* 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.
Example 7; 4-(4-piperidinyl)-morpholine (O) 41.59 g (0.16 Mol) 4-[1-(phenylmethyl)-4-piperidinyl]-morpholine (N) are dissolved in 400 mL methanol, combined with 5.2 g palladium on activated charcoal (10percent) and hydrogenated for 18 hours at ambient temperature with 50 psi hydrogen. The catalyst is filtered off and the filtrate is evaporated down. A colourless oil remains, which crystallises after a short time.Yield: 25.29 g (93percent of theory)
91%
With hydrogenchloride In methanol
4-(1-benzyl-piperidin-4-yl)-morpholine (1.56 g, 6.0 mmol) was hydrogenated using Pd(OH)2 (20percent on carbon, 390 mg, 25 wtpercent), 1.7 M HCl (10.6 mL) in methanol (50 mL) at 50° C. for 10 hours. The resulted amine dihydrochloride off-white solid was subjected to free-basing using excess basic resin to give 932 mg (91percent) of 4-piperidin-4-yl-morpholine as waxy crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 3.53 (br s, 4H), 3.30 (v br s, 1H), 2.92 (br d, 1H), 2.41 (s, 4H), 2.35 (m, 2H), 2.12 (br t, 1H), 1.65 (br d, 2H), 1.18 (br q, 2H). MS m/z 171 [M++1].
91%
With hydrogenchloride In methanol
4-(1-benzyl-piperidin-4-yl)-morpholine (1.56 g, 6.0 mmol) was hydrogenated using Pd(OH)2 (20percent on carbon, 390 mg, 25 wt percent), 1.7 M HCl (10.6 mL) in methanol (50 mL) at 50° C. for 10 hours. The resulted amine dihydrochloride off-white solid was subjected to free-basing using excess basic resin to give 932 mg (91percent) of 4-piperidin-4-yl-morpholine as waxy crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 3.53 (br s, 4H), 3.30 (v br s, 1H), 2.92 (br d, 1H), 2.41 (s, 4H), 2.35 (m, 2H), 2.12 (br t, 1H), 1.65 (br d, 2H), 1.18 (br q, 2H). MS m/z 171 [M++1].
With trifluoroacetic acid In dichloromethane at 20℃; for 6 h;
(0766) Tert-butyl 4-morpholinopiperidin-1-carboxylate (3.0 g, 11.1 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 6 h, and the solvent was removed under reduced pressure. Saturated sodium bicarbonate solution was added dropwisely to adjust pH of the mixture to pH=8. The mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to get the title compound (1.5 g, yield: 79percent).
1.52 g
With hydrogenchloride In methanol at 40℃; for 12 h;
Reference Example 20 Synthesis of 4-(morpholin-4-yl)piperidine (0395) (0396) Morpholine (0.792 g, 9.09 mmol), sodium triacetoxyborohydride (1.93 g, 9.09 mmol), and acetic acid (0.0460 g, 0.758 mmol) were added to a solution of 1-tert-butoxycarbonyl-4-piperidinone (1.51 g, 7.58 mmol) in dichloromethane (25.0 mL) at 0° C., and the resulting mixture was stirred at room temperature for 16 hours. The reaction liquid was cooled to 0° C. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction liquid, and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hydrochloric acid (1.0 N), and the resulting mixture was extracted with ethyl acetate. A 48percent aqueous solution of sodium hydroxide was added to the aqueous layer for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (25.0 mL), and concentrated hydrochloric acid (5.0 mL) was added, and then the resulting mixture was stirred at 40° C. for 12 hours. The reaction liquid was concentrated and exsiccated, and then the residue was dissolved in distilled water. A 48percent aqueous solution of sodium hydroxide was added for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. 4-(Morpholin-4-yl)piperidine (1.52 g, 5.63 mmol, 74percent) was obtained as a yellow solid. (0397) 1H-NMR (400 MHz, CDCl3) δ: 1.34 (2H, dd, J=12.0, 4.0 Hz), 1.40 (2H, dd, J=12.0, 4.0 Hz), 1.85 (2H, d, J=12.4 Hz), 2.28 (1H, tt, J=11.2, 4.0 Hz), 3.53-3.63 (6H, m), 3.15 (2H, d, J=12.4 Hz), 3.73 (4H, t, J=4.4 Hz). (0398) ESI-MS: m/z=171 (M+H)+
3 g
With trifluoroacetic acid In dichloromethane at 20℃;
To a stirred solution of tert-butyl 4-morpholinopiperidine-1-carboxylate (step 3, 4.0 g,14.848 mmol, 1.0 eq) in DCM (40 mL) was added TFA (20 mL). The reaction mixture wasstirred at room temperature for overnight. After completion of the reaction (monitored byTLC), the reaction mixture was evaporated under reduced pressure then pH adjusted to 8.05 with saturated NaHC03 solution and extracted with 10percent methanol in DCM (2x50 mL). Thecombined organic layer was dried over sodium sulfate, filtered and evaporated under reducedpressure to obtain the title compound (3.0 g) as a solid. 1H NMR (300 MHz, DMSO-d6): 8ppm 3.55 (t, J = 4.5 Hz, 4H), 3.02-2.94 (m, 2H), 2.44-2.39 (m, 4H), 2.26-2.12 (m, lH), 2.07(m, 2H), 1.73-1.64 (m, 2H), 1.32-1.16 (m, 2H); ESI-MS: m/z 171.03 (M+Ht
With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 0 - 20℃; for 16 h;
Morpholine (0.792 g, 9.09 mmol), sodium triacetoxyborohydride (1.93 g, 9.09 mmol), and acetic acid (0.0460 g, 0.758 mmol) were added to a solution of 1-tert-butoxycarbonyl-4-piperidinone (1.51 g, 7.58 mmol) in dichloromethane (25.0 mL) at 0° C., and the resulting mixture was stirred at room temperature for 16 hours. The reaction liquid was cooled to 0° C. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction liquid, and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hydrochloric acid (1.0 N), and the resulting mixture was extracted with ethyl acetate. A 48percent aqueous solution of sodium hydroxide was added to the aqueous layer for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (25.0 mL), and concentrated hydrochloric acid (5.0 mL) was added, and then the resulting mixture was stirred at 40° C. for 12 hours. The reaction liquid was concentrated and exsiccated, and then the residue was dissolved in distilled water. A 48percent aqueous solution of sodium hydroxide was added for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. 4-(Morpholin-4-yl)piperidine (1.52 g, 5.63 mmol, 74percent) was obtained as a yellow solid.
74%
With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 0 - 20℃; for 16 h;
Morpholin (0.792 g, 9.09 mmol), sodium triacetoxyborohydride (1.93 g, 9.09 mmol), acetic acid (0.0460 g, 0.758 mmol) were added to a solution of 1-tert-butoxycarbonyl-4-piperidinone (1.51 g, 7.58 mmol) in dichloromethane (25.0 mL) at 0° C., and the resulting mixture was stirred at room temperature for 16 hours. The reaction liquid was cooled to 0° C. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction liquid, and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hydrochloric acid (1.0 N), and the resulting mixture was extracted with ethyl acetate. A 48percent aqueous solution of sodium hydroxide was added to the aqueous layer for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (25.0 mL), and concentrated hydrochloric acid (5.0 mL) was added, and then the resulting mixture was stirred at 40° C. for 12 hours. The reaction liquid was concentrated and exsiccated, and then the residue was dissolved in distilled water. A 48percent aqueous solution of sodium hydroxide was added for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. 4-(Piperidin-4-yl) morpholin (1.52 g, 5.63 mmol, 74percent) was obtained as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 1.34 (2H, dd, J=12.0, 4.0 Hz), 1.40 (2H, dd, J=12.0, 4.0 Hz), 1.85 (2H, d, J=12.4 Hz), 2.28 (1H, tt, J=11.2, 4.0 Hz), 3.53-3.63 (6H, m), 3.15 (2H, d, J=12.4 Hz), 3.73 (4H, t, J=4.4 Hz). ESI-MS: m/z=171 (M+H)+
Reference：
[1] Patent: TW2016/2093, 2016, A, . Location in patent: Paragraph 0318
[2] Patent: US2018/104221, 2018, A1, . Location in patent: Paragraph 0170; 0171; 0172; 0173
[3] Patent: US2005/239843, 2005, A1, . Location in patent: Page/Page column 15
Reference：
[1] Journal of Organic Chemistry, 1961, vol. 26, p. 3805 - 3808
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[ 186650-77-1 ]
[ 1194-02-1 ]
[ 53617-35-9 ]
Reference：
[1] Patent: US6288061, 2001, B1,
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[ 3612-20-2 ]
[ 53617-35-9 ]
Reference：
[1] Patent: US2011/87021, 2011, A1,
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[ 5382-16-1 ]
[ 53617-35-9 ]
Reference：
[1] Patent: WO2018/29604, 2018, A1,
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[ 109384-19-2 ]
[ 53617-35-9 ]
Reference：
[1] Patent: WO2018/29604, 2018, A1,
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[ 19099-93-5 ]
[ 53617-35-9 ]
Reference：
[1] Patent: WO2009/131246, 2009, A1,
13
[ 76-05-1 ]
[ 53617-35-9 ]
[ 436099-97-7 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 20℃; for 1 h;
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (Aldrich, 3.0 g, 15 mmol) in THF (25 mL), morpholine (Aldrich, 1.56 g, 18 mmol) and Ti(OiPr)4 (Aldrich, 5.58 mL) were added successively and the mixture was stirred at room temperature for 1 hour. Then, 15 mL of ethanol was added and followed by sodium cyanoborohydride (0.63 g, 10.05 mmol). The resulting mixture was stirred at room temperature over night and the reaction was quenched with addition of water (4 mL). The mixture was stirred for 30 minutes and the white solid was filtered out and the filtrate was evaporated. The residue was partitioned between ether and water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave a white solid which was treated with 40 mL of 50percent TFA in methylene chloride. The solution was stirred at room temperature for 1 hour and the solvent was removed. The residue was lyophilized to give a white solid. 5.48 g, 98percent. MS (m+H)+: 171.
With potassium carbonate In dimethyl sulfoxide at 90℃;
195.195a
l-Fluoro-3-nitro-benzene (1.00 g, 0.00709 mol) and Potassium carbonate (1.47 g, 0.0106 mol) were dissolved in Dimethyl sulfoxide (7.50 mL) and 4-Piperidin-4-yl-morpholine (2.41 g, 0.0142 mol) was added. The reaction was allowed to stir overnight at 90 0C. Upon completion of the reaction, the mixture was diluted with ethyl acetate and was poured over water. Combined extracts were then washed with brine and the organics were dried over magnesium sulfate, filtered and reduced. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 1.6Og of 4-[l-(3-Nitro-phenyl)-piperidin-4-yl]-morpholine.
With allylchloro[1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidine]palladium(II); sodium hexamethyldisilazane In tetrahydrofuran at 20 - 45℃; for 1h; Inert atmosphere;
8 EXAMPLE-08: PREPARATION OF tert-BUTYL 6-CYANO-2-[l-[4-ETHYL-3- (MORPHOLINO-l-PIPERIDYL)PHENYL]-l-METHYL-ETHYL]-lH- INDOLE-3- CARBOXYLA TE .
Compound obtained in example-07 (200 g; 0.38 moles) and 4-morpholin-4-yl piperidine (79.43 g; 0.46 moles) were dissolved in THF under N2 atmosphere at 20- 30°C. NaHMDS (2.0M) in THF (437 g; 1.02 moles) was added at 20-40°C followed by l,3-bis-(2,6-diisopropylphenyl)-imidazoyl-2-ylidene(allyl) palladium- ill) chloride (6.7 g; 0.01 moles) at 30-40°C. Heated the reaction mass to 40-45°C and stirred for ~lh. After completion of the reaction by HPLC, reaction mass was diluted with ethyl acetate and aqueous ammonium chloride solution. Separated the organic layer and extracted the aqueous layer with ethyl acetate. Combined organic layer was washed with brine solution, treated with activated carbon and concentrated under vacuum at < 45°C. Co-distilled with acetone under vacuum at < 45°C, resulting residues were dissolved in acetone and added Cone. HC1. The precipitated solid was filtered, washed with acetone and dried under vacuum at 65- 70°C to obtain the title compound as a light cream colored powder (171.9 g; 74.53% of theory). HPLC Purity: 99.25%.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium hexamethyldisilazane In tetrahydrofuran; 1,4-dioxane at 60℃; Inert atmosphere;
25 Synthesis of 8-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (7c)
To a solution of 6b (150 mg, 0.34 mmol), tert-butyl 2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (109 mg, 0.51 mmol), Pd2(dba)3 (16 mg, 0.017 mmol) and S-Phos (28 mg, 0.068 mmol) in dry 1,4-dioxane (8.5 mL) was added NaHMDS (2 M in THF, 0.6 mL) under a nitrogen atmosphere. The mixture was purged with nitrogen for 5 min, and then heated at 60 °C until the completion of the reaction. After cooled to room temperature, the mixture was diluted with DCM (20 mL) and filtered. The filtrate was concentrated in vacuum and purified by chromatograph (CHCl3/MeOH) to give the coupling intermediate as pale yellow solid (103 mg, 59% yield): Subsequent deprotection of the intermediate with TFA (100 equiv) in DCM at room temperature afforded compound 7c as a yellow solid (69 mg, 49% yield in two steps).
Stage #1: methyl 7-bromoquinoline-2-carboxylate; 4-(piperidin-4-yl)morpholine With chloro(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)[2-(2’-amino-1,1‘-biphenyl)]palladium(II) 2nd generation; caesium carbonate In <i>tert</i>-butyl alcohol at 100℃; for 10h; Inert atmosphere; Sealed tube;
Stage #2: trifluoroacetic acid In acetonitrile
26.1 Step 1. 7-(4-Morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxylic acid [1.0]-trifluoroacetic acid
To a screw-cap vial equipped with a magnetic stir bar was added methyl 7-bromoquinoline-2-carboxylate (154.9 mg, 0.5821 mmol), dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (RuPhos Pd G2, Aldrich, 57.1 mg, 0.0735 mmol), and Cs2CO3 (623.3 mg, 1.913 mmol). The vial was sealed with a PTFE-lined septum, evacuated and backfilled with N2 (this process was repeated a total of three times). A solution of 4-piperidin-4-ylmorpholine (215.7 mg, 1.267 mmol) in anhydrous t-BuOH (4.00 mL) was added via syringe. The mixture was heated to 100° C. for 10 h. After cooling to room temperature, the reaction mixture was diluted with MeOH (20 mL). AcOH (1.00 mL, 17.6 mmol) was added. The mixture was filtered through a pad of diatomaceous earth (eluted with MeOH). The filtrate was concentrated under reduced pressure, and the residue was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of MeCN/water containing 0.05% TFA, at flow rate of 30 mL/min.) to afford the title product as a red solid (147.0 mg, 55%). LCMS calc. for C19H24N3O3 (M+H)+: m/z=342.2; found 342.2.
4-(1-(2-methoxy-4-nitrophenyl)piperidin-4-yl)morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile; at 100℃;
<strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (5000 mg, 29.22 mmol), 4-(piperidin-4-yl)morpholine (4974 mg, 29.22 mmol), potassium carbonate (80764 mg, 58.44 mmol) in acetonitrile (45 ml) was stirred at 100° C. for overnight. The reaction was diluted with ethyl acetate, washed with water, dried, concentrated and purified by flash chromatography (silica gel) to provide 4-(1-(2-methoxy-4-nitrophenyl)piperidin-4-yl)morpholine. LCMS-ESI+ (m/z): [M+H]+ calcd for C16H23N3O4: 321.4. found: 322.0
9-ethyl-8-(trifluoroacetyloxy)-6,6-dimethyl-11-oxo-5H,6H-benzo[b]carbazole-3-carbonitrile[ No CAS ]
[ 53617-35-9 ]
[ 1256580-46-7 ]
Yield
Reaction Conditions
Operation in experiment
81.9%
To a 100 mL three-necked flask was added 1.70 g (0.01 mol) of 4- (4-piperidinyl) morpholine and 40 mL of anhydrous tetrahydrofuran, and after cooling to 0 to 5 C, To the system was slowly added 0.48 g (0.012 mol) of 60% sodium hydride. After stirring for 15 min, 3.30 g (0.007 mol) of Ethyl-6,6-dimethyl-8-trifluoroacetate-11-oxa-6-11-dihydro-5H-benzo [b] carbazole-3-carbonitrile was dissolved in 20 mL Tetrahydrofuran was added dropwise to the reaction system and the temperature was raised to room temperature. After stirring for 3 to 4 hours, 20 mL of water was added to the reaction solution to quench the reaction. The resulting solution was extracted three times with dichloromethane and the resulting organic phase was concentrated under reduced pressure to a solid precipitate which was recrystallized from a mixture of methanol / water = 1: 1 to give a white solid Alectinib, 2.77 g (0.006 mol).
4-acetyl-2-(4-morpholin-4-yl-1-piperidinyl)-1-ethylbenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94.9%
With potassium tert-butylate; In dimethyl sulfoxide; at 5 - 80℃;Microwave irradiation;
Add 4-acetyl-2-bromo-ethylbenzene (VII) (2.26 g, 10 mmol), 4-(morpholin-4-yl) piperidin (VIII) (2.55 g, 15 mmol), potassium tert-butoxide (2.24 g, 20 mmol) and 50 mE dimethyl sulfoxide into the microwave reaction flask; place the reaction flask into the microwave reactor (700 W), and have them react for 5-10 minutes. Cool the reaction flask to ambient temperature, pour the reaction liquid into the ice water and keep stirring for 10 minutes; filter the solution and filter out the insoluble substances; extract the solution with ethyl acetate for three times, and combine the organic phases; then wash them with water saturated ammonium chloride and saturated salt solution successively, and dry them with anhydrous sodium sulfate. Concentrate them to dry state, and recrystallize the residue with n-hexane and ethyl acetate to obtain the white solid, 4-acetyl-2-(4-mor- pholin-4-yl- 1 -piperidinyl)ethylbenzene (IX), 3.0 g; yield rate is 94.9%; mass spectrum (El): mlz m1z317 (M+H).
9-ethyl-8-iodo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile[ No CAS ]
[ 53617-35-9 ]
[ 1256580-46-7 ]
Yield
Reaction Conditions
Operation in experiment
92%
With sodium methylate; In N,N-dimethyl-formamide; at 100℃; for 12.0h;
9-ethyl-8-iodo-6,6-dimethyl-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonitril (5.0 g,Was dissolved in N, N-dimethylformamide (120 mL) and 4- (4-piperidinyl) morpholine (4.4 g, 26 mmol)(1.5 g, 28 mmol). The reaction mixture was stirred at 100 C for 12 hours. The reaction mixture was cooled to room temperature, water (45 mL) was added, cooledCrystallization was carried out at 0 C for 4 hours and filtered to give alectinib, a white solid (4.9 g) in 92% yield.
89%
With sodium methylate; In toluene; at 100℃; for 10.0h;
9-Ethyl-6,6-dimethyl-8-iodo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(4.40 g, 10 mmol) was added to 30 ml of toluene.Add 4-(4-piperidinyl)morpholine (3.4 g, 20 mmol),Sodium methoxide (1.08 g, 20 mmol), reacted at 100 C for 10 h, cooled to room temperature.Add 20 ml of water, cool to -10 C for 3 hours, filter,Get alectinib (4.29g, 8.9mmol),Mass Spectrum (ESI): M/Z = 483.24 (M+H), purity 93%, yield 89%.
10.3 g
With potassium tert-butylate; L-proline; In 1,4-dioxane; at 120℃; for 24.0h;Inert atmosphere;
The 9-ethyl-8-iodo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile obtained as the starting material ( 10.7g, 0.021mol)With 4- (4-piperidinyl) morpholine (8.3 g, 0.048 mol),Potassium tert-butoxide (108mg, 0.001mol),L-proline (105mg, 0.001mol) was dissolved in 1,4-dioxane under the protection of N2, and reacted at 120 C for 24h.After the reaction of the raw materials was detected by TLC, it was extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and recrystallized with ethanol.Yield 10.3 g of white solid,Its reaction formula is as follows:
methyl 4-(4-morpholinopiperidin-1-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With C22H24N6; copper(II) acetylacetonate; Cs2CO3 In acetonitrile at 100℃; for 12h;
Synthesize the compound of formula -1 with L7:.
To methyl 4-bromobenzoate (21.5g, 100mmol), 4-(piperidin-4-yl)morpholine (18.7g, 110mmol) and Cs2CO3 (35.8g, 110mmol) in CH3CN (100mL) was added Cu (acac) 2 (2.6 g, 10 mmol) and L7 (3.7 g, 10 mmol). The reaction mixture was stirred at 100°C for 12 h, and then extracted and separated with ethyl acetate (300 mL) and water (100 mL). The organic mixture was dried over MgSO4, concentrated by vacuum filtration to obtain a crude product, which was purified by flash column chromatography (eluent of n-hexane/ethyl acetate 5/1). The target compound of formula III-1 is obtained as a colorless oil. Yield: 24 grams, 80%
80%
With C22H24N6; copper(II) acetylacetonate; Cs2CO3 In acetonitrile at 100℃; for 12h;
Use L7 to synthesize the compound of formula III-1:
To methyl 4-bromobenzoate (21.5 g, 100 mmol), 4-(piperidin-4-yl)morpholine (18.7 g, 110 mmol) and Cs2CO3(35.8g, 110 mmol) inCH3CN(100 mL)) solution was added Cu(acac)2(2.6 g, 10 mmol) and L7 (3.7 g, 10 mmol).The reaction mixture was stirred at 100 °C for 12 h, then extracted with ethyl acetate (300 mL) and water (100 mL).The organic mixture was dried over MgSO4andconcentrated by vacuum filtration to give the crude product, which was purified by flash column chromatography (n-hexane/ethyl acetate 5/1 eluent).The target compound of formula III-1 is obtained as a colorless oil.Yield: 24 g, 80%.
18.65%
With palladium diacetate; Cs2CO3; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl at 100℃; Inert atmosphere;
5 Step 5: Synthesis of Methyl 4 -( 4-morpholinopipe ridin-1-yl )benzoate
To a stirred solution of methyl 4-bromobenzoate (4.54 g, 21.14 mmol, 1.2 eq) intoluene (30 mL) was added 4-(piperidin-4-yl)morpholine (step 4, 3.0 g, 17.62 mmol, 1.0 eq)and Cs2C03 (17.2 g, 52.86 mmol, 3.0 eq). The reaction mixture was purged with nitrogen for15 10 minutes. Next, palladium acetate (0.039 g, 0.176 mmol, 0.01 eq) and BINAP (0.164 g,0.264 mmol, 0.015 eq) were added and the reaction mixture was degassed for 30 minutes andheated at 100 oc for overnight. After completion of the reaction (monitored by TLC), thereaction mixture was allowed to cool to room temperature, filtered through celite pad and waswashed with ethyl acetate (50 mL). The organic layer was washed with saturated sodium20 bicarbonate solution and followed by water (50 mL). The organic layer was dried overNa2S04, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 1% methanol in dichloromethane as an eluent to obtainthe title compound (1 g, yield: 18.65%) as an off-white solid. 1H NMR (300 MHz, CDCh): 8ppm 7.90 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 3.97-3.86 (m, 2H), 3.85 (s, 3H), 3.7325 (t, J = 4.5 Hz, 4H), 2.92-2.81 (m, 2H), 2.57 (t, J = 4.5 Hz, 4H), 2.47-2.35 (m, 1H), 2.10-1.90(m, 2H), 1.70-1.52 (m, 2H); ESI-MS: m/z 305.11 (M+Ht
9-ethyl-6,6-dimethyl-8-hydroxy-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile[ No CAS ]
[ 53617-35-9 ]
[ 1256580-46-7 ]
Yield
Reaction Conditions
Operation in experiment
22.8 g
With sulfuric acid; sodium hydrogensulfite; at 230℃; under 22502.3 Torr;
9-Ethyl-6,6-dimethyl-8-hydroxy-11-oxa-6,11-dihydro-5H-benzo[b] produced in Step HCarbazole-3-carbonitrile 9 (11.27 g, 3.77 mol) and 4-morpholin-4-yl-piperidine (16.8 g, 4.9 mol)After mixing, it is added to the reaction vessel.In the presence of 100 ml of 85% concentrated sulfuric acid solution, add the catalyst sodium bisulfite to fully mix and stir.Increase pressure to 3MPa, increase temperature to 230C,Condensation reaction occurs. After the reaction is complete, the mixture is cooled and cooled. Ethyl acetate is added for extraction 3 times. The aqueous phase is collected, and the precipitated solid is stirred and filtered. The filter cake is recrystallized to give 9-ethyl-6,6-dimethyl-8- (4-Morpholin-4-yl-piperidin-1-yl)-11-oxa-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile 10 (22.8 g, 8.7 Mol).
sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate[ No CAS ]
[ 132705-51-2 ]
[ 53617-35-9 ]
2-((1r,4r)-4-(2-(2-(4-morpholinopiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9%
A solution of sodium 2-( 1 -((ir, 4r)-4-(cyanomethyl)cyclohexyl)- 1, 6-dihydroimidazo[4, 5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate (Intermediate 4, 200 mg, 0.557 mmol), 4-(piperidin-4-yl)morpholine (94.8 mg, 0.557 mmol ), DIPEA (144 mg, 1.11 mmol), and DMF (5 mL) was stirred at 0 C for 1 h. Then PyBrOP (311 mg, 0.668 mmol) was added and stirred at room- temperature overnight. The mixture was quenched with 10 mL water and was purified by preparative acidic HPLC using a Boston Green ODS 150 mm x30 mm, Sjim column (eluent:water (0.05% HC1)-ACN from 0% to 30%, v/v) and then by preparative basic HPLC using a Kromasil 150 mm x 25 mm, lOjim column (eluent: water (0.05% ammonia hydroxide v/v)-ACN from 10% to 40%, v/v) to provide the title compound (25 mg, 9% yield) as a white solid. MS (ESI): mass calcd. for C27H35N702, 489.29; m/z found, 490.3 [M+H]t ?H NIVIR (400MHz, DMSO-d6): oe 11.85 (br s, 1H), 8.51 -8.47 (m, 1H), 7.48-7.44 (m, 1H), 6.72-6.68 (m, 1H),4.42-4.29 (m, 2H), 4.25 (d, J= 8.4 Hz, 2H), 4.16-4.07 (m, 1H), 3.59- 3.52 (m, 4H), 3.15 -3.05 (m, 1H), 2.69-2.63 (m, 1H), 2.58 (d, J= 6.0 Hz, 3H), 2.47 - 2.41 (m, 5H), 2.07 - 1.90 (m,6H), 1.85 - 1.74 (m, 2H), 1.42 - 1.27 (m, 3H), 1.27 - 1.13 (m, 1H)
Stage #1: tert-butyl 6-cyano-2-[1-(4-ethyl-3-iodo-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylate; 4-(piperidin-4-yl)morpholine With allylchloro[1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidene]palladium(II); sodium hexamethyldisilazane In 1,2-dimethoxyethane at 25 - 50℃; for 5h; Large scale;
Stage #2: With pyridine; hydrogenchloride In water; acetone at 10 - 15℃; for 0.333333h; Large scale;
8; 16 Example-16: Preparation of tert-butyl 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin- l-yl)phenyl)propan-2-yl)-lH-indole-3-carboxylate hydrochloride
Toluene (280 lts) was added to 4-(piperidin-4-yl)morpholine (26.40 kgs) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to H0-l l5°C and collect the water azeotropically and distilled off the solvent under reduced pressure. Dimethoxyethane (200 lts) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodo phenyl)propan-2- yl)-lH-indole-3-carboxylate (40.0 kgs) was added to the reaction mixture. Allylchloro[l,3- bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]palladium (II) (1.60 kgs) and sodium hexamethyldisilazane (200 lts) was added to the reaction mixture at 25-30°C. Raised the temperature of the reaction mixture to 45-50°C and stirred for 5 hours at the same temperature. Isopropyl acetate (200 lts) was added to the reaction mixture at 25-30°C. Aqueous ammonium chloride solution was slowly added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Aqueous sodium chloride solution was added to the organic layer and stirred for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated. Distilled off the solvent completely from the organic layer under reduced pressure. Dimethoxyethane (200 lts) and water (4.0 lts) was added to the obtained compound at 25-30°C and stirred for 15 minutes at the same temperature. N-acetyl cysteine (1.28 kgs) was added to the reaction mixture. Raised the temperature of the reaction mixture to 45-50°C and stirred for 1 hour at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with dimethoxyethane. Distilled off the solvent from the filtrate under reduced pressure. Acetone (400 lts) was added to the obtained compound. Pyridine (5.0 kgs) was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to l0-l5°C. Hydrochloric acid (5.0 lts) was added to the reaction mixture at 10-15°C and stirred for 20 minutes at the same temperature. Ethanol (8.0 lts) and acetone (80 lts) was added to the reaction mixture at l0-l5°C and stirred for 10 minutes at the same temperature. Filtered the solid and pyridine was added at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with acetone and dried to get the title compound. Yield 35.20 kgs.
4-[1-(2-chloro-5-methoxy-4-nitrophenyl)piperidin-4-yl]morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium carbonate; In N,N-dimethyl-formamide;
170 mg (1 mmol) of 4- (piperidin-4-yl) morpholine and 205 mg (1 mmol) of <strong>[1089280-66-9]1-chloro-2-fluoro-4-methoxy-5-nitrobenzene</strong> were placed in a reaction flask and added 2 ml of DMF and potassium carbonate 138 mg (1 mmol) were stirred until the reaction was completed. Water was added and suction filtered to obtain 300 mg of the product with a yield of 85%.
1.1 Step 1: Synthesis of 32b:
Step 1: Synthesis of 34b: (Ref: WO 20160400858): To a stirred mixture of compound 34a (4.0 g,23.5 mmol) and compound 26b (3.4 g, 21 .4 mmol) in DMSO (20 mL) at room temperature wasadded triethylamine (9.8 mL, 71 mmol) and stirred at 120 °C for overnight. After TLC showedcompletion of starting material the mixture was diluted with water (100 mL) and the solid formed was filtered and dried under vacuum to give the product 34b (6.3 g, 84% yield) as yellow solid which is used in the next step without further purification. MS(ESI) m/z 310.1 [M+H].
84%
With triethylamine In dimethyl sulfoxide at 120℃;
1.1 Step 1 : Synthesis of 34b: (Ref: WO 20160400858):
To a stirred mixture of compound 34a (4.0 g, 23.5 mmol) and compound 26b (3.4 g, 21 .4 mmol) in DMSO (20 ml.) at room temperature was added triethylamine (9.8 ml_, 71 mmol) and stirred at 120 °C for overnight. After TLC showed completion of starting material the mixture was diluted with water (100 ml.) and the solid formed was filtered and dried under vacuum to give the product 34b (6.3 g, 84% yield) as yellow solid which is used in the next step without further purification. MS(ESI) m/z 310.1 [M+H]+.
84%
With triethylamine In dimethyl sulfoxide at 120℃;
1.1 Step 1 : Synthesis of 34b:
To a stirred mixture of compound 34a (4.0 g, 23.5 mmol) and compound 26b (3.4 g, 21.4 mmol) in DMSO (20 ml.) at room temperature was added triethylamine (9.8 ml_, 71 mmol) and stirred at 120 °C for overnight. After TLC showed completion of starting material the mixture was diluted with water (100 ml.) and the solid formed was filtered and dried under vacuum to give the product 34b (6.3 g, 84% yield) as yellow solid which is used in the next step without further purification. MS(ESI) m/z 310.1 [M+H]+.
With triethylamine In dimethyl sulfoxide at 120℃;
1.1 Step 1 : Synthesis of 34b : (Ref: WO 20160400858):
To a stirred mixture of compound 34a (4.0 g, 23.5 mmol) and compound 26b (3.4 g, 21.4 mmol) in DMSO (20 ml.) at room temperature was added triethylamine (9.8 ml_, 71 mmol) and stirred at 120 °C for overnight. After TLC showed completion of starting material the mixture was diluted with water (100 ml.) and the solid formed was filtered and dried under vacuum to give the product 34b (6.3 g, 84% yield) as yellow solid which is used in the next step without further purification. MS(ESI) m/z 310.1 [M+H]+.
4-(1-(5-nitropyridin-2-yl)piperidin-4-yl)morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With potassium carbonate In acetonitrile at 70℃; for 1h;
1 Step 1: 4-(1-(5-nitropyridin-2-yl)piperidin-4-yl)morpholine
To a solution of 4-(piperidin-4-yl)morpholine (851 mg, 5.00 mmol, 1.00 equiv), K2CO3 (1381 mg, 9.99 mmol, 2.00 equiv) in ACN (15 mL) was added 2-fluoro-5-nitropyridine (710 mg, 5.00 mmol, 1.00 equiv) and the mixture was stirred at 70° C. for 1 h. The resulting solution was quenched by water (50 mL). The solids were collected by filtration and washed with water to afford the title compound (1.15 g, 79%) as a yellow solid. LCMS: [M+H]+ 293.15.
(7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-morpholinopiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: bis(trichloromethyl) carbonate; fulvestrant With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.333333h;
Stage #2: 4-(piperidin-4-yl)morpholine In dichloromethane at 0 - 20℃; for 16h;
20 Example-20: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5- pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- cyclopenta[a]phenanthren-3-yl 4-morpholinopiperidine-l-carboxylate
To a solution of Fulvestrant (0.5 g) in DCM (8 mL) were added DIPEA (0.21 mL) and triphosgene (0.122 g) at 0°C and stirred the reaction mixture for 10 min at the same temperature. After 10 min, 4-(piperidin-4-yl)morpholine (0.209 g) was added in the reaction mixture at 0°C and the reaction mixture was stirred at room temperature for 16h. After completion of reaction on TLC, the reaction mixture was diluted with water (5 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.56 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5- pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- cyclopenta[a]phenanthren-3-yl 4-morpholinopiperidine-l-carboxylate as a light brown solid. LCMS purity: 48%
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 4h;
General procedures for preparation of the target intermediates (5a-h)
General procedure: Intermediate 4a (1.00mmol), amines (1.5mmol), K2CO3 (2.00mmol) were mixed in dried DMF (6mL) at room temperature, then heated to 85°C in oil bath and stirred for 4h. The reactions were monitored by TLC until the process finished completely, then cool to room temperature. Sequentially, ethyl acetate (20mL) was added, then washed with brine (10mL×3). The organic phase was separated, dried over anhydrous Na2SO4, filtered, then the filtrate was evaporated under reduced pressure. The crude products were purified by silica gel chromatography and dried in a vacuum oven to give pure intermediates (5a-h).
89.7%
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 4h;
General procedures for preparation of the target intermediates (5a-h)
General procedure: Intermediate 4a (1.00mmol), amines (1.5mmol), K2CO3 (2.00mmol) were mixed in dried DMF (6mL) at room temperature, then heated to 85°C in oil bath and stirred for 4h. The reactions were monitored by TLC until the process finished completely, then cool to room temperature. Sequentially, ethyl acetate (20mL) was added, then washed with brine (10mL×3). The organic phase was separated, dried over anhydrous Na2SO4, filtered, then the filtrate was evaporated under reduced pressure. The crude products were purified by silica gel chromatography and dried in a vacuum oven to give pure intermediates (5a-h).
Stage #1: 2-(4-(bromomethyl)-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; 4-(piperidin-4-yl)morpholine With potassium carbonate In acetonitrile at 60℃; for 1h;
Stage #2: methyl 3-amino-6-bromopyrazine-2-carboxylate With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct In water monomer; acetonitrile at 80℃; for 2h;
Step a:
4-(Piperidin-4-yl)morpholine (26) (1.467 g, 8.62 mmol), 2-(4-(bromomethyl)-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25) (2.86 g, 8.62 mmol) and potassium carbonate (3.57 g, 25.9 mmol) were dissolved in acetonitrile (50 mL) and heated at 60°C for one hour. Methyl 3-amino-6-bromopyrazine-2-carboxylate (24) (2 g, 8.62 mmol), PdCl2(dppf).CH2Cl2 (0.124 g, 0.151 mmol) and 5 mL of water were added to the mixture, which was stirred for another two hours at 80°C. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layer was back-extracted with ethyl acetate. Both organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was flash-chromatographed on a 120 g silica gel column and eluted from CH2Cl2 (100%) to CH2Cl2/MeOH (4:1) to give 3.08 g (80%) of methyl 3-amino-6-(2-chloro-4-((4-morpholinopiperidin-1-yl)methyl) phenyl)pyrazine-2-carboxylate (27) as a yellow solid.
80%
Stage #1: 2-(4-(bromomethyl)-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; 4-(piperidin-4-yl)morpholine With potassium carbonate In acetonitrile at 60℃; for 1h;
Stage #2: methyl 3-amino-6-bromopyrazine-2-carboxylate With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct In water monomer; acetonitrile at 80℃; for 2h;
Step a:
4-(Piperidin-4-yl)morpholine (26) (1.467 g, 8.62 mmol), 2-(4-(bromomethyl)-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25) (2.86 g, 8.62 mmol) and potassium carbonate (3.57 g, 25.9 mmol) were dissolved in acetonitrile (50 mL) and heated at 60°C for one hour. Methyl 3-amino-6-bromopyrazine-2-carboxylate (24) (2 g, 8.62 mmol), PdCl2(dppf).CH2Cl2 (0.124 g, 0.151 mmol) and 5 mL of water were added to the mixture, which was stirred for another two hours at 80°C. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layer was back-extracted with ethyl acetate. Both organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was flash-chromatographed on a 120 g silica gel column and eluted from CH2Cl2 (100%) to CH2Cl2/MeOH (4:1) to give 3.08 g (80%) of methyl 3-amino-6-(2-chloro-4-((4-morpholinopiperidin-1-yl)methyl) phenyl)pyrazine-2-carboxylate (27) as a yellow solid.
General procedure: Compound 4j (2.0mmol) and compound 5j (4.0mmol) were dissolved in DMSO (15mL), then K2CO3 (6.0mmol) was added in the mixed solution. The resulting mixture was stirred at 120°C overnight, then cooled down to room temperature and separated by FC column to obtain compound 6j. 1H NMR (400MHz, CDCl3) δ: 7.78(1H, s), 6.50 (1H,s), 3.90 (3H, s), 3.48 (2H, d, J=6.4Hz), 3.38 (2H, t, J=7.6Hz), 3.34 (3H, s), 3.20-3.23 (2H, m), 2.93 (2H, t, J=6.4Hz), 2.68-2.73 (3H, m), 2.18-2.20 (4H, m), 1.77-1.81 (2H, m), 1.40-1.49 (2H, m); 13C NMR (100MHz, CDCl3) δ: 158.41, 153.30, 132.64, 129.01, 123.41, 103.30, 74.96, 63.71, 58.91, 56.43, 55.48, 49.44, 30.05, 29.13, 17.60; MS (ESI): m/z calcd for C18H27N3O4 [M+H]+ 350.21, found: 350.25;
With potassium carbonate Heating;
General procedure: Compound 4j (2.0mmol) and compound 5j (4.0mmol) were dissolved in DMSO (15mL), then K2CO3 (6.0mmol) was added in the mixed solution. The resulting mixture was stirred at 120°C overnight, then cooled down to room temperature and separated by FC column to obtain compound 6j. 1H NMR (400MHz, CDCl3) δ: 7.78(1H, s), 6.50 (1H,s), 3.90 (3H, s), 3.48 (2H, d, J=6.4Hz), 3.38 (2H, t, J=7.6Hz), 3.34 (3H, s), 3.20-3.23 (2H, m), 2.93 (2H, t, J=6.4Hz), 2.68-2.73 (3H, m), 2.18-2.20 (4H, m), 1.77-1.81 (2H, m), 1.40-1.49 (2H, m); 13C NMR (100MHz, CDCl3) δ: 158.41, 153.30, 132.64, 129.01, 123.41, 103.30, 74.96, 63.71, 58.91, 56.43, 55.48, 49.44, 30.05, 29.13, 17.60; MS (ESI): m/z calcd for C18H27N3O4 [M+H]+ 350.21, found: 350.25;
Stage #1: tert-butyl 6-cyano-2-[1-(4-ethyl-3-iodo-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylate; 4-(piperidin-4-yl)morpholine With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; 1,3-dimethyl-2-imidazolidinone; bis(η3-allyl-μ-chloropalladium(II)); sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
Stage #2: With ammonium chloride In Isopropyl acetate; water at 50℃;
Stage #3: With pyridine hydrochloride In ethanol; acetone at 35℃;
1.3 (3) Production of tert-Butyl 6-cyano-2-[1-[4-ethyl-3-(4-morpholino-1-piperidyl)phenyl]-1-methyl-ethyl]-1H-indole-3-carboxylate hydrochloride (hydrochloride of VIIa) [Step 3]
In a nitrogen atmosphere, π-allylpalladium chloride dimer (0.453 g, 2.48 mmol) and S-Phos (1.02 g, 2.48 mmol) were dissolved in THF (275 mL), and the inside of the reaction vessel was purged with nitrogen. To the obtained mixture, tert-butyl 6-cyano-2-[1-(4-ethyl-3-iodo-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylate (VIa, 65 g, 165 mmol) yielded in Step 2, 4-(4-piperidinyl)-morpholine (33.8 g, 198 mmol), and 1,3-dimethyl-2-imidazolidinone (149 mL) were added, and the inside of the reaction vessel was purged again with nitrogen. The mixture was cooled to 0° C., and NaHMDS (40% solution of THF, 280 mL, 545 mmol) was added such that the reaction temperature did not exceed 20° C. After completion of the addition, the reaction temperature was set at 25° C., and the mixture was stirred for 1 hour. Isopropyl acetate (340 mL), and an aqueous solution of ammonium chloride (15%, 255 g) were added thereto, the reaction temperature was heated to 50° C., and the liquid was stirred at the same temperature for 1 hour. The aqueous layer was discharged, and the resulting organic layer was concentrated at an outside temperature of 50° C. under a reduced pressure until the organic layer was concentrated to about 210 mL. Isopropyl acetate (340 mL) was added, then the liquid was concentrated to about 210 mL under a reduced pressure at the same temperature, and the residue was dissolved in acetone (255 mL). The solution was filtrated with a 1 μm-pore filter paper, and acetone (935 mL) was added to the obtained filtrate. After raising the temperature of the solution to 35° C., a mixed solution of an ethanol solution (21.3 mL) of pyridine hydrochloride (21 g, 182 mmol) and acetone (42.5 mL) was added dropwise over 1 hour to crystallize the objective substance. The resulting slurry was cooled to -4° C. over 1 hour, and filtrated to obtain a wet powder, which was then washed with acetone (425 mL). The wet powder was dried under a reduced pressure at an outside temperature of 40° C., to yield 97.1 g of tert-butyl 6-cyano-2-[1-[4-ethyl-3-(4-morpholino-1-piperidyl)phenyl]-1-methyl-ethyl]-1H-indole-3-carboxylate hydrochloride (hydrochloride of VIIa) (yield: 91%). (0182) HPLC purity: 99.13% (0183) Acetone content: 7.8% (0184) Powder X-ray diffraction analysis: Compound (VIIa) exhibited patterns as shown in FIG. 2, FIG. 3, and FIG. 4.
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