaction with 2 steps
1: tetrahydrofuran / 0.33 h / -20 °C / Green chemistry
2: piperdinium acetate; piperidine / tetrahydrofuran / 8 h / 68 °C / Green chemistry
Multi-step reaction with 2 steps
1: tetrahydrofuran / -20 - 20 °C
2: piperidine; piperidinyl acetate / tetrahydrofuran / 3 h / Reflux
Multi-step reaction with 2 steps
1: lithium diisopropyl amide / tetrahydrofuran / 1.25 h / -10 - 0 °C / Inert atmosphere
2: potassium carbonate; formaldehyd / N,N-dimethyl-formamide; water / 3.3 h / 0 - 20 °C
Multi-step reaction with 2 steps
1: tetrahydrofuran / 6 h / -20 °C
2: piperdinium acetate; piperidine / tetrahydrofuran / 12 h / 68 °C
Multi-step reaction with 2 steps
1: tetrahydrofuran / 8 h / -20 - 20 °C
2: piperdinium acetate; piperidine / tetrahydrofuran / 3 h / Reflux
tert-butyl [(1R)-3-methyl-1-[[(2S)-2-methyloxiran-2-yl]carbonyl]butyl]carbamate[ No CAS ]
[ 247068-82-2 ]
Yield
Reaction Conditions
Operation in experiment
With dihydrogen peroxide; potassium hydroxide; N-(4-iodobenzyl)cinchoninium bromide; at 0 - 4℃;Catalytic behavior;
1L reaction flask was added sequentially to a phase transfer catalyst 8.85 g of PTC A (0.015 mol, 3 mol%), 56 g of potassium hydroxide (1.0 mol, 2.0 eq), 500 mL of n-butyl ether, and 127 g of compound III (0.5 mol, 1.0 eq) were added under stirring at room temperature. Cooling to 0 C, 113.3 g of 30% hydrogen peroxide (1.0 mol, 2.0 eq) was slowly added dropwise and the temperature was maintained below 4 C. The temperature was raised above 0 C and below 4 C for 36 h. TLC monitoring, the reaction was completely filtered and the filtrate was quenched with 300 mL of saturated sodium sulfite solution. The upper organic phase was separated and concentrated to dryness. The residue was washed with 600 mL of ethyl acetate, 150 mL of saturated brine, dried over anhydrous sodium sulfate, dried in vacuo to give 131 g of pale yellow oil as Compound I, the yield was 97.0% and the ee value was 84%.
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