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[ CAS No. 143254-82-4 ] {[proInfo.proName]}

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Chemical Structure| 143254-82-4
Chemical Structure| 143254-82-4
Structure of 143254-82-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 143254-82-4 ]

CAS No. :143254-82-4 MDL No. :MFCD08445613
Formula : C11H20Cl2N2O Boiling Point : -
Linear Structure Formula :- InChI Key :VBXXNCHZAMNCBX-UHFFFAOYSA-N
M.W : 267.20 Pubchem ID :11637553
Synonyms :

Calculated chemistry of [ 143254-82-4 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.91
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 76.73
TPSA : 23.55 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.79 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 3.02
Log Po/w (WLOGP) : 2.34
Log Po/w (MLOGP) : 2.15
Log Po/w (SILICOS-IT) : 1.64
Consensus Log Po/w : 1.83

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.27
Solubility : 0.144 mg/ml ; 0.00054 mol/l
Class : Soluble
Log S (Ali) : -3.18
Solubility : 0.177 mg/ml ; 0.000661 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.67
Solubility : 5.7 mg/ml ; 0.0213 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.02

Safety of [ 143254-82-4 ]

Signal Word:Danger Class:8
Precautionary Statements:P260-P261-P264-P270-P271-P280-P301+P312-P301+P330+P331-P302+P352-P303+P361+P353-P304+P340-P305+P351+P338-P310-P312-P321-P322-P330-P363-P405-P501 UN#:3261
Hazard Statements:H302-H312-H314-H332 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 143254-82-4 ]

* 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.

  • Downstream synthetic route of [ 143254-82-4 ]

[ 143254-82-4 ] Synthesis Path-Downstream   1~12

  • 1
  • 4-piperidinopiperidine-1-carbonyl chloride hydrochloride [ No CAS ]
  • [ 86639-52-3 ]
  • [ 97682-44-5 ]
YieldReaction ConditionsOperation in experiment
94.3% With dmap; In acetonitrile; at 75℃; for 5h;Sonication; Into a beaker in a sonication bath are placed 10 G (0.0247 mol) of 7-ethyl-10-hydroxy- camptothecin and 99 ML of acetonitrile. The obtained suspension is stirred in the sonication bath to homogeneity. Then the suspension is transferred quantitatively into a three-necked Keller flask equipped with a mechanical STIRRER, thermometer and reflux condenser. Into the now empty beaker are now placed 6.2 g (0.0502 mol) of crystalline 4-DIMETHYLAMINOPYRIDINE and 40 ml of acetonitrile. The mixture is stirred until the crystalline portion dissolves. The obtained solution is then added quantitatively to the suspension of 7-ETHYL-10-HYDROXY- camptothecin. Into the empty beaker are then added 13.6 g (0.0434 mol) of 1-CHLOROCARBONYL- - 4-PIPERIDINOPIPERIDINE hydrochloride and 79 ML of acetonitrile and the suspension is stirred in the sonication bath until homogeneous. The obtained suspension is transferred quantitatively into the three-necked Keller flask already containing 7-ethyl-10- hydroxycamptothecin and 4-dimethylaminopyridine in acetonitrile, and 382 ml of acetonitrile is added to the mixture. The obtained reaction suspension in the Keller flask is stirred at 75 °C for 5 h. After 2 h the lightly yellow suspension becomes thicker and its colour turns into a coffee-white one, indicating thus correct course of the reaction. After 5 h, the suspension is cooled to 18 to 20 °C, filtered and the filtration cake is washed with 300 ml of acetonitrile. After removing the acetonitrile by suction filtration, the obtained 7-ethyl- - 10- [4- (L-PIPERIDINO)-1-PIPERIDINO]-CARBONYLOXYCAMPTOTHECIN is dried at 60 to 65 °C to constant weight in a drier. This affords 14.1 g (yield 94.3 percent) of product which, according to high-performance liquid chromatography, contains 98.9 percent of 7-ETHYL-10- [4- (1-PIPERIDINO)- -L-PIPERIDINO]-CARBONYLOXYCAMPTOTHECIN.
91% With N,N-dimethyl-ethanamine; In dichloromethane; at 20℃; for 2.5h; To the flask were added 10.0 g (25.5 mmol) of 7-ethyl-10-hydroxycamptothecin (SN-38)And 200.0 mL of methylene chloride were mixed.To the mixture was added 19.3 mL (178.4 mmol) of N, N-dimethylethylamine,And 8.17 g (30.6 mmol) of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride were added at room temperature,The reaction solution was stirred at room temperature for 2.5 hours,The mixture was concentrated in vacuo under vacuum.The residue was dissolved in methylene chloride (200.0 mL)And fractionated using distilled water (100.0 mL)The aqueous layer was extracted with methylene chloride (100.0 mL).The combined organic layers were washed with brine,Dry over sodium sulfate,And concentrated using a vacuum condenser.The residue was dissolved in methyl t-butyl ether (600 mL)To give 13.6 g (yield 91percent) of the title compound as a solid.
With 1-Methylpyrrolidine; In dichloromethane; at 20 - 45℃; Example 4: Irinotecan hydrochloride7-Ethyl-lO-hydroxycamptothecin (20 g) was suspended in methylene chloride (400 ml). To this while stirring at room temperature l-chlorocarbonyl-4-piperidinopiperidine hydrochloride (27.2 g; 2 eq.) and N-methylpyrrolidine (40.0 ml; 7 eq.) was added. There was visible temperature raise of 5°C in the next 10 to 20 minutes and stirred for further 30 minutes to dissolve, all the suspended material into solution. The clear solution was further stirred for additional 2 hours (In process check shows the absence of SN-38). The solvent was removed along with excess of N-Methylpyrrolidine under reduced pressure, keeping the temperature below 45°C. After cooling the solid mass was treated with water (250 ml) and stirred. To this aqueous solution, methylene chloride (1 L) was added and stirred well to extract all the free base of irinotecan. The organic layer was collected, washed with water twice (250 ml x 2), solvent was removed to give pale yellowish solid The free base is suspended in 280 ml of water and to this 16.3 ml of concentrated hydrochloride (3 eq.) was added and stirred at room temperature for 15 minutes to form clear solution. The solution was then heated to 70°C for 3 hrs and slowly allowed to cool to room temperature. It was further cooled to 0-5°C for 30 minutes, collected the solid, washed with water (60 ml), ethanol (60 ml) and dried at room temperature to give 30 g of irinotecan hydrochloride, purity 99.5percent (yield 90percent).The above compound is further purified by taking in isopropyl alcohol -water mixture (24 ml); (6 ml isopropyl alcohol and 18 ml of H20) and heated to 70°C and adjusted the pH to 3.5 to 3.8 by adding 5percent hydrochloride (0.2 ml) to form clear solution. The solution was then allowed to cool to room temperature, collected the product by filtration, washed with IPA-H20 (1 :3) and dried at room temperature to give 2.6 g of colourless crystalline compound of irinotecan hydrochloride of 99.78percent purity by HPLC with no impurity >0.1percent.
  • 2
  • [ 143254-82-4 ]
  • [ 35364-15-9 ]
  • [ 620160-86-3 ]
YieldReaction ConditionsOperation in experiment
With pyridine at 20℃; for 13h; 1 A solution of 3.26 g (19.6 mmol) 2-amino-5-hydroxypropiophenone and 6.97 g (26.1 mmol) 4-piperidinopiperidinecarbamoyl chloride hydrochloride in 35 ml pyridine was stirred at room temperature for 13 hours. The pyridine was then evaporated and 20 ml water and 120 ml ethyl acetate were added. The resulting organic phase was separated and dried over sodium sulfate. The sodium sulfate was removed by filtration and 10 g silica-60 was added to the filtrate, which was stirred to form a slurry. The slurry was loaded onto a column of 20 g silica-60 (230-400 mesh) and eluted with a 95:5 (v/v) methylene chloride/methanol mixture. The resulting product fractions were combined and evaporated to provide a residue, which was then redissolved in a mixture of 20 ml methylene chloride and 50 ml heptane. The resulting solution was evaporated to yield 6.22 g of 4-amino-3-propionylphenyl-1,4'-bipiperidine-1'-carboxylate as a yellow-green solid, melting point 132.0-133.5° C. 1H NMR (400.13 MHz, CDCl3) δ 7.46 (s, 1H) 7.03 (d, 1H, J=8.8 Hz), 6.64 (d, 1H, J=8.8 Hz), 6.2 (s, 2H), 4.35 (s, 2H), 2.95 (q, 2H, J=7.2 Hz), 2.5-2.9 (m, 9H), 1.4-1.7 (m, 8H), 1.20 (t, 3H, J=7.6 Hz). 13C NMR (75.47 MHz, CDCl3) δ 204.39, 155.88, 149.69, 142.2, 130.28, 124.84, 119.71, 119.16, 85.91, 64.38, 51.99, 45.72, 34.11, 29.78, 29.16, 27.62, 26.18, 10.33. IR (KBr) 3455, 3345, 2965, 2953, 2948, 2932, 2913, 2850, 2783, 2749, 1713, 1662, 1587, 1555, 1421, 1285, 1237, 1219, 1184, 1155, 1149, 1128, 793, 753. Analysis calculated for C20H29N3O3: C, 66.83; H, 8.13; N, 11.69. Found: C, 66.46; H, 8.04; N, 11.58.
With pyridine at 20℃; for 13h; 6-7 4-Amino-3-propionphenvl-1,4';-bipiperidine-1';-carbox,late [0023] A solution of 3.26 g (19.6 mmol) 2-amino-5-hydroxypropiophenone and 6.97 g (26.1 mmol) 4-piperidinopiperidinecarbamoyl chloride hydrochloride in 35 n--d pyridine was stirred at room temperature for 13 hours. The pyridine was then evaporated and 20 rnl water and 120 ml ethyl acetate were added. The resulting organic phase was separated and dried over sodium sulfate. The sodium sulfate was removed by filtration and 10 g silica-60 was added to the filtrate, which was stirred to form a slurry. The slurry was loaded onto a column of 20 g silica-60 (230-400 mesh) and eluted with a 95: 5 (v/v) methylene chloride/methanol mixture. The resulting product fractions were combined and evaporated to provide a residue, which was then redissolved in a mixture of 20 ml methylene chloride and 50 rnl heptane. The resulting solution was evaporated to yield 6.22 g of 4-amino-3-propionylphenyl-1, 4';-bipiperidine-1';-carboxylate as a yellow-green solid, melting point 132.0-133. 5C. [0024] 1H NMR (400.13 MHz, CDC13) 6 7.46 (s, 1H) 7.03 (d, 1H, J=8.8 Hz), 6.64 (d, 1H, J=8.8 Hz), 6.2 (s, 2H), 4.35 (s, 2H), 2.95 (q, 2H, J=7.2 Hz), 2.5-2. 9 (m, 9H), 1.4-1. 7 (m, 8H), 1.20 (t, 3H, J=7.6 Hz). [0025] 13C NMR (75.47 MHz, CDC13) 5 204.39, 155.88, 149.69, 142.2, 130.28, 124.84, 119.71, 119.16, 85.91, 64.38, 51.99, 45.72, 34.11, 29.78, 29.16, 27.62, 26.18, 10. 33. [0026] IR (KBr) 3455,3345, 2965,2953, 2948,2932, 2913,2850, 2783,2749, 1713, 1662, 1587, 1555,1421, 1285,1237, 1219,1184, 1155,1149, 1128,793, 753. [0027] Analysis calculated for C20H29N303 : C, 66.83 ; H, 8.13 ; N, 11.69. Found: C, 66.46 ; H, 8. 04; N, 11.58.
  • 3
  • [ 4897-50-1 ]
  • [ 32315-10-9 ]
  • [ 143254-82-4 ]
YieldReaction ConditionsOperation in experiment
85.5% In dichloromethane 1 Scrubber system was used during the reaction and distillation. Phosgene is formed during the reaction. Triphosgene (100 g) was dissolved in 1280 ml of methylene chloride. Solution of 129.5 g of 4-piperidinopiperidme was dissolved in 1280 ml of methylene chloride and this solution was added at 20r25 0C into the triphosgene solution while cooling the mixture (exothermic reaction). Part of the methylene chloride (1500 ml) was distilled off. Acetonitrile (580 ml) was added gradually. Methylene chloride was distilled off until the temperature rose to 63 °C. Toluene (2000 ml) was added gradually. The mixture was cooled to room temperature. The crystalline compound was filtered and washed with toluene (about 1000 ml). The compound was dried under reduced pressure at about 40 °C. The yield was 175.9 g (85.5 %). HPLC purity 99.2 %, dimeric impurity 0.8 %.
In dichloromethane at 5 - 40℃; for 10 - 18h; 2 Example-2.; Preparation of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride(IRT-4.HC1):; Dissolving triphosgene (110g) in dichloromethane (300 ml) with stirring for 15 to 30 minutes at room temperature, adding a solution of 4-piperidinopiperidine (100 g) in dichloromethane (300-ml) slowly over a period of 2 hour to 6 hours, maintaining the temperature between 5° to 10°C. Stirring the mixture keeping the temperature same for further period of 2 hours to 4 hours, raising the temperature up to 30°C, maintaining at this temperature for further period of 6 to 8 hours and distilling the dichloromethane completely at a temperature up to below 45°C under vacuum. Cooling the residue to room temperature and adding n-hexane (200 ml), stirring filtering and drying to obtain 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (120 g)
In chloroform at 5 - 40℃; for 10 - 18h; 3 Example-3; Preparation of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride(IRT-4.HCI).; Procedure followed is same as in Example2 except the solvent used is chloroform.; Example-2.; Preparation of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride(IRT-4.HC1):; Dissolving triphosgene (110g) in dichloromethane (300 ml) with stirring for 15 to 30 minutes at room temperature, adding a solution of 4-piperidinopiperidine (100 g) in dichloromethane (300-ml) slowly over a period of 2 hour to 6 hours, maintaining the temperature between 5° to 10°C. Stirring the mixture keeping the temperature same for further period of 2 hours to 4 hours, raising the temperature up to 30°C, maintaining at this temperature for further period of 6 to 8 hours and distilling the dichloromethane completely at a temperature up to below 45°C under vacuum. Cooling the residue to room temperature and adding n-hexane (200 ml), stirring filtering and drying to obtain 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (120 g)
In dichloromethane at 0 - 20℃; 3 Example 3: l-Chlorocarbamoyl-4-piperidinopiperidine hydrochlorideTriphosgene (120 g; 0.68 eq.) is taken in dichloromethylene (1 L) and to this cold solution (keeping the temperature between 0-5 °C) 4-Piperidinopiperidine (100 g) in CH2C12 (1 L) was added slowly for 4 hrs. The solution was then allowed to cool to room temperature and stirred for further 12 hours. The solvent was removed, ethyl acetate (1 L) was added, stirred and collected the compound by filtration. The white solid was then dried at room temperature under reduced pressure. The product thus obtained is 94-95% pure and contains mostly bis-urea derived from 4-piperidinopiperidine with an yield of 140 g (88.6%). The product was used as such in the next step of making irinotecan hydrochloride.

  • 4
  • 4-piperidinopiperidine-1-carbonyl chloride hydrochloride [ No CAS ]
  • [ 103816-19-9 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In dichloromethane; for 1h; [l,4']bipiperidinyl-l'-carbonyl chloride hydrochloride (9.7 g), methylene chloride (150 ml) and K2CO3 (10.5 g, 2.1 ekv) were charged. The mixture was stirred for about 1 hour. The solution was filtered and the cake washed with 10 ml of methylene chloride. The solution (containing 8.4 g of [l,4']bipiperidinyl-l'-carbonyl chloride) can be used as such for the preparation of Irinotecan
  • 5
  • 4-piperidinopiperidine-1-carbonyl chloride hydrochloride [ No CAS ]
  • [ 86639-52-3 ]
  • [ 100286-90-6 ]
YieldReaction ConditionsOperation in experiment
90% Example 4. Mnotecan hydrochloride; 7-Ethyl-10-hydroxycamptothecin (4.5 g) and pyridine (60 ml) were charged in a reaction vessel. A solution of [l,4']-bipiperidinyl-l '-carbonyl chloride hydrochloride (3.44 g) and triethylamine (4.8 ml) in 75 ml of methylene chloride was added at 30-40 C. The mixture was stirred for 1.5 hours at 30-40 C. 4- piperidinopiperidine (0.58 g) was added and the mixture was stirred for 0.5 hour. Methylene chloride and pyridine were distilled off until the volume of the residue EPO <DP n="8"/>was about 25 ml. Acetonitrile (100 ml) was added and the mixture was heated to about 60 C. The mixture was cooled to room temperature and 15 ml of 5 % aqueous hydrochloric acid was added. The mixture was stirred about 20 hours at room temperature. The mixture was cooled to 0 +/- 5. The crystalline compound was filtered and washed with acetonitrile:water 10:1 mixture (10 ml) and acetonitrile (10 ml). The product was dried under reduced pressure. The yield was 6.4 g (90 %).
80% Example 3. Mnotecan hydrochloride; 7-Ethyl-lO-hydroxycamptothecin * H2O (10 g) and pyridine (120 ml) were charged. A solution of [l,4']bipiperidinyl-r-carbonyl chloride hydrochloride (9.6 g, 1.4 ekv) and triethylamine (8.5 ml, 2.5 ekv) in methylene chloride (150 ml) was added. The mixture was stirred for 2 hours at room temperature. The mixture was distilled to dryness under reduced pressure. Water (150 ml) was added and the pH was adjusted to 4.0 by hydrochloric acid (5 %) at about 80 0C. The mixture was cooled to 0-5 0C and stirred for about 20 hours. The crystalline compound was filtered and washed with water. The product was dried under reduced pressure. The yield was 13.2 g (80 %).
80% With triethylamine; In pyridine; dichloromethane; water; at 20℃; for 2h; 7-Ethyl-lO-hydroxycamptothecin * H2O (10 g) and pyridine (120 ml) were charged. A solution of [l,4']bipiperidinyl-r-carbonyl chloride hydrochloride (9.6 g) and triethylamine (8.5 ml) in methylene chloride (150 ml) was added. The mixture was stirred for 2 hours at room temperature. The mixture was distilled to dryness under reduced pressure. Water (150 ml) was added and the pH was adjusted to 4.0 by hydrochloric acid (5 %) at about 80 C. The mixture was cooled to 0-5 C and stirred for about 20 hours. The crystalline compound was filtered and washed with water. The product was dried under reduced pressure. The yield was 13.2 g (80 %).
With pyridine; at 65℃; for 4h; Example 1 - Preparation of form H from the crude product of reaction between 7-ethyl-10-hydroxy camptothecin and 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride A suspension of 7-ethyl-10-hydroxy camptothecin (20.0 g) and 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (18.0 g) in pyridine (700 ml) was heated to 65C and left under stirring until the reaction was complete (HPLC analysis), which took 4 hours; at the end, the reaction mixture was a solution. The solvent was distilled at a pressure of under 50 mbars at 50C until a dry residue was obtained. The concentrated mass was taken up with dichloromethane (410 ml) and left under stirring at 35C until a solution was obtained. The solvent was distilled at a pressure of under 300 mbars at 35C until a concentrated solution (300 ml) was obtained. The temperature was adjusted to 25C, and formation of the first crystals of the product was observed after approx. 30 minutes; after 15 hours' curing at 25C, the crystallised mass was filtered through a Buchner funnel under suction, and the wet product was washed with dichloromethane (100 ml). After oven-drying under vacuum (residual pressure under 50 mbars), irinotecan hydrochloride form H (15.3 g) with high purity (HPLC purity = 99.6%) and a 2.8% water content was obtained. This product (13.0 g) was then hydrated by exposure in an atmosphere with 90% relative humidity; after 18 hours the weight proved stable (14.5 g; HPLC purity = 99.6%; water = 12%).
With pyridine; at 65℃; for 4h; A suspension of 7-ethyl-10-hydroxy camptothecin (20.0 g) and 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (18.0 g) in pyridine (700 ml) was heated to 65 C. and left under stirring until the reaction was complete (HPLC analysis), which took 4 hours; at the end, the reaction mixture was a solution. The solvent was distilled at a pressure of under 50 mbars at 50 C. until a dry residue was obtained. The concentrated mass was taken up with dichloromethane (410 ml) and left under stirring at 35 C. until a solution was obtained. The solvent was distilled at a pressure of under 300 mbars at 35 C. until a concentrated solution (300 ml) was obtained. The temperature was adjusted to 25 C., and formation of the first crystals of the product was observed after approx. 30 minutes; after 15 hours' curing at 25 C., the crystallised mass was filtered through a Buchner funnel under suction, and the wet product was washed with dichloromethane (100 ml). After oven-drying under vacuum (residual pressure under 50 mbars), irinotecan hydrochloride form H (15.3 g) with high purity (HPLC purity=99.6%) and a 2.8% water content was obtained.This product (13.0 g) was then hydrated by exposure in an atmosphere with 90% relative humidity; after 18 hours the weight proved stable (14.5 g; HPLC purity=99.6%; water=12%).
Product distribution / selectivity; Example-7; 7-ethyl-10-hydroxycampothecin (semi-synthetic) obtained in example 4 (c) and 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (90g) are used as reactants. Following the procedure described in examples (5) and (6) irinotecan (32g) and irinotecan hydrochloride trihydrate (30g) respectively are obtained.; Example-9; 7-ethyl-10-hydroxy camptothecin (50g; synthetic) and 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (90g) are used as reactants. By following the procedure of examples (8) and (6) irinotecan (80g) and irinotecan hydrochloride trihydrate (60g) are obtained respectively.
161 g The compound D (175 g) obtained in the above step was added to the reaction flask 10L, methylene chloride (dry), 2.3 L,Triethylamine 1.7 L,Rinidine (dry) 230ml, stirring at room temperature.Weigh 4-piperidinopiperidine-1-carbonyl chloride hydrochloride200 g, 1.3 L dichloromethane (dry) to partially dissolve it (turbid liquid), slowly dissolve the turbid solution into the reaction flask,Control reaction temperature 25 C ~ 40 C, reaction about 0.5 hours or so, point plate test to determine the completion of the reaction.The reaction solution poured into the 25L is burning, the Buchner funnel filter, get solid, n-hexane washed twice, dried out of irinotecan crude 265g.The crude 265g of irinotecan was placed in a 25L extraction tank, poured into 6L saturated sodium bicarbonate solution, poured into dichloromethane 4L, mechanically stirred until dissolved, the solution was separated and the aqueous phase was extracted with dichloromethane (3X1 .5L). The organic layers were combined and the organic phase was washed with 5 L of saturated brine. The organic phase was separated and dried over anhydrous magnesium sulfate for 20 minutes. After concentrating to about 2.0 L of the remaining pressure, the mixture (about 200 ml) of methanolic hydrochloric acid was added and shaken until the solution was pH = 2-3, and the insoluble matter was removed by filtration.The remaining solvent was evaporated under reduced pressure to about 1.0 L. After addition, 1.0 L of methanol was added and the mixture was concentrated and concentrated to give an oil (1.0% solids remaining in methanol).The methanolic water mixture (methanol: water = 1: 1,1.0 L) was poured into an oil, shake and filtered. The solution was allowed to stand at room temperature to precipitate a large number of products.Filter, filter cake with methanol water mixture washing, dry after drying to irrigate hydrochloride about 161g.

  • 6
  • [ 143254-82-4 ]
  • [ 19685-09-7 ]
  • [ 103816-16-6 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In acetonitrile at 60℃; for 6h; 1 Example 1 Example 1 [0050] 20 g of 10-hydroxycamptothecin are dissolved in 100 ml of acetonitrile, before adding 30 g of anhydrous K2CO3. Subsequently, a solution of 17.6 g of 1-chlorocarbonyl-4-piperidino-piperidine hydrochloride is added to 300 ml of acetonitrile under stirring. Stirring is continued for about 6 hours at 60°C. [0051] Acetonitrile is evaporated, and the dry residue is dissolved in 200 ml dichloromethane. The organic layer is rinsed with 4 x 100 ml distilled water in order to remove non-organic impurities, and the solvent is evaporated. 400 ml of 40% H2SO4 are added to the dry residue at 20°C. After dissolution, 10.5 g of FeSO4 x 7 H2O is added, cooled to -10°C and mixed with 10 ml of propionic aldehyde. [0052] The resulting solution of H2O2 and propionic aldehyde is cooled to 0°C (75 ml of distilled water are cooled to 0°C and 3.3 ml of 32% H2O2 and 5 ml of propionic aldehyde are added) and incubated in a smooth flowing manner for 150 min. The reaction product (i.e. irinotecan) is diluted with water to a volume of 3 I and transferred to chromatographic purification (Diaion sorbent resin).
  • 7
  • [ 143254-82-4 ]
  • [ 19685-09-7 ]
  • [ 207683-84-9 ]
YieldReaction ConditionsOperation in experiment
97% With potassium carbonate; triethylamine In acetonitrile at 60℃; for 6h; 1 Example 1 20 g of 1 0-hydroxycamptothecin are dissolved in 100 ml of acetonitrile, before adding 30 g of anhydrous K2003. Subsequently, a solution of 17.6 g of 1-chlorocarbonyl-4-piperidino- piperidine hydrochloride is added to 300 ml of acetonitrile under stirring. Stirring is continued for about 6 hours at 60°C.Acetonitrile is evaporated, and the dry residue is dissolved in 200 ml dichloromethane. The organic layer is rinsed with 4 x 100 ml distilled water in order to remove non-organic impurities, and the solvent is evaporated. 400 ml of 40% H2504 are added to the dry residue at 20°C. After dissolution, 10.5 g of Fe504 x 7 H20 is added, cooled to -10°C and mixed with 10 ml of propionic aldehyde.The resulting solution of H202 and propionic aldehyde is cooled to 0°C (75 ml of distilled water are cooled to 0°C and 3.3 ml of 32% H202 and 5 ml of propionic aldehyde are added) and incubated in a smooth flowing manner for 150 mm. The reaction product (i.e. irinotecan) is diluted with water to a volume of 3 I and transferred to chromatographic purification (Diaion sorbent resin).
  • 8
  • [ 143254-82-4 ]
  • [ CAS Unavailable ]
  • [ 1310903-47-9 ]
YieldReaction ConditionsOperation in experiment
1.45 g With dmap; triethylamine In dichloromethane at 35℃; for 5h; 2 7-ethyl-10-hydroxycamptothecin 100g,4-piperidylpiperidinecarbonyl chloride hydrochloride 80g,Triethylamine 72.8g, DMAP 2.0g,1060 g of dichloromethane was added to a 2 L three-necked flask.The temperature was raised to 35 ° C under mechanical stirring for 5 h.Filter out insolubles,The filtrate was added to 100 g of 100 mesh silica gel and concentrated to dryness.Obtained 342g of dark red sand,It contained 142 g of crude irinotecan free base with a yield of 94.5%.The above-mentioned sand was collected by column chromatography to collect product points, and the volume ratio of the column chromatography eluate: dichloromethane:Methanol: Triethylamine = 100:2:1, and the solvent was concentrated to afford 1.45 g of an orange-yellow solid.
  • 9
  • 4-piperidinopiperidine-1-carbonyl chloride hydrochloride [ No CAS ]
  • [ 491833-29-5 ]
  • (1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-octanamido-3-(pyrrolidin-1-yl)propyl [1,4'-bipiperidine]-1'-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
27% Eliglustat (0.200 g) was dissolved into THF (7 ml) at room temperature under nitrogen atmosphere. The reaction mass was cooled to 5-10 C under nitrogen atmosphere. NaH (55%) (0.06 g) was added to the reaction mass to get suspension, the reaction mass was stirred at 5-10 C for 15-20 min. Step-l product (Vl-q, 0.140 g) in THF (1 ml) was drop wise added to the reaction mass and stirred at room temperature for 16-18 hrs light yellow colored suspension formed after completion of addition. After completion of the reaction, the reaction mass was poured into water (10 ml) and product was extracted by dichloromethane (10 ml *2). The organic layer was separated, washed with saturated NaHCCh solution (10 ml *2). The organic layer was separated, dried over sodium sulphate and dried under vacuum at 40 C to afford the crude product. The crude product was purified by column chromatography using silica gel (100- 200 mesh) with elution of 6-7% MeOH in dichloromethane to get pure product (0.080 g). Mass (m/z): 599.5 [M+H] NMR (400 MHz, DMSO-d6) d 7.729 (bs, 1H), 6.701-6.795 (m, 3H), 5.497 (bs, 1H), 4.32 (bs, 1H), 4.206 (s, 4H), 3.991 (bs, 1H), 2.73-2.93 (bs, 3H), 2.043-2.077 (t, 2H), 1.83-1.91 (m, 2H), 1.59-1.8 (m, 8H), 1.31-1.54 (m, 6H), 1.15-1.31 (m, 10H), 0.843-0.877 (t, 3H). Yield: 27%
  • 10
  • [ 32315-10-9 ]
  • [ 4876-60-2 ]
  • [ 143254-82-4 ]
YieldReaction ConditionsOperation in experiment
87% Stage #1: bis(trichloromethyl) carbonate In dichloromethane for 0.5h; Inert atmosphere; Stage #2: 4-piperidinopiperidine hydrochloride In dichloromethane at 5 - 30℃; for 4.5h; Inert atmosphere; 17.1 Step-1: Preparation of compound of formula (Vl-q) ([l,4'-bipiperidine]-l'-carbonyl chloride hydrochloride) Triphosgen (380 g) was dissolved into dichloromethane (4.86 ml) at room temperature for 30 minutes under nitrogen atmosphere. 4-piperidino piperidine-HCl (0.500 g) in dichloromethane (4.94 ml) was drop wise added at 5-10° C within 30 minutes. The reaction mass was stirred at 5- 10° C for 2 hours and at 30° C for 2 hours. After completion of the reaction, the reaction mass was dried under vacuum at 40 °C to afford the pure solid product (0.600 g). Yield: 87%
  • 11
  • 4-piperidinopiperidine-1-carbonyl chloride hydrochloride [ No CAS ]
  • [ 118525-40-9 ]
  • 5,7-dihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4-oxo-4H-(chromen-3-yl)[1,4'-dipiperidinyl]-1'-carboxylic acid ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% With pyridine; at 20℃;Inert atmosphere; 3,5,7-Trihydroxy-2- (4-methoxyphenyl) -8- (3-methylbut-2-en-1-yl) -4H-chromen-4-one (150 mg , 0.41 mmol) was dissolved in drypyridine (10 mL), and then 1-chloroformyl-4-piperidinylpiperidine hydrochloride (109 mg, 0.41 mmol) was added, and the mixture was stirred at roomtemperatureunder nitrogenovernight for reaction.Dichloromethane was added for extraction (40 mL x 3), and the organic phases were combined, washed with a saturated sodium chloride solution (30 mL), dried over anhydroussodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to give the title compound (70 mg, yield: 31%, HPLC: 98%)as a yellow solid.
  • 12
  • [ 143254-82-4 ]
  • [ 802918-57-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
102.1 mg With potassium carbonate In N,N-dimethyl-formamide at 0 - 5℃; for 14h; Inert atmosphere; 10 Synthesis of Compound 10 At room temperature, silibinin (241.2 mg, 0.50 mmol, 1.0 eq) and N,N-dimethylformamide (3.6 mL, 15.0 vol) were added to a 5 mL three-neck round-bottom flask, and argon was replaced 6 times. Turn on stirring, cool the system to 0-5°C,Potassium carbonate (193.5mg, 1.40mmol, 2.8eq) was added to the reaction flask, argon was replaced 6 times, [1,4']bipiperidine-1'-carbonyl chloride hydrochloride (213.8mg, 0.80mmol, 1.6eq) was added to the reaction flask, replaced by argon 6 times, the system was naturally warmed to room temperature and stirred for 14 hours. After the reaction was detected by TLC, 12 mL of water was added to the system, a large amount of yellow solid was precipitated, and suction filtration was performed to obtain 251.1 mg of yellow solid, which was dissolved in 3.0 mL of dichloromethane and 0.3 mL of methanol, and the crude product solution was drawn with a capillary and placed on the preparation plate, after the sample is finished, blow dry. Put it into a developing cylinder prepared with dichloromethane/methanol=8/1 developing agent in advance, and carry out one development.Wash with 100 mL of developing agent, filter with suction, shrink the mother liquor to dryness, add 15 mL of dichloromethane to dissolve the liquid, pass through a microporous membrane, and concentrate the mother liquor to 2-3 mL,15mL of petroleum ether was added to the filtrate, a large amount of solid was precipitated, suction filtration to obtain 102.1mg of yellow solid,
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