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CAS No. : | 137730-67-7 | MDL No. : | MFCD01632538 |
Formula : | C13H16ClN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CNFMPMUITJAJKC-UHFFFAOYSA-N |
M.W : | 221.73 | Pubchem ID : | 22509344 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.38 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 70.06 |
TPSA : | 12.03 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.26 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 3.37 |
Log Po/w (WLOGP) : | 2.65 |
Log Po/w (MLOGP) : | 3.12 |
Log Po/w (SILICOS-IT) : | 3.0 |
Consensus Log Po/w : | 2.43 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.63 |
Solubility : | 0.0515 mg/ml ; 0.000232 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.3 |
Solubility : | 0.111 mg/ml ; 0.0005 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.91 |
Solubility : | 0.0273 mg/ml ; 0.000123 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.01 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; | 1'-(t-Butyloxycarbonyl)spiro(indene-1,4'-piperidine) (16 g, 56 mmole) in ethyl acetate (250 ml) was stirred in an ice bath and saturated with HCl(g) for 30 minutes. The mixture was evaporated to dryness. Ethyl acetate was added and removed in vacuo three times, and the residue was triturated with diethyl ether and filtered to provide spiro(1H-indene-1,4'-piperidine) hydrochloride. | |
In ethyl acetate; | 3 1'-(t-Butyloxycarbonyl)spiro(indene-1,4'-piperidine) (16 g, 56 mmole) in ethyl acetate (250 ml) was stirred in an ice bath and saturated with HCl(g) for 30 min. The mixture was evaporated to dryness. Ethyl acetate was added and removed in vacuo three times, and the residue was triturated with diethyl ether and filtered to provide spiro(1H-indene-1,4'-piperidine) hydrochloride. The free base was obtained by slurrying the hydrochloride in aqueous sodium bicarbonate solution and extracting with CH2 Cl2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium triacetoxyborohydride; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃;Molecular sieve; | A solution of Intermediate 12 (Intermediate 12,100. 0 mg, 0.256 mmol) spiroindenylpiperidine hydrochloride (70.0 mg, 0.315 mmol), diisopropylethylamine (55, UL, 0.315 mmol) and crushed molecular sieves (4A, 50 mg) in dichloroethane (5 ML) was treated with sodium triacetoxyborohydride (378 mg, 1.783 mmol) and stirred at room temperature overnight. The sieves were filtered off (plug of Celite), washed with dichloromethane and the combined organic washings were extracted with a saturated solution of sodium bicarbonate (1 x 10 mL), water (2 x 10 mL), brine (1 x 10 ML) and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to yield 133 mg (91 %) of the crude product. The residue was purified by preparative TLC (eluent: 100 % ethyl acetate) to yield 105.2 mg (72 %) of the final pure desired product. LC-MS for C32H30N2OF6 [M + H] + calculated 572.24, found 573. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With sodium triacetoxyborohydride; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; | A solution of the Intermediate 24 (56 mg, 0.18 mmol) and 4-spiroindenylpiperidine hydrochloride (40.3 mg, 0.182 mmol) in dry dichloroethane (5 ML) was treated with diisopropylethylamine (40, UL, 0.22 mmol) and to this mixture, sodium triacetoxyborohydride (193 mg, 5.0 mmol) were added. The reaction was allowed to proceed overnight. It was quenched with saturated solution of sodium bicarbonate (20 mL), and the product was extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried with anhydrous sodium sulfate and evaporated to dryness (78 mg). The crude product was further purified by preparative TLC using ethyl acetate/hexane (1: 1) as eluent to obtain 28 mg, 27 %) of pure PRODUCT.'H NNR (CDC13, 500 MHz) : 7.77 (s, 1H), 7.67 (s, 2H), 7.38 (dd, J = 5.0, 3.0 HZ, 1H), 7.34 (bt, J = 7. 8 HZ, 2H), 7.23 (m, 3H), 7.10 (dd, J = 5. 0,1. 4 HZ, 1H), 6.83, (d, J = 5. 5 HZ, 1H), 6.76 (d, J = 5. 7 Hz, 1H), 6.62 (bs, 1H), 4.60 (dd, J=15. 6HZ, LH), 4.54 (dd, J=15. 8,6. 2 HZ, 1H), 3.90 (t, J = 7. 55 HZ, 1H), 3.2 (bd, J = 11. 4 Hz, 1H), 2.96 (bd, J=11.4 Hz, 1H), 2.42 (m, 6H), 2,12 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium triacetoxyborohydride; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃; | A dichloroethane (10 mL) solution containing the aldehyde from previous step (530 mg, 2.67 MMOL), 4-spiroindenylpiperidine hydrochloride (475 mg, 2.14 mmol), diisopropylethylamine (390 P, L, 2.20 mmol) was treated with sodium triacetoxyborohydride (2.27 g, 10.7 mmol) and stirred at room temperature overnight. The reaction was quenched by pouring onto saturated aqueous solution of sodium bicarbonate (20 mL), and extracted with dichloromethane (4 x 50 mL). The combined extracts were washed with brine (1 x 30 mL), and the solvent was evaporated under reduced pressure to leave 711 mg (90 %) of the desired product. It was used in the subsequent step without any additional purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium triacetoxyborohydride; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃; for 2h; | The solution of Intermediate 27 (210 mg, 1.05 mmol) and 4-spiroindenylpiperidine hydrochloride (222 mg, 1.00 mmol) in dichloroethane (15 mL) was treated with diisopropylethylamine (130 mg, 1 mmol) followed by sodium triacetoxyborohydride (1.06 g, 5.0 mmol) and stirred at ambient temperature for 2 hours. The reaction was quenched with saturated solution of sodium bicarbonate, back-washed with dichloromethane. The combined organic extracts were dried (anhydrous sodium sulfate) and evaporated to dryness. MS: for C21H24N202S [M + H] + calculated : 369.16, found 369.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With sodium triacetoxyborohydride; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃;Molecular sieve; | Intermediate 47 (50 mg, 0.134 mmol) was treated with a solution of 90% trifluoroacetic ACID/WATER (1 ml) for 10 minutes. The reaction mixture was diluted with water (2 mL) and extracted with ether (3x 10 ml). The organic layers were combined, washed with saturated sodium bicarbonate (3 x 3 mL), brine (1 x 5 mL), dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo to yield 45 mg (96 %) of the crude product. A solution of the above crude product (45 mg, 0.129 mmol), spiroindenylpiperidine hydrochloride (30 mg, 0.134 MMOL), diisopropylethylamine (24, UT, 0.134 mmol) and crushed molecular sieves (4A, 25 mg) in dichloroethane (2 mL) was treated with sodium triacetoxyborohydride (143 mg, 0.134 mmol) and stirred at room temperature overnight. The sieves were filtered off (plug of Celite), washed with dichloromethane and the combined organic washings were extracted with a saturated solution of sodium bicarbonate (1 x 5 mL), brine (1 x 5 mL) and dried over anhydrous sodium sulfate. Solvent was evaporated to dryness and. the residue was purified by preparative TLC (eluent: 5% methanol/95 % ethyl acetate) to yield 30.1 mg (41 %) of the final pure desired PRODUCT.. 1H NMR (400 MHz, CD30D) : 7.94 (s, 2H), 7.83 (s, 1H), 7.36-7. 34 (m, 2H), 7.27-7. 23 (m, 2H), 7.00 (d, J = 5.7 Hz, 1H), 6.90 (d, J = 5.5 Hz, 1H), 4.58 (ABq, J = 4.6 Hz, 2H), 3.94 (dd, J = 4.8, 6.6 Hz, 1H), 3.74-3. 65 (m, 2H), 3.47 (s, 3H), 3.37-3. 29 (m, 4H), 2.43 (br t, J = 4.6 Hz, 1H), 2.36-2. 25 (m, 1H), 2.23-2. 14 (m, 1H). 1.50 (br d, J = 4.6 Hz, 1H), 1.37-1. 28 (m, 2H). LC-MS for C27H28N2OF6 [M + H] + calculated 526.21, found 527. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In ethanol; water; at 80℃; for 5h; | 100 mg (0.222 mmol) of the chloroethylamine (Example 22, step 3), 100 mg (0.45 mmol) of spiroindenepiperidine (available from Arch Corp) hydrochloride and 100 mg of sodium bicarbonate in 5 mL of ethanol/water (95/5) was stirred at 80 C. for 5 h, filtered and evaporated to dryness. The residue was purified on preparative TLC (10%[aq.NH4OH/MeOH 1/9]/DCM), 82 mg of the title compound was obtained as free diamine. Mass Spectrum (NH3-CI): m/z 600.2 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
...ropionic acid (prepared according to the method of Sugano. H, and Miyoshi. M, J. Org. Chem 1976, 41, 2352) and the appropriate substituted piperidine or piperazine, followed by reductive amination with benzaldehyde or 3,4-dichlorobenzaldehyde, according to the method of Example 1: References: N-(4-Phenylpiperidin-4-yl)acetamide (EP512901A1) Spiro[1H-indene-1,4'-piperidine]Hydrochloride (J. Med. Chem. 1992, 35, 2033-2039) 2,3-Dihydrospiro[1H-indene-1,4'-piperidine]Hydrochloride (J. Med. Chem. 1992, 35, 2033-2039) [Spiro[piperidine-4,6'-[6'H]thieno[2,3-b]thiopyran]-4'(5'H)-one]Hydrochloride (U.S. Pat. No. 5,206,240, Example 2A) (RS)-Spiro[2H-1-benzopyran-2,3'-piperidine]-4-(3H)-one Hydrochloride (U.S. Pat. No. 5,206,240, Example 52B) 6-methoxyspiro[2H-1-benzopyran-2,4'-piperidine]-4-(3H)-one Hydrochloride (U.S. Pat. No. 5,206,240, Example 231) Spiro[2H-1-benzopyran-2,4'-piperidine]-4-(3H)-one Hydrochloride (U.S. Pat. No. 5,206,240, Example 67A) | ||
Step 3 1--(t-Butyloxycarbonyl)spiro(indene-1,4--piperidine) (16g, 56mmole) in ethyl acetate (250ml) was stirred in an ice bath and saturated with HCl(g) for 30 min. The mixture was evaporated to dryness. Ethyl acetate was added and removed in vacuo three times, and the residue was triturated with diethyl ether and filtered to provide spiro(1H-indene-1,4--piperidine) hydrochloride. | ||
Spiro(1H-indene-1,4--piperidine) hydrochloride 1--(t-Butyloxycarbonyl)spiro(indene-1,4--piperidine) (60.7 g) in ethyl acetate (700 mL) was stirred in an ice bath and saturated with HCl (g) for 30 minutes, keeping the internal temperature <= 12C. The mixture was stirred in the cold an additional 30 minutes, then evaporated to dryness. Ethyl acetate was added and removed in vacuo three times, and the residue was triturated with diethyl ether and filtered to provide spiro(1H-indene-1,4--piperidine) hydrochloride. |
1--(t-Butyloxycarbonyl)spiro(indene-1,4--piperidine) (16 g, 56 mmole) in ethyl acetate (250 ml) was stirred in an ice bath and saturated with HCl(g) for 30 minutes. The mixture was evaporated to dryness. Ethyl acetate was added and removed in vacuo three times, and the residue was triturated with diethyl ether and filtered to provide spiro(1H-indene-1,4--piperidine) hydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; methanol; | EXAMPLE 38 1'-[3-(S)-(3,4-dichlorophenyl)-4-(t-butoxycarbonyl(methylamino))butyl]-spiro(1H-indene-1,4'-piperidine). To a solution of 3.46 g (10 mmol) of 3-(S)-(3,4-dichlorophenyl)-4-(t-butoxycarbonyl-methylamino)butanal (Example 1) in 20 mL of methanol were added 3.11 g (14 mmol) of <strong>[137730-67-7]spiro(1H-indene-1,4'-piperidine) hydrochloride</strong> and 3 g of powdered 4 A molecular sieves. After 15 min a solution of 2.52 g (40 mmol) of NaCNBH3 in 30 mL of THF was dropwise added. Some gas evolution was observed. After stirring the reaction overnight, the mixture was filtered through a pad of celite, the reaction flask and the pad were rinsed with methanol. The filtrate was concentrated to approximately 10 ml and the residue was partitioned between saturated NaHCO3 and Et2O:EtOAC. The organic layer was washed with water, brine and dried over NA2SO4. The filtrate was concentrated and the residue was chromatographed on a flash column using a gradient of 49:49:2 to 98:0:2 EtOAc:Hexane:triethylamine to furnish 4.05 g (79%) of the title compound as a foam. 1 H NMR (CDCl3, ppm ranges are given because of amide rotomers and line broadening) delta 1.37 (s, 9H), 1.5-3.6 (m, 15H), 2.63 & 2.73 (2 s, 3H), 6.70 (d, 1 H, J=6 Hz), 6.77 (d, 1 H, J=6 Hz), 6.95-7.4 (m, 7H). | |
In tetrahydrofuran; methanol; | EXAMPLE 38 1'-[3-(S)-(3,4-dichlorophenyl)-4-(t-butoxycarbonyl(methylamino))-butyl]-spiro(1H-indene-1,4'-piperidine). To a solution of 3.46 g (10 mmol) of 3-(S)-(3,4-dichlorophenyl)-4-(t-butoxycarbonyl-methylamino)butanal (Example 1) in 20 mL of methanol were added 3.11 g (14 mmol) of <strong>[137730-67-7]spiro(1H-indene-1,4'-piperidine) hydrochloride</strong> and 3 g of powdered 4 A molecular sieves. After 15 min a solution of 2.52 g (40 mmol) of NaCNBH3 in 30 mL of THF was dropwise added. Some gas evolution was observed. After stirring the reaction overnight, the mixture was filtered through a pad of celite, the reaction flask and the pad were rinsed with methanol. The filtrate was concentrated to approximately 10 ml and the residue was partitioned between saturated NaHCO3 and Et2O:EtOAC. The organic layer was washed with water, brine and dried over NA2SO4. The filtrate was concentrated and the residue was chromatographed on a flash column using a gradient of 49:49:2 to 98:0:2 EtOAc: Hexane: triethylamine to furnish 4.05 g (79%) of the title compound as a foam. 1 H NMR (CDCl3, ppm ranges are given because of amide rotomers and line broadening) delta 1.37 (s, 9 H), 1.5-3.6 (m, 15 H), 2.63 & 2.73 (2 s, 3 H), 6.70 (d, 1 H, J=6 Hz), 6.77 (d, 1 H, J=6 Hz), 6.95-7.4 (m, 7 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In ethanol; palladium; ethyl acetate; | Step 3: Spiro[indane-1,4'-piperidine]hydrochloride A solution of 1'-(tert-butyloxycarbonyl)spiro[indene-1,4'-piperidine] (3.0 g, 0.011 mol) in ethyl acetate (150 ml) was stirred at 0 C., and treated with hydrogen chloride for 30 minutes. The mixture was then evaporated to dryness, ethyl acetate (100 ml) was added, then removed in vacuo three times. The residue was stirred with anhydrous ether (200 ml), and the solid filtered off, to give <strong>[137730-67-7]spiro[indene-1,4'-piperidine] hydrochloride</strong> (2.3 g, 99%) as a pale yellow solid. The product was not purified further. A solution of spiro[indene-1,4'-piperidine]hydrochloride (1.9 g, 8.6 mmol) in ethanol (50 ml) was hydrogenated at 50 p.s.i. for 1 hour, in the present of 10% palladium on carbon (0.3 g, 16% (w/w)). The catalyst was filtered off, and the ethanol removed in vacuo. The remaining solid was recrystallized from 4:1 ethyl acetate:ethanol to give spiro[indane-1,4'-piperidine] hydrochloride (814 mg, 43%) as a white crystalline solid. N.M.R. (D2 O)delta 1.79 (2H, d, J=14 Hz), 2.06 (2H, t of d, J=14 and 4 Hz), 2.14 (2H, t, J=7 Hz), 2.98 (2H, t, j=7 Hz), 3.25 (2H, t of d, J=14 and 2 Hz), 3.48 (2H, m), 7.33 (4H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In aq. NaOH; ethanol; dichloromethane; chloroform; | 1'-(2-Hydroxy-1,2,3,4-tetrahydronaphth-3-yl)-spiro[1H-indene-1,4'-piperidine]Hydrochloride (11b). A biphasic mixture of the bromohydrin (1.14 g, 5.0 mmol) in 2M aq. NaOH (100 mL) and CHCl3 (100 mL) was refluxed for 2.5 h. TLC (silica gel; 50% hexane-CH2 Cl2) confirmed that formation of the epoxide was complete. The mixture was cooled to room temperature and the two layers were separated. The aq. phase was re-extracted with CHCl3 (2*30 mL) and discarded. The organic extracts were combined, dried over anhydrous Na2 SO4 and concentrated under reduced pressure to yield the crude epoxide as a pale yellow syrup which was redissolved in EtOH (30 mL) and Et3 N (2 mL). Spiro[1H-indene-1,4'-piperidine] hydrochloride (1.11 g, 5.0 mmol) was added to this solution, and the resulting mixture was refluxed overnight. After 17 h, heating was stopped. The mixture was cooled to room temperature and concentrated to a residue in vacuo. The residue was dissolved in CH2 Cl2 (50 mL) and the solution was washed with satd aq. NaHCO3 (30 mL). The aqueous extract was washed with CH2 Cl2 (30 mL) and discarded. The organic extracts were combined, dried over anhydrous Na2 SO4 and concentrated to a residue. The latter was dissolved in a minimum volume of CH2 Cl2 and applied to a short column of silica gel which was subsequently eluted with 25% acetone-hexane. Concentration of the eluent yielded the product (0.91 g, 55%) as a brown syrup. The latter was estimated by tlc (silica gel, acetone(25):hexane (74):Et3 N (1)) to be greater than 97% pure. The corresponding hydrochloride was prepared in MeOH as outlined for (11a) above, and recrystallized from isopropyl alcohol; mp 254-257 C.; 1 H NMR (CDCl3)delta1.46 (d, 2, piperidyl beta-Heq., J= 12.8 Hz), 2.17 (m, 2, piperidyl beta-Hax.), 2.86-3.49 (m, 8, tetrahydronaphthyl C1-H, C3-H, C4-H & piperidyl alpha-Hax.,eq.), 3.93-4.20 (m, 3, piperidyl alpha-Heq & CHOH), 6.79 (d, 1, indenyl C2-H, J=5.6 Hz), 6.90 (d, 1, indenyl C3-H, J=5.7 Hz), 7.03-7.42 (m, 8, aryl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 4-methyl-morpholine; hydrogenchloride; benzotriazol-1-ol; 1,2-dichloro-ethane; In hexane; dichloromethane; ethyl acetate; | Step A N-[1(R)-[(spiro[1H-indene-1,4'-piperidin]-1'-yl)carbonyl]-2-(indol-3-yl)ethyl]-2-[[(1,1-dimethylethyloxy)carbonyl]amino ]-2-methylpropanamide To a stirred solution of alpha(R)-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-2,2-dimethyl-1-oxoethyl]amino]-1H-indole-3-propanoic acid (50 mg, 0.13 mmol), (Example 4, Step D) spiro[1H-indene-1,4'-piperidine]hydrochloride (28.5 mg, 0.13 mmol) (Chambers, M. et al, J. Med. Chem. 1992, 35, 2033-2039), HOBT (17.3 mg, 0.13 mmol) and N-methylmorpholine (14.1 muL, 0.13 mmol) in dichloromethane (5 mL) at room temperature was added EDC (49.3 mg, 0.26 mmol). The reaction mixture was stirred for four hours and poured into a mixture of brine (10 mL) and HCl (3N, 1 mL). The mixture was extracted with ethyl acetate (20 mL) and the organic extract was dried (MgSO4) and evaporated. The residue was purified by silica gel column eluding with a solvent gradient of 40-60% ethyl acetate in hexane to give the product (63.6 mg, 89%). 1 H NMR (400 MHz, CDCl3): compound exists as a mixture of conformers (ratio 2:1): delta8.28, 8.24 (2 br. s, 1H), 7.74, 7.62 (2d, 7.7 Hz, 1H), 7.62, 7.39 (2d, 8.0 Hz, 1H), 7.30-7.10 (m, 7H), 6.68-6.30 (m, 2H), 5.35-5.20 (2m, 1H), 5.00 (br. s, 1H), 4.45-4.36 (m, 1H), 3.62, 3.53 (br. d, 14 Hz, 1H), 3.30-3.00 (m, 2H), 2.86-2.71 (m, 1H), 2.42-2.23 (m, 1/3H), 1.71 (v. br. s, 2H), 1.51, 1.49, 1.47 (3s, 6H), 1.44, 1.43, (2s, 9H), 1.40-1.07 (m, 2H), 0.88, 0.72 (2 br. d, 1H), 0.42 (dt, 4 Hz, 12 Hz, 1/3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,2-dichloro-ethane; In dichloromethane; water; N,N-dimethyl-formamide; | EXAMPLE 1 1'-(2,4-Dimethoxyphenylacetyl)-spiro[1H]inden-1,4'-piperidine STR21 Spiro[1H]indene-1,4'-piperidine hydrochloride (100 mg, 0.45 mmol) was dissolved in DMF (2 ml) and treated with 2,4-dimethoxy-phenylacetic acid (97.3 mg, 0.5 mmol), EDC (95 mg, 0.5 is mmol), and HBT (67 mg, 0.5 mmol). The pH of the mixture was adjusted to ca. 9.5 (moistened E. Merck colorpHast indicator) with triethylamine, and the mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was treated with water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 8% ether in methylene chloride. The combined product fractions were evaporated to dryness in vacuo and the residue crystallized from ether to give 1'-(2,4-dimethoxyphenylacetyl)spiro[1H]indene-1,4'-piperidine: mp 93-108 C. 1 H-NMR: Consistent with structure TLC: silica gel, 10% ether in methylene chloride: single component, Rf =0.41 FABMS: M+H a m/e=364 HPLC: 98% Anal. cal'd for C23 H25 NO3.0.55 H2 O: C, 73.98; H, 7.05, N, 3.75. Found: C, 73.70; H, 7.30; N, 4.04. | |
With 1,2-dichloro-ethane; In dichloromethane; water; N,N-dimethyl-formamide; | EXAMPLE 1 1'-(2,4-Dimethoxyphenylacetyl)-spiro[1H]indene-1,4'-piperidine STR25 Spiro[1H]indene-1,4'-piperidine hydrochloride (100 mg, 0.45 mmol) was dissolved in DMF (2 ml) and treated with 2,4-dimethoxy-phenylacetic acid (97.3 mg, 0.5 mmol), EDC (95 mg, 0.5 mmol), and HBT (67 mg, 0.5 mmol). The pH of the mixture was adjusted to ca. 9.5 (moistened E. Merck colorpHast indicator) with triethylamine, and the mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was treated with water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 8% ether in methylene chloride. The combined product fractions were evaporated to dryness in vacuo and the residue crystallized from ether to give 1'-(2,4-dimethoxyphenylacetyl)-spiro[1H]indene-1,4'-piperidine: mp 93-108 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In water; at 150℃; for 0.833333h;Microwave irradiation; | 1.2: 1'-(3,4-Dihydroquinolin-1(2H)-ylcarbonyl)spiro[indene-1,4'-piperidine]; 0.4 g of 4-nitrophenyl 3,4-dihydroquinoline-1(2H)-carboxylate, 0.357 g of 4-spiroindene-piperidine hydrochloride, 0.28 ml of triethylamine and 2 ml of water are introduced into a 10 ml glass tube. The tube is sealed and then heated at 150 C. under microwave irradiation for 50 minutes. Dichloromethane is added. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a heptane/ethyl acetate gradient from 9/1 to 0/1. 0.393 g of 1'-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)spiro[indene-1,4'-piperidine] is obtained.Melting point=130-133 C.; M+H+=345.31H NMR (CDCl3, 200 MHz), delta (ppm): 1.34 (m, 2H); 1.95-2.15 (m, 2H); 2.8 (t, 2H); 3.15 (dt, 2H); 3.7 (t, 2H); 4.0 (m, 2H); 6.8 (d, 1H); 6.9 (d, 1H); 6.91-7 (m, 1H); 7.1-7.4 (m, 7H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | A solution of Intermediate 14 (100 mg, 0.307 mmol) in dichloromethane (5ML) was cooled to-78 C and a stream of ozone was passed through until a permanent blue color indicated complete consumption of the olefin. The excess ozone was purged with a stream of nitrogen and the reaction mixture was allowed to warm up to ambient temperature. The solution was dried with magnesium sulfate, the drying agent was filtered off, and to the filtrate was added spiroindenylpiperidine hydrochloride (68 mg, 0.307 mmol), diisopropylethylamine (42 IL, 0.307 mmol), crushed 4 A molecular sieves (50 mg) and the resulting mixture was treated with sodium triacetoxyborohydride (325 g, 1.54 mmol). After stirring at ambient temperature for 24 hours, the sieves were filtered off, the filtrate was washed with a saturated solution of sodium bicarbonate (1 x 10 mL), water (3 x 5 mL) and brine (1 x 10 mL). After drying (anhydrous sodium sulfate) the solvent was evaporated to dryness under reduced pressure to leave 200 mg of crude product, which was further purified by preparative TLC (eluant: 5% methanol/95% ethyl acetate) to give 137 mg (68%) of the pure final PRODUCT. 1H NMR (500 MHz, CDC13) : 7.80 (s, 3H), 7.32 (d, J = 7.3 Hz, 1H), 7.27-7. 23 (m, 1H), 7.20-7. 15 (m, 2H), 6.79 (d, J = 5.7, 1H), 6.75 (d, J = 5. 7 Hz, 1H), 4.62 (d, J = 6. 0 Hz, 2H), 2.99 (BRD, J=12. 1HZ, 2H), 2.58 (t, J = 6. 6 Hz, 2H), 2.48 (t, J = 6.7 Hz, 2H), 2.37 (br t, J = 12. 0 Hz. 2H), 2.04 (br t, J = 11. 8 Hz, 2H), 1.96 (t, J = 6.7 Hz, 2H), 1.34 (br d, 12.3 Hz, 2H). LC-MS: for C26H26N20F6 [M + H] calculated 496.19, found 497. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | The prepared resin (Intermediate 16,50 mg, 0.027 mmol) was swelled in dichloroethane (2 ml) for 15 minutes after which the solvent was drain. A fresh cocktail of 5% trimethyl orthoformate in dichloroethane (2 ml) was added to the resin. To this suspension was then added spiroindenylpiperidine hydrochloride (30 mg, 0.14 mmol), diisopropylethylamine (24 , UL, 0.14 MMOL), and sodium triacetoxyborohydride (57 g, 0.27 mmol) and the resulting mixture was spun on a mechanical rotary for 15 hours, releasing pressure every 15 minutes for the first 3 hours. The solvent was drained and the resin beads washed with methanol (3 X 2 ML), DICHLOROETHANE (5 X 2 ml), dimethyl formamide (5 x 2ml), dichloromethane (10 x 2 ml). The resin was then immediately treated with a pre-mixed cocktail of 25% trifluoroacetic acid in dichloromethane (2 ml) for 2 hours. The beads became dark red after treatment with the acidic solution. The solvent was collected along with the dichloromethane washings (3 x 2 ml) and concentrated to dryness under reduced pressure to afford 2.5 mg (31%) of the desired final product with an HPLC purity analysis of 91%. 1H NMR (500 MHz, CD30D): 7.87 (s, 1H), 7.78 (s, 2H), 7.36 (d, J = 7.3 Hz, 1H), 7.28-7. 22 (m, 1H), 7.18-7. 10 (m, 2H), 6.99 (br s, 1H), 6.90 (br d, J = 5.5 Hz, 1H), 4.55 (d, J = 15. 1 Hz, 1H), 4.28 (d, J = 15.1 Hz, 1H), 3.74-3. 66 (m, 1H), 3.30 (p, J = 1. 6 Hz, 1H), 3.36-3. 26 (m, J = 3H) 3.18-3. 12 (m, 1H), 2.95 (dd, J = 9. 1,13. 3 Hz, 1H), 2.85 (dd, J = 6.1, 13.2 Hz, 1H), 2.76- 2.70 (m, 1H), 2.50-2. 40 (m, 1H), 2.22-2. 12 (m, 1H), 2.08-1. 97 (m, 1H), 1.52 (br d, J = 14.0 Hz, 2H). LC-MS: for C33H32N2OF6 [M + H] calculated 586.24, found 587. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | The product from Step C, Intermediate 17 (400 mg, 1.20 mmol) was treated with solution of 90% trifluoroacetic ACID/WATER (8 ml) for 10 minutes. The reaction mixture was diluted with water (12 mL) and extracted with ether (3 x 10 ml). The organic layers were combined, washed with saturated sodium bicarbonate (3 x 10 mL), brine (1 x 10 mL), dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo to yield 361 mg (100 %) of the crude product. A solution of the above crude product (361 mg, 1.20 mmol), spiroindenylpiperidine hydrochloride (266 mg, 1.20 mmol), diisopropylethylamine (205, UL, 1.20 mmol) and crushed molecular sieves (4A, 150 mg) in dichloroethane (20 mL) was treated with sodium triacetoxyborohydride (1.3 g, 6.0 mmol) and stirred at room temperature overnight. The sieves were filtered off (plug of Celite), washed with dichloromethane and the combined organic washings were extracted with a saturated solution of sodium bicarbonate (1 x 20 mL), brine (1 x 20 mL) and dried over anhydrous sodium sulfate. Solvent was evaporated to dryness and. the residue was purified by preparative TLC (eluent: 5% methanol/95 % ethyl acetate) to yield 245 mg (46 %) of the desired PRODUCT. 1H NMR (500 MHz, CDC13) : 7.38-7. 14 (m, 9H), 6.84 (d, J = 5.7 Hz, 1H), 6.75 (d, J = 5.5 Hz, 1H), 4. 81-4. 75 (m, 1H), 4.30-4. 21 (m, 2H) 3.93-3. 86 (m, 1H), 3.35 (dd, J = 3.4, 13.3 Hz, 1H), 3.00 (br d, J = 11.2 Hz, 2H) 2.82 (dd, J = 9.6, 13.3 Hz, 1H), 2.52 (br t, J = 7.3 Hz, 2H), 2.38-2. 26 (m, 2H), 2.17-2. 08 (m, 3H), 1.73-1. 64 (m, 2H), 1.36 (br d, J = 13.3 Hz, 2H), 1.29 (d, J = 7.1 Hz, 3H). LC-MS: for C28H32N203 [M + H] calculated 444.24, found 445. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | A solution of the compound synthesized in Step A, Intermediate 20 (500 mg, 1.68 mmol) in dichloromethane (20 ML) was cooled to-78 C and a stream of ozone was passed through until the permanent blue color indicated complete consumption of the olefin. The excess ozone was purged with a stream of nitrogen and allowed to warm up to ambient temperature. The solution was dried with magnesium sulfate, the drying agent was filtered off, and to the filtrate was added spiroindenylpiperidine hydrochloride (419 mg, 1.80 mmol), diisopropylethylamine (328 CL, 1.80 mmol), crushed 4 A molecular sieves (250 mg) and the resulting mixture was treated with sodium triacetoxyborohydride (2.00 g, 9.46 mmol). After stirring at ambient temperature for 24 hours, the sieves were filtered off, the filtrate was washed with a saturated solution of sodium bicarbonate (1 x 100 mL), water (3 x 50 mL) and brine (1 x 100 mL). After drying (anhydrous sodium sulfate) the solvent was evaporated to dryness under reduced pressure to leave 620 mg of crude product, which was further purified by preparative TLC (eluant: 100% ethyl acetate) to give 456 mg (66%) of the pure desired product. LC-MS for C25H35NO2 [M + H] + CALCULATED 381.27, found 382. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | A solution of the compound synthesized in Step B, Intermediate 21 (1.00 g, 3.36 mmol) in dichloromethane (35 mL) was cooled to-78 C and a stream of ozone was passed through until the permanent blue color indicated complete consumption of the olefin. The excess ozone was purged with a stream of nitrogen and allowed to warm up to ambient temperature. The solution was dried with magnesium sulfate, the drying agent was filtered off, and to the filtrate was added spiroindenylpiperidine hydrochloride (745 mg, 3.36 MMOL), diisopropylethylamine (585 uL, 3.36 mmol), crushed 4 A molecular sieves (500 mg) and the resulting mixture was treated with sodium triacetoxyborohydride (3.56 g, 16.8 mmol). After stirring at ambient temperature for 24 hours, the sieves were filtered off, the filtrate was washed with a saturated solution of sodium bicarbonate (1 x 100 mL), water (3 x 50 mL) and brine (1 x 100 mL). After drying (anhydrous sodium sulfate) the solvent was evaporated to dryness under reduced pressure to leave 750 mg of crude product, which was further purified by preparative TLC (eluant: 100% ethyl acetate) to give 640 mg (51%) of the pure desired product. 1 H NMR (500 MHz, CDC13) : 7.37 (d, J = 7.3 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.26-7. 18 (m, 2H), 6.84 (d, J = 5.7, 1H), 6.75 (d, J = 5.5 Hz, 1H), 4.26-4. 17 (m, 1H), 4.06-3. 86 (m, 1H), 3.04-2. 96 (m, 2H), 2.68 (app t, J = 12. 4 Hz, 1H), 2. 51-2. 44 (m, 1H), 2.43-2. 37 (m, 1H), 2.31 (br t, J = 9.8 Hz, 2H), 2.24-2. 12 (m, 2H), 2.00-1. 88 (m, 2H), 1.82-1. 64 (m, 4H), 1.47 (br s, 9H), 1.33 (t, J = 7.1 Hz, 3H). LC-MS: for C28H40N204 [M + H] calculated 468.30, found 469. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | A solution of the olefin from previous step (910 mg, 3.4264 mmol) in dichloromethane (30 mL) was cooled to-78C and ozone was passed through until a permanent blue color indicated consumption of the olefin. Excess ozone was purged with nitrogen, and 3 mL of dimethyl sulfide was added. Cooling bath was removed, and the reaction mixture was allowed to wann up to room temperature. The solvent was removed in vacuo and the crude aldehyde was dissolved in dichloroethane (20 mL). 4-Spiroindenyl piperidine hydrochloride (772 mg, 3.4822 mmol), diisopropylethylamine (600, UT, 3.4822 mmol) and finally sodium triacetoxyborohydride (3.70 g, 17.4 mmol) were added and the reaction mixture was stirred at room temperature overnight. It was diluted with dichloromethane (100 mL) and extracted with water (2 x 50 ML), dried with anhydrous sodium sulfate and evaporated to dryness. The crude product (1.60 g, 100 %) was taken into the next step without additional purification. MS: for C26H26N204 [M+H] + calculated: 431.19, found 431.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 3; Intermediate 2 (410 mg, 0.68 mmol) was subject to standard ozonolysis conditions. The resulting ozonide was combined with 4-spiroindene-piperidine hydrochloride (150 mg, 0.68 mmol), diisopropylethylamine (237 pL, 1.36 mmol), sodium triacetoxyborohydride (721 mg, 3.40 mmol), and 4A molecular sieves, in DCM. The resulting reaction mixture was stirred for 4 days at room temperature before being filtered through celite and quenched with saturated aqueous sodium bicarbonate. The resulting mixture was washed with water (3 x) and brine and dried over MgS04. The resulting material was purified by preparative TLC (60% ethyl acetate/hexanes) to give 11 mg of the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.333333h;Sealed tube; | To a solution of tert-butyl [5-(2-bromo-l,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate (80 mg, 0.231 mmol) and spiro [indene- 1 ,4'-piperidinium] chloride (87 mg, 0.393 mmol) in NMP (1.25 mL) was added DBU (87 muL, 0.577 mmol). The tube was sealed and immersed into a preheated oil bath at 130 C, and stirred at this temperature for 20 min. The reaction was diluted with EtOAc, poured into 0.5 N HCl, extracted with EtOAc, washed with water (3x) and brine, dried (Na2SO4), filtered and concentrated. After evaporation of the solvents, the residue was purified by flash chromatography on SiO2 (12 g) (gradient 0 to 60% EtOAc/hexanes) to afford the title product as a white solid. LC-MS : m/z = 451.1 (MH+). |
Tags: 137730-67-7 synthesis path| 137730-67-7 SDS| 137730-67-7 COA| 137730-67-7 purity| 137730-67-7 application| 137730-67-7 NMR| 137730-67-7 COA| 137730-67-7 structure
[ 83949-37-5 ]
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