* 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.
The flaky solid NaOH (42.1 g, 1052.5 mmol, 1.0 equiv.) was dissolved in 142.1 g of water, a large amount of heat was released to give an aqueous solution of NaOH, which was cooled to 30 ° C. A solution of CPA.HCl (104 g, 658 mol, 1.0 equiv.) and the above aqueous solution of NaOH was added to a 500 mL two-necked flask and the temperature was raised to 45 ° C and the reaction was started and stirred for 2 h. Reaction post-treatment: The reaction solution was cooled to room temperature (30 ° C). The organic layer was separated and collected, and 74.93 g of wet CPA was obtained. The water content was found to be 2.755percent and the yield was 91.07percent (excluding moisture in the CPA).
83%
With triethylamine In diethyl ether at 20℃;
A 250 mL three-necked flask was charged with 10.0 g of Intermediate V,100ml anhydrous ether, 12.8g triethylamine, reaction at room temperature,TLC monitored the reaction was complete. Add saturated sodium bicarbonate solution 100ml,Stirring, extracting with anhydrous ether, collecting the organic phase, washing with water, washing with salt,Drying over anhydrous sodium sulfate. Filtered and evaporated to remove the organic solvent under reduced pressure,The intermediate VI was obtained as a colorless oil 6.4 g, yield 83percent.
80%
With sodium hydroxide In water at 45 - 50℃; for 2 h;
Example 3 4-Dimethylamino- 1 -(5-[ 1 ,3]dioxolan-2-yl-furan-2-yl)- 1 -(4-fluoro-phenyl)-butan- 1 -ol (3) In a 1 L round bottomed flask equipped with magnetic bar and condenser, a mixture of 3- (dimethylamino)propyl-l -chloride hydrochloride (DMPCHCl) (260 g, 1.65 mol) and aqueous NaOH solution (240 g, 30 percent w/v, 1.8mol, 1.1 eq.) was heated at 45-50 °C for 2 hours. The mixture was then extracted with ether (3 x 400 mL) and the collected organic phase was dried (solid NaOH) and filtered. Distillation of ether at atmospheric pressure afforded DMPC as a colourless oil (160 g, 80 percent).
75%
With sodium hydrogencarbonate In diethyl ether; water at 20℃; for 1 h;
A saturated solution of NaHCO3 (205 ml) was slowly added to a suspension of 3- chloro-W,N-dimethyl-l-propanamine hydrochloride (25 g, 0.158mol, CAS [4584-46-7]) in Et2O (200ml). The mixture was stirred at RT for lhour, then saturated with K2CO3 (solid). The mixture was extracted with Et2O. The organic layer was dried over MgSO4 and concentrated at RT under vacuum to afford 15.5g of 3-chloro-iV,iV-dimethyl-l- propanamine (yield 75percent) .
Reference：
[1] Patent: CN105294496, 2016, A, . Location in patent: Paragraph 0128; 0129; 0130; 0131; 0132
[2] Patent: CN106810523, 2017, A, . Location in patent: Paragraph 0021
[3] Patent: WO2007/54105, 2007, A2, . Location in patent: Page/Page column 20
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 2033 - 2038
[5] Patent: WO2009/133052, 2009, A1, . Location in patent: Page/Page column 42
[6] Patent: WO2005/42473, 2005, A1, . Location in patent: Page/Page column 9-10
[7] Patent: WO2003/87081, 2003, A1, . Location in patent: Page/Page column 9
[8] Patent: WO2003/101931, 2003, A2, . Location in patent: Page 10-15; 19
[9] Patent: US2004/14997, 2004, A1, . Location in patent: Page 10
[10] Patent: JP2005/507900, 2005, A, . Location in patent: Page/Page column 24-25
[11] Patent: WO2010/4575, 2010, A2, . Location in patent: Page/Page column 16-17
[12] Dyes and Pigments, 2012, vol. 93, # 1-3, p. 1512 - 1518
[13] Patent: WO2008/136017, 2008, A1, . Location in patent: Page/Page column 30
3
[ 3179-63-3 ]
[ 109-54-6 ]
Yield
Reaction Conditions
Operation in experiment
83%
With thionyl chloride In chloroform at 0 - 70℃; for 4 h; Inert atmosphere
To a stirred solution of 3-(dimethylamino) propan-1-ol 86 (2.0 g, 1.94 mmol) inCHC13 (50 mL) under inert atmosphere was added thionyl chloride (4.22 mL, 58.23 mmol) at 0°C; heated to 70 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with diethyl ether (2 x 30 mL) to afford compound 87 (2.5 g, 83percent) as white solid. TLC: 5percent MeOH/ CH2C12 (Rf: 0.2); ‘H-NMR (DMSO-d6, 500 MHz): ö 10.97 (br s, 1H), 3.74 (t, J = 6.4Hz, 2H), 3.12 (t, J= 7.8 Hz, 2H), 2.72 (s, 6H), 2.20-2.12 (m, 2H).
Reference：
[1] Patent: WO2018/53157, 2018, A1, . Location in patent: Page/Page column 116
[2] Annales Pharmaceutiques Francaises, 1946, vol. 4, p. 173[3] Chem.Abstr., 1947, p. 5099
[4] Tetrahedron, 1962, vol. 18, p. 245 - 255
[5] Arzneimittel-Forschung, 1962, vol. 12, p. 25 - 29
[6] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6875 - 6884
4
[ 124-40-3 ]
[ 109-70-6 ]
[ 109-54-6 ]
Reference：
[1] Helv.Engi-Festschr., <1941>215,
[2] Journal of the American Chemical Society, 1955, vol. 77, p. 3536,3540
[3] Helv.Engi-Festschr., <1941>215,
[4] Patent: WO2004/99141, 2004, A1, . Location in patent: Page 9-10
[5] Archiv der Pharmazie, 2018, vol. 351, # 8,
[6] Patent: CH221596, 1941, ,
[7] Patent: CH221596, 1941, ,
5
[ 20904-57-8 ]
[ 109-54-6 ]
Reference：
[1] Chemische Berichte, 1906, vol. 39, p. 1425
6
[ 17268-49-4 ]
[ 109-54-6 ]
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1962, vol. 32, p. 432 - 438[2] Zhurnal Obshchei Khimii, 1962, vol. 32, p. 439 - 445
7
[ 110129-11-8 ]
[ 110129-14-1 ]
[ 109-54-6 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1986, vol. 51, # 12, p. 2848 - 2868
8
[ 30340-95-5 ]
[ 109-54-6 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1970, vol. 6, # 10, p. 2035 - 2037[2] Zhurnal Organicheskoi Khimii, 1970, vol. 6, # 10, p. 2026 - 2028
9
[ 926-63-6 ]
[ 67-66-3 ]
[ 7782-50-5 ]
[ 108-14-5 ]
[ 109-54-6 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 1494,1497
10
[ 7647-01-0 ]
[ 20904-57-8 ]
[ 109-54-6 ]
[ 108-95-2 ]
Reference：
[1] Chemische Berichte, 1906, vol. 39, p. 1425
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1977, vol. 42, p. 1838 - 1850
[2] Farmaco, Edizione Scientifica, 1962, vol. 17, p. 753 - 772
[3] , 1968, vol. 4, # 4, p. 122 - 125[4] Zhurnal Organicheskoi Khimii, 1968, vol. 4, # 4, p. 128 - 133
13
[ 151-50-8 ]
[ 109-54-6 ]
[ 13989-82-7 ]
Reference：
[1] Journal of Organic Chemistry, 1961, vol. 26, p. 1826 - 1831
14
[ 109-54-6 ]
[ 122-51-0 ]
[ 1116-77-4 ]
Yield
Reaction Conditions
Operation in experiment
75.8%
With iodine; magnesium In benzene for 3.25 - 4.33333 h; Heating / reflux
Into a 2L four-necked round bottom flask was charged magnesium turnings (25gr) under nitrogen atmosphere. Benzene [(50ML),] the above benzene solution [(50ML),] triethyl orthoformate (20gr), and a small crystal of iodine were added to the reaction flask and slowly heated to reflux temperature. Within 15-20min of refluxing period, a vigorous reaction took place indicating the initiation of Grignard reaction. Remaining quantity of benzene solution and triethyl orthoformate of the [FORMULA-XVII] where [R3 = R5] = Et (174gr) were separately taken into two addition funnels and slowly added in 3-4hrs period to the reaction mixture under reflux temperature. The reaction mass was cooled to [25°C] and filtered through celite pad. The cake was washed with benzene [(100ML).] Benzene was removed from the reaction mass using 20cm Vigroux column at atmospheric pressure. The residue was distilled under mild vaccum keeping mass temperature below [100°C] to get the excess triethyl orthoformate (60gr). Finally, [4- (N,] N- dimethylamino)-butyraldehyde diethyl acetal was distilled under vaccum to get 125gr (75.8percent) as colourless liquid. B. p.: [140-150°C/15-20MM.]
72.8%
With iodine; magnesium In cyclohexane for 5.25 - 6.33333 h; Heating / reflux
Into a 2L four-necked round bottom flask was charged magnesium turnings (25gr), cyclohexane [(50ML),] the above cyclohexane solution [(50ML),] triethyl orthoformate (20gr), and a small crystal of iodine were added into the flask and heated to reflux temperature. Within [15-20MIN] of reflux, vigorous reaction took place indicating the initiation of Grignard reaction. Remaining quantity of the cyclohexane solution [(600ML)] and triethyl orthoformate of the [FORMULA-XVII] where R3 = [R5] = Et (175gr) were taken into two separate addition funnels and added to the reaction mass at reflux temperature over a period of [3-4] hrs. After the addition, the reaction mass was maintained at reflux for another 2hrs and cooled to [25°C.] The reaction mass was filtered over a celite pad and washed the cake with 100ml of cyclohexane. Cyclohexane was removed from the reaction mass by ordinary distillation keeping a 20cm vigroux column. Excess triethyl orthoformate was distilled under mild vaccum keeping the mass below [80°C.] Finally, the residue was distilled under vaccum to afford 120gr (72.8percent) of 4- (N, N- dimethylamino) butyraldehyde diethyl acetal as a colorless liquid.
Stage #1: With iodine; magnesium In benzene for 3.25 - 4.25 h; Heating / reflux Stage #2: for 3 h;
Into a 2L three-necked round bottom flask was added magnesium turnings (25gr) under nitrogen atmosphere and [50ML] of the above benzene solution added to the reaction flask. After adding a small crystal of iodine, reaction mass was heated to reflux temperature. After maintaining for 15 min, reaction got initiated and to the reaction mass remaining quantity of benzene solution was added slowly in 2-3hrs period. After the addition, reaction mass was maintained for lhr and a solution of phenyl diethyl orthoformate (171gr) in benzene [(200ML)] was added slowly over a period of lhr. After maintaining for 2hrs, reaction was cooled to [25°C] and filtered on a celite pad. Solvent was removed from the reaction mass and the residue fractionally distilled to get 120gr (72.7percent) [OF 4- (N,] N- dimethylamino) butyraldehyde diethyl acetal.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 19, p. 5299 - 5302
26
[ 109-54-6 ]
[ 103146-26-5 ]
Yield
Reaction Conditions
Operation in experiment
76.9%
Stage #1: With iodine; magnesium In 2-methyltetrahydrofuran at 60℃; for 4.83333 h; Inert atmosphere Stage #2: at -20℃; for 17.6167 h; Inert atmosphere Stage #3: With hydrogen bromide In 2-methyltetrahydrofuran at 3℃; for 1 h;
Example 3 Preparation of N,N-dimethyl-3-chloromagnesiopropylamine Grignard reagent 2-methyl tetrahydrofuran as solvent: Reaction process: At room temperature, Mg (7.28 g, 300 mmol) and iodine granules (0.506 g, 2 mmol) were suspended in anhydrous 2-methyltetrahydrofuran (80 mL, moisture content: 0.016percent), the reaction mixture was purged with nitrogen for 6 times. The reaction mixture was heated to 60 deg. C and stirred for 15min, the mixture was orange-red. 3-chloro-N, N-dimethylpropylamine (CPA) (24.32 g, 200 mmol) was dissolved in anhydrous 2-methyltetrahydrofuran (120 mL) was added dropwise to the above reaction mixture, reaction liquid from milky white to gray-green, 110min dropwise additon was finished, reaction at 60 ° C for 3 h, the solution of N,N-dimethyl-3-chloromagnesiopropylamine Grignard reagent in 2-methyltetrahydrofuran was cooled to room temperature and was directly used in the next reaction. Example 4 Preparation of 4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrile hydrobromide 2-methyl tetrahydrofuran as solvent: Reaction process: To a solution of the Grignard reagent of formula (III) (200 mL, 200 mmol) in anhydrous 2-methyltetrahydrofuran (541 mL) was added dropwise a solution of 2-methyltetrahydrofuran (541 mL) of formula (II) (54.30 g, 151.50 mmol), the solution was added dropwise over 97 min and the reaction mixture was stirred at -20 ° C for 16 h under nitrogen. Reaction post-treatment: Samples were quenched with saturated NH4Cl solution, and 2-methyltetrahydrofuran was analyzed by HPLC. The reaction mixture was allowed to warm to 0 ° C, and a saturated NH4Cl solution (120 mL) was added dropwise to the reaction mixture to quench the reaction mixture. The temperature of the reaction solution was maintained at 10 ° C or less, the white viscous solid was removed by suction filtration, the filtrate was cooled to 3 ° C and hydrogen bromide (30.30 g, 48percent, 179.70 mmol) was added dropwise to the filtrate, the reaction mixture was stirred at 3 ° C for 1 hour. The filtrate was concentrated under reduced pressure to remove 2-methyltetrahydrofuran. The reaction mixture was stirred at room temperature with CH2Cl2 (500 mL) and H2O (250 mL). The reaction mixture was cooled to room temperature, was added to the mixture, a white solid precipitated from the mixture, the reaction mixture was stirred at 15 ° C for 6 h, filtered, the white filter cake was washed with CH2Cl2 (3 x 80 mL) and dried in vacuo at 60 ° C for 16 h to give a white solid (49.33 g, yield: 76.9percent, based on 5-cyanophthalocyanine).
Reference：
[1] Patent: CN105294496, 2016, A, . Location in patent: Paragraph 0120-0125; 0141- 0147; 0155-0167
3
The flaky solid NaOH (42.1 g, 1052.5 mmol, 1.0 equiv.) was dissolved in 142.1 g of water, a large amount of heat was released to give an aqueous solution of NaOH, which was cooled to 30 ° C. A solution of CPA.HCl (104 g, 658 mol, 1.0 equiv.) and the above aqueous solution of NaOH was added to a 500 mL two-necked flask and the temperature was raised to 45 ° C and the reaction was started and stirred for 2 h. Reaction post-treatment: The reaction solution was cooled to room temperature (30 ° C). The organic layer was separated and collected, and 74.93 g of wet CPA was obtained. The water content was found to be 2.755% and the yield was 91.07% (excluding moisture in the CPA).
83%
With triethylamine In diethyl ether at 20℃;
4 Example 4
A 250 mL three-necked flask was charged with 10.0 g of Intermediate V,100ml anhydrous ether, 12.8g triethylamine, reaction at room temperature,TLC monitored the reaction was complete. Add saturated sodium bicarbonate solution 100ml,Stirring, extracting with anhydrous ether, collecting the organic phase, washing with water, washing with salt,Drying over anhydrous sodium sulfate. Filtered and evaporated to remove the organic solvent under reduced pressure,The intermediate VI was obtained as a colorless oil 6.4 g, yield 83%.
80%
With sodium hydroxide In water at 45 - 50℃; for 2h;
3
Example 3 4-Dimethylamino- 1 -(5-[ 1 ,3]dioxolan-2-yl-furan-2-yl)- 1 -(4-fluoro-phenyl)-butan- 1 -ol (3) In a 1 L round bottomed flask equipped with magnetic bar and condenser, a mixture of 3- (dimethylamino)propyl-l -chloride hydrochloride (DMPCHCl) (260 g, 1.65 mol) and aqueous NaOH solution (240 g, 30 % w/v, 1.8mol, 1.1 eq.) was heated at 45-50 °C for 2 hours. The mixture was then extracted with ether (3 x 400 mL) and the collected organic phase was dried (solid NaOH) and filtered. Distillation of ether at atmospheric pressure afforded DMPC as a colourless oil (160 g, 80 %).
78%
With potassium carbonate In water
75%
With sodium hydrogencarbonate In diethyl ether; water at 20℃; for 1h;
B1.b
A saturated solution of NaHCO3 (205 ml) was slowly added to a suspension of 3- chloro-W,N-dimethyl-l-propanamine hydrochloride (25 g, 0.158mol, CAS [4584-46-7]) in Et2O (200ml). The mixture was stirred at RT for lhour, then saturated with K2CO3 (solid). The mixture was extracted with Et2O. The organic layer was dried over MgSO4 and concentrated at RT under vacuum to afford 15.5g of 3-chloro-iV,iV-dimethyl-l- propanamine (yield 75%) .
With sodium hydroxide In water at 0 - 20℃;
1
EXAMPLE 1 (4-Bromo-2-hydroxymethyl)phenyl-(4-fluorophenyl)-3-(dimethylaminopropyl)methanol, (Bromodiol) 1.0 Ltr N, N-Dimethylaminopropyl chloride hydrochloride (in form of 60% aqueous solution) is cooled to 0 °C and 0.40 Kg 50 % caustic lye is added to it under constant stirring. The solution is allowed to warm to room temperature and layer is separated. Upper organic layer is dried over Sodium Hydroxide flakes and distilled under vacuum, fractions boiling between 50 to 55 °C at 60 mm of Hg is collected to get 425 gm of pure dry N, N-Dimethyl-aminopropyl chloride. In a 10 Ltr three necked round bottom flask carrying stirrer thermowell and nitrogen inlet is charged magnesium turnings (104 gm), 200 ml tetrahydrofuran and a crystal of iodine. To this a solution of 4-Fluorobromobenzene (0.624 Kg) in tetrahydrofuran (800 ml) is added slowly over 2 hours to get Grignard reagent. In a separate set 10 Ltr three necked round bottom flask, magnesium turnings (104 gm), 200 ml tetrahydrofuran and a crystal of iodine is taken. To this a solution of N, N-Dimethylaminopropyl chloride (410 gm) in 500 ml tetrahydrofuran is added over 2 hours to get the second Grignard reagent. In a 20 Ltr round bottom flask is charged 5-Bromophthalide (532 gm), tetrahydrofuran (800 ml) and cooled to-5 to-10 °C. To this a solution of 4-Fluorophenylmagnesium bromide in tetrahydrofuran is added slowly over 4 to 6 Hours; followed by addition of N, N-Dimethylamino- propylmagnesium chloride in tetrahydrofuran in 4 to 6 hours at-5 to-6 °C. The reaction mixture is stirred at-5 to-10 °C for 2 hours and then allowed to warm to room temperature and is stirred for further 3 hours. After the reaction is completed it is cooled to 0 to-5 °C, water (10 Ltr) is added and distilled under industrial vacuum at 60 to 65 °C to recover tetrahydrofuran, acetic acid (500 ml) is added to get pH in the range of 7.0 to 8. 0. The reaction mass is extracted with ethyl acetate (3 X 2.5 Ltr). Combined ethyl acetate layer is re-extracted with 20% acetic acid in water (3 X 2.5 Ltr). Acetic acid extract is basified with concentrated ammonia (1.90 Ltr) to pH 8.0 to 9.0. The bromodiol is extracted with fresh ethyl acetate (3 X 3.0 Ltr). Combined ethyl acetate extract is cooled to 0 °C and stirred for 3 hours which results in complete crystal- zation of bromodiol. It is filtered and dried in oven at 60 °C for 4 hours. Yield of bromodiol = 556 gm, HPLC Purity = 99. 20%, Melting Point = 155 to 160 °C, Moisture Content = 2.30 %.
With sodium hydroxide In water for 0.25h;
2
To a 500 mL round-bottomed flask ("rbf) equipped with a stirring bar was charged the commercially available 3-dimethylaminopropyl chloride hydrochloride (50 g, 0.315 mol) as a white solid. An aqueous 3 M solution of NaOH (120 mL,-1. 1 eq) was added to the solid followed by stirring moderately for 15 minutes to generate an oily suspension. Methyl-t-butyl ether (MTBE) (100 mL) was added to this suspension followed by stirring for 10 minutes. The top MTBE layer was collected. The lower aqueous layer was extracted with 50 mL of MTBE. The combined MTBE layers were washed with water (20 mL). This MTBE solution of the amine was dried under azeotropic conditions under nitrogen for 4 hours to remove residual water. MTBE (125 mL) was then distilled out. The contents of the pot were transferred to a 100 mL rbf and the weight of this solution was determined. This solution was then subjected to distillation at atmospheric pressure (bath temperature 80°-90°C) to remove the remaining MTBE. The content remained was then distilled at the same bath temperature but under reduced pressure (aspirator). The distillate (31.86 g) was then assayed by'H nmr to determine the amount of residual MTBE present with respect to 3-dimethylaminopropyl chloride. It was found that the distillate contains about 3 % by weight of MTBE.
With sodium hydroxide In water at 15 - 20℃; for 0.5h;
1; 2; 3; 4; 5; 8 Example 1; Preparation of 4- (N, N-dimethylamino) butyraldehyde dimethyl acetal of the formula-I where [RL = RZ = R3] = Me using Benzene as solvent :; Preparation of [3- (N, N-DIMETHYLAMINO) PROPYL] chloride solution in benzene:
Commercially available aqueous [3- (N,] N-dimethylamino) propyl chloride hydrochloride (230gr, 60% w/w) was taken into a IL three-necked round bottom flask and cooled to 15- [20°C.] Aqueous sodium hydroxide (40gr in [60ML] water) solution was slowly added to the above salt solution keeping the temperature below [20°C.] After stirring for 30min, [300ML] of benzene was added to the reaction mixture and stirred for [15MIN.] The benzene layer was separated and the aqueous layer extracted with benzene [(200ML).] The combined benzene layer was taken into a clean and dry 1L three-necked round bottom flask and heated under reflux with a Dean-Stark apparatus. After removing moisture completely, the benzene solution was cooled to [25°C] and decanted the colorless supernatant liquid into a 1L round bottom flask. Chemical assay of this benzene solution was 17% w/w.; Commercially available aqueous 3- (N, N-dimethylamino) propyl chloride hydrochloride (230gr, 60% w/w) was taken into a 1L three-necked round bottom flask and cooled to 15- [20°C.] Aqueous sodium hydroxide (40gr in [60ML] water) solution was slowly added to the above salt solution keeping the temperature [BELOW 20°C.] After stirring for 30min, [300ML] of toluene was added to the reaction mixture and stirred for [15MIN.] The toluene layer was separated and the aqueous layer extracted with toluene [(200ML).] The combined toluene layer was taken into a clean and dry 1L three-necked round bottom flask and heated under reflux with a Dean-Stark apparatus. After removing moisture completely, the toluene solution was cooled to [25°C] and decanted the colorless supernatant liquid into a 1L round bottom flask. Chemical assay of this toluene solution was 17% w/w.; Commercially available aqueous 3- (N, N-dimethylamino) propyl chloride hydrochloride (230gr, 60% w/w) was taken into a 1L three-necked round bottom flask and cooled to 15- [20°C.] Aqueous sodium hydroxide (40gr in [60ML] water) solution was slowly added to the above salt solution keeping the temperature below [20°C.] After stirring for 30min, 3- (N, N-dimethylamino) propyl chloride separated as an oil. The oil layer was separated and dried over 20gr of sodium hydroxide pellets. The compound layer was decanted and dissolved in 500 ml of THF. About [100ML] of THF was distilled off from this layer and the residue to cooled to [25°C.] Chemical assay of this THF solution [(SOOGR)] was 15% w/w.; A solution of 106gr [OF 3- (N,] N-dimethylamino) propyl chloride in benzene [(500ML)] was prepared by following the procedure given in Example 1 (i) above.; Commercially available aqueous [3- (N, N-DIMETHYLAMINO) PROPYL] chloride hydrochloride (230gr, 60% w/w) was taken into a 1L three-necked round bottom flask and cooled to 15- [20°C.] Aqueous sodium hydroxide (40gr in [60ML] water) solution was slowly added to the above salt solution keeping the temperature below [20°C.] After stirring for [30MIN, 300ML] of cyclohexane was added to the reaction mixture and stirred for [15MIN.] The cyclohexane layer was separated and the aqueous layer extracted with cyclohexane [(200ML).] The combined cyclohexane layer was taken into a clean and dry 1L three-necked round bottom flask and heated under reflux with a Dean-Stark apparatus. After removing moisture completely, the cyclohexane solution was cooled to [25°C] and decanted the colorless supernatant liquid into a 1L round bottom flask. Chemical assay of this cyclohexane solution [(650ML)] [WAS 16.] 5% w/w.; A solution of 3- (N, N-dimethylamino) propyl chloride (106gr) in benzene [(500ML)] was prepared as per the procedure given in Example 1 above.
With sodium hydroxide In water
IV.II (II) Aliphatic Grignard Reagent
A solution of 3-dimethylaminopropyl chloride hydrochloride in water/toluene was basified by the addition of sodium hydroxide solution. The layers were separated and the aqueous layer was extracted with toluene. The combined toluene phases were washed with water and dried by azeotropic distillation in vacuo at less than 35° C. The solution was then diluted with tetrahydrofuran. A portion of this solution was added to magnesium and a catalytic quantity of 1,2-dibromoethane under a nitrogen atmosphere. The mixture was heated to reflux to initiate the reaction, and one the initial exotherm had subsided, the remaining THF solution prepared above was added at a steady constant rate so that the mixture was maintained at reflux. After the addition was complete
With sodium hydroxide In water; toluene at 20℃;
With potassium hydroxide In water at 0 - 5℃;
1.b
56 gm of KOH flakes were added in a flask containing water (170 ml) and stirred for clear solution. The solution was cooled to 0-5 0C and 156 gm of l-[3-(dimethylamino) propyl] chloride HCl salt was charged. Separated the upper layer containing the l-[3-(dimethylamino) propyl] chloride and kept aside. Aqueous layer was extracted with toluene (3 X 50 ml) and the organic layer was mixed with the above l-[3-(dimethylamino) propyl] chloride layer separated initially. Dry the total organic layer with KOH till the moisture content is below 0.1 % w/w. 12 gm of Mg turnings was charged in a flask containing 50 ml of dry THF and heated to about 100 0C. A pinch of molecular Iodine was added to the reaction contents. A mixture of THF (120 ml) and organic layer containing l-[3-(dimethylamino) propyl] chloride obtained above was added slowly to the reaction mixture at 100- HO 0C for about 2 hours. The reaction mixture was stirred at reflux for about 2 hours and the whole reaction mixture was used directly in the reaction.
With potassium carbonate In 5,5-dimethyl-1,3-cyclohexadiene for 48h; Reflux;
16
l-(3-Hydroxy-4-methyl) benzenesulfonyl-lH-indole (0.622 mmol, 0.2 grams)(obtained from preparation 2) was dissolved in tetrahydrofiiran (7 mL). To the above mixture, potassium carbonate (1.024 mmol, 0.171 grams) was added and stirred for a period of 15 - 20 minutes. The free base generated from 3-dimetiiylaminopropylchIoride hydrochloride (2.48 mmol, 0.393 grams) was extracted with toluene (3 mL) and directly charged into the reaction mixture. The reaction mixture was refluxed while monitoring the progress of the reaction. After completion of reaction, the mass was cooled to room temperature and poured it on to water (25 mL) and extracted the product with ethyl acetate (10 mL x 4). Combined organic extracts dried over sodium sulfate and the volatiles were removed under the reduced pressure to obtain 0.219 grams of crude compound. The compound was purified by column chromatography using silica gel (100-200 mesh) to obtain 0.143 grams of pure compound. _IR (cm"1): 2944, 1373, 1171;'H-NMR (ppm): 1.91 - 1.98 (2H, m), 2.16 (3H, s), 2.26 (6H, s), 2.43 - 2.46 (2H, t, J = 7.12 Hz),3.96 - 3.99 (2H, t, J = 6.24 Hz), 6.64 - 6.65 (I H, d, J = 3.68 Hz), 7.13 - 7.15 (IH, d, J = 7.88 Hz), 7.22 - 7.30 (3H, m), 7.34 - 7.37 (IH, dd, J = 7.84, 1.76 Hz), 7.51 - 7.53 (IH, d, J = 7.8Hz), 7.55 (I H, d, J = 3.72 Hz), 7.98 - 8.00 (IH, d, J = 8.28 Hz);Mass (m/z): 373 (M+H)+.
With triethylamine In tetrahydrofuran
40.2 g
With sodium hydroxide In water; pentane at 20℃; for 1.5h;
1 [Production Example 1] Synthesis of Compound No. 13
59.7 g of 3-dimethylaminopropyl chloride hydrochloride, 133 g of ultrapure water, and 59.3 g of dehydrated pentane were added to a reaction flask, followed by mixing. 130 g of a 22% sodium hydroxide aqueous solution was added dropwise to the obtained solution at room temperature, and the mixture was stirred for 1.5 hours. The obtained reaction solution was separated into an organic phase and an aqueous phase through use of a separating funnel, and then extraction from the aqueous phase was performed three times through use of each 50 mL of dehydrated pentane. The obtained organic phases were combined, and magnesium sulfate was added thereto. The mixture was stirred at room temperature for 30 minutes, and dehydrated and dried. After filtration and separation of magnesium sulfate, the filtrate was subjected to solvent removal in an oil bath at 50° C. The obtained ligand was distilled under reduced pressure in an oil bath at 65° C. to obtain 40.2 g of 3-dimethylaminopropyl chloride as a colorless transparent liquid
Stage #1: 4-hydroxy-benzaldehyde With potassium carbonate In acetone at 60℃; for 2h;
Stage #2: 3-(Dimethylamino)propyl chloride In acetone at 60℃; for 2h;
2.3 5.2.3 O-alkylation of 4-hydroxybenzaldehyde
General procedure: To a solution of 4-hydroxybenzaldehyde (0.4 g, 3.275 mmol) in acetone (13 mL) was added K2CO3 (1.38 g, 10 mmol). The reaction mixture was vigourously stirred with heating at 60 °C for 2 h. The reaction mixture was then cooled to room temperature, followed by the addition of appropriate chlorides (4.585 mmol) dissolved in acetone. The reaction mixture was allowed to stir again with heating at 60 °C for 2 h. The reaction mixture was then filtered to remove K2CO3. The filtrate was evaporated to dryness to yield crude products which were subjected to column chromatography to obtain pure 4-O-alkylated benzaldehydes.
With sodium methylate In N,N-dimethyl-formamide 1) 50 deg C, 3 h, 2) r.t., 12 h;
With potassium carbonate In N,N-dimethyl-formamide for 6h; Reflux;
68.8 g (67%)
With hydrogenchloride; NaH In <i>N</i>-methyl-acetamide; ice-water; toluene
2.A A.
A. 4-(3-Dimethylaminopropoxy)benzaldehyde A stirred solution of 61.0 g (0.50 mole) of 4-hydroxybenzaldehyde in 400 ml of dimethylformamide (nitrogen atmosphere) is gradually treated with 24.0 g of 50% NaH. The temperature is kept below 35° using an ice water bath. When the addition is completed, the thick mixture is heated to 70° for several minutes, then cooled to 35° before the addition of 417 ml of 1.8N (0.75 mole) of 3-dimethylaminopropyl chloride in toluene. The mixture is stirred and heated at 100°-105° for 3 hours. The sodium salt of the hydroxybenzaldehyde, which has limited solubility in dimethylformamide, appears to react with the halide when the temperature approaches 90°. The color changes from lavender to brown. After cooling, the mixture is poured over 1 liter of ice-water, then extracted with 300 ml of ether (2x). The ether phases are combined, washed with water, then treated with 125 ml of 6N HCl. After separation of the aqueous layer, the ether fraction is washed with water. The aquesou portions are combined and treated with an excess of K2 CO3 to liberate the base into ether. The solvent is dried (MgSO4), evaporated, and the residue is distilled to give 68.8 g (67%) of colorless product, bp 145°-147°/1.5 mm.
(i) Mg, (ii) /BRN= 743171/, THF; Multistep reaction;
Stage #1: 3-(Dimethylamino)propyl chloride With magnesium In tetrahydrofuran for 2h; Reflux;
Stage #2: dibenzosuberenon In tetrahydrofuran at 0 - 15℃; for 0.75h;
Stage #3: With hydrogenchloride; water In tetrahydrofuran at 10℃;
In a reaction vessel, THF (1 10ml), magnesium turnings 20gm (0.823mole) were charged and the mixture was warmed to 45-55°C for 20 min. A solution of l OOgm (0.823mole) of 3-dimethylaminopropyl chloride prepared in 1 10ml THF was added dropwise to the reaction mixture by controlling the reflux generated due to reaction initiation and maintained for 2hrs. The formed Grignard reagent was then cooled to 0-5°C and a solution of lOOgm (0.485mole) 5-dibenzosuberenone prepared in 220ml THF was charged to the reaction mass at temperature below 10°C. The reaction mass was stirred for 45 min at temperature 10-15°C. The absence of 5-dibenzosuberenone was checked by TLC and 770ml of 20% aq. HC1 was charged to the reaction mass at a temperature below 10°C. The reaction mass was then heated to 70-80°C for 3 hrs. The acidic mass was neutralized by using aqueous Na2C03 solution and extracted with 900ml methylene dichloride. The solvent was removed completely under reduced pressure and oil thus formed was dissolved in 450ml IPA and acidified with 240 ml of 20% IPA .HC1 solution and stirred for 2 hrs at 0-5°C for complete precipitation. The precipitate is filtered, recrystallized from IPA (800 ml) and dried to obtain 1 18 gm (78%) white crystalline cyclobenzaprine hydrochloride with purity 99.93% by HPLC.
Stage #1: 2-hydroxy-4-nitro-benzoic acid methyl ester With potassium carbonate In N,N-dimethyl-formamide at 20℃;
Stage #2: 3-(Dimethylamino)propyl chloride In N,N-dimethyl-formamide at 100℃;
With iodine; magnesium; In benzene; for 3.25 - 4.33333h;Heating / reflux;
Into a 2L four-necked round bottom flask was charged magnesium turnings (25gr) under nitrogen atmosphere. Benzene [(50ML),] the above benzene solution [(50ML),] triethyl orthoformate (20gr), and a small crystal of iodine were added to the reaction flask and slowly heated to reflux temperature. Within 15-20min of refluxing period, a vigorous reaction took place indicating the initiation of Grignard reaction. Remaining quantity of benzene solution and triethyl orthoformate of the [FORMULA-XVII] where [R3 = R5] = Et (174gr) were separately taken into two addition funnels and slowly added in 3-4hrs period to the reaction mixture under reflux temperature. The reaction mass was cooled to [25C] and filtered through celite pad. The cake was washed with benzene [(100ML).] Benzene was removed from the reaction mass using 20cm Vigroux column at atmospheric pressure. The residue was distilled under mild vaccum keeping mass temperature below [100C] to get the excess triethyl orthoformate (60gr). Finally, [4- (N,] N- dimethylamino)-butyraldehyde diethyl acetal was distilled under vaccum to get 125gr (75.8%) as colourless liquid. B. p.: [140-150C/15-20MM.]
72.8%
With iodine; magnesium; In cyclohexane; for 5.25 - 6.33333h;Heating / reflux;
Into a 2L four-necked round bottom flask was charged magnesium turnings (25gr), cyclohexane [(50ML),] the above cyclohexane solution [(50ML),] triethyl orthoformate (20gr), and a small crystal of iodine were added into the flask and heated to reflux temperature. Within [15-20MIN] of reflux, vigorous reaction took place indicating the initiation of Grignard reaction. Remaining quantity of the cyclohexane solution [(600ML)] and triethyl orthoformate of the [FORMULA-XVII] where R3 = [R5] = Et (175gr) were taken into two separate addition funnels and added to the reaction mass at reflux temperature over a period of [3-4] hrs. After the addition, the reaction mass was maintained at reflux for another 2hrs and cooled to [25C.] The reaction mass was filtered over a celite pad and washed the cake with 100ml of cyclohexane. Cyclohexane was removed from the reaction mass by ordinary distillation keeping a 20cm vigroux column. Excess triethyl orthoformate was distilled under mild vaccum keeping the mass below [80C.] Finally, the residue was distilled under vaccum to afford 120gr (72.8%) of 4- (N, N- dimethylamino) butyraldehyde diethyl acetal as a colorless liquid.
With magnesium; In cyclohexane; at 65 - 70℃; for 6h;
100GMS (0. 66MOL) of chloro bromo propane was taken in 100ML of cyclohexane and 125gms of 42% caustic soda lye was added at 20-25C. The mass was stirred for 60min at 25-30 C and LOOGMS of 40% DIMETHYLAMINE was added. The mass was stirred for 24 hours at 25-30 C and 200ML of cyclohexane was added. The organic layer was separated and dried with sodium sulfate. The organic layer was used for next stage without ISOLATION/PURIFICATION. 20 gms of magnesium turnings was taken the flask and 80ML of TRIETHYLORTHO formate was taken in a well-dried flask which was equipped with an addition funnel, thermometer socket and reflux condenser. The reaction mass was heated to 65-70C and the above organic layer was added in 4 hours. The reaction mixture was stirred for 2 hours at G5-70 C and cooled to 25-30C, The mass was filtered and filtrate was stripped off solvent under reduced pressure. The product was distilled under 1 OMM/HG at 135-140 C to get 30gms of the >94% PURE (GC) 4, 4-DIMETHYLAMINO butyraldehyde dimethyl acetal, which can be used straight away for the next stage
(-)-(S)-N-(α-Ethylbenzyl)-3-(3-dimethylaminopropoxy)-2-phenylquinoline-4-carboxamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In hydrogenchloride; Et2O;
EXAMPLE 100 (-)-(S)-N-(alpha-Ethylbenzyl)-3-(3-dimethylaminopropoxy)-2-phenylquinoline-4-carboxamide hydrochloride 1.2 g (3.1 mmol) of (-)-(S)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Ex. 85) were dissolved in 15 ml of dry THF.. 1.0 g (8.2 mmol) of 3-dimethylaminopropylchloride, dissolved in 10 ml of Et2O, 1.3 g (9.4 mmol) of K2CO3and 0.16 g of KI were added and the reaction mixture was stirred at room temperature for 30 minutes and then refluxed for 2 hours.. Further 0.77 g (6.3 mmol), 1.0 g (8.2 mmol), 0.6 g (4.9 mmol) and additional 0.6 g (4.9 mmol) of 3-dimethylaminopropylchloride, dissolved each time in 10 ml of Et2O, and some KI were added every 12 hours and the reaction refluxed.. The K2CO3was filtered off and the mixture was evaporated in-vacuoto dryness, dissolved in EtOAc and washed with H2O and with 20% citric acid.. The aqueous layer was made alkaline with 2 N NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over Na2SO4and evaporated in-vacuoto dryness.. The residue was flash chromatographed on 230-400 mesh silica gel, eluding with CH2Cl2/MeOH 95: 5 containing 0.5% of conc. NH4OH to yield 0.9 g of a crude product which was dissolved in EtOAc and treated with HCl/Et2O to obtain 0.62 g of the title compound. d. C30H33N3O2.HCl M.P. = 108C dec.
To A mixture 5. 42 G sodium hydride in 120 ml of dimethylsulfoxide, previously heated at 60C for 30 minutes, under nitrogen flow, a solution of 30 g of 1-(4-FLUOROPHENYL)-1, 3-DIHYDRO-5-ISOBENZOFURANCARBONITRILE obtained in Example 2 in 75 ML of dimethylsulfoxide is added, without exceeding 25C. The solution is maintained under stirring for 30 minutes and, in 10 minutes, 33 g of 3- (dimethylamino) propylchloride are added without exceeding 25C. After about 2-hour stirring at 25C, the mixture is cooled at 10C and 300 mi of water are added dropwise and then 120 ml of ethyl acetate. The mixture is stirred and diluted with 1650 ml of water and 120 ML of ethyl acetate. The mixture is let 1 hour under stirring, then the phases are separated; the organic one is collected and the aqueous one is washed with 3 x 150 ml of ethyl acetate. After separation of the phases, the aqueous one is discarded and the collected organic ones are washed with 900 ml of water. The organic phase is dehydrated with anhydrous NA2SO4 and is concentrated under vacuum at 50C until an oil is obtained, which is treated with 60 ml of acetone. The mixture is stirred in order to obtain a solution, that is cooled at 10C and treated with about 10 ml of 48% HBr in order to adjust the pH value from 9. 8-9. 5 to 7.0. After 1 hour-stirring at pH = 7 constant, the solvent is evaporated under vacuum at 50C and the residue is treated with 100 mi of acetone. The suspension is stirred at 25C for 30 minutes, then it is cooled at 0-5C AND it is let at cold for 15 HOURS. The product is filtered, washed with cold acetone (0- .-50C) AND is dried under vacuum at 50C. Thus 34. 88 g of CITALOPRAM hydrobromide with A purity (HPLC) = 99.15% are obtained
(-)-(S)-N-(α-Ethylbenzyl)-3-(3-dimethylaminopropoxy)-2-phenylquinoline-4-carboxamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium hydroxide; Ki; potassium carbonate; In tetrahydrofuran; diethyl ether; ethyl acetate;
EXAMPLE 100 (-)-(S)-N-(alpha-Ethylbenzyl)-3-(3-dimethylaminopropoxy)-2-phenylquinoline-4-carboxamide hydrochloride 1.2 g (3.1 mmol) of (-)-(S)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Ex. 85) were dissolved in 15 ml of dry THF. 1.0 g (8.2 mmol) of 3-dimethylaminopropylchloride, dissolved in 10 ml of Et2O, 1.3 g (9.4 mmol) of K2CO3 and 0.16 g of KI were added and the reaction mixture was stirred at room temperature for 30 minutes and then refluxed for 2 hours. Further 0.77 g (6.3 mmol), 1.0 g (8.2 mmol), 0.6 g (4.9 mmol) and additional 0.6 g (4.9 mmol) of 3-dimethylaminopropylchloride, dissolved each time in 10 ml of Et2O, and some KI were added every 12 hours and the reaction refluxed. The K2CO3 was filtered off and the mixture was evaporated in-vacuo to dryness, dissolved in EtOAc and washed with H2O and with 20% citric acid. The aqueous layer was made alkaline with 2 N NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over Na2SO4 and evaporated in-vacuo to dryness. The residue was flash chromatographed on 230-400 mesh silica gel eluding with CH2Cl2/MeOH 95:5 containing 0.5% of conc. NH4OH to yield 0.9 g of a crude product which was dissolved in EtOAc and treated with HCl/Et2O to obtain 0.62 g of the title compound.
2-(1H-indol-3-yl)-3-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-maleic acid anhydride hydrochloride[ No CAS ]
[ 119139-20-7 ]
[ 109-54-6 ]
[ 133052-90-1 ]
Yield
Reaction Conditions
Operation in experiment
With ammonium acetate; potassium hydroxide; sodium hydrogencarbonate; potassium carbonate; In methanol; ethanol; water; acetone; toluene;
EXAMPLE 2 2-(1H-Indol-3-yl)-3-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-maleinimide 0.20 g (0,44 mmol) 2-(1H-indol-3-yl)-3-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-maleic acid anhydride hydrochloride and 10 g ammonium acetate are heated to 140 C. for 30 minutes. After cooling, the reaction mixture is mixed with water and extracted with ethyl acetate. The organic phase is well washed out with an aqueous solution of sodium bicarbonate and thereafter with water and dried over anhydrous sodium sulphate. The ethyl acetate is removed by rotary evaporation, the red residue obtained is stirred with a little water and the precipitated red product is filtered off with suction. After drying in a vacuum at 0.1 Torr and 140 C., there is obtained 0.156 g (91% of theory) of red product; m.p. about 280 C. (decomp.); RF=0.16 (chloroform/methanol 10:2 v.v). The 2-(1H-indol-3-yl)-3-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-maleic acid anhydride used as starting material is prepared as follows: 0.5 g (0.95 mmol) 2-(1-tert.-butoxycarbonyl-1H-indol-3-yl)-3-[1-(3-dimethylaminopropyl)-1H-indol-3-yl)-N-methylmaleinimide and 50 ml of a 10% solution of potassium hydroxide in methanol/water (1:1 v/v) are heated under reflux for 30 minutes. After cooling, the reaction mixture is carefully acidified with concentrated hydrochloric acid and extracted with chloroform. The organic phase is washed out with water and evaporated to dryness. The red residue is triturated with a little methanol/toluene, filtered off with suction and dried at 80 C. There are obtained 0.34 g (79.5% of theory) of a dark red product; m.p. 232-234 C. (decomp.). The 2-(1-tert. -butoxycarbonyl-1H-indol-3-yl)-3-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-N-methylmaleinimide used as starting material is prepared as follows: A mixture of 0.9 g (2.03 mmol) 2-(1-tert.-butoxycarbonyl-1H-indol-3-yl)-3-(1H-indol-3-yl)-N-methylmaleinimide (Tetrahedron, 44, 2887/1988), 0,3 g potassium carbonate and 0.3 g (2.4 mmol) 3-dimethylaminopropyl chloride in 10 ml acetone is stirred for 12 hours at ambient temperature and for 8 hours under reflux. After cooling, the reaction mixture is poured into water and extracted with ethyl acetate. The red extract is evaporated and the residue flash chromatographed on silica gel (Merck Type 7734) using, as elution agent, a mixture of toluene/ethanol (10+1.5 v/v). The desired product is obtained in the form of a red oil and used as such in the above reaction. Yield 0.8 g (74% of theory); RF=0,20 (toluene/ethanol 1:2 v/v).
(-)-(S)-N-(α-Ethylbenzyl)-3-(3-dimethylaminopropoxy)-2-phenylquinoline-4-carboxamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium hydroxide; Ki; In tetrahydrofuran; diethyl ether; ethyl acetate;
EXAMPLE 100 (-)-(S)-N-(alpha-Ethylbenzyl)-3-(3-dimethylaminopropoxy)-2-phenylquinoline-4-carboxamide hydrochloride 1.2 g (3.1 mmol) of (-)-(S)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Ex. 85) were dissolved in 15 ml of dry THF. 1.0 g (8.2 mmol) of 3-dimethylaminopropylchloride, dissolved in 10 ml of Et2 O, 1.3 g (9.4 mmol) of K2 CO3 and 0.16 g of KI were added and the reaction mixture was stirred at room temperature for 30 minutes and then refluxed for 2 hours. Further 0.77 g (6.3 mmol), 1.0 g (8.2 mmol), 0.6 g (4.9 mmol) and additional 0.6 g (4.9 mmol) of 3-dimethylaminopropylchloride, dissolved each time in 10 ml of Et2 O, and some KI were added every 12 hours and the reaction refluxed. The K2 CO3 was filtered off and the mixture was evaporated in-vacuo to dryness, dissolved in EtOAc and washed with H2 O and with 20% citric acid. The aqueous layer was made alkaline with 2N NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over Na2 SO4 and evaporated in-vacuo to dryness. The residue was flash chromatographed on 230-400 mesh silica gel, eluding with CH2 Cl2 /MeOH 95:5 containing 0.5% of conc. NH4 OH to yield 0.9 g of a crude product which was dissolved in EtOAc and treated with HCl/Et2 O to obtain 0.62 g of the title compound.
In 5,5-dimethyl-1,3-cyclohexadiene; hexane; water;
EXAMPLE I The sodium salt of 1-benzyl-3-hydroxy-1H-indazole (15 g) was suspended in xylene (130 ml). A solution of 1-chloro-3-dimethylaminopropane (6.5 g) in 10 ml of xylene was rapidly added. Additional 2 g of the same chlorobase from the same xylenic solution were added after a 2 hours heating. A third 2 g portion was added after one hour's interval and the mixture was refluxed for 4 more hours. After this time the mixture was cooled, washed thrice with 50 ml of water each time, and the xylene was distilled off. Steam was bubbled into the crude residue (20 g) until 4 ml of water were distilled off. After cooling n.hexane (100 ml) was added to the remaining mixture. The aqueous phase was discharged and the hexane solution, after treatment with charcoal, was filtered. Gaseous HCl was then bubbled into the hexane solution until pH3 was reached. The precipitated hydrochloride was collected by suction and recrystallized by isobutanol containing 5% H2 O. 15.5 g (yield 73.6%) of benzydamine hydrochloride (m.p. 159.5 C. on Mettler F P5) were obtained. A GC analysis showed no presence of 1-chloro-3-dimethylaminopropane (sensitivity of the method=10 ppm).
2 EXAMPLE 2
EXAMPLE 2 9-(3-Dimethylaminopropyl)-9-cyanofluorene. To a stirred solution of 2.6 g. of sodium amide in 200 ml. of tetrahydrofuran was added dropwise over thirty minutes a solution of 12.7 g. of 9-cyanofluorene in 300 ml. of tetrahydrofuran. The reaction mixture was next heated to reflux for three hours, and then cooled to room temperature. While the reaction mixture was being stirred at room temperature, a solution of 14.2 g. of 3-dimethylaminopropyl chloride in 500 ml. of tetrahydrofuran was added dropwise over one hour. Following complete addition, the reaction mixture was again heated to reflux and stirred for sixteen hours. After cooling the mixture to room temperature, it was added to 500 ml. of water. The product was extracted into diethyl ether, and the ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure afforded, after distillation, 2.3 g. of 9-(3-dimethylaminopropyl)-9-cyanofluorene. B.P. 195°-201° C.at 0.1 torr.
In tetrahydrofuran; water
7 9-(3-Dimethylaminopropyl)-9-cyanofluorene
EXAMPLE 7 9-(3-Dimethylaminopropyl)-9-cyanofluorene To a stirred solution of 2.6 g. of sodium amide in 200 ml. of tetrahydrofuran was added dropwise over thirty minutes a solution of 12.7 g. of 9-cyanofluorene in 300 ml. of tetrahydrofuran. The reaction mixture was next heated to reflux for three hours, and then cooled to room temperature. While the reaction mixture was being stirred at room temperature, a solution of 14.2 g. of 3-dimethylaminopropyl chloride in 500 ml. of tetrahydrofuran was added dropwise over one hour. Following complete addition, the reaction mixture was again heated to reflux and stirred for sixteen hours. After cooling the mixture to room temperature, it was added to 500 ml. of water. The product was extracted into diethyl ether, and the ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure afforded, after distillation, 2.3 g. of 9-(3-dimethylaminopropyl)-9-cyanofluorene. B.P. 195°-201° C. at 0.1 torr.
With sodium iodide; NaH In N,N-dimethyl-formamide; toluene
2.A A.
A. 4-[3-(Dimethylamino)propyl]-2H-1,4-benzothiazin-3(4H)-one The title product is prepared by reacting sixty grams (0.36 mole) of 1,4-benzothiazin-3(4H)-one in 360 of DMF with 18 g (0.37 mole) of 50% NaH, 260 ml (0.55 mole) of a 2.1 N toluene solution of 3-dimethylaminopropyl chloride, and 4 g of sodium iodide according to the procedure described in Example 1, part A; yield, 57.7 g; bp 157°-160°/0.2 mm.
In N,N,N,N,N,N-hexamethylphosphoric triamide; petroleumether; isopropyl alcohol;
EXAMPLE XXV A mixture of 10.4 parts of p-(2-thenoyl)hydratropic acid in 75 parts of hexamethylphosphoramide is heated to 50 C and there are added 1.3 parts of sodium hydride dispersion 78.3%. When the reaction is ceased, there are added 10 parts of N-(3-chloropropyl)-N,N-dimethyl amine. The whole is stirred overnight at 50 C. The reaction mixture is cooled and extracted with 240 parts of benzene and 100 parts of water. The organic phase is washed successively with 100 parts of diluted sodium hydroxide solution and with 100 parts of water, dried and evaporated. The oily residue is triturated twice in petroleumether. The latter is decanted and the residue is converted into the oxalate salt in 2-propanol. The solid salt is filtered off and crystallized from 120 parts of 2-propanol (activated charcoal) at room temperature, yielding 3-(dimethylamino)propyl p-(2-thenoyl)hydratropate oxalate; mp. 135-145 C.
2.A (A)
(A) 9,10-Dihydro-N,N-dimethyl-9-anthracenepropanamine Sodium amide is prepared in 1.5 liters of liquid ammonia from 23 g of sodium and a slurry of 90.1 g (0.5M) of 9,10-dihydroanthracene in 400 ml of ether is added. A solution of 36.2 g of 3-(dimethylamino)propyl chloride in 60 ml of ether is added steadily in 3 minutes. After stirring for 1 hour, solid ammonium chloride is added in 15 minutes. More ether is added and the ammonia is boiled off. The solids are removed by filtration and washed with ether, and the filtrate is dried and taken to dryness in vacuo. The sample is redissolved in ether and the basic material is extracted into dilute hydrochloric acid. The acidic aqueous layer is washed twice with ether and basified. The product is extracted into ether, dried and freed of solvent leaving 68.2 g of the title compound.
1'-(3-dimethylaminopropyl)-1'H-spiro[cyclopropane-1,2'-indolin]-3'-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ice-water; nitrogen; dimethyl sulfoxide
12 EXAMPLE 13
Elemental analysis, for C18 H17 NO2 EXAMPLE 13 In nitrogen streams, while a mixture of 0.144 g of 50% (weight/volume) sodium hydride in oil and 5 ml of dry dimethyl sulfoxide was stirred under ice-cooling, a solution of 0.319 g of 1'H-spiro[cyclopropane-1,2'-indolin]-3'-one in 3 ml of dry dimethyl sulfoxide was added. The mixture was stirred at room temperature for 20 minutes and, then, a solution of 0.487 g of 3-dimethylaminopropyl chloride in 3 ml of dry dimethyl sulfoxide was added. The mixture was reacted with stirring at room temperature for 30 minutes and, then, at 50° C for 75 minutes. Ice-water was added to the reaction mixture which was then extracted with chloroform. The extract was washed with water and dried over magnesium sulfate. The chloroform was distilled off and the residue was purified by column chromatography on alumina. By the above procedure was obtained 0.58 g of 1'-(3-dimethylaminopropyl)-1'H-spiro[cyclopropane-1,2'-indolin]-3'-one as an oil.
With sodium hydroxide; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; toluene;
EXAMPLE 25 N,N-Dimethyl-4-cyano-4-(1,1'-biphenyl-2-yl)butylamine To a stirred solution of 3.5 g. of sodium amide in 250 ml. of dry toluene was added dropwise over thirty minutes a solution of 16.7 g. of (1,1'-biphenyl-2-yl)acetonitrile in 200 ml. of toluene. The reaction mixture was heated to reflux and stirred for three hours following complete addition of the nitrile. The reaction mixture next was cooled to room temperature, and to the stirred solution was added dropwise over one hour a solution of 17.4 g. of N,N-dimethyl-3-chloropropylamine in 200 ml. of dry toluene. When the addition was complete, the reaction mixture was heated to reflux and stirred for sixteen hours. After cooling the reactionmixture to room temperature, it was added to 500 ml. of ice water. The product was extracted from the aqueous mixture into diethyl ether, and theethereal extracts were combined, washed with water and then extracted several times with 6 N hydrochloric acid. The acidic extracts were combined, washed with fresh diethyl ether and then made alkaline with 10% sodium hydroxide. The alkaline solution was extracted with fresh diethyl ether, and the ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure and distillation of the product provided 11.3 g. of N,N-dimethyl-4-cyano-4-(1,1'-biphenyl-2-yl)butylamine. B.P. 157-162 C. at 0.5 torr. Analysis calc. for C19 H22 N2: Theory: C, 81.97; H, 7.97; N, 10.06. Found: C, 81.74; H, 7.71; N, 9.89.
Into a 2L three-necked round bottom flask was added magnesium turnings (25gr) under nitrogen atmosphere and [50ML] of the above benzene solution added to the reaction flask. After adding a small crystal of iodine, reaction mass was heated to reflux temperature. After maintaining for 15 min, reaction got initiated and to the reaction mass remaining quantity of benzene solution was added slowly in 2-3hrs period. After the addition, reaction mass was maintained for lhr and a solution of phenyl diethyl orthoformate (171gr) in benzene [(200ML)] was added slowly over a period of lhr. After maintaining for 2hrs, reaction was cooled to [25C] and filtered on a celite pad. Solvent was removed from the reaction mass and the residue fractionally distilled to get 120gr (72.7%) [OF 4- (N,] N- dimethylamino) butyraldehyde diethyl acetal.
Stage #1: 3-(dimethylamino)propyl chloride hydrochloride; 3-(Dimethylamino)propyl chloride With magnesium; ethylene dibromide In tetrahydrofuran at 60℃; for 1h;
Stage #2: C16H14O2 In tetrahydrofuran at 20 - 50℃;
Stage #3: With water; ammonium chloride In tetrahydrofuran
B3
Compound 8a (CIS, relative stereochemistry; free base) Compound 8 (CIS, relative stereochemistry; oxalate salt)A small quantity of 3-chloro-λf,λf-dimethyl-l-propanamine (obtained as described in BIb), Mg (0.5 g, 0.02 mol) and 1 ,2-dibromoethane (small amount) in THF (2 ml) was stirred at 60 0C. A solution of 3-chloro-λf,λf-dimethyl-l-propanamine hydrochloride (0.02 mol) in THF (15ml) was added slowly. The mixture was stirred for 1 hour and was then cooled to 50 0C. A solution of intermediate 6 (1.1 g, 0.0070 mol) in THF (10 ml) was added slowly. The mixture was stirred at r.t. overnight. A saturated aqueous NH4Cl solution was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.5 g) was purified by column chromatography over Kromasil (eluent: DCM/MeOH/NH4OH 93/7/0.5; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 1.1 g of compound 8a (free base; 80 %). This fraction was dissolved in 2-propanone and converted into the ethanedioic acid salt (= oxalate salt). The precipitate was filtered off and dried. Yield: 0.6 g of compound 8.
A solution of dimsyl sodium in DMSO was prepared by adding 22gr of 50% sodium hydride in paraffin oil to DMSO (1000ML) at 20-25C and slowly heating to 60-65C under nitrogen. To this solution kept at a temperature in the range of 20-25C, was added a solution of 1-(4-FLUOROPHENYL)-5-CYANOPHTHALAN (LOOGR) in DMSO (200ML) slowly in 2- 3hrs. After maintaining for 15-20min, a solution of 3- (dimethylamino) propyl chloride (56gr) in toluene (120ML) was slowly added keeping the temperature between 25-30C. After the addition is over, reaction mixture was maintained at this temperature for 30min and decomposed by adding 50ML of methanol. The reaction mixture was poured into 3000ML of WATER AND EXTRACTED WITH 1000ML of toluene. Aqueous layer WAS AGAIN EXTRACTED WITH 500ML of toluene to obtain crude citalopram base. The combined organic layer containing crude citalopram base was extracted with 2 X 1000ml of 20% aqueous acetic acid. The combined aqueous acetic acid layer was treated with 20gr of active carbon, filtered and the filtrate neutralized with aqueous ammonia (25%) to get the pH of 8.5-9. 0. After the pH adjustment, 500ML of toluene was added and stirred for 15MIN. Toluene layer was separated and the aqueous layer extracted with 2 x 200ML of toluene. The combined toluene layer was treated with carbon (LOGR) and filtered. The toluene solution was treated with aqueous hydrobromic acid (60ML of CONC. HBr dissolved in 200ML of water) and kept under stirring for lhr. Aqueous layer was separated and kept under stirring for lOhrs. The crystalline citalopram hydrobromide thus formed was isolated by filtration and dried at 60C to get dry citalopram hydrobromide. This material was recrystallized from aqueous isopropyl alcohol (300ML isopropyl alcohol and 30ML water) to get pure citalopram hydrobromide (115GR). Purity by HPLC is 99.9%.
To a stirred suspension OF 22GR of sodium hydride (50-55% in paraffin oil) in 1000ml of dimethyl sulfoxide at 20-25C was added a solution of 1- (4-fluorophenyl)-5- cyanophthalan (LOOGR) in dimethyl sulfoxide (200ML) slowly in 2-3HRS. After maintaining for 15-20min, a solution OF 3- (DIMETHYLAMINO) propylchloride (56gr) in toluene (120ml) was slowly added keeping the temperature between 25-30C. After the addition is over, reaction mixture was maintained at this temperature for 30min and decomposed by adding 50ML of methanol. The reaction mixture was poured into 3000ML of water and extracted with 1000ML of toluene. Aqueous layer was again extracted with 500ML of toluene to obtain crude citalopram base. The combined toluene layer was washed with WATER (500ML) to get crude citalopram base. The above toluene layer containing crude CITALOPRAM WAS EXTRACTED WITH 2 X 1000ml of 20% aqueous acetic acid. The combined aqueous acetic acid layer was treated with carbon (lOgr) and neutralized with aqueous ammonia (25% w/v) to get the pH of 8-8. 5. After the pH adjustment, product was extracted into 3 X 500ML of toluene. The combined toluene layer WAS TREATED WITH CARBON (LOGR) and filtered. The filtrate was taken into A 3L three-necked RB flask and added dilute hydrobromic acid (90ML of CONC. hydrobromic acid dissolved in 250ML water) keeping the temperature 25-30C. After stirring for lhr toluene layer was separated from the reaction mixture and the aqueous layer kept under stirring for 10hr. The reaction mixture was cooled to 10C and maintained for 2hr before filtration. The wet cake of citalopram hydrobromide thus obtained was recrystallized from aqueous isopropanol (350ML isopropanol and 35ML water) to get pure citalopram hydrobromide (135GR). Purity by HPLC is 99. 9%.
A few drops of ethyl bromide are added to a mixture of 1.5 g magnesium and 15 ml anhydrous ether, and when <n="22"/>the reaction is started a solution of 9 ml 3-dimethylaminopropyl chloride in 15 ml ether are added. The reaction mixture is heated under reflux to boil gently for 2 hours. Thereupon, while stirring, a solution of 6.5 g l l-oxo-6,1 1 -dihydrodibenz-(b,e)thiepin in 25 ml benzene is drop wise introduced. The reaction mixture is stirred for 18 hours and boiled under reflux, and after cooling decomposed by the addition of 100 ml 10% ammonium chloride solution. There is further added 100 ml chloroform, the mixture is thoroughly shaken, the organic phase separated and the aqueous phase extracted with chloroform. The chloroform extracts are united, dried over potash and evaporated. The residue (9.0 g) crystallizes through on standing. Upon re-crystallization from benzene- petroleum ether mixture the l l-oxo-l l-(dimethylaminopropyl)-6,l l-dihydrodibenz- (b,e)thiepin thus obtained has a melting point of 130-1310C.[0067] 8.0 g of the latter crude carbinol, dissolved in 70 ml of 3 N H2SO4, are heated for 5 min. to boiling, treated with charcoal and filtered. The filtrate is made alkaline with a 20% NaOH solution, the base eliminated extraction with chloroform, the extract dried over potash and evaporated to dryness. The residue is then distilled under vacuum. There is obtained 4.3 g 1 l-(3-dimethylaminopropylidene)-6,l l-dihydrodibenz- (b,e)thiepin, having B.P.o,2 162-1640C. By dissolving in ethanol and neutralizing with ethereal HCl solution the crystalline hydrochloride is obtained, which on re-crystallization from an ethanol-ether mixture melts at 215-217C.
Example 14: Preparation of (Z)-ll-[3-(dimehylamino)propylidene]-6,ll- dihydrodibenz[b,e] oxepin-2-acetic acid hydrochlorideIodine (0.5 g) was added to a mixture of magnesium (43 g) and tetrahydrofuran (150 ml) under nitrogen condition. Heated the reaction mixture to reflux temperature. 3- dimethyl amino propyl chloride (5 ml) followed by 1,2-dibromo ethane (2 g) were added to the reaction mixture at same reflux temperature. A solution of 3 -dimethyl amino propyl chloride (225 g) in tetrahydrofuran (200 ml) was added drop wise to the reaction mixture at reflux temperature and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C, further cooled to 5-10°C. A solution of l l-oxo-6,11- dihydrobenz[b,e]oxepin-2-acetic acid (50 g) in tetrahydrofuran (150 ml) was added to the reaction mixture slowly at 5-10°C and stirred for 45 minutes at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred the reaction mixture for 5 hours at same temperature. After completion of the reaction, the reaction mixture was quenched with aqueous acetic acid. Aqueous hydrochloric acid [hydrochloric acid (300 ml) in water (100 ml)] was added to the reaction mixture at a temperature below 25 °C and stirred for 10 minutes at 25-30°C. Toluene was added to the reaction mixture and stirred for 10 minutes. Both the toluene and aqueous layers were separated and the aqueous layer was washed with toluene. Both the toluene layers were combined and washed with hydrochloric acid. Both the aqueous layer and hydrochloric acid layers were combined. Heated the aqueous layer to 90-95 °C and stirred for 24 hours at same temperature Cooled the reaction mixture to 25-30°C and dichloromethane was added to the reaction mixture. Stirred the reaction mixture for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both the dichloromethane layers were combined and then dried with sodium sulfate. Distilled off the solvent completely under reduced pressure and co- distilled with acetone. Acetone was added to the reaction mixture and stirred for 45 minutes at 25-30°C. Filtered the precipitated solid, washed with acetone and then dried to get the title compound.Yield: 30 grams; Purity by HPLC: 98.9percent (Z-isomer)
Stage #1: Sudan-IV With potassium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene; water Reflux;
Stage #2: 3-(Dimethylamino)propyl chloride In 5,5-dimethyl-1,3-cyclohexadiene; water at 70℃; for 48h; Reflux;
With sodium hydroxide; In chloroform; water; at 140℃; for 0.166667h;pH 10.0;Microwave irradiation;
General procedure: A mixture of substituted phenylethanamine (0.1 mmol), alkylchloride (0.12 mmol) in a waterechloroform (70:30, 0.5 mL) andNaOH in water to reach pH10 (2 M solution) was placed in a microwavetube (2 mL). The tube was subjected to MW irradiation at140 C for 10 min. After completion of the reaction (monitored by LC/MS), the product was extracted into ethyl acetate. Removal of the solvent under reduced pressure, followed by reversed-phaseHPLC chromatography using wateremethanol as eluent in agradient system for 60 min afforded final product and confirmed bysatisfactory 1H and 13C or 2D (g-COSY, HSQC, HMBC) NMR spectra.
With sodium hydroxide; In chloroform; water; at 140℃; for 0.166667h;pH 10.0;Microwave irradiation;
General procedure: A mixture of substituted phenylethanamine (0.1 mmol), alkylchloride (0.12 mmol) in a waterechloroform (70:30, 0.5 mL) andNaOH in water to reach pH10 (2 M solution) was placed in a microwavetube (2 mL). The tube was subjected to MW irradiation at140 C for 10 min. After completion of the reaction (monitored by LC/MS), the product was extracted into ethyl acetate. Removal of the solvent under reduced pressure, followed by reversed-phaseHPLC chromatography using wateremethanol as eluent in agradient system for 60 min afforded final product and confirmed bysatisfactory 1H and 13C or 2D (g-COSY, HSQC, HMBC) NMR spectra.
With sodium hydroxide In chloroform; water at 140℃; for 0.166667h; Microwave irradiation;
Typical procedure for N-alkylation
General procedure: A mixture of substituted phenylethanamine (0.1 mmol), alkylchloride (0.12 mmol) in a waterechloroform (70:30, 0.5 mL) andNaOH in water to reach pH10 (2 M solution) was placed in a microwavetube (2 mL). The tube was subjected to MW irradiation at140 C for 10 min. After completion of the reaction (monitored by LC/MS), the product was extracted into ethyl acetate. Removal of the solvent under reduced pressure, followed by reversed-phaseHPLC chromatography using wateremethanol as eluent in agradient system for 60 min afforded final product and confirmed bysatisfactory 1H and 13C or 2D (g-COSY, HSQC, HMBC) NMR spectra.
3-(5-bromo-2,3-dimethyl-1H-indol-1-yl)-N,N-dimethylpropan-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
Preparation of 3-(5bromo*2,3-dimethyM W-indoM -y)-N, W~dimethylpropan-1 - amine To a mixture of NaH (1.4 g, 35.6 mmoi) in DMF (30 mL) was added 5-bromo-2,3- dimethylindole (2.0 g, 8.9 mmol) at 0 C After 20 minutes, 3-chloro-/V,W- dimethylpropan-1 -amine (1.98 g, 12.5 mmoi) was added slowiy. The solution was stirred at 50 overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, dried over Na2SG4, filtered, and concentrated to give of the desired intermediate (2.5 g, 91 %). LCMS: m/z 309.1 , 31 1.1 [M+H]+
N<SUP>1</SUP>,N<SUP>1</SUP>-dimethyl-4-(5-methylpyridin-2-yl)butane-1,4-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Reference Example 23-7 Magnesium (48 mg) and 1,2-dibromoethane (28 mg) were added to tetrahydrofuran (1 mL), followed by refluxing for 10 minutes. The resultant product was cooled to room temperature, and a solution of 3-chloro-N,N-dimethyl propane-1-amine (180 mg) in tetrahydrofuran (1 mL) was added thereto, followed by refluxing for 1 hour. The reaction mixture was added to a solution of 5-methyl picolinonitrile (118 mg) in tetrahydrofuran (1 mL) under ice-cooling, followed by stirring for 10 minutes. The reaction mixture (1 mL) was added to a solution of sodium borohydride (38 mg) in methanol (1 mL) under ice-cooling, followed by stirring for 1 hour. 1 mol/L hydrochloric acid was added thereto, and sodium hydrogen carbonate was added thereto, followed by stirring. The solvent was distilled off under reduced pressure, and the obtained residues were purified by silica gel column chromatography (chloroform:methanol=19:1), whereby N1,N1-dimethyl-4-(5-methylpyridin-2-yl)butane-1,4-diamine (19 mg) was obtained. MS(ESI m/z): 208 (M+H)
N-(3-dimethylaminopropyl)-N-tert-butoxycarbonyl-4-iodoaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20 - 80℃; for 48h;
Under room temperature, will N-tert-butoxycarbonyl-4-iodo aniline (2.0 g, 6 . 27 mmol), N, N-dimethyl-3- chlorine propylamine (0.9 g, 7 . 40 mmol), cesium carbonate (3.0 g, 9 . 21 millimoles) and potassium iodide (0.1 g, 0 . 63 mmol) in DMF (20 ml) in. The obtained mixture is heated to 80 C and reaction 48 hours. Then the obtained mixture into ice water (100 ml) in. The resulting mixture is extracted with ethyl acetate. The resulting organic phase is concentrated to obtain crude product under reduced pressure. The resulting crude product is purified with silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 1.0 g yellow solid, that is, the target compound (yield: 40%).
10,10-dimethyl-anthracene-9-one with 3-dimethylamino-1-chloropropane in the presence of an initiator Grignard reaction, Get melitracen intermediate procedure is as follows: The 340g magnesium ribbon and 17.5L anhydrous ether was added 20L glass reactor, stirring warming up to 30 ~ 35 , added 1.75kg3- dimethyl-amino-1-chloropropane, plus complete insulation stirring, 1g of iodine and 2mL1,2 - dibromoethane as an initiator, was stirred at reflux for 9h is, the magnesium bar disappears completely, the temperature was decreased to 10 ~ 20 reaction system was slowly added 1.5kg 10,10- Dimethylanthracen-9-one, and then heated up to 30 ~ 35 deg.] C, the reaction was refluxed for 1 hour; TLC monitored the reaction was complete, the temperature was decreased to 10 ~ 20 the reaction system, together with 5.5L of water, ether layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give intermediate melitracen 2.03 kg, 97.2% yield, 98.5% purity. TLC monitoring: After the sample was quenched with water, the organic layer gussets; eluent petroleum ether: ethyl acetate = 2: 1 (by volume); 10,10-dimethyl anthracene-9-one Rf 0.6 , Rf melitracen intermediate 0.1.
3-(N,N-dimethylamino)propylmagnesium chloride was prepared from magnesium turnings(0.04 mol) activated with iodine at 75 C for 1 h. THF (1 mL), toluene (4 mL) and some drops of methyl iodide was added at 65 C and stirred for 30 min. 3-chloro-N,N-dimethylpropylamine(0.03 mol) in toluene (15 mL) was added slowly. After 30 min 1a (0.02mol) in 10 mL toluene was added. The reaction mixture was stirred vigorously at 65 C for 2h. Concentrated hydrochloric acid (20 mL) was added slowly (30 min) and the reaction mixture stirred for 1 h. The organic phase was separated and the aqueous phase extracted with~ S16 ~diethyl ether (200 mL). The aqueous phase was made alkaline with aqueous ammonia and extracted with diethyl ether. The organic phase was dried over anhydrous Na2SO4, filtered and the diethyl ether was removed under reduced pressure to give 0.19 g (0.7 mmol, 70%) of 3 as a colourless oil. The 1H NMR spectrum of the reaction crude product showed it to consist of a mixture the expected geometric E- (80%) and Z- (20%) isomers in different proportions. The majority (E)-diastereoisomer was easily separated by crystallisation of the corresponding maleate. 1.H NMR (CDCl3, 300 MHz) 2.60-2.74 (m, 4H), 2.70 (s, 6H), 4.80 (brs, 1H), 5.50 (brs, 1H),14 5.91 (t, J = 7.0 Hz, 1H), 6.75-7.40 (m, 8H); 13C NMR (CDCl3, 75 MHz) 24.9, 42.4, 60.2, 73.7, 119.2, 121.2, 127.5, 127.9, 128.2, 128.3, 128.5, 128.8, 129.4, 130.3, 134.4, 141.1, 141.3, 155.2. MS m/z: 279 (40), 219 (22), 282 (25), 189 (30), 178 (40), 165 (45), 115 (25), 59 (50), 58 (100). IR (KBr) nu [cm-1] = 3050, 3025, 1698, 1582, 1483, 1431. HRMS (EI) m/z = 279.1623 calcd for C19H21NO, found 279.1628.
With potassium carbonate In N,N-dimethyl-formamide at 55℃;
1.1.21 (21) Synthesis of Compound B21
N,N-dimethyl-3-chloro-propylamine (251.3 mg, 1.59 mmol) was added to a solution of the compound B1 (107.2 mg, 0.53 mmol) and potassium carbonate (219.7 mg, 1.59 mmol) in dimethylformamide Then, transferred to a thermostatic magnetic stirrer, stirred at 55 ° C for 4-6 h, and the reaction was detected by TLC. After the reaction was completed, 5 mL of water was added to quench, 10 mL of 1 M hydrochloric acid was added dropwise to the mixture, extracted with chloroform (3×20 mL), and the organic phase was extracted with saturated brine (2×10 mL). The organic phase was concentrated under reduced pressure on silica gel column chromatography (PE: EA = 1:2). Collecting separated targets,The lyophilizer was lyophilized to give a pale yellow solid (i.e., compound B21) 77.3 mg. Yield: 50.6%.
2-chloro-10-[3-(dimethylamino)propyl]-phenothiazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.24%
To a mixture of <strong>[92-39-7]2-chlorophenothiazine</strong> compound of formula II (100 g) and toluene (450 ml), aqueous potassium hydroxide (96.02 g of potassium hydroxide in 100 ml of water) was added at 30 C. and then heated to 98 C. A toluene solution of 3-dimethylaminopropylchloride of formula III (135.24 g of 3-dimethylaminopropylchloride in 200 ml of toluene) was added to the heated reaction mixture at 98 C. and maintained for 6 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was cooled to 40 C. and quenched with water (1000 ml). The organic layer was separated, from the reaction mass and washed with water (1000 ml) then concentrated to obtain a residue. The residue was dissolved in toluene (400 ml) and the contents were extracted with an aqueous solution of 0.5N hydrochloric acid (1000 ml). Toluene (100 ml) was added to the obtained aqueous hydrochloride solution containing Chlorpromazine, followed by the addition 30% sodium hydroxide solution (90 ml). The organic layer was then separated and washed with water (300 ml). Activated charcoal (Pencarb-A, 10 gm) was added to the washed organic layer and stirred for 30 minutes at 30 C. The contents were then filtered and the filtrate was concentrated under reduced pressure to obtain a residue. Toluene (700 ml) was added to the residue at 65 C. and then cooled to 30 C. Methanolic hydrochloride solution (71.15 g (29.4% w/v)) was slowly added to the cooled mixture, stirred for 15 minutes at 30 C. and the mass was concentrated under vacuum at 70 C. Ethyl acetate (600 ml) was added to the concentrated residue at 60 C. and stirred for 1 hour at 75 C. The contents were cooled to 30 C. and stirred for 90 minutes at the same temperature. The resulting solid was filtered and washed with ethyl acetate (200 ml). The wet solid was dissolved in a mixture of toluene (600 ml) and methanol (100 ml) and concentrated under vacuum. Ethyl acetate (500 ml) was added to the concentrate at 60 C. and stirred for one hour at 75 C. The contents were cooled to 30 C. and stirred for 2 hours at the same temperature. The resulted solid was filtered, washed with ethyl acetate (100 ml) and dried to obtain the desired Chlorpromazine hydrochloride. Yield: 82.24%; Dimeric impurity: 0.05% w/w.
ethyl 1-[3-(dimethylamino)propyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: ethyl 7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃;
Stage #2: 3-(Dimethylamino)propyl chloride In N,N-dimethyl-formamide at 60℃; for 16h;
General procedure for the synthesis of l,4,5,6-tetrahydro-7//-indolones (7a n = 1) e 4,5,6,7-tetrahydrocyclohepta[6]pyrrole-8(l//)-ones (7b n = 2) 1-substituted.
General procedure: To a solution of the suitable ketones 6a, b (15 mmol) in anhydrous THF or DMF (20 mL), NaH (0.64 g, 16 mmol) was added at 0°C and the reaction mixture was stirred at room temperature for 1 h. Then the suitable alkyl or aralkyl halide was added at (16 mmol). The reaction mixture was stirred at room temperature or heated at reflux up to completeness (TLC). Then the reaction mixture was poured onto crushed ice and the precipitate was filtered off and dried, in absence the solution was extracted with DCM (3 x 30 mL). The organic layer was dried over Na2S04 and the solvent was removed under reduced pressure. The crude product was purified by chromatography (DCM) giving the desired ketones.
1-(4-(3-(dimethylamino)propoxy)-2-methoxyphenyl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90.4%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4.0h;
General procedure: The solution of 2-methoxyacetophenone (1 equiv) and inorganicbase (3 equiv) in DMF were stirred at 100 C, and then added halogenatedflexible fragments (1.5 equiv). The subsequent reaction mixturewas stirred over 4 h. The mixture was extracted three times with EtOAc,dried over MgSO4 and the solvent was removed in vacuo. The crudeproduct was purified by the flash chromatography.
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h;
General procedure: The solution of 2-methoxyacetophenone (1 equiv) and inorganicbase (3 equiv) in DMF were stirred at 100 C, and then added halogenatedflexible fragments (1.5 equiv). The subsequent reaction mixturewas stirred over 4 h. The mixture was extracted three times with EtOAc,dried over MgSO4 and the solvent was removed in vacuo. The crudeproduct was purified by the flash chromatography.
N1-(3-(dimethoxy(methyl)silyl)propyl)-N3,N3-dimethylpropan-1,3-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With pyridine In lithium hydroxide monohydrate for 10h; Inert atmosphere; Schlenk technique; Reflux;
2.1; 5.1 (1) Preparation of N1-(3-(dimethoxy(methyl)silyl)propyl)-N3,N3-dimethylpropan-1,3-diamine
To a 1 L, round-bottom flask connected with a schlenk line, 1.22 g (10 mmol) of 3-chloro-N,N-dimethylpropan-1-amine and 3.27 g (20 mmol) of 3-(dimethoxy(methyl)silyl)propan-1-amine were added, and water was completely removed under a reduced pressure. Then, under an argon atmosphere, 500 ml of pyridine was added thereto and reacted for 10 hours while refluxing to prepare an intermediate, N1-(3-(dimethoxy(methyl)silyl)propyl)-N3,N3-dimethylpropan-1,3-diamine (yield 80%). After purification, 1H nuclear magnetic resonance spectroscopic spectrum was observed, and the synthesis was confirmed. 1H NMR (CDCl3, 500 MHz): δ 3.55 (s, 9H), 2.53-2.55 (m, 4H), 2.36-2.40 (m, 2H), 2.15 (s, 6H), 1.53-1.60 (m, 2H), 1.50 (s, 1H), 1.33-1.39 (m, 2H), 0.59-0.62 (m, 2H), 0.15 (s, 3H).
80%
With pyridine for 10h; Inert atmosphere; Schlenk technique; Reflux;
2.1; 5.1 (1) Preparation of N1-(3-(dimethoxy(methyl)silyl)propyl)-N3,N3-dimethylpropan-1,3-diamine
To a 1 L, round-bottom flask connected with a schlenk line, 1.22 g (10 mmol) of 3-chloro-N,N-dimethylpropan-1-amine and 3.27 g (20 mmol) of 3-(dimethoxy(methyl)silyl)propan-1-amine were added, and water was completely removed under a reduced pressure. Then, under an argon atmosphere, 500 ml of pyridine was added thereto and reacted for 10 hours while refluxing to prepare an intermediate, N1-(3-(dimethoxy(methyl)silyl)propyl)-N3,N3-dimethylpropan-1,3-diamine (yield 80%). After purification, 1H nuclear magnetic resonance spectroscopic spectrum was observed, and the synthesis was confirmed. 1H NMR (CDCl3, 500 MHz): δ 3.55 (s, 9H), 2.53-2.55 (m, 4H), 2.36-2.40 (m, 2H), 2.15 (s, 6H), 1.53-1.60 (m, 2H), 1.50 (s, 1H), 1.33-1.39 (m, 2H), 0.59-0.62 (m, 2H), 0.15 (s, 3H).
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