Structure of 871658-02-5
*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. : | 871658-02-5 |
Formula : | C5H10ClN |
M.W : | 119.59 |
SMILES Code : | C1(C2)NCC2C1.Cl |
MDL No. : | MFCD19160638 |
InChI Key : | ILHPSPUYHFANIX-UHFFFAOYSA-N |
Pubchem ID : | 55219746 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-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 |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 24.0h; | DIPEA (0.80 mL, 4.32 mmol) was added to a suspension of 3-fluoro-4-(3-[(1S)-2-hydroxy-l- methylethoxy]-5-[(1=methyl-1H pyrazol-3-yl)amino]carbonyl{phenoxy)benzoic acid (230 mg, 0.54 mmol), HATU (430 mg, 1.29 mmol) and <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> salt (96 mg, 0.81 mmol) in DMF (4 mL) and the mixture stirred at RT for 24 hours. Ethyl acetate was added and washed with water (3 x 30 mL), brine (30 mL), dried (MgS04), and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0- 10% methanol in DCM, to give the desired compound (51 mg). ' H NMR 8 (CDC13): .1.21 (d, 3H), 1.40 (m, 1 H), 1.51 (brm, 1 H), 1.92 (m, 2H), 2.15 (t, 1 H), 2.90 (m, 1H), 3.42 (m, 1H), 3.55 (m, 1H), 3.69 (m, 2H), 3.71 (s, 3H), 4.37 (m, 1H), 4.45 (m, 1H), 6.70 (m, 1H), 6.73 (s, 1H), 6.98 (m, 1H), 7.05 (t, 1 H), 7.12 (s, 1H), 7.27 (m, 2H), 7.30- 7.50 (brm, 1H), 8.61 (brs, 1H); m/z 495 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; for 4.0h;Heating / reflux; | A mixture of ethyl 2-azabicyclo[2.1.1]hexane-2-carboxylate (0.35 g, 2.25 mmol) and concentrated hydrochloric acid (10 mL) was refluxed for 4 hours, cooled and the volatiles removed in vacuo. Toluene was added then removed in vacuo and the resultant product dried under reduced pressure to give the desired compound which was used without further purification (0.24 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 5.0h; | To the mixture of 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5?-bipyrimidin]-2?-amine (380 mg, 1.09 mmol) and potassium carbonate (754 mg, 5.45 mmol) in DMSO (5 mL) was added <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> (326 mg, 2.73 mmol). The mixture was stirred at 100 C. for 5 h. After removal of the solvent, the residue was purified by Prep-HPLC (formic acid) to afford 2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-[4,5?-bipyrimidin]-2?-amine (220 mg, 57% yield). LCMS (ESI): [MH]+=352.1; 1H NMR (400 MHz, DMSO-d6) delta 8.91 (s, 2H), 7.00 (s, 2H), 6.30-6.10 (m, 1H), 5.10-4.90 (m, 1H), 4.83 (d, J=6.4 Hz, 1H), 4.70-4.64 (m, 1H), 3.78-3.76 (m, 1H), 3.66-3.64 (m, 1H), 3.45-3.38 (m, 4H), 2.89-2.87 (m, 1H), 1.93-1.86 (m, 4H), 1.32-1.31 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.7% | With potassium carbonate; In dimethyl sulfoxide; at 90℃; for 16.0h; | To a solution of (1S,4S)-tert-butyl 5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-chloropyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (220 mg, 0.47 mmol) in DMSO (2 mL) was added <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> (68 mg, 0.56 mmol) and potassium carbonate (130 mg, 0.93 mmol). The mixture was heated at 90 C. for 16 h. After cooling to room temperature, water (50 mL) was added to. The mixture was extracted with ethyl acetate (30 mL (3 times)). The organic layer was dried over sodium sulfate, concentrated and purified by flash column chromatography (50% ethyl acetate in petroleum ether to 100% ethyl acetate) to provide (1S,4S)-tert-butyl 5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (130 mg, 53.7% yield). LCMS (ESI): [MH]+=518.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 2.0h; | To a solution of (1R,5S,6r)-tert-butyl 6-(2?-amino-2-(methylsulfonyl)-[4,5?-bipyrimidin]-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.46 mmol) in DMSO (15 mL) was added <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> (109.5 mg, 0.92 mmol) and potassium carbonate (127 mg, 0.92 mmol). The mixture was stirred at 120 C. for 2 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (2×20 mL). The organic layer was concentrated and purified by flash column chromatography (75% ethyl acetate in petroleum ether) to provide (1R,5S,6r)-tert-butyl 6-(2?-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5?-bipyrimidin]-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (140 mg, 70% yield). TLC (EA, Rf=0.30.4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.7% | With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 150℃; for 18.0h;Microwave irradiation; | To a microwave vial charged with (1S,4S)-5-(2,6-dichloropyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (100 mg, 0.41 mmol) and <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> (244 mg, 2.04 mmol) in NMP (3 mL) was added cesium carbonate (1.33 g, 4.08 mmol). The vial was sealed and heated by microwave irradiation at 150 C. for 18 h. The reaction mixture was concentrated in vacuo, and resulting residue was purified by TLC (PE:EA=1:1) to afford compound 5 (80 mg, 77.7% yield). LCMS (ESI) [MH]+=291.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 92.0h;Sealed tube; | To a solution of 1-(2,6-dichloro-4-pyridyl)cyclobutanecarbonitrile (100 mg, 0.440 mmol) in anhydrous DMSO (0.44 mL) was added <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> (60 mg, 0.48 mmol) and potassium carbonate (122 mg, 0.881 mmol). The vessel was sealed and the reaction mixture stirred at 100 C. for 92 h. After cooling to rt, the mixture was diluted with diethyl ether and washed with water (2×), brine (1×) and dried over MgSO4 and concentrated to dryness. The following compounds were added to the crude product: 2-aminopyridine-5-boronic acid pinacol ester (110 mg, 0.48 mmol), chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (16.6 mg, 0.0220 mmol), 2-Dicyclohexylphosphino-2?,4?,6?-triisopropylbiphenyl (21.4 mg, 0.0440 mmol), and potassium phosphate tribasic (289 mg, 1.32 mmol). Under a stream of nitrogen, anhydrous, degassed THF (1.3 mL) and degassed water (0.22 mL) were added and the vial was sealed tightly. The reaction mixture was stirred at 80 C. for 3 h, cooled to rt, and filtered through Celite, rinsing with CH2Cl2. The residue obtained after concentration was purified by RPLC to afford the title compound as a white solid (85.4 mg, 58% over 2 steps); 1H NMR (400 MHz, DMSO) delta 8.92 (s, 2H), 7.10 (d, J=1.1 Hz, 1H), 6.91 (br s, 2H), 6.46 (d, J=1.1 Hz, 1H), 4.95-4.81 (m, 1H), 3.44 (s, 2H), 3.01-2.90 (m, 1H), 2.75-2.64 (m, 4H), 2.39-2.18 (m, 1H), 2.11-1.92 (m, 3H), 1.41-1.27 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.9 mg | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 4.5h;Sealed tube; | Into a vial was weighed 1-(2,6-dichloropyrimidin-4-yl)cyclobutanecarbonitrile (64.2 mg, 0.281 mmol), 2-aminopyridine-5-boronic acid pinacol ester (64.2 mg, 0.281 mmol), tetrakis(triphenylphosphine)palladium(0) (16.3 mg, 5 mol %), and sodium carbonate (90 mg, 0.84 mmol). Under a stream of nitrogen, anhydrous, degassed THF (0.84 mL) and degassed water (0.14 mL) were added and the vial was sealed tightly. The reaction mixture was stirred at 90 C. for 68 h, cooled to rt, filtered through Celite rinsing with CH2Cl2, and concentrated to dryness. To this crude product was added <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> (49 mg, 0.39 mmol), N,N-diisopropylethylamine (0.147 mL, 0.844 mmol), and anhydrous DMF (1.1 mL). The vessel was sealed and the reaction mixture stirred at 80 C. for 4.5 h. After cooling to rt, the mixture was concentrated and the residue subjected to RPLC purification to yield the title compound as a white solid (36.9 mg, 39% over 2 steps); 1H NMR (400 MHz, DMSO) delta 8.69 (s, 1H), 8.05 (s, 1H), 7.23 (t, J=74.0 Hz, 2H), 7.20 (s, 1H), 6.70 (br s, 2H), 4.95 (m, 1H), 3.54 (s, 2H), 2.99-2.91 (m, 1H), 2.81 (m, 2H), 2.72-2.60 (m, 2H), 2.32-2.18 (m, 1H), 2.13-1.94 (m, 3H), 1.45-1.38 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2.0h; | Examples 93 and 94 Step 1: 6-(3-azabicyclo[2.1.1]hexan-3-yl)-2-chloro-9-tetrahydropyran-2-yl-purine To a solution of 2,6-dichloro-9-tetrahydropyran-2-yl -purine (1.50 g, 5.49 mmol) in N,N- dimethylformaldehyde (10 niL) was added <strong>[871658-02-5]3-azabicyclo[2.1.1]hexane hydrochloride</strong> (722 mg, 6.04 mmol) followed by N,N'-diisopropylethylamine (2.4 niL, 13.7 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was then poured into water and extracted with ethyl acetate (3 x 75 rriL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in heptane) affording 6-(3-azabicyclo[2.1.1]hexan-3-yl)-2- chloro-9-tetrahydropyran-2-yl-purine as a white foam (1.15 g, 66%). LC-MS (Method A): m/z = 320.2 (M+H)+, 1.02 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.9% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16.0h; | Example 137 Step 1: 2-(6-(2-azabicyclo[2.1.1]hexan-2-yl)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8- yl)propan-2-ol To a solution of 2-(2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)propan-2-ol (770 mg, 2.32 mmol) and N,N-diisopropylethylamine (899 mg, 6.97 mmol) in acetonitrile (10 rriL) was added <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> (277 mg, 2.32 mmol). The resulting mixture was stirred at room temperature for 16 h and subsequently concentrated to dryness in vacuo. The resulting mixture was diluted with water and extracted with ethyl acetate (2 x 60 rriL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 200-300 mesh, 30% ethyl acetate in petroleum ether) affording 2-(6-(2-azabicyclo[2.1. l]hexan-2-yl)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8- yl)propan-2-ol (700 mg, 79.9%): LCMS (ESI, 5-95AB /1.5 min): RT = 0.834 min, m/z 378.1 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; | Step 3: 4-(3-azabicyclo[2.1.1]hexan-3-yl)-2-chloro-6,6,9-trimethyl-8,9-dihydropurino[8,9- c][l,4]oxazine To a solution of 2,4-dichloro-6,6,9-trimethyl-8,9-dihydropurino[8,9-c] [l,4]oxazine (60.6 mg, 0.211 mmol) and <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> (28.6 mg, 0.232 mmol) in N,N- dimethylformamide (2.0 mL) was added N,N-diisopropylethylamine (0.093 mL, 0.528 mmol). The solution was stirred at 60 C overnight. The reaction mixture was poured into water and extracted with dichloromethane (3 x 50mL). The organic layer was dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give a brown solid that was used as crude in the following reaction (65.1 mg, 92%): LC-MS (Method A): m/z = 334.1 (M+H)+, 1.16 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃; for 19.0h; | Step 4: 4-(2-azabicyclo[2.1.1]hexan-2-yl)-2-chloro-6-methyl-8,9-dihydro-6H-[l,4]oxazino[4,3- e] purine To a solution of racemic 2,4-dichloro-6-methyl-8,9-dihydro-6H-[l,4]oxazino[4,3-e]purine (223 mg, 0.860 mmol) and <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> (149 mg, 1.20 mmol) in N,N- dimethylformaldehyde (3.4 mL) was added N,N-diisopropylethylamine (0.38 mL, 2.2 mmol) and the mixture was stirred at 50 C for 19 h. The mixture was then diluted with dichloromethane and washed with aqueous saturated sodium bicarbonate. The organics were dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 40% ethyl acetate in hexane) affording racemic 4-(2-azabicyclo[2.1.1]hexan-2-yl)-2- chloro-6-methyl-8,9-dihydro-6H-[l,4]oxazino[4,3-e]purine as a yellow solid (199 mg, 76%): H NMR (400 MHz, Chloroform-d) delta 5.60 - 5.40 (m, 1H), 5.18 - 4.79 (m, 1H), 4.67 - 3.80 (m, 5H), 3.76 - 3.62 (m, 1H), 3.06 - 2.95 (m, 1H), 2.19 - 1.95 (m, 2H), 1.69 (d, = 6.7 Hz, 3H), 1.54 - 1.44 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 70℃; for 16.0h; | Step 4: 5-(4-(2-azabicyclo[2.1.1]hexan-2-yl)-8,9-dihydrospiro[[l,4]oxazino[4,3-e]purine-6,l'- cyclobutan]-2-yl)pyrimidin-2-amine To a solution of 2,4-dichloro-8,9-dihydrospiro[[l,4]oxazino[4,3-e]purine-6,l'-cyclobutane] (80.0 mg, 0.281 mmol) in N,N-dimethylformaldehyde (1.1 mL) was added 3-azabicyclo[2.2.1]hexane hydrochloride (40.3 mg, 0.337 mmol) and N,N-diisopropylethylamine (0.148 mL, 0.842 mmol). The reaction mixture was shaken at 70 C for 16 h and concentrated to dryness in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 150℃; for 12.0h; | Step 5: 9-(2-azabicyclo[2.1.1]hexan-2-yl)-7-chloro-l,l-dimethyl-3,4-dihydro-lH- pyrido[3',4':4,5]imidazo[2,l-c][l,4]oxazine To a stirred solution of 7,9-dichloro-l,l-dimethyl-3,4-dihydro-lH-pyrido[34 ,5]imidazo[2,l- c][l,4]oxazine (140 mg, 0.514 mmol) in isopropanol (2 mL) was added 3-azabicyclo[2.2.1]hexane hydrochloride (73.8 mg, 0.618 mmol) and diisopropylamine (0.272 mL, 1.54 mmol). After addition was complete the reaction mixture was stirred at 150 C in a sealed tube for 12 h. The reaction mixture was allowed to cool to RT and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in heptane) affording9-(2-azabicyclo[2.1.1 ]hexan-2-yl)-7-chloro- 1 , 1 -dimethyl-3 ,4-dihydro- 1 H- pyrido[3',4':4,5]imidazo[2,l-c] [l,4]oxazine (134 mg, 82%) use as is in the next step |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16.0h; | Example 133 Step 1: 2-(6-(2-azabicyclo[2.1.1]hexan-2-yl)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8- yl)ethanol To a solution of 2-(2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)ethanol (900 mg, 2.84 mmol) and N,N-diisopropylethylamine (919 mg, 7.13 mmol) in dichloromethane (10 mL) was added 2-azabicyclo [2.1.1] hexane hydrochloride (355 mg, 2.99mmol). The reaction mixture was stirred at room temperature for 16 h and subsequently concentrated to dryness in vacuo. The resulting mixture was diluted with water (60 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 100% ethyl acetate) affording 2- (6-(2-azabicyclo[2.1.1]hexan-2-yl)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)ethanol (750 mg, 73%): LCMS (ESI, 0-60AB 12 min): RT = 1.309 min, m/z 364.1 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16.0h; | Example 132 Step 1 : (6-(2-azabicyclo[2.1.1]hexan-2-yl)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8- yl)methanol To a solution of (2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)methanol (100 mg, 0.33 mmol) and N,N-diisopropylethylamine (128 mg, 0.99 mmol) in acetonitrile (1 mL) was added 2- azabicyclo[2.1.1]hexane hydrochloride (39 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 16 h and concentrated to dryness in vacuo. The resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by preparative TLC (50% ethyl acetate in petroleum ether) affording (6-(2-azabicyclo[2.1.1]hexan-2-yl)- 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)methanol (97 mg, 84%): LCMS (ESI, 5-95AB /1.5 min): RT = 0.825 min, m/z 349.8 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃; for 43.5h; | Step 2: 4-(2-azabicyclo[2.1.1]hexan-2-yl)-2-chloro-6,6,8-trimethyl-8,9-dihydro-6H- [l,4]oxazino[4,3-e]purine To a solution of racemic 2,4-dichloro-6,6,8-trimethyl-8,9-dihydro-6H-[l,4]oxazino[4,3-e]purine (300 mg, 1.04 mmol) and <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> (180 mg, 1.46 mmol) in N,N- dimethylformaldehyde (4.2 mL) was added N,N-diisopropylethylamine (0.46 mL, 2.6 mmol) and the mixture was stirred at 50 C for 43.5 h. The mixture was then diluted with dichloromethane, washed with saturated sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 25% ethyl acetate in hexane) affording racemic 4-(2-azabicyclo[2.1.1]hexan-2-yl)-2-chloro-6,6,8-trimethyl-8,9- dihydro-6H-[l,4]oxazino[4,3-e]purine as a white solid (287 mg, 82%); H NMR (400 MHz, Chloroform-d) delta 5.63 (br m, 1H), 4.29 - 4.11 (m, 2H), 3.84 (br m, 2H), 3.72 - 3.57 (m, 1H), 2.97 (m, 1H), 2.11 (m, 2H), 1.67 (s, 3H), 1.62 (s, 3H), 1.53 (m, 2H), 1.40 (d, = 6.1 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With hydrogenchloride; In ethanol; at 20℃; for 3.0h; | To a 2 L four-necked round-bottomed flask was added 2-(2-methylpropane-2-sulfinyl)-2-azabicyclo[2.1.1]hexane (75.0 g, 0.400 mol) and ethanol (1000 mL). Hydrogen chloride gas was bubbledthrough the solution via an inlet and the resulting solution was stirred at room temperature for 3 h. Followingconcentration under vacuum, the mixture was diluted with diethyl ether (500 mL) and stirred for 1 h. The solidmaterial was collected by filtration, washing with diethyl ether (2×200 mL). This procedure was conducted 5times to afford 2-azabicyclo[2.1.1]hexane hydrochloride as a brown solid (195 g, 81%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 19.0h; | To a solution of <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> (20.0 g, 159 mmol) in 1,4-dioxane (300 mL) and water (300 mL) cooled to 0 C was added sodium hydroxide (1 mol/L) in water (318 mL, 318 mmol). Di -tert-butyl di carbonate (75 mL, 318 mmol) was then added by addition funnel over 30 min. The reaction was stirred at 0C for 30 min then warmed to room temperature and stirred for 18 h. The reaction mixture was concentrated in vacuo to remove dioxane and the aqueous residue was extracted with petroleum ether (3x). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was adsorbed onto silica and purified by flash column chromatography with 0-50% EtOAc in heptane to yield the title compound as a pale yellow solid (25.7 g, 88%). NMR (400 MHz, CDC13) delta 4.34 (s, 1H), 3.29 (s, 2H), 2.86 - 2.77 (m, 1H), 1.92 - 1.83 (m, 2H), 1.47 (s, 9H), 1.42 - 1.31 (m, 2H). |
76% | With sodium hydroxide; In 1,4-dioxane; water; at 20℃;Inert atmosphere; | To a 2 L round-bottomed flask purged and maintained with an atmosphere of nitrogen was added <strong>[871658-02-5]2-azabicyclo[2.1.1]hexane hydrochloride</strong> (50.0 g, 418 mmol), 1,4-dioxane (420 mL), 1M aqueous sodiumhydroxide (840 mL) and di-tert-butyl dicarbonate (183 g). The resulting solution was stirred at roomtemperature overnight and then concentrated to remove organic solvent. The remaining slurry was extractedwith petroleum ether (3×500 mL). The combined organic layers were dried over anhydrous sodium sulfate andconcentrated. The residue was purified via flash column chromatography on silica gel (10:1 - 1:0 petroleumether/ethyl acetate) to afford tert-butyl 2-azabicyclo[2.1.1]hexane-2-carboxylate as an orange solid (58 g, 76%); |