Structure of 107259-06-3
*Storage: {[sel_prStorage]}
*Shipping: {[sel_prShipping]}
The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
*For Research Use Only !
Change View
Size | Price | VIP Price | US Stock |
Global Stock |
In Stock | ||
{[ item.pr_size ]} |
Inquiry
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.discount_usd) ]} {[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} |
Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]} | Inquiry {[ item.pr_usastock ]} In Stock Inquiry - | {[ item.pr_chinastock ]} {[ item.pr_remark ]} In Stock 1-2 weeks - Inquiry - | Login | - + | Inquiry |
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days
1-2weeks
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd,1,item.mem_rate,item.pr_is_large_size_no_price, item.pr_usd) ]}
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
In Stock
- +
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
CAS No. : | 107259-06-3 |
Formula : | C9H15NO3 |
M.W : | 185.22 |
SMILES Code : | CC(C)(C)OC(=O)NC1(CC1)C=O |
MDL No. : | MFCD10697899 |
InChI Key : | ACMHCEYCNRURST-UHFFFAOYSA-N |
Pubchem ID : | 10352385 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
* 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 |
---|---|---|
99% | With oxalyl dichloride; triethylamine; In dichloromethane; dimethyl sulfoxide; at -78℃; for 1h; | To a solution of oxalyl dichloride (277 mg, 2.2 mmol) in DCM (5 mL) was added DMSO (1 mL) and NEt3 (333 mg, 3.3 mmol). The resulting solution was stirred at -78C for lh. Then a solution of compound 2 (200 mg, 1.1 mmol) in 2 mL DCM was added. The reaction was stirred at -78 C for 1 h. Quenched by NH4C1 aq. and extracted by ethyl acetate. Organic layer was combined, dried over Na2SO4 and concentrated to give tert-butyl 1 -formylcyclopropylcarbamate (196 mg, 99%). |
90% | With 4-methylmorpholine N-oxide;tetrapropylammonium perruthennate; In dichloromethane; at 0 - 20℃; for 1h; | [0505] To a suspension of 1-aminocyclopropanecarboxylic acid (998 mg, 9.87 mmol) in EtOH (25 mL), cooled to 0 C., was added SOCl2 (2.0 mL, 27 mmol) dropwise over 10 minutes. The resulting solution was heated at reflux under nitrogen for 2 hours, then was evaporated under reduced pressure, giving the ester as a light brown oil. [0506] This material was dissolved into EtOAc (25 mL) and a solution of KHCO3 (1.51 g, 15.1 mmol) in H2O (9 mL) was added dropwise. The resulting solution was cooled to 0 C. and a solution of Boc2O (2.97 g, 13.6 mmol) in EtOAc (10 mL) was added. The reaction was stirred at room temperature for 16 hours, the layers were separated and the aqueous solution was extracted with EtOAc (25 mL). The combined organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (EtOAc/hexane, 1:3) gave the protected amine as light brown solid (1.27 g, 5.54 mmol, 56%). 1H NMR (CDCl3) δ 1.08-1.18 (m, 2H), 1.23 (t, 3H, J=7.2 Hz), 1.44 (s, 9H), 1.46-1.53 (m, 2H), 4.14 (q, 2H, J=7.2 Hz), 5.13 (br. s, 1H). [0507] Preparation of (1-hydroxymethyl-cyclopropyl)-carbamic Acid Tert-Butyl Ester: [0508] To a solution of the ester (1.18 g, 5.15 mL) in THF (10 mL) under nitrogen was added a solution of LiBH4 (200 mg, 9.2 mmol) in THF (10 mL) dropwise over 10 minutes. The reaction was stirred at room temperature for 17.5 hours, then was cooled to 0 C. A solution of 50% HOAc was added dropwise until the evolution of gas had ceased (approx. 8 mL). The resulting white suspension was diluted with H2O (15 mL) and was extracted with Et2O (30 mL). The organic solution was washed with 15% aqueous NaHCO3 (15 mL) and brine (15 mL), then dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (EtOAc/hexane, 1:1) gave the alcohol as a white solid (592 mg, 3.16 mmol, 61%).2 1H NMR (CDCl3) δ 0.81 (s, 4H), 1.43 (s, 9H), 3.52 (br. s, 1H), 3.58 (s, 2H), 5.12 (br. s, 1H). [0509] Preparation of (1-formyl-cyclopropyl)-carbamic Acid Tert-Butyl Ester: [0510] To a solution of the alcohol (389 mg, 2.08 mmol) in CH2Cl2 (11 mL), cooled to 0 C., was added crushed, dried 3 molecular sieves (1.05 g), NMO (382 mg, 3.26 mmol) and TPAP (76 mg, 0.22 mmol). The black mixture was stirred at 0 C. for 30 minutes and at room temperature for a further 30 minutes. The mixture was diluted with EtOAc (20 mL) and flushed through a short silica column, rinsing with EtOAc. The product containing material was concentrated under reduced pressure giving the aldehyde as a white solid (345 mg, 1.86 mmol, 90%). 1H NMR (CDCl3) δ 1.27-1.37 (m, 2H), 1.40-1.52 (m, 2H), 1.46 (s, 9H), 5.22 (br. s, 1H), 9.16 (s, 1H). [0511] Preparation of (E)-3-(i-tert-butoxycarbonylamino-cyclopropyl)-acrylic Acid Ethyl Ester: [0512] Triethyl phosphonoacetate (0.62 mL, 3.13 mmol) was added dropwise to a suspension of 60% NaH in mineral oil (120 mg, 3.00 mmol) in THF (5 mL). The resulting solution was stirred at room temperature for 10 minutes, then cooled to 0 C. for the dropwise addition of a solution of the aldehyde (463 mg, 2.50 mmol) in THF (5 mL). The reaction was stirred at 0 C. for 15 minutes, then heated to reflux for 1 hour. Once cooled to room temperature, saturated aqueous NH4Cl (10 mL) was added, the layers were separated and the aqueous solution was extracted with CH2Cl2 (10 mL×2). The organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (EtOAc/hexane, 1:1) gave the unsaturated ester as a pale yellow solid (539 mg, 2.11 mmol, 84%). 1H NMR (CDCl3) δ 1.11-1.18 (m, 2H), 1.24-1.29 (m, 5H), 1.44 (s, 9H), 4.17 (q, 2H, J=7.1 Hz), 5.02 (br. s, 1H), 5.84 (d, 1H, J=15.3 Hz), 6.47 (d, 1H, J=15.6 Hz). [0513] Preparation of 3-(1-tert-butoxycarbonylamino-cyclopropyl)-propionic Acid Ethyl Ester: [0514] A solution of the unsaturated ester (495 mg, 1.94 mmol) in EtOAc (10 mL) was hydrogenated (H2 balloon) over 10% Pd/C (25 mg, 0.023 mmol) at room temperature for 3 hours. The mixture was suction filtered through Celite, washing with EtOAc and evaporation of the filtrate under reduced pressure gave the saturated ester as a colourless oil (500 mg, 1.94 mmol, 100%). 1H NMR (CDCl3) δ 0.61-0.65 (m, 1H), 0.73-0.78 (m, 1H), 0.91 (t, 2H, J=7.4 Hz), 1.25 (td, 3H, J=7.1, 1.4 Hz), 1.43 (s, 9H), 1.78-1.90 (m, 2H), 2.36 (t, 1H, J=7.7 Hz), 2.44 (t, 1H, J=7.5 Hz), 4.12 (q, 2H, J=7.1 Hz). [0515] Preparation of [1-(3-hydroxy-propyl)-cyclopropyl]-carbamic Acid Tert-Butyl Ester: [0516] LiBH4 (70 mg, 3.2 mmol) was added to a solution of the ester (500 mg, 1.94 mmol) in THF (8 mL). The reaction was stirred at room temperature under nitrogen for 18 hours, then was quenched by the dropwise addition of 50% aqueous HOAc until the evolution of gas had ceased (approx. 2 mL). The suspension was diluted with H2O (10 mL) and extracted with Et2O (15 mL). The organic solution was washed with saturated aq... |
89% | With sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine; In dichloromethane; dimethyl sulfoxide; at -20 - -5℃; for 3.75h; | To a solution of tert-butyl (1 -(hydroxymethyl)cyclopropyl)carbamate (commercial, 15 g; 80.3 mmol) in DCM (235 mL), cooled to -20C, was slowly added DIPEA (45 mL;263 mmol). A solution of Pyr.S03 (38.75 g; 110 mmol) in DMSO (108 mL, 1.5 mol) was added dropwise over 45 mm, keeping the IT below -5C. The reaction mixture was stirred at this temperature for 3 h. The reaction mixture was partitioned between water (1 L) and DCM (200 mL). The two layers were separated and the aq. layer was extracted once more with DCM (300 mL). The evaporation residue was evaporated further with toluene(2 x 300 mL) and purified by CC (Hept-EA) to afford the title product (13.18 g, 89% yield) as a white solid.‘H NMR (d6-DMSO) ö: 8.99 (s, 1H); 7.56 (s, 1H); 1.41-1.34 (overlapped m, 2H); 1.39 (s, 9H); 1.16-1.13 (m, 2H). |
89% | To a solution of tert-butyl (l-(hydroxymethyl)cyclopropyl)carbamate (commercial, 15 g; 80.3 mmol) in DCM (235 mL), cooled to -20C, was slowly added DIPEA (45 mL; 263 mmol) over 15min. A solution of Pyr.S03 (38.75 g; 110 mmol ) in DMSO (108 mL; 1.52 mol) was added dropwise over 45min. The reaction mixture was stirred at 0C for 2h45. The reaction mixture was partitioned between water (1 L) and DCM (200 mL). The two layers were separated and the aq. layer was extracted once more with DCM (300 mL). The evaporation residue was purified by CC (Hept-EA) to afford the title compound (13.18 g; 89% yield) as a white solid. 1H NMR (d6-DMSO) δ: 8.99 (s, 1H); 7.55 (s, 1H); 1.44-1.31 (overlapped m, 2H); 1.39 (s, 9H); 1.19-1.10 (m, 2H). MS (ESI, m/z): 186.2 [M+H+] for C9H15N03; tR = 0.62 min | |
87% | With Dess-Martin periodane; In dichloromethane; for 1h; | To a solution of tert-butyl ( 1 -(hydroxymethyl)cydopropyl)carbamate (Bioorg. Med. Chem. Lett., 2008, 18(6), 2388) (135 mg, 0.72 mmoles) in DCM (8 mL) was added Dess- Martin periodinane (277 mg, 0.65 mmole). After stirring 1 hr, the reaction was filtered through ceiite and concentrated to a yellow oil which was further purified by isolera (7%~ 70% ethyl acetate hexanes) to provide 84 mg (87 %) of tert-butyl (1-forrnylcyclopropyl)- carbamate as a white solid. |
87% | With Dess-Martin periodane; In dichloromethane; for 1h; | To a solution of tert-butyl (1-(hydroxyrnethyl)cyclopropyl)carbamate (Bioorg. Med. Chem. Left., 2008, 18(6), 2188) (135 mg, 0.72 mmoles) in DCM (8 rnL) was added Dess Martin periodinane (277 mg, 0.65 mmole). After stiuing I hr, the reaction was filtered through celite and concentrated to a yellow oil which was further purified by Isolera (7%- 70% ethyl acetate/hexanes) to provide 84 mg (87 %) of tert-butyl (1-formylcyclopropyl)carbamate as a white solid. |
87% | With Dess-Martin periodane; In dichloromethane; for 1h; | Step 1. To a solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (Bioorg. Med. Chem. Lett., 2008, 18(6), 2188) (135 mg, 0.72 mmoles) in DCM (8 mL) was added Dess Martin periodinane (277 mg, 0.65 mmole). After stirring 1 hr, the reaction was filtered through celite and concentrated to a yellow oil which was further purified by Isolera (7%-70% ethyl acetate/hexanes) to provide 84 mg (87 %) of tert-butyl (1-formylcyclopropyl)carbamate as a white solid. |
87% | With Dess-Martin periodane; In dichloromethane; for 1h; | Step 1 To a solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (Bioorg. Med. Chem. Lett., 2008, 18(6), 2188) (135 mg, 0.72 mmoles) in DCM (8 mL) was added Dess-Martin periodinane (277 mg, 0.65 mmole). After stirring 1 hr, the reaction was filtered through celite and concentrated to a yellow oil which was further purified by Isolera (7%-70% ethyl acetate/hexanes) to provide 84 mg (87%) of tert-butyl (l-formylcyclopropyl)-carbamate as a white solid. |
70% | To a solution of oxalyl chloride (2.01 mL, 23.1 mmol) in CH2Cl2 (50 mL) at -55 C was added dropwise a solution of DMSO (1.64 mL, 23.1 mmol) in CH2Cl2 (10 mL). Upon complete addition, the reaction was stirred for 5 min then the Boc-protected amino alcohol (3.6 g, 19.2 mmol) was added as a solution in CH2Cl2 (10 mL) and stirring was continued for 15 min. Triethylamine (13.9 mL, 99.9 mmol) was added and the reaction <n="127"/>was stirred for 5 min then allowed to slowly warm to room temperature. After Ih, H2O (50 mL) was added and the reaction was poured into CH2Cl2. The aqueous phase was separated and extracted two more times with CH2Cl2. The organic layers were combined and washed with brine, dried (Na2SO4), decanted and concentrated. The resultant residue was purified via SiO2 flash chromatography (10-40% EtOAc-Hexanes) to afford Boc-1- aminocyclopropane-1-carboxaldehyde as a white solid (2.5g, 70%). | |
60% | A solution of DMSO (0.391 mL, 5.51 mmol) in DCM (2.4 mL) was added dropwise to a solution of oxalyl chloride (0.482 mL, 5.51 mmol) in DCM (12 mL) at -70 C with stirring under nitrogen. The mixture was stirred for 5 mm, then a solution of 5A (0.860 g, 4.59 mmol) in DCM (2.4 mL) was addeddropwise. The mixture was stirred at -70 C for 15 mm, and then TEA (3.20 mL,23.0 mmol) was added. After an additional 5 mm at -70 C, the cooling bath was removed, and the reaction mixture was allowed to slowly warm to rt. Stirring was continued for 1 h. The reaction was quenched with water and poured into DCM. The phases were separated, and the aq. layer was extracted with DCM(2x). The combined extracts were washed with brine, dried over Na2504 and filtered. The filtrate was evaporated, and the residue was purified by flash chromatography to provide SB as a white crystalline solid (0.5 13 g, 60 %) was obtained. MS (ESI) m/z 186.4 (M+H). | |
With sodium hypochlorite; TEMPOL; sodium hydrogencarbonate; In dichloromethane; water; at 0 - 25℃; for 1h; | Three 500mL flask was added compound 1A (7g, 0.037mol, 1eq) and dichloromethane (50mL), addThe 4-OH-TEMPO (0.06g, 0.37mmol, 0.01eq), was added saturated aqueous NaHCO3 (200mL),Cooled to 0 deg.] C, was added dropwise an aqueous solution of 10% NaClO (50g, 0.067mol, 1.8eq), naturally warmed to room temperature,The reaction 1h. Water was added 100mL, extracted with dichloromethane (150mL * 2), the combined organic phases were washed with water (200 mL)Washed once, the organic phase was concentrated to give compound 2A as a pale yellow solid (6.3 g of, yield: 91%, purity:94.2%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diisobutylaluminium hydride; In hexane; | REFERENTIAL EXAMPLE 13 Synthesis of 1-tert-butoxycarbonylaminocyclopropanecarboaldehyde (P-13) STR22 7.1 g of the ester compound (P-12) was dissolved in 200 ml of anhydrous n-hexane. 46 ml of diisobutylaluminum hydride (1M solution in n-phexane) was added dropwise to the solution under cooling to -65 C. in argon atmosphere and the mixture was stirred at -60 to -70 C. for 4 h. The temperature was elevated to room temperature and the product was extracted sufficiently with saturated sodium hydrogensulfite solution. The precipitate thus formed was filtered off and the aqueous layer was adjusted to pH 9 with 10% NaOH under cooling with ice. After extraction with ether several times, the ether layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Ether was distilled off to obtain 2.6 g of the desired aldehyde (P-13) in the form of a colorless solid. NMR(CDCl3) δ ppm: 1.36(4H, m), 1.48(9H, s), 5.20(1H, bs), 9.20(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium aluminium tetrahydride; In diethyl ether; at 20℃; for 0.666667h; | To a 0.05 M solution of [l-(methoxy-methyl-carbamoyl)cyclopropyl]carbamic acid fert-butyl ester in Et2O (80 mL, 4.0 mmol) at room temperature was added dropwise lithium aluminum hydride (1.0 M in Et2O, 5 mL, 5.0 mmol). The reaction mixture was stirred for another 20 min and then quenched with 6 mL of a solution OfKHSO4 in water. The layers were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with 1 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), and concentrated to yield (l-formylcyclopropyl)carbamic acid tert-butyl ester as a colorless oil (393 mg) which was used immediately in the next step without further purification. | |
Step 1-D:To a solution of Id (1.39 g, 5.73 mmol) in methylene chloride (20 mL) is cooled to -78C and is added dropwise a IM solution of DiBAl-H in methylene chloride. The reaction is stirred at -78C for 3 hours and then quenched with IN solution of Rochelle salt (25 mL). The aqueous phase is then extracted with methylene chloride. The combined organic layers are dried over MgSO4, filtered and concentrated in vacuo. The residue is chromatographed on silica gel (gradient: EtOAc/hexane; 0: 1 to 1 :1) to afford Ie (0.57 g). Found m/z ES+ = 186. | ||
Step 5; [0201] To a 0.05 M solution of [l-(methoxy-methyl-carbamoyl)cyclopropyl]carbamic acid tert-butyl ester in Et2O (80 mL, 4.0 mmol) at room temperature was added dropwise lithium aluminum hydride (1.0 M in Et2O, 5 mL, 5.0 mmol). The reaction mixture was stirred for another 20 min and then quenched with 6 mL of a solution of KHSO4 in water. The layers were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with 1 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), and concentrated EPO <DP n="72"/>to yield (l-formylcyclopropyl)carbamic acid tert-butyl ester as a colorless oil (393 mg) which was used immediately in the next step without further purification. |
With lithium aluminium tetrahydride; In diethyl ether; at 0℃; for 2h;Inert atmosphere; | Tert-butyl (1-(methoxy(methyl)carbamoyl)cyclopropyl) carbamate 13 (500 mg) was dissolved in anhydrous Et20 (50 ml_) under argon and cooled to 0C. Lithium Aluminum Hydride(3 mL, 1 M in Et20) was added dropwise and the reaction mixture was stirred for 2h at this temperature. The reaction was quenched by addition of 1 N HCI (2.5 mL) and stirred vigorously for a few minutes. The organic layer was extracted with 1 N HCI and brine, dried over Na2S04, filtered and concentrated to obtain the product aldehyde 14 as a colorless oil. Use crude in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.178 g (63.9%) | With n-butyllithium; sodium chloride; In tetrahydrofuran; hexane; | Referential Example 9-1 Ethyl 3-(1-tert-butoxycarbonylaminocyclopropyl)propiolate STR109 Under a nitrogen atmosphere, chloromethyltrimethyl-phosphonium chloride (5.156 g, 14.85 mmol) was suspended in dry tetrahydrofuran (30 ml). After cooling the suspension to provide an internal temperature of -55 C., a 1.68 M solution of n-butyllithium in n-hexane (8.87 ml, 14.90 mmol) was added dropwise thereinto over a period of 5 minutes. Then, the reaction suspension was stirred under ice cooling for 30 minutes and then at room temperature for an additional 3 hours followed by cooling to provide an internal temperature of -55 C. Into this reaction suspension was added dropwise a solution of 1-tert-butoxycarbonylaminocyclopropane carbaldehyde (2.49 g, 13.50mmol) in dry tetrahydrofuran (10 ml) over a period of 10 minutes and the resultant mixture was stirred at -50 C. for 1 hour and then under ice cooling for additional 30 minutes. The reaction suspension was cooled to -78 C. and a 1.68 M solution of n-butyllithium in n-hexane (17.68 ml, 29.70 mmol) was added dropwise thereinto over a period of 10 minutes followed by stirring at -78 C. for 20 minutes. Next, ethyl chloroformate (1.61 ml, 16.88 mmol) was added dropwise into this reaction suspension followed by stirring at -78 C. for 1.5 hours and then under ice cooling for 1 hour. Under ice cooling, a saturated aqueous solution of sodium chloride (30 ml) was added to the reaction suspension and the organic layer was separated. The aqueous layer was extracted with diethyl ether (30 ml*2) and the combined organic layer was washed with a saturated aqueous solution of sodium chloride (30 ml) and dried over anhydrous magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure and the residue was subjected to flash silica gel column chromatography (eluent: n-hexane:ethyl acetate=5:1) to obtain 2.178 g (63.9%) of the title compound as a colorless oily substance. 1 H-NMR (400 MHz, CDCl3) δ: 5.04 (brs, 1H), 4.27 (q, J=7.16 Hz, 2H), 1.44 (s, 9H), 1.28 (t, J=7.16 Hz, 3H), 1.15 (m, 2H),1.06 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.178 g (63.9%) | With n-butyllithium; In tetrahydrofuran; hexane; | Reference Example 2-1 Ethyl 3-(1-tert-butoxycarbonylaminocyclopropyl)propiolate STR50 Under a nitrogen atmosphere, chloromethyltrimethylphosphonium chloride (5.156 g, 14.85 mmol) was suspended in anhydrous tetrahydrofuran (30 ml) to which, after cooling to -55 C., was subsequently added dropwise a 1.68 M n-butyl lithium n-hexane solution (8.87 ml, 14.90 mmol) over a period of 5 minutes. The reaction suspension was stirred for 30 minutes in an ice bath and for 3 hours at room temperature and then cooled to -55 C. To the reaction suspension was added dropwise an anhydrous tetrahydrofuran (10 ml) solution of 1-tert-butoxycarbonylaminocyclopropane carbaldehyde (2.498 g, 13.50 mmol) over a period of 10 minutes, subsequently stirring the mixture for 1 hour at -50 C. and then for 30 minutes in an ice bath. The reaction suspension was cooled to -78 C., an n-hexane solution of 1.68 M an n-butyl lithium (17.68 ml, 29.70 mmol) was added dropwise thereto over a period of 10 minutes and then the mixture was stirred at -78 C. for 20 minutes. Ethyl chloroformate (1.61 ml, 16.88 mmol) was added dropwise to the reaction suspension which was subsequently stirred for 1.5 hours at -78 C. and then for 1 hour in an ice bath. While cooling in an ice bath, the reaction suspension was mixed-with saturated brine (30 ml), the organic layer was separated and the aqueous layer was extracted with diethyl ether (30 ml*2). The organic layers were combined, washed with saturated brine (30 ml) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was applied to a flash silica gel chromatography column and eluted with an eluant of n-hexane:ethyl acetate=5:1, to-thereby obtain 2.178 g (63.9%) of the title compound as a colorless oil. 1 H-NMR (400 MHz, CDCl3) δ: 5.04 (brs, 1 H), 4.27 (q, J=7.16 Hz, 2 H), 1.44 (s, 9 H), 1.28 (t, J=7.16 Hz, 3 H), 1.15 (m, 2 H), 1.06 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; | To a solution of (l-formylcyclopropyl)carbamic acid tert-butyl ester (393 mg, 2.12 mmol) in CH2Cl2 (4 mL) was added acetic acid (191 mg, 0.182 mL, 3.18 mmol), and cyclopropyl isocyanide (142 mg, 2.12 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure to yield crude acetic acid (1- tert-butoxycarbonylaminocyclopropyl)cyclopropylcarbamoyl methyl ester which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; | Step 6; [0202] To a solution of (l-formylcyclopropyl)carbamic acid tert-butyl ester (393 mg, 2.12 mmol) in CH2Cl2 (4 niL) was added acetic acid (191 mg, 0.182 mL, 3.18 mmol), and cyclopropyl isocyanide (142 mg, 2.12 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure to yield crude acetic acid (1- tert-butoxycarbonylammocyclopropyi)cyclopropylcarbamoyl methyl ester which was used in the next step without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | N-Boc-1-amino-1-cyclopropanecarboxylic acid is dissolved in tetrahydrofuran and stirred at 0 C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture is heated to reflux overnight. Ether is then added, and the excess hydride is quenched with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over Na2 SO4 and evaporated to yield N-Boc-1-amino-1-cyclopropanecarboxaldehyde. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of Preparation 91 (425 mg, 0.89 mmol) in toluene/dichloroethane (4:1, 12 ml) was heated at 90 C. for 5 min, before addition of (1-formyl-cyclopropyl)-carbamic acid tert-butyl ester (0.50 g, 2.70 mmol) and p-toluenesulphonic acid (17 mg). The reaction mixture was heated at 90 C. for 1 h and then at reflux for 2 h, using a Dean-Stark apparatus. The mixture was concentrated in vacuo and the residue was azeotroped with toluene. To a solution of the residue in methanol (16 ml), at 0 C., was added sodium borohydride (85 mg, 2.23 mmol) and the reaction mixture was stirred at 0 C. for 30 min and then at room temperature for 1 h. To the mixture was added hydrochloric acid (1M) and ethyl acetate. The organic phase was separated, dried (MgSO4) and concentrated in vacuo to give the titled compound (226 mg). Experimental MH+ 646.2; expected 646.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.74 g | With sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine; In dichloromethane; dimethyl sulfoxide; at -10 - 20℃; for 2.33333h; | General procedure: J. in. ( lR,2R)-2-( (S)-2, 2-dimethyl-l, 3-dioxolan-4-yl)cyclopropane-l-carbaldehyde: To a solution of intermediate J.ii (2.52 g; 14.6 mmol) in DCM (34 mL), cooled to -10C, was added DIPEA (7.83 mL; 45.7 mmol) over 5 min. A solution of Pyr.SCh complex (6.35 g; 20 mmol) in DMSO (18 mL) was added dropwise over 20 min. The reaction mixture was stirred for 1 h at 0C and then at rt for 1 h. The reaction mixture was partitioned between water (50 mL) and DCM (50 mL). The org. layer was washed with water (20 mL). The evaporation residue was purified by CC (PE-EA) to afford the title compound as a yellowish oil (1.78 g; 71% yield). XH NMR (CDCI3) δ: 9.12 (d, J = 5.1 Hz, 1H); 4.1 1 (dd, J = 6.1, 8.2 Hz, 1H); 3.81 (q, J = 6.6 Hz, 1H); 3.70 (dd, J = 6.8, 8.2 Hz, 1H); 1.90-1.84 (m, 1H); 1.73-1.67 (m, 1H); 1.43 (s, 3H); 1.34 (s, 3H); 1.21-1.27 (m, 2H). |
Preparation of (1-formyl-cyclopropyl)-carbamic Acid Tert-Butyl Ester: To a solution of the alcohol (389 mg, 2.08 mmol) in CH2Cl2 (11 mL), cooled to 0 C., was added crushed, dried 3 Å molecular sieves (1.05 g), NMO (382 mg, 3.26 mmol) and TPAP (76 mg, 0.22 mmol). The black mixture was stirred at 0 C. for 30 minutes and at room temperature for a further 30 minutes. The mixture was diluted with EtOAc (20 mL) and flushed through a short silica column, rinsing with EtOAc. The product containing material was concentrated under reduced pressure giving the aldehyde as a white solid (345 mg, 1.86 mmol, 90%). 1H NMR (CDCl3) δ 1.27-1.37 (m, 2H), 1.40-1.52 (m, 2H), 1.46 (s, 9H), 5.22 (br. s, 1H), 9.16 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | [0505] To a suspension of 1-aminocyclopropanecarboxylic acid (998 mg, 9.87 mmol) in EtOH (25 mL), cooled to 0 C., was added SOCl2 (2.0 mL, 27 mmol) dropwise over 10 minutes. The resulting solution was heated at reflux under nitrogen for 2 hours, then was evaporated under reduced pressure, giving the ester as a light brown oil. [0506] This material was dissolved into EtOAc (25 mL) and a solution of KHCO3 (1.51 g, 15.1 mmol) in H2O (9 mL) was added dropwise. The resulting solution was cooled to 0 C. and a solution of Boc2O (2.97 g, 13.6 mmol) in EtOAc (10 mL) was added. The reaction was stirred at room temperature for 16 hours, the layers were separated and the aqueous solution was extracted with EtOAc (25 mL). The combined organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (EtOAc/hexane, 1:3) gave the protected amine as light brown solid (1.27 g, 5.54 mmol, 56%). 1H NMR (CDCl3) δ 1.08-1.18 (m, 2H), 1.23 (t, 3H, J=7.2 Hz), 1.44 (s, 9H), 1.46-1.53 (m, 2H), 4.14 (q, 2H, J=7.2 Hz), 5.13 (br. s, 1H). [0507] Preparation of (1-hydroxymethyl-cyclopropyl)-carbamic Acid Tert-Butyl Ester: [0508] To a solution of the ester (1.18 g, 5.15 mL) in THF (10 mL) under nitrogen was added a solution of LiBH4 (200 mg, 9.2 mmol) in THF (10 mL) dropwise over 10 minutes. The reaction was stirred at room temperature for 17.5 hours, then was cooled to 0 C. A solution of 50% HOAc was added dropwise until the evolution of gas had ceased (approx. 8 mL). The resulting white suspension was diluted with H2O (15 mL) and was extracted with Et2O (30 mL). The organic solution was washed with 15% aqueous NaHCO3 (15 mL) and brine (15 mL), then dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (EtOAc/hexane, 1:1) gave the alcohol as a white solid (592 mg, 3.16 mmol, 61%).2 1H NMR (CDCl3) δ 0.81 (s, 4H), 1.43 (s, 9H), 3.52 (br. s, 1H), 3.58 (s, 2H), 5.12 (br. s, 1H). [0509] Preparation of <strong>[107259-06-3](1-formyl-cyclopropyl)-carbamic Acid Tert-Butyl Ester</strong>: [0510] To a solution of the alcohol (389 mg, 2.08 mmol) in CH2Cl2 (11 mL), cooled to 0 C., was added crushed, dried 3 molecular sieves (1.05 g), NMO (382 mg, 3.26 mmol) and TPAP (76 mg, 0.22 mmol). The black mixture was stirred at 0 C. for 30 minutes and at room temperature for a further 30 minutes. The mixture was diluted with EtOAc (20 mL) and flushed through a short silica column, rinsing with EtOAc. The product containing material was concentrated under reduced pressure giving the aldehyde as a white solid (345 mg, 1.86 mmol, 90%). 1H NMR (CDCl3) δ 1.27-1.37 (m, 2H), 1.40-1.52 (m, 2H), 1.46 (s, 9H), 5.22 (br. s, 1H), 9.16 (s, 1H). [0511] Preparation of (E)-3-(i-tert-butoxycarbonylamino-cyclopropyl)-acrylic Acid Ethyl Ester: [0512] Triethyl phosphonoacetate (0.62 mL, 3.13 mmol) was added dropwise to a suspension of 60% NaH in mineral oil (120 mg, 3.00 mmol) in THF (5 mL). The resulting solution was stirred at room temperature for 10 minutes, then cooled to 0 C. for the dropwise addition of a solution of the aldehyde (463 mg, 2.50 mmol) in THF (5 mL). The reaction was stirred at 0 C. for 15 minutes, then heated to reflux for 1 hour. Once cooled to room temperature, saturated aqueous NH4Cl (10 mL) was added, the layers were separated and the aqueous solution was extracted with CH2Cl2 (10 mL×2). The organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (EtOAc/hexane, 1:1) gave the unsaturated ester as a pale yellow solid (539 mg, 2.11 mmol, 84%). 1H NMR (CDCl3) δ 1.11-1.18 (m, 2H), 1.24-1.29 (m, 5H), 1.44 (s, 9H), 4.17 (q, 2H, J=7.1 Hz), 5.02 (br. s, 1H), 5.84 (d, 1H, J=15.3 Hz), 6.47 (d, 1H, J=15.6 Hz). [0513] Preparation of 3-(1-tert-butoxycarbonylamino-cyclopropyl)-propionic Acid Ethyl Ester: [0514] A solution of the unsaturated ester (495 mg, 1.94 mmol) in EtOAc (10 mL) was hydrogenated (H2 balloon) over 10% Pd/C (25 mg, 0.023 mmol) at room temperature for 3 hours. The mixture was suction filtered through Celite, washing with EtOAc and evaporation of the filtrate under reduced pressure gave the saturated ester as a colourless oil (500 mg, 1.94 mmol, 100%). 1H NMR (CDCl3) δ 0.61-0.65 (m, 1H), 0.73-0.78 (m, 1H), 0.91 (t, 2H, J=7.4 Hz), 1.25 (td, 3H, J=7.1, 1.4 Hz), 1.43 (s, 9H), 1.78-1.90 (m, 2H), 2.36 (t, 1H, J=7.7 Hz), 2.44 (t, 1H, J=7.5 Hz), 4.12 (q, 2H, J=7.1 Hz). [0515] Preparation of [1-(3-hydroxy-propyl)-cyclopropyl]-carbamic Acid Tert-Butyl Ester: [0516] LiBH4 (70 mg, 3.2 mmol) was added to a solution of the ester (500 mg, 1.94 mmol) in THF (8 mL). The reaction was stirred at room temperature under nitrogen for 18 hours, then was quenched by the dropwise addition of 50% aqueous HOAc until the evolution of gas had ceased (approx. 2 mL). The suspension was diluted with H2O (10 mL) and extracted with Et2O (15 mL). The organic solution was washed with saturated aq... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Boc-1-aminocyclopropane-1-carboxaldehyde (0.150 g, 0.81 mmol) and 2-amino-3- hydroxypyridine (0.094 g, 0.85 mmol) were combined in anhydrous methanol (2.5 mL). To this solution was added freshly activated 3 A molecular sieves (~25 beads). The reaction vessel was sealed and heated to 45 C for 18h. The volatiles were removed in vacuo and the resultant residue was dissolved in CH2Cl2 (2.5 mL). To this solution was added DDQ (0.202 g, 0.89 mmol) and the reaction was stirred for Ih. The reaction was diluted with saturated aqueous NH4Cl and poured into a separatory funnel. An additional 15 mL of CH2Cl2 was added. The aqueous phase was separated and extracted two more times with CH2Cl2. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude residue was absorbed onto SiO2 and purified via SiO2 flash chromatography (25-75% EtOAc-Hexanes) to afford the Boc-protected 1-(1-oxazolo[4,5- b]pyridin-2-yl-cyclopropylamine as a tan solid (0.044 mg, 20%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; In methanol; at 45℃; for 12h; | Step 1-E:To a solution of compound Ie in water (20 mL) and methanol (16 mL) is added potassium cyanide (401 mg, 6.15 mmol) and ammonium chloride (329 mg, 6.15 mmol). The reaction is then heated up to 45C for 12 hours. The reaction is then quenched by addition of a saturated solution of sodium bicarbonate. The aqueous phase is then extracted with ethyl acetate. The combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo to afford If (0.20 g). Found m/z ES+ = 212. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With piperidine; In methanol; dichloromethane; for 6h;Reflux; | Step 2To a solution of 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin- l-yi]methyl]pyrrolidin-l-yl]-3-oxo-propanenitrile (lOO.mg, 0.2100mmol) dissolved in methanol (4mL) and DCM (4mL) was added piperidine (O. lrnL, 0.8500mmol) and tert-butyl N-( 1 ~formylcyclopropyl)carbamate (58.9rog, 0.3200mmol). The reaction was heated to reflux for 6 3irs and then cooled and coneentrated. The residue was and dissolved in ethyl acetate (50 mL) and washed with water (50mL) and then brine. The organic layer was dried iMgS04), filtered and concentrated. The residue was purified by isolera (l %-8%MeOH DCM) to provide 39 mg ( 13% yield) of tert-butyl N-[ l-[3-[(2R)-2-[[4-amino-3-(2- fluoro-4-phenoxy-phenyl)pyrazoio[3,4-d]pyrimidin-l-yl3raethyl]pyrrolidin-l-yl]-2-cyano-3- oxo-prop- 1 -enyljcyclopropyljcarbamate. |
13% | With piperidine; In methanol; dichloromethane; for 6h;Reflux; | To a solution of 3[(2R)-2-[[4amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidinyl]-3’-oxo-propanenitrile (100.mg, 0,2 lOOmmol) dissolved in methanol (4mL) and DCM (4mL) was added piperidine (0.lmL, 0.SSOOmmol) and tertbutyl N..(1-formylcyclopropyl)carbarnate (58.9mg, 0.3200mmol). The reaction was heated to reflux for 6 hrs and then cooled and concentrated. The residue was and dissolved in ethyl acetate (50 mL) and washed with water (5OmL) and then brine. The organic layer was dried (Mg504), filtered and concentrated. rme residue was purified by isolera (1 %-8% MeOH/DCM) to provide 39 mg (13% yield) of tertbutyl N-[1-[3-(2R)-2[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxoprop-1-enyl]cyclopropyl]carbamate. |
13% | With piperidine; In dichloromethane; for 6h;Reflux; | Step 2. To a solution of 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (1 00.mg, 0.2100 mmol)dissolved in methanol (4mL) and DCM (4mL) was added piperidine (0.1mL, 0.8500mmol) and <strong>[107259-06-3]tert-butyl N-(1-formylcyclopropyl)carbamate</strong> (58.9mg, 0.3200mmol). The reaction was heated to reflux for 6 hrs and then cooled and concentrated. The residue was and dissolved in ethyl acetate (50 mL) and washed with water (50 mL) and then brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by Isolera (1 %-8%MeOH/DCM) to provide 39 mg (13% yield) of tert-butyl N-[1-[3-[(2R)-2-[[4-amino-3-(2- fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyllpyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]cyclopropyl]carbamate. |
13% | With piperidine; In methanol; dichloromethane; for 6h;Reflux; | Step 2 To a solution of 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (100. mg, 0.2100 mmol) dissolved in methanol (4 mL) and DCM (4 mL) was added piperidine (0.1 mL, 0.8500 mmol) and tert-butyl N-(l-formylcyclopropyl)carbamate (58.9 mg, 0.3200 mmol). The reaction was heated to reflux for 6 hrs and then cooled and concentrated. The residue was and dissolved in ethyl acetate (50 mL) and washed with water (50 mL) and then brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by Isolera (1%-8% MeOH/DCM) to provide 39 mg (13% yield) of tert-butyl N-[1-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]cyclopropyl]carbamate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 45℃; for 5h;Inert atmosphere; | tert-Butyl (l-formylcyclopropyl)carbamate (47.0 mg, 0.254 mmol) was added to 3-((lr,4r)-4-aminocyclohexyl)-N-(4-methoxybenzyl)-2-(l-(4-methoxybenzyl)-lH-tetrazol-5-yl)- 6-(trifluoromethyl)benzenesulfonamide (80 mg, 0.127 mmol)in DCE. Followed by adding sodium triacetoxyborohydride (67.2 mg, 0.317 mmol) and acetic acid (10.89 μ, 0.190 mmol). The reaction mixture was stirred at 45 C under 2 for 5 hr. The mixture was diluted with water and extracted with EtOAc twice (2X30 ml). The combined organic phase was washed with saturated aHC03, brine (30 mL), dried (MgS04), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtO Ac/is ohexane to give the intermediate tert-butyl (l-((((lr,4r)-4-(2-(l-(4-methoxybenzyl)- lH-tetrazol-5-yl)-3-(N-(4-methoxybenzyl)sulfamoyl)-4- (trifluoromethyl)phenyl)cyclohexyl)amino)methyl)cyclopropyl)carbamate. This intermediate product was treated with Method 3 and 4 to afford the title product. LC/MS: Calc'd mass 459.17; Observed mass 460.45 [M+l . | |
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 45℃; for 5h;Inert atmosphere; | tert-Butyl (1-formylcyclopropyl)carbamate (47.0 mg, 0.254 mmol) was added to 3-((1r,4r)-4-aminocyclohexyl)-N-(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-(trifluoromethyl)benzenesulfonamide (80 mg, 0.127 mmol) in DCE. Followed by adding sodium triacetoxyborohydride (67.2 mg, 0.317 mmol) and acetic acid (10.89 μl, 0.190 mmol). The reaction mixture was stirred at 45 C. under N2 for 5 hr. The mixture was diluted with water and extracted with EtOAc twice (2×30 ml). The combined organic phase was washed with saturated NaHCO3, brine (30 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/isohexane to give the intermediate tert-butyl (1-((((1r,4r)-4-(2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-3-(N-(4-methoxybenzyl)sulfamoyl)-4-(trifluoromethyl)phenyl)cyclohexyl)amino)methyl)cyclopropyl)carbamate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 4h;Inert atmosphere; | tert-Butyl (l-formylcyclopropyl)carbamate (108 mg, 0.584 mmol) was added to N-(4-methoxybenzyl)-2-( 1 -(4-methoxybenzyl)- 1 H-tetrazol-5-yl)-3 -(3 -azaspiro [5.5 ]undecan-9- yl)-6-(trifluoromethyl)benzenesulfonamide (200 mg, 0.292 mmol) in DCE (2.5 mL). Sodium triacetoxyborohydride (155 mg, 0.730 mmol) and acetic acid (0.025 ml, 0.438 mmol) were added. The mixture was stirred at RT under nitrogen for 4 hr. Then mixture was diluted with water and extracted with EtOAc twice (50mL). The combined organic phase was washed with saturated NaHC03, brine ( 2 x 30 ml), dried (MgS04), filtered through a celite pad and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane to give tert-butyl (l-((9-(2-(l-(4- methoxybenzyl)-lH-tetrazol-5-yl)-3-(N-(4-methoxybenzyl)sulfamoyl)-4- (trifluoromethyl)phenyl)-3-azaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)carbamate. Followed by using deprotection Method 3 and 4 to afford the title product. LC/MS: Calc'd mass 513.21 ; Observed mass 514.50 [M+l . | |
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 4h;Inert atmosphere; | Example 834 3-[3-[(1-aminocyclopropyl)methyl]-3-azaspiro[5.5]undecan-9-yl]-2-(1H-tetrazol-5-yl)-6-(trifluoromethyl)benzenesulfonamide (1296) (1297) tert-Butyl (1-formylcyclopropyl)carbamate (108 mg, 0.584 mmol) was added to N-(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-3-(3-azaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)benzenesulfonamide (200 mg, 0.292 mmol) in DCE (2.5 mL). Sodium triacetoxyborohydride (155 mg, 0.730 mmol) and acetic acid (0.025 ml, 0.438 mmol) were added. The mixture was stirred at RT under nitrogen for 4 hr. Then mixture was diluted with water and extracted with EtOAc twice (50 mL). The combined organic phase was washed with saturated NaHCO3, brine (2×30 ml), dried (MgSO4), filtered through a celite pad and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane to give tert-butyl (1-((9-(2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-3-(N-(4-methoxybenzyl)sulfamoyl)-4-(trifluoromethyl)phenyl)-3-azaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)carbamate. Followed by using deprotection Method 3 and 4 to afford the title product. LC/MS: Calc'd mass 513.21; Observed mass 514.50 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Three 250mL flask was added triphenylphosphine (45. 4g, 0 · 17mol, 4eq) and DCM (255g), the reaction solution was cooled down to0~5 C, was added CBr4 (28. 6g, 0. 086mol, 2eq), the red color of the solution no mention, 20min after the solid precipitation.Four batches Compound 2Α (8g, 0. 043πο1, leq), heat obvious, 0 C reaction 0. 5h. The solid was removed by filtration, and concentrated,Brush silica gel, the eluent was concentrated to give a pale yellow solid 13. 7g.[0047] 4 NMR (400MHz, CDC13):... Δ = 6. 687 (s, 1H), 1 453 (s, 9H), 1 288 (m, 2H), 1 253 (m,2H) ppm; ESI / MS: m / z = 342 (Μ + Η) +.[0048] The light yellow solid (270mL) was added in THF, cooled to -78 C, dropping 2. 5Mn-BuLi / hexane solutionLiquid (53mL, 0 130mol, 3eq.), - 78 C reaction 30min, was slowly warmed to -40 C, the reaction 30min. Slowly at -40 CDropwise addition of water (lmL), was slowly warmed to room temperature and extracted with ethyl acetate (100mL * 2), dried and concentrated to give a solid. N-heptylDioxane (20g) was added to the solid, stirred 30min, filtered and dried to afford Compound 3A as a white solid (6. 6g, yield:84%, purity: 94.1%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | three flask was added compound 24 (28,0.0111111,169) and 01 ^ (201 ^), added dropwise at room temperatureTCA (2 · 6g, 0 · 016mol, 1 · 5eq), at room temperature was added in three portions sodium trichloroacetate (3g, 0 · 015mol, 1 · 6eq),Room temperature 4h. Cooled to 0 C, was added dropwise acetic anhydride (2. 2g, 0. 022mol, 2eq), was slowly warmed to room temperature, room temperaturelh. Acetic acid (25mL), cooled to 0 C, was added zinc dust (1.48,0.02 111,269), warmed to 55~60 (:, transShould lh. Slow cooling to room temperature, water (200 mL), filtered, MTBE extract (50mL * 2), the combined organic phases with saturated common saltWashed with water (30mL * l), the organic phase was concentrated, brush silica, eluant was concentrated to give a pale yellow solid 2. 4g.2. 4g solid was added to the three 100mL flask was added THF (30mL), cooled to -30 C, was added dropwise 1. 6M AButyl lithium / diethyl ether solution (18mL, 0. 03mol, 3eq), low temperature reaction lh, slowly warmed to room temperature. Aqueous solution of ammonium chloride(100 mL), extracted with ethyl acetate (50mL * 2), and the combined organic phase was concentrated to give a solid, n-heptane (10g) was added to the solid,Stirred for 30min, filtered and dried to afford Compound 3A as a white solid (1. 5g, Yield: 77%, purity: 952%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | 250mL three neck flask was added triphenylphosphine (11. 3g, 0. 044mol, 4eq) and DCM (255g), the reaction solutionCooled to 0~5 C, was added CC14 (11. 4g, 0 · 022mol, 2eq), stirred for 30min. Compound was added in four batches2Α (2g, 0. 01 lmo 1,1 eq), heat obvious, 0 C reaction 0. 5h. Filtered to remove solids, and concentrated, brush silica gel, eluent concentrationCondensing pale yellow solid 2. 5g. ESI / MS: m / z = 253 (M + H) +.[0078] (50mL) of the pale yellow solid was added THF, cooled to -78 C, was added dropwise 2. 5Μ n-BuLi / hexane solution(13mL, 0 · 033mol, 3eq), - 78. . The reaction 30min, slowly warmed to -40. . The reaction 30min. -40. . Slowly droppedWater (50 mL), was slowly warmed to room temperature and extracted with ethyl acetate (50mL * 2), dried and concentrated to give a solid. N-Heptane (10g)Was added to the solid, stirred for 30min, filtered and dried to afford Compound 3A as a white solid (1. 45g, yield: 74%, pureDegree: 95 · 1%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
250mL three neck flask was added triphenylphosphine (11. 3g, 0 · 044mol, 4eq) and DCM (255g), the reactionWas cooled to 0~5 C, was added CI4 (11. 4g, 0. 022mol, 2eq), stirred for 30min. Four batches Compound 2Α (2g, 0. 01 lmo 1,1 eq), heat obvious, 0 C reaction 0. 5h. Filtered to remove solids, and concentrated, brush silica gel, eluent concentrationReduced to give a yellow solid 4. 3g. ESI / MS: m / z = 436 (M + H) +.[0073] (50mL) of the pale yellow solid was added THF, cooled to -78 C, was added dropwise 2. 5Μ n-BuLi / hexane solution(13mL, 0 · 033mol, 3eq), - 78. . The reaction 30min, slowly warmed to -40. . The reaction 30min. -40. . Slowly droppedWater (50 mL), was slowly warmed to room temperature and extracted with ethyl acetate (50mL * 2), dried and concentrated to give a solid. N-Heptane (10g)Was added to the solid, stirred for 30min, filtered and dried to afford Compound 3A as a white solid (1. 55g, yield: 79%, pureDegree: 94 · 6%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | X.iv. Tert-butyl (l-(2,2-dibromovinyl)cyclopropyl)carbamate: To a solution of CBr4 (18.3 g; 54.8 mmol) in DCM (40 mL) cooled at -20C, was added dropwise over 1 h a solution of PPI13 (29.6 g; 107 mmol) in DCM (65 mL). The solution was allowed to slowly warm to 0C and then cooled to -78C. TEA (7.5 mL; 53.9 mmol) was added. A solution of intermediate X.iii (5.0 g, 26.9 mmol) in DCM (50 mL) was added dropwise over 45 min keeping IT under -72C. The suspension was kept stirring at this temperature for 30 min before warming to 15C. The mixture was diluted in Et20 (20 mL), and the solids were filtered off. The filtrate was concentrated to dryness and the residue was purified by CC (EA-Hept) to afford the title compound as a white solid (7.7 g; 84% yield). XH NMR (i -DMSO) δ: 7.46 (s, 1H); 6.48 (s, 1H); 1.37 (s, 9H); 0.97-0.94 (m, 2H); 0.92-0.89 (m, 2H) | |
84% | With triethylamine; triphenylphosphine; In dichloromethane; at -78 - 15℃; for 2.25h; | To a solution of CBr4 (18.3g, 54.8mmol) in DCM (40 mL) cooled at -20C, was added dropwise over lh a solution of triphenylphosphine (29.6 g; 107 mmol) in DCM (65 mL). The solution was allowed to slowly warm to 0C and then cooled to -78C. TEA (7.5 mL; 53.9 mmol) was added. A solution of intermediate F.i (5.0 g, 26.9 mmol) in DCM (50 mL) was added dropwise over 45 min at -78C. The IT was kept under -72C. The suspension was kept stirring at this temperature for 30 min before warming to 15C. The mixture was diluted in Et20 (20 mL), and the solids were filtered off. The filtrate was concentrated to dryness and the residue was purified by CC (EA-Hept) to afford the title compound (7.7g, 84% yield) as a white solid. 1H NMR (d6-DMSO) δ: 7.46 (s, 1H); 6.48 (s, 1H); 1.37 (s, 9H); 0.97-0.94 (m, 2H); 0.92-0.89 (m, 2H). |
13.7 g | Three 250mL flask was added triphenylphosphine (45.4g, 0.17mol, 4eq) and DCM (255g), the reaction solutionCooled to 0 ~ 5 , added CBr4 (28.6g, 0.086mol, 2eq), the red color of the solution no mention, 20minAfter the solid separated. Four batches Compound 2A (8g, 0.043mol, 1eq), heat obvious, 0 reaction0.5h. The solid was removed by filtration, concentrated and silica gel brush, the eluent was concentrated to give a pale yellow solid 13.7g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.4 g | Three 100mL flask was added compound 2A (2g, 0.011mol, 1eq) and DMF (20mL), at room temperatureTCA was added dropwise (2.6g, 0.016mol, 1.5eq), added in three portions at room temperature, sodium trichloroacetate (3g,0.015mol, 1.6eq), room temperature 4h. Cooled to 0 , was added dropwise acetic anhydride (2.2g, 0.022mol, 2eq),It was slowly warmed to room temperature, room temperature 1h. Acetic acid (25mL), cooled to 0 , was added zinc dust (1.4g,0.02mol, 2eq), warmed to 55 ~ 60 , the reaction 1h. Slow cooling to room temperature, water (200 mL),Filtered, MTBE extract (50mL * 2), the combined organic phase was washed with brine (30mL * 1), the organic was concentratedPhase, brush silica, eluant was concentrated to give a pale yellow solid 2.4g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.3 g | 250mL three neck flask was added triphenylphosphine (11. 3g, 0 · 044mol, 4eq) and DCM (255g), the reactionWas cooled to 0~5 C, was added CI4 (11. 4g, 0. 022mol, 2eq), stirred for 30min. Four batches Compound 2Α (2g, 0. 01 lmo 1,1 eq), heat obvious, 0 C reaction 0. 5h. Filtered to remove solids, and concentrated, brush silica gel, eluent concentrationReduced to give a yellow solid 4. 3g. |
A217613 [168539-99-9]
tert-Butyl (1-formylcyclopentyl)carbamate
Similarity: 0.90
A432783 [163554-55-0]
tert-Butyl (1-formylcyclobutyl)carbamate
Similarity: 0.90
A217613 [168539-99-9]
tert-Butyl (1-formylcyclopentyl)carbamate
Similarity: 0.90
A432783 [163554-55-0]
tert-Butyl (1-formylcyclobutyl)carbamate
Similarity: 0.90
A457847 [104062-70-6]
(S)-tert-Butyl (1-oxohexan-2-yl)carbamate
Similarity: 0.90
A743858 [160801-74-1]
(S)-tert-Butyl (1-oxopentan-2-yl)carbamate
Similarity: 0.90
A443361 [171560-22-8]
(R)-tert-Butyl (1-oxopentan-2-yl)carbamate
Similarity: 0.90
A217613 [168539-99-9]
tert-Butyl (1-formylcyclopentyl)carbamate
Similarity: 0.90
A432783 [163554-55-0]
tert-Butyl (1-formylcyclobutyl)carbamate
Similarity: 0.90
A457847 [104062-70-6]
(S)-tert-Butyl (1-oxohexan-2-yl)carbamate
Similarity: 0.90
A743858 [160801-74-1]
(S)-tert-Butyl (1-oxopentan-2-yl)carbamate
Similarity: 0.90
A443361 [171560-22-8]
(R)-tert-Butyl (1-oxopentan-2-yl)carbamate
Similarity: 0.90
A217613 [168539-99-9]
tert-Butyl (1-formylcyclopentyl)carbamate
Similarity: 0.90
A432783 [163554-55-0]
tert-Butyl (1-formylcyclobutyl)carbamate
Similarity: 0.90
A457847 [104062-70-6]
(S)-tert-Butyl (1-oxohexan-2-yl)carbamate
Similarity: 0.90
A743858 [160801-74-1]
(S)-tert-Butyl (1-oxopentan-2-yl)carbamate
Similarity: 0.90
A443361 [171560-22-8]
(R)-tert-Butyl (1-oxopentan-2-yl)carbamate
Similarity: 0.90