Structure of 135865-78-0
*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. : | 135865-78-0 |
Formula : | C14H19NO3 |
M.W : | 249.31 |
SMILES Code : | CC(C)(C)OC(=O)N[C@@H](CC=O)C1=CC=CC=C1 |
MDL No. : | MFCD11559103 |
InChI Key : | ZGPCDZZHEWGTEU-LBPRGKRZSA-N |
Pubchem ID : | 11817535 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 18 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.43 |
Num. rotatable bonds | 7 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 69.77 |
TPSA ? Topological Polar Surface Area: Calculated from |
55.4 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.26 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.89 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.52 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.98 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.37 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.2 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.36 |
Solubility | 1.09 mg/ml ; 0.00435 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.68 |
Solubility | 0.526 mg/ml ; 0.00211 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.76 |
Solubility | 0.0437 mg/ml ; 0.000175 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.48 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.43 |
* 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 |
---|---|---|
To a dry, cooled (-78° C.) solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate from Step A (1.00 g, 3.41 mmol) was added a solution of DiBAl-H (6.82 mL, 6.82 mmol, 1 M in CH2Cl2) slowly over 30 min. After an additional 30 min of stirring at -78° C., the reaction was quenched by the rapid addition of saturated aqueous Rochelle's salt (32 mL). The cooling bath was then removed and the reaction was allowed to rapidly stir until a noticeable decrease in the amount of emulsion was observed. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2.x.30 mL). Combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of EtOAc:hexanes 5:95 to 40:60, to give the title compound. MS: m/z=150 (M-CO2C4H7). | ||
With diisobutylaluminium hydride; | Synthesis of compounds 69-71 see tableScheme V (for compounds 69-71 ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of tert-butyl [(1S)-3-oxo-1-phenylpropyl]carbamate from Step B (0.820 g, 3.29 mmol) and methyl 1-aminocyclopentanecarboxylate hydrochloride (0.591 g, 3.29 mmol) in chloroform (33 mL) was added Hunig's base (0.574 mL, 3.29 mmol). After stirring at ambient temperature for 20 min, NaHB(OAc)3 (1.74 g, 8.22 mmol) was added as a solid. Upon completion of the reaction, saturated aqueous NaHCO3 (3 mL) was added and the mixture was allowed to stir for at least 2 h. Water (5 mL) and additional saturated NaHCO3 (3 mL) was then added to form two layers. The aqueous layer was extracted once with chloroform (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM 1:99 to 6:94, to give the title compound. MS: m/z=377 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Preparation 7; [ (S) -3- (l-Isopropyl-3- (tetrahydropyran-4-ylmethyl) - bicyclo [3.2.1] -2-oxo-lbeta, 3 , 8-triaza-spiro [4.5] dodec-8-yl) -1- phenyl -propyl] - carbamic acid tert-butyl ester; To 500 mg (1.55 mmol) of l-isopropyl-3 - (tetrahydropyran-4- ylmethyl) -bicyclo [3.2.1] -lbeta, 3, 8-triaza-spiro [4.5] dodecan-2-one in anhydrous DCE (40 mL) was added 388 mg (1.55 mmol) of ((S) -3- oxo-1-phenyl-propyl) -carbamic acid tert-butyl ester and 260 muL (1.86 mmol) of triethylamine . The reaction mixture was stirred for 30 minutes and 412 mg (1.94 mmol) of sodium triacetoxyborohydride was added in one portion. Then the reaction mixture was agitated overnight at room temperature, diluted with DCM, washed with saturated solution of sodium bicarbonate and dried over sodium sulfate. The residue was purified by flash chromatography on silica gel eluting with DCM/Methanol (0 to 8percent) to yield 731 mg (85percent) of [(S)-3-(l- isopropyl-3 - (tetrahydropyran-4-ylmethyl) -bicyclo [3.2.1] -2 -oxo- lbeta, 3 , 8-triaza-spiro [4.5] dodec-8-yl) -1 -phenyl -propyl] - carbamic acid tert-butyl ester as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
This Example illustrates the preparation of [(S)- [3- (4- F ETHYL- [2- (4-METHANESULFONYL-] [PHENYL)-ACETYL]-AMINO}-PIPERIDIN-1-YL)-1-PHENYL-PROPYL]-CARBAMIC] acid tert-butyl ester (Compound No. [1] of Table [: Q.] To a stirred solution of [(S)-(3-OXO-1-PHENYL-PROPYL)-CARBAMIC] acid tert-butyl ester (Method C, 25g, 100 [MMOL),] N-ethyl-2- (4-methanesulfonyl-phenyl)-N-piperidin-4-yl- acetamide (Method A, 36g, 110 mmol) and glacial acetic acid (6. [0ML)] in a 1 : 1 mixture of DCM and methanol [(500ML)] was added portionwise sodium triacetoxyborohydride (25g, 120 mmol) at ambient temperature. The reaction mixture was stirred for a further 12 hours, then 2N sodium hydroxide solution (500mL) was cautiously added during 30 minutes and the resulting mixture extracted into DCM [(500ML).] The crude product was purified by chromatography on silica eluting with a 9: 1 mixture of ethyl acetate and methanol to give the title compound as a colourless gum, which slowly solidified (40g). A portion was [CRYSTALLISED] from ethyl acetate to give a white solid, m. p. [115-116°C.] 1H NMR : [1.] 0 and 1.1 (t, 3H), [1.] 35 (s, 9H), 1.5 (m, 2H), 1.7 (m, 4H), 1.9 (m, 2H), 2.2 (t, 2H), 2.8 (m, 2H), 3.15 (s, 3H), 3.2 and 3.3 (q, 2H), 3.6 and 4.1 (m, 1H), 3.8 and 3.85 (s, 2H), 4.5 (m, 1H), 7.2 (m, 5H), 7.4 (br d, 1H), 7.5 (d, 2H), 7.8 (d, 2H). LCMS: 558 [(MH+).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium bis(2-methoxyethoxy)aluminum hydride; In toluene; at -20 - 15℃; for 1h; | To a solution of (S)-N-methyl-N-methoxy-3-phenyl-3-Bocaminopropionamide (5.52g, 17. [9MMOL)] in toluene [(180ML)] at-20°C was added sodium bis (2-methoxyethoxy) aluminium hydride (65percent solution [IN TOLUENE,] 35. 8mmol) dropwise. The resulting mixture was stirred at- [15°C] for [LH.] The mixture was washed with saturated aqueous sodium dihydrogen phosphate solution (250mL). The organic phase was dried [(NA2S04).] and concentrated to give the title compound (5g). [1H NMR] : 1.4 (s, 9H), 2.8 (m, 2H), 5.1 (m, 1H), 7. 3 (m, [5H),] 8.6 (m, [IH),] 9.6 (t, [IH).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In dichloromethane; for 16h; | Method U (S) N- (3-Amino-3-phenylpropyl)-4- [2- (4-methanesulphonylphenylsulphonyl) ethyl] piperidine Sodium triacetoxyborohydride (1.6g) was added to a mixture of (S) 3-phenyl-3- (tert- BUTOXYCARBONYLAMINO) propionaldehyde (1.23g) and 4- [2- (4-METHANESULPHONYLPHENYL- sulphonyl) ethyl] piperidine hydrochloride (1.215g) (Method B) in dichloromethane (50ML) and the mixture was stirred for 16 hours. The reaction mixture was washed successively with 2M sodium hydroxide (15ML), water (15ML) and brine (15ML) and dried. The dichloromethane solution was stirred with PS-NCO (isocyanate resin, 1. 5G) for 16 hours and filtered. The filtrate was chromatographed on a 50g silica Bond Elut column eluting with ethyl acetate to give the Boc protected title compound as a white solid, yield 1.595g, MHF 565. The Boc protected compound (1.59g) was dissolved in 4M HCI/DIOXANE (LOML) and allowed to stand at room temperature for 1 hour. The reaction mixture was evaporated to dryness, redissolved in 2M sodium hydroxide (10ML) and extracted with dichloromethane (2X20ML) and dried. Removal of the solvent gave the title compound, yield 0.56g, MH+ 465. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 18h; | Preparation 12 tert-Butyl (1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate acetic acid (0.6 ml, 10.4 mmol) was added to a stirred solution of 3-(8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (Preparation 11) (2.0 g, 6 mmol) and <strong>[135865-78-0]tert-butyl (1S)-3-oxo-1-phenylpropylcarbamate</strong> (WO0039125) (1.7 g, 6.8 mmol) dissolved in dichloromethane (40 ml) under nitrogen at room temperature.sodium triacetoxyborohydride (2.0 g, 9.4 mmol) was then added and the reaction was held at room temperature for 18 hours.The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate solution (50 ml) and dichloromethane (50 ml).The organic phase was removed and the aqueous phase was washed with dichloromethane (50 ml).The combined organic phases were dried (MgSO4) and the solvent was evaporated under reduced pressure.The residue was purified by flash column chromatography on silica gel eluding with a solvent gradient of dichloromethane:methanol:concentrated aqueous ammonia (96:4:0.4, by volume, changing to 94:6:0.6).Product containing fractions were evaporated to afford the title compound as a white foam (2.53 g). 1H NMR (400 MHz, CDCl3): delta: 7.40-7.20 (10H, m), 5.90 (1H, br s), 4.80 (1H, br s), 4.40 (1H, m), 3.70 (2H, s), 3.50 (2H, s), 3.30 (1H, m), 3.20 (1H, m), 2.85 (2H, m), 2.65 (2H, m), 2.45-2.30 (5H, m), 2.20 (2H, m), 2.00-1.70 (4H, m), 1.45-1.20 (13H, m) ppm. LRMS (electrospray): m/z [M+Na]+ 592, [M+H]+ 570. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 18h; | Preparation 33 tert-Butyl (1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate acetic acid (0.14 g, 2.37 mmol) was added to a stirred solution of 1-endo-(8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (Preparation 32) (0.8 g, 2.37 mmol) and <strong>[135865-78-0]tert-butyl (1S)-3-oxo-1-phenylpropylcarbamate</strong> (WO0039125) (0.711 g, 2.85 mmol) dissolved in dichloromethane (12 ml) under nitrogen at room temperature.sodium triacetoxyborohydride (0.60 g, 2.85 mmol) was then added and the reaction was held at room temperature for 18 hours.The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate solution (50 ml) and dichloromethane (50 ml).The organic phase was removed and the aqueous phase was washed with dichloromethane (50 ml).The combined organic phases were dried (MgSO4) and the solvent was evaporated under reduced pressure.The residue was purified by flash column chromatography on silica gel eluding with a solvent gradient of dichloromethane:methanol:concentrated aqueous ammonia (99:1:0.1, by volume, changing to 90:10:1).Product containing fractions were evaporated to afford the title compound as a white foam (1.17 g). 1H NMR (400 MHz, CDCl3): delta: 7.40-7.20 (10H, m), 5.80 (1H, m), 4.80 (1H, m), 4.40 (1H, m), 3.65 (2H, s), 3.50 (2H, m), 3.40-3.20 (2H, m), 2.70-2.60 (4H, m), 2.55-2.35 (5H, m), 2.20 (2H, t), 2.10-1.10 (17H, m) ppm. LRMS (electrospray): m/z [M+H]+ 570. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step B tert-Butyl (1S)-3-oxo-1-phenylpropylcarbamate The compound was prepared from the title compound in Example 1, Step A (4 mmol, 1.1 g) as described in WO 00/39125, pp. 57-58. The aldehyde was further purified by flash chromatography on silica gel using a step gradient of hexanes, 4percent EtOAc/hexanes, 8percent EtOAc/hexanes, 12percent EtOAc/hexanes and 16percent EtOAc/hexanes. The aldehyde eluted in 16percent EtOAc/hexanes. Removal of solvent under reduced pressure afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3): delta 9.78 (s, 1H), 7.36-7.41 (m, 2H), 7.28-7.35 (m, 3H), 5.23 (br s, 1H), 5.12 (br s, 1H), 2.84-3.04 (m, 2H), 1.45 (s, 9H). MS (ESI): m/z 290 (dihydrate+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | To a solution of the title compound from Step B (10 mmol, 2.5 g was added the product of Step E (11 mmol, 4.5 g) and N,N-diisopropylethylamine (40 mmol, 7 mL) in 40 mL of DCM was added NaBH(OAc)3 (30 mmol, 6.4 g). The slurry was sonicated briefly and the reaction mixture was allowed to stand at RT for 1 h. The reaction mixture was washed with 20 mL of H2O. The organic phase was dried with MgSO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluding with 1:20:79 NH4OH/EtOAc/hexanes and 1:40:59 NH4OH/EtOAc/hexanes, affording the title compound as a white foamy solid. MS (ESI): m/z 503 (M+H). HPLC B: 1.78 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.8% | Example 2. {3-[3-(4-Bromobenzyl)-2,4-dioxo-1, 3,8-triaza- spiro [4.5] dec-8-yl]-1-(S)-phenylpropyl}-carbamic acid tart-butyl ester (Compound 4); To a solution of 115 mg (0.307 mmol) of 3- (4- bromobenzyl) -1, 3,8-triaza-spiro [4.5] decane-2,4-dione hydrochloride in 5 mL of anhydrous DCE were added successively 76.6 mg (0.307 mmol) of (3-OXO-1- (S)- PHENYLPROPYL)-CARBAMIC acid tert-butyl ester and 50 pL (0.358 mmol) of triethylamine. The reaction mixture was agitated at room temperature for 10 minutes before adding 85 mg (0.382 mmol) of sodium triacetoxyborohydride. After an overnight agitation, 10 mL of saturated solution of sodium bicarbonate were added. Then the solution was extracted with DCM, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography on bond elute silica gel eluting with 20percent ETHANOL/ETHYL acetate and Compound 4, as a colorless solid, was obtained (133 mg, 75. 8percent). 1H NMR (400 MHz, CDC13) 6 [PPM] 7.44 (D, 2H), 7.36-7. 2 (m, 7H), 6.06 (br S, 1H), 4.85-4. 7 (m, 1H), 4.58 (m, 2H), 3.0-2. 8 (m, 2H), 2.5-1. 5 (m, 10 H), 1. 42 (s, 9H). LC/MS: m/z 572.52 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | A solution of 4a (6.25g , 31 mmol) in DCM (200 mL) was added to 35 (1.0 g, 4.97 mmol). To the resulting mixture was added NaBH(OAc)3 (9.86 g, 47 mmol) in two portions and the reaction stirred for 18 h at RT. The reaction was washed with a solution 5percent NaHC03 (100 mL). The organic phase was dried (Na2S04) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with DCM/ 3.5percent MeOH (containing 10percent NH40H) to afford 6.8 g (46percent) of 36a as a viscous liquid: MS (ES+) m/z 436 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To the mixture of 35 (0.20 g, 0.82 mmol, CAS 135865-78-0) and 44 (0.18 g, 0.75 mmol) in DCM (10 mL) was added sodium triacetoxyborohydride (0.24g, 1.12 mmol) and the resulting solution was stirred at RT for 3 h. The mixture was diluted with DCM and washed with saturated NaHC03. The organic layer was dried (MgS04), filtered and evaporated. The crude product and purified by Si02 column chromatography eluting with DCM:MeOH:NH40H (140:10:1) to afford 0.29 g (80 percent) of 53a: ms (ES+) m/z 480 (M + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To 300 mg (1.19 mmol) of l-isopropyl-3-methyl- bicyclo[3.2.1]-lbeta,3, 8-triaza-spiro[4.5]dodecan-2, 4-dione in anhydrous DCE (30 itiL) was added 309 mg (1.24 mmol) of ((S)- 3-oxo-l-phenyl-propyl) -carbamic acid tert-butyl ester. The reaction mixture was stirred for 30 minutes and 380 mg (1.79 mmol) of sodium triacetoxyborohydride was added in one portion. Then the reaction mixture was agitated overnight at room temperature, diluted with DCM, washed with saturated solution of sodium bicarbonate and dried over sodium sulfate. The residue was purified by flash silica gel chromatography eluting with ethyl acetate:hexanes (0 to 100percent) then DCM.-methanol (9:1) to yield 509 mg (85percent) of [(S)- 3- (l-isopropyl-3-methyl-bicyclo[3.2.1]-2,4-dioxo-lbeta,3, 8- triaza-spiro [4.5]dodec-8-yl) -1-phenyl-propyl]-carbamic acid tert-butyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 3 tert-Butyl (1S)-3-oxo-1-phenylpropylcarbamate Diisobutylaluminium hydride (1 M in dichloromethane, 60 ml, 60 mmol) was cooled to -78° C. and added dropwise to a solution of the title compound from Preparation 2 (8.39 g, 30 mmol) in dichloromethane (150 ml) at -78° C. The reaction was stirred for 90 minutes then methanol (pre-cooled to -78° C., 40 ml) was added. The mixture was allowed to warm to room temperature and poured into 2 M aqueous hydrochloric acid (200 ml). The layers were separated and the aqueous phase extracted with dichloromethane (2*). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a white solid, 6.72 g. 1H NMR (400 MHz, CDCl3): delta [ppm] 1.42 (9H, s), 2.86-3.00 (2H, m), 5.06 (1H, bs), 5.20 (1H, bs), 7.22-7.38 (5H, m), 9.75 (1H, s). LRMS: m/z 250.1 (MH30). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step F tert-Butyl-(1S)-1-phenyl-3-(4-[3-benzyl-1-ethyl(1H-pyrazol-5-yl)]piperidin-1-yl)propylcarbamate To a solution of the title compound from preparation Example 1, Step B (10 mmol, 2.5 g), 4-[3-benzyl-1-ethyl-pyrazol-5-yl]piperidine, bis HCl salt (Example 1, Step E, 11 mmol, 4.5 g) and N,N-diisopropylethylamine (40 mmol, 7 mL) in 40 mL of DCM was added NaBH(OAc)3 (30 mmol, 6.4 g). The slurry was sonicated briefly and the reaction mixture was allowed to stand at ambient temperature for 1 h. The reaction mixture was washed with 20 mL of H2O. The organic phase was dried with MgSO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluding with 1:20:79 NH40OH/EtOAc/hexanes and 1:40:59 NH4OH/EtOAc/hexanes, affording the title compound as a white foamy solid. MS (ESI): m/z 503 (M+H). HPLC B: 1.78 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.7% | To a solution of 109 mg (0.35 mmol) of 3- (4-methoxy- benzyl) -1,3, 8-triaza-spiro [4.5] decan-2-one hydrochloride in 10 mL of anhydrous DCE were added successively 87.1 mg (0.35 mmol) of ( (S) -3-oxo-l-phenyl-propyl) -carbamic acid tert-butyl ester and 49 muL (0.35 mmol) of triethylamine . The reaction mixture was agitated at room <n="56"/>temperature for 10 minutes before adding 117 mg (0.525 mmol) of sodium triacetoxyborohydride . After an overnight agitation, 10 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2 x 20 mL) , dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with methanol/DCM (0percent to 4percent) giving { (S) -3- [3- (4-methoxy-benzyl) -2-oxo-l, 3 , 8-triaza-spiro [4.5] dec- 8 -yl] -1 -phenyl -propyl } -carbamic acid tert-butyl ester as a white solid (104.6 mg, 58.7percent).1H NMR (400 MHz, DMSO-ds): delta [ppm] 7.38 (d, IH), 7.28- 7.14 (m, 5H), 7.10 (d, 2H), 6.86 (d, 2H), 6.78 (br S, IH), 4.46 (q, IH), 4.12 (s, 2H), 3.70 (s, 3H), 3.28 (m, 2H), 2.90 (s, 2H), 2.14 (m, 4H), 1.72 (m, 2H), 1.51 (m, 4H) , 1.31 (S, 9H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.1% | To a solution of 220 mg (0.63 mmol) of 2- (4-methoxy- benzyl) -1,2, 8-triaza-spiro [4.5] decan-3-one dihydrochloride in 12 mL of anhydrous DCE were added successively 157.5 mg (0.63 mmol) of ( (S) -3-oxo-l- phenyl -propyl ) -carbamic acid tert-butyl ester and 176 muL (1.26 mmol) of triethylamine . The reaction mixture was agitated at room temperature for 10 minutes before adding 209 mg (0.94 mmol) of sodium triacetoxyborohydride . After an overnight agitation, 10 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2 x 20 mL) , dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with methanol/DCM (0percent to 6percent) giving 269.6 mg (84.1percent) of ((S)- 3- [2- (4-methoxy-benzyl) -3-oxo-l, 2 , 8-triaza- spiro [4.5] dec-8-yl] -1 -phenyl -propyl} -carbamic acid tert- butyl ester as a pale yellow oil.1H NMR (400 MHz, DMSO-d6) : delta [ppm] 7.41 (d, IH), 7.27- 7.14 (m, 7H), 6.84 (d, 2H), 5.31 (s, IH), 4.46 (q, IH), <n="58"/>4.29 (S, 2H) , 3.69 (s, 3H) , 2.26 (m, 2H) , 2.20 (s, 2H) , 2.12 (m, 4H) , 1.68 (m, 2H) , 1.45 (m, 4H) , 1.31 (s, 9H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.4% | To a solution of 374 mg (1.29 mmol) of 2- (4-methoxy- benzyl) -2, 8-diaza-spiro [4.5] decane-1, 3-dione in 20 mL of anhydrous DCE was added 322 mg (1.29 mmol) of ((S) -3- oxo-1-phenyl -propyl) -carbamic acid tert-butyl ester. The reaction mixture was agitated at room temperature for 10 minutes before adding 432 mg (1.94 mmol) of sodium triacetoxyborohydride . After an overnight agitation, 40 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2 x 50 mL) , dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with methanol/DCM (0percent to 3percent) giving 466.9 mg (69.4percent) of ((S)- 3- [2- (4-methoxy-benzyl) -1, 3-dioxo-2 , 8-diaza- spiro [4.5] dec- 8 -yl] -1 -phenyl -propyl} -carbamic acid tert- butyl ester as a colorless solid.1H NMR (400 MHz, DMSOd6): delta [ppm] 7.43 (d, IH), 7.26 (m, 4H), 7.18 (m, IH), 7.13 (d, 2H), 6.84 (d, 2H), 4.51 (q, IH), 4.44 (S, 2H), 3.69 (s, 3H), 2.70 (m, 2H), 2.60 (s, 2H), 2.18 (m, 2H), 1.89 (m, 2H), 1.80-1.72 (m, 4H), 1.47 (d, 2H) , 1.33 (S, 9H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.4% | To a solution of 806 mg (2.58 mmol) of 3- (4-methoxy- benzyl) -l-oxa-3 , 8-diaza-spiro [4.5] decan-2-one hydrochloride in 50 mL of anhydrous DCE were added successively 643 mg (2 58 mmol) of ( (S) -3 -oxo-1 -phenyl - propyl) -carbamic acid tert-butyl ester and 360 muL (2.58 mmol) of triethylamine . The reaction mixture was agitated at room temperature for 10 minutes before adding 860 mg (3.87 mmol) of sodium triacetoxyborohydpide . After an overnight agitation, 40 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2 x 50 mL) , dried over sodium sulfate, filtered and concentrated m vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with methanol/DCM (0percent to 2percent) giving { (S) -3- [3- (4-methoxy- benzyl) -2-oxo- l-oxa-3 , 8-diaza-spiro [4.5] dec-8-yl] -1- phenyl -propyl} -carbamic acid tert-butyl ester as a white solid (922 mg, 70 4percent) . 1H NMR (400 MHz, DMSO-d6) . delta [ppm] 7.39 (d, IH), 7.26 (m, 4H), 7.16 (m, 3H), 6.89 (d, 2H), 4.48 (m, IH), 4.23 (s, 2H), 3.70 (s, 3H), 3.10 (s, 2H), 2.31 (m, 4H), 2 18 (m, 2H) , 1.70 (m, 6H) , 1.31 (s, 9H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 4h; | EXAMPLE 3; 2-Cyclohexyl-N-{(S)-3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-malonamic acid methyl ester (I-20) and 2-cyclohexyl-N-{(S)-3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-1-phenyl-propyl}-malonamic acid; trifluoroacetate salt (I-14); Step 1-; A mixture of 43 (4.07 g, 16.3 mmol), 11a (3.0 g, 14.8 mmol), NaBH(OAc)3 (4.71 g, 22.2 mmol) and HOAc (2.1 mL, 37.1 mmol) in DCM (100 mL) was stirred at RT for 4 h. The reaction was quenched by addition of 5percent NaHCO3. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic extracts were dried (MgSO2), filtered and concentrated in vacuo. The residue was purified via SiO2 chromatography eluting with DCM/MeOH to afford 44a. |
A102542 [718611-17-7]
(S)-Boc-3-Amino-3-phenylpropan-1-ol
Similarity: 0.90
A185238 [158807-47-7]
(R)-N-Boc-3-Amino-3-phenylpropan-1-ol
Similarity: 0.90
A135173 [71420-95-6]
3-[(Boc-amino)methyl]phenylacetic Acid
Similarity: 0.85
A832123 [137102-30-8]
(S)-tert-Butyl (2-amino-1-phenylethyl)carbamate
Similarity: 0.85
A105737 [156866-52-3]
tert-Butyl 4-formylbenzylcarbamate
Similarity: 0.82
A265216 [59830-60-3]
(S)-Benzyl (1-oxo-3-phenylpropan-2-yl)carbamate
Similarity: 0.78
A280392 [63219-70-5]
(R)-Benzyl (1-oxo-3-phenylpropan-2-yl)carbamate
Similarity: 0.78
A101142 [497861-77-5]
(R)-tert-Butyl (4-oxobutan-2-yl)carbamate
Similarity: 0.72
A442429 [186743-06-6]
tert-Butyl (4-oxobutan-2-yl)carbamate
Similarity: 0.72
A102542 [718611-17-7]
(S)-Boc-3-Amino-3-phenylpropan-1-ol
Similarity: 0.90
A185238 [158807-47-7]
(R)-N-Boc-3-Amino-3-phenylpropan-1-ol
Similarity: 0.90
A135173 [71420-95-6]
3-[(Boc-amino)methyl]phenylacetic Acid
Similarity: 0.85
A832123 [137102-30-8]
(S)-tert-Butyl (2-amino-1-phenylethyl)carbamate
Similarity: 0.85
A102542 [718611-17-7]
(S)-Boc-3-Amino-3-phenylpropan-1-ol
Similarity: 0.90
A185238 [158807-47-7]
(R)-N-Boc-3-Amino-3-phenylpropan-1-ol
Similarity: 0.90
A114420 [67341-01-9]
tert-Butyl (2-hydroxy-1-phenylethyl)carbamate
Similarity: 0.85
A135173 [71420-95-6]
3-[(Boc-amino)methyl]phenylacetic Acid
Similarity: 0.85
A832123 [137102-30-8]
(S)-tert-Butyl (2-amino-1-phenylethyl)carbamate
Similarity: 0.85