* 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.
With sodium hypophosphite In 2-methoxy-ethanol; water at 70 - 80℃; for 2 - 2.5 h;
Under nitrogen, 430 g (1.34 mol) N-(4-Hydroxyphenyl)-N'-(4'-nitrophenyl)-piperazine are suspended in 2.8 liters methoxyethanol at 20° - 25° C. After the addition of 52 g palladium ((5percent on charcoal, 50percent water wet) (Degussa Typ E1049)) the suspension is degassed (3 times) and heated to 70° - 75° C. A solution of 497 g sodium hypophosphite monohydrate in 1.12 liters water is slowly added over 2 -2.5 hours at 70° - 75° C. (After addition of about 10 ml the evolution of hydrogenation starts and the temperature has to be kept at 75° - 80° C; towards the end of the addition external heating is needed). After complete addition, the reaction mixture is stirred at 70° - 75° C and the reaction is followed by TLC (silicagel, n-hexane/ethylacetate 1/2). After complete conversion (30 - 45 minutes, color turns from brown-yellow to grey) the suspension is cooled to 25° - 30° C and diluted with 2.4 liters water. The pH is adjusted to <=2 by the addition of about 400 ml concentrated HCl (about 10 minutes) at 25° to 30° C and stirred at this temperature for about 15 minutes. The catalyst is filtered off and washed with 600 ml water. The combined filtrates are warmed to 35° to 40° C and the pH is adjusted to 7.1 +/- 1 at 35° to 40° C by the addition of about 760 ml concentrated sodium hydroxide (slightly exothermic). The resulting suspension is cooled to 20° - 25° C and stirred at that temperature for 30 minutes. The product is filtered off under nitrogen (about 40 minutes) and washed twice with 1.6 liters water, followed by 400 ml water/methanol (1:1) and 800 ml methanol. The product is dried under vacuum at 50° C (slight stream of nitrogen) to constant weight. [] Yield317 g (88percent)Assay (HPLC)99.7percent pure by area
Reference：
[1] Patent: EP1230231, 2005, B1, . Location in patent: Page/Page column 4
[2] Tetrahedron Letters, 1999, vol. 40, # 31, p. 5655 - 5659
[3] Patent: CN108003118, 2018, A, . Location in patent: Paragraph 0030
Will be 4.00kg1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine (VII) and 35.57 kg of tetrahydrofuran100L glass reactor, open the stirring, cooling to 0 ~ 10 .Maintain the temperature below 25 drop 2.56kgPhenyl chloroformate (VIII),0.5 to 1 hour drop finished, temperature control 20 ~ 25 to continue the reaction of 0.5 to 1.0 hours. TLC monitoring reaction, the reaction finishedAfter the completion of the cooling to 0 ~ 10 ,Add saturated aqueous sodium bicarbonate solution (sodium bicarbonate 2.00kg dissolved in purified water 38kg), then add purified water 20kg,Stirring for 10 ~ 20min. Centrifuge the filter to the basic solvent-free effluent, and then rinse with 8kg of purified water, centrifugal rejection to the basic solvent-free effluent.The whole batch of wet goods in the vacuum -0.06MPa ~ -0.1MPa, the control temperature of 40-50 conditions,Dry under reduced pressure 12 to 16 hours. 5.47 kg of a gray solid,Phenyl (4- (4- (4-hydroxy) -1-piperazinyl) phenyl) carbamate(V);HPLC purity: 98.5percent yield: 94.6percent
215 g
at 0 - 30℃; for 3 h;
Example-8 Preparation of Phenyl-4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl carbamate (Formula-19) Phenyl chloroformate (139.5 g) was added to a pre-cooled solution of 4-(4-(4-aminophenyl)piperazin-1-yl)phenol compound of formula-18 (200 g) in dimethyl formamide (1400 ml) at 0-10° C. Temperature of the reaction mixture was raised to 25-30° C. and then stirred for 3 hours at 25-30° C. After completion of the reaction, the reaction mixture was quenched with water. Filtered the precipitated solid and washed with water.
Reference：
[1] Patent: CN106749207, 2017, A, . Location in patent: Paragraph 0028; 0029; 0030; 0031
[2] Patent: US2014/343285, 2014, A1, . Location in patent: Paragraph 0325
14
[ 1885-14-9 ]
[ 74853-08-0 ]
[ 170985-85-0 ]
[ 184177-83-1 ]
Reference：
[1] Patent: CN105461644, 2016, A, . Location in patent: Paragraph 0072-0078
15
[ 74853-08-0 ]
[ 184177-83-1 ]
Reference：
[1] Patent: US2014/343285, 2014, A1,
[2] Patent: CN106632284, 2017, A,
[3] Patent: CN106749207, 2017, A,
With sodium hypophosphite;5%-palladium/activated carbon; In 2-methoxy-ethanol; water; at 70 - 80℃; for 2 - 2.5h;
Under nitrogen, 430 g (1.34 mol) <strong>[112559-81-6]N-(4-Hydroxyphenyl)-N'-(4'-nitrophenyl)-piperazine</strong> are suspended in 2.8 liters methoxyethanol at 20 - 25 C. After the addition of 52 g palladium ((5% on charcoal, 50% water wet) (Degussa Typ E1049)) the suspension is degassed (3 times) and heated to 70 - 75 C. A solution of 497 g sodium hypophosphite monohydrate in 1.12 liters water is slowly added over 2 -2.5 hours at 70 - 75 C. (After addition of about 10 ml the evolution of hydrogenation starts and the temperature has to be kept at 75 - 80 C; towards the end of the addition external heating is needed). After complete addition, the reaction mixture is stirred at 70 - 75 C and the reaction is followed by TLC (silicagel, n-hexane/ethylacetate 1/2). After complete conversion (30 - 45 minutes, color turns from brown-yellow to grey) the suspension is cooled to 25 - 30 C and diluted with 2.4 liters water. The pH is adjusted to ?2 by the addition of about 400 ml concentrated HCl (about 10 minutes) at 25 to 30 C and stirred at this temperature for about 15 minutes. The catalyst is filtered off and washed with 600 ml water. The combined filtrates are warmed to 35 to 40 C and the pH is adjusted to 7.1 +/- 1 at 35 to 40 C by the addition of about 760 ml concentrated sodium hydroxide (slightly exothermic). The resulting suspension is cooled to 20 - 25 C and stirred at that temperature for 30 minutes. The product is filtered off under nitrogen (about 40 minutes) and washed twice with 1.6 liters water, followed by 400 ml water/methanol (1:1) and 800 ml methanol. The product is dried under vacuum at 50 C (slight stream of nitrogen) to constant weight. [] Yield317 g (88%)Assay (HPLC)99.7% pure by area
With hydrogen; In methanol; ethyl acetate; at 35 - 40℃; under 2250.23 Torr;Large scale;
Proportioning parts: 400 parts by mass of methanol, 250 parts by mass of ethyl acetate, 25 parts by mass of 1-(4-hydroxyphenyl)-4-(4-nitrophenyl)-piperazine, active nickel (AMC-1000) ) 5 parts by mass;In a 1000 L autoclave, under a nitrogen atmosphere, 400.0 kg of methanol and 250.0 kg of ethyl acetate were added. After stirring, 1-(4-hydroxyphenyl)-4-(4-nitrophenyl)- After piperazine 25.0 kg, and then nitrogen substitution three times, 5.0 kg of activated nickel (AMC-1000) was added, the reaction kettle was sealed, replaced with nitrogen three times, and after three hydrogen substitutions,Hydrogenation pressure to 0.3MPa slowly warmed to 35 C -40 C, after 10-15h reaction, using TLC point plate analysis, the volume ratio of the developing agent is ethyl acetate: methanol = 4:1, the amount is 5ml, in the UV lamp The reaction was observed at a wavelength of 254 nm until no starting material, 1-(4-hydroxyphenyl)-4-(4-nitrophenyl)-piperazine. Nitrogen replacement three times, transfer to the desolvation kettle, decompose the mixed solvent under reduced pressure, add 250.0 kg of water, stir and cool to 0-5 C, adjust pH=2 with 10% hydrochloric acid aqueous solution, filter, and use 10% ammonia water for the filtrate. Adjust pH=7, filter, and obtain 50.0 kg of wet crude. The mother liquor is collected and collected separately.
N-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.3 parts (42.5%)
In pyridine; methanol; chloroform; toluene;
Example 20 To a stirred solution of 10.8 parts of <strong>[74853-08-0]4-[4-(4-aminophenyl)-1-piperazinyl]phenol</strong> in 3.2 parts of pyridine and 90 parts of N , N -dimethylformamide was added dropwise a solution of 3.1 parts of acetyl chloride in 27 parts of methylbenzene at 20C (exothermic reaction). Upon completion, stirring was continued for 1 hour at 20C. The reaction mixture was poured into water while stirring. The product was filtered off, washed with water and dissolved in a mixture of trichloromethane and methanol (3:1 by volume). The whole was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was crystallized from a mixture of ethanol and methylbenzene (1:1 by volume) + (activated charcoal). The product was filtered off and dried, yielding 5.3 parts (42.5%) of N -[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]acetamide; mp. 256.2C (compound 1.03).
N-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.3 parts (42.5%)
In pyridine; methanol; chloroform; N,N-dimethyl-formamide; toluene;
Example 20 To a stirred solution of 10.8 parts of <strong>[74853-08-0]4-[4-(4-aminophenyl)-1-piperazinyl]phenol</strong> in 3.2 parts of pyridine and 90 parts of N,N-dimethylformamide was added dropwise a solution of 3.1 parts of acetyl chloride in 27 parts of methylbenzene at 20 C. (exothermic reaction). Upon completion, stirring was continued for 1 hour at 20 C. The reaction mixture was poured into water while stirring. The product was filtered off, washed with water and dissolved in a mixture of trichloromethane and methanol (3:1 by volume). The whole was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was crystallized from a mixture of ethanol and methylbenzene (1:1 by volume)+(activated charcoal). The produce was filtered off and dried yielding 5.3 parts (42.5%) of N-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]acetamide; mp. 256.2 C. (compound
cis-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-2-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate[ No CAS ]
[ 67-66-3 ]
[ 74853-08-0 ]
cis-4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-1-piperazinyl]benzenamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.3 parts (22%)
In methanol; dimethyl sulfoxide;
Example XIX To a stirred solution of 3 parts of <strong>[74853-08-0]4-[4-(4-aminophenyl)-1-piperazinyl]phenol</strong> in 50 parts of dimethylsulfoxide are added 0.5 parts of a sodium hydride dispersion 50%. The whole is stirred at 50 C. till foaming has ceased. Then there are added 4.1 parts of cis-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-2-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate and stirring is continued for 2 hours at 70 C. The reaction mixture is cooled and poured onto water. The product is extracted with dichloromethane. The extract is washed with a diluted sodium hydroxide solution, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 1.3 parts (22%) of cis-4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-1-piperazinyl]benzenamine; mp. 174.4 C.
A solution of 297 mg of BHT (butylated hydroxytoluene; M=220.35 g/mol; 1.35 mmol; 500 ppm) and 727 g of the compound of formula (A) [0417] (MW: 269.35 g/mol; 2.698 mol; 1.0 equiv.; obtainable, for example, according to example 1 of EP 1 230 231 B1 (on page 4)) in 4.7 l of DMSO was prepared at a mass temperature of 30±2 C. To this was added a solution (30±2 C.) of 161.9 g of NaOH (MW: 40.0 g/mol, 4.047 mol, 1.5 equiv.) in 161.9 g of oxygen-free H2O upon keeping the mass temperature at ?32 C. The mixture was stirred for 10 min at 30±2 C. Then, a solution (30±2 C.) of 1335 g of the compound of formula (B) contained in the product as obtained according to Reference Example 1.1 (Reference Example 1.1.j) above (12.968 mol=1.1 equiv., MW=449.48 g/mol) in 6.6 l of DMSO was added at a mass temperature of ?32 C. within 10 min. The pH of the reaction mixture was checked after a reaction time of 60 min and at least also after 5 and 8 hours. After stirring for 60 to 90 min at 30±2 C. the crystallization of the product started. The dark brownish, thin suspension was stirred for 10-15 h at 30±2 C. At minimum agitation rate, the addition of 21.8 l of H2O was started at 30±2 C. and was carried out at a constant rate whereby the reaction temperature was allowed to rise simultaneously to 45±5 C. Then, the remaining water was added at a rate to keep the temperature at 45±5 C. (overall addition time: about 60 min in total). Subsequently, the suspension was cooled to 20±2 C. in 60 min and stirred for further 60 min at 20±2 C. The resulting solid was filtered off and washed with 8.5 l of cold 1% oxygen-free aqueous NaOH (5-10 C.), then 2×8.5 l of cold oxygen-free H2O (15-10 C.) followed by 2×8.5 l of isopropanol (22±3 C.). [0419] All operations being part of the following purification procedure were carried out under a positive nitrogen atmosphere. [0420] The wet crude product (approx. 2.44 kg) in 72.7 l of acetonitrile was heated to reflux temperature. The mixture was refluxed for 10-15 minutes. To the resulting solution 116 g of charcoal (Ceca Eno) were added and the suspension was stirred for 10 min at reflux temperature. The charcoal was filtered off and the filter cake was washed with 11.6 l of hot acetonitrile. Under stirring the yellow coloured filtrate was cooled to 20±2 C. during 1 hour. Crystallization started at approx. 60 C. Under stirring the crystal suspension was cooled to 0±2 C. over 30 min and stirred at this temperature for one hour. The resulting crystals were filtered off and washed with 6 l of cold acetonitrile (?5 C.). [0421] The product was dried at ?75 C. (preferred temperature 70±5 C.) under reduced pressure (?55 mbar) until a level of ?1.4% of residual water was achieved. 1180 g of the compound of formula (Ia) (MW: 546.63 g/mol; 2.18 mol, 80.0% yield ?as is?) were obtained as a white to yellow crystalline powder.
Example 2: Synthesis of the compound of formula (la)A solution of 297 mg of BHT (butylated hydroxytoluene; M = 220.35 g/mol; 1.35 mmol; 500 ppm) and 727 g of the compound of formula (A)(MW: 269.35 g/mol; 2,698 mol; 1.0 equiv.; obtainable, for example, according to example 1 of EP 1 230 231 Bl (on page 4)) in 4.7 L of DMSO was prepared at a mass temperature of 30 +/- 2 C. To this was added a solution (30 +/- 2 C) of 161.9 g of NaOH (MW: 40.0 g/mol, 4.047 mol, 1.5 equiv.) in 161.9 g of oxygen-free H20 upon keeping the mass temperatui'e at < 32 C. The mixture was stirred for 10 min at 30 +/- 2 C. Then, a solution (30 +/- 2 C) of 1335 g of the compound of formula (B) contained in the product as obtained according to Example 1 (E l .j) above (12.968 mol = 1.1 equiv., MW = 449.48 g/ mol) in 6.6 L of DMSO was added at a mass temperature of < 32C within 10 min. The pH of the reaction mixture was checked after a reaction time of 60 min and at least also after 5 and 8 hours. After stirring for 60 to 90 min at 30 +/- 2 C the crystallization of the product started. The dark brownish, thin suspension was stirred for 10-15 h at 30 +/- 2 C. At minimum agitation rate, the addition of 21.8 L of H20 was started at 30 +/- 2 C and was carried out at a constant rate whereby the reaction temperature was allowed to rise simultaneously to 45 +/- 5 C. Then, the remaining water was added at a rate to keep the temperature at 45 +/- 5 C (overall addition time: about 60 min in total) . Subsequently, the suspension was cooled to 20 +/- 2 C in 60 min and stirred for further 60 min at 20 +/- 2 C. The resulting solid was filtered off and washed with 8.5 L of cold 1 % oxygen-free aqueous NaOH (5-10 C), then 2 x 8.5 L of cold oxygen-free H20 (15-10 C) followed by 2 x 8.5 L of isopropanol (22 +/- 3 C).
A solution of 297 mg of BHT (butylated hydroxytoluene; M = 220.35 g/mol; 1.35 mmol; 500 ppm) and 727 g of the compound of formula (A)(A)(MW: 269.35 g/mol; 2.698 mol; 1.0 equiv.; obtainable, for example, according to example 1 of EP 1 230 231 Bl (on page 4)) in 4.7 1 of DMSO was prepared at a mass temperature of 30 +/- 2 C. To this was added a solution (30 +/- 2 C) of 161.9 g of NaOH (MW: 40.0 g/mol, 4.047 mol, 1.5 equiv.) in 161.9 g of oxygen- free H20 upon keeping the mass temperature at < 32 C. The mixture was stirred for 10 min at 30 +/- 2 C. Then, a solution (30 +/- 2 C) of 1335 g of the compound of formula (B) contained in the product as obtained according to Reference Example 1.1 (Reference Example 1.1.j) above (12.968 mol = 1.1 equiv., MW = 449.48 g/ mol) in 6.6 1 of DMSO was added at a mass temperature of < 32C within 10 min. The pH of the reaction mixture was checked after a reaction time of 60 min and at least also after 5 and 8 hours. After stirring for 60 to 90 min at 30 +/- 2 C the crystallization of the product started. The dark brownish, thin suspension was stirred for 10-15 h at 30 +/- 2 C. At minimum agitation rate, the addition of 21.8 1 of H20 was started at 30 +/- 2 C and was carried out at a constant rate whereby the reaction temperature was allowed to rise simultaneously to 45 +/- 5 C. Then, the remaining water was added at a rate to keep the temperature at 45 +/- 5 C (overall addition time: about 60 min in total). Subsequently, the suspension was cooled to 20 +/- 2 C in 60 min and stirred for further 60 min at 20 +/- 2 C. The resulting solid was filtered off and washed with 8.5 1 of cold 1 % oxygen-free aqueous NaOH (5-10 C), then 2 x 8.5 1 of cold oxygen-free H20 (15-10 C) followed by 2 x 8.5 1 of isopropanol (22 +/- 3 C). All operations being part of the following purification procedure were carried out under a positive nitrogen atmosphere.The wet crude product (approx. 2.44 kg) in 72.7 1 of acetonitrile was heated to reflux temperature. The mixture was refluxed for 10-15 minutes. To the resulting solution 116 g of charcoal (Ceca Eno) were added and the suspension was stirred for 10 min at reflux temperature. The charcoal was filtered off and the filter cake was washed with 11.6 1 of hot acetonitrile. Under stirring the yellow coloured filtrate was cooled to 20 +/- 2 C during 1 hour. Crystallization started at approx. 60 C. Under stirring the crystal suspension was cooled to 0 +/- 2 C over 30 min and stirred at this temperature for one hour. The resulting crystals were filtered off and washed with 6 1 of cold acetonitrile (< 5 C).The product was dried at < 75 C (preferred temperature 70 +/- 5 C) under reduced pressure (< 55 mbar) until a level of < 1.4 % of residual water was achieved. 1180 g of the compound of formula (la) (MW: 546.63 g/mol; 2.18 mol, 80.0 % yield "as is") were obtained as a white to yellow crystalline powder.
Will be 4.00kg1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine (VII) and 35.57 kg of tetrahydrofuran100L glass reactor, open the stirring, cooling to 0 ~ 10 .Maintain the temperature below 25 drop 2.56kgPhenyl chloroformate (VIII),0.5 to 1 hour drop finished, temperature control 20 ~ 25 to continue the reaction of 0.5 to 1.0 hours. TLC monitoring reaction, the reaction finishedAfter the completion of the cooling to 0 ~ 10 ,Add saturated aqueous sodium bicarbonate solution (sodium bicarbonate 2.00kg dissolved in purified water 38kg), then add purified water 20kg,Stirring for 10 ~ 20min. Centrifuge the filter to the basic solvent-free effluent, and then rinse with 8kg of purified water, centrifugal rejection to the basic solvent-free effluent.The whole batch of wet goods in the vacuum -0.06MPa ~ -0.1MPa, the control temperature of 40-50 conditions,Dry under reduced pressure 12 to 16 hours. 5.47 kg of a gray solid,Phenyl (4- (4- (4-hydroxy) -1-piperazinyl) phenyl) carbamate(V);HPLC purity: 98.5% yield: 94.6%
215 g
In N,N-dimethyl-formamide; at 0 - 30℃; for 3h;
Example-8 Preparation of Phenyl-4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl carbamate (Formula-19) Phenyl chloroformate (139.5 g) was added to a pre-cooled solution of 4-(4-(4-aminophenyl)piperazin-1-yl)phenol compound of formula-18 (200 g) in dimethyl formamide (1400 ml) at 0-10 C. Temperature of the reaction mixture was raised to 25-30 C. and then stirred for 3 hours at 25-30 C. After completion of the reaction, the reaction mixture was quenched with water. Filtered the precipitated solid and washed with water.
In N,N-dimethyl-formamide; at 0 - 10℃;
Phenyl chloroformate (13.95 g, 0.089 mol) was added to a pre-cooled solution of compound 2 (20 g, 0.074 mol) in dimethylformamide (140 mL) at 0-10 C. After the completion of the reaction, the reaction mixture was quenched with water. Ispropyl alcohol (IPA, 60 mL) was added to the solid and the mixture was heated to 60-65 C and stirred for 1 h at the same temperature. Compound 4 was filtered off, washed with IPA, and dried. 1H NMR (DMSO-d6, 400 MHz): delta 3.155 (t, 8H, piperazine-CH2), 6.685 (d, 2H, p-aminophenol-3-CH), 6.859 (d, 2H, p-aminophenol-2-CH), 6.981 (d, 2H, aniline-3-CH), 7.237 (m, 2H, aniline-2-CH), 7.406 (t, 2H, phenol-CH), 7.447 (d, 2H, phenol-CH), 8.871 (s, 1H, p-aminophenol-OH), 9.989 (s, 1H, CO2NH). IR (KBr, lambda, cm-1) 3460 (s), 3368 (m), 1662 (s), 1568 (s), 1340 (s), 1160(s).
To a solution of the compound of formula (VII), prepared according to the teaching of Example 1 of WO 01/34587A2, page 6, line 1 to page 7, line 25, (149 mg, 0.554 mmol) in 925 microL of DMSO, solid NaOH (35.5 mg, 0.886 mmol,1.6 equiv.) was added followed by solid NaI (83.0 mg, 0.554 mmol, 1.0 equiv.). The mixture is stirred for 10 min at +20to +30 C. Then, a solution of the compound of formula (Va) (200 mg, 0.638 mmol, 1.15 equiv.), prepared by treatingthe HCl salt of the compound (IVa) as obtained in Example 2 with aq. NaOH as described in Example 5 , in 925 microLof DMSO was added and the resulting brown mixture was allowed to stir for a period of 3 h at a temperature of +50 Cfollowed by a period of 3 h at +100 C to achieve complete conversion (monitored by the HPLC method described below)of the compound of formula (Va). Subsequently, the mixture was cooled to +20 to +25 C and water (2 mL) was slowlyadded to the reaction mixture. Next, the resulting solid was filtered off and washed with cold 1 % aq. NaOH (2 mL)followed by cold H2O (2 x 2 mL). The crude product was purified by flash-chromatography on silica gel (eluent: DCM/EtOH : 30/1 (v/v)), yielding 106 mg (0.194 mmol, 35%) of the compound of formula (VIII). The compound of formula(VIII) thus purified was then reacted to give Posaconazole according to the teaching of Examples 4 and 5 as describedin WO 2011/144653 A1. The thus obtained Posaconazole was then treated according to the teaching of example 6 ofWO 2011/144653 A1, wherefrom Posaconazole of polymorphic form IV was obtained.
1L 4-neck flask was added 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine (Compound II) (10.0g, 37mmol) and DMF (50mL) with a mixed solvent of toluene (250mL) , dissolved under stirring.-10 ~ 0 C, was slowly added dropwise phenyl chloroformate (5.6mL, 44.4mmol), After the addition the reaction continued at room temperature 4h, after the end of the reaction was monitored by HPLC, the reaction solution was added successively 2-[(1S,2S)-2-benzyloxy-1-ethyl-propyl]hydrazine carbaldehyde (compound III) (12.3g, 51.8mmol) and triethylamine (7.4mL, 51.8mmol), was heated to 100 ~ 110 C reaction was continued for 6 ~ 8h after the end of the reaction was monitored by HPLC, heating was stopped, the reaction was cooled to room temperature. Compound I isolated: At room temperature, the reaction solution was transferred to a conical flask, was added a saturated sodium chloride solution (400mL), ethyl acetate (200 mL), stirred vigorously for 30min settled and separated, and the aqueous phase was extracted with ethyl acetate (200 mL), The combined organic phase was washed with saturated sodium bicarbonate solution (400mL), saturated sodium chloride solution (400mL), dried over anhydrous sodium sulfate, the solution was added activated charcoal, heated to reflux for decolorization 1h, the crude compound I obtained after filtration the filtrate was concentrated (22g, slightly wet), HPLC purity was 82.5%. Purification of Compound I: The crude Compound I was added acetonitrile (200 mL), warmed to reflux to dissolve clarified, stirring was continued for 1h, the precipitated solid was gradually decreased to 0 deg.] C After the stirring was continued for 1h, filtered and the filter cake washed with cold acetonitrile (20mL * 3), on a solid a vacuum oven at 50C 24h after drying was taken out of the final compound I, HPLC purity 99.5%.
The compound 1 was dissolved in N, N-dimethylformamide and the temperature was lowered to 0 to 10 C under argon protection,Titration of p-nitrophenyl chloroformate, Dropping 1 ~ 2h. After completion of the dropwise addition, the reaction was stirred at room temperature for 30 hours. Add about 1L of water quenching reaction, stirring to be solid precipitation, continue stirring 1h, filter, filter cake washed with water. The filter cake was added to isopropanol, refluxed for about 1 h, cooled and filtered to give off-white solid product 2b in 81% yield and HPLC purity 97%.
In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;
The compound 1 was dissolved in N, N-dimethylformamide and the temperature was lowered to 0 to 10 C under argon protection,P-chlorophenyl chloroformate was added dropwise, and the mixture was added dropwise for 1 to 2 hours. After completion of the dropwise addition, the reaction was stirred at room temperature for 30 hours. Add about 1L of water quenching reaction, stirring to be solid precipitation, continue stirring 1h, filter, filter cake washed with water. The filter cake was added to isopropanol, refluxed for about 1 h, filtered and filtered to give off-white solid product 2c, yield 84%, HPLC purity 95%.
In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;
The compound 1 was dissolved in DMF, the temperature was lowered to 0 to 10 C under argon, and di-t-butyl dicarbonate was added dropwise dropwisePlus 1 ~ 2h. After completion of the dropwise addition, the reaction was stirred at room temperature for 30 hours. Add about 1L of water quenching reaction,Stirring to be solid precipitation,Continue stirring for 1 h, filter and filter the cake with water. The filter cake was added to isopropanol, refluxed for about 1 h, cooled and filtered to give off-white solid product 2a, yield 86%, HPLC purity 97%.
With pyridine; In N,N-dimethyl-formamide; at 0 - 25℃; for 4h;
12g (0.045 mol) of the compound III was added to 120 mL of DMF, 3.8 g (0.048 mol) of pyridine was added under stirring, the temperature was lowered to 0-5 DEG C, and 9.1 g (0.054 mol) of benzyl chloroformate was slowly added dropwise, after the addition was completed. The reaction was heated at 20-25C for 4 hours, and the system was cooled at 0-5C. 360 mL of purified water was added to the reaction solution, which was crystallized for 3 h in an ice-water bath, filtered, and dried to give 14.6 g of a gray solid. Yield: 84.5%
With triethylamine; In tetrachloromethane; 1,2-dichloro-ethane; at 10 - 35℃; for 20h;Inert atmosphere;
TEA (22 mmol, 3.1 ml), DOPO (40 mmol, 8.64 g) and dichloroethane (50 ml) were added to a three-necked flask under inert gas.Then, <strong>[74853-08-0]1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine</strong> (20 mmol, 4.35 ml) was added dropwise, and finally CCl4 (22 mmol, 2.13 ml) was slowly dropped into the reaction system at 10 C. After the dropwise addition was completed, the temperature was raised to 35 C for 20 hours. After the reaction is completed, the filtrate is collected by suction filtration, and the solvent is distilled off, and then washed with ethanol, and dried in a vacuum to obtain a DOPO-based reactive flame retardant containing a piperazine structure, and the structural formula is:
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