Name: 3308-94-9|2-(3-Chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane|98% GC
Brand: Ambeed
SKU: A593150
Price: 39.0 USD
Availability: InStock
Rating: 94 (30 reviews)

1
[ 59143-46-3 ]
[ 3308-94-9 ]
[ 59143-36-1 ]

Yield	Reaction Conditions	Operation in experiment
	(i) K₂CO₃, (ii) aq. HCl; Multistep reaction;
	With hydrogenchloride; potassium carbonate In ethanol; butan-1-ol	99 1,3-Dihydro-1'-[3-(p-fluorobenzoyl)propyl]-3-phenylspiro[isobenzofuran-1,4'-piperidine] EXAMPLE 99 1,3-Dihydro-1'-[3-(p-fluorobenzoyl)propyl]-3-phenylspiro[isobenzofuran-1,4'-piperidine] A stirred mixture of 4.9 g. of 1.3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] (Example 65), 4.9 g. of ω-chloro-p-fluorobutyrophenone ethylene ketal, 10 g. of potassium carbonate, and 50 ml. of butanol is heated under reflux for 46 hours and filtered. The filtrate is concentrated to an oil, which is stirred with 50 ml. of 3N hydrochloric acid and 50 ml. of ethanol. The mixture is made basic with sodium hydroxide and extracted with benzene. The benzene solution is dried over sodium sulfate and concentrated. The residue is recrystallized from ether to provide colorless crystals, m.p. 137°-138°. Analysis: Calc. for C28 H28 FNO2: C 78.30%; H 6.57%; N 3.26%; Found: C 78.28%; H 6.59%; N 3.12%.

Reference： [1]Allen,R.C. et al. [Journal of Medicinal Chemistry, 1978, vol. 21, p. 1149 - 1154]
[2]Current Patent Assignee: SANOFI - US3959475, 1976, A

2
[ 110-89-4 ]
[ 3308-94-9 ]
1-{3-[2-(4-Fluoro-phenyl)-[1,3]dioxolan-2-yl]-propyl}-piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 50℃; for 16h;

Reference： [1]Sui; De Voss; DeCamp; Li; Craik; Ortiz De Montellano [Synthesis, 1993, # 8, p. 803 - 808]

3
[ 20980-22-7 ]
[ 3308-94-9 ]
[ 801-12-7 ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium carbonate; potassium iodide In acetonitrile for 36h; Heating;

Reference： [1]Yevich, Joseph P.; New, James S.; Lobeck, Walter G.; Dextraze, Pierre; Brenstein, Edith; et al. [Journal of Medicinal Chemistry, 1992, vol. 35, # 24, p. 4516 - 4525]

4
[ 39512-49-7 ]
[ 3308-94-9 ]
[ 56660-99-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 100℃; for 17.5h;

Reference： [1]Moerlein, Stephen M.; Stoecklin, Gerhard L. [Journal of Medicinal Chemistry, 1985, vol. 28, # 9, p. 1319 - 1324]

5
[ 107-21-1 ]
[ 3874-54-2 ]
[ 3308-94-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With toluene-4-sulfonic acid In water; toluene for 16h; Inert atmosphere; Reflux;	2-(3-Chloropropyl)-2-(4-fluorophenyl)[1,3]dioxolane (12) A solution of 4-chloro-4'-fluorobutyrophenone (3.29 mL, 20.0 mmol), ethylene glycol (3.25 mL, 60.0 mmol, 3.0 equiv.), and p-TsOH*H2O (304 mg, 1.60 mmol, 0.08 equiv.) in PhMe (200 mL) was refluxed under Dean-Stark conditions for 16 h. The solution was cooled and washed with 5% aq. NaHCO3 (2 × 50 mL). The organic layer was dried (Na2SO4) and the solvent evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel, eluting with hexanes-EtOAc (90:10) to give 12 (4.82 g, 98%) as a pale yellow oil, the spectroscopic data of which corresponded with that previously described: Rf 0.54 (silica gel, hexanes-EtOAc; 90:10); 1H NMR (400.2 MHz, CDCl3); δ 7.43-7.40 (2H, m, ArH), 7.04-6.99 (2H, m, ArH), 4.03-4.00 (2H, m), 3.78-3.74 (2H, m), 3.53 (2H, t, J = 6.7 Hz), 2.04-1.99 (2H, m), 1.88-1.81 (2H, m).
93%	With toluene-4-sulfonic acid In benzene for 18h; Heating;
90%	With toluene-4-sulfonic acid In benzene for 15h; Heating;

89%	With toluene-4-sulfonic acid In benzene Heating;
	With toluene-4-sulfonic acid In benzene for 12h; Heating;
	With toluene-4-sulfonic acid In toluene for 16h; Heating;
	With toluene-4-sulfonic acid In benzene for 10h; Reflux; Dean-Stark;	Preparation of alkylating agents (IIa)-(IIm) General procedure: A solution of the phenone prepared at the previous step (10 mmol), the corresponding diol (100 mmol),and TSA (0.5 g, 2.6 mmol) were mixed in dry benzene (70 mL). The resulting solution was refluxed for 10 h using a Dean-Stark trap. The reaction mixture was cooled and a solution semisaturated sodium hydrocarbonate (50 mL) was added. The organic layer was separated, and the aqueous phase was extracted with benzene (3 × 30 mL). The united organic extracts were dried with anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by column chromatography (l = 5 cm, d = 5 cm) on silica gel eluting with methylene chloride.

Reference： [1]Banister, Samuel D.; Moussa, Iman A.; Jorgensen, William T.; Chua, Sook Wern; Kassiou, Michael [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 12, p. 3622 - 3626]
[2]Yevich, Joseph P.; New, James S.; Lobeck, Walter G.; Dextraze, Pierre; Brenstein, Edith; et al. [Journal of Medicinal Chemistry, 1992, vol. 35, # 24, p. 4516 - 4525]
[3]Repke; Clark; Kluge; Muchowski; Strosberg; Lee; Whiting [Journal of Pharmaceutical Sciences, 1985, vol. 74, # 1, p. 37 - 39]
[4]Vincent; Shambhu; Digenis [Journal of medicinal chemistry, 1980, vol. 23, # 1, p. 75 - 79]
[5]Moerlein, Stephen M.; Stoecklin, Gerhard L. [Journal of Medicinal Chemistry, 1985, vol. 28, # 9, p. 1319 - 1324]
[6]Orjales; Bordell; Rubio [Journal of Heterocyclic Chemistry, 1995, vol. 32, # 3, p. 707 - 718]
[7]Komissarov; Valuev-Elliston; Ivanova; Kochetkov; Kritzyn [Russian Journal of Bioorganic Chemistry, 2015, vol. 41, # 1, p. 37 - 45][Bioorg. Khim., 2015, vol. 41, # 1, p. 44 - 53,10]

6
[ 1074-82-4 ]
[ 3308-94-9 ]
[ 3308-95-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	In N,N-dimethyl-formamide at 110℃; for 20h;
	In N,N-dimethyl-formamide at 80℃; for 18h;

Reference： [1]Repke; Clark; Kluge; Muchowski; Strosberg; Lee; Whiting [Journal of Pharmaceutical Sciences, 1985, vol. 74, # 1, p. 37 - 39]
[2]Ismaiel; De los Angeles; Teitler; Ingher; Glennon [Journal of Medicinal Chemistry, 1993, vol. 36, # 17, p. 2519 - 2525]

7
[ 40064-34-4 ]
[ 3308-94-9 ]
[ 56660-98-1 ]

Yield	Reaction Conditions	Operation in experiment
75.4%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide 1.) room temp., overnight, 2.) reflux, 1 h;

Reference： [1]Sui; De Voss; DeCamp; Li; Craik; Ortiz De Montellano [Synthesis, 1993, # 8, p. 803 - 808]

8
[ 99931-82-5 ]
[ 3308-94-9 ]
[ 99931-65-4 ]

Yield	Reaction Conditions	Operation in experiment
33%	With potassium carbonate; potassium iodide In acetonitrile for 36h; Heating;

Reference： [1]Yevich, Joseph P.; New, James S.; Lobeck, Walter G.; Dextraze, Pierre; Brenstein, Edith; et al. [Journal of Medicinal Chemistry, 1992, vol. 35, # 24, p. 4516 - 4525]

9
<dimethyl-2,6 (piperidinyl-4 methyl)-1 dihydro-1,4 pyridylidene-4 yl>-2 indanedione-1,3 [ No CAS ]
[ 3308-94-9 ]
[ 81960-01-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; potassium iodide In ethanol for 24h; Heating;

Reference： [1]Ploquin; Le Baut; Floc'h; et al. [European Journal of Medicinal Chemistry, 1982, vol. 17, # 2, p. 149 - 158]

10
[ 59215-40-6 ]
[ 3308-94-9 ]
[ 99931-64-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	With potassium carbonate; potassium iodide In acetonitrile for 36h; Heating;

Reference： [1]Yevich, Joseph P.; New, James S.; Lobeck, Walter G.; Dextraze, Pierre; Brenstein, Edith; et al. [Journal of Medicinal Chemistry, 1992, vol. 35, # 24, p. 4516 - 4525]

11
[ 81078-84-4 ]
[ 3308-94-9 ]
4-(4-{3-[2-(4-Fluoro-phenyl)-[1,3]dioxolan-2-yl]-propyl}-piperazin-1-yl)-furo[3,2-c]pyridine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 1147 - 1156

12
[ 106261-27-2 ]
[ 3308-94-9 ]
[ 119924-11-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate In acetonitrile for 72h; Heating;

Reference： [1]New, James S.; Christopher, William L.; Yevich, Joseph P.; Butler, Rhett; Schlemmer, R. Francis; et al. [Journal of Medicinal Chemistry, 1989, vol. 32, # 6, p. 1147 - 1156]

13
[ 3308-94-9 ]
(Z)-8-(4-Fluoro-phenyl)-2,3,5,6-tetrahydro-[1,4]dioxocine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; potassium iodide In N,N-dimethyl-formamide for 16h; Heating;

Reference： [1]Voss, James J. De; Sui, Zhihua [Tetrahedron Letters, 1994, vol. 35, # 1, p. 49 - 52]

14
[ 5382-16-1 ]
[ 3308-94-9 ]
[ 19668-18-9 ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 110 - 120℃; for 6h;

Reference： [1]Vincent; Shambhu; Digenis [Journal of medicinal chemistry, 1980, vol. 23, # 1, p. 75 - 79]

15
[ 50693-75-9 ]
[ 3308-94-9 ]
[ 161331-20-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium carbonate; potassium iodide In various solvent(s) for 8h; Heating;

Reference： [1]Castro, M. E.; Rosa, E.; A-Osuna, J.; Garcia-Ferreiro, T.; Loza, M.; et al. [European Journal of Medicinal Chemistry, 1994, vol. 29, # 11, p. 831 - 840]

16
[ 51784-03-3 ]
[ 3308-94-9 ]
[ 1026272-98-9 ]

Reference： [1]Journal of Heterocyclic Chemistry,1995,vol. 32,p. 707 - 718

17
[ 14527-26-5 ]
[ 3308-94-9 ]
N-[4-(4-Fluoro-phenyl)-4-oxo-butyl]-guanidine [ No CAS ]

Reference： [1]Farmaco, Edizione Pratica,1976,vol. 31,p. 442 - 456

18
[ 31252-42-3 ]
[ 3308-94-9 ]
[ 153208-89-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide In acetonitrile for 24h; Heating;
20 g (91%)	With potassium iodide; potassium carbonate In acetonitrile	2 4-Benzyl-1-(4-p-fluorophenyl-4,4-ethylendioxy)butylpiperidine EXAMPLE 2 4-Benzyl-1-(4-p-fluorophenyl-4,4-ethylendioxy)butylpiperidine A mixture of 4-benzylpiperidine (10 g, 57 mmol), 2-(3-chloro-propyl)-2-(p-fluorophenyl))1,3-dioxolane (14 g, 57 mmol), potassium carbonate (5 g, 36 mmol) and potassium iodide (0.5 g, 3 mmol) in acetonitrile (50 ml) is heated under reflux for 16 hours. The resulting solution is allowed to cool and filtered, and the residue is washed with acetonitrile. The filtrates are evaporated to give 20 g (91%) of an oil, which is used in the next step without additional purification. IR (cm-1): 1600, 1500, 1450, 1220, 1040. NMR (CDCl3): 1.2-2.0 (m, 11H, 3-H, 4-H, 5-H, 2-Hax, 6-Hax, Bu-2H and Bu-3H), 2.27 (t, J=7Hz, 2H, Bu-1H), 2.52 (d, J=4Hz, 2H, PhCH2), 2.85 (da, J=11Hz, 2H, 2-Heq and 6-Heq), 3.6-4.1 (m, 4H, OCH2 CH2 O), 6.97 (t, J=8Hz, 2H, FPh-3H and -5H), 7.1-7.2 (m, 5H, Ph--H), 7.4 (dd, J=8 and 5Hz, 2H, FPh-2H and -6H).

Reference： [1]Bolós, Jordi; Gubert, Santiago; Anglada, Lluís; Planas, Josep M.; Burgarolas, Carme; Castelló, Josep M.; Sacristán, Aurelio; Ortiz, José A. [Journal of Medicinal Chemistry, 1996, vol. 39, # 15, p. 2962 - 2970]
[2]Current Patent Assignee: FERRER INTERNACIONAL SA - US5395841, 1995, A

19
[ 102-11-4 ]
[ 3308-94-9 ]
[ 785751-76-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide In acetonitrile for 24h; Heating;

Reference： [1]Bolós, Jordi; Gubert, Santiago; Anglada, Lluís; Planas, Josep M.; Burgarolas, Carme; Castelló, Josep M.; Sacristán, Aurelio; Ortiz, José A. [Journal of Medicinal Chemistry, 1996, vol. 39, # 15, p. 2962 - 2970]

20
[ 41979-39-9 ]
[ 3308-94-9 ]
[ 56660-98-1 ]

Yield	Reaction Conditions	Operation in experiment
45%	With sodium carbonate; sodium iodide In N,N-dimethyl-formamide at 80℃; for 24h;

Reference： [1]Metwally, Kamel A.; Dukat, Malgorzata; Egan, Christina T.; Smith, Carol; DuPre, Ann; Gauthier, Colleen B.; Herrick-Davis, Katharine; Teitler, Milt; Glennon, Richard A. [Journal of Medicinal Chemistry, 1998, vol. 41, # 25, p. 5084 - 5093]

21
[ 3308-94-9 ]
[ 660844-86-0 ]

Yield	Reaction Conditions	Operation in experiment
97.4%	With sodium azide; potassium iodide In N,N-dimethyl-formamide at 130℃;
96%	With sodium azide; potassium iodide In N,N-dimethyl-formamide at 60℃; for 26h; Inert atmosphere;	2-(3-Azidopropyl)-2-(4-fluorophenyl)[1,3]dioxolane (13) A mixture of 12 (1.22 g, 5.00 mmol), sodium azide (1.300 g, 20.00 mmol, 4.0 equiv.), and KI (515 mg, 3.10 mmol, 0.62 equiv.) in DMF (10 mL) was stirred at 60 °C for 26 h. The mixture was poured into H2O (150 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and the solvent evaporated under reduced pressure. Purification by flash chromatography on silica gel, eluting with hexanes-EtOAc (90:10) afforded 13 as a pale yellow oil (1.21 g, 96%) of consistent spectroscopic properties to those previously reported: Rf 0.50 (silica gel, hexanes-EtOAc; 90:10); 1H NMR (400.2 MHz, CDCl3); δ 7.43-7.49 (2H, m, ArH), 7.04-7.00 (2H, m, ArH), 4.03-4.00 (2H, m), 3.78-3.74 (2H, m), 3.27 (2H, t, J = 7.0 Hz), 1.96-1.92 (2H, m), 1.69-1.62 (2H, m).

Reference： [1]Lyles-Eggleston; Altundas; Xia; Sikazwe; Fan; Yang; Li; Zhang; Zhu; Schmidt; Vanase-Frawley; Shrihkande; Villalobos; Borne; Ablordeppey [Journal of Medicinal Chemistry, 2004, vol. 47, # 3, p. 497 - 508]
[2]Banister, Samuel D.; Moussa, Iman A.; Jorgensen, William T.; Chua, Sook Wern; Kassiou, Michael [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 12, p. 3622 - 3626]

22
[ 3308-94-9 ]
[ 3874-54-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	In acetone at 100℃; for 0.0833333h; microwave irradiation;

Reference： [1]Gregg, Brian T.; Golden, Kathryn C.; Quinn, John F. [Journal of Organic Chemistry, 2007, vol. 72, # 15, p. 5890 - 5893]

23
[ 3308-94-9 ]
[ 52-86-8 ]

Reference： [1]Journal of Medicinal Chemistry,1985,vol. 28,p. 1319 - 1324

24
4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride [ No CAS ]
[ 3308-94-9 ]
[ 206440-27-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In methanol for 25h; Heating / reflux;	10.1 EXAMPLE 10 Production of 5-(4-fluorophenyl)-4-[2-[4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl]ethyl]pyrazole 3-(4-fluorophenyl)-4-[2-[4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl]ethyl]pyrazole (1) A mixture of 1.5 g of 2-(4-fluorophenyl)-2-(3-chloropropyl)-1,3-dioxolane, 1.5 g of 4-(6-fluorobenzo[b]thiophen-3-yl)piperidine hydrochloride, 3.3 ml of diisopropylethylamine and 2.5 ml of methanol was stirred with heating under reflux for 25 hours. The reaction mixture was separated with chloroform and a saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted with chloroform. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a flush chromatography (silica gel: Merckkieselgel 60 230-to 400-mesh, eluent: hexane-ethyl acetate=1:2) to obtain 0.71 g of 2-(4-fluorophenyl)-2-[3-[4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl]propyl]-1,3-dioxolane. This compound was stirred at room temperature for 20 hours in a mixture of 3 ml of 1N hydrochloric acid and 4 ml of tetrahydrofuran. After the solvent was distilled off under reduced pressure, the residue was separated with ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in 20 ml of ethyl acetate and treated with 1 ml of a 4N hydrogen chloride/1,4-dioxane solution to obtain 0.54 g of 6-fluoro-3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]benzo[b]thiophene hydrochloride

Reference： [1]Current Patent Assignee: TAISHO PHARMACEUTICAL HOLDINGS CO., LTD.; ADEKA CORP. - US6407121, 2002, B1 Location in patent: Page column 14-15

25
[ 178043-12-4 ]
[ 3308-94-9 ]
[ 847344-42-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide In acetone at 60℃; for 48h;	P5.1 Example P5): Preparation of 1, 3-dichloro-5- (3, 3-dichloro-allyloxy)-2- [4- (4-fluoro- phenyl)-pent-4-enyloxy]-benzene P5.1) 2.0 g of 2- (3-CHLORO-PROPYL)-2- (4-FLUORO-PHENYL)- [1, 3] DIOXOLANE are added to a suspension of 2.36 g of 2, 6-DICHLORO-4- (3, 3-DICHLORO-ALLYLOXY)-PHENOL, 1.7 g of potassium carbonate and 120 mg of potassium iodide in 50 ml of acetone. The mixture is then stirred for 48 hours at 60°C. The reaction mixture is concentrated and the residue is taken up in water and extracted with ethyl acetate. After concentration of the organic phase and purification over silica gel, 2- {3- [2, 6-dichloro-4- (3, 3-dichloro-allyloxy)-phenoxy]-propyl}-2- (4- fluoro-phenyl)- [1, 3] dioxolane is obtained.

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2005/19147, 2005, A2 Location in patent: Page/Page column 39-40

26
6-chloro-3-(4-pyridinylamino)benzo[b]thiophene [ No CAS ]
[ 110-17-8 ]
[ 3308-94-9 ]
6-Chloro-3-[(4-fluorobenzoylpropyl)(4-pyridinyl)amino]benzo[b]thiophene fumarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; NaH In methanol; N,N-dimethyl-formamide	57 6-Chloro-3-[(4-fluorobenzoylpropyl)(4-pyridinyl)amino]benzo[b]thiophene fumarate EXAMPLE 57 6-Chloro-3-[(4-fluorobenzoylpropyl)(4-pyridinyl)amino]benzo[b]thiophene fumarate A solution of 6-chloro-3-[(4-pyridinyl)amino]benzo[b]thiophene (2.88 g, 11.0 mmole) in 30 mL of DMF was added to a suspension of NaH (0.53 g of 60% in oil, 13.3 mmole, washed with heptane) in 6 mL of DMF. To this mixture was added 2-(3-chloropropyl)-2-(4-fluorophenyl)dioxolane (3.2 g, 13.3 mmole) and the reaction mixture was heated at 70° C. for 0.5 hour. The reaction mixture was then quenched into water and extracted with ethyl acetate (3*). The organics were washed with water, dried (MgSO4), filtered and concentrated. Purification of the residue through a column of florisil (EtOAc→2% MeOH/EtOAc) gave 4.24 g of a green oil. A mixture of the oil and 40 mL of concentrated HCl was heated on a steam bath for 45 minutes. The reaction was then quenched into iced water and basified with solid K2 CO3. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with water, dried (MgSO4) and concentrated to give an oil. This oil was passed through a column of alumina (EtOAc) and then purified via flash chromatography (EtOAc) to give 1.8 g of a green oil. The free base was dissolved in methanol and treated with 1.1 eq. of fumaric acid. Removal of the solvent and crystallization of the residue with DCM gave 1.44 g of a white powder. This was recrystallized from methanol/water to give 0.856 g of a white powder, mp: 107°-110° C. (dec.). ANALYSIS Calculated for C23 H18 ClFN2 OS.C4 H4 O4: 59.94% C; 4.10% H; 5.18% N; Found: 60.35% C; 4.09% H; 5.36% N.

Reference： [1]Current Patent Assignee: SANOFI - US5328920, 1994, A

27
7-chloro-3-(4-pyridinyl)aminobenzo[b]thiophene [ No CAS ]
[ 3308-94-9 ]
7-Chloro-3-[(3-(4-fluorobenzoyl)propyl)(4-pyridinyl)amino]benzo[b]thiophene hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide In methanol; N,N-dimethyl-formamide	71 7-Chloro-3-[(3-(4-fluorobenzoyl)propyl)(4-pyridinyl)amino]benzo[b]thiophene hydrochloride EXAMPLE 71 7-Chloro-3-[(3-(4-fluorobenzoyl)propyl)(4-pyridinyl)amino]benzo[b]thiophene hydrochloride To a mixture of sodium hydride (645 mg, 16.13 mmole) in DMF (10 mL) was added dropwise a solution of 7-chloro-3-(4-pyridinyl)aminobenzo[b]thiophene (3.5 g, 13.44 mmole) in DMF (35 mL) and then 4'-fluoro-4-chlorobutyrophenone ethylene ketal (3.95 g, 16.13 mmole) was added. This mixture was heated with stirring at 70° C. for three hours, poured into ice and extracted with ethyl acetate. The organics were washed twice with water, dried (MgSO4), and then concentrated. The residue was flash chromatographed (silica gel; EtOAc, then 5% MeOH/EtOAc) to obtain a dark oil, which was dissolved in methanol and treated with "Norite" to obtain 2.88 g of a white froth after concentration. Concentrated HCl (30 mL) was added and the mixture was heated on a steam bath for 45 minutes. The reaction mixture was cooled, made basic with 10% sodium hydroxide and extracted with diethyl ether. The organics were washed with water and brine, dried (MgSO4), and concentrated to obtain a froth. The froth was dissolved in methanol and ethereal hydrogen chloride, concentrated, and the frothy oil was triturated with diethyl ether. The organics were decanted and the resulting solid was recrystallized from methanol and diethyl ether to obtain 2.09 g of a white solid, mp 229° C. (dec.), after drying under high vacuum, P2 O5, and refluxing xylenes. ANALYSIS: Calculated for C23 H18 N2 ClFOS.HCl: 59.87% C; 4.15% H; 6.07% N; Found: 59.47% C; 3.98% H; 5.96% N.

Reference： [1]Current Patent Assignee: SANOFI - US5328920, 1994, A

28
4-(2-methyl-(aminoethoxy)-1,3-dihydro-indol-2-one [ No CAS ]
[ 3308-94-9 ]
4-(2-[4-(4-fluoro-phenyl)-4-oxo-butyl]-methyl-amino}-ethoxy)-1,3-dihydro-indol-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium iodide; potassium carbonate In <i>N</i>-methyl-acetamide; dichloromethane	27 4-(2-[4-(4-Fluoro-phenyl)-4-oxo-butyl]-methyl-amino}-ethoxy)-1,3-dihydro-indol-2-one EXAMPLE 27 4-(2-[4-(4-Fluoro-phenyl)-4-oxo-butyl]-methyl-amino}-ethoxy)-1,3-dihydro-indol-2-one A mixture of 4-(2-methyl-(aminoethoxy)-1,3-dihydro-indol-2-one (600 mg, 2.91 mmol), 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (1.16 g, 4.76 mmol) and potassium carbonate (844 mg, 6.1 mmol) in anhydrous dimethylformamide (12 mL) containing potassium iodide (80 mg) was allowed to stir 12 hours at 85° C. The solvent was removed under high vacuum and the residue dissolved in methylene chloride (150 mL) and extracted with water (2*50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by chromatography (5% methanol-methylene chloride) afford 800 mg of a red oil: MS EI m/e 414 (M+).
	With potassium iodide; potassium carbonate In <i>N</i>-methyl-acetamide; dichloromethane	27 4-(2-[4-(4-Fluoro-phenyl)-4-oxo-butyl]-methyl-amino}-ethoxy)-1,3-dihydro-indol-2-one EXAMPLE 27 4-(2-[4-(4-Fluoro-phenyl)-4-oxo-butyl]-methyl-amino}-ethoxy)-1,3-dihydro-indol-2-one A mixture of 4-(2-methyl-(aminoethoxy)-1,3-dihydro-indol-2-one (600 mg, 2.91 mmol), 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (1.16 g, 4.76 mmol) and potassium carbonate (844 mg, 6.1 mmol) in anhydrous dimethylformamide (12 mL) containing potassium iodide (80 mg) was allowed to stir 12 hours at 85 °C. The solvent was removed under high vacuum and the residue dissolved in methylene chloride (150 mL) and extracted with water (2x 50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by chromatography (5 % methanol-methylene chloride) afford 800 mg of a red oil: MS EI m/e 414 (M+).

Reference： [1]Current Patent Assignee: PFIZER INC - US5817690, 1998, A
[2]Current Patent Assignee: PFIZER INC - EP923551, 2002, B1

29
[ 160419-40-9 ]
[ 497-19-8 ]
[ 3308-94-9 ]
5-methoxy-3-[N-(4-(4-fluoro-phenyl)-4-oxo-butyl)-1,2,5,6-tetrahydro-pyridin-3-ylmethyl]-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; Ki; potassium carbonate In <i>N</i>-methyl-acetamide; methanol; ethanol	2 (Compound 9) EXAMPLE 2 5-methoxy-3-[N-(4-(4-fluoro-phenyl)-4-oxo-butyl)-1,2,5,6-tetrahydro-pyridin-3-ylmethyl]-1H-indole (Compound 9) A mixture of compound of Description 5 [5-methoxy-3-(1,2,5,6-tetrahydro-pyridin-3-ylmethyl)-1H-indole] (1.5 g; 0.0062 mol), potassium carbonate (4.3 g; 0.031 mol), KI (0.06 g; 0.0004 mol) and 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (1.3 ml; 0.0064 mol) in dry dimethylformamide (30 ml) was heated at 80° C. for 6 hours. The reaction mixture was cool down to room temperature, quenched with water and then extracted with diethyl ether. The organic extract was dried (MgSO4) and evaporated under vacuum. The residue was taken up in a solution of hydrochloric acid (37%; 6 ml) in methanol (30 ml). The resulting mixture was stirred for 2 hours at room temperature. The reaction was then quenched with a saturated solution of aqueous sodium carbonate and the solvent (methanol) was evaporated under vacuum. The residual alkaline aqueous solution was extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol/ammonia (95/5/0,5), the desired compound was obtained (1,72 g). A solution of the compound in ethanol was saturated with gaseous hydrogen chloride. A white solid was precipitated. The title compound hydrochloride was collected by filtration, washed with ethanol and dried under vacuum. Mp 95°-97° C. 1 H NMR (DMSO+CDCl3) δ=12.18 (b, 1H), 8.59 (s, 1H), 7.88 (m, 2H), 7.3-6.7 (6H), 5.84 (b, 1H), 3.81 (s, 3H), 4.1-1.9 (14H); MS (C.I.): [M+H]+ 407 m/z Following the above described process and using the appropriate indole derivative already described in Description 5, the following compound was prepared:

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US5834493, 1998, A

30
[ 584-08-7 ]
[ 87789-49-9 ]
[ 3308-94-9 ]
1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butanone hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.6 g (50%)	With hydrogenchloride In ethanol; acetonitrile	4 1-(4-Fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butanone hydrochloride (IA) Example 4 1-(4-Fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butanone hydrochloride (IA) A mixture of 1-(5-fluoro-2-pyrimidinyl)piperazine (7.3 g, 0.04 mole), γ-chloro-p-fluorobutyrophenone ethylene ketal (14.5 g, 0.06 mole), anhydrous K2 CO3 (24.8 g) and a catalytic amount of KI in MeCN (100 mL) was stirred and heated under reflux for 36 h. The hot mixture was filtered, concentrated in vacuo and the residue treated with 20 mL of 3N HCl and 100 mL EtOH. After cooling in ice, the product was collected by filtration and dried to give 7.6 g (50%) of product as a white solid, m.p. 234°-236° C. Anal. Calcd. for C18 H20 F2 N4 O.HCl: C, 56.48; H, 5.53; N, 14.64. Found: C, 56.27; H, 5.52; N, 14.27. 1 H NMR (DMSO-d6): 2.10 (2.m); 3.20 (6.m); 3.54 (4.m); 4.58 (2.m); 7.34 (2.m); 8.08 (2.m); 8.55 (2.s); 11.60 (1. bs). IR (KBr): 960, 1235, 1245, 1365, 1510, 1560, 1600, 1680, 2550, and 2920 cm-1.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US4994460, 1991, A

31
[ 3874-54-2 ]
[ 3308-94-9 ]

Yield	Reaction Conditions	Operation in experiment
57.7 g (93%)	With toluene-4-sulfonic acid In ethylene glycol; benzene	1 γ-Chloro-p-fluorobutyrophenone ethylene ketal Example 1 γ-Chloro-p-fluorobutyrophenone ethylene ketal A solution of γ-chloro-p-fluorobutyrophenone (50 g. 025 mole, commercially available); ethylene glycol (50 mL); p-toluene sulfonic acid (0.1 g) in 300 mL benzene is refluxed for 18 h with water of reaction being removed by means of a Dean Stark water trap. Upon cooling to room temperature, the reaction mixture is washed with dilute sodium bicarbonate, dried (MgSO4), filtered and the benzene removed by concentration in vacuo. The residual oil was distilled to give 57.7 g (93%) of product, b.p. 106-112/0.01 Torr.
57.7 g (93%)	With toluene-4-sulfonic acid In ethylene glycol; benzene	1 γ-Chloro-p-fluorobutyrophenone Ethylene Ketal (III) EXAMPLE 1 γ-Chloro-p-fluorobutyrophenone Ethylene Ketal (III) A solution of γ-chloro-p-fluorobutyrophenone (50 g, 0.25 mole, commercially available); ethylene glycol (50 mL); p-toluene sulfonic acid (0.1 g) in 300 mL benzene is refluxed for 18 hrs with water of reaction being removed by means of a Dean Stark water trap. Upon cooling to room temperature, the reaction mixture is washed with dilute sodium bicarbonate, dried (MgSO4), filtered and the benzene removed by concentration in vacuo. The residual oil was distilled to give 57.7 g (93%) of product, b.p. 106-112/0.01 Torr.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US4994460, 1991, A
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US4605655, 1986, A

32
[ 584-08-7 ]
[ 87789-49-9 ]
[ 3308-94-9 ]
BMY 14786 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.6 g (50%)	With hydrogenchloride In ethanol; acetonitrile	6 1-(4-Fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butanone Hydrochloride (Ia) EXAMPLE 6 1-(4-Fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butanone Hydrochloride (Ia) A mixture of 5-fluoro-2-(1-piperazinyl)pyrimdine (IIa, 7.3 g, 0.04 mole), γ-chloro-p-fluorobutyrophenone ethylene ketal (IV, 14.5 g, 0.06 mole), anhydrous K2 CO3 (24.8 g) and a catalytic amount of KI in acetonitrile (100 mL) was stirred and heated under reflux for 36 hrs. The hot mixture was filtered, concentrated in vacuo and the residue treated with 20 mL of 3N HCl and 100 mL ethanol. After cooling in ice, the product was collected by filtration and dried to give 7.6 g (50%) of product as a white solid, m.p. 234°-236°. Anal. Calcd. for C18 H20 F2 N4 O.HCl: C, 56.48; H, 5.53; N, 14.64. Found: C, 56.27; H, 5.52; H, 14.27. NMR (DMSO-d6): 2.10 (2,m); 3.20 (6,m); 3.54 (4,m); 4.58 (2,m); 7.34 (2,m); 8.08 (2.m); 8.55 (2,s); 11.60 (1,bs). IR (KBr): 960, 1235, 1245, 1365, 1510, 1560, 1600, 1680, 2550, and 2920 cm-1.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US4605655, 1986, A

33
ethereal hydrogen chloride [ No CAS ]
[ 78263-00-0 ]
[ 3308-94-9 ]
cis-4-{N-[3-(4-Fluorobenzoyl)prop-1-yl]-N-methyl}amino-3'-(4-fluorophenyl)-spiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; potassium iodide; sodium hydrogencarbonate In <i>N</i>-methyl-acetamide; methanol; ethanol; dichloromethane	36 cis-4-{N-[3-(4-Fluorobenzoyl)prop-1-yl]-N-methyl}amino-3'-(4-fluorophenyl)-spiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride EXAMPLE 36 cis-4-{N-[3-(4-Fluorobenzoyl)prop-1-yl]-N-methyl}amino-3'-(4-fluorophenyl)-spiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride A stirred suspension of 4.26 g of cis-3'-(4-fluorophenyl)-4-methylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran], 2.61 g of potassium iodide, 2.69 g of anhydrous sodium bicarbonate, 3.67 g of 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane and 50 ml of sieve dried dimethylformamide is held at 90° C. overnight with exclusion of moisture. The cooled mixture is diluted with 60 ml of dichloromethane, vacuum, filtered and concentrated on a rotary evaporator to an oil. A solution of the oil and 100 ml of dichloromethane is washed with 100 ml of 10% sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to an oil. A filtered solution of the oil and 100 ml of anhydrous ether is treated with ethereal hydrogen chloride. The precipitated gum is triturated with fresh ether to afford a yellow powder which is dried at 40° C. over sodium hydroxide pellets. A stirred solution of the crude ketal hydrochloride, 70 ml of methanol and 40 ml of 3 N hydrochloric acid is heated under reflux for 1.5 hours and allowed to stand overnight at ambient temperature. The mixture is vacuum filtered and the filtrate concentrated on a rotary evaporator to remove the methanol. The residue is made alkaline with 10% sodium hydroxide solution and extracted with dichloromethane. The organic phase is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to an oil. A solution of the oil and 70 ml of anhydrous ether is filtered through anhydrous sodium sulfate and the filtrate is treated with ethereal hydrogen chloride. Recrystallization of the precipitate from 50 ml of 95% ethanol affords 30% of product, mp 230°-233° C. Analysis: Calculated for C30 H31 F2 NO2.HCl: 70.36% C; 6.31% H; 2.74% N. Found: 70.29% C; 6.35% H; 2.68% N.

Reference： [1]Current Patent Assignee: SANOFI - US4263317, 1981, A

34
ethereal hydrogen chloride [ No CAS ]
cis-3'-(4-chlorophenyl)-4-methylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride [ No CAS ]
[ 3308-94-9 ]
cis-3'-(4-Chlorophenyl)-4-{N-[3-(4-fluorobenzoyl)prop-1-yl]-N-methyl}aminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; potassium iodide; sodium hydrogencarbonate In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; acetonitrile	35 cis-3'-(4-Chlorophenyl)-4-{N-[3-(4-fluorobenzoyl)prop-1-yl]-N-methyl}aminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride EXAMPLE 35 cis-3'-(4-Chlorophenyl)-4-{N-[3-(4-fluorobenzoyl)prop-1-yl]-N-methyl}aminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride A suspension of 4.07 g of cis-3'-(4-chlorophenyl)-4-methylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride and 70 ml of methanol is treated with 10 ml of 10% sodium hydroxide solution. The methanol is removed on a rotary evaporator and the residue is diluted with 100 ml of water and extracted thrice with 70 ml portions of dichloromethane. The combined organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to an oil. A stirred suspension of the oil, 2.06 g of potassium iodide, 2.08 g of anhydrous sodium bicarbonate, 3.06 g of 4-chloro-p-fluorobutyrophenone ethylene ketal and 50 ml of sieve dried dimethylformamide is held at 88°-90° C. (bath temperature) overnight with exclusion of moisture. The cooled mixture is diluted with 100 ml of dichloromethane, vacuum filtered and the filtrate concentrated at 40°-90° C. on a rotary evaporator. The solid residue is diluted with 100 ml of water and extracted with a total of 200 ml of dichloromethane. The organic phase is washed with 50 ml of 10% sodium hydroxide solution, 50 ml of water, dried over anhydrous sodium sulfate, vacuum filtered and concentrated to an oil. A solution of the oil and 100 ml of anhydrous ether is treated with excess ethereal hydrogen chloride. A gum separates. A solution of the gum, 70 ml of methanol and 40 ml of 3 N hydrochloric acid solution is heated under reflux for 1.5 hours, then allowed to stand overnight at ambient temperature. The solution is decanted from a small amount of tar and the methanol is evaporated. The residue is made alkaline with 10% sodium hydroxide solution and extracted with a total of 200 ml of dichloromethane. The dried(anhydrous sodium sulfate)organic phase is concentrated to an oil which is dissolved in 300 ml of anhydrous ether and filtered to remove an amorphorous precipitate. The filtrate is treated with ethereal hydrogen chloride and the precipitate is collected by vacuum filtration and dried to afford a crude material. Recrystallization from 150 ml of acetonitrile affords 18.6% of product, mp 240°-242° C. (dec). Analysis: Calculated for C30 H31 ClFNO2.HCl: 68.17% C; 6.12% H; 2.65% N. Found: 67.90% C; 5.97% H; 2.40% N.

Reference： [1]Current Patent Assignee: SANOFI - US4263317, 1981, A

35
[ 60-29-7 ]
[ 75-09-2 ]
[ 13449-79-1 ]
[ 3308-94-9 ]
5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2,5-benzodiazocine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16.5 g (81.7%)	With hydrogenchloride; sodium hydrogencarbonate In <i>N</i>-methyl-acetamide; methanol; water	6 5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2,5-benzodiazocine (Compound I-f) EXAMPLE 6 5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2,5-benzodiazocine (Compound I-f) 10.72 g (39.95 mmol) of 1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2,5-benzodiazocine, 10.27 g (41.97 mmol) of 4,4-ethylenedioxy-4-(p-fluorophenyl)-butyl chloride, 4.2 g (50.00 mmol) of NaHCO3 and 250 ml of dimethylformamide were stirred at 145° C. for 4 hours and then the solvent was distilled off. After having added 30 ml of CH2 Cl2 and 300 ml of ethyl ether, filtered off insoluble materials and distilled off the filtrate, the remaining oily substance was refined through a silica gel column chromatography (ethyl ether-ethyl ether/triethylamine=10/1) to obtain 15.8 g (83.0%) of the objective compound (free base) as substantially colorless oil. To the oil, 450 ml of methanol, 180 ml of water and 60 ml of conc. HCl were added, refluxed for 1 hour with stirring, distilled off the solvent and then the residue was recrystallized from water/ethanol to obtain 16.5 g (81.7%) of the desired compound (hydrochloride) as colorless prism crystals having melting point of 217°-234° C. (dec.).

Reference： [1]Current Patent Assignee: SUZUKEN CO LTD - US4435392, 1984, A

36
0.8 N-NaOH [ No CAS ]
3 N-HCl [ No CAS ]
ClCOOC₂ H₅ [ No CAS ]
[ 60-29-7 ]
[ 3045-09-8 ]
[ 3308-94-9 ]
5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-phenyl-2-methyl-2,5-benzodiazocine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; LiAlH₄; ammonia; sodium hydrogencarbonate; triethylamine In tetrahydrofuran; <i>N</i>-methyl-acetamide; methanol; chloroform; water	3 5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-phenyl-2-methyl-2,5-benzodiazocine (Compound I-c) (hydrochloride) EXAMPLE 3 5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-phenyl-2-methyl-2,5-benzodiazocine (Compound I-c) (hydrochloride) 50 g (0.21 mol) of 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine, 56 g (0.23 mol) of 4,4-ethylenedioxy-4-(p-fluorophenyl)-butyl chloride, 26.5 g (0.315 mol) of NaHCO3 and 373 ml of dimethylformamide were stirred at 100° C. for 4 hours and then subjected to distillation under a reduced pressure to remove the solvent. To the remaining substance, ethyl ether/water was added to extract the reaction products which was washed with water and dried on Na2 SO4. The solvent therein was distilled off and then the remaining oily substance was separated and refined through a silica gel column chromatography (ethyl ether-ethyl ether/triethylamine=10/15) to obtain 76 g of an oily substance. To a mixture of 4.00 g (8.97 mmol) of the oil, 1.18 g (11.7 mmol) of triethylamine and 100 ml of CHCl3, 30 ml CHCl3 solution of 1.07 g (9.87 mmol) of ClCOOC2 H5 were added in dropwise for 1 hour, while stirring under inert gas atmosphere. The reaction mixture was washed with water, dried on Na2 SO4 and subjected to distillation under a reduced pressure to remove the solvent. The remaining oily substance was dissolved in a mixture of 300 ml of ethyl ether and 100 ml of tetrahydrofuran and in the solution, 4 g of LiAlH4 were added at 0° C. under inert gas atmosphere. The mixture was refluxed for 4 hours, while stirring same under inert gas atmosphere and then ice-cooled to add 0.8 N-NaOH for causing decomposition of the catalyzer. The reaction mixture was filtered to remove a formed precipitate. The filtrate was washed with ethyl acetate/CHCl3 and condensed under a reduced pressure. The remaining oily substance was dissolved in methanol, 100 ml of 3 N-HCl were added thereto and then the mixture was stirred at room temperature for 15 minutes. Thereafter the solution was made into an alkali state by adding ammonia, extracted with CHCl3, washed with water, dried on Na2 SO4, subjected to distillation under a reduced pressure to remove the solvent and then refined through a silica gel column chromatography (triethylamine/ethyl ether/n-hexane=1/1/10) to obtain 2.42 g (52.6%) of substantially colorless oily substance. The oil was treated by hydrogen chloride in methanol to convert the same into hydrochloride and recrystallized from 5% water/methanol/methylethylketone to obtain the objective compound (hydrochloride) as colorless prism crystals having melting point of 186°-192° C. (dec.). The salt may be converted into free base in a conventional manner. Elementary Analysis: C27 H29 FN2 O.2HCl; Cal. C 66.26, H 6.38, N 5.72; Found C 65.88, H 6.59, N 5.42. IR (νmaxKBr) cm-1: 2450 (NH+), 1680 (C=O) MS: EI/DI (m/z); 416 (M+), 210 (base) CI/DI (i-Bu) (m/z); 417 (M+1) High MS (m/z); C27 H29 FN2 O (M+) Cal. 416, 2264 Found 416, 2272 NMR (CDCl3) δ ppm: 8.2-7.8 (2H, m, C2', 6'-H) 7.6-6.6 (11H, m, Ar--H) 5.26 (1H, s, C1-H) 4.02 (2H, s, C6-H) 3.3-1.8 (10H, m, --CH2 and NCH2 CH2 CH2 --) 2.28 (3H, s, N--CH3)

Reference： [1]Current Patent Assignee: SUZUKEN CO LTD - US4435392, 1984, A

37
0.8 N-NaOH [ No CAS ]
2 N-HCl [ No CAS ]
ClCOOC₂ H₅ [ No CAS ]
[ 13449-79-1 ]
[ 3308-94-9 ]
5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2-methyl-2,5-benzodiazocine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.9%	With LiAlH₄; sodium hydrogencarbonate; triethylamine In <i>N</i>-methyl-acetamide; methanol; diethyl ether; chloroform	1 5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2-methyl-2,5-benzodiazocine (compound I-a) (hydrochloride) EXAMPLE 1 5-[3-(p-fluorobenzoyl)propyl]-1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2-methyl-2,5-benzodiazocine (compound I-a) (hydrochloride) 200 g (745.3 mmol) of 1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2,5-benzodiazocine, 190 g (776.5 mmol) of 4,4-ethylenedioxy-4-(p-fluorophenyl)-butyl chloride, 80 g (952.3 mmol) of NaHCO3 and 1.5 liter of dimethylformamide were stirred at 100° C. for 4 hours and then the solvent was removed under a reduced pressure. The reaction product was extracted with ethyl ether, washed with water, dried on Na2 SO4. The solvent was distilled off and then the resulting oily substance was refined through a silica gel column chromatography (ethyl ether-ethyl ether/triethylamine=10/1) to obtain 253 g (71.3%) of an intermediate as oily substance. To a mixture of 53 g (111.2 mmol) of this oily substance, 16.7 g (165.2 mmol) of triethylamine and 60 mg of CHCl3, 100 ml CHCl3 solution of 13.3 g (122.6 mmol) of ClCOOC2 H5 was added in dropwise for 1 hour at room temperature and under inert gas atmosphere and after completion of the addition, the resulting solution was further stirred for 1 hour. The resulting reaction mixture was washed with water, dried on Na2 SO4, and subjected to distillation to remove the solvent. The remaining oily substance was dissolved in 1 liter of ethyl ether, ice-cooled to add 17.5 g of LiAlH4 and then refluxed for 4.5 hours under stirring. The reaction mixture was cooled and 70 ml of 0.8 N-NaOH was added thereto to cause a decomposition of the catalyzer. A forming precipitate was filtered off. The filtrate was washed with CH2 Cl2 and subjected to distillation under a reduced pressure. The remaining oily substance was refined through a silica gel column chromatography (CH2 Cl2 -ethyl ether) to obtain 47 g of an oily substance. The oily substance was dissolved in 350 ml of methanol, 375 ml of 2 N-HCl were added thereto and then the resulting solution was stirred at room temperature for 1 hour to obtain 33.2 g of forming crystals. The filtrate was concentrated under a reduced pressure, made into alkali state with ammonia, extracted with CH2 Cl2, dried, subjected to distillation to remove the solvent, and then the remaining oily substance was separated and refined through a silica gel column chromatography (ethyl ether-ethyl ether/triethylamine=10/1) and converted in methanol into its hydrochloride to obtain 8 g thereof in the form of crystal. These crystals were combined (total 41.7 g, yield 52.9%) and then recrystallized from water/ethanol/methylethylketone to obtain the objective compound (chloride) as colorless prism crystals having melting point of 188°-194° C. (dec.). This salt may be made into free base, in a conventional manner. Elementary Analysis: C28 H31 FN2 O2.2HCl.1/2H2 O; Cal. C 63.35, H 6.48, N 5.30; Found C 63.47, H 6.48, N 5.39. IR (νmaxKBr) cm-1: 2550 (>N≈ =O) MS: EI/DI (m/z); 446 (M+), 252 (base) CI/DI (i-Bu) (m/z); 447 (M+1) High MS (m/z); C28 H31 FN2 O2 (M+) Cal. 446, 2369 Found 446, 2374 NMR (CDCl3) δ ppm: 8.1-7.78 (2H, m, 2,6-positions of benzoyl, Ar--H) 7.4-6.7 (10H, m, Ar--H) 5.2 (1H, s, C1-H) 4.0 (2H, s, C6-H) 3.72 (3H, s, OCH3) 3.18-1.83 (10H, m, Methylene-H excepting C6) 2.28 (3H, s, N--CH3)

Reference： [1]Current Patent Assignee: SUZUKEN CO LTD - US4435392, 1984, A

38
[ 103-67-3 ]
[ 3308-94-9 ]
2-[3-(N-benzyl-N-methylamino)propyl]-2-(4-fluorophenyl)-1,3-dioxolane hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium iodide; potassium carbonate In diethyl ether; 2-methyl-propan-1-ol; N,N-dimethyl-formamide	4 2-[3-(N-Benzyl-N-methylamino)propyl]-2-(4-fluorophenyl)-1,3-dioxolane hydrochloride EXAMPLE 4 2-[3-(N-Benzyl-N-methylamino)propyl]-2-(4-fluorophenyl)-1,3-dioxolane hydrochloride A suspension of 17 g of potassium iodide, 424 g (3.07 mol) of potassium carbonate, 1125 ml of DMF, 150 g (1.23 mol) of benzylmethylamine and 292 g (1.19 mol) of 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane was heated at 80° for 1 hour and at 90°-105° for 2 hours and allowed to cool to room temperature. The suspension was poured into water, extracted with methylene chloride, washed four times with water and dried over potassium carbonate. Evaporation of the solvent provided an oil. Formation of the hydrochloride was carried out in 20% iPrOH/Et2 O. The yield of the hydrochloride was 274 g (0.749 mol, 62%). Analysis: Calculated for C20 H24 FNO2;HCl: 65.65%C, 6.89%H, 3.83%N. Found: 65.35%C, 6.81%H, 3.86%N.

Reference： [1]Current Patent Assignee: SANOFI - US4518713, 1985, A

39
[ 14321-27-8 ]
[ 3308-94-9 ]
2-[3-(N-benzyl-N-ethylamino)propyl]-2-(4-fluorophenyl)-1,3-dioxolane hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium iodide; potassium carbonate In N,N-dimethyl-formamide	8 2-[3-(N-Benzyl-N-ethylamino)propyl]-2-(4-fluorophenyl)-dioxolane hydrochloride EXAMPLE 8 2-[3-(N-Benzyl-N-ethylamino)propyl]-2-(4-fluorophenyl)-dioxolane hydrochloride A suspension prepared from 5.0 g of potassium iodide, 127 g of potassium carbonate, 335 ml of DMF, 50 g (0.37 mol) of ethyl benzyl amine and 87.2 g (0.357 mol) of 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane was heated at 80°-90° for 2.5 hours and at 100°-105° for 1 hour. The mixture was allowed to cool to room temperature, poured into water, extracted with ether, washed four times with water and once with saturated sodium chloride. The solution was dried over potassium carbonate and the solvent evaporated to provide an oil. The yield of the hydrochloride was 86.6 g (0.228 mol, 63%). Analysis: Calculated for C21 H26 FNO2.HCl: 66.40%C, 7.17%H, 3.69%N. Found: 66.10%C, 7.00%H, 3.48%N.

Reference： [1]Current Patent Assignee: SANOFI - US4518713, 1985, A

40
[ 64061-56-9 ]
[ 3308-94-9 ]
[ 71-36-3 ]
[ 60284-61-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydrogencarbonate In ethanol	2 1-[3-(p-Fluorobenzoyl)propyl]-4-(α-cyclohexyl-α-hydroxy) benzylpiperidine Hydrochloride EXAMPLE 2 1-[3-(p-Fluorobenzoyl)propyl]-4-(α-cyclohexyl-α-hydroxy) benzylpiperidine Hydrochloride A mixture of 4.0 g. (0.0147 mole) of 4-(α-cyclohexyl-α-hydroxybenzyl)piperidine, 3.9 g. (0.016 mole) of 2-(3-chloropropyl)-2-(p-fluorophenyl)dioxolane, 2.7 g. (0.032 mole) of sodium bicarbonate and 100 ml. of 1-butanol was refluxed for 20 hours. The mixture was filtered, the filtrate concentrated under reduced pressure, and the residual oil was stirred overnight in a mixture of 100 ml. of ethanol and 50 ml. of 6N hydrochloric acid. The reaction mixture was diluted to 600 ml. with water and made basic, the mixture extracted with benzene and the combined extracts were dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 4.9 g. (64.5%) of crude product. The oil was dissolved in ether and an excess of ethereal hydrogen chloride was added. The resulting hydrochloride salt was recrystallized from methanol-isopropyl ether to give 2.7 g. of product melting at 274°-275° C. Analysis: Calculated for C28 H37 ClFNO2: C,70.94; H,7.87; N,2.96. Found: C,70.99; H,7.88; N,2.89.

Reference： [1]Current Patent Assignee: PFIZER INC - US3956296, 1976, A

41
4-(2-nitroanilino)piperidine [ No CAS ]
[ 3308-94-9 ]
[ 71-36-3 ]
[ 57718-48-6 ]
[ 60703-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium iodide; sodium carbonate In ethanol; chloroform; benzene	P.1 PREPARATION EXAMPLE 1 PREPARATION EXAMPLE 1 A mixture of 7.34 g of 4-chloro-1-(4-fluorophenyl)-1-butanone ethylene ketal, 6.8 g of 4-(2-nitroanilino)piperidine, 1.59 g of sodium carbonate, 0.1 g of potassium iodide and 10 ml of n-butanol was refluxed while stirring for 30 hours. After the reaction, the reaction solution was concentrated and subjected to alumina column chromatography. After the fraction eluted with benzene and a mixture of benzene and chloroform (1:1 by volume) was discarded, the fraction eluted with chloroform and a mixture of chloroform and ethanol (4:1 by volume) was collected and concentrated. The residue was recrystallized from a mixture of diethyl ether and n-hexane to obtain 7.29 g of yellow needles of 1-[3-(4-fluorobenzoyl)propyl]-4-(2-nitroanilino)piperidine ethylene ketal having a melting point of 78° to 80.5°C. Elemental Analysis for C23 H28 FN3 O4: Calculated (%): C, 64.32; H, 6.57; N, 9.78. Found (%): C, 64.49; H, 6.66; N, 9.86. A mixture of 4 g of the crystals, 100 ml of methanol and 4 ml of Raney nickel was stirred. After the absorption of hydrogen was completed, the catalyst was removed by filtration, and the solution was concentrated. The residue was recrystallized from diethyl ether to give needles of 1-[3-(4-fluorobenzoyl)-propyl]-4-(2-aminoanilino)piperidine ethylene ketal having a melting point of 113° to 113.5°C. Elemental Analysis for C23 H30 FN3 O2: Calculated (%): C, 69.14; H, 7.57; N, 10.52. Found (%): C, 69.18; H, 7.38; N, 10.44.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US3963727, 1976, A

42
[ 40877-22-3 ]
[ 3308-94-9 ]
2-[3-(3-hydroxyspiro[indan-1,3'-pyrrolidin]-1'-yl)propyl]-2-(p-fluorophenyl)-1,3-dioxolane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In chloroform; N,N-dimethyl-formamide	1.A p-Fluoro-4-(3-hydroxyspiro[indan-1,3'-pyrrolidin]-1'-yl) butyrophenone A. 15 g of spiro[indan-1,3'-pyrrolidin]-3-ol are dissolved in 200 cc of dimethyl formamide, and the solution is heated to 100° with 18 g of sodium carbonate and 23 g of 2-(3-chloropropyl)-2-(p-fluorophenyl)-1,3'-dioxolane for 20 hours. Filtration is subsequently effected, the filter residue is washed with 150 cc of chloroform, and the organic phases are concentrated. The 2-[3-(3-hydroxyspiro[indan-1,3'-pyrrolidin]-1'-yl)propyl]-2-(p-fluorophenyl)-1,3-dioxolane obtained as yellow oil is taken up in 300 cc of chloroform without previous purification and is stirred with 250 cc of 2 N hydrochloric acid at room temperature for 11/2 hours.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - US3958003, 1976, A

43
[ 57648-17-6 ]
[ 3308-94-9 ]
[ 57648-21-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; potassium iodide In ethanol; chloroform; butan-1-ol; benzene	1 EXAMPLE 1 EXAMPLE 1 A mixture of 3.53 g of 4-chloro-1-(4-fluorophenyl)-1-butanone ethylene ketal, 6.4 g of 1-(4-piperidyl)-2-mercaptobenzimidazole as prepared in Preparation Example 1, 0.14 g of potassium iodide and 72 ml of normal butanol was heated at 130°C for 16 hours in a sealed tube. After cooling, benzene was added thereto and the resulting solution was filtered and evaporated. To the residue, 100 ml of ethanol and 100 ml of a 10% hydrochloric acid solution were added, refluxed for 1 hour, cooled, neutralized with a 10% sodium hydroxide solution, concentrated and extracted with 100 ml of chloroform three times. The chloroform solution was subsequently washed with water, dried and concentrated to give a gummy substance. The gummy substance thus-obtained was dissolved in chloroform and subjected to silica gel chromatography and eluted successively with chloroform, a mixture of chloroform and ethanol (4:1 by volume), and a mixture of chloroform and ethanol (1:1 by volume). After removing the fraction eluted with chloroform, the fraction eluted with the chloroform-ethanol mixture was collected and the solvent was removed. The residue was recrystallized from acetone to give 1.82 g of colorless crystals of 1-[1-(3-(4-fluorobenzoyl)propyl)-4-piperidyl]-2-mercaptobenzimidazole having a melting point of 201° to 203°C. Elemental Analysis for C22 H24 FN3 OS: Calculated (%): C, 66.47; H, 6.09; N, 1.57. Found (%): C, 66.30; H, 6.26; N, 10.65.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US3963727, 1976, A

44
[ 25519-78-2 ]
[ 3308-94-9 ]
[ 55695-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In butan-1-ol; benzene;	EXAMPLE 7 2-(p-Fluorophenyl)-2-{3-[4-(p-fluorobenzoyl)piperidino]propyl}-1,3-dioxolan A mixture of 24.4 g. (0.1 mole) of 4-(p-fluorobenzoyl)piperidine hydrochloride, 24.5 g. (0.1 mole) of 2-(p-fluorophenyl)-2-(omega-chloropropyl)-1,3-dioxolane, and 33.6 g. (0.4 mole) of sodium bicarbonate in 450 ml. of 1-butanol was refluxed for 17 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was dissolved in benzene and placed on a magnesium silicate column. Elution with a benzene-acetone gradient gave 16.0 g. (24%) of pure product which crystallized. Recrystallization from isooctane gave the pure product melting at 62-64 C. Analysis: Calculated for C24 H27 F2 NO3: C,69.38; H,6.55; N,3.37. Found: C,69.51; H,6.55; N,3.16.

Reference： [1]Patent: US4101662,1978,A

45
ethereal hydrogen chloride [ No CAS ]
[ 25519-78-2 ]
[ 3308-94-9 ]
4-(p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; potassium carbonate; In methanediol; butan-1-ol;	EXAMPLE 1 4-(p-Fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidine Hydrochloride A mixture of 13.9 g. (0.057 mole) of 4-(p-fluorobenzoyl)piperidine hydrochloride, 15.5 g. (0.063 mole) of 2-(p-fluorophenyl)-2-(omega-chloropropyl)-1,3-dioxolane, and 27.6 g. (0.2 mole) of potassium carbonate in 150 ml. of 1-butanol was refluxed 20 hours. The mixture was filtered, the filtrate concentrated, the oily residue dissolved in 50 ml. of an ether-methanol mixture and this solution stirred with 100 ml. of 3N HCl for one hour. The mixture was cooled, the layers separated, the aqueous layer basified and the basic mixture extracted with ether. The ethereal extracts were dried over anhydrous sodium sulfate, the mixture filtered and the filtrate treated with ethereal hydrogen chloride. The salt, which weighed 17.2 g. (74%), was recrystallized from an isopropanol-methanol mixture. The dried hydrochloride salt melted at 255-257 C. The free base which was prepared by neutralization of a portion of the hydrochloride salt melted at 133-135 C. Analysis: Calculated for C22 H24 ClF2 NO2: C,64.78; H,5.93; N,3.44. Found: C,64.77; H,6.02; N,3.34.

Reference： [1]Patent: US4101662,1978,A

46
[ 3308-94-9 ]
[ 71917-04-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; potassium carbonate In methanol; butan-1-ol	5.D EXAMPLE 5 D. A stirred suspension of 5.2 g of 2,3-dihydro-5-nitrospiro[benzofuran-2,4'-piperidine] free base of C, 7.0 g of potassium carbonate, a few grains of potassium iodide and 6.2 g of γ-chloro-p-fluorobutyrophenone ethylene ketal in 200 ml of n-butyl alcohol is refluxed for 24 hours. Thereafter, the reaction mixture is permitted to cool to ambient temperature and then filtered. The filtrate is evaporated to dryness, leaving a brown oil. The oil is dissolved in 200 ml of methyl alcohol and 100 ml of 3N hydrochloric acid and this solution is stirred at ambient temperature for 18 hours and then basified with 6 N sodium hydroxide. The alkaline mixture is extracted with ethyl acetate and the ethyl acetate extracts are successively dried and evaporated to dryness, leaving an oil. The oil is chromatographed on a silica gel column eluding with chloroform which leads to a solid. The solid is dissolved in ether where it is converted to its hydrochloric acid salt, a white precipitate. The precipitate is recrystallized twice from ethyl alcohol to give the product 2,3-dihydro-1'-[3-(4-fluorobenzoyl)propyl]-5-nitrospiro[benzofuran-2,4'-piperidine]hydrochloride, mp 245°-247° C. Analysis: Calculated for C22 H23 FN2 O4.HCl: 60.76%, C; 5.56%, H; 6.44%, N. Found: 60.95%, C; 5.61%, H; 6.45%, N.