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CAS No. : | 27710-82-3 | MDL No. : | MFCD00077740 |
Formula : | C23H28Br2NP | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NEQVFHFOWYYPBS-UHFFFAOYSA-M |
M.W : | 509.26 | Pubchem ID : | 23651404 |
Synonyms : |
|
Num. heavy atoms : | 27 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 132.1 |
TPSA : | 16.83 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -4.46 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 6.96 |
Log Po/w (WLOGP) : | 1.89 |
Log Po/w (MLOGP) : | 5.83 |
Log Po/w (SILICOS-IT) : | 5.01 |
Consensus Log Po/w : | 3.94 |
Lipinski : | 2.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.17 |
Log S (ESOL) : | -7.41 |
Solubility : | 0.0000197 mg/ml ; 0.0000000386 mol/l |
Class : | Poorly soluble |
Log S (Ali) : | -7.13 |
Solubility : | 0.000038 mg/ml ; 0.0000000746 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -8.83 |
Solubility : | 0.000000752 mg/ml ; 0.0000000015 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.88 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | at 20 - 100℃; Sealed tube | Preparation of (3-(Dimethylamino)propyl)triphenylphosphonium bromide hydrobromide salt. To a suspension of 3-bromopropyltriphenylphosphonium bromide (1.0 g, 2.1 mmol) in ethanol (5 mL) was added a solution of 40percent dimethylamine in water (3 mL) at room temperature. The mixture was stirred and heated at 100 °C for 30 min in a sealed microwave tube. After the reaction mixture was concentrated under reduced pressure, the solid residue was recrystallized in acetonitrile to afford (3- (dimethylamino)propyl)triphenylphosphonium bromide hydrobromide salt (0.90 g, 82percent) as a white solid, and was used in the following step. ESI MS m/z 348.3(Ph3PCH2CH2CH2NMe2)+. |
74.2% | Stage #1: at 20℃; for 1.5 h; Heating / reflux Stage #2: With Acetyl bromide In ethanol at 0 - 25℃; |
Example 4; Synthesis of the Wittig Reagent 3-dimethylaminopropyltriphenylphosphonium Bromide *HBr (Olo-IM4) To a stirred suspension of 3-bromopropyltriphenylphosphonium bromide (Olo-IM3) (420 g, 0.90 mol) in absolute ethanol (664 g) a solution of dimethylamine in absolute ethanol (368 g, 2.69 mol, assay: 33percent) was added slowly within 30 minutes at room temperature. After complete addition the suspension was stirred 1 hour at reflux whereupon a solution was obtained. The solution was cooled to a temperature of 0-10° C. and acetyl bromide (202.7 g, 1.65 mol) was added dropwise until the pH was 1, and the resulting suspension was allowed to warm to 20-25° C. After the white suspension was filtered the wet product washed with absolute ethanol (237 g) and then dried under vacuum (15 h, 70° C.) to give 3-dimethylaminopropyltriphenylphosphonium bromide*HBr (Olo-IM4) as a white solid (yield: 471.2 g, 0.77 mol, 85.1percent; HPLC assay: 83.2percent, HPLC purity: 98.72percent). The crude material (460 g, 0.75 mol; assay: 83.2percent) was further purified by suspending it in absolute ethanol (395 g) and stirring at reflux temperature. After addition of further absolute ethanol (435 g) all material was dissolved and the solution was allowed to cool to room temperature, with seeding at 69° C. to initiate crystallization. After 4 hours stirring at room temperature the product was filtered off, washed with ethanol (140 g) and then dried under vacuum (15 h, 70° C.) to give 3-dimethylaminopropyltriphenylphosphonium bromide*HBr (Olo-IM4) as a crystalline white solid (yield: 333.7 g, 0.66 mol, 87.2percent; HPLC assay >99.9percent, HPLC purity: 99.85percent, overall yield: 74.2percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Then, 100.0 g of (3-bromopropyl)-triphenylphosphonium bromide hydrobromide is suspended in 500 ml of ethanol and 300 ml of 50% aqueous dimethylamine solution is added thereto. After heating the mixture at reflux for 10 minutes, the mixture is allowed to stand for cooling. The solvent is distilled away under reduced pressure and the resultant crude product is recrystallized from ethanol to obtain 64.0 g of the desired product having the physicochemical properties as identified in Table 8. | ||
EXAMPLE 5 3-Chloro-5-(3-diethylaminopropyl)-7H-dibenzo(a,c)cyclohepten-5-one(7).oxalate One hundred fourty-five grams (0.6M) diphenic acid and 93.5 g (0.3M) Ag2 SO4 are dissolved while stirring in a mixture of 1.2 liter of concentrated sulphuric acid and 120 ml water. Fourty-two grams gaseous chlorine are then introduced (over a period of approximately 15 hours). It is placed on sufficient ice, the organic product separated off and extracted with one liter of boiling ethanol. After the concentration of the ethanol phase to 400 ml it is diluted with 800 ml hot water. There are obtained 122 g 4-chlorodiphenyl-1,1'-dicarbonic acid, mp 260 C. (benzene). Seventy-one grams (0.27M) 4-chlorodiphenyl-1,1'-dicarbonic acid are heated with 900 ml triethylamine to 90 C. and mixed within three hours with 57 g (0.35M) malonic acid diethylester. After 2.5 hours at 100 C., it is cooled and the product transferred to ice water. The surface layer is decanted off and the residue recrystallized from 2-propanol. Sixty-six grams (melting point 80 C.) o-diethylmalonylide derivative of the 4-chlorodiphenyl-1,1'-dicarbonic acid anhydride. Fourty-one grams (0.11M) 4-chlorodiphenyl-1,1'-dicarbonic acid anhydride are heated for 24 hours under reflux in 230 ml formic acid with 10 ml water added. The precipitated oil crystallizes after transfer to ice water. Thirty grams 1'-acetyl-4-chlorodiphenyl-1-carbonic acid with a melting point of 132 C. (benzene/cycohexane 1:1). In 150 ml anhydrous ethanol, 2.6 g sodium (0.11M) are dissolved. Twenty-six grams (0.1M) of the above compound are introduced and cyclized by heating for six hours under reflux. By transfer to 0.7 l ice water and mixing with 2N hydrochloric acid up to pH 4, there are obtained 23.6 g 3-chlorodibenzo(a,c)cyclohepten-5,7-dione with a melting point of 210-215 C. This is sufficiently pure to be processed further. Twenty-three grams (0.09M) 3-chlorodibenzo(a,c)cyclohepten-5,7-dione are dissolved in 400 ml ethanol and converted using 15.5 g (0.11M) potassium carbonate and 15 ml diethyl sulphate in an analogous manner to Example 4, Variant C, into the corresponding enolether, mp 114 C. (cyclohexane). 7.7 g (0.015M) (3-dimethylaminopropyl)-triphenylphosphoniumbromide HBr are prepared in an analogous manner to Example 4, Variant B, under nitrogen and converted into the ylide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; In tetrahydrofuran; methanol; diethyl ether; water; | EXAMPLE 9 Methyl 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetate (Compound 18) In this example, 48 g of <strong>[27710-82-3](3-dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide</strong> is suspended in 200 ml of tetrahydrofuran under a nitrogen atmosphere and 80 ml of 1.6N-n-butyl lithium hexane solution is added thereto under ice-cooling. The mixture is stirred under ice-cooling for one hour. A solution obtained by dissolving 5.0 g of 11-oxo-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid in 120 ml of tetrahydrofuran is dropwise added under ice-cooling. After stirring the mixture at room temperature for two hours, the solvent is distilled away under reduced pressure. Then, 200 ml of water is added to the residue and the mixture is washed with 200 ml of diethyl ether. The pH of the mixture is adjusted to 1 with aqueous 4N-hydrochloric acid solution and the mixture is washed with diethyl ether. Then, aqueous 10N-sodium hydrooxide solution is added thereto to adjust the pH of the mixture to 7 and the solvent is distilled away under reduced pressure. The resultant residue is dissolved in 400 ml of methanol and 5 g of p-toluene sulfonic acid is added thereto. After heating the mixture at reflux for two hours, the solvent is distilled away under reduced pressure. The residue is extracted with 300 ml of ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in order and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure and the resultant residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate:triethylamine=10:10:1) to obtain 4.0 g of the desired product as a colorless oily matter. Cis form NMR (CDClc, delta, ppm): 2.06-2.67(m, 4H), 2.16(s, 6H), 3.46(s, 2H), 3.58(s, 3H), 5.08(bs, 2H), 5.69 (t, 1H, J=7Hz), 6.53-7.30(m, 7H) Trans form NMR (CDCl3, delta, ppm): 2.06-2.67(m, 4H), 2.16(s, 6H), 3.46(s, 2H), 3.58(s, 3H), 5.08(bs, 2H), 6.06 (t, 1H, J=7Hz), 6.53-7.30(m, 7H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | EXAMPLE 5 Methyl 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound 1) In this Example, 45 g of (3-dimethylaminopropyl)triphenylphosphonium bromide hydrobromide is suspended in 200 ml of tetrahydrofuran under a nitrogen atmosphere and 82 ml of 1.6N-n-butyl lithium hexane solution is added thereto under ice-cooling. The mixture is stirred under ice-cooling for one hour. To the mixture is dropwise added under ice-cooling a solution obtained by dissolving 10 g of methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate in 200 ml of tetrahydrofuran. After stirring the mixture at room temperature for 2 hours, the mixture is extracted with 800 ml of ethyl acetate. After washing the extract with saturated aqueous sodium chloride solution and drying the extract over anhydrous sodium sulfate, the solvent is distilled away under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate:triethylamine=10:10:1) to obtain 2.0 g of trans form and 5.6 g of cis form of the desired product. Cis form: NMR (CDCl3, delta, ppm): 2.23(s, 6H), 2.17-2.81(m, 4H), 5.28(bs, 2H), 5.61(t, 1H), 6.80-8.10(m, 7H) Trans form: NMR (CDCl3, delta, ppm): 2.15(s, 6H), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; hexane; ethyl acetate; | (d) (E)/(Z)-3-(3-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (24.5 g, 48.0 mmole), 96 mmole of n-butyl lithium in hexane, and 3-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (10 g, 34.6 mmole) were reacted in 580 mL dry tetrahydrofuran by the procedure of Example I, step b. This provided an (E)/(Z)-(1:3) isomeric mixture of bromoamines (6.0 g). Recrystallization of half of the mixtures (3.0 g) from ethyl acetate gave 1.45 g of Z-isomer of ?93% stereoisomeric purity (assayed by 'H-NMR) as a white solid. pmr (CDCl3) delta: 7.23-7.31 (m, 4H, aromatic H), 6.92-7.05 (m, 3H, aromatic H), 5.91 (t, 1H, CH=, 7% E-isomer), 5.60 (t, 1H, CH=, 93% Z-isomer) 5.15 (very br s, 2H, ArCH2 O), 3.12 (m, 2H, CH2), 2.99 (m, 2H, NCH2), 2.78 (s, 6H, NMe 2, 93% Z-isomer), 2.71 (s, 6H, NMe2, 3% E-isomer). Analysis: Calcd. for C19 H20 BrNO.1.0 HCl: C, 57.81; H, 5.36; N, 3.55. Found: C, 57.62; H, 5.33; N, 3.54. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; diethyl ether; hexane; | (b) (E)/(Z)-3-(8-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (24.5 g, 48 mmole), 96 mmole of n-butyl lithium in hexane, and 8-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (10 g, 34.6 mmole) were reacted in 580 mL dry tetrahydrofuran by the procedure of Example I, step b. This provided an E/Z (1:3.5) isomeric mixture of bromoamines. Recrystallization of the mixture from diethyl ether gave 0.17 g of Z-isomer and 1.8 g of an E/Z (1:4) (assayed by HPLC on C18) isomeric mixture which was used in the next step without further purification. pmr (Z-isomer) (CDCl3) delta: 7.38-7.44 (m, 2H, H7 and H9); 7.13-7.18 (m, 3H, aromaatic H); 6.84-6.93 (m, 2H, H2 and H4); 5.70 (t, 1H, CH=); 5.15 (br s, 2H, ArCH2 O); 2.55 (q, 2H, CH2); 2.43 (t, 2H, NCH2); 2.22 (s, 6H, NMe2). Analysis: Calcd. for C19 H20 BrNO: C, 63.70; H, 5.63; N, 3.91. Found (Z-isomer): C, 63.85; H, 5.65; N, 3.92. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; triethylamine; In tetrahydrofuran; methanol; hexane; water; | (a) (E)/(Z)-3-(3-Bromo-10,11-dihydrodibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethylpropylamine Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (21 g., 40.8 mmole) was suspended in 400 ml. of dry tetrahydrofuran and n-butyl lithium in hexane (82 mmole) was added dropwise at 0 C. under a nitrogen atmosphere during a period of 0.5 hour. After an additional 10 minutes, 9.0 g. (31.3 mmole) of 3-bromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one, prepared as described in C. A. Stone, J. M. Stavorski, H. C. Wenger and C. T. Ludden, J. Med. Chem. (1965) 8, 829, in 100 ml. dry tetrahydrofuran was added slowly to the deep red solution and the reaction was then refluxed for 18 hours. The solution was poured into ice-water and the mixture was extracted with diethyl ether. Evaporation of the ether under reduced pressure gave an oily residue which was suspended in water and the mixture was then acidified with 6N hydrochloric acid. The acidic aqueous solution was washed with hexanes, and then concentrated under reduced pressure. The residue was chromatographed on a silica gel Prep 500 column with methanol to provide an E/Z (1:1) stereoisomeric mixture of bromoamines. Recrystallization of the isomeric mixture from methanol gave 0.5 g. of the pure E-isomer as its hydrochloric salt, m.p. 239-240 C. The residue from the mother liquor was chromatographed on a reverse phase C18 semi-preparative column with 70% methanol in water (containing 0.1% triethylamine). The appropriate fractions were pooled and recrystallized from methanol/water to yield 1.13 g. of the Z-isomer (with the presence of 5% E-isomer) as the free base, m.p. 73-75 C. Also, the fractions containing the E-isomer were pooled, evaporated and recrystallized from methanol/ethyl acetate to give 0.70 g. of the E-isomer as the free base. From other fractions 3.5 g. of E/Z (1:1) isomeric mixture was collected which could be used either for further separation or for carboxylation in the next step. pmr (E-isomer, free base) (CDCl3) delta: 7.43 (d, J=1.9 Hz, 1H, H4), 7.12-7.26 (m, 5H, aromatic), 6.89 (d, J=8.3 Hz, 1H, H1), 5.88 (t, J=7.3 Hz, 1H, CH=), 3.30 (m, 2H, CH2 Ar), 2.84 (m, 2H, CH2 Ar), 2.28-2.38 (m, 4H, NCH2 CH2), 2.16 (s, 6H, NMe2). pmr (?95% stereoisomeric pure Z-isomer, free base) (CDCl3) delta: 7.00-7.33 (m, 7H, aromatic), 5.86 (t, J=7.3 Hz, 1H, CH=), 3.30 (m, 2H, CH2 Ar), 2.90 (m, 1H, CHAr), 2.70 (m, 1H, CHAr), 2.26-2.37 (m, 4H, NCH2 CH2), 2.18 (s, 6H, NMe2). Analysis: Calcd. for C20 H22 BrN.HCl: C, 61.16; H, 5.90; N, 3.57. Found: (E-isomer): C, 61.24; H, 5.89; N, 3.51. Calcd. for C20 H22 BrN: C, 67.42; H, 6.22; N, 3.93. Found: (?95% stereoisomeric pure Z-isomer): C, 67.72; H, 6.42; N, 3.86. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; methanol; hexane; water; | (b) (E)/(Z)-3-(2-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (39.4 g., 0.08 mole) was suspended in 450 mL of dry tetrahydrofuran and 100 mL of a solution of n-butyl lithium in hexane (1.6M) was added dropwise at 0 C. under a nitrogen atmosphere during a 30 minute period. After an additional 10 minutes, 2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (16.8 g., 0.06 mole) in 150 mL dry tetrahydrofuran was added slowly to the deep red solution and the reaction mixture was then refluxed for 18 hours. The reaction mixture was poured onto ice-water, and the mixture was extracted with diethyl ether. The ether layer was concentrated under reduced pressure and the residue was suspended in water and then acidified with 6N hydrochloric acid. The acidic aqueous layer was washed with hexanes and then was concentrated to give a gummy residue. The residue was crystallized from ethyl acetate/methanol to provide 5.3 g. of pure Z-isomer as its hydrochloride salt, m.p. 201-204 C. The mother liquor was chromatographed on a silica gel column (Waters Associates-Prep. 500) with ethyl acetate/methanol (8:2) to give an additional 2.55 g. of pure Z-isomer as the hydrochloride salt and 2.79 g. of E-isomer as its hydrochloride salt, m.p. 230-233 C. pmr (Z-isomer) (DMSO/d6) delta: 7.25-7.44 (m, 6H, aromatic), 6.81 (degenerate d, J=9.1 Hz, 1H, H4), 5.72 (t, J=7.1 Hz, 1H, CH=), 5.22 (s, 2H, CH2 O), 3.18 (m, 2H, NCH2), 2.70 (m, 2H, CH2), 2.66 (s, 6H, NMe2). pmr (E-isomer) (DMSO/d6) delta: 7.23-7.50 (m, 6H, aromatic), 6.70 (d, J=8.6 Hz, 1H, H4), 6.10 (t, J=7.2 Hz, 1H, CH=) 5.15 (br s, 2H, CH2 O), 3.07 (m, 2H, NCH2), 2.65 (s, 6H, NMe2), 2.50 (m overlap with DMSO, 2H, CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; methanol; hexane; ethyl acetate; | (b) (E)/(Z)-3-(9-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine. Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (31 g., 60.9 mmole), 122 mmole of n-butyl lithium in hexane, and 9-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (12.7 g., 43.8 mmole) were reacted in 750 mL dry tetrahydrofuran by the procedure of Example I, Step b. This provided an E/Z (1:6) isomeric mixture of bromoamines. Recrystallization of the mixture from ethyl acetate/methanol gave 1.2 g. of pure Z-isomer as its hydrochloride salt, melting range 91-100 C. and 2.16 g. of an E/Z (1:4) isomeric mixture which was used in the next step without further purification. pmr (Z-isomer) (CDCl3) delta: 6.94-7.46 (m, 7H, aromatic), 5.64 (t, J=8.0 Hz, 1H, CH=), 5.15 (br s, 2H, CH2 O), 3.07 (m, 4H, NCH2 CH2), 2.75 (s, 6H, NMe2). Analysis: Calcd. for C19 H20 BrNO.HCl: C, 57.80; H, 5.36; N, 3.54. Found (Z-isomer): C, 57.56; H, 5.41; N, 3.45. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In ethanol; water; at 20 - 100℃;Sealed tube; | Preparation of (3-(Dimethylamino)propyl)triphenylphosphonium bromide hydrobromide salt. To a suspension of 3-bromopropyltriphenylphosphonium bromide (1.0 g, 2.1 mmol) in ethanol (5 mL) was added a solution of 40% dimethylamine in water (3 mL) at room temperature. The mixture was stirred and heated at 100 C for 30 min in a sealed microwave tube. After the reaction mixture was concentrated under reduced pressure, the solid residue was recrystallized in acetonitrile to afford (3- (dimethylamino)propyl)triphenylphosphonium bromide hydrobromide salt (0.90 g, 82%) as a white solid, and was used in the following step. ESI MS m/z 348.3(Ph3PCH2CH2CH2NMe2)+. |
74.2% | Example 4; Synthesis of the Wittig Reagent 3-dimethylaminopropyltriphenylphosphonium Bromide *HBr (Olo-IM4) To a stirred suspension of 3-bromopropyltriphenylphosphonium bromide (Olo-IM3) (420 g, 0.90 mol) in absolute ethanol (664 g) a solution of dimethylamine in absolute ethanol (368 g, 2.69 mol, assay: 33%) was added slowly within 30 minutes at room temperature. After complete addition the suspension was stirred 1 hour at reflux whereupon a solution was obtained. The solution was cooled to a temperature of 0-10 C. and acetyl bromide (202.7 g, 1.65 mol) was added dropwise until the pH was 1, and the resulting suspension was allowed to warm to 20-25 C. After the white suspension was filtered the wet product washed with absolute ethanol (237 g) and then dried under vacuum (15 h, 70 C.) to give 3-dimethylaminopropyltriphenylphosphonium bromide*HBr (Olo-IM4) as a white solid (yield: 471.2 g, 0.77 mol, 85.1%; HPLC assay: 83.2%, HPLC purity: 98.72%). The crude material (460 g, 0.75 mol; assay: 83.2%) was further purified by suspending it in absolute ethanol (395 g) and stirring at reflux temperature. After addition of further absolute ethanol (435 g) all material was dissolved and the solution was allowed to cool to room temperature, with seeding at 69 C. to initiate crystallization. After 4 hours stirring at room temperature the product was filtered off, washed with ethanol (140 g) and then dried under vacuum (15 h, 70 C.) to give 3-dimethylaminopropyltriphenylphosphonium bromide*HBr (Olo-IM4) as a crystalline white solid (yield: 333.7 g, 0.66 mol, 87.2%; HPLC assay >99.9%, HPLC purity: 99.85%, overall yield: 74.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.4% | With sodium carbonate; In isopropyl alcohol; at 50℃; for 6h;Product distribution / selectivity; | (a) from 3-dimethylaminopropyltriphenylphosphonium Bromide*HBr (Olo-IM4) A flask containing 3-dimethylaminopropyltriphenylphosphonium bromide*HBr (128.1 g, 0.25 mol), Na2CO3 (31.8 g, 0.30 mol) and 2-propanol (590 g) was stirred at 50 C. for 6 hours. The mixture was then cooled to room temperature, filtered through celite (15 g) and the cake was washed with 2-propanol (2*186 g). Under reduced pressure (45 C., 100 mbar) most of the solvent was removed to obtain a supersaturated product solution (170 g). Under stirring this solution was seeded with Olo-IM4 (free base) crystals to initiate the crystallization. To the white suspension was added MTBE (240 g) and cyclohexane (253 g), and the mixture was stirred overnight for complete crystallization. The product was filtered off, washed with MTBE (2*74 g) and dried under vacuum for 7 hours at 50 C. to give 3-dimethylaminopropyltriphenylphosphonium bromide (Olo-IM4, free base) as a white, crystalline solid (yield: 101.7 g, 0.24 mol, 94.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
< 0.5%; > 99% | Charged 238 gms [3 - (Dimethylamino) propylamine] triphenyl phosphonium bromide hydrobromide in 1400 ml tetrahydrofuran under nitrogen atmosphere. Slowly charged 130.5 gms sodium hydride and raised the temperature to reflux to maintain for 3.0 hrs. The <n="13"/>suspension cooled and chilled to 00C and charged solution of 100 gms benzyl ester of 1 1 - oxo - 6, 1 1 - Dihydrodibenz [b, e] oxepin - 2 - acetic acid in 400 ml tetrahydrofuran and stirred the reaction mass at 25 - 300C for 3.0 hours. Cooled the reaction mass to -10 to 50C and quenched in 1700 ml water. The organic layer separated and washed with water. Combined aqueous layer washed with diisopropyl ether and acidified with dilute hydrochloric acid to pH 2. The acidified aqueous layer extracted with dichloromethane 2500 ml. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was taken in the mixture of 500 ml dichloromethane and diethyl ether solvent. The product was filtered and dried. The HPLC purity of the product Olopatadine hydrochloride obtained; Cis / Z Isomer = > 99.0%; Trans / E Isomer = < 0.5%. |
Yield | Reaction Conditions | Operation in experiment |
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Example 3; Preparation of Olopatadine Hydrochloride Form A Through Wittig Reaction Using Sodium Hydride3-[bromo(triphenyl)phosphoranyl]-N,N-dimethyl propan-1-amine hydrobromide (phosphonium salt) (205 g; 0.40 mol) was suspended in 545.5 g (615 mL) of tetrahydrofuran under a nitrogen atmosphere. After stirring for 40 minutes, 64.48 g (1.61 mol) of sodium hydride 60percent in mineral oil was added over five minutes. After addition of the sodium hydride, the reaction mixture was heated to reflux (approximately 65° C.) with continuous stirring and maintained at this temperature for 1 hour. An intense orange suspension was obtained. The reactor contents were then cooled to room temperature and 36 g (0.13 mol) of (11-oxo-6,1'-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid (Compound II, R1H) was added with stirring. The mixture was then stirred for 15 hours at room temperature.Thereafter, a mixture of 153.5 g (153.5 mL) of deionized water and 136.1 g (153.5 mL) of tetrahydrofuran was slowly added with continuous stirring. Next, 615 g (615 mL) of deionized water was added, and stirring was continued for 20 minutes. The resulting two phase mixture was then acidified with hydrochloric acid (37percent) with stirring to adjust the pH to approximately 3 (actual reading 2.27). The aqueous and organic phases were then separated, and the aqueous phase was salified with 180 g of sodium chloride and extracted with 607.5 g (750 mL) of 1-butanol. The phases were then separated, and the organic phase was washed three times with water.The solvent of the organic phase was then removed by distillation under reduced pressure to yield 119.61 g of an orange oil. To this oil was added 157 g (200 mL) of 2-propanol, which produced a yellow suspension. The mixture was then stirred and maintained at this temperature for 1 hour. Thereafter, the suspension was filtered, and the collected wet solid was dried under vacuum at 60° C. until constant weight to yield 37.23 g (0.10 mol, 74.21percent) of olopatadine hydrochloride. (HPLC Purity: 54.28percent, cis: 6.44percent, trans; Cis/Trans Ratio: 8.43).A 36 g portion of the olopatadine hydrochloride obtained was then suspended in 226.08 g (288 mL) of 2-propanol. The mixture was heated to reflux (approximately 82° C.) with continuous stirring and maintained at this temperature for a minimum 20 minutes. The reactor was then cooled to room temperature, and the suspension was filtered to yield a slight yellow solid that was dried under vacuum at 60° C. (Partial Yield 37.62percent; HPLC Purity: 97.23percent cis, 0.76percent trans; Cis/Trans Ratio: 128. 50).A 17 g portion of the olopatadine hydrochloride obtained in the previous step was then treated with 120.1 g (153 mL) of 2-propanol. The white to white off suspension obtained was stirred and heated to reflux for 55 minutes. Then, it was allowed to cool to room temperature. The suspension was then filtered, and the solid was washed with 2-propanol and dried under vacuum at 60° C. (Partial Yield 35.67percent; HPLC Purity: 99.56percent cis, 0.18percent trans; Cis/Trans Ratio: 538.54).A 15 g portion of the olopatadine hydrochloride obtained in the previous step was then treated with 58.8 g (75 mL) of 2-propanol. The resulting white suspension was stirred and heated to reflux for 30 minutes. Thereafter, the reactor content was cooled to room temperature. The white suspension was then filtered, and the solid was washed with 2-propanol and dried under vacuum at 60° C. to yield 14.42 g of olopatadine hydrochloride. (Global Yield 34.29percent; HPLC Purity: 99.73percent cis; 0.10percent trans; Cis/Trans Ratio: 760.46).A 10 g portion of the olopatadine hydrochloride obtained in the previous step was treated with a mixture of 23.5 g (30 mL) of 2-propanol and 15 g of deionized water. The resulting white suspension was stirred and heated to reflux for 15 minutes. Thereafter, the reactor content was cooled to room temperature. The white suspension was then filtered, and the solid was washed with 2-propanol and dried under vacuum at 60° C. to yield 7.49 g of olopatadine hydrochloride. (Global Yield 25.68percent; HPLC Purity: 99.98percent cis; 0.02percent trans; Cis/Trans Ratio: 4999.35).A 6.7 g portion of the olopatadine hydrochloride obtained in the previous step was treated with a mixture of 15.8 g (20 mL) of 2-propanol and 10 g of deionized water. The resulting white suspension was then stirred and heated to reflux for 10 minutes. Thereafter, the reactor content was cooled to room temperature. The white suspension was then filtered, and the solid was washed with 2-propanol and dried under vacuum at 60° C. to yield 3.44 g of olopatadine hydrochloride Form A. (Global Yield 13.18percent; HPLC Purity: 99.91percent cis, 0.01percent trans; Cis/Trans Ratio: 11708.08).Analytical data: HPLC purity: 99.91percent; Assay: 101.62percent; XRD (2psi): 6.33°, 10.92°, 12.66°, 15.44°, 17.60°, 18.30°, 19.04°, 19.34°; 20.61°, 24.08°, 25.45°, 28.34° (substantially identical to FIG. 1); ... | ||
Example-1: Preparation of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-lan-Butyl lithium (100 ml) was added to the solution of 3-dimethylaminopropyl)- triphenyl phosphoniumbromide HBr compound of formula-3 (37.94 grams) in tetrahydrofuran (200 ml) at 0-5 °C under nitrogen atmosphere. The reaction mixture was stirred for an hour at the same temperature. A mixture of l l-oxo-6, 11-dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml) was added to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 65-70°C and then hated to reflux. The reaction mixture was stirred for 12 hours at 65-70°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and then the aqueous layer was neutralizing with aqueous sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 15 minutes and then dichloromethane was added to it. Both organic and aqueous layers were separated. The organic layer was washed with brine solution and the organic layer was distilled off under reduced pressure. Acetone (100 ml) was added to the residue at 25-30°C and stirred the reaction mixture for 45 minutes at 25-30°C. The solid was filtered, washed with acetone and dried to get the title compound. Yield: 5 grams,M.P: 238-241°C (Decomposition)Purity by HPLC: 97.7percent (Z-isomer), 1.15percent (E-isomer) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 2The process according to Example 1 is repeated, but proceeding to isolate the olopatadine butyl ester intermediate in step b) , as described below.Load 29.6 g of 60% sodium hydride in mineral oil (4.0 eq.), 164.85 g of (3-dimethylaminopropyl) triphenylphosphine bromide-HBr (1.75 eq.) and 360 ml of THF (6 V) into a flask. Stir at T=0/5C for 30 minutes and then heat the mixture slowly to T=60C and stir at said temperature for 3 hours. Chill to a temperature of 0-50C and add a mixture consisting of 60 g of isoxepac butyl ester in 210 ml of THF over molecular sieves (3.5 V). Heat the reaction mixture to T=27-30C and stir at said temperature for at least 15 hours.Having verified that the reaction has completed, chill to T=0-5C, add 80 ml of purified water and then neutralise by adding 32% HCl until reaching pH 7.Distil under vacuum until all the THF (at least 550 ml) is collected. Add 400 ml of toluene and 200 ml of purified water. Stir and then separate the phases.Add 300 ml of heptane to the toluene phase and stir for at least 1 hour. Filter the phosphines obtained and concentrate the organic phase containing the olopatadine butyl ester isomers. Collect the oil thus obtained with 150 ml of n-butanol, chill to T=-10/-15C and stir for 1 hour until the product has crystallised. Filter and wash with 20 ml of n-butanol and chill to T=-15C. The olopatadine butyl ester thus obtained has the following NMR spectrum:(DMSO d6) : 0.90 (t, 3H), 1.32 (sest., 2H), 1.60 (quint., 2H), 2.23 (s, 6H), 2.45 (t, 2H), 2.6 (q., 2H), 3.51 (s, 2H), 4.08 (t, 2H), 5.40 (sb, 2H), 5.7 (t, IH), 6.80 (d, IH), 7.06 (dd, 2H), 7.30 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
b) Preparation of Olopatadine Hydrobromide (Crude)Load 29.6 g of 60% sodium hydride in mineral oil (4.0 eq.), 164.85 g of (3-dimethylaminopropyl)triphenylphosphine bromide-HBr (1.75 eq.) and 360 ml of THF (6 V) into a flask. Stir at T=0/5 C. for 30 minutes, then heat the mixture slowly to T=60 C. and stir at said temperature for 3 hours. Chill to a temperature of 0-5 C. and add a mixture consisting of 60 g of isoxepac butyl ester in 210 ml of THF over molecular sieves (3.5 V). Heat the reaction mixture to T=27-30 C. and stir at said temperature for at least 15 hours.Having verified that the reaction has completed, chill to T=0-5 C., add 80 ml of purified water and then neutralise by adding 32% HCl until reaching pH 7.Distil under vacuum until all the THF (at least 550 ml) is collected. Add 400 ml of toluene and 200 ml of purified water. Stir and then separate the phases.Add 300 ml of heptane to the toluene phase and stir for at least 1 hour. Filter the phosphines obtained and concentrate the organic phase containing the olopatadine butyl ester isomers.Collect the oil thus obtained with 150 ml of n-butanol, chill to T=-10/-15 C. and stir for 1 hour until the product has crystallised. Filter and wash with 20 ml of n-butanol and chill to T=-15 C.The olopatadine butyl ester thus obtained has the following NMR spectrum:(DMSO d6): 0.90 (t, 3H), 1.32 (sest., 2H), 1.60 (quint., 2H), 2.23 (s, 6H), 2.45 (t, 2H), 2.6 (q., 2H), 3.51 (s, 2H), 4.08 (t, 2H), 5.40 (sb, 2H), 5.7 (t, 1H), 6.80 (d, 1H), 7.06 (dd, 2H), 7.30 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
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58% | Preparation of Dimethyl-{3-[2-triisopropylsiianyloxy-10,ll-dihydro- dibenzo[ ,(/]cyclohepten-(5)-ylidene]-propyl}-amine (16). 2-Triisopropylsilanyloxy-10,l 1- dihydro-dibenzo[a,if]cyclohepten-5-one (15) (2.00 g, 5.26 mmol) was dissolved in 40 mL dry tetrahydrofuran. In a separate flask, (3-dimethylamino-propyl)-triphenyl-phosphonium bromide hydrobromide salt (2,72 g, 6.32 mmol) was suspended in 40 mL dry tetrahydrofuran and cooled to 5 C in an ice bath. 2.5 M n-Butyllithium in hexanes (2.94 mL, 7.36 mmol) was added slowly and then the reaction was allowed to stir for 20 minutes. The 2- triisopropylsilanyloxy-10,1 l-dihydro-dibenzo[a,d]cyclohepten-5-one solution was then added slowly and the reaction heated to 60 C. When the reaction was complete, it was cooled in an ice bath and water was added slowly to quench the reaction. Tetrahydrofuran was then evaporated off and the residue separated between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with saturated sodium bicarbonate (3 X 100 mL), brine (50 mL), dried over magnesium sulfate, filtered, and evaporated. The residue was re- dissolved in dichloromethane and run through a silica gel plug to remove remaining triphenylphosphine. The resulting solution was evaporated to yield 1.4 g (58%) of dimethyl - {3-[2-triisopropylsilanyloxy-l 0,1 1 -dihydro-dibenzo[a,d]cyclohepten-(5)-ylidene]-propyl}- amine (16) as a yellow oil. ESI MS m/z 451.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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At room temperature and under an argon atmosphere, a solution of 6,1 1-dihydro-li- oxo-dibenz[b,e]oxepin-2-acetic acid (5.0 g, 18.64 mmol, I eq) in anhydrous THF (20 ml) was prepared. N,O-bis(trimethyl-silyl)acetamide (4.56 ml, 18.64 mmol, 1 eq) was added and the solution stirred for 1 hour. At room temperature and under an argon atmosphere, a suspension of 3-dimethylaminopropyltriphenylphosphoniumbromide hydrobromide (23.7 g, 46.6 mmol, 2.5 eq) in anhydrous THF (80 ml) was prepared. To this suspension the previously prepared solution of trimethylsilyl ester was then added, followed by the sodium hydride (60% in mineral oil, 6.08 g, 152.1 mmol, 7.85 eq). The resulting mixture was heated at 60C for 3 hours and the consumption of the starting material was followed by LC-MS. The reaction mixturewas cooled to 0C and carefully quenched with 40 ml of THF/H20 1/1 (v/v). After dilution with water (100 ml), the mixture was washed with toluene (100 ml) and two times with 2-methylTllF (100 ml). The aqueous phase was acidified to pH 1 with 37% hydrochloric acid (8 ml) and then washed with toluene (100 ml). Sodium acetate was added up to pH 5 and the aqueous phase was extracted two times with a mixture of 2-methylTHF/2-propanol 2:1 (v/v) (300 ml). The organic layer wasevaporated under reduced pressure. The crude material (8.7 g) was taken up with acetone (90 ml) and acidified with 37% hydrochloric acid, obtaining the precipitation of the cis isomer of olopatadine hydrochloride. The white solid was filtered and washed with acetone. Yield = 55%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.63% | To the 50L dry reaction kettle without adding water treatment of tetrahydrofuran 24L, dimethyl sulfoxide 900ml, water bath cold1.64 kg (41.0 mol) of sodium hydride (60percent) was added with stirring, and triphenylphosphonium bromide (3-dimethylaminopropyl) hydrobromide(16.0 mol) were added, and the mixture was stirred at room temperature for 1.5 to 2 hours. The temperature was raised to 45 ° C and reacted for 1.5 hours. Cool to 20 & lt; 0 & gt; C and add Isoxepac Acid (2.15 g, 8.0 mol) at room temperature for 10 to 12 hours. The reaction was complete by TLC. The mixture was cooled to 10 to 15 ° C, and water and tetrahydrofuran solution (water: 0.8 L, THF: 2.0 L) was added dropwise thereto over about 1 hour.Stirred for 30 minutes, filtered, and the filter cake rinsed with 1 L of THF. The filtrate was combined, concentrated hydrochloric acid was added with stirring to pH ~ 3, and stirring was continued for 30 minutesClock, filter. The filter cake was washed with 2 L of tetrahydrofuran and allowed to dry. The solid was transferred to a reaction vessel, 12 L of water was added and the pH was adjusted with 10 N sodium hydroxide(About 65 ° C), stirred for 5 hours at 5 to 10 ° C, and filtered. The solids were then washed 3 L x 2 in deionized waterTimes, drained. 80 degrees for 2 hours in the blast drying dry olorotatin 1.5kg. Purity 98.72percent (HPLC), Isomer: 0.48percent(HPLC), Yield: 55.63percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.1 g | [3-(Dimethylamino)propyl]triphenylphosphonium bromide hydrobromide (230 g) and anhydrous tetrahydrofuran (1200 ml) were added to a 3 L glass reactor (mechanical stirring), and cooled to below -10 C. Add butyl lithium solution (2.5N, 250ml) dropwise, the reaction exotherm is obvious, keep the temperature below -10 C, stir for 1-2 hours, add 2-allyloxy-2-(11-oxo-6,11-dihydro-dibenzo[b,e]oxepin-2-yl)acetic acid (32.4g) in anhydrous tetrahydrofuran (200ml), the reaction exotherm is obvious, keep the temperature below -5 C, keep warm Stir for 1-2 hours, slowly warm to room temperature, continue stirring for 4-5 hours, slowly add deionized water (200 ml), and destroy excess butyl lithium. The reaction solution was concentrated under reduced pressure toDry, add water (1200ml) to dissolve, add methyl tert-butyl ether extraction (500ml × 2), the aqueous phase is adjusted to pH less than 2 with hydrochloric acid (1N), extracted with methyl tert-butyl ether (500ml × 2). The aqueous phase was adjusted to a pH of about 6, and the aqueous phase was concentrated to dryness under reduced pressure. The mixture was recrystallized three times with a mixture of methyl isobutyl ketone and acetone (400 ml, volume ratio 1:1) to obtain 2-allyloxy-2-((Z)-11-[3-(dimethylamino)propenyl]-6,11-dihydro-dibenzo[b,e]oxepin-2-yl)acetic acid (21.1 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.8% | [3-(Dimethylamino)propyl]triphenylphosphonium bromide hydrobromide (230 g) and anhydrous tetrahydrofuran (1200 ml) were added to a 3 L glass reactor (mechanical stirring), and cooled to below -10 C. Add butyl lithium solution (2.5N, 250ml), the reaction exotherm is obvious, keep the temperature below -10 C, stir for 1-2 hours, add dropwise a solution of 2-benzyloxy-2-(11-oxo-6,11-dihydro-dibenzo[b,e]oxepin-2-yl)acetic acid (37.4 g) in anhydrous tetrahydrofuran (200 ml). The reaction exotherm was obvious, the temperature was kept below -5 C, the mixture was stirred for 1-2 hours, slowly raised to room temperature, stirring was continued for 4-5 hours, and deionized water (200 ml) was slowly added dropwise to destroy excess butyl lithium. The reaction solution was concentrated to dryness under reduced pressure, water (1200 ml of) dissolve, extracted with methyl tert-butyl ether (500ml × 2) was added, the aqueous phase with hydrochloric acid (1N) was adjusted to pH less than 2, was added methyl tert-butyl Ether extraction (500 ml x 2). The aqueous phase was adjusted to a pH of about 6, and the aqueous phase was concentrated to dryness under reduced pressure. Recrystallization 3 times by adding acetone water (400 ml, volume ratio 8:1) to obtain (Z)-11-[3-(dimethylamino)propenyl]-6,11-dihydrodibenzo[b,e ]gheptin-2-benzyloxy-2-acetic acid (21.1 g). The yield is about 72.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.09% | Stage #1: anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1h; Stage #2: isoxepac In tetrahydrofuran; hexane for 12h; Reflux; Stage #3: olopatadine With hydrogenchloride In tetrahydrofuran; hexane; isopropyl alcohol at 20℃; for 1h; | 4-5 In a 250mL three-necked flask , Add 14.4g (28mmol) of 3-dimethylaminopropyl triphenylphosphonium hydrobromide, 80mL of THF, and slowly add 1.92mol/L of n-butyllithium to 40mL of n-hexane solution under ice-salt bath cooling, add After completion, the reaction was stirred for 1 hour below 0°C, 4g (14mmol) of compound 6 was added in 20mL THF solution, heated to reflux for 12 hours, cooled, evaporated to remove THF, the residue was dissolved with 20mL of water, extracted with ether (15mL×2), and the aqueous solution Adjust the pH to 2 with concentrated hydrochloric acid, extract with ethyl acetate (15mL×2), and then neutralize the aqueous solution with 4mol/L sodium hydroxide solution to a pH of 7, and concentrate to remove water to obtain 3.1g of the crude product of compound 7. 65%. The crude product was recrystallized twice with isopropanol to obtain (Z)-70.97g, with a yield of 31.2%; Dissolve 0.45 g of olopatadine prepared above in 2 mL of isopropanol, pass hydrogen chloride gas, stir at room temperature for 1 h, concentrate, and recrystallize the residue with acetone. 0.25 g of white powdery solid was obtained, the yield was 50%, and the total yield was 9.09%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5 % | Stage #1: [3-(dimethylamino)propyl]triphenylphosphonium bromide hydrobromide With potassium hydride In tetrahydrofuran at 20 - 66℃; Stage #2: 10,10-dimethyl-9,10-dihydroanthracen-9-one In tetrahydrofuran Reflux; | 1.5 (5) Synthesis of melitracen (V) Add [3-(dimethylamino)propyl]triphenylphosphine bromide hydrobromide (50.9g, 0.1mol) into the three-necked flask, then add 200g tetrahydrofuran, start stirring, and control the temperature at 20~22°C. Add KH solution (29.4 g, 0.22 mol) with a mass concentration of 30%, raise the temperature to 60~66°C after the addition, and react for 1 h.Then add 10,10-dimethylanthrone (11.0g, 0.05mol), reflux and stir for 2 hours, then cool down to 0~15°C, slowly add 20g of methanol, then add 100g of 50% tetrahydrofuran aqueous solution, and finally 300 g of water was added to quench the reaction.Adjust the pH of the reaction solution to 6±0.2 with concentrated hydrochloric acid, then distill it to dryness under reduced pressure, evaporate to dryness to obtain a solid, dissolve the solid in 100g of acetone and filter with suction to obtain a filtrate, start stirring the filtrate, pass in hydrogen chloride gas until the pH is 1~2, and cool down To 10~15°C, filter with suction to obtain light yellow solid.Add 40g of chloroform and 8.0g of 25% sodium hydroxide solution to the light yellow solid, raise the temperature to 55~60°C and stir for 10 minutes, heat suction filtration, cool the filtrate to 10~15°C, and suction again to obtain a white solid, the white solid It is the wet product of melitracen.The wet product of melitracen was dried with hot air circulation at 50~60 to obtain a dry product of 12.9g, with a molar yield of 88.5% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.3 % | Stage #1: [3-(dimethylamino)propyl]triphenylphosphonium bromide hydrobromide With sodium hydride In toluene at 10 - 110℃; Inert atmosphere; Stage #2: 10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-one In toluene at 105 - 110℃; Inert atmosphere; | 1.2 (2) Synthesis of amitriptyline in route A2: Under nitrogen protection, add (3-dimethylaminopropyl)triphenylphosphine bromide hydrobromide (6.1g, 12mmol) into the three-necked flask, then add toluene (100g, 1085mmol), start stirring,Control the temperature between 10-15°C, add 60% sodium hydride (12g, 30mmol), keep the reaction at 10-15°C for 1h after the addition, and then slowly raise the temperature to 105-110°C. Dibenzosuberone (2.1 g, 10 mmol) was added, the temperature was raised to 105-110° C. and stirred for 3 hours after dropping, and the temperature was lowered. Control the temperature between 30~35°C), slowly drop into methanol (0.5g, 16mmol), and then drop into water (3.6g, 200mmol). The aqueous layer of the reaction solution was adjusted to pH 8-10 with 30% hydrochloric acid solution, and then the whole was distilled under reduced pressure to dryness to obtain a brown oily substance. The oil was subjected to column chromatography with dichloromethane:methanol=10:1 to obtain a colorless oily liquid, which was amitriptyline (2.2 g, 7.9 mmol), and the molar yield was 79.3%. |
Tags: 27710-82-3 synthesis path| 27710-82-3 SDS| 27710-82-3 COA| 27710-82-3 purity| 27710-82-3 application| 27710-82-3 NMR| 27710-82-3 COA| 27710-82-3 structure
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P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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