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Chemical Structure| 97682-44-5
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CAS No. :97682-44-5 MDL No. :
Formula : C33H38N4O6 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W :586.68 Pubchem ID :-
Synonyms :
Irinotecan

Safety of [ 97682-44-5 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P501-P270-P264-P301+P310+P330-P405 UN#:1544
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Application In Synthesis of [ 97682-44-5 ]

* 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.

  • Upstream synthesis route of [ 97682-44-5 ]
  • Downstream synthetic route of [ 97682-44-5 ]

[ 97682-44-5 ] Synthesis Path-Upstream   1~53

  • 1
  • [ 97682-44-5 ]
  • [ 4897-50-1 ]
  • [ 86639-52-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 12, p. 3742 - 3752
  • 2
  • [ 97682-44-5 ]
  • [ 100286-90-6 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride In dichloromethane; water at 0℃; for 2 - 3 h; The product from Example 1 was dissolved in DCM and cooled down to 0° C. 12N HCl was added drop wise to this solution and stirred for 2-3 hours. The solvent was evaporated to get a solid which was dissolved in methanol and precipitated by addition of diethyl ether. The precipitate is washed by ether 3 times to afford the pure product, namely, the salt form of irinotecan (i.e., the compound of formula III-A). The yield of the desired product is quantitative. Alternatively, the product from Example 1 is dissolved in water and 12N HCl is added drop wise to the solution. The product precipitates out and is obtained by filtration. The yield is 95percent.
100% With hydrogenchloride In tetrahydrofuran; water One gram of irinotecan was added to 120 mL of tetrahydrofuran. The resultant solution was stirred for 30 minutes in the presence or absence of 0.2 g of medicinal carbon. The medicinal carbon was filtered off by a membrane filter. While stirring the filtrate, 6 mol/L hydrochloric acid was added in an amount 1.05 times by mole as large as irinotecan and subjected to the same process as in Example 1. Note that the moisture absorbing time until the solution reached constant weight was about 100 hours. The results of infrared absorption spectrum and thermoanalysis (differential scanning calorimetry) for crystals obtained ina systemhavingmedicinal carbon added thereto are shown in Figures 4 and 5. It was confirmed that the obtained crystals is c-type crystals. The yield of the c-type crystals was 85.6percent in the case where medicinal carbon was added and 100percent in the case where no medicinal carbon was added.
95% With hydrogenchloride In water The product from Example 1 was dissolved in DCM and cooled down to 0° C. 12N HCl was added drop wise to this solution and stirred for 2-3 hours. The solvent was evaporated to get a solid which was dissolved in methanol and precipitated by addition of diethyl ether. The precipitate is washed by ether 3 times to afford the pure product, namely, the salt form of irinotecan (i.e., the compound of formula III-A). The yield of the desired product is quantitative. Alternatively, the product from Example 1 is dissolved in water and 12N HCl is added drop wise to the solution. The product precipitates out and is obtained by filtration. The yield is 95percent.
91.7% With hydrogenchloride In water; acetone at 22℃; for 25 - 46 h; Irinotecan was suspended in acetonitrile or acetone in accordance with the amounts shown in Table 1 and dissolved by adding, 6 mol/L hydrochloric acid. To each mixture solution, 1 mg of c-type crystals separately prepared was added and the solution was stirred at 22°C for 25 to 46 hours. The formed crystals were obtained by filtration, dried under reduced pressure, and subjected to a moisture absorption process performed by a saturated aqueous sodium chloride solution method until the crystals showed constant weight (about 80 hours). In this manner, the crystals of irinotecan hydrochloride were obtained. Table 1 shows the results of the preparations. [Table 1] No.Irinotecan (g)Solvent1) Hydrochloric acid2) Seed crystalsCrystallization time (hour)Yield (percent)AcetonitrileAcetone 15.0801.0-4683.425.01201.0c form2580.5310.01201.05c form4176.341.03601.05c form4191.71) mL/g (Irinotecan)2) Times by mole relative to irinotecan The crystals of irinotecan hydrochloride obtained above were subjected to infrared absorption spectrum analysis, powder X-ray diffraction analysis, and thermoanalysis. The results are shown in Figures 1 to 3. In the infrared absorption spectrum, strong absorption was observed at wavelengths of about 1757 cm-1, 1712 cm-1, 1667 cm-1 (Figure 1). In the powder X-ray diffraction, diffraction peaks (2ψ) were observed at 9.15°, 10.00°, 11.80°, 12.20°, 13.00° and 13.40°; however no strong peak was observed at 11.00°, which is intrinsic to the b-type crystals (Figure 2). In the thermoanalysis (differential scanning calorimetry), an endothermic peak near 90°C due to dehydration was not observed, which is intrinsically observed in the b-type crystals (Figure 3). The moisture content of the crystals was measured by the Karl Fischer method. As a result, the moisture content of No.3 was 3.96percent. Therefore, it turned out that the crystals above were obtained in the form of sesquihydrates (calculation value: 4.15percent). From the results above, it was confirmed that the crystals of irinotecan hydrochloride prepared in accordance with Nos. 1 to 4 are c-type, which are different from the b-type crystals conventionally crystallized from water.
90% With hydrogenchloride In water Example 3
7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (I)
In a suitable vessel were charged 7-Ethyl-10-hydroxycamptothecin (1 g), methylene dichloride, dimethylformamide (0.186 gm) and pyridine (3 ml) under nitrogen atmosphere.
A solution of [1,4']bipiperidinyl-1'-carbonyl chloride (0.88 g), methylene dichloride and triethylamine (1 ml) was prepared and added to the above suspension and stirred at 30-40° C. for 2 hours.
The solvent was distilled out under reduced pressure at 50° C. and hexane was added under stirring as an antisolvent to isolate crystalline compound, which was then filtered, washed with hexane and dried under reduced pressure at 50° C.
The yield was 1.30 g (86.89percent); HPLC purity-99.8percent
90% With hydrogenchloride In water at 2 - 70℃; for 20 h; Example 5 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin hydrochloride Trihydrate (CPT-11) In a suitable vessel were charged 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin (27gm) obtained in Example 2 and purified water. Subsequently, concentrated hydrochloric acid (5.76 gm) was added to dissolve the reaction mass completely. Reaction mass was treated with activated carbon and filtered. Further concentrated hydrochloric acid (13.5 gm) was added to the filtrate at 60-70 °C and the reaction mixture was maintained at 2-5 °C for 20 hours. The product so obtained was filtered, washed with isopropanol and dried under reduced pressure at 50°C. The yield was 28 g (90percent); HPLC purity 100percent. i) a powder X-ray diffraction pattern substantially in accordance with Figure 1; ii) a powder X-ray diffraction pattern having peaks at about 7.60, 8.21, 9.55, 10.96, 12.34, 14.33, 15.79, 19.92, 21.25, 22.73, 24.79, 25.99 and 27.68 +/- 0.2 degrees 20;
90% With hydrogenchloride In water at 70℃; for 3 h; 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.
89.8%
Stage #1: With hydrogenchloride In water at 80℃;
Stage #2: at 20℃; for 12 h;
SN-38B-11 (1.00 g, 1.7 mmol) obtained in Example 10 was suspended in 1/10 N hydrochloric acid (20 mL, 2.0 mmol), and the suspension was heated at about 80°C to dissolve in. Acetonitrile (100 mL) was added to the solution, and the mixture was stirred at room temperature for overnight. The precipitates were filtered, dried, and humidified under 75percent RH afforded CPT-11 (0.95 mg, yield 89.8percent) as pale yellow crystalline powder.
85.6% With hydrogenchloride In tetrahydrofuran; waterMedicinal carbon present One gram of irinotecan was added to 120 mL of tetrahydrofuran. The resultant solution was stirred for 30 minutes in the presence or absence of 0.2 g of medicinal carbon. The medicinal carbon was filtered off by a membrane filter. While stirring the filtrate, 6 mol/L hydrochloric acid was added in an amount 1.05 times by mole as large as irinotecan and subjected to the same process as in Example 1. Note that the moisture absorbing time until the solution reached constant weight was about 100 hours. The results of infrared absorption spectrum and thermoanalysis (differential scanning calorimetry) for crystals obtained ina systemhavingmedicinal carbon added thereto are shown in Figures 4 and 5. It was confirmed that the obtained crystals is c-type crystals. The yield of the c-type crystals was 85.6percent in the case where medicinal carbon was added and 100percent in the case where no medicinal carbon was added.
76.3% With hydrogenchloride In water; acetonitrile at 22℃; for 25 - 46 h; Irinotecan was suspended in acetonitrile or acetone in accordance with the amounts shown in Table 1 and dissolved by adding, 6 mol/L hydrochloric acid. To each mixture solution, 1 mg of c-type crystals separately prepared was added and the solution was stirred at 22°C for 25 to 46 hours. The formed crystals were obtained by filtration, dried under reduced pressure, and subjected to a moisture absorption process performed by a saturated aqueous sodium chloride solution method until the crystals showed constant weight (about 80 hours). In this manner, the crystals of irinotecan hydrochloride were obtained. Table 1 shows the results of the preparations. [Table 1] No.Irinotecan (g)Solvent1) Hydrochloric acid2) Seed crystalsCrystallization time (hour)Yield (percent)AcetonitrileAcetone 15.0801.0-4683.425.01201.0c form2580.5310.01201.05c form4176.341.03601.05c form4191.71) mL/g (Irinotecan)2) Times by mole relative to irinotecan The crystals of irinotecan hydrochloride obtained above were subjected to infrared absorption spectrum analysis, powder X-ray diffraction analysis, and thermoanalysis. The results are shown in Figures 1 to 3. In the infrared absorption spectrum, strong absorption was observed at wavelengths of about 1757 cm-1, 1712 cm-1, 1667 cm-1 (Figure 1). In the powder X-ray diffraction, diffraction peaks (2ψ) were observed at 9.15°, 10.00°, 11.80°, 12.20°, 13.00° and 13.40°; however no strong peak was observed at 11.00°, which is intrinsic to the b-type crystals (Figure 2). In the thermoanalysis (differential scanning calorimetry), an endothermic peak near 90°C due to dehydration was not observed, which is intrinsically observed in the b-type crystals (Figure 3). The moisture content of the crystals was measured by the Karl Fischer method. As a result, the moisture content of No.3 was 3.96percent. Therefore, it turned out that the crystals above were obtained in the form of sesquihydrates (calculation value: 4.15percent). From the results above, it was confirmed that the crystals of irinotecan hydrochloride prepared in accordance with Nos. 1 to 4 are c-type, which are different from the b-type crystals conventionally crystallized from water.

Reference: [1] Patent: US2005/267141, 2005, A1, . Location in patent: Page/Page column 6
[2] Patent: EP1598356, 2005, A1, . Location in patent: Page/Page column 5
[3] Patent: US2005/267141, 2005, A1, . Location in patent: Page/Page column 6
[4] Patent: EP1598356, 2005, A1, . Location in patent: Page/Page column 4
[5] Patent: US2011/144342, 2011, A1, . Location in patent: Page/Page column 7
[6] Patent: EP2341046, 2011, A2, . Location in patent: Page/Page column 10
[7] Patent: WO2012/32531, 2012, A1, . Location in patent: Page/Page column 9
[8] Patent: EP1378505, 2004, A1, . Location in patent: Page 27, 41
[9] Patent: EP1598356, 2005, A1, . Location in patent: Page/Page column 5
[10] Patent: EP1598356, 2005, A1, . Location in patent: Page/Page column 4
[11] Patent: US2005/197355, 2005, A1, . Location in patent: Page/Page column 3
[12] Patent: EP1598356, 2005, A1, . Location in patent: Page/Page column 4
[13] Patent: WO2003/89413, 2003, A1, . Location in patent: Page/Page column 7
[14] Patent: US2007/208050, 2007, A1, . Location in patent: Page/Page column 9
[15] Patent: WO2008/35377, 2008, A2, . Location in patent: Page/Page column 8; 9; 10
[16] Patent: EP2189461, 2010, A1, . Location in patent: Page/Page column 4
[17] Patent: US2010/179180, 2010, A1, . Location in patent: Page/Page column 3
[18] Patent: WO2006/16203, 2006, A1, . Location in patent: Page/Page column 11
[19] Synthetic Communications, 2013, vol. 43, # 12, p. 1661 - 1667
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YieldReaction ConditionsOperation in experiment
94.3% With dmap In acetonitrile at 75℃; for 5 h; 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 2.5 h; 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.
Reference: [1] Patent: WO2005/19223, 2005, A1, . Location in patent: Page/Page column 4
[2] Patent: JP5863846, 2016, B2, . Location in patent: Paragraph 0036-0040
[3] Chinese Journal of Chemistry, 2018, vol. 36, # 11, p. 1035 - 1040
[4] Patent: WO2012/32531, 2012, A1, . Location in patent: Page/Page column 9
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  • [ 103816-19-9 ]
  • [ 86639-52-3 ]
  • [ 97682-44-5 ]
YieldReaction ConditionsOperation in experiment
95% With pyridine; acetamide; triethylamine In dichloromethane at 30 - 40℃; for 2 h; Inert atmosphere Example 2
7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (I)
In a suitable vessel were charged 7-Ethyl-10-hydroxycamptothecin (20 g), methylene dichloride, acetamide (3 gm) and pyridine (60 ml) under nitrogen atmosphere.
A solution of [1,4']bipiperidinyl-1'-carbonyl chloride (17.6 g), methylene dichloride and triethylamine (20 ml) was prepared and added to the above suspension and stirred at 30-40° C. for 2 hours.
The solvent was distilled out under reduced pressure at 50° C. and hexane was added under stirring as an antisolvent to isolate crystalline compound.
The crystalline compound was filtered, washed with hexane and dried under reduced pressure at 50° C.
The yield was 28.4 g (95percent). HPLC Purity-99.9percent
95% With pyridine In acetamide; dichloromethane at 30 - 40℃; for 2 h; Inert atmosphere Example 2
7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy- camptothecin (I)
In a suitable vessel were charged 7-Ethyl-10-hydroxycamptothecin (20 g), methylene dichloride, acetamide (3 gm) and pyridine (60ml) under nitrogen atmosphere.
A solution of [1,4']bipiperidinyl-1'-carbonyl chloride (17.6 g), methylene dichloride and triethylamine (20ml) was prepared and added to the above suspension and stirred at 30-40 °C for 2 hours.
The solvent was distilled out under reduced pressure at 50°C and hexane was added under stirring as an antisolvent to isolate crystalline compound.
The crystalline compound was filtered, washed with hexane and dried under reduced pressure at 50 °C.
The yield was 28.4 g (95 percent). HPLC Purity - 99.9percent
88% With 1,4-diaza-bicyclo[2.2.2]octane; N-ethyl-N,N-diisopropylamine In dichloromethane at 35 - 40℃; for 0.5 h; EXAMPLE 1
A mixture of 25.02 g (0.0637 mol) 7-ethyl-10-hydroxycamptothecin, 18.72 g (0.07 mmol) of 4-piperidinopiperidinecarbonylchloride, 0.99 g (6.4 mmol) DABCO and 400 ml dichloromethane is treated with 18.93 g (0.146 mol) N,N-Diisopropylethylamine (DIEA) at 35 to 40° C. After 0.5 h complete conversion (>99percent), is observed. Subsequently, the organic layer is washed 3 times with NH4Cl-solution (27percent), KHCO3-solution (25percent) and NaCl-solution (26percent). Active charcoal is added, and the suspension is warmed to reflux for at least 1 h. Charcoal is filtered off and subsequently 800 ml t-Butylmethylether (t-BME) is added within 30 min at reflux. The mixture is cooled to 35-40° C. (precipitation of the product) and stirred for at least 1 h at 35-40° C. The suspension is cooled to 0-5° C., stirred for at least 1 additional hour and subsequently filtered off and dried in vacuo. The crude product (Irinotecan free base) is crystallized from 2-methoxyethanol. Yield: 32.9 g (88percent of theory) Appearance: yellow, crystalline powder
63.5% With sodium hydrogencarbonate In pyridine; chloroform EXAMPLE 28
7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin
7-Ethyl-10-hydroxycamptothecin (790 mg, 2.01 mmol) and 1-chlorocarbonyl-4-piperidinopiperidine (910 mg, 3.95 mmol) were dissolved in anhydrous pyridine (50 ml), and the mixture was stirred for 1 hour at room temperature.
The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in CHCl3 (200 ml).
The solution was washed successively with a 7percent aqueous solution of NaHCO3 (200 ml), a saturated aqueous solution NaCl, and the CHCl3 layer was dried with MgSO4, filtered, and evaporated in vacuo.
The residual material was decolorized by passing it through a short silica gel column whereby 1.11 g (94.8percent in yield) of the title compound was obtained as a pale yellow mass, which was recrystallized from ethanol (ca. 60 ml) to give colorless needles (750 mg, 63.5percent in yield).
63.5% at 20℃; for 1 h; 790 mg (2.01 mmol) of 7-ethyl-10-hydroxycamptothecin (SN-38)And 910 mg (3.9 5 mmol) of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride,Was mixed with anhydrous pyridine (50 mL).The dissolved mixture was stirred at ambient temperature for 1 hour.The mixture was concentrated under reduced pressure.The concentrated residue was dried under reduced pressure.The dried residue was dissolved in chloroform (200 mL).The dissolved solution was washed successively with 7percent sodium bicarbonate (NaHCO 3) (200 mL) and saturated brine,Dry over sodium sulfate,And concentrated using a vacuum condenser.After concentration,The product was refined by liquid chromatography,Recrystallization with ethanol (60 mL) gave 750 mg (yield: 63.5percent) of the title compound.

Reference: [1] Patent: US2011/144342, 2011, A1, . Location in patent: Page/Page column 7
[2] Patent: EP2341046, 2011, A2, . Location in patent: Page/Page column 9
[3] Patent: EP1378505, 2004, A1, . Location in patent: Page 26, 41
[4] Patent: US2007/135471, 2007, A1, . Location in patent: Page/Page column 2-3
[5] Patent: US4604463, 1986, A,
[6] Patent: JP5863846, 2016, B2, . Location in patent: Paragraph 0041
[7] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 6, p. 1446 - 1454
[8] Journal of Organic Chemistry, 1997, vol. 62, # 19, p. 6588 - 6597
[9] Patent: US2005/272757, 2005, A1, . Location in patent: Page/Page column 13; 4/8
[10] Patent: US2007/208050, 2007, A1, . Location in patent: Page/Page column 7; 7-8
[11] Patent: WO2006/16203, 2006, A1, . Location in patent: Page/Page column 10
[12] Synthetic Communications, 2013, vol. 43, # 12, p. 1661 - 1667
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  • [ 75-44-5 ]
  • [ 86639-52-3 ]
  • [ 97682-44-5 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: at -10 - 20℃; for 3 h;
Stage #2: for 0.5 - 2 h;
Phosgene trihydrate was dissolved in a chlorinated solvent, such as DCM under an argon atmosphere and cooled down to a low temperature in the range of -10 to 0° C. To this solution was added sequentially, piperidinopiperidine in DCM drop wise, followed by the addition of N,N-diisopropylethylamine (Huenig's base) or TEA drop wise. The reaction mixture was stirred at this temperature for one hour and slowly warmed to around room temperature and kept at this temperature for 2 hours. After this time, a solution of SN-38 in pyridine was added drop wise and the solution was left to react for 30 minutes to 2 hours or until the complete consumption of starting material as evidenced by TLC. The reaction was filtered and concentrated under vacuum to get the crude product. The crude product was dissolved in DCM and washed with water, dried over anhydrous Na2SO4 or MgSO4 and evaporated. This material was purified either by column chromatography using silica gel and eluted with mixture of DCM/MeOH or precipitation or crystallization to obtain the pure product, namely, irinotecan (i.e., the compound of formula III-A). The yield of the desired product is 94percent.
Reference: [1] Patent: US2005/267141, 2005, A1, . Location in patent: Page/Page column 6
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Reference: [1] Patent: WO2008/35377, 2008, A2, . Location in patent: Page/Page column 7
  • 7
  • [ 86639-52-3 ]
  • [ 97682-44-5 ]
Reference: [1] Patent: WO2012/7952, 2012, A1, . Location in patent: Page/Page column 5-6
  • 8
  • [ 103816-16-6 ]
  • [ 123-38-6 ]
  • [ 97682-44-5 ]
Reference: [1] Patent: EP2881396, 2015, A1, . Location in patent: Paragraph 0050-0052; 0053-0055
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  • [ 4897-50-1 ]
  • [ 97682-44-5 ]
Reference: [1] Chemistry - A European Journal, 1998, vol. 4, # 1, p. 67 - 83
[2] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 6, p. 1446 - 1454
[3] Patent: US2011/144342, 2011, A1,
[4] Patent: EP2341046, 2011, A2,
[5] Patent: WO2012/7952, 2012, A1,
[6] Patent: WO2012/32531, 2012, A1,
  • 10
  • [ 4897-50-1 ]
  • [ 32315-10-9 ]
  • [ 86639-52-3 ]
  • [ 97682-44-5 ]
YieldReaction ConditionsOperation in experiment
85.2%
Stage #1: With 1,4-diaza-bicyclo[2.2.2]octane; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.583333 h;
Stage #2: at 22 - 25℃; for 2.25 - 4.25 h;
EXAMPLE 2
4.00 g (10.2 mmol) 7-Ethyl-10-hydroxycamptothecin (purity 80percent) are dissolved in 60 ml CH2Cl2. 2.15 g (16.3 mmol) diisopropylethylamine, dissolved in 10 ml CH2Cl2, 0.16 g (1 mmol) DABCO and 1.1 g (36 mmol) bis(trichloromethyl)carbonate, dissolved in 10 ml CH2Cl2 are added at a temperature of 20° C. within 15 min. The solution is stirred for a further 20 min. Then 1.80 g (16 mmol) piperidinopiperidine, dissolved in 10 ml CH2Cl2, and 2.15 g (16.2 mmol) diisopropylethylamine, dissolved in 10 ml CH2Cl2, are added simultaneously within 15 min at 22° C. The resulting clear solution is stirred for 2-4 h at 25° C. The organic layer is extracted with 2.x.80 ml saturated NaHCO3 solution and 3.x.60 ml H2O. The aqueous layers are collected and extracted with 2.x.40 ml CH2Cl2. The combined organic layers are extracted again with 2.x.60 ml H2O, dried over 2 g Na2SO4, filtered and concentrated. The residue is recrystallized from 2-methoxyethanol and dried in vacuo. Yield: 5.1 g 85.2percent of theory Appearance: yellow powder
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