There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type | HazMat fee for 500 gram (Estimated) |
Excepted Quantity | USD 0.00 |
Limited Quantity | USD 15-60 |
Inaccessible (Haz class 6.1), Domestic | USD 80+ |
Inaccessible (Haz class 6.1), International | USD 150+ |
Accessible (Haz class 3, 4, 5 or 8), Domestic | USD 100+ |
Accessible (Haz class 3, 4, 5 or 8), International | USD 200+ |
Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 27374-25-0 | MDL No. : | MFCD00074986 |
Formula : | C8H18O2Si | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BZMMRNKDONDVIB-UHFFFAOYSA-N |
M.W : | 174.31 | Pubchem ID : | 2734686 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 48.53 |
TPSA : | 18.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.81 cm/s |
Log Po/w (iLOGP) : | 2.96 |
Log Po/w (XLOGP3) : | 2.19 |
Log Po/w (WLOGP) : | 2.3 |
Log Po/w (MLOGP) : | 1.31 |
Log Po/w (SILICOS-IT) : | 0.6 |
Consensus Log Po/w : | 1.87 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.04 |
Solubility : | 1.6 mg/ml ; 0.0092 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.21 |
Solubility : | 1.07 mg/ml ; 0.00615 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.23 |
Solubility : | 1.02 mg/ml ; 0.00583 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.79 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P210-P302+P352-P305+P351+P338 | UN#: | 1993 |
Hazard Statements: | H225-H315-H319-H335 | Packing Group: | Ⅱ |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | at 20℃; for 1.16667 h; Molecular sieve; Reflux | Example 65 1-Cyclopropyl-4-{4-[(5-methyl-3-{3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-1H-pyrazol-1-yl)methyl]pyridin-2-yl}piperazine 66 ml (1.15 mmol) of glacial acetic acid, 13.9 g of dried, powdered molecular sieve (3 Å) and 139 ml (0.692) of 1-ethoxy-1-(trimethylsilyl)oxycyclopropane were added successively to a solution of 56.0 g (0.115 mol) of the compound from Example 64 in 1.13 l of methanol. After stirring at RT for 10 min, 21.7 g (0.346 mol) of solid sodium cyanoborohydride were added. The mixture was then heated under reflux for 1 h. After cooling to RT, the undissolved material was filtered off with suction and the filtrate was concentrated on a rotary evaporator. The residue obtained was taken up in 1 l of ethyl acetate and the mixture was washed twice with approx. 750 ml of saturated sodium bicarbonate solution each time and then with approx. 750 ml of saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture was filtered and the filtrate was freed from the solvent on a rotary evaporator. The residue (53 g) was recrystallized from a boiling mixture of 293 ml of ethanol and 59 ml of water. When the crystallization was complete (after approx. 20 h at RT), the mixture was filtered with suction. The solid was washed with 36 ml of ethanol/water (5:1) and then dried under a high vacuum. 26.4 g of the title compound were obtained as the first batch in this way. The mother liquor of the crystallization was concentrated on a rotary evaporator. A further 20.3 g of the product were obtained in the form of the formate salt by means of preparative HPLC (method N). For liberation of the base, a suspension of this formate in 1 l of ethyl acetate was washed successively with approx. 200 ml each of saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture was filtered and the filtrate was freed from the solvent on a rotary evaporator. The residue (13 g) was recrystallized from a boiling mixture of 80 ml of ethanol and 16 ml of water. When the crystallization was complete (after approx. 4 h at RT), the mixture was filtered with suction and the solid was dried under a high vacuum. A further 11.2 g of the title compound were obtained in this manner (yield in total 37.6 g, 62percent of th.). Melting point: 140° C. 1H-NMR (400 MHz, CDCl3, δ/ppm): 8.26 (d, 2H), 8.13 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.33 (d, 1H), 6.32 (s, 1H), 5.35 (s, 2H), 3.47 (dd, 4H), 2.69 (dd, 4H), 2.30 (s, 3H), 1.65-1.60 (m, 1H), 0.48-0.42 (m, 4H). LC/MS (method D, ESIpos): Rt=1.91 min, m/z=526 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With hydrogenchloride; In methanol; water; at 20℃; for 2h; | Synthesis of 1-ethoxycyclopropanol To a solution of (1-ethoxycyclopropoxy)trimethylsilane (17 mL, 84.6 mmol) in methanol (60 mL) was added 2 drops of 12M hydrochloric acid. The reaction was stirred at room temperature for 2 hours then the solvents were removed under reduced pressure at low temperature to afford 1-ethoxycyclopropanol (6.5 g, 75% yield). 1H NMR (300 MHz, CDCl3): 3.75 (q, 2H), 3.23 (br s, 1H), 1.21 (t, 3H), 0.96-0.90 (m, 4H). |
70.3% | With methanol; at 20℃; for 24h; | A solution of compound H1 (25 g, 143.6 mmol) in MeOH (70 mL) was stirred at room temperature for 24 hours. The solvent was carefully removed under reduced pressure at room temperature, and the residue was distilled (50 mbar, 65 ) to provide compound H2 (10.3 g) as a clear, colorless liquid, yield: 70.3%. 1H NMR (400 MHz, CDCl 3) : deltappm 0.89-0.96 (m, 4H) , 1.21 (t, J = 7.2 Hz, 3H) , 3.76 (q, J = 7.1 Hz, 2H) , 4.12 (s, 1H) . |
65.6% | With hydrogenchloride; In methanol; at 25℃; for 16h; | 1-ethoxycyclopropanol A solution of (1-ethoxycyclopropoxy)trimethylsilane (1.499 mL, 7.46 mmol) and a drop of hydrogen chloride (7.16 mg, 0.075 mmol) in CH3OH (6 mL) was stirred at 25 C. for 16 hours. The mixture was concentrated to provide the title compound 1-ethoxycyclopropanol (0.5 g, 4.90 mmol, 65.6% yield). 1H NMR (400 MHz, CDCl3) delta ppm 3.76 (q, J=8 Hz, 2H), 1.22 (t, J=8 Hz, 4H), 0.93-0.95 (m, 4H). |
65.6% | With hydrogenchloride; In methanol; water; at 25℃; for 16h; | A solution of [(1-ethoxycyclopropyl)oxy](trimethyl)silane (1.499 mL, 7.46 mmol), a drop of hydrogen chloride (7.16 mg, 0.075 mmol) in methanol (6 mL) was stuffed at 25 C for 16 hours. The mixture was concentrated to give the title compound (0.5 g, 4.90 mmol, 65.6 % yield). ?H NMR: (400 MHz, CDC13) oe 3.76 (q, J= 8 Hz, 2H), 1.22 (t, J= 8 Hz, 4H), 0.93-0.95 (m, 4H). |
6.26 g | With hydrogenchloride; In methanol; water; at 20℃; | 60 ml of methanol and a drop of concentrated hydrochloric acid were added to 12.32 g (70.7 mmol) of [(1-ethoxycyclopropyl)oxy](trimethyl)silane, and the mixture was stirred at RT overnight. The solvent was then removed at RT and under a reduced pressure of not less than 30 mbar on a rotary evaporator. This gave 6.26 g (61.27 mmol) of 1-ethoxycyclopropanol, which were dissolved in 80 ml of THF. Under argon, this solution was then cooled to -70 C., and 30.6 ml (61.27 mmol) of a 2 M solution of ethylmagnesium chloride in THF were added. The cooling bath was then removed, and the solution was stirred without cooling until an internal temperature of 0 C. had been reached. |
With methanol; at 20℃; for 21h; | A solution of(1-ethoxycyclopropyl)oxy-trimethylsilane (12 mL, 59.60 mmol) in MeOH (10 mL) was stirred at ambient temperature for 21 h. The solvent was evaporated under reduced pressure to give the crude title compound (5.60 g, 92% yield) as a colorless oil. | |
With hydrogenchloride; In methanol; at 20℃; for 14h; | To a solution of 436 (1-ethoxycyclopropoxy)trimethylsilane (5.0 g, 28.7 mmol) in 139 MeOH (35 mL) was added 4.0 M 141 HCl (0.07 mL, 0.274 mmol, in MeOH) with stirring at RT. The reaction mixture was stirred at RT for 14 h. The solvent was removed and the residue was purified by distillation under reduced pressure (65 C., 10-12 mbar) to afford the 437 title compound as an oil. 1H NMR (400 MHz, CDCl3) delta 3.76 (q, 2H), 3.14 (br s, 1H), 1.22 (t, 3H), 0.91-0.99 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With zinc(II) chloride 1.) ether, vac., room temp.; 2.) THF, room temp.; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With titanium tetrachloride; In dichloromethane; at -78 - 20℃; for 18.5h; | The title compound was prepared in a similar manner to Intermediate 15. To asolution of benzaldehyde (1.00 g, 9.43 mmol) in DCM (30 mL) at -78C was added TiCL4(15.0 mL, 15.0 mmol, 1 M in DCM). A solution of (1-ethoxycyclopropoxy)-trimethyl-silane (2.90 g, 14.10 mmol) in DCM (20 mL) was added and the reaction was stirred at -78C for 30 mm and warmed to r.t. for 18 h. The reaction was treated with sat. aq. NH4C1(20 mL) and extracted with DCM (20 mL). The organic layer was separated, dried(MgSO4) and concentrated in vacuo. The residue was purified by column chromatography(Si02, 0-10 % EtOAc/hexanes), yielding the title compound as a yellow oil (1.60 g, 84%). 1H NMR (400 MHz, CDC13) oe 7.30-7.20 (m, 5 H), 4.95 (m, 1 H), 4.10 (q, 2 H), 2.45-2.30 (m, 4 H), 1.25 (t, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | tert-Butyl 4-cyclopropylpiperazine-1-carboxylate. A mixture of tert-butyl piperazine-1-carboxylate (75.0 g), tetrahydrofuran (THF) (500 mL), methanol (500 mL), [(1-ethoxycyclopropyl)oxy]trimethylsilane (161 mL), NaBH3CN (38.0 g), and acetic acid (37 mL) was heated at 60 C. for 5 h. The mixture was cooled to rt, treated with water (30 mL) and stirred for 5 min. The mixture was then treated with 1 N NaOH (130 mL) and was further stirred for 15 min. The mixture was concentrated, and the remaining aqueous solution was extracted with CH2Cl2 (500 mL). The organic layer was washed with 1 N NaOH (500 mL). The combined aqueous layers were extracted with CH2Cl2 (150 mL). The combined organic layers were washed with brine (400 mL), dried (Na2SO4), and concentrated to give the title compound as a white solid (92 g, 100%). MS (ESI): mass calcd. for C12H22N2O2, 226.17; m/z found, 227.2 [M+H+]. 1H NMR (400 MHz, CDCl3): 3.39 (t, J=5.0 Hz, 4H), 2.55 (t, J=4.9 Hz, 4H), 1.60 (ddd, J=10.3, 6.5, 3.8 Hz, 1H), 1.46 (s, 9H), 0.49-0.38 (m, 4H). | |
71% | With sodium cyanoborohydride; acetic acid; In methanol; for 120h; | 1) 1-Cyclopropylpiperazine-4-carboxylic acid tert-butyl ester To a solution of piperazine-1-carboxylic acid tert-butyl ester (1.87 g), [(1-ethoxycyclopropyl)oxy]trimethylsilane (8.05 mL), and acetic acid (5.72 mL) in methanol (60 mL), at room temperature, sodium cyanoborohydride (1.89 g) was added, and the mixture was stirred for 5 days. The reaction solvent was removed under reduced pressure, and diethyl ether was added to the residue. Insoluble matter was removed through filtration. 1N Aqueous sodium hydroxide was added to the filtrate for partitioning the resultant mixture. The organic layer was washed with saturated brine and then dried over magnesium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (hexane - ethyl acetate), to thereby give 1-cyclopropylpiperazine-4-carboxylic acid tert-butyl ester as a solid product (1.62 g, 71%). 1H-NMR (400MHz, CDCl3) delta:0.41-0.48 (4H, m), 1.46(9H,s), 2.54-2.56 (4H,m), 3.37-3.44 (4H, m). MS (ESI)m/z:268 (M+MeCN)+. |
71% | With sodium cyanoborohydride; acetic acid; In methanol; for 120h; | 1) 4-Cyclopropylpiperazine-1-carboxylic acid tert-butyl ester Sodium cyanoborohydride (1.89 g) was added at room temperature to piperazine-1-carboxylic acid tert-butyl ester (1.87 g), [(1-ethoxycyclopropyl)oxy]trimethylsilane (8.05 mL), and acetic acid (5.72 mL) in methanol (60 mL), followed by stirring for 5 days. The reaction solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and then the insoluble matter was removed by filtration. 1N Aqueous solution of sodium hydroxide was added for partitioning the solvent of the filtrate. The organic layer was washed with saturated brine, followed by drying over magnesium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give 4-cyclopropylpiperazine-1-carboxylic acid tert-butyl ester as a solid product (1.62 g, 71%). 1H-NMR(400MHz,CDCl3)delta:0.41-0.48(4H,m), 1.46(9H,s), 2.54-2.56(4H,m), 3.37-3.44 (4H,m). MS(ESI) m/z:268(M+MeCN)+. |
71% | With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 120h; | [Referential Example 98] ;1-Cyclopropylpiperazine-4-carboxylic acid tert-butyl ester ; Piperazine-1-carboxylic acid tert-butyl ester (1.87 g), [(1-ethoxycyclopropyl)oxy]trimethylsilane (8.05 mL), and acetic acid (5.72 mL) were dissolved in methanol (60 mL). To the resultant solution, sodium.cyanoborohydride (1.89 g) was added at room temperature, followed by stirring for 5 days. Diethyl ether was added to the residue obtained by removal through evaporation of the reaction solvent under reduced pressure, and insoluble matter was filtered off. The filtrate was partitioned by addition of aqueous 1N sodium hydroxide thereto. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (hexane - ethyl acetate), to thereby give the title compound as a solid (1.62 g, 71%).1H-NMR(400MHz,CDCl3)delta: 0.41-0.48(4H,m), 1.46(9H,s), 2.54-2.56(4H,m), 3.37-3.44(4H,m). MS(ESI)m/z: 268(M+MeCN)+. |
61.1 - 68.3% | MeOH (0.3 mL), ((1-ethoxycyclopropyl)oxy)trimethylsilane (2 g, 11.47 mmol) and acetic acid (1.051 mL, 18.35 mmol) were added to a stirred solution of tert-butyl piperazine-1-carboxylate (1.068 g, 5.735 mmol) in THF (40 mL) under nitrogen. Sodium cyanoborohydride (0.541 g, 8.60 mmol) was added portionwise over a period of 10 mins. The resulting mixture was stirred at 60 C. for 24 h. The reaction mixture was evaporated to dryness and mixed with water (80 mL) and 1M HCl (25 mL). This solution was washed with EtOAc (2×50 mL), the aqueous layer was basified with K2CO3, and extracted with EtOAc (2×30 mL). The organic layers were combined, washed with saturated brine (30 mL), dried over MgSO4, filtered and evaporated to afford tert-butyl 4-cyclopropylpiperazine-1-carboxylate (0.792 g, 61.1%) as a colourless oil which crystallised on standing. 1H NMR (399.9 MHz, DMSO-d6) delta 0.30-0.34 (2H, m), 0.40-0.44 (2H, m), 1.41 (9H, s), 1.60-1.65 (1H, m), 2.47 (4H, t), 3.26 (4H, t); A solution of tert-butyl piperazine-1-carboxylate (9.31 g, 50 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (20.11 mL, 100.00 mmol) and acetic acid(14.31 mL, 250.00 mmol) in tetrahydrofuran (100 mL), methanol (10 mL) was treated with sodium cyanoborohydride (4.71 g, 75.00 mmol) at 20 C. The resulting solution was stirred at 60 C. for 18 h. The reaction mixture was cooled, filtered and evaporated to dryness. 1N HCl (40 ml) and water (60 ml) were added and the solution extracted with ethyl acetate (3×50 ml). The aqueous layer was basified to pH 10 with solid potassium carbonate and extracted with ethyl acetate (4×50 ml). The organic extracts were washed with saturated sodium chloride solution (50 ml) and dried over MgSO4, filtered and evaporated to dryness to give tert-butyl 4-cyclopropylpiperazine-1-carboxylate (7.73 g, 68.3%) as a white waxy solid. 1H NMR (399.9 MHz, CDCl3) delta 0.33-0.40 (4H, m), 1.39 (9H, s), 1.52-1.55 (1H, m), 2.48 (4H, t), 3.31 (4H, t). | |
50% | With methanol; sodium cyanoborohydride; acetic acid; In tetrahydrofuran; at 60℃; for 5h; | To a mixture of (1-ethoxycyclopropoxy)trimethylsilane (1.74 g, 10.0 mmol), tert-butyl piperazine-1-carboxylate (930 mg, 5.00 mmol), and AcOH (450 mg, 7.50 mmol) in a mixed solvent (THF/MeOH, 1:1, 12 mL) was added NaBH3CN (473 mg, 7.50 mmol). After heating at 60C for 5 hrs, the mixture was added of H20 (5 mL), stirred for 5 minutes. Aqueous solution of NaOH (1N, 5 mL) was added and the resulted mixture was extracted with DCM (10 mL x 3). The combined extracts was dried and concentrated to give the title product (1.11 g, 50%) as a white solid which was used for the next step directly. ?H NMR (400 MHz, CDC13) 3.39 (t, J 4.4 Hz, 4H), 2.55 (t, J= 4.4 Hz, 4H), 1.67 - 1.54 (m, 1H), 1.46 (s, 9H), 0.48 - 0.47 (m, 2H), 0.44- 0.42 (m, 2H).MS: M/e 227 (M+1). |
Step A; 1-Cvclopropyl-piperazine bis-hvdrochloride.; A solution of N-Boc- piperazine (29.82 g, 160 mmol), 1 :1 THF/MeOH (300 ml_), (1- ethoxycyclopropoxy)-thmethylsilane (64 mL, 320 mmol), acetic acid (15 mL, 262 mmol), and NaBH3CN (15.10 g, 240 mmol) was stirred at 50 0C for 5 h. The reaction was cooled to rt and quenched by addition of H2O (15 mL). After <n="40"/>5 min, 1 N NaOH (60 ml.) was added, and the mixture was stirred for 15 min. The mixture was concentrated removing the bulk of the THF and MeOH. The residue was diluted with CH2CI2 (300 ml.) and washed with 1 N NaOH (300 ml_). The aqueous layer was back-extracted once with CH2CI2, and the combined organic layers were washed with satd. aq. NaCI (2x300 ml_), dried (Na2SO4) and concentrated to provide N-Boc-N'-cyclopropyl-piperazine as white solid. 1H NMR (CDCI3): 3.39 (br [, J = 5.0, 4H), 2.55 (br [, J = 4.6, 4H), 1.64-1.56 (m, 1 H), 1.46 (s, 9H), 0.50-0.38 (m, 4H). The unpurified N-Boc-N'- cyclopropyl-piperazine was stirred rapidly in 1 ,4-dioxane (75 mL) at rt as HCI (4.0 M in 1 ,4-dioxane; 195 mL) was added at a moderate rate. A very thick suspension formed immediately but thinned as more HCI in 1 ,4-dioxane was added. The suspension was heated to 45 0C and stirred for 6 h. The mixture was cooled to rt, and the precipitated product was collected by suction filtration, washed with 1 ,4-dioxane, and dried under vacuum to provide the desired hydrochloride salt as a white powder (28.71 g, 90%, 2 steps). 1H NMR (CD3OD): 9.90-9.40 (br s, 2H), 3.80-3.20 (br m, 9H), 1.20-0.90 (br m, 2H), 0.85-0.58 (br m, 2H). | ||
Step A. te/f-Butyl 4-cyclopropylpiperazine-1-carboxylateA mixture of terf-butyl piperazine-1-carboxylate (75.0 g), THF (500 ml_), methanol (500 mL), [(1 -ethoxycyclopropyl)oxy]trimethylsilane (161 ml_),NaBH3CN (38.0 g), and acetic acid (37 mL) was heated at 60 0C for 5 h. The mixture was cooled to room temperature, treated with water (30 mL) and stirred for 5 min. The mixture was then treated with 1 N NaOH (130 mL) and was further stirred for 15 min. The mixture was concentrated, and the remaining aqueous solution was extracted with CH2CI2 (500 mL). The organic layer was washed with 1 N NaOH (500 mL). The combined aqueous layers were extracted with CH2CI2 (150 mL). The combined organic layers were washed with brine (400 mL), dried (Na2SO4), and concentrated to yield the title compound as a white solid. MS (ESI): mass calcd. for C12H22N2O2, 226.17; m/z found, 227.2 {M+H+]1H NMR (400 MHz, CDCI3): 3.39 (t, J = 5.0 Hz, 4H), 2.55 (t, J = 4.9 Hz, 4H), 1.60 (ddd, J = 10.3, 6.5, 3.8 Hz, 1 H), 1.46 (s, 9H), 0.49-0.38 (m, 4H). | ||
With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; at 60℃; for 5h; | Example 25 (^Cvclopropyl-piperazin-i-ylH^morpholin^-ylmethyl-phenyl)- methanone Step A. terf-Butyl 4-cvclopropylpiperazine-1-carboxylate A mixture of t°/t-butyl piperazine-1-carboxyIate (75.0 g), THF (500 mL), methanol (500 mL), [(1 -ethoxycyclopropyl)oxy]trimethylsilane (161 mL),NaBH3CN (38.0 g), and acetic acid (37 mL) was heated at 60 0C for 5 h. The mixture was cooled to room temperature, treated with water (30 mL) and stirred for 5 min. The mixture was then treated with 1 N NaOH (130 mL) and was further stirred for 15 min. The mixture was concentrated, and the remaining aqueous solution was extracted with CH2CI2 (500 mL). The organic layer was washed with 1 N NaOH (500 mL). The combined aqueous layers were extracted with CH2CI2 (150 mL). The combined organic layers were washed with brine (400 mL), dried (Na2SO4), and concentrated to yield the title compound as a white solid. MS (ESI): mass calcd. for C12H22N2O2, 226.17; m/z found, 227.2 [M+H+]1H NMR (400 MHz, CDCI3): 3.39 (t, J= 5.0 Hz, 4H), 2.55 (t, J= 4.9 Hz, 4H), 1.60 (ddd, J = 10.3, 6.5, 3.8 Hz, 1 H), 1.46 (s, 9H), 0.49-0.38 (m, 4H). | |
With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; at 60℃; for 5h; | A mixture of piperazine-1-carboxylic acid tert-buty ester (2.5 g, 13.4 mmol), (1- ethoxy-cyclo propoxy)-trimethyl-silane (5 g, 28.7 mmol), NaBH3CN (7.6 g, 120.9 mmol) and acetic acid (1.3 mL) in THF (30 mL) and MeOH (30 mL) was heated at <n="70"/>60 0C for 5 hrs. The mixture was treated with water and aqueous IN NaOH solution. The mixture was concentrated and the remained aqueous layer was extracted with DCM (50 mL*3). The combined organic layer was dried and concentrated to give the crude product, which was purified by silica column chromatography to give tert-buty 4-cyclopropylpiperazine-l-carboxylate (1.5 g, crude). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With acetic acid; In dichloromethane; at 90 - 100℃; for 3h;Inert atmosphere; | To a mixture solutionof 100 g of 1-ethoxy-1-(trimethylsiloxy)cyclopropane(3) and 17.1 g AcOH in 400 mL tetraethylene glycoldimethyl ether, was added 180 g of (2-ethoxy-2-oxoethylidene)triphenylphosphorane(7) which was dissolved in 270 mL of dichloromethane dropwiseat 90-100 oC for 3 h under stirring. During the adding period,dichloromethane was removed by distillation to keep the process temperature at90-100 oC. The mixture was stirred at 90-100 oC foranother 1 h, which allowed dichloromethane to be removed completely bydistillation. Then the product was purified by fractional distillation at 10mbar between 90-100 oC (cooling temperature of fluid in condensershould not be above -10 oC, all distillate under this condition wascollected as the product). A total of 50-55 g (yield: 69-76%) of Compound 8was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3) delta 6.15 (m, 1H), 4.13 (q, 2H, J = 7.1 Hz), 1.40-1.35 (m, 2H), 1.23 (t, 3H, J = 7.1 Hz), 1.18-1.13 (m, 2H); 13C NMR(100 MHz, CDCl3) delta 166.09, 144.83, 110.83, 59.96, 14.19, 4.42, 1.85; MS (m/z) [M - 28] 98.1. ESI-HRMSm/z calcd for C7H10O2 [M+ H]+ 127.0754,found 127.0755. |
76% | In 1,2-dimethoxyethane; dichloromethane; at 90 - 100℃; for 4h; | To a mixture solution of 100 g of 1-ethoxy-1- (trimethylsiloxy) cyclopropane (1) and 17.1 g AcOH in 400 mL tetraethylene glycol dimethyl ether, was added 180 g (2-ethoxy-2-oxoethylidene) triphenylphosphorane which was dissolved in 270 mL of dichloromethane dropwise at 90-100 for 3 h. During the adding period, dichloromethane was removed by distillation to keep the process temperature at 90-100 . The mixture was stirred at 90-100 for another 1 h, which allowed dichloromethane be removed completely by distillation. Then the product (10) was purified by fractional distillation at 10 mbar (cooling temperature of fluid in condenser should not be above -10 , all distillate was collected as the product) . A total 50-55 g (yield: 69-76) of Compound 10 was obtained as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) delta6.22 (m, 1H) , 4.13 (q, 2H, J 7.2 Hz) , 1.45-1.38 (m, 2H) , 1.30-1.20 (m, 2H) , 1.22 (t, 3H, J 7.2 Hz) 13C NMR (100 MHz, CDCl3) delta165.7, 144.5, 110.4, 59.6, 20.1, 13.7, 13.5 MS (m/z) [M -28] 98.1. |
64% | With benzoic acid; In toluene; at 90℃; for 18h; | Example 1A Ethyl cyclopropylideneacetate A suspension of 38.49 g (220.80 mmol) of [(1-ethoxycyclopropyl)oxy](trimethyl)silane, 100.0 g (287.04 mmol) of ethyl (triphenylphosphoranylidene)acetate and 3.51 g (28.70 mmol) of benzoic acid in 600 ml of toluene is stirred at a bath temperature of 90 C. for 18 hours. After cooling, the mixture is poured onto 800 g of silica gel 60 and eluted successively with in each case 3 liters of petroleum ether 40-60 and dichloromethane. The dichloromethane elude is, after removal of the solvent, distilled at 160 C. and 14 mbar in a kugelrohr. This gives 17.95 g (64% of theory) of the title compound as a colorless liquid. GC-MS (method 1): Rt=3.38 min; MS: m/z=98 [M-28]+. 1H-NMR (400 MHz, CDCl3): delta=1.23 (m, 2H), 1.31 (t, 3H), 1.45 (m, 2H), 4.21 (q, 2H), 6.23 (m, 1H). |
44% | With benzoic acid; In toluene; at 90℃;Inert atmosphere; | To a stirred solution of 1-ethoxy-1-[(trimethylsilyl)oxy]-cyclopropane (CAS 27374-25-0, 10 g, 57 mmol) in toluene (50 mL) was added (carbethoxymethylene)triphenylphosphorane (CAS 1099-45-2, 26 g, 74 mmol) followed by benzoic acid (0.91 g, 7.5 mmol) at about 25 C. The mixture was heated overnight at about 90 C., then cooled and concentrated. The residue was purified by chromatography to provide the title compound C180. Yield: 3.2 g (44%). 1H NMR (400 MHz, CDCl3) delta 6.22 (s, 1H), 4.14 (q, 2H), 1.40-1.46 (m, 2H), 1.27 (t, 3H), 1.20-1.24 (m, 2H). |
34.2% | With acetic acid; In dichloromethane; at 100℃; for 16h; | To a solution of 81-1 (2 g, 11.47 mmol, 2.31 mL, 1.1 eq) and AcOH (375.7 mg, 6.26 mmol, 0.36 mL, 0.6 eq) in dioxane (30 mL) at l00C was added 81-la (3.63 g, 10.43 mmol, 1 eq) in DCM (10 mL) drop-wise, and the mixture was stirred at l00C for 16 h. The mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography to give 81-2 (450 mg, 3.57 mmol, 34.2% yield) (volatile). 1H NMR (400 MHz, CDCl3) d 6.23 (quin, J =1.9 Hz, 1H), 4.22 (q, 7= 7.1 Hz, 2H), 1.49 - 1.42 (m, 2H), 1.31 (t, 7= 7.2 Hz, 3H), 1.26 - 1.21 (m, 2H). |
Step A: ethyl 2-cyclopropylideneacetate: (l-Ethoxycyclopropoxy)trimethylsilane (1700 mg, 9.75 mmol) was dissolved in MeOH (4.3 mL) and the mixture was stirred for 17 h at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in benzene (16.0 mL) and benzoic acid (232 mg, 1.9 mmol) was added. This flask was brought to gentle reflux. To the refluxing solution was added ethyl 2-(triphenylphosphoranylidene)acetate (3.0 g, 8.6 mmol) in benzene(16.0 mL) at a rate so as to maintain reflux. After completion of the addition the mixture was allowed to reflux for 2 h. After cooling to room temperature, benzene was removed under reduced pressure and the residue was purified by flash column chromatography (n-hexane/EtOAc = 3 : 1) to afford the title compound. | ||
Step A: ethyl 2-cyclopropylideneacetate: (l-Ethoxycyclopropoxy)trimethylsilane (1700 mg, 9.75 mmol) was dissolved in MeOH (4.3 mL) and the mixture was stirred for 17 h at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in benzene (16.0 mL) and benzoic acid (232 mg, 1.9 mmol) was added. This flask was brought to gentle reflux. To the refluxing solution was added ethyl 2-(triphenylphosphoranylidene)acetate (3.0 g, 8.6 mmol) in benzene(16.0 mL) at a rate so as to maintain reflux. After completion of the addition the mixture was allowed to reflux for 2 h. After cooling to room temperature, benzene was removed under reduced pressure and the residue was purified by flash column chromatography (n-hexane/EtOAc = 3: 1) to afford the title compound. | ||
With benzoic acid; In toluene; at 90℃; for 18h; | Benzoic acid (1.59 g, 1.3 mmol) was added to a solution of (1-ethoxy-cyclopropoxy)trimethylsilane (17.4 g, 100 mmol) and ethyl (triphenyl-phosphoranylidene)acetate (45 g, 130 mmol) in toluene (250 mL). The mixture was stirred at 90 C. for 18 hours, then cooled to room temperature, the mixture was filtrated through silica gel (300 g), washed with petroleum ether (1000 mL), the filtrate was concentrated to 100 mL under reduced pressure. The solution was used directly for the next step |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In 1,2-dimethoxyethane; acetonitrile at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reference Example 14 3-Bromo-2-chloro-N-cyclopropylaniline hydrochloride To a solution of <strong>[56131-46-5]3-bromo-2-chloroaniline</strong> in methanol (25 ml)-acetic acid (5.4 ml), [(1-ethoxycyclopropyl)oxy]trimethylsilane was added dropwise at room temperature, and the mixture was stirred at 68°C for 3 hr. The reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure (residue A). To a suspension of sodium borohydride (1.8 g) in THF(25 ml), boron trifluoride diethyl ether complex (6.0 ml) was added dropwise under nitrogen atmosphere at 0°C, and the mixture was further stirred for 1 hr. A solution of residue A in THF (15 ml) was added dropwise to the mixture at 0°C, and the mixture was stirred at room temperature for 3 hr, and at 60°C overnight. Water was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. 4N Hydrogen chloride-ethyl acetate (60 ml) was added, and the mixture was stirred for 10 min. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate to give the object (3.46 g) as crystals. 1H-NMR (DMSO-d6) delta0.47-0.54 (2H, m), 0.70-0.78 (2H, m), 2.35-2.44 (1H, m), 6.26 (2H, br s), 6.97 (1H, dd), 7.03 (1H, dd), 7.11 (1H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Dissolve ((R)-l-{5-[2-(4-chloro-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3- c]pyridin-6-yl]-pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (0.393 g, 0.750 mmol) in CHCl3 (5 mL) and treat with TFA (2 mL). Stir the mixture at RT for 30 min. Remove the excess reagent in vacuo. Dissolve the crude material in CH3OH (10 mL) and treat with HOAc (90.22 mL, 3.93 mmol), and (1-ethoxy- cyclopropoxy)trimethylsilane (0.47 mL, 2.36 mmol). Stir the mixture at RT for 10 min. Add NaBH3CN (90.36 g, 5.69 mmol) and reflux the reaction overnight. Dilute the mixture with EtOAc (50 mL) and 2.0 M NaOH (920 mL) and then stir at RT for 5 min. Filter and wash the mixture with EtOAc (30 mL). Separate the organic layer and dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 5% CH3OH (2M NH3)/CHC13 to give 0.35 g (93%) of 2-(4-chloro-phenyl)-6-[6- ((R)-3 -dicyclopropylamino-pyrrolidin- 1 -yl)-pyridin-3 -yl] -5 ,6-dihydro-4H-thieno [2,3 - c]pyridin-7-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.3% | With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; dichloromethane; at 60℃; for 18h; | Methyl 4-piperidin-4-ylbenzoate (1.279 g, 5 mmol) was dissolved in a mixture of THF (15 mL) and methanol (1 mL). <strong>[27374-25-0][(1-Ethoxycyclopropyl)oxy]trimethylsilane</strong> (2.001 mL, 10.00 mmol) added followed by acetic acid (0.916 mL, 16.00 mmol). DCM (15.00 mL) was added to aid solubility. Solid sodium cyanoborohydride (0.471 g, 7.50 mmol) was added in portions over 5 mins. The reaction was stirred at 60 C. for 18 h. This was cooled, quenched with saturated ammonium chloride solution (5 ml), diluted with methanol (20 ml) and partly purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford an oil The crude product was purified by silica column chromatography, eluting with 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford the desired compound (0.548 g, 42.3%) as a white solid. 1H NMR (399.9 MHz, CDCl3) delta 0.42-0.50 (4H, m), 1.60-1.65 (2H, m), 1.70-1.75 (1H, m), 1.80-1.85 (2H, m), 2.25-2.32 (2H, m), 2.55-2.61 (1H, m), 3.15-3.18 (2H, m), 3.89 (3H, s), 7.27-7.30 (2H, m), 7.94-7.97 (2H, m). MS: m/z 260 (MH+). |
Methyl 4-(piperidin-4-yl)benzoate (CAS 281235-04-9, 0.5 g, 2.27 mmol) was dissolved in a mixture of THF (10 mL) and MeOH (10 mL). Acetic acid (1.38 g, 22.7 mmol) and [(l-ethoxycyclopropyl)oxy]trimethylsilane (0.8 g, 4.6 mmol) were added followed by sodium cyanoborohydride (0.433 g, 6.9 mmol). The mixture was stirred for 7 h then reduced in vacuo. The residue was dissolved in IN HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2 x 10 mL). The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with ethyl acetate (3 x 10 mL). The <n="72"/>combined organics were washed with brine then dried (MgSO4), filtered and reduced in vacuo to give crude methyl ester (0.35 g). The crude ester was purified over silica gel eluting with hexane : ethyl acetate (85 : 15 v/v). | ||
With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; for 7h; | Methyl 4-(piperidin-4-yl)benzoate (CAS 281235-04-9, 0.5 g, 2.27 mmol) was dissolved in a mixture of THF (10 mL) and MeOH (10 mL). Acetic acid (1.38 g, 22.7 mmol) and [(l-ethoxycyclopropyl)oxy]trimethylsilane (0.8 g, 4.6 mmol) were added followed by sodium cyanoborohydride (0.433 g, 6.9 mmol). The mixture was stirred for 7 h then reduced in vacuo. The residue was dissolved in IN HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2 x 10 mL). The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine then dried (MgSO4), filtered and reduced in vacuo to give crude methyl ester (0.35 g). The crude ester was purified over silica gel eluting with hexane : ethyl acetate (85 : 15 v/v). |
With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; for 7h; | Methyl 4-(piperidin-4-yl)benzoate (CAS 281235-04-9, 0.5 g, 2.27 mmol) was dissolved in a mixture of THF (10 mL) and MeOH (10 mL). Acetic acid (1.38 g, 22.7 mmol) and [(l-ethoxycyclopropyOoxyJtrimethylsilane (0.8 g, 4.6 mmol) were added followed by sodium cyanoborohydride (0.433 g, 6.9 mmol). The mixture was stirred for 7 h then reduced in vacuo. The residue was dissolved in IN HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2 x 10 mL). The aqueous layer was adjusted to <n="173"/>pH 10 with potassium carbonate and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine then dried (MgSO4), filtered and reduced in vacuo to give crude methyl ester (0.35 g). The crude ester was purified over silica gel eluting with hexane : ethyl acetate (85 : 15 v/v).(ii) Methyl ester (0.20 g, assume 0.77 mmol) was suspended in 10% NaOH (2.5 mL) and water (2.5 mL) added. The mixture was heated at 8O0C for 2 h, then cooled to O0C. The mixture was acidified to pH 2 with 6N HCl, then cooled for 2 h at -50C. A solid was filtered and washed thoroughly with hexane and dried in vacuo to give acid (66) (yield 0.04 g). | |
With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; for 7h; | Methyl 4-(piperidin-4-yl)benzoate (CAS 281235-04-9, 0.5 g, 2.27 mmol) was dissolved in a mixture of THF (10 mL) and MeOH (10 mL). Acetic acid (1.38 g, 22.7 mmol) and [(l-ethoxycyclopropyl)oxy]trimethylsilane (0.8 g, 4.6 mmol) were added followed by sodium cyanoborohydride (0.433 g, 6.9 mmol). The mixture was stirred for 7 h then reduced in vacuo. The residue was dissolved in IN HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2 x 10 mL). The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with ethyl acetate (3 x 10 mL). The <n="92"/>combined organics were washed with brine then dried (MgSO4), filtered and reduced in vacuo to give crude methyl ester (0.35 g). The crude ester was purified over silica gel eluting with hexane : ethyl acetate (85 : 15 v/v). | |
With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; for 7h; | Methyl 4-(piperidin-4-yl)benzoate (CAS 281235-04-9, 0.5 g, 2.27 mmol) was dissolved in a mixture of THF (10 mL) and MeOH (10 mL). Acetic acid (1.38 g, 22.7 mmol) and [(l-ethoxycyclopropyl)oxy]trimethylsilane (0.8 g, 4.6 mmol) were added followed by sodium cyanoborohydride (0.433 g, 6.9 mmol). The mixture was stirred for 7 h then reduced in vacuo. The residue was dissolved in IN HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2 x 10 mL). The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine then dried (MgSO4), filtered and reduced in vacuo to give crude methyl ester (0.35 g). The crude ester was purified over silica gel eluting with hexane : ethyl acetate (85 : 15 v/v). | |
With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; for 7h; | Methyl 4-(piperidin-4-yl)benzoate (CAS 281235-04-9, 0.5 g, 2.27 mmol) was dissolved in a mixture of THF (10 mL) and MeOH (10 mL). Acetic acid (1.38 g, 22.7 mmol) and [(l-ethoxycyclopropyl)oxy]trimethylsilane (0.8 g, 4.6 mmol) were added followed by sodium cyanoborohydride (0.433 g, 6.9 mmol). The mixture was stirred for 7 h then reduced in vacuo. The residue was dissolved in IN HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2 x 10 mL). The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine then dried (MgSO4), filtered and reduced in <n="73"/>vacuo to give crude methyl ester (0.35 g). The crude ester was purified over silica gel eluting with hexane : ethyl acetate (85 : 15 v/v). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium cyanoborohydride; acetic acid;3 A molecular sieve; In methanol; acetic acid; | Example 95 1-Cyclopropyl-4-[5-(4-phenyl-1H-imidazol-2-yl)-pyridin-2-yl]-piperazine: (Reference: Tetrahedron Lett. 1995, 36 (41), 7399) To a solution of 1-[5-(5-phenyl-1H-imidazol-2-yl)-pyridin-2-yl]-piperazine (99 mg, 0.32 mmol) in anhydrous methanol (5 ml) under nitrogen atmosphere was added 3A molecular sieves (50 mg).. This solution was stirred for 5 min, then glacial acetic acid (0.19 ml, 200 mg, 3.3 mmol, 10 equiv), (1-ethoxy-cyclopropoxy)-trimethyl-silane (0.32 ml, 281 mg, 1.62 mmol, 5 equiv), and sodium cyanoborohydride (81 mg, 1.29 mmol, 4.0 equiv) were added.. The reaction was heated at reflux overnight, then cooled to room temperature.. The mixture was filtered, then diluted with an aqueous solution of 1 N NaOH and extracted with ethyl acetate.. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the desired product (74 mg, 66%). MS m/z 346 (M++1). |
66% | With sodium hydroxide; sodium cyanoborohydride;silica gel; In methanol; acetic acid; | EXAMPLE 95 1-Cyclopropyl-4-[5-(4-phenyl-1H-imidazol-2-yl)-pyridin-2-yl]-piperazine: (Reference: Tetrahedron Lett. 1995, 36 (41), 7399) To a solution of 1-[5-(5-phenyl-1H-imidazol-2-yl)-pyridin-2-yl]-piperazine (99 mg, 0.32 mmol) in anhydrous methanol (5 ml) under nitrogen atmosphere was added 3 A molecular sieves (50 mg). This solution was stirred for 5 min, then glacial acetic acid (0.19 ml, 200 mg, 3.3 mmol, 10 equiv), (1-ethoxy-cyclopropoxy)-trimethyl-silane (0.32 ml, 281 mg, 1.62 mmol, 5 equiv), and sodium cyanoborohydride (81 mg, 1.29 mmol, 4.0 equiv) were added. The reaction was heated at reflux overnight, then cooled to room temperature. The mixture was filtered, then diluted with an aqueous solution of 1N NaOH and extracted with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the desired product (74 mg, 66%). MS m/z 346 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 60h; | To a solution of 1-(4-nitrophenyl)piperazine (1.04 g, 5.00 mmol) in methanol (25 mL) under nitrogen was added molecular sieves (1.0 g), acetic acid (3.00 g, 2.86 mL, 50.0 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (5.22 g, 5.99 mL, 30.0 mmol), sodium cyanoborohydride (1.41 g, 22.5 mmol). The mixture was stirred at room temperature for 2.5 d, filtered, and concentrated. To the residue was added water and 1N aq. NaOH to adjust the PH>11. The mixture was extracted ethyl acetate, and the organic layer was dried over Na2SO4, concentrated to give the title compound (1.24 g, 100%) as a yellow solid. MS (ES+): m/z = 247.8. |
100% | With sodium cyanoborohydride; acetic acid; In methanol; at 60 - 65℃; for 4h;Molecular sieve; | F.13 l-Cyclopropyl-4-(4-nitrophenyl)piperazine[0373] A mixture of [(l-ethoxycyclopropyFjoxy] trimethylsilane (4.5 mL. 22.4 mmol, 2 eq.), 1-(4-nitrophenyl)piperazine (2.32 g, 11.1 mmol, acetic acid (6.4 mL, 5 eq.), molecule sieves (3 A, 5 g), and sodium cyanoborohydride (2.1 g, 33.3 mmol, 3 eq.) in dry methanol (50 mL) is heated at 60-65 0C for 4 h. The reaction mixture is filtered, and the filtration is evaporated. The residue is dissolved in DCM (200 mL) and the resulting solution is washed with 2 N NaOH (100 mL), brine (100 mL x T), dried over MgSO4, and evaporated to provide a yellow solid (2.75 g, 100%). The compound is used in the next reaction without further purification. 1H NMR (300 MHz, DMSO-^6), delta 8.02 (d, J = 9.6 Hz, 2H), 7.00 (d, J = 9.6 Hz, 2H), 3.38 - 3.42 (m, 4H), 2.60 - 2.68 (m, 4H), 1.60 -1.67 (m, IH), 0.40 - 0.46 (m, 2H), 0.35 - 0.38(m, 2H). LCMS-ESI (m/z): calcd for C13H17N3O2, 247.1; [M+H]+ found, 248.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium tetrahydroborate; 4 A molecular sieve; acetic acid; In methanol; for 4.5h;Heating / reflux; | To a solution of the product from Part E (10.0 g, 28.4 mmol) in methanol (100 mL) was added acetic acid (16.2 mL, 284 mmol), powdered 4A molecular sieves (9.1 g), and [(1-ethoxycyclopropyl)oxyl trimethyl silane (17.1 mL, 85.2 mmol). Sodium cyanoborohydride (4,82 g, 76.7 mmol) was then added slowly. The reaction was heated at reflux with vigorous stirring for 4.5 hr. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate solution (3×) and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material crystallized upon standing providing 10.9 g (100%) of the alkylated amine compound as a pale yellow oily crystal. ESMS m/z=356 (M+H)+. This material was used without purification. |
88.8% | With sodium tetrahydroborate; 4 A molecular sieve; acetic acid; In methanol; at 20℃; for 6h;Heating / reflux; | To a solution of ethyl 4-[(4-fluorophenyl)sulfonyl]piperidine-4-carboxylate hydrochloride (60.0 g, 170 mmol) in methanol (600 mL), were added acetic acid (97 mL, 1.7 mole), [(1-ethoxycyclopropyl)oxy]trimethylsilane (102 mL, 510 mmol) and 4A molecular sieves (55 g) followed by sodium cyanoborohydride (28.8 g, 459 mmol). The solution was stirred at ambient temperature overnight, then refluxed for 6 hr. The reaction mixture was filtered through celite and concentrated to solid/oil mix. Ethyl acetate and saturated sodium bicarbonate were added very carefully. When aqueous layer stayed basic, the layers were separated and the organic layer was washed 3 times with saturated sodium bicarbonate, then with brine and then dried over sodium sulfate. Concentration in vacuo and crystallization from ethyl acetate/hexane provided the n-cyclopropyl compound as an off white solid (53.8 g, 88.8%). ESMS m/z=356 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium cyanoborohydride; acetic acid; In methanol;Molecular sieve; Heating / reflux; | 3-({2-[4-(BTo a solution of 3-{2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethylamino}-propionic acid ethyl ester (500 mg, 1.29 mmol) in CH3OH (15 mL) was added acetic acid (0.73 mL, 12.9 mmol), 3 molecular sieves and [(1-ethoxycyclopropyl)oxy]trimethylsilane (1.55 mL, 7.7 mmol). Sodium cyanoborohydride (365 mg, 5.8 mmol) was added, and the mixture was heated at reflux overnight. The mixture was cooled, filtered and concentrated. The residue was dissolved in CH2Cl2, and the resulting solution was washed with sat. aq. NaHCO3 then brine, dried, and concentrated. This residue was purified on SiO2 (40 g; 10-50% ethyl acetate/hexanes), giving 374 mg (68% yield) of a colorless oil. MS (ESI): mass calculated for C23H26N2O4S, 426.16; m/z found, 427.1.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.73 (d, J=8.3, 1H), 7.64 (d, J=8.1, 1H), 7.38 (d, J=7.8, 1H), 7.29-7.22 (m, 3H), 6.94 (d, J=9.1, 2H), 4.14 (dd, J=7.1, 7.1, 2H), 4.10 (t, J=6.1, 2H), 3.07 (t, J=7.1, 2H), 3.05 (t, J=6.1, 2H), 2.58 (t, J=7.3, 2H), 1.92-1.86 (m, 1H), 1.26 (t, J=7.1, 3H), 0.54-0.43 (m, 4H). |
68% | With sodium cyanoborohydride; acetic acid;molecular sieve; In methanol;Heating / reflux; | C. C. 3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclopropyl-amino)- propionic acid ethyl ester. To a solution of 3- {2- [4- (BENZOTHIAZOL-2-YLOXY)- PHENOXY]-ETHYLAMINO}-PROPIONIC acid ethyl ester (500 mg, 1.29 MMOL) in CH30H (15 mL) was added acetic acid (0.73 mL, 12.9 MMOL), 3 A molecular sieves and [ (1-ethoxycyclopropyl) oxy] TRIMETHYLSILANE (1.55 mL, 7.7 MMOL). Sodium CYANOBOROHYDRIDE (365 mg, 5.8 MMOL) was added, and the mixture was heated at reflux overnight. The mixture was cooled, filtered and concentrated. The residue was dissolved in CH2CI2, and the resulting solution was washed with sat. aq. NAHCO3 then brine, dried, and concentrated. This residue was purified on SI02 (40 g; 10-50% ethyl acetate/hexanes), giving 374 mg (68% yield) of a colorless oil. MS (ESI) : mass calculated for C23H26N204S, 426.16 ; m/z found, 427.1. 1 [M+H] . H NMR (400 MHz, CDC13) : 7.73 (d, J = 8.3, 1 H), 7.64 (d, J = 8.1, 1 H), 7.38 (d, J = 7.8, 1 H), 7. 29-7. 22 (m, 3H), 6.94 (d, J = 9.1, 2H), 4.14 (dd, J= 7. 1,7. 1,2H), 4.10 (t, J= 6. 1,2H), 3.07 (t, J= 7. 1,2H), 3.05 (t, J = 6.1, 2H), 2.58 (t, J = 7.3, 2H), 1.92-1. 86 (m, 1 H), 1.26 (t, J = 7.1, 3H), 0.54-0. 43 (m, 4H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; at 63℃; for 16h; | To a solution of 1-tert-butyloxycarbonylpiperazine (1.16 g, 6.23 mmol) in THF (10 ml) and methanol (5 ml) were added 1-ethoxy-1-trimethylsilyloxycyclopropane (2.40 ml, 12.0 mmol), acetic acid (0.75 ml), and sodium cyanoborohydride (7.8 ml of a 1M solution in THF, 7.8 mmol), and the mixture was stirred at 63 C. for 16 hours. The mixture was concentrated under reduced pressure, and the residue was mixed with water (20 ml) and potassium carbonate (6.6 g). The product was extracted with ethyl acetate (3×30 ml), the combined extracts were dried over magnesium sulphate, and concentrated under reduced pressure. 1.79 g (100%) of the title compound was obtained as an oil, which completely crystallized after a few hours. 1H NMR (DMSO-d6) delta 0.29 (m, 2H), 0.42 (m, 2H), 1.38 (s, 9H), 1.60 (m, 1H), 2.43 (m, 4H), 3.23 (m, 4H); HPLC-MS: m/z 227 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Example 245 6-chloro-3-[4-[(1-cyclopropylpiperidin-4-yl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (1) Manufacture of 1-cyclopropyl-4-(4-nitrophenoxy)piperidine 4-(4-nitrophenoxy)piperidine (1.92 g, 8.63 mmol) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane (2.27 g, 12.9 mmol) were dissolved in a mixed solvent of acetic acid (20 mL) and methanol (20 mL), sodium cyanoborohydride (1.08 g, 17.3 mmol) was added, and the mixture stirred at 65 C. for 18 hours. The solvent was distilled off under reduced pressure, ethyl acetate and 1N sodium hydroxide aqueous solution were added, the mixture was extracted with ethyl acetate, and the organic phase was washed with distilled water. After drying with anhydrous sodium sulfate, the product was concentrated, and the target compound (1.94 g, 86%) was thus obtained as a light brown oily substance. 4-(4-nitrophenoxy)piperidine was that manufactured in Example 94. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | b N-[S-Acetyl-2'-benzyl-3'-mercaptopropionyl]cystine methyl ester Prepared by Method B of Example 19 but utilising a 1:1 mixture of D and L-cystine methyl ester hydrochlorides (120 mg, 0.35 mmol, L-isomer from Aldrich) and 2-acetylthiomethyl-3-phenylpropanoic acid (150 mg, 0.63 mmol). This afforded the title compound a s a clear oil, an approximately equimolar mixture of diastereoisomers, in 43% overall yield. deltaH (CDCI3) 2.34, 2.35 (6H, 2s, MeCS), 2.60-3.15 (14H, m, CH2 CHCH2, CH2 S), 3.70, 3.74 (6H, 2s, MeO), 4.6-4.8 (1H, m, HCN), 6.35 (2H, bs, NH), 7.15-7.30 (10H, m, Ar-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With toluene-4-sulfonic acid; 1,2-dichloro-benzene; at 100℃; for 4h; | (1 -Ethoxycyclopropoxy)trimethylsilane (7.58 g, 43.5 mmol), 1 - (triphenylphosphoranylidene)propan-2-one (18 g, 56.5 mmol) and p-toluenesulfonic acid (0.75 g, 4.35 mmol), are dissolved in 1 ,2-dichlorobenzene (50 mL), and the mixture is heated to 100 C for 4 h, then cooled to r.t. and directly purified by flash column chromatography on silica gel petroleum ether, DCM) to provide the intermediate 1 - cyclopropylidenepropan-2-one (2.67 g, 64%). |
64% | toluene-4-sulfonic acid; In 1,2-dichloro-benzene; at 100℃; for 4h; | Example 27 2,-((4-Chlorophenyl)amino)-6 8,-dihydro-5,H-spiro[cyclopropane-1,7,-quinazolin]- 5'-one[00167](1 -Ethoxycyclopropoxy)trimethylsilane (7.58 g, 43.5 mmol), 1 - (triphenylphosphoranylidene)propan-2-one (18 g, 56.5 mmol) and p-toluenesulfonic acid (0.75 g, 4.35 mmol) are dissolved in 1 ,2-dichlorobenzene (50 ml_), and the mixture is heated to 100 C for 4 h, then cooled to room temperature and directly purified by flash column chromatography on silica gel (eluent first petroleum ether, then DCM) to provide the intermediate 1 -cyclopropylidenepropan-2-one (2.67 g, 64%). |
44% | With toluene-4-sulfonic acid; In 1,2-dichloro-benzene; at 105℃; for 5h;Autoclave; | Intermediate 1 : -Aminospiro[2.5]non-6-en-5-one -Cyclopropylidenepropan A mixture of 219 g 1 -(triphenylphosphoraniliden)-2-propanone 100 g (1 -Ethoxy- cyclopropoxy)-trimethyl-silane and 13.1 g para-toluenesulfonic acid in 280 ml 1 ,2- Dichlorobenzene is heated in an autoclave to 105C for 5 hours. The this mixture was cooled to room temperature and stirred for 18hours. The product is purified by distillation. Yield: 350 g of a 7% solution (based on 1 H-NMR) in 1 ,2-dichlorobenzene (44 % of theory) |
44% | With toluene-4-sulfonic acid; In 1,2-dichloro-benzene; at 20 - 105℃; for 23h;Autoclave; | Step 1: 1-Cyclopropylidenepropan-2-one A mixture of 219 g 1-(triphenylphosphoraniliden)-2-propanone 100 g (1-Ethoxy-cyclopropoxy)-trimethyl-silane and 13.1 g para-toluenesulfonic acid in 280 ml 1,2-Dichlorobenzene is heated in an autoclave to 105 C. for 5 hours. The this mixture was cooled to room temperature and stirred for 18 hours. The product is purified by distillation. [0259] Yield: 350 g of a 7% solution (based on 1H-NMR) in 1,2-dichlorobenzene (44% of theory) |
a) 1-Ethoxycyclopropanol/1-methoxycyclopropanolA solution of (1-ethoxycyclopropyl)oxy-trimethylsilane (25 ml, 124.9 mmol) in methanol (60 ml) was treated with conc. HCl (3 drops), stirred at 20 C. for 16 h, concentrated at 20 C., and the residue distilled (55 C., 19-20 mbar) to give 1-ethoxycyclopropanol/1-methoxycyclopropanol (92:8, 10.36 g, 82%).1H-NMR (400 MHz, CDCl3): data of 1-Ethoxycyclopropanol: 53.76 (q, 2H, J=8.0, OCH2), 3.44 (s, OH), 1.21 (t, 3H, J=8.0, Me), 0.96-0.89 (m, 4H).b) 1-Cyclopropylidenepropan-2-oneUnder N2, a mixture of 1-ethoxycyclopropanol/1-methoxycyclopropanol (92:8, 10.36 g, 102.4 mmol), 1-triphenylphosphoranylidenepropan-2-one (38.84 g, 121.9 mmol) and benzoic acid (24 g, 10.2 mmol) in anhydrous benzene (500 ml) was refluxed for 20 h and then concentrated. The residue was filtered, and distilled (68 C., 40 mbar) giving 1-cyclopropylidenepropan-2-one (4.35 g, 45%).1H-NMR (400 MHz, CDCl3): delta6.47-6.43 (m, H-C(1)), 2.34 (s, Me), 1.54-1.48 (m, 2H), 1.40-1.32 (m, 2H).13C-NMR (100 MHz, CDCl3): delta198.8 (s, CO), 143.8 (s, C(1)=C), 121.6 (d, C(1)), 27.1 (q, Me), 5.1 (t), 2.6 (t). | ||
2.1 g | With toluene-4-sulfonic acid; In toluene; at 100℃; for 12h; | To 50 g (150 mmol) of acetonyl triphenylphosphonium chloride in 2 L of water is added 10% NaOH solution until the pH reaches 8. The mixture is filtered and filter cake is dried to provide 45 g (140 mmol) of l-(triphenyl- 5-phosphanylidene)propan-2-one (I-AAG). To a mixture of 8.2 g (47 mmol) of (l-ethoxy-cyclopropoxy)-trimethyl-silane in 22 mL of toluene is added 14 g (44 mmol) of I-AAG and 0.8 g (5 mmol) of p-TsOH. The mixture is heated at 100 C for 12 h. The mixture is cooled, concentrated, and purified by flash (0163) chromatography (0-100% CH2CI2 in hexanes to provide 2.1 g (22 mmol) of 1- cyclopropylidenepropan-2-one (I- AAH) . The general method used to prepare I-AAA is used to prepare I-AAF from I-AAH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In dichloromethane | 127 γ-Chloro-3-methyl-5-nitrobenzenebutanoic acid ethyl ester EXAMPLE 127 γ-Chloro-3-methyl-5-nitrobenzenebutanoic acid ethyl ester To a solution of 1-ethoxy-1-trimethylsilyl oxycyclopropane (12 g) in methylene chloride (100 ml) at 0° C. was added a solution of titanium tetrachloride in methylene chloride (1M, 55 ml). The reaction mixture turned to a homogeneous wine-red solution with evolution of heat. The reaction was warmed to room temperature for 30 minutes and cooled back to -50° C. Then a solution of the product from Example 126 (6 g) in methylene chloride (50 ml) was added. The reaction mixture was allowed to warm to room temperature, stirred for 1.5 hours and quenched with saturated ammonium chloride solution. The organic layer was separated, washed with brine, dried, and evaporated affording the desired product (9.4 g) in 96% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 27.5; (1-Ethoxycyclopropoxy)trimethylsilane (3.9 g, 23.4 mmol) is slowly added to a mixture of <strong>[119-34-6]4-amino-2-nitrophenol</strong> (3 g, 19.5 mmol) in AcOH (80 mL) and MeOH (20 mL), and the resulting mixture is heated at 70 C. for 3 h. The reaction mixture is cooled at RT, and evaporated in vacuo, the residue is used further. BF3-EtO2 (3 mL, 23.4 mmol) is added to NaBH4 (889 mg, 23.4 mmol) in THF (20 mL) dropwise at 0 C. Then, the residue in THF (80 mL) is added dropwise at 40 C. over 30 min. After stirring at 0 C. for 2 h, the reaction mixture is quenched with cold water and extracted with EtOAc. The combined organic phases are washed H2O, brine and dried. Concentration under reduce pressure and Silica gel flash chromatography give Intermediate 27.5 as red solid; ES-MS: M+H=195PLC: tRet=3.47. | ||
Intermediate 27.5 EPO <DP n="96"/>(I-Ethoxycyclopropoxy)trimethylsilane (3.9 g, 23.4 mmol) is slowly added to a mixture of 4- amino-2-nitrophenol (3 g, 19.5 mmol) in AcOH (80 ml.) and MeOH (20 ml_), and the resulting mixture is heated at 70 C for 3 h. The reaction mixture is cooled at RT, and evaporated in vacuo, the residue is used further. BF3-EtO2 (3 mL, 23.4 mmol) is added to NaBH4 (889 mg, 23.4 mmol) in THF (20 mL) dropwise at 0 C. Then, the residue in THF (80 mL) is added dropwise at -40 C over 30 min. After stirring at 0 C for 2 h, the reaction mixture is quenched with cold water and extracted with EtOAc. The combined organic phases are washed H2O, brine and dried. Concentration under reduce pressure and Silica gel flash chromatography give Intermediate 27.5 as red solid; ES-MS: M+H = 195PLC: tRe< = 3.47. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Preparation of Intermediate 1-(4-chloro-phenyl)-5-(2-chloro-phenyl)-pyrrolidin-2-one (l-2a):t2aA solution of 5.0 g (36 mmol) of 2-chiorobenzaldehyde in 70 ml dry methylene chloride under nitrogen atmosphere was chilled to -78C and titanium tetrachloride was added (39 ml, 1.0 M in methlene chloride). A solution of 8.6 ml (43 mmol) of [(1-ethoxycyclo- propyl)oxy]trimethylsilane in 25 ml dry methylene chloride was added over 10 minutes. After 20 minutes, the reaction was allowed to warm to 0C for 1 hour and allowed to warm to room temperature overnight. The mixture was poured into 100 ml of satd ammonium chloride, the layers were separated and the aqueous phase extracted with methylele chloride (2x). The combined organic layers were dried (magnesium sulfate), filtered and evaportated to give 8.7 g (100%) of ethyl 4-(2-chloro-phenyl)-4-hydroxy-butyrate of sufficient purity for use in the next step. Ethyl 4-(2-chloro-phenyl)-4-hydroxy-butyrate (9.9 g, 41 mmol) and 7.8 g (61 mmol) of 2- chloroaniline were heated under nitrogen until the mixture melted. Seven drops of concentrated sulfuric acid was added carefully, and the mixture heated at 18O0C (external temperature, sand bath) for 4 hours. The mixture was cooled to room temperature, dissolved in methylene chloride EPO <DP n="28"/>and washed with 1 M HCI. The organic layer was dried (magnesium sulfate), filtered and evaporated. Purification by silica gel MPLC with chloroform gave 5.63 g (45%) of the title compound (L2a). MH+ 307. 1 H NMR (CDCI3): 52.05 (m, 1 H)1 2.6-2.85 (m, 3H), 5.76 (dd, J = 7.6, 5.6, 1 H), 7.1 -7.5 (m, 8H). | |
60% | With titanium tetrachloride; In dichloromethane; at -78 - 20℃; for 18.5h; | The title compound was prepared by a similar method to Intermediate 1.To a solution of 2-chlorobenzaldehyde (1.5 g, 10.71 mmol) in DCM (12 mL), was added dropwise TiCL4 (11.8 mL, 1M in DCM) and [(l-ethoxycyclopropyl)oxy](trimethyl)silane (2.6mL, 12.8 mmol) at -78C. After stirring at -78C for 30 mm, the reaction was warmed r.t for 1 8h. The reaction was quenched by addition of sat. aq. NH4C1 (5 mL). The aq. layer was extracted by DCM (2 x 10 mL) and dried (Na2SO4), concentrated in vacuo. The residue was purified by column chromatography (Si02, 0-10 % EtOAc/hexanes), yieldingthe title compound as a yellow oil (1.4 g, 60%). LCMS (ESj 243.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; In methanol; at 60℃; for 24h; | 5g of 4-hydroxypiperidine were dissolved in methanol. 23.8 ml_ of 1[(1- ethoxycyclopropyl)oxy]trimethylsilane and 5.8 g of sodium cyano borohydride were added and the mixture was reacted at 600C for 12h. The same amounts of the two reagents were added again and stirring was continued at 600C for another 12h.The mixture was diluted with methanol, filtered over celite and evaporated to dryness.The residue was taken up in ethyl acetate, extracted twice with 2N sodium hydroxide and once with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography to yield 2g of product 20, MS: 141 (M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | A mixture of compound 1-5 (0.5 g, 1.25 mmol) and l-ethoxy-l-[(trimethylsilyl)oxy]- cyclopropane (0.260 ml, 0.0013 mol) in MeOH (methanol; 6 ml) and acetic acid (0.2 ml) was stirred at room temperature for 30 minutes. Then sodium cyanoborohydride (0.113 g, 0.0018 mol) was added. The reaction mixture was heated at 80 0C for 24 hours. Then NaHCO3 (aqueous saturated solution) and NH4OH (30 %) were added. The mixture was extracted with DCM. The separated organic layer was dried (Na2SO4) and the solvent was evaporated. The residue was purified by flash column chromatography <n="47"/>over silica gel (eluent: DCM/MeOH 95/5 and DCM/(MeOH/NH3) 95/5. The desired fractions were collected and the solvent was evaporated. The residue was treated with ethyl ether, yielding 0.470 g of compound 1-9 (86%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; dichloromethane; at 20 - 60℃; for 18h; | A solution of ethyl 4-(1,4-diazepan-1-yl)benzoate (0.621 g, 2.5 mmol), (1-ethoxycyclopropoxy)trimethylsilane (2.51 mL, 12.50 mmol) and acetic acid (0.286 mL, 5.00 mmol) in tetrahydrofuran (50 mL), methanol (5 mL) was treated with sodium cyanoborohydride (0.393 g, 6.25 mmol) at 20 C. The resulting solution was stirred at 60 C. for 18 h. The reaction mixture was cooled, filtered and evaporated to dryness. 1N HCl (40 ml) and water (60 ml) were added and the solution extracted with ethyl acetate (3×50 ml). The aqueous layer was basified to pH 10 with solid potassium carbonate and extracted with ethyl acetate (4×50 ml). The organic extracts washed with saturated NaCl (50 ml) and dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-cyclopropyl-1,4-diazepan-1-yl)benzoate (0.849 g, 118%) as a colourless oil. 1H NMR (399.9 MHz, CDCl3) delta 0.33 (1H, t), 0.34-0.35 (1H, m), 0.36-0.41 (1H, m), 0.37-0.40 (1H, m), 1.29 (3H, t), 1.74-1.79 (1H, m), 1.84-1.90 (2H, m), 2.69 (2H, t), 2.86 (2H, t), 3.47 (2H, t), 3.49 (2H, t), 4.24 (2H, q), 6.58 (1H, d), 6.60 (1H, s), 7.81-7.84 (2H, m). MS: m/z 289 (MH+) (ESI+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; acetic acid In methanol at 50℃; for 24h; | 74.a a) 1 -cyclopropyl-4-(4-nitro-phenyl)-piperidine0.50 g 4-(4-nitro-phenyl)-piperidine are dissolved in 1.5 mL methanol and combined with0.80 g sodium cyanoborohydride and 2 μL glacial acetic acid. Then 0.97 mL [(l-ethoxycyclopropyl)oxy]trimethylsilane are added and the mixture is stirred for 24 h at 500C. After cooling, 100 mL potassium hydrogen sulphate solution (10%) are added and the mixture is extracted twice with dichloromethane. The combined organic phases are dried, the solvent is eliminated in vacuo. The residue is used in the next stage of the synthesis without any further purification. Yield: 0.57 g | |
Stage #1: [(1-Ethoxycyclopropyl)oxy]trimethylsilane; 4-(4-Nitrophenyl)piperidine With acetic acid In methanol at 20℃; for 0.666667h; Stage #2: With sodium cyanoborohydride at 65℃; | 206 11293] 4-(4-Nitrophenyl)piperidine (1.00 g, 4.85 mmol) was dissolved in 80 mE MeOH and 2 mE HOAc. To it was added (1 -ethoxycycloproxy)trimethylsilane, and the mixture was stirred at RT for 40 mm To it was then added NaI3H3CN (1.83 g, 29.0 mmol), andthe mixture was stirred in 65°C. bath for overnight. It was concentrated in vacuo to dryness, diluted with 120 mE EtOAc, washed with iN NaOH and water x2, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 4% MeOh in DCM to isolate 1 -cyclopropyl-4-(4-nitrophenyl)piperidine (256). It was dissolved in 50 mE EtOAc. To it was added 10% Pd/C (0.5 g), andthe mixture was hydrogenated using a H2 balloon at RT for overnight. The mixture was filtered through celite, and concentrated in vacuoto give 4-(1 -cyclopropylpiperidin-4-yl)aniline (257) (960 mg, 91% overall) as a white solid. | |
Stage #1: [(1-Ethoxycyclopropyl)oxy]trimethylsilane; 4-(4-Nitrophenyl)piperidine With acetic acid In methanol at 20℃; for 2h; Stage #2: With sodium cyanoborohydride In methanol at 65℃; for 16h; | 237 11377] 4-(4-Nitrophenyl)piperidine (3.0 g, 14.5 mmol) was dissolved in 200 mE MeOH and 6 mE acetic acid. To it was added (1 -ethoxycycloproxy)trimethylsilane (8.8 mE, 43.6 mmol), and the mixture was stirred at RT for 2 hours. To it was then added NaI3H3CN (5.5 g, 87.3 mmol), and the mixture was sent to 65° C. bath with a condenser attached. The reaction was found cleanly complete in 16 hours. The mixture was concentrated on a rotavap, and EtOAc was poured into the residue. The organic mixture was washed with iN NaOH and water (x2), dried over MgSO4, concentrated on rotavap and subjected to silica flash column using 0 to 4% MeOH in DCM to isolate 1 -cyclopropyl-4-(4-nitrophenyl)piperidine (321) as a thick oil. It was dissolved in 300 mE iPrOH. To it were added 40 IL 6N HC1 and 10% Pd/C (1.0 g). The mixture was hydrogenated at 40 psi on a Parr shaker for 16 hours. It was filtered through celite, and the solid cake was thoroughly rinsed with MeOH. The filtrate was concentrated in vacuo to yield 4-(1 -cyclopropylpiperidin-4-yl)aniline (322, HC1 salt) as a white solid (3.06 g, 83% for two steps). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Example 2 N-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-cyclopropylpiperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide Acetic acid (0.075 mL, 1.3 mmol) was added to a solution of N-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide (50 mg, 0.13 mmol) in methanol (2 mL) and the then (1-ethoxycyclopropoxy)trimethylsilane (138 mg, 1.79 mmol) was added to the reaction solution and reaction mixture was stirred at room temperature for 10 min, then sodium cyanoborohydride (37 mg, 0.59 mmol) was added carefully. The reaction mixture was stirred at 50 C. 24 hours. Saturated sodium bicarbonate solution (10 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, dried over MgSO4, and concentrated. Product was purified by Companion (ReadySep, 12 g, silica gel packed) with CH3OH/CH2Cl2 from 1%-5% to give the named compound as a white solid 46 mg (85%). LC-MS: 419.2, 417.3 (t=1.7 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; at 60℃; for 24h; | A sample of <strong>[17680-55-6]7-bromo-1,2,3,4-tetrahydroisoquinoline</strong> hydrochloride (1.31 g, 5.27 mmol) was partitioned between 1.0 N NaOH (10 mL) and EtOAc (30 mL). The organic layer was concentrated. A solution of the resulting free amine in MeOH (7 mL), THF (7 mL) and acetic acid (1.5 mL) was treated with (1-ethoxy-cyclopropoxy)-trimethyl-silane (1.84 g, 10.5 mmol) followed by sodium cyanoborohydride (1.09 g. 17.4 mmol). The mixture was heated at 60 C. for 24 h. The mixture was partitioned between EtOAc and satd. aq. NaHCO3. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried and concentrated. Purification of the residue (SiO2; hexanes to 30% EtOAc/hexanes) afforded the desired product (1.17 g, 88%). 1H NMR (CDCl3): 7.22 (dd, J=8.2, 2.0, 1H), 7.18-7.15 (m, 1H), 6.94 (d, J=8.2, 1H), 3.74 (s, 2H), 2.90 (t, J=5.9, 2H), 2.80 (t, J=5.9, 2H), 1.82-1.74 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In methanol; at 20 - 69℃; for 3h;Heating / reflux; | To a solution of 4-bromo-2-chloroaniline [C.A.S. 38762-41-3], (1 g, 4.843 mmol) in AcOH (19 ml) and MeOH (10 mL) stirred at room temperature and under nitrogen atmosphere was added dropwise (1-ethoxycyclopropyloxy-trimethylsilane [C.A.S. 27374-25-0] (1.199 ml, 5.57 mmol). The reaction mixture was then refluxed at 67-69 0C for 3 h. The mixture was then concentrated in vacuo to yield intermediate D30'. In another flask, NaBH4 (0.366 g, 9.687 mmol) was suspended in THF (10 mL) and cooled to 50C. Then, BF3-Et2O complex (1.228 ml, 9.687 mmol) was added dropwise. The resulting reaction mixture was stirred under a N2 atmosphere at 5 0C for 1 h. Then, to this mixture was added a solution of D30' in THF (5 mL) dropwise at 5-10 0C over 20 min. After stirring at r.t. for 5 h., at reflux temperature for 2 h., and then removing THF by distillation, the mixture was cooled to r.t. and poured into water. The resulting mixture was extracted with Et2O. The organic layer was washed with water and dried (Na2SO4) followed by the removal of the volatiles under vacuo. The crude product thus obtained was purified by column chromatography (silica gel; Heptane/EtOAc 99:1 as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D30 (0.390 g, 32.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Stage #1: 2-(1,3-dimethylbutyl)-aniline; [(1-Ethoxycyclopropyl)oxy]trimethylsilane With acetic acid In methanol at 20℃; for 0.333333h; Molecular sieves 3Å; Stage #2: With sodium cyanoborohydride In methanol at 20 - 50℃; for 16h; | III-1 Example (III-1) At room temperature, 1.7 ml (30.0 mmol) of acetic acid and 627.5 mg (3.6 mmol) of [(1-ethoxycyclopropyl)oxy](trimethyl)silane are added to a solution consisting of 531.9 mg (3.0 mmol) of 2-(1,3-dimethylbutyl)aniline in 5 ml of methanol over 1.0 g of 3 Å molecular sieve. The reaction mixture is stirred at room temperature for 20 minutes, and 1.04 g (16.5 mmol) of sodium cyanoborohydride are then added. The reaction mixture is stirred at 50° C. for 16 hours. At room temperature, 10 ml of water are added. The reaction mixture is filtered and the filtrate is concentrated. 10 ml of 1 mol/l aqueous sodium hydroxide solution are added to the residue, and the mixture is extracted 3 times with in each case 20 ml of diethyl ether. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. This gives, after column chromatography (gradient cyclohexane/ethyl acetate), 220.0 mg (1.0 mmol, 34% of theory) of N-cyclopropyl-2-(1,3-dimethylbutyl)aniline [log P (pH 2.3) 5.33]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Example 2584-(3-(4-Cvclopropylpiperazin-1-yl)-5-fluorophenyl)-N-(4-(3-(trifluoromethyl)-lH-1,2,4- triazol-1-yl)phenyl)pyrimidin-2-aminePart I: l-(3-Bromo-5-fluorophenyl)-4-cyclopropylpiperazine[0456] To mixture of l-(3-bromo-5-fluorophenyl)piperazine (2.91 g, 11 mmol) in MeOH (50 rnL) was added (l-ethoxycyclopropoxy)trimethylsilane (13.5 rnL, 67.2 mmol), acetic acid (6.5 mL, 112 mmol) and NaBCNH4 (1.0 M in THF) (51 mL, 50.4 mmol). The resulting mixture was heated to 70 C overnight and concentrated in vacuuo to give crude residue which was diluted with EtOAc and washed with 1 N NaOH followed by brine. The organic layer was separated, dried with anhydrous MgSO4, filtered and concentrated in vaccuo to give desired l-(3-bromo-5-fluorophenyl)-4-cyclopropylpiperazine in quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | [(1-Ethoxycyclopropyl)oxy](trimethyl)silane (5.6 mL, 27.85 mmol) was added drop wise over 10 minutes to a stirred solution of 4-bromo-2-chloroaniline (5.0 g, 24.22 mmol) in a mixture of methanol (50 mL) and acetic acid (95 mL) and the resulting solution was heated to 70 oC and stirred at this temperature for 4 hours. After this time, the reaction mixture was cooled to room temperature and concentrated. The resulting residue was then dissolved in THF (25 mL) and added drop wise to a cooled (0 oC), stirred solution of sodium borohydride (1.87 g, 49.4 mmol) and (diethyl ether)(trifluoro)boron (6.2 mL, 48.9 mmol) in THF (50 mL). The resulting mixture was then heated to 70 oC and stirred at this temperature for 4 hours before being cooled to room temperature and allowed to stand overnight. The resulting reaction mixture was quenched by the addition of water (100 mL) before being extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed sequentially with water (100 mL) and brine (100 mL) before being dried (MgS04), filtered and concentrated. The resulting residue was purified on a Biotage isolera (5% ethyl acetate, 95% heptanes) to give the desired compound (4.8 g, 76% yield) as a colourless oil. Tr = 2.44min m/z (ES+) (M+H+) 246/248. | |
32.6% | To a solution of 4-bromo-2-chloroaniline (C.A.S. 38762-41-3), (1 g, 4.843 mmol) inAcOH (19 ml) and MeOH (10 mL) was added [(1-ethoxycyclopropyl) oxy]- trimethylsilane (1.199 ml, 5.57 mmol) dropwise at r.t. The reaction mixture was then refluxed at 67-69 C for 3 h. under a N2 atmosphere. The mixture was then concentrated in vacuo to obtain a crude oil. Into a 200 mL four-necked flask fitted with a reflux condenser, a mechanical stirrer and a thermometer were added NaBH4 (0.366 g, 9.687 mmol) and anhydrous THF (10 mL). After cooling to 5 0C, BF3 Et2O complex (1.228 ml, 9.687 mmol) was added dropwise and the mixture stirred under a N2 atmosphere at 5 C for 1 h. The crude oil dissolved in THF (5 mL), was added dropwise at 5-10 C over 20 min. After stirring at r.t. for 5 h, at reflux for 2 h. and then removing THF by distillation, the mixture was cooled to r.t. and poured into water. The resulting mixture was extracted with Et2O. The Et2O layer was washed with water and dried (Na2SO4) followed by the removal of Et2O in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; Heptane/AcOEt 99:1 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D34 (0.390 g, 32.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | A mixture of 2-(6,6-dimethyl-2-oxomorpholin-3-yl)-A/-(4-isopropylphenyl)acetamide (0.080 g; 0.263 mmol), 3A molecular sieves, (l-ethoxycyclopropoxy)trimethylsilane (0.211 mL; 1.049 mmol), sodium cyanoborohydride (0.050 g; 0.796 mmol) and acetic acid (0.151 mL; 2.638 mmol) in tetrahydrofuran (3 mL) was stirred at room temperature for 22 h and refluxed for 4 h. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (20 - 60%) in heptane to give 0.047 g (52%) of the title compound as a white powder.1H NMR (CDCI3) delta 0.33 (1 H, m); 0.56 (1 H, m); 0.72 (1 H, m); 0.82 (1 H, m); 1.22 (6H, d); 1.39 (3H, s); 1.41 (3H, s); 1.77 (1 H, m); 2.63 (1 H, d); 2.86 (1 H, m); 3.01 (1 H, m); 3.16 (2H, m); 3.62 (1 H, m); 7.16 (2H, d); 7.38 (2H, m); 7.86 (1 H, brs).ESI/APCI(+): 345 (M+H); 367 (M+Na); 711 (2M+Na).ESI/APCI(+): 343 (M+H). | |
52% | With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; at 20℃; for 26h;Molecular sieve; Reflux; | A mixture of 2-(6,6-dimethyl-2-oxomorpholin-3-yl)-N-(4-isopropylphenyl)acetamide (0.080 g; 0.263 mmol), 3 molecular sieves, (1-ethoxycyclopropoxy)trimethylsilane (0.211 mL; 1.049 mmol), sodium cyanoborohydride (0.050 g; 0.796 mmol) and acetic acid (0.151 mL; 2.638 mmol) in tetrahydrofuran (3 mL) was stirred at room temperature for 22 h and refluxed for 4 h. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (20-60%) in heptane to give 0.047 g (52%) of the title compound as a white powder.1H NMR (CDCl3) delta 0.33 (1H, m); 0.56 (1H, m); 0.72 (1H, m); 0.82 (1H, m); 1.22 (6H, d); 1.39 (3H, s); 1.41 (3H, s); 1.77 (1H, m); 2.63 (1H, d); 2.86 (1H, m); 3.01 (1H, m); 3.16 (2H, m); 3.62 (1H, m); 7.16 (2H, d); 7.38 (2H, m); 7.86 (1H, brs).ESI/APCx+): 345 (M+H); 367 (M+Na); 711 (2M+Na).ESI/APCx+): 343 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: [(1-Ethoxycyclopropyl)oxy]trimethylsilane With titanium tetrachloride at 20℃; Stage #2: With titanium(IV) tert-butoxide Stage #3: (E)-non-6-enal |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium cyanoborohydride; acetic acid In methanol at 70℃; for 3.5h; Molecular sieve; | 2.3 2.3/4-Cyclopropyl-morpholine-3-carboxamide; 2.9 g of molecular sieve 3A, 4.3 g (72 mmol) of acetic acid, 7.6 g (43.2 mmol) of 2(1-ethoxy-cyclopropyl)oxy]trimethylsilane and 4.4 g (31.7 mmol) of sodium cyanoborohydride are added successively to 1.2 g (7.2 mmol) of morpholine-3-carboxylic acid amide hydrochloride (WO2005026156 Hennequin L. F. A. et al.) in solution in methanol (36 ml). The reaction mixture is heated at 70° C. for 3.5 hours, then cooled to room temperature and filtered. The filtrate is concentrated under reduced pressure, then the residue is taken up in dichloromethane (200 ml) and washed 3 times with an aqueous solution of NaOH (1N) (100 ml). The organic phase is dried over Na2SO4, filtered and then concentrated under reduced pressure. 0.58 g of product is obtained, in the form of a white powder. Yield 47%. Melting point 116° C. MH+: 171 (Tr: 1.03 min, condition 2).1H NMR (250 MHz, DMSO-d6), δ (ppm):7.33 (s, 1H); 6.98 (s, 1H); 3.67-3.43 (m broad, 4H); 2.97 (dd, 2H, 7.3-3.6 Hz); 2.35 (ddd, 1H, 11.7-8.3-3.4 Hz); 1.89 (ddd, 1H, 10.3-6.6-3.6 Hz); 0.56-0.22 (m broad, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With methanol; sodium cyanoborohydride; In acetic acid; at 20℃;Molecular sieve; Reflux; | Step 2: [2-(4-Cyclopropylpiperazin-1-yl)pyridin-4-yl]methanol 13.1 g (67.9 mmol) of the compound from Example 32A/Step 1 were dissolved in a mixture of 535 ml of methanol and 39 ml (679 mmol) of acetic acid. 9.2 g of molecular sieve (3 A) and 82 ml (407 mmol) of [(1-ethoxycyclopropyl)oxy](trimethyl)silane were added. After 10 min of stirring at RT, 12.8 g (203 mmol) sodium cyanoborohydride were added and, with stiffing, the mixture was heated at reflux for 2 h. After cooling to RT, the solid formed was filtered off and washed twice with in each case 20 ml of methanol. The filtrate was concentrated and the residue was taken up in 550 ml of dichloromethane. The mixture was washed twice with in each case 500 ml of saturated aqueous sodium bicarbonate solution and once with 500 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was purified by column chromatography (silica gel, mobile phase dichloromethane/methanol 95:5). Drying under reduced pressure gave 9.59 g (61% of theory) of the title compound. 1H NMR (400 MHz, CDCl3, delta/ppm): 8.13 (d, 1H), 6.67 (s, 1H), 6.57 (d, 1H), 4.63 (s, 2H), 3.58-3.46 (m, 4H), 2.77-2.66 (m, 4H), 1.70-1.60 (m, 1H), 0.55-0.41 (m, 4H). LC/MS (Method 5, ESIpos): Rt=0.17 min, m/z=234 [M+H]+. |
61% | Step 2: [2-(4-Cyclopropylpiperazin-1-yl)pyridin-4-yl]methanol 13.1 g (67.9 mmol) of the compound from Example 135A/step 1 were dissolved in a mixture of 535 ml of methanol and 39 ml (679 mmol) of acetic acid. 9.2 g of molecular sieve (3 A) and 82 ml (407 mmol) of [(1-ethoxycyclopropyl)oxy](trimethyl)silane were added. After stirring at RT for 10 min, 12.8 g (203 mmol) of sodium cyanoborohydride were added and the mixture was heated under reflux for 2 h, while stirring. After cooling to RT, the solid present was filtered off and rinsed twice with 20 ml of methanol each time. The filtrate was concentrated and the residue was taken up in 550 ml of methylene chloride. The mixture was washed twice with 500 ml of saturated aqueous sodium bicarbonate solution each time and once with 500 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of column chromatography (silica gel, mobile phase: methylene chloride/methanol 95:5). After drying in vacuo, 9.59 g (61% of th.) of the title compound were obtained. 1H-NMR (400 MHz, CDCl3, delta/ppm): 8.13 (d, 1H), 6.67 (s, 1H), 6.57 (d, 1H), 4.63 (s, 2H), 3.58-3.46 (m, 4H), 2.77-2.66 (m, 4H), 1.70-1.60 (m, 1H), 0.55-0.41 (m, 4H). LC/MS (method I, ESIpos): Rt=0.17 min, m/z=234 [M+H]+. | |
61% | 13.1 g (67.9 mmol) of the compound from Example 5A/step 1 were dissolved in a mixture of 535 ml of methanol and 39 ml (679 mmol) of acetic acid. 9.2 g of molecular sieve (3 A) and 82 ml (407 mmol) of [(1-ethoxycyclopropyl)oxy](trimethyl)silane were added. After stirring at RT for 10 min, 12.8 g (203 mmol) of sodium cyanoborohydride were added and the mixture was heated under reflux for 2 h, while stirring. After cooling to RT, the solid present was filtered off and rinsed twice with 20 ml of methanol each time. The filtrate was concentrated and the residue was taken up in 550 ml of dichloromethane. The mixture was washed twice with 500 ml of saturated aqueous sodium bicarbonate solution each time and once with 500 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was purified by means of column chromatography (silica gel, mobile phase: dichloromethane/methanol 95:5). Drying under reduced pressure gave 9.59 g (61% of theory) of the title compound. 1H NMR (400 MHz, CDCl3, delta/ppm): 8.13 (d, 1H), 6.67 (s, 1H), 6.57 (d, 1H), 4.63 (s, 2H), 3.58-3.46 (m, 4H), 2.77-2.66 (m, 4H), 1.70-1.60 (m, 1H), 0.55-0.41 (m, 4H). LC/MS (Method 3, ESIpos): Rt=0.17 min; m/z=234 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With acetic acid; at 20.0℃; for 1.16667h;Molecular sieve; Reflux; | Example 65 1-Cyclopropyl-4-{4-[(5-methyl-3-{3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-1H-pyrazol-1-yl)methyl]pyridin-2-yl}piperazine 66 ml (1.15 mmol) of glacial acetic acid, 13.9 g of dried, powdered molecular sieve (3 A) and 139 ml (0.692) of 1-ethoxy-1-(trimethylsilyl)oxycyclopropane were added successively to a solution of 56.0 g (0.115 mol) of the compound from Example 64 in 1.13 l of methanol. After stirring at RT for 10 min, 21.7 g (0.346 mol) of solid sodium cyanoborohydride were added. The mixture was then heated under reflux for 1 h. After cooling to RT, the undissolved material was filtered off with suction and the filtrate was concentrated on a rotary evaporator. The residue obtained was taken up in 1 l of ethyl acetate and the mixture was washed twice with approx. 750 ml of saturated sodium bicarbonate solution each time and then with approx. 750 ml of saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture was filtered and the filtrate was freed from the solvent on a rotary evaporator. The residue (53 g) was recrystallized from a boiling mixture of 293 ml of ethanol and 59 ml of water. When the crystallization was complete (after approx. 20 h at RT), the mixture was filtered with suction. The solid was washed with 36 ml of ethanol/water (5:1) and then dried under a high vacuum. 26.4 g of the title compound were obtained as the first batch in this way. The mother liquor of the crystallization was concentrated on a rotary evaporator. A further 20.3 g of the product were obtained in the form of the formate salt by means of preparative HPLC (method N). For liberation of the base, a suspension of this formate in 1 l of ethyl acetate was washed successively with approx. 200 ml each of saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture was filtered and the filtrate was freed from the solvent on a rotary evaporator. The residue (13 g) was recrystallized from a boiling mixture of 80 ml of ethanol and 16 ml of water. When the crystallization was complete (after approx. 4 h at RT), the mixture was filtered with suction and the solid was dried under a high vacuum. A further 11.2 g of the title compound were obtained in this manner (yield in total 37.6 g, 62% of th.). Melting point: 140 C. 1H-NMR (400 MHz, CDCl3, delta/ppm): 8.26 (d, 2H), 8.13 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.33 (d, 1H), 6.32 (s, 1H), 5.35 (s, 2H), 3.47 (dd, 4H), 2.69 (dd, 4H), 2.30 (s, 3H), 1.65-1.60 (m, 1H), 0.48-0.42 (m, 4H). LC/MS (method D, ESIpos): Rt=1.91 min, m/z=526 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium cyanoborohydride; acetic acid; In ethanol; at 60℃; | Stir the mixture of 4-(3-nitro-5-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine (150 mg, 0.55 mmol), (1-ethoxycyclopropoxy)trimethylsilane (700 mg, 2.4 mmol), sodium cyanoborohydride (200 mg, 3.3 mmol) and acetic acid (240 mg, 4.0 mmol) in ethanol (10 mL) at 60 C. overnight. Concentrate the mixture to get a residue, partition between EtOAc and water, collect the organic layer, wash with water and brine sequentially, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to give the product as a yellow solid (135 mg, 79%). MS: (M+1): 313.1. |
135 mg | With sodium cyanoborohydride; acetic acid; In ethanol; at 60℃; | Stir the mixture of 4-(3-nitro-5-(trifluoromethyl)phenyl)-l,2,3,6-tetrahydropyridine (150 mg, 0.55 mmol), (l-ethoxycyclopropoxy)trimethylsilane (700 mg, 2.4 mmol), sodium cyanoborohydride (200 mg, 3.3 mmol) and acetic acid (240 mg, 4.0 mmol) in ethanol (10 mL) at 60C overnight. Concentrate the mixture to get a residue, partition between EtOAc and water, collect the organic layer, wash with water and brine sequentially, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to give the product as a yellow solid (135 mg, 79%). MS: (M+l): 313.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; methanol; at 60℃; for 16h; | To a solution of ethyl l-(piperazin-l-yl)cyclopropanecarboxylate hydrochloride (12.8 g, 54.5 mmol) in a mixture of anhydrous THF (68 mL) and methanol (68 mL) (l-ethoxycyclopropoxy)trimethylsilane (21.9 ml, 108.9 mmol) and acetic acid (10 mL) were added. Then sodium cyanoborohydride (5.14 g, 81.8 mmol) was added in portions. After the addition, the mixture was stirred at 60 C for 16 h. TLC (dichloromethane:methanol = 4:1,f= 0.9) showed that the reaction was complete. It was cooled to 18 C and quenched with water (5 mL). It was concentrated to dryness and the residue was partitioned between dichloromethane (100 mL) and aqueous saturated sodium hydrogen carbonate (20 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were washed with water (15 mL) and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:EtOAc = 20:1 to 8:1) to give ethyl 1- (4-cyclopropylpiperazin-l-yl)cyclopropanecarboxylate (12 g, 92%) as a light yellow oil.1H-NMR (400MHz, methanol-d4): delta [ppm] = 0.40-0.45 (m, 4H), 0.91-0.97 (m, 2H), 1.19-1.28 (m, 5H), 1.58-1.66 (m, 1H), 2.40-2.70 (m, 4H), 2.87-3.09 (m, 4H), 4.10 (q, 2H). |
92% | With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; at 60℃; for 16h; | To a solution of ethyl l-(piperazin-l-yl)cyclopropanecarboxylate hydrochloride (12.8 g, 54.5 mmol) in a mixture of anhydrous THF (68 mL) and methanol (68 mL) (l-ethoxycyclopropoxy)trimethylsilane (21.9 ml, 108.9 mmol) and acetic acid (10 mL) were added. Then sodium cyanoborohydride (5.14 g, 81.8 mmol) was added in portions. After the addition, the mixture was stirred at 60 C for 16 h. TLC (dichloromethane:methanol = 4:1, f = 0.9) showed that the reaction was complete. It was cooled to 18 C and quenched with water (5 mL). It was concentrated to dryness and the residue was partitioned between dichloromethane (100 mL) and aqueous saturated sodium hydrogen carbonate (20 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were washed with water (15 mL) and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:EtOAc = 20:1 to 8:1) to give ethyl 1- (4-cyclopropylpiperazin-l-yl)cyclopropanecarboxylate (12 g, 92%) as a light yellow oil. 1H-NM (400MHz, methanol-d4): delta [ppm] = 0.40-0.45 (m, 4H), 0.91-0.97 (m, 2H), 1.19-1.28 (m, 5H), 1.58-1.66 (m, 1H), 2.40-2.70 (m, 4H), 2.87-3.09 (m, 4H), 4.10 (q, 2H). |
92% | With methanol; sodium cyanoborohydride; acetic acid; In tetrahydrofuran; at 60℃; for 16h; | To a solution of ethyl 1-(piperazin-1-yl)cyclopropanecarboxylate hydrochloride (12.8 g, 54.5 mmol) in a mixture of anhydrous THE (68 mL) and methanol (68 mL) (1-ethoxycyclopropoxy)trimethylsilane (21.9 ml, 108.9 mmol) and acetic acid (10 mL) were added. Then sodium cyanoborohydride (5.14 g,81.8 mmol) was added in portions. After the addition, the mixture was stirred at 60C for 16 h. TLC(dichloromethane:methanol = 4:1, Rf= 0.9) showed that the reaction was complete. It was cooled to18 C and quenched with water (5 mL). It was concentrated to dryness and the residue waspartitioned between dichloromethane (100 mL) and aqueous saturated sodium hydrogen carbonate(20 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (100mL). The combined organic layers were washed with water (15 mL) and concentrated to dryness. Theresidue was purified by column chromatography on silica gel (PE:EtOAc = 20:1 to 8:1) to give ethyl 1- (4-cyclopropylpiperazin-1-yl)cyclopropanecarboxylate (12 g, 92%) as a light yellow oil.?H-NMR (400MHz, methanol-d4): 6 [ppm] = 0.40-0.45 (m, 4H), 0.91-0.97 (m, 2H), 1.19-1.28 (m, 5H), 1.58-1.66 (m, 1H), 2.40-2.70 (m, 4H), 2.87-3.09 (m, 4H), 4.10 (q, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With titanium tetrachloride In dichloromethane at -78 - 20℃; for 18.5h; | 1 Ethyl 4-(2,5 -dimethylphenyl)-4-hydroxybutanoate To a solution of 2,5-dimethylbenzaldehyde (5.00 g, 37.27 mmol) in DCM (75 mL) at -78°C was added TiC14 (41.0 mL, 40.99 mmol, 1 M in DCM). A solution of (1- ethoxycyclopropoxy)-trimethyl-silane (7.79 g, 44.72 mmol) in DCM (30 mL) was added and the reaction was stirred at -78°C for 30 mm and warmed to r.t. for 18 h. The reactionwas treated with a sat. aq. solution of NH4C1 (100 mL) and extracted with DCM (100 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to afford the title compound (8.25 g, 94 %). 1H NMR (400 MHz, CDC13) ö 7.31 (m, 1 H), 7.06 (m, 2 H), 5.26 (m, 1 H), 4.15 (m, 3 H), 2.57 (m, 2 H), 2.39 (m, 8 H), 1.28 (m, 3 H). GC-MS mlz 218.1 (M-18). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium cyanoborohydride; acetic acid; In methanol; at 0 - 65℃; for 4h; | (1-Ethoxycyclopropoxy)trimethylsilane (977 mg, 5.6 mmol) was slowly added to the solution of <strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydroisoquinoline</strong> (33.1) (460 mg, 2.6 mmol), NaBH3CN (980 mg, 15.6 mmol), and acetic acid (1.6 g, 25.9 mmol) in MeOH (20 mL) at 0 C. The resulting mixture was heated at 65 C for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated to afford the crude product. The crude product was purified by column chromatography (ethyl acetate/hexane: 1/5) to afford 2-cyclopropyl-7-nitro-1,2,3,4- tetrahydroisoquinoline (48.1) as a yellow solid (500 mg, 88%). [00684] LCMS: 219.1 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; at 60℃; for 16h;Inert atmosphere; | A MeOH (15 ml)/THF (15 ml) solution of 3-Boc-3,6-diaza-bicyclo[3.1.1]heptane (2.5 g, 12.6 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (5.1 ml, 25 mmol) in a 200-ml recovery flask was treated with sodiumcyanoborohydride (1.189 g, 18.91 mmol) and acetic acid (3.6 ml, 63 mmol). The colorless solution was flushedwith N2 and was then heated to 60 C for 16 h. The reaction was then cooled to rt and treated with water (2ml). After stirring for 5 min, the mixture was treated with NaOH (1 N in water, 5 ml). After stirring for at least another 15 min, volatiles were removed in vacuo. The aqueous residue was extracted with CH2Cl2, and thisCH2Cl2 extract was washed with 1 N NaOH. Aqueous layers were combined and extracted twice with CH2Cl2. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated invacuo to provide tert-butyl 6-cyclopropyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (2.86 g, 12.0 mmol, 95% yield) as a slight yellow oil that was used without further purification. |
With methanol; sodium cyanoborohydride; acetic acid; In tetrahydrofuran; at 60℃; for 12h;Inert atmosphere; | [001092] To a solution of tert-butyl 3,6-diaza-bicyclo[3.1.1]heptane-3-carboxylate (1.5g, 7.58mmol) and (l-ethoxycyclopropoxy)trimethylsilane (3.1ml, 15.45mmol) in 10 ml of MeOH and 10 ml of THF were added sodium cyanoborohydride (715mg, 11.35mmol) and acetic acid (2.2ml, 38.50mmol). The mixture was stirred at 60 C under N2 for 12 h. After cooling to r.t., 1 ml of water was added and the mixture was stirred for 5 min. It was then treated with 1 N NaOH (2.5ml) and stirred for 15 min. The mixture was concentrated and the aqueous phase was extracted with DCM (100ml). The organic phase was washed with 1 N NaOH (50ml). The combined aqueous phase was extracted with DCM (2x100ml). The combined organics were washed with brine, dried over sodium sulphate and concentrated to give crude product which was used for the next step without further purification. LC-MS: m/z = 239 (M+H)+, RT = 2.26 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; acetic acid In tetrahydrofuran; methanol at 60℃; for 6h; Molecular sieve; | 135.3 [821] Step 3: benzyl N-[(3S)-1-cyclopropyl-3-piperidyl]carbamate To a mixture of benzyl N-[(3S)-3-piperidyl]carbamate (300 mg, 1.28 mmol, 1 eq) and (1-ethoxycyclopropoxy)-trimethylsilane (446.39 mg, 2.56 mmol, 514.87 uL, 2 eq) in THF (8 mL) and MeOH (8 mL) were added HOAc (384.47 mg, 6.40 mmol, 366.16 uL, 5 eq), NaBH3CN (120.70 mg, 1.92 mmol, 1.5 eq) and 4A MS (0.5 g). The reaction mixture was stirred at 60 °C for 6 hr. The reaction mixture was poured into H2O (20 mL). EtOAc (30 mL x 3) was used to extract the product. The organic layer was washed by brine (30 mL), dried over Na2SO4, filtered and evaporated to afford the crude product. The crude product was purified by MPLC (SiO2, PE: EtOAc = 5: 1-1:1) to afford the title compound (300 mg, 702.77 umol, 54.88% yield, 64.27% purity) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; ethanol; at 60℃; for 2.0h; | A flask was charged with ethyl 5H,6H,7H,8H-[l,2,4]triazolo[4,3-a]pyrazine-3- carboxylate (300 mg, 1.53 mmol, 1.00 equiv), (l-ethoxycyclopropoxy)trimethylsilane (799 mg, 4.58 mmol, 3.00 equiv), sodium cyanoborohydride (289 mg, 4.60 mmol, 3.00 equiv), acetic acid (918 mg, 15.3 mmol, 10.0 equiv), EtOH (5 mL) and THF (5 mL). The resulting solution was stirred for 2 hours at 60 C and quenched by water (10 mL), as described in Example 2, Step 1. The residue was chromatographed on a silica gel column to provide 217 mg (60% yield) of ethyl 7-cyclopropyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine-3-carboxylate as a yellow solid. LCMS (ESI, m/z): 237 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium cyanoborohydride; acetic acid In methanol at 60℃; for 4h; Inert atmosphere; | Preparation of 2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-5-ol (304) To a mixture of 1,2,3,4-tetrahydroisoquinolin-5-ol hydrochloride (303) (186 mg, 1.0 mmol) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane (210 mg, 1.2 mmol) in MeOH (8 mL) was added NaBH3CN (76 mg, 1.2 mmol) and AcOH (73 mg, 1.2 mmol). The mixture was stirred at 60° C. for 4 h under N2. LCMS analysis showed consumption of starting material with formation of the product. The mixture was concentrated. The residue was diluted with DCM (80 mL) and washed with saturated aqueous NaHCO3 (2*20 mL) and brine (20 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography (SiO2, 1/15 DCM/petroleum ether) provided (304) (200 mg, 71% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 6.89 (t, J=7.8 Hz, 1H), 6.57 (d, J=7.9 Hz, 1H), 6.49 (d, J=7.6 Hz, 1H), 3.62 (s, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.55 (t, J=6.0 Hz, 2H), 1.78-1.67 (m, 1H), 0.53-0.43 (m, 2H), 0.42-0.33 (m, 2H). LCMS (ESI) m/z 190 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 mg | With sodium cyanoborohydride; acetic acid; In methanol; at 20℃;Molecular sieve; | 200 mg of 7-1 was converted to 7-3 using 7-2, HOAc, NaBH3CN, 4A sieves, MeOH at RT overnight. After purification, 200 mg of pure 7-3 was obtained. LCMS and HNMR were clean. 180 mg of 7-3 was converted to 7-4 using Fe and HOAc at 80oC for 4 hours. After purification, 62 mg of 7-4 was obtained. HNMR was clean. 62 mg of 7-4 was converted to Compound 15 by coupling 7-5 in the presence of Pd(OAc)2, X-phos, and Cs2CO3 in dioxane at 100oC overnight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: [(1-Ethoxycyclopropyl)oxy]trimethylsilane; FLUOXETINE With acetic acid In tetrahydrofuran; methanol at 23℃; for 0.166667h; Stage #2: With sodium cyanoborohydride In tetrahydrofuran; methanol at 65℃; | 1 Example 1: Compound 103 A magnetic stirrer was added to a 250ml three-necked reaction flask with free fluoxetine (16.8g, 0.0745mol, 1eq) at room temperature of about 23 ° C and humidity of about 52%. Methanol (50ml) and tetrahydrofuran (50ml) were added as Solvents, Add 1-ethoxy-1-trimethylsilyloxycyclopropane (19.0g, 0.109mol, 2eq) and acetic acid (6.5g, 0.108mol, 2eq) dropwise with stirring, stir for ten minutes, and slowly add sodium cyanoborohydride (7.0 g, 0.108 mol, 2 eq), a slight heat is released, the color of the reaction solution is colorless, the temperature rises to about 65 ° C and the reaction is refluxed. TLC monitors the completion of the raw material reaction. The reaction solution was adjusted to a slightly alkaline pH with a saturated NaHCO3 solution, extracted with 200 ml of EA, added with 20 g of anhydrous sodium sulfate and dried for 1 h, filtered by suction, and the filtrate was concentrated to obtain 19 g of a crude product. The crude product was purified by column chromatography, specifically: A column of 200 g of silica gel was used for loading by wet method. The eluent was EA and PE, and 14.8 g of pure colorless oily liquid was obtained. Yield: 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium cyanoborohydride; acetic acid In tetrahydrofuran; methanol at 65℃; | 1 Example 1: Preparation of compound B-2 A magnetic stirrer was added in a 250 ml three-necked reaction flask with free duloxetine (12.0 g, 0.0403 mol, 1 eq), methanol (50 ml), at room temperature of about 30 °C and humidity of about 45%. tetrahydrofuran (50ml), 1-ethoxy-1-trimethylsilylcyclopropane (14.0g, 0.0805mol, 2eq), acetic acid (4.84g, 0.0806mol, 2eq), sodium cyanoborohydride (5.0g, 0.0806mol, 2eq), the color of the reaction solution was colorless,The temperature was raised to about 65 °C and the reaction was refluxed. TLC monitored until the reaction of the raw materials was completed. The reaction solution was adjusted to neutral pH with 1mol / L NaHCO3, extracted with EA (200ml * 2), dried by adding 50g of anhydrous sodium sulfate for 1h, and distilled under reduced pressure at 50 ° C to obtain 14.0g of crude product. TLC of the crude product was impure. 120 g of silica gel column chromatography was used for purification to obtain 9.8 g of a pure yellow oily liquid with a yield of 75% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; acetic acid In tetrahydrofuran; methanol at 65℃; for 16h; Molecular sieve; | 29.1 Step-1: Synthesis of feri-butyl (2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)carbamate To a stirred solution of tert-butyl (2-azaspiro[3.3]heptan-6-yl)carbamate (0.2 g, 0.94 mmol) in THF:MeOH 9: 1 (5 mL) was added 4A molecular sieves (0.2 g), (1- ethoxycyclopropoxy)trimethylsilane (0.492 g, 2.8 mmol), acetic acid (0.1 mL, 0.18 mmol) and sodium cyano borohydride (0.175 g, 2.8 mmol) at room temperature. The reaction was heated at 65 °C for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was filtered and concentrated. The crude was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by Biotage isolara using silica gel (230-400) with gradient elution of 0-90% ethyl acetate in petroleum ether to obtain tert-butyl (2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)carbamate (0.1 g, 42 % yield). LC purity: 48.20%; m/z: 253.3 [M+H]+ (Mol. formula C14H24N2O2, calcd. mol. wt. 252.36) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With titanium tetrachloride In dichloromethane at 20℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With titanium tetrachloride In dichloromethane at 20℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With titanium tetrachloride In dichloromethane at 20℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; acetic acid In methanol at 55℃; for 20h; | 365 Example 365: 5-(((1-Cyclopropylpiperidin-3-yl)methyl)amino)-N-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)pyrazine-2-carboxamide 3-(Boc-aminomethyl)piperidine (514 mg, 2.40 mmol, 1.00 eq), (1- ethoxycyclopropoxy)trimethylsilane (0.48 mL, 2.40 mmol, 1.00 eq), and methyl alcohol (50.00 mL) were combined. Sodium cyanoborohydride (166 mg, 2.64 mmol, 1.10 eq) was added, followed by acetic acid (0.20 mL). The reaction was then hot block heated to 55 C for 20 hours, then cooled to room temperature. The reaction was then diluted with dichloromethane, washed with 10% NaOH solution, dried (MgSO4), and concentrated in vacuo to give tert-butyl N-[(1-cyclopropyl-3- piperidyl)methyl]carbamate, which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium cyanotrihydridoborate; glacial acetic acid In methanol at 20℃; for 6h; | 105.3 4-Cyclopropyl-1-(4-nitrophenyl)piperazin-2-one Compound 1-(4-nitrophenyl)piperazin-2-one 105c (442 mg, 2.0 mmol), acetic acid (1.2 g, 20 mmol), (1-ethoxycyclopropoxy)trimethylsilane ( 2.09 g, 12 mmol) and methanol (20 mL) were mixed, then sodium cyanoborohydride (629 mg, 10 mmol) was added.After stirring at room temperature for 6 hours, the filtrate was filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 10/1) to obtain the target product 4-cyclopropyl- 1-(4-Nitrophenyl)piperazin-2-one 105d (530 mg, yellow solid), yield: 100%. |
100% | With sodium cyanotrihydridoborate; glacial acetic acid In methanol at 20℃; for 6h; | 105.3 4-Cyclopropyl-1-(4-nitrophenyl)piperazin-2-one Compound 1-(4-nitrophenyl)piperazin-2-one 105c (442 mg, 2.0 mmol), acetic acid (1.2 g, 20 mmol), (1-ethoxycyclopropoxy)trimethylsilane ( 2.09 g, 12 mmol) and methanol (20 mL) were mixed, then sodium cyanoborohydride (629 mg, 10 mmol) was added.After stirring at room temperature for 6 hours, the filtrate was filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 10/1) to obtain the target product 4-cyclopropyl- 1-(4-Nitrophenyl)piperazin-2-one 105d (530 mg, yellow solid), yield: 100%. |
Tags: 27374-25-0 synthesis path| 27374-25-0 SDS| 27374-25-0 COA| 27374-25-0 purity| 27374-25-0 application| 27374-25-0 NMR| 27374-25-0 COA| 27374-25-0 structure
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :