[ CAS No. 86639-52-3 ] {[proInfo.proName]}

Name: 86639-52-3|(S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione|98%
Brand: Ambeed
SKU: A366170
Rating: 92 (32 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 86639-52-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 86639-52-3 ]

SDS Specification

Alternatived Products of [ 86639-52-3 ]

Product Details of [ 86639-52-3 ]

CAS No. :	86639-52-3	MDL No. :	MFCD00871873
Formula :	C₂₂H₂₀N₂O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FJHBVJOVLFPMQE-QFIPXVFZSA-N
M.W :	392.40	Pubchem ID :	104842
Synonyms :	7-Ethyl-10-hydroxycamptothecin;NK 012;irinotecan metabolite.;10-hydroxy-7-ethylcamptothecin;7-ethyl-10-hydroxy-20(S)-Camptothecin

Calculated chemistry of [ 86639-52-3 ]

Physicochemical Properties

Num. heavy atoms :	29
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.32
Num. rotatable bonds :	2
Num. H-bond acceptors :	6.0
Num. H-bond donors :	2.0
Molar Refractivity :	107.11
TPSA :	101.65 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-7.15 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.75
Log Po/w (XLOGP3) :	2.18
Log Po/w (WLOGP) :	2.09
Log Po/w (MLOGP) :	1.55
Log Po/w (SILICOS-IT) :	3.71
Consensus Log Po/w :	2.46

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.92
Solubility :	0.0469 mg/ml ; 0.00012 mol/l
Class :	Soluble
Log S (Ali) :	-3.95
Solubility :	0.0442 mg/ml ; 0.000113 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-6.01
Solubility :	0.000383 mg/ml ; 0.000000977 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	4.07

Safety of [ 86639-52-3 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P501-P270-P264-P301+P310+P330-P405	UN#:	1544
Hazard Statements:	H301	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 86639-52-3 ]

* 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 [ 86639-52-3 ]
Downstream synthetic route of [ 86639-52-3 ]

[ 86639-52-3 ] Synthesis Path-Upstream 1~10

1
[ 97682-44-5 ]
[ 4897-50-1 ]
[ 86639-52-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 12, p. 3742 - 3752

2
[ 4897-50-1 ]
[ 86639-52-3 ]
[ 100286-90-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: With triethylamine In pyridine; dichloromethane at 30 - 40℃; for 1.5 h; Stage #2: for 0.5 h;	7-Ethyl-lO-hydroxycamptothecin (4.5 g) and pyridine (60 ml) were charged in a reaction vessel. A solution of [l,4']-bipiperidinyl-r-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 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 percent 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 percent).

Reference： [1] Patent: WO2006/84940, 2006, A1, . Location in patent: Page/Page column 5-6

3
[ 86639-52-3 ]
[ 100286-90-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: With pyridine; triethylamine In dichloromethane at 30 - 40℃; for 1.5 h; Stage #2: With 4-piperidinopiperidin In dichloromethane at 0 - 80℃; for 0.5 h; Stage #3: With hydrogenchloride In water; acetonitrile at 20℃; for 20 h;	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 percent 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 percent).
80%	Stage #1: With pyridine; triethylamine In dichloromethane at 20℃; for 2 h; Stage #2: With hydrogenchloride In water at 0 - 80℃; for 20 h;	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 percent) 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 percent).
80%	With triethylamine In pyridine; dichloromethane; water at 20℃; for 2 h;	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 percent) 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 percent).

161 g

Stage #1: With pyridine; triethylamine In dichloromethane at 20 - 40℃;
Stage #2: With hydrogenchloride In methanol

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 (1.0percent 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.

Reference： [1] Patent: WO2006/82279, 2006, A1, . Location in patent: Page/Page column 6-7
[2] Patent: WO2006/82279, 2006, A1, . Location in patent: Page/Page column 6
[3] Patent: WO2006/84940, 2006, A1, . Location in patent: Page/Page column 5
[4] Patent: EP2189461, 2010, A1, . Location in patent: Page/Page column 4
[5] Patent: US2010/179180, 2010, A1, . Location in patent: Page/Page column 2-3
[6] Patent: WO2006/16203, 2006, A1, . Location in patent: Page/Page column 11
[7] Patent: CN106632368, 2017, A, . Location in patent: Paragraph 0062; 0066

4
[ 103816-19-9 ]
[ 86639-52-3 ]
[ 100286-90-6 ]

Yield	Reaction Conditions	Operation in experiment
14.1 g	Stage #1: With dmap; triethylamine In dichloromethane at 20℃; Stage #2: With hydrogenchloride In methanol	7-ethyl-10-hydroxycamptothecin (10. 0 g) was added to dichloromethane (250 mL), and triethylamine (3 mL), 4-dimethylaminopyridine (0.5 g) (7.0 g) was added and the reaction stirred at room temperature overnight(20 ° C) and filtered to remove insolubles. The organic layer was separated, dried over anhydrous magnesium sulphate (5 g) for 0.5 h, and filtered to remove magnesium sulphate, bis (2-ethoxybenzoic acid), and sodium bisulfate (100 mL) The filter cake was rinsed twice with methylene chloride (50 mL) and the organic layers were combined. The solvent was distilled off under reduced pressure at 30 ° C to obtain crude irinotecan (14 g).The crude product of irinotecan obtained in step 1) was added to methanol (100 mL), and methanol solution of hydrogen chloride(20percent), to pH = 1 ~ 2, vacuum removal of excess hydrogen chloride and methanol solution, in hydrochloric acid irinotecan crude about16gThe crude irinotecan hydrochloride obtained in Step 2) was added to a mixed solution of purified water (100 mL) and acetone (300 mL)Liquid, heating dissolved, filtered hot, stirring crystallization at room temperature for 24 hours to obtain refined products 14. lg, purity 99. 9percent

Reference： [1] Patent: CN102260272, 2016, B, . Location in patent: Paragraph 0045; 0046; 0047; 0048; 0049; 0050; 0051

5
[ 86639-52-3 ]
[ 100286-90-6 ]

Reference： [1] Patent: US2011/144342, 2011, A1,
[2] Patent: EP2341046, 2011, A2,

6
[ 86639-52-3 ]
[ 97682-44-5 ]

Yield	Reaction Conditions	Operation 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 ]

Yield	Reaction Conditions	Operation 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

8
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[ 97682-44-5 ]

Yield	Reaction Conditions	Operation 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 Na₂SO₄or MgSO₄and 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

9
[ 86639-52-3 ]
[ 97682-44-5 ]

Reference： [1] Patent: WO2012/7952, 2012, A1, . Location in patent: Page/Page column 5-6

10
[ 4897-50-1 ]
[ 32315-10-9 ]
[ 86639-52-3 ]
[ 97682-44-5 ]

Yield	Reaction Conditions	Operation 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 CH₂Cl₂are 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 NaHCO₃solution 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

Reference： [1] Patent: US2007/135471, 2007, A1, . Location in patent: Page/Page column 4

[ 86639-52-3 ] Synthesis Path-Downstream 1~47

1
[ 103816-19-9 ]
[ 86639-52-3 ]
[ 97682-44-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With pyridine; acetamide; triethylamine; In dichloromethane; at 30 - 40℃; for 2h;Inert atmosphere;Product distribution / selectivity;	Example 27-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 2h;Inert atmosphere;Product distribution / selectivity;	Example 27-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
89%		SN-38B-11 (1.22 g, 2.08 mmol, yield 89percent, enantiopurity 99.8percent ee) was obtained from SN-38 (0.91 g, 2 .32 mmol) synthesized in Example 9 by the reported procedure (Sawada, S.; Okajima, S.; Aiyama, R.; Nokata, K.; Furuta, T.; Yokokura, T.; Sugino, E.; Yamaguchi, K.; Miyasaka, T. Chem. Pharm. Bull. 1991, 39, 1446.).Chiral HPLC operation conditions Column: DAICEL CHIRALCEL OD-H, 0.46cmID.x.25cm (No.ODH0CE-AK031) Guard cartridge: DAICEL CHIRALCEL OD-H, 0.4cmIDxlcm Injection amount:10mug/10muL Temperature: constant temperature about 40°C Flow rate: 1mL/min Mobile phase: dimethylamine : hexane : ethanol mixture(1 : 250 : 250) Detect: 254nm

88%	With 1,4-diaza-bicyclo[2.2.2]octane; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 35 - 40℃; for 0.5h;Product distribution / selectivity;	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 <strong>[103816-19-9]1-chlorocarbonyl-4-piperidinopiperidine</strong> (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%	With pyridine; at 20℃; for 1h;	790 mg (2.01 mmol) of 7-ethyl-10-hydroxycamptothecin (SN-38)And 910 mg (3.9 5 mmol) of <strong>[103816-19-9]1-chlorocarbonyl-4-piperidinopiperidine</strong> 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.
		The compound 4 was dissolved in pyridine and reacted with 4-piperidinopiperidinecarbamyl chloride dissolved in DCM. The DCM and pyridine are removed by distillation and the crude mixture was worked up by dissolving the crude mixture in DCM and treating with saturated aqueous sodium bicarbonate solution, collecting the organic phase and purifying using column chromatography to afford pure compound 2.
	With pyridine; at 40℃; for 2h;Product distribution / selectivity;	EXAMPLE 4 Preparation of Irinotecan 4-piperidinopiperidine carbamoyl chloride obtained from Example 3 was dissolved in 3.24 L of pyridine, followed by the addition of 54 g (0.137 moles) of 7-ethyl 10-hydroxy camptothecin, prepared according to Example 2. The mixture was heated to 40° C. with simultaneous stirring for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to about 27° C.; then filtered through a celite bed and the celite was washed with 200 ml of pyridine. The filtrate was concentrated to get 250 ml solvent remaining at 50° C. under a vacuum of 650 mm Hg. The obtained residue was dissolved in 1 L of water and filtered through celite. The obtained filtrate was washed with 500 ml of n-heptane and with 2500 ml of ethyl acetate. The aqueous layer was concentrated at 50° C. to a 250 ml volume remained and then codistilled with 21 L of isopropyl alcohol at 50° C. to get 500 ml solvent remaining. The obtained suspension was allowed to cool to room temperature and then filtered. The filtered solid was washed with 100 ml of isopropyl alcohol and finally subjected to drying at 70° C. for 3 hours under a vacuum of 650 mm Hg to afford 69.6 g of crude irinotecan. Purity: 94.7percent by HPLC. EXAMPLE 5; Preparation of Irinotecan; 18 g of 4-piperidinopiperidine carbamoyl chloride, obtained according to Example 3, was dissolved in 637 ml of pyridine, followed by the addition of 10 g of 7-ethyl 10-hydroxy camptothecin, prepared according to Example 2. The mixture was heated to 40° C. with simultaneous stirring for 2 hours under a nitrogen atmosphere. The above reaction mixture was cooled to about 27° C., and then filtered through a celite bed. The filtrate was concentrated at 50° C. under a vacuum of 650 mm Hg to a volume of 40 ml. 185 ml of n-heptane was added to the residue and concentrated at 50° C. under vacuum of 580 mm Hg to a volume of 50 ml. The above step was repeated two more times and then 185 ml of water was charged to the resultant residue. Adjusted the pH of the reaction mixture to 5.7 with 1 ml of acetic acid and then separated the two layers, and washed the aqueous layer with 2.x.92.5 ml of ethyl acetate. The obtained aqueous layer was concentrated at 45° C. under a vacuum of 590 mm Hg to a volume of 50 ml. 185 ml of isopropyl alcohol was charged to the residue and concentrated to a volume of 50 ml. Again 185 ml of isopropyl alcohol was charged to the above obtained residue and concentrated at 45° C. under a vacuum of 580 mm Hg to a volume of 50 ml. The suspension was cooled to 27° C. and stirred for 1 hour. The obtained suspension was filtered and washed with 20 ml of isopropyl alcohol and the solid dried at 65° C. under a vacuum of 580 mm Hg for 4 hours to afford 11.5 g of the title compound. Purity: 96.47percent by HPLC.
	With pyridine; for 6 - 12h;	Example - 5; Preparation of Irinotecan (IRT-5); Dissolving 7-ethyl-10-hydroxycamptothecin (50g) obtained in example 4(c) in pyridine (200 ml) under stirring at room temperature. Adding to it a solution of 1-chlorocarbonyl-4-piperidino-piperidine base (90g) in pyridine (2000 ml) and stirring for further 6 hours to 12 hours. Distilling off pyridine completely under vacuum at a temperature preferably below 45°C, cool the residue to room temperature, dissolving in chloroform (2500 ml), washing the chloroform solution with an aqueous sodium bicarbonate, followed by water. Separating chloroform layer, removing chloroform completely under vacuum, adding n-hexane filtering, drying the solid, purifying by column chromatography to obtain purified Irinotecan (IRT-5, 30g)

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,p. 1446 - 1454
[8]Journal of Organic Chemistry,1997,vol. 62,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,p. 1661 - 1667

2
[ 35364-15-9 ]
[ 110351-94-5 ]
[ 86639-52-3 ]

Yield	Reaction Conditions	Operation in experiment
90.5 - 91.0%	With toluene-4-sulfonic acid; acetic acid; In toluene; at 103℃; for 5.25 - 5.33h;Product distribution / selectivity;	EXAMPLES; Example 1. 7-ethyl-10-hydroxy camptothecin hydrate; 100 g of (4S)-4-Ethyl-7,8-dihydro-4-hydroxy-lH-pyrano[3,4-fJindolizine-3,6,10(4H)-trione, 68 g of l-(2-amino-5-hydroxyphenyl)propan-l-one, 7.2 g of p- toluene sulfonic acid, 800 ml of toluene and 600 ml of acetic acid were charged. The mixture was heated to reflux (about 103 C) in about 20 minutes and refluxed for 2 hours whereafter 300 ml was distilled off. The mixture was refluxed for an additional 3 hours. 1-Butanol (2400 ml) was added at 80-90 0C. The mixture was refluxed for 10-15 minutes. The mixture was cooled to room temperature and stirred for about 20 hours. The crystalline product was filtered and washed with 1-butanol (100 ml) and ethanol (600 ml). The slightly yellowish product was dried under reduced pressure at 60-70 C. The yield was 141 g (90.5 %). The HPLC-purity was 99.9 %.; Example 2. 7-ethyl- 10-hydroxy camptothecin hydrate; 25 g of (4S)-4-Ethyl-7,8-dihydro-4-hydroxy-lH-pyrano[3,4-f]indolizine- 3,6,10(4H)-trione, 17 g of l-(2-amino-5-hydroxyphenyl)propan-l-one, 2.5 g of p- toluene sulfonic acid, 150 ml of toluene and 200 ml of acetic acid were charged. The mixture was heated to reflux (about 103 C) in 15 minutes. The mixture was refluxed for 2 hours and then 50 ml was distilled off. The mixture was refluxed for an additional 3 hours. Ethanol (400 ml) was added at 60-70 0C. The mixture was refluxed for 10-15 minutes. The mixture was cooled to room temperature and stirred for about 20 hours. The mixture was cooled to 0 +/- 5 0C and stirred for about 2 hours. The crystalline product was filtered and washed with ethanol (15 ml). The product was dried under reduced pressure at 40-50 C. The yield was 35.5 g (91.0 %). The HPLC-purity was 99.9 %.
89%		Compound (e) (0.36 g, 2.14 mmol) obtained in Example 7 and Compound (h) (0.50 g, 1. 82 mmol) were suspended in a mixture of acetic acid and toluene (AcOH-toluene; 1 : 1, 10 mL). p-Toluenesulfonic acid monohydrate (p-TsOH·H2O; 10 mg) was added to the suspens ion at room temperature, and the mixture was stirred at 100 C for 18 hours. The reaction mixture was condensed under reduced pressure, toluene (10 mL) was added to the residue, and mixture was condensed under reduced pressure again. Acetone (9 mL) was added to the residue and the mixture was stirred at room temperature 2 hours, the insoluble material was filtered and washed with acetone (2 mL, twice). The filtered material was dried under reduced pressure to give SN-38 (0.63 g, purity 97.7% by HPLC, yield 89%) as black solid. HPLC operation conditions Column: Inertsil ODS-2, 5 mum, 4.6 mm ID×250 mm(GL science-made) Temperature: constant temperature about 40C Flow rate: 1 mL/min Mobile phase: methanol - acetonitrile - 10 mM potassium dihydrogenphosphate (1 : 1 : 3) Detect: 254 nm SN-38;1H-NMR (400MHz, CDCl3) delta: 0.98 (3H, t, J = 7 Hz, CH3), 1.38 (3H, t, J = 7 Hz, CH3), 1.90 (2H, q, J = 7 Hz, CH2), 3.08 (2H, q, J = 7 Hz, CH2), 5.17 (2H, s, CH2O), 5.23 (1H, d, J = 16 Hz), 5.54 (1H, d, J = 16 Hz), 6.83 (1H, d, J = 9 Hz), 7.34-7.39 (3H, m).
89%	With toluene-4-sulfonic acid; In acetic acid; toluene; at 90℃; for 7h;Nitrogen atm.;	A mixture of Compound (h) (0.50 g, 1.82 mmol, content: 96.6%) and Compound (e) (0.36 g, 2.18 mmol) in a mixture of toluene - acetic acid (1:1, 10 mL) in the presence of p-TsOH · H2O (10 mg) was heated at 90 C with stirring under nitrogen gas atmosphere for 7 hrs. After cooling, the mixture was evaporated under reduced pressure to dryness. After 2 times of azeotoropic removal of acetic acid with toluene (10 mL), acetone (9 mL) was added to the residue and the suspension was stirred under nitrogen atmosphere for 30 min. The solid was collected by filtration, washed with acetone (2 mL × 2) and then dried under reduced pressure. SN-38 (Exp. 45): ocherous solid, 0. 63 g (89.1% yield), purity; 99.6% by HPLC (see Example 9). Exp. 44 in Table 17 shows the results of an experiment under the reported conditions; Henegar, K. E. ; Ashford, S. W. ; Baughman, T. A.; Sih, J. C.; Gu, R. L., J. Org. Chem. 1997, 62, 6588-6597. Under nitrogen gas atmosphere, the purity and yield of SN-38 are improved as shown in Table 17. [[Table 17]] Purity (%)Yield (%)Exp. 44Open vessel97.675Exp. 45N2 atm.99.689

75%	With toluene-4-sulfonic acid; In acetic acid; toluene; at 90℃; for 7h;open vessel;	A mixture of Compound (h) (0.50 g, 1.82 mmol, content: 96.6%) and Compound (e) (0.36 g, 2.18 mmol) in a mixture of toluene - acetic acid (1:1, 10 mL) in the presence of p-TsOH · H2O (10 mg) was heated at 90 C with stirring under nitrogen gas atmosphere for 7 hrs. After cooling, the mixture was evaporated under reduced pressure to dryness. After 2 times of azeotoropic removal of acetic acid with toluene (10 mL), acetone (9 mL) was added to the residue and the suspension was stirred under nitrogen atmosphere for 30 min. The solid was collected by filtration, washed with acetone (2 mL × 2) and then dried under reduced pressure. SN-38 (Exp. 45): ocherous solid, 0. 63 g (89.1% yield), purity; 99.6% by HPLC (see Example 9). Exp. 44 in Table 17 shows the results of an experiment under the reported conditions; Henegar, K. E. ; Ashford, S. W. ; Baughman, T. A.; Sih, J. C.; Gu, R. L., J. Org. Chem. 1997, 62, 6588-6597. Under nitrogen gas atmosphere, the purity and yield of SN-38 are improved as shown in Table 17. [[Table 17]] Purity (%)Yield (%)Exp. 44Open vessel97.675Exp. 45N2 atm.99.689
	With trifluoroacetic acid; In toluene; at 85 - 90℃; for 20h;Industry scale;Product distribution / selectivity;	Example 1 : 7-Ethyl-lO-hydroxycamptothecin (2)2-Amino-5-hydroxypropiophenone (AHPP; 2.08 kg) and (S)-Trione (2.70kg) along with trifluoroacetic acid (2.7 L) were taken in toluene (13.5 L) in a 25 L reactor. The contents were heated to 85-90C for 15 to 20 hrs (in process check shows the absence of (S)- Trione by HPLC). The contents were allowed to cool to room temperature and the upper toluene layer was removed and rejected. To the viscous bottom acidic layer, isopropyl alcohol (40.0 L) was added and the contents were heated to reflux (80-90C) for. 30 minutes and allowed to cool to room temperature. The solid was collected, washed with acetone (20 L) and air dried. Yield 3.9 kg (95%).The above compound was recrystalized by taking into dilute acetic acid (2.5% water in acetic acid; 40 L), heating to 100C for 1 hour, cooled to room temperature with stirring. The colourless crystalline product was filtered and washed with isopropyl alcohol (14 L) followed by acetone (20 L) and dried at 40C under vacuum. The yield was 3.20 kg (82%), HPLC purity 99.8% [a]D = -32C.

Reference： [1]Synthetic Communications,2013,vol. 43,p. 1661 - 1667
[2]Patent: WO2006/82279,2006,A1 .Location in patent: Page/Page column 5-6
[3]Patent: EP1378505,2004,A1 .Location in patent: Page 25-26, 40-41
[4]Patent: EP1378505,2004,A1 .Location in patent: Page 37
[5]Tetrahedron Asymmetry,2017,vol. 28,p. 843 - 848
[6]Patent: EP1378505,2004,A1 .Location in patent: Page 37
[7]Journal of Organic Chemistry,1997,vol. 62,p. 6588 - 6597
[8]Patent: WO2012/32531,2012,A1 .Location in patent: Page/Page column 8

3
[ 86639-53-4 ]
[ 86639-52-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With boron tribromide; sodium iodide; In N,N-dimethyl-formamide; at -10 - 20℃; for 3h;	The obtained 90.3 g of the intermediate VI was dissolved in 900 mL of DMF solvent, and then 167 g of NaI solvent was added thereto, and the temperature was lowered to -10 C.Thereafter, 139 g of BBr3 solution was added, and after completion of the reaction, the reaction was resumed at room temperature for 3 hours.Under the rapid stirring operation, the above reaction liquid was poured into a large amount of ice water, and a large amount of pale yellow solid was precipitated, and filtered by suction.The filter cake was washed with water and dried to give 77.1 g of 7-ethyl-10-hydroxycamptothecin in a yield of 92% and a purity of 98%.

Reference： [1]Patent: CN108570057,2018,A .Location in patent: Paragraph 0021; 0027-0028; 0037-0038; 0045-0046
[2]Chemistry - A European Journal,1998,vol. 4,p. 67 - 83
[3]Chinese Journal of Chemistry,2018,vol. 36,p. 1035 - 1040
[4]Chemistry - A European Journal,2011,vol. 17,p. 10462 - 10469
[5]Journal of Organic Chemistry,2012,vol. 77,p. 713 - 717

4
[ 97682-44-5 ]
[ 86639-52-3 ]
[1,4']bipiperidinyl-1'-carboxylic acid [ No CAS ]

Reference： [1]Biological and Pharmaceutical Bulletin,1997,vol. 20,p. 869 - 873

5
[ 86639-52-3 ]
[ 107-30-2 ]
SN-38 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h;	Compound [1] (<strong>[86639-52-3]SN-38</strong>) (2.0 g, 5.10 mmol) was suspended in methylene chloride (30 mL). Diisopropylethyl amine (DIPEA) (3.30 g, 25.5 mmol) was added followed by the addition of MOM-C1 (2.05 g, 25.5 mmol). The reaction mixture was stirred at ambient temperature for 24 h resulting in a mixture containing the 10-OH methoxymethyl <strong>[86639-52-3]SN-38</strong> derivative [2]. This mixture was diluted with methylene chloride, and washed with water, brine, dried (sodium sulfate) and filtered. The methylene chloride was removed under reduced pressure to isolate the 10-OH methoxymethyl <strong>[86639-52-3]SN-38</strong> derivative as a yellow solid. To remove impurities this yellow solid was triturated with a 1:1 (400 mL) mixture of ether and methylene chloride to isolate pure compound [2] (2.11 g, 95%).
80%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h;	Anhydrous CH2Cl2 (30 ml) was added into the flask with <strong>[86639-52-3]SN-38</strong> (2 g)and the mixture was stirred for 20 min at room temperature. Then ethyldiisopropylamine(3.3 g) and chloromethyl methyl ether (2.05 g)were added and the mixture was stirred for 24 h under room temperature. The solvent was removed under reduced pressure to give a crude product. And then, the crude product was purified by column chromatography (CH2Cl2:Methanol = 80:1) to afford compound 4 (1.78 g,80%). (M + H)+ = 437.1724; (M + Na)+ = 459.1522; 1H NMR (400 MHz, CDCl3):delta 7.86-7.70 (m, 1H), 7.36 (s, 1 H), 7.27 (d, 1H,J =11.3 Hz), 6.82 (d, 1H,J = 4.6 Hz), 5.20 (s, 2H), 5.13 (s, 2H), 4.99 (s,2H), 3.31 (s, 1H), 3.16 (s, 3H), 2.67-2.54 (m, 2H), 2.00-1.75 (m, 2H),0.98 (t, 3H, J = 7.6 Hz), 0.63 (t, 3H, J = 7.3 Hz).
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	Briefly, <strong>[86639-52-3]SN-38</strong> (1 equiv) was dissolved in anhydrous dichloromethane, and diisopropyl ethyl amine (DIPEA) (5 equiv) was added under nitrogen atmosphere. The reaction mixture was stirred for 10 min at room temperature followed by the addition of methoxylmethylchloride (MOMCl) (5 equiv). The resulting solution was left stirring overnight. The reaction was terminated. Then the reaction mixture was diluted by dichloromethane and washed several times with water, dried (MgSO4), filtered, and concentrated. Purification by chromatography on silica gel gave 10-MOM protected compound. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 3 equiv) was slowly added to a solution of 10-MOM protected compound (1 equiv), tert-butoxycarbonylamino acid (3equiv) and 4-(dimethylamino)pyridine (DMAP, 0.6 equiv) and anhydrous dichloromethane, which had been precooled to 0 C. The resulting solution was allowed to warm to room temperature and stirred overnight. The organic fraction was washed with HCl (0.1 N) and water and then extracted several times with CH2Cl2. Organic layers were combined and dried with MgSO4, followed by filtration and concentration. Purification of this residue by flash chromatography on silica gel gave chloromethyl methyl ether (MOM) and N-BOC protected prodrug. Deprotection of MOM and N-BOC groups was achieved simultaneously by stirring MOM and N-BOC protected prodrug in dichloromethane and trifluoracetic acid for 30 minutes at room temperature, followed by concentration under high vacuum and recrystalization in methanol and ethyl ether. Purity of final products was determined by HPLC and prodrug purity was found to be greater than 98% pure.

Reference： [1]Patent: WO2011/71672,2011,A1 .Location in patent: Page/Page column 26; 29
[2]Journal of Controlled Release,2015,vol. 220,p. 5 - 17
[3]Journal of the American Chemical Society,2002,vol. 124,p. 7650 - 7651
[4]Patent: US7064202,2006,B1 .Location in patent: Page/Page column 11
[5]Journal of Materials Chemistry B,2017,vol. 5,p. 661 - 670

6
[ 78287-27-1 ]
[ 86639-52-3 ]

Yield	Reaction Conditions	Operation in experiment
80.3%	With dihydrogen peroxide; acetic anhydride; acetic acid; at 50℃;	In a 20 L reactor, 150 g of <strong>[78287-27-1]7-ethyl<strong>[78287-27-1]camptothecin</strong></strong>, 15.0 kg of glacial acetic acid, and 1.6 kg of acetic anhydride were added, and 1.5 kg of hydrogen peroxide was slowly added dropwise under mechanical stirring, and the reaction was heated to 50 C.Waiting for the reaction to be complete,concentrate,Add the concentrate to purified water 10.0kg,Stirring for 12h,Drying by suction filtration gave 125.6 g of 7-ethyl-10-hydroxy<strong>[78287-27-1]camptothecin</strong> in a yield of 80.3%.
		Step - b:; Charging platinum oxide (14g) in glacial acetic acid (600 ml) flushing with hydrogen and heating to 50 - 60C under hydrogen atmosphere around 60 psi for about 2 hours. Cooling to room temperature and adding <strong>[78287-27-1]7-ethyl<strong>[78287-27-1]camptothecin</strong></strong> (70g) in DMSO (5 ml) and hydrogenating at a temperature of about 60c for a period of about 8 hours. Filtering the mixture, collecting the filtrate and adding DM water (300 ml) to it under nitrogen atmosphere, adding iodobenzene diacetate (168g) in three lots at room temperature, stirring for further 3 hours, adding aqueous sodium acetate solution (1600 ml), stirring for an hour.filtering, washing to obtain wet 7-ethyl-10-hydroxy<strong>[78287-27-1]camptothecin</strong>,[ 280g];

Reference： [1]Patent: CN108484624,2018,A .Location in patent: Paragraph 0032; 0038; 0040; 0045
[2]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 3183 - 3188
[3]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1446 - 1454
[4]Patent: WO2006/16203,2006,A1 .Location in patent: Page/Page column 10
[5]Patent: CN109796462,2019,A

7
4-piperidinopiperidine-1-carbonyl chloride hydrochloride [ No CAS ]
[ 86639-52-3 ]
[ 97682-44-5 ]

Yield	Reaction Conditions	Operation 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.

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,p. 1035 - 1040
[4]Patent: WO2012/32531,2012,A1 .Location in patent: Page/Page column 9

8
[ 75-44-5 ]
[ 86639-52-3 ]
[ 97682-44-5 ]

Yield	Reaction Conditions	Operation in experiment
94%		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

9
[ 4897-50-1 ]
[ 86639-52-3 ]
[ 100286-90-6 ]

Yield	Reaction Conditions	Operation in experiment
90%		7-Ethyl-lO-hydroxycamptothecin (4.5 g) and pyridine (60 ml) were charged in a reaction vessel. A solution of [l,4']-bipiperidinyl-r-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 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 %).

Reference： [1]Patent: WO2006/84940,2006,A1 .Location in patent: Page/Page column 5-6

10
4-piperidinopiperidine-1-carbonyl chloride hydrochloride [ No CAS ]
[ 86639-52-3 ]
[ 100286-90-6 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Patent: WO2006/82279,2006,A1 .Location in patent: Page/Page column 6-7
[2]Patent: WO2006/82279,2006,A1 .Location in patent: Page/Page column 6
[3]Patent: WO2006/84940,2006,A1 .Location in patent: Page/Page column 5
[4]Patent: EP2189461,2010,A1 .Location in patent: Page/Page column 4
[5]Patent: US2010/179180,2010,A1 .Location in patent: Page/Page column 2-3
[6]Patent: WO2006/16203,2006,A1 .Location in patent: Page/Page column 11
[7]Patent: CN106632368,2017,A .Location in patent: Paragraph 0062; 0066

11
[ 111-20-6 ]
7-ethyl-10-hydroxycamptothecin [ No CAS ]
decanedioic acid bis[(4S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3,4:6,7]indolizino[1,2-b]quinolin-9-yl]ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28.7%	With 2-chloro-1-methyl-pyridinium iodide In N,N-dimethyl-formamide at 20℃;	1 The Preparation of a Representative Lipophilic Di(Anticancer Drug) Compound: Sebacate bis(7-ethylcamptothecin-10-yl)ester Example 1 The Preparation of a Representative Lipophilic Di(Anticancer Drug) Compound: Sebacate bis(7-ethylcamptothecin-10-yl)ester A mixture containing 196 mg (0.5 mmol) of 7-ethyl-10-hydroxycamptothecin, 51 mg (0.25 mmol) of sebacic acid, 128 mg (0.5 mmol) of 2-chloro-1-methylpyridinium iodide, 122 mg (1 mmol) of 4-(dimethylamino)pyridine, and 25 mL of N,N-dimethylformamide was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated to about 5 mL under reduced pressure. The crude product was then purified by column chromatography on silica gel (chloroform-methanol) to provide sebacate bis(7-ethylcamptothecin-10-yl)ester, 68 mg, 28.7%. IR (νmax cm-1): 3303.03, 2925.01, 2867.67, 1749.25, 1659.00, 1598.38, 1556.79, 1509.37, 1460.94, 1414.50, 1376.89, 1306.83, 1226.71, 1155.73, 1107.40, 1052.28, 1032.45, 946.97, 918.77, 833.20, 807.82, 723.37, 665.93. MS (Positive ESI): m/z 951.7=[M+H]+ 1H NMR (300 MHz, CDCl3): δ 7.994-7.963 (2H, d, J=9.3 Hz), 7.778-7.770 (2H, d, J=9.0 Hz), 7.501 (2H, s), 7.447-7.408 (2H, dd, J1=9.0 Hz & J2=2.4 Hz), 5.746-5.239 (4H, q, J1=135.6 Hz & J2=16.2 Hz), 5.239-5.215 (4H, m), 3.959 (2H, s), 3.184-3.109 (4H, q, J=7.2 Hz, 2.711-2.663 (4H, t, J=7.2 Hz), 1.926-1.913 (4H, m), 1.584-1.494 (12H, m), 1.453-1.402 (6H, t, J=7.5 Hz), 1.046-0.997 (6H, t, J=7.2 Hz).

Reference： [1]Current Patent Assignee: ACHIEVE LIFE SCIENCES INC - US2007/141093, 2007, A1 Location in patent: Page/Page column 8-9

12
[ 24424-99-5 ]
[ 86639-52-3 ]
[ 362497-15-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With pyridine; In dichloromethane; at 20℃;	Disperse SN38 (2.0 g, 5.1 mmol) in 150 mL DCM.Boc2O (1.45 g, 6.64 mmol), pyridine (12.3 mL, 0.15 mol) was added thereto, and the mixture was reacted at room temperature overnight.After the reaction was completed, it was washed three times with 40 mL of 0.5 N HCl (aq), and washed with a saturated NaHCO3 solution.Dry anhydrous Na2SO4, filter and spin dry, lightThe yellow solid powder was 2.56 g, and the yield was 100%.
97.3%	In dichloromethane; at 20℃;	Di-tert-butyl dicarbonate (144 mg, 0.629 mol) was added into a suspension of 7-ethyl-10-hydroxy-camptothecin (<strong>[86639-52-3]SN-38</strong>, 190 mg, 0.484 mmol) in 19 mL of anhydrous dichloromethane, followed by the addition of anhydrous pyridine (1.157 mL, 14.365 mmol). The reaction suspension was stirred overnight at room temperature. The suspension was filtered and the filtrate was extracted with 0.5 N HCl (312 mL) and saturated NaHCO3 (112 mL). The organic phase was dried overMgSO4, filtered and evaporated under vacuum to give a pale yellow solid (compound 26, 232 mg, yield: 97.3%).
96%	With pyridine; In dichloromethane; at 20℃; for 24h;	To a solution of <strong>[86639-52-3]SN-38</strong> (1.64 g, 4.18 mmol) in dichloromethane (15 mL) and pyridine (3.04 mL, 37.6 mmol) was added di-tert-butyl dicarbonate (1.82 g, 8.36 mmol). The reaction was stirred at room temperature for 24 h, and all solvent was removed under vacuum. The remaining residue was redissolved in dichloromethane (20 mL), and this solution loaded onto an 80 g silica gel column. Eluting with 0% to 10% methanol in dichloromethane provided Boc-<strong>[86639-52-3]SN-38</strong> (1.98 g, 4.02 mmol, 96% yield).

96%	With pyridine; In dichloromethane; at 20℃; for 24h;	1003861 To a solution of <strong>[86639-52-3]SN-38</strong> (1.64 g, 4.18 mmol) in dichloromethane (15 mL)and pyridine (3.04 mL, 37.6 mmol) was added di-tert-butyl dicarbonate (1.82 g, 8.36mmol). The reaction was stirred at room temperature for 24 h, and all solvent wasremoved under vacuum. The remaining residue was redissolved in dichloromethane(20 mL), and this solution loaded onto an 80 g silica gel column. Eluting with 0% to10% methanol in dichloromethane provided Boc-<strong>[86639-52-3]SN-38</strong> (1.98 g, 4.02 mmol, 96%yield).
95.2%	With pyridine; In dichloromethane; at 20℃;	Compound 2 was prepared according to the method, with some modifications [31]. Briefly, di-tert-butyldicarbonate (2.7 g, 12.37mmol) and pyridine (25 ml) were added in a suspension of SN38 (9.17 mmol) in 360 ml CH2Cl2. The suspension was stirred overnight at room temperature. The mixture was washed with 0.5 N HCl (3100 ml) and saturated NaHCO3 (1100 ml). The organic phase was filtered through a Na2SO4 pump, dried, and evaporated at 30C under vacuum. The solids obtained were dried under vacuum at 50C to yield compound 2 (4.3 g, 95.2% yield).
95.2%	With pyridine; In dichloromethane; at 20℃;	Compound 8 was prepared according to the method that was described in our previous studies [41]. Briefly, di-tertbutyldicarbonate(2.7 g) and pyridine (25 ml) were added to the suspension of <strong>[86639-52-3]SN-38</strong> (3.6 g) in 360 ml CH2Cl2. The suspension was stirred overnight at room temperature. The mixture was washed with 0.5 N HCl (3 × 100 ml)and saturated NaHCO3 (1 × 100 ml). The organic phase was filtered, dried over Na2SO4, evaporated at 30C under vacuum. The obtained solids were dried under vacuum at 50C to give compound 7 (4.3 g,95.2% yield). (M + H)+ = 493.1989; (M + Na)+ = 515.1796; 1HNMR (400 MHz, CDCl3): delta 1.04 (3H, t, J = 7.2 Hz), 1.41 (t, 3H, J =7.6 Hz), 1.61 (s, 9H), 1.85-1.93 (m, 2H), 3.17(q, 2H, J = 7.6 Hz), 3.81(brs, 1H),5.27 (s, 2H), 5.31 (d, 1H, J = 16.4 Hz), 5.75 (d, 1H, J =16.0 Hz), 7.67 (dd, 1H, J = 2.4, 9.2 Hz), 7.72 (s,1H), 7.91 (d,1H, J =2.4 Hz), 8.28 (d,1H, J=9.2Hz).
90%	With pyridine; In dichloromethane; at 20℃; for 3h;	1 g (2.5 mmol) SN38 and 1 g (4.5 mmol) Di-tert-butyl dicarbonate were dissolved in CH2Cl2 and 5 mLpyridinewas used as a catalyst. After stirring for 3 h at room temperature, the reaction mixture was washed by aqueous hydrochloric acid solution and then dried over anhydrous MgSO4 to obtain 1.2 g Boc-SN38 in 90% yield, as characterized by 1H NMR spectroscopy (Fig. S2).
86%	With pyridine; In dichloromethane; at 20℃; for 12h;	To a solution of (S)-4,1 1 -diethyl-4, 9-dihydroxy- 1 ,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1 ,2- b]quinoline-3,14(4H)-dione (2.5 g, 6.37 mmol, 1 equiv.) in DCM (15 ml_) was added B C O (2.09 g, 9.56 mmol, 2.20 mL, 1 .5 equiv.) and pyridine (1 .01 g, 12.7 mmol, 1 .03 mL, 2 equiv.) at 20 C. The mixture was stirred at 20 C for 12 hr. The reaction mixture was concentrated under reduced pressure to give (S)-tert- butyl (4,1 1 -diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1 H-pyrano[3',4':6,7]indolizino[1 ,2-b]quinolin- 9-yl) carbonate (2.7 g, 86%) as a white solid.
82%	With pyridine; In dichloromethane; at 20℃;	Example 8 Boc-(10)-(<strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong>) (Compound 10) To a suspension of <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (compound 4, 2.45 g, 1 eq.) in 250 mL of anhydrous DCM at room temperature under N2 were added di-tert-butyl dicarbonate (1.764 g, 1.3 eq.) and anhydrous pyridine (15.2 mL, 30 eq.). The suspension was stirred overnight at room temperature. The hazy solution was filtered through celite (10 g) and the filtrate was washed with 0.5 N HCl three times (3150 mL) and a NaHCO3 saturated solution (1150 ml). The solution was dried over MgSO4 (1.25 g). The solvent was removed under vacuum at 30 C. The product was dried under vacuum at 40 C. (yield=82%, 2.525 g) 13C NMR (75.4 MHz, CDCl3) d 173.53, 157.38, 151.60, 151.28, 150.02, 149.70, 147.00, 146.50, 145.15, 131.83, 127.19, 127.13, 124.98, 118.53, 113.88, 98.06, 84.26, 72.80, 66.18, 49.33, 31.62, 27.73, 23.17, 13.98, 7.90.
82%	With pyridine; In dichloromethane; at 20℃;Inert atmosphere;	EXAMPLE 8. Boc-(10)-(<strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong>) (compound 10):; To a suspension of 7-ethyl-lO-hydroxycamptothecin (compound 4, 2.45 g, 1 eq.) in 250 mL of anhydrous DCM at room temperature under N2 were added di-tert-butyl dicarbonate (1.764 g, 1.3 eq.) and anhydrous pyridine (15.2 mL, 30 eq.). The suspension was stirred overnight at room temperature. The hazy solution was filtered through celite (10 g) and the filtrate was washed with 0.5 N HCl three times (3 x 150 mL) and a NaHCO3 saturated solution (1 x 150ml). The solution was dried over MgSO4 (1.25 g). The solvent was removed under vacuum at 30 C. The product was dried under vacuum at 40 C (yield = 82%, 2.525g) 13C NMR (75.4 MHz, CDCI3) 8 173.53, 157.38, 151.60, 151.28, 150.02, 149.70, 147.00, 146.50, 145.15, 131.83, 127.19, 127.13, 124.98, 118.53, 113.88, 98.06, 84.26, 72.80, 66.18, 49.33, 31.62, 27.73, 23.17, 13.98, 7.90.
81%	With pyridine; In dichloromethane; at 20℃;	Take Boc2O (361.5 mg, 1.66 mmol), SN38 (500 mg, 1.28 mmol) dissolved in 8 mL DCM.2 mL of pyridine was added and allowed to stand overnight at room temperature, followed by HCl (0.3 M) aqueous solution.The organic layer was dried over anhydrous sodium sulfate and filtered.After collecting the filtrate, the solvent was removed under reduced pressure; the solid was purified by column chromatography (dichloromethane:methanol=100:1).The objective product 4 (510 mg, yield 81%) was obtained.
80%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 50℃; for 4h;	(Boc)2O (145 mg, 0.66 mmol) and SN38 (200 mg, 0.51 mmol) were added to a 100 mL round bottom flask, dissolved in 15 mL of anhydrous dichloromethane and EDC (118.8 mg, 0.77 mmol) was added. After stirring at 50 C for 4 hours, the reaction solvent was removed and washed with saturated sodium bicarbonate and saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and the solvent was removed under reduced pressure. The residue 7a, Boc-SN38 (180 mg, 80%) was isolated by column chromatography (DCM: MeOH=120:1).
80%	With pyridine; In dichloromethane; at 20℃;	2.0g<strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (SN38),1.0 g of di-tert-butyl dicarbonate was suspended and suspended in 150 mL of anhydrous dichloromethane.8 mL of anhydrous pyridine was added dropwise, and the reaction was stirred at room temperature overnight. filter,The filtrate was washed three times with 0.5 M hydrochloric acid and once with saturated sodium bicarbonate solution.The organic phase was separated and dried over anhydrous magnesium sulfate. After drying, remove the solvent in vacuo.There was obtained 10-tert-butyl carbonate-7-ethyl-camptothecin (BOC-SN38, 1.22 g, 80%).
48%	pyridine; In N,N-dimethyl-formamide; at 20℃; for 12h;	Example 7: Synthesis and In vitro Analysis of CDP-Gly-<strong>[86639-52-3]SN-38</strong><strong>[86639-52-3]SN-38</strong> was derivatized with the amino acid glycine at the 20-OH position as shown in Scheme VIII. Briefly, 20(S)-<strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (<strong>[86639-52-3]SN-38</strong>, l.Og, 2.5 mmol) was dissolved in a mixture of 70 mL dimethylformamide (DMF) and 30 mL pyridine. A solution of di-tert-butyl-dicarbonate (0.83 g, 3.8 mmol) in 10 mL DMF was added and the mixture stirred at room temperature overnight (12 hours). The solvent was removed under vacuum to yield a yellow solid and re-crystallized from boiling 2-propanol (75 mL) to yield 20(s)-10-tert-butoxycarbonyloxy-7-ethyl- camptothecin (Boc-<strong>[86639-52-3]SN-38</strong>) as a yellow solid (0.6 g, 48% yield).
48%	With pyridine; In N,N-dimethyl-formamide; at 20℃; for 12h;	Example 153: Synthesis of CDP-Gly-<strong>[86639-52-3]SN-38</strong> Conjugate<strong>[86639-52-3]SN-38</strong> was derivatized with the amino acid glycine at the 20-OH position as shown in Scheme 1. Briefly, 20(S)-<strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (<strong>[86639-52-3]SN-38</strong>, l.Og, 2.5 mmol) was dissolved in a mixture of 70 mL dimethylformamide (DMF) and 30 mL pyridine. A solution of di-tert-butyl-dicarbonate (0.83 g, 3.8 mmol) in 10 mL DMF was added and the mixture stirred at room temperature overnight (12 hours). The solvent was removed under vacuum to yield a yellow solid and re-crystallized from boiling 2-propanol (75 mL) to yield 20(s)-10-tert-butoxycarbonyloxy-7-ethyl- camptothecin (Boc-<strong>[86639-52-3]SN-38</strong>) as a yellow solid (0.6 g, 48% yield).
48%	With pyridine; In N,N-dimethyl-formamide; at 20℃; for 12h;	Example 6 Synthesis of CDP-Gly-<strong>[86639-52-3]SN-38</strong> Conjugate <strong>[86639-52-3]SN-38</strong> was derivatized with the amino acid glycine at the 20-OH position as shown in Scheme 1. Briefly, 20(S)-<strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (<strong>[86639-52-3]SN-38</strong>, 1.0 g, 2.5 mmol) was dissolved in a mixture of 70 mL dimethylformamide (DMF) and 30 mL pyridine. A solution of di-tert-butyl-dicarbonate (0.83 g, 3.8 mmol) in 10 mL DMF was added and the mixture stirred at room temperature overnight (12 hours). The solvent was removed under vacuum to yield a yellow solid and re-crystallized from boiling 2-propanol (75 mL) to yield 20(s)-10-tert-butoxycarbonyloxy-7-ethyl-camptothecin (Boc-<strong>[86639-52-3]SN-38</strong>) as a yellow solid (0.6 g, 48% yield).
48%	With pyridine; In N,N-dimethyl-formamide; at 20℃; for 12h;	<strong>[86639-52-3]SN-38</strong> was derivatized with the amino acid glycine at the 20-OH position as shown in Scheme VIII. Briefly, 20(S)-<strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (<strong>[86639-52-3]SN-38</strong>, 1.0 g, 2.5 mmol) was dissolved in a mixture of 70 mL dimethylformamide (DMF) and 30 mL pyridine. A solution of di-tert-butyl-dicarbonate (0.83 g, 3.8 mmol) in 10 mL DMF was added and the mixture stirred at room temperature overnight (12 hours). The solvent was removed under vacuum to yield a yellow solid and re-crystallized from boiling 2-propanol (75 mL) to yield 20(s)-10-tert-butoxycarbonyloxy-7-ethyl-camptothecin (Boc-<strong>[86639-52-3]SN-38</strong>) as a yellow solid (0.6 g, 48% yield). Boc-<strong>[86639-52-3]SN-38</strong> (0.73g, 1.5 mmol), N-(tertbutoxycarbonyl)glycine (0.26g, 1.5 mmol) and 4- dimethylaminopyridine (DMAP, 0.18g, 1.5 mmol) were dissolved in anhydrous methylene chloride (30 mL) and chilled to 0C. 1,3-Diisopropylcarbodiimide (DIPC, 0.19g, 1.5 mmol) was added, the mixture stirred at 0 C for 30 minutes followed by stirring for 4 hours at room temperature. The mixture was diluted with methylene chloride to 100 mL, washed twice with an aqueous solution of 0.1N hydrochloric acid (25 mL), dried over magnesium sulfate and the solvent removed under vacuum. The resulting yellow solid was purified by flash chromatography in methylene chloride:acetone (9:1) followed by solvent removal under vacuum to yield 20-O-(N-(tert-butoxycarbonyl)glycyl)-10-tert- butyoxycarbonyloxy-7-ethylcamptothecin (diBoc-Gly-<strong>[86639-52-3]SN-38</strong>, 640 mg, 67% yield).
48%	With pyridine; In N,N-dimethyl-formamide; at 20℃;	<strong>[86639-52-3]SN-38</strong> was derivatized with the amino acid glycine at the 20-OH position as shown in Scheme 1. Briefly, 20(S)-<strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (<strong>[86639-52-3]SN-38</strong>, 1.0g, 2.5 mmol) was dissolved in a mixture of 70 mL dimethylformamide (DMF) and 30 mL pyridine. A solution of di-tert-butyl-dicarbonate (0.83 g, 3.8 mmol) in 10 mL DMF was added and the mixture stirred at room temperature overnight (12 hours). The solvent was removed under vacuum to yield a yellow solid and re-crystallized from boiling 2-propanol (75 mL) to yield 20(s)-10-tert-butoxycarbonyloxy-7-ethyl-camptothecin (Boc-<strong>[86639-52-3]SN-38</strong>) as a yellow solid (0.6 g, 48% yield).
2 g	With pyridine; at 20℃;	. Compound 9 (1.9 g) was dissolved into 15 ml pyridine and cooled down in an ice bath. (l3oc)20 (2.4 g) was added. The reaction was stirred at RT overnight. Volatiles were removed. The organic phase was separated and the aqueous phase was extracted with DCM, and washed with iN HC1. The combined the organic phase was dried over Na2 SO4 and concentrated to give compound 10(2.0 g) as a white solid.10107] 1H NMR (300 MHz, CDC13) 8.4-8.5 (s, 1H), 8.2-8.3(t, 1H), 7.9-8.0 (t, 1H), 7.8-7.9 (t, 1H), 7.6-7.7 (t, 1H), 7.3-7.4(t, 1H), 3.1-3.2 (t, 2H), 1.4-1.5 (s, 9H), 0.8-0.9 (m, 3H).
2 g	With pyridine; at 20℃;Cooling with ice;	1. Compound 9 (1.9g) was dissolved into 15ml pyridine and cooled down in an ice bath. (Boc)20 (2.4g) was added. The reaction was stirred at RT overnight. Volatiles were removed .The organic phase was separated and the aqueous phase was extracted with DCM, and washed with IN HC1. The combined the organic phase was dried over Na2S04 and concentrated to give compound 10 (2.0g) as a white solid. 1H NMR (300MHz, CDC13) 8.4-8.5(s, 1H), 8.2-8.3(t, 1H), 7.9-8.0(t, 1H), 7.8-7.9(t, 1H) , 7.6-7.7(t, 1H), 7.3-7.4(t, 1H), 3.1-3.2(t, 2H), 1.4-1.5(s, 9H), 0.8-0.9(m, 3H).
	With pyridine; In tetrahydrofuran; dichloromethane; at 20℃;	To a solution of <strong>[86639-52-3]SN-38</strong> (3g, 7.65 mmol) in DCM/THF (150 mL/150niL) was added (Boc)20 (2g, 9.16 mmol) and pyridine (20 mL). The suspension was stirred at room temperature until the solution turned clear. The solution was diluted with DCM (100 mL) and washed with 2N HCl (100 mLx3). The organic phase was collected, dried over Na2S04 and concentrated. The resulting crude product was used directly for the next step without purification.
	With pyridine;	Under the condition of pyridine, (Boc) 2O was used according to the common method known in the art to protect the hydroxyl at site 10 of <strong>[86639-52-3]SN-38</strong>, thereby giving Compound 23-2.
	With pyridine; In tetrahydrofuran; dichloromethane; at 20℃; for 6h;	SN38 (AK Scientifi, Inc., Mountain View, Calif.)was conjugated as described in literature (Bioorg Med Chem 1998, 6 (5), 55 1-62) with slight modification. 5N38 was dissolved in CH2C12/THF and treated with dit-butyl dicarbonate, and pyridine and stirred at room temperature for 6 h to selectively protect iO-hydroxy group of 5N38. The product will then be treated with boc glycine followed by DMAP, and DIPC was added dropwise at 0C. The stirring was continued for 6 hours at 0 C. and then at room temperature overnight. The reaction mixture was concentrated, treated with TFA, vortexed for 5 mm. The product was neutralized with diisopropylethylamine followed by the treatment of tert-butyldimethylsilylchioride (THDMS-Cl). The product was coupled with PEG using EDC and DMAP in DMF/DCM. The solvent was removed and purified by PD-b column to yield PEG5N38.
	With pyridine; In dichloromethane; at 20℃; for 36h;	To a solution of SN38 (1 g, 2.55 mmol, 1.0 eq.) in dichloromethane (400 mL) were added pyridine (5 mL) and Boc anhydride (6.39 g, 6.371 mmol, 2.5 eq.) and the reaction mixture was stirred at room temperature for 36 h. The reaction mixture was filtered and washed with 0.01N HCl (3×). The organic phase was separated, dried (sodium sulfate) and evaporated under reduced pressure to provide compound 1 (1.26 g), which was used in the next step without further purification.
	With pyridine; In dichloromethane; at 20℃; for 36h;	Example 1: Preparation of Compound 1 (0177) (0178) To a solution of SN38 (1 g, 2.55 mmol, 1.0 eq.) in dichloromethane (400 mL) were added pyridine (5 mL) and Boc anhydride (6.39 g, 6.371 mmol, 2.5 eq.) and the reaction mixture was stirred at room temperature for 36 h. The reaction mixture was filtered and washed with 0.01N HCl (3×). The organic phase was separated, dried (sodium sulfate) and evaporated under reduced pressure to provide compound 1 (1.26 g), which was used in the next step without further purification
11.82 g	With pyridine; In dichloromethane;	To an oven-dried 1000 mL 3-neck round bottom flask fitted with a stir bar was added <strong>[86639-52-3]SN-38</strong> (6, 10 g, 25.5 mmol). Cannula transferred DCM (489 mL) to the flask. Added pyridine (525.3 mmol, 42.3 mL) and di-tert-butyl dicarbonate (Boc2O) (42.3 mL, 33.2 mmol) sequentially to the flask. Stir overnight. To work up, transferred the reaction to a 1 L recovery flask and removed the solvent on a rotary evaporator. Recrystallized the product from boiling isopropanol. Collected the solid by filtration and washed the filtrate with cold isopropanol. Blew dry the solid under argon overnight to yield the product as a light-yellow solid (11.82 g).
	With pyridine; In dichloromethane; at 20℃;	Boc2O (362 mg, 1.3 eq) and pyridine (3.08 mL, 30 eq) was added tothe suspension of <strong>[86639-52-3]SN-38</strong> in DCM. The mixture was stirring at roomtemperature for overnight. The solution was washed by 1 N HCl, Sat.NaHCO3, brine, and dried with Na2SO4. The solvent was removed undervacuum to give the crude product (1.25 g, 100%).1H NMR (400 MHz,CDCl3) delta 8.22 (d, J=9.2 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.67 (s,1H), 7.63 (dd, J=9.2, 2.5 Hz, 1H), 5.72 (d, J=16.3 Hz, 1H), 5.29 (d,J=16.3 Hz, 1H), 5.23 (d, J=0.8 Hz, 2H), 4.25 (s, 1H), 3.14 (q,J=7.7 Hz, 2H), 1.94-1.85 (m, 2H), 1.62 (s, 9H), 1.40 (t, J=7.7 Hz,3H), 1.02 (t, J=7.4 Hz, 3H).

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13
[ 86639-52-3 ]
[ 58479-61-1 ]
[ 946062-01-7 ]

Yield	Reaction Conditions	Operation in experiment
95.8%	With triethylamine; In dichloromethane; at 20℃;Reflux;	2.0 g of 7-ethyl-10 hydroxycamptothecin (5.1 mmol, 1 eq) was weighed into a 250 mL reaction flask, and 100 mL of dichloromethane was added thereto, followed by stirring and suspension.After stirring at room temperature for 10 minutes, tert-butyldiphenylchlorosilane (7.8 ml, 30.58 mmol, 6 eq) and triethylamine (4.3 ml, 30.58 mmol, 6 eq) were successively added. The suspension was heated at reflux overnightThe HPLC reaction was almost complete. The reaction solution was concentrated under reduced pressure at 30-40C to give a thick slurry. 40 ml of isopropanol was added to the slurry to dissolve it at 40 C., and 40 ml of purified water was added dropwise to the solution. The resulting suspension was stirred for 1 hour, filtered on a Buchner funnel, and washed with 10 ml of isopropanol/water (1:1).Poly cake. The wet cake was transferred, beaten with 80 ml of isopropanol/water (1:3) for 1 hour, filtered on a Buchner funnel, 10 ml of isopropanol/water (1:3)Wash the filter cake. The filter cake is vacuum dried under vacuum at 45-55C.7-ethyl-10-O-tert-butyldiphenylsilylcamptothecin (1) was obtained as 3.08g. The purity and yield of compound 1 were determined by HPLC.
93%	With triethylamine; In dichloromethane;Reflux;	7-Ethyl-10-hydroxycamptothecin (2.0 g, 5.1 mmol) was added to 100 mL of dichloromethane, triethylamine (3.2 mL, 23 mmol) and TBDPSCl (5.3 mL, 20.4 mmol) were added, and the mixture was refluxed overnight.After cooling to room temperature, the organic phase was washed successively with diluted hydrochloric acid, saturated sodium bicarbonate, and saturated brine, separated, dried, and concentrated under reduced pressure.The concentrated liquid was dropped into a large amount of n-hexane for precipitation, filtered, and vacuum dried to obtain 3.0 g of yellow solid with a yield of 93%.
93%	With triethylamine; In dichloromethane;Reflux;	<strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (2.0g, 5.1mmol)Add 100mL of dichloromethane,Triethylamine (3.2 mL, 23 mmol) and TBDPSCl (5.3 mL, 20.4 mmol) were added thereto, and refluxed overnight.Cooled to room temperature, followed by dilute hydrochloric acid, saturated sodium bicarbonate,The organic phase was washed with saturated brine, separated, dried, and concentrated under reduced pressure.The concentrated droplets are poured into a large amount of n-hexane for precipitation,Filtration and vacuum drying gave 3.0 g of a yellow solid with a yield of 93%.

65%		Example 3 TBDPS-(10)-(<strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong>) (Compound 5) To a suspension of <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (compound 4, 2.0 g, 5.10 mmol, 1 eq.) in 100 mL of anhydrous DCM were added Et3N (4.3 mL, 30.58 mmol, 6 eq.) and TBDPSC1 (7.8 mL, 30.58 mmol, 6 eq.). The reaction mixture was heated to reflux overnight and then, was washed with a 0.2 N HCl solution (2*50 mL), a saturated NaHCO3 solution (100 mL) and brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated under vacuum. The residue was dissolved in anhydrous DCM and precipitated by addition of hexanes. The precipitation with DCM/hexanes was repeated to get rid of excess TBDPSCl. The solids were filtered and dried under vacuum to give 2.09 g of product. (65% yield). 1H NMR (300 MHz, CDCl3): delta 0.90 (3H, t, J=7.6 Hz), 1.01 (3H, t, J=7.3 Hz), 1.17 (9H, s), 1.83-1.92 (2H, m), 2.64 (2H, q, 6.9 Hz), 3.89 (1H, s, OH), 5.11 (2H, s), 5.27 (1H, d, J=16.1 Hz), 5.72 (1H, d, J=16.4 Hz), 7.07 (2H, d, J=2.63 Hz), 7.36-7.49 (7H, m), 7.58 (1H, s), 7.75-7.79 (4H, m), 8.05 (1H, d, J=9.4 Hz). 13C NMR (75.4 MHz, CDCl3): delta 7.82, 13.28, 19.52, 22.86, 26.48, 31.52, 49.23, 66.25, 72.69, 97.25, 110.09, 117.57, 125.67, 126.57, 127.65, 127.81, 130.02, 131.69, 131.97, 135.26, 143.51, 145.05, 147.12, 149.55, 149.92, 154.73, 157.43, 173.72.
65%	With triethylamine; In dichloromethane;Reflux;	EXAMPLE 3. TBDPS-(10)-(<strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong>) (compound 5):; To a suspension of 7-ethyl-lO-hydroxycamptothecm (compound 4, 2.0 g, 5.10 mmol, 1 eq.) in 100 mL of anhydrous DCM were added Et3N (4.3 mL, 30.58 mmol, 6 eq.) and TBDPSCl (7.8 mL, 30.58 mmol, 6 eq.). The reaction mixture was heated to reflux overnight and then, was washed with a 0.2 N HCl solution (2 x 50 mL), a saturated NaHCO3 solution (100 mL) and brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated under vacuum. The residue was dissolved in anhydrous DCM and precipitated by addition of hexanes. The precipitation with DCM/hexanes was repeated to get rid of excess TBDPSCl. The solids were filtered and dried under vacuum to give 2.09 g of product. (65% yield). H NMR (300 MHz, CDCl3): delta 0.90 (3 H, t, J = 7.6 Hz), 1.01 (3 H, t, J = 7.3 Hz), 1.17 (9H, s), 1.83-1.92 (2H. m), 2.64 (2H, q, 6.9 Hz), 3.89 (1 H, s, OH), 5.11 (2H, s), 5.27 (1H, d, J = 16.1 Hz), 5.72 (1H, d, J = 16.4 Hz), 7.07 (2 H, d, J = 2.63 Hz), 7.36-7.49 (7 H, m), 7.58 (1 H, s), 7.75-7.79 (4H, m), 8.05 (1 H, d, J = 9.4 Hz). 13C NMR (75.4 MHz, CDCl3): delta 7.82, 13.28, 19.52, 22.86, 26.48, 31.52, 49.23, 66.25, 72.69, 97.25, 110.09, 117.57, 125.67, 126.57, 127.65, 127.81, 130.02, 131.69, 131.97, 135.26, 143.51, 145.05, 147.12, 149.55, 149.92, 154.73, 157.43, 173.72.
3.62 g	With triethylamine; In dichloromethane;	In a 250 mL round bottom flask, 5.00 g of Compound 20 (1.0 eq),100 ml of DCM, 3.89 g of TEA (3.0 eq) were added,3.50 g of TBDPS-Cl (1.0 eq) was added dropwise and dissolved in a solution of 20 ml of DCM and monitored by TLC, after which the reaction was washed with water,Washed with saturated brine,Dried over anhydrous sodium sulfate, and subjected to column chromatography, To obtain 3.62 g of a light yellow solid compound 21.

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[3]Patent: CN111110860,2020,A .Location in patent: Paragraph 0066; 0075; 0076; 0084
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14
[ 86639-52-3 ]
[ 18162-48-6 ]
[ 1023758-14-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 0.5h;	<strong>[86639-52-3]SN-38</strong> (compound 1, 160.0 mg, 0.4077 mmol), purchased from MedChemExpress, was suspended in anhydrous DCM (2 mL). DIPEA (0.22 mL, 1.3 mmol) was added followed by TBSC1 (154 mg, 1.02 mmol). The reaction was stirred for 30 minutes until compound 1 becomes soluble and complete conversion was observed by UPLC-MS. The reaction was quenched with MeOH, filtered through plug of silica, and concentrated in vacuo. The colorless oil obtained was triturated with Hex. The product precipitated out of solution. The precipitate was collected by filtration and rinsed with Hex to afford compound 2 (TBS-<strong>[86639-52-3]SN-38</strong>) as an off-white solid (200 mg, 0.395 mmol, 97%). LC-MS (Method B): tR = 1.86 min; MS (m/z) [M + H]+ calc for C28H35N2O5S1 507.23, found 506.96.
97%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 0.5h;	7-Ethyl-lO-hydroxy-camptothecin (<strong>[86639-52-3]SN-38</strong>) (160.0 mg, 0.4077 mmmol) purchased from MedChemExpress was suspended in anhydrous DCM (2 mL). DIPEA (0.22 mL, 1.3 mmol) was added followed by TBSC1 (154 mg, 1.02 mmol). The reaction was stirred for 30 minutes until <strong>[86639-52-3]SN-38</strong> becomes soluble and complete conversion was observed by UPLC-MS. The reaction was quenched with MeOH, filtered through plug of silica, and concentrated in vacuo. The colorless oil obtained was triturated with Hex. The product precipitated out of solution. The precipitate was collected by filtration and rinsed with Hex to afford TBS-<strong>[86639-52-3]SN-38</strong> (1) as an off-white solid (200 mg, 0.395 mmol, 97%). Rt = 1.86 min Hydrophobic Method UPLC. MS (m/z) [M + H]+ calc for C28H35N2O5S1 507.23, found 506.96.
85.2%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h;	<strong>[86639-52-3]SN-38</strong> (1.0 g, 2.55 mmol) was dispersed in 20 mL DMF, and DIEA(1.15 g, 8.93 mmol) was added. Then TBSCl (1.15 g, 7.65 mmol) wasadded in batches at 0 C. Then the mixture was stirring at room temperaturefor 4 h. The solvent was removed under vacuum to give thecrude product which was washed by petroleum ether and further purifiedby column chromatograph to afford yellow solid (1.1 g, 85.2%).

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6916 - 6926
[2]Patent: WO2019/236954,2019,A1 .Location in patent: Paragraph 0761-0762; 0795-0796
[3]Patent: WO2019/195665,2019,A1 .Location in patent: Paragraph 0308
[4]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 4706 - 4715

15
[ 97682-44-5 ]
[ 4897-50-1 ]
[ 86639-52-3 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 3742 - 3752

16
[ 4897-50-1 ]
[ 32315-10-9 ]
[ 86639-52-3 ]
[ 97682-44-5 ]

Yield	Reaction Conditions	Operation in experiment
85.2%		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

Reference： [1]Patent: US2007/135471,2007,A1 .Location in patent: Page/Page column 4

17
[ 86639-52-3 ]
[ 100286-90-6 ]

Reference： [1]Patent: US2011/144342,2011,A1
[2]Patent: EP2341046,2011,A2

18
C₁₂H₁₉Cl₃N₂O₂ [ No CAS ]
[ 86639-52-3 ]
[ 97682-44-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; at 20 - 40℃; for 22h;	Triphosgene (45 gm) was added to methylene dichloride (500 ml) at room temperature and then cooled to 0 to 10°C. A solution of 4-piperidinopiperidine (50 gm) in methylene dichloride (500 ml) was added to the reaction mass for 2 hours 30 minutes at 0 to 10°C. The temperature of the reaction mass was raised to room temperature, stirred for 1 hour and then added sodium bicarbonate (50 gm). The reaction mass was stirred for 1 hour at room temperature and the mass was filtered through hi-flow bed. To the mixture of 7-ethyl- 10-hydroxy camptothecin (50 gm) in pyridine (1250 ml) was added filtrate obtained above slowly for 2 hours at room temperature. The reaction mass was stirred for 20 hours at 35 to 40°C and the solvent was distilled off completely under reduced pressure at 45°C to obtained residue. To the residue was added methylene dichloride at room temperature. The organic layer was separated and dried over sodium sulfate. The solvent was distilled off completely under reduced pressure at 45°C and co- distilled with hexane. The reaction mass was cooled to room temperature and then added hexane (1000 ml). The reaction mass was stirred for 30 minutes at room temperature and filtered. To the wet solid obtained was added acetonitrile (1000 ml) and stirred for 30 minutes at room temperature. The solid obtained was collected by filtration and dried at room temperature for 8 hours to obtain 63 gm of irinotecan.

Reference： [1]Patent: WO2012/7952,2012,A1 .Location in patent: Page/Page column 5-6

19
[ 455-67-4 ]
[ 86639-52-3 ]

Reference： [1]Synthetic Communications,2013,vol. 43,p. 1661 - 1667

20
[ 86639-52-3 ]
[ 106-96-7 ]
[ 1436411-00-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium carbonate In dimethyl sulfoxide at 20℃; for 24h;	7-Ethyl-10-(Prop-2-ynyloxy) camptothecin (2a) To a stirring solution of 1a (1.00 g, 2.55 mmol), K2CO3 (0.61 g, 4.4 mmol) in DMSO (15 mL), propargyl bromide (0.36 mL, 3.21 mmol) was added dropwise. Reaction mixture was stirred for 24 h at room temperature and then diluted with 10 % MeOH in CH2Cl2 (80 mL). The resulting suspension was filtered and the residue was washed with 10 % MeOH in CH2Cl2 (~ 20 mL). The filtrate was washed with saturated K2CO3 (2 x 50 mL), saturated brine (1 x 40 mL) and dried on Na2SO4. Solvent was evaporated to approximately 1/10th of volume. Hexane:EtOAc (1:1 ratio, 60 mL) was added to the concentrate and the resulting suspension was filtered and washed with hexane:EtOAc (1:1 ratio, 40 mL) to give pure pale yellow solid 2a (0.84 g, 77%). 1H NMR (DMSO-d6, 400 MHz) δ 0.86 (3H, t, J = 7.2 Hz), 1.30 (3H, t, J = 7.6 Hz), 1.79-1.90 (2H, m), 3.15 (2H, q, J = 7.6 Hz), 3.65 (1H, t, J = 2.4 Hz), 5.03 (2H, d, J = 2.8 Hz), 5.25 (2H, s), 5.40 (2H, s), 6.50 (1H, s), 7.24 (1H, s), 7.48-7.51 (1H, dd, J = 2.4, 9.2 Hz), 7.57 (1H, d, J = 2.8 Hz), 8.06 (1H, d, J = 9.2 Hz). 13C NMR (DMSO-d6, 100 MHz) δ 7.8, 13.5, 22.3, 30.2, 49.4, 55.9, 65.2, 72.3, 78.7, 95.9, 103.8, 118.1, 122.0, 127.3, 128.1, 131.2, 143.6, 144.2, 145.9, 149.5, 149.7, 155.5, 156.5, 172.2.
64%	With potassium carbonate In N,N-dimethyl-formamide at 20℃;

Reference： [1]Guerrant, William; Patil, Vishal; Canzoneri, Joshua C.; Yao, Li-Pan; Hood, Rebecca; Oyelere, Adegboyega K. [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 11, p. 3283 - 3287]
[2]Adam, Catherine; Pérez-López, Ana M.; Hamilton, Lloyd; Rubio-Ruiz, Belén; Bray, Thomas L.; Sieger, Dirk; Brennan, Paul M.; Unciti-Broceta, Asier [Chemistry - A European Journal, 2018, vol. 24, # 63, p. 16783 - 16790]

21
[ 1510-21-0 ]
[ 86639-52-3 ]
cholesterol succinate-10-(7-ethyl-10-hydroxycamptothecin) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;	To a suspension of <strong>[86639-52-3]SN-38</strong> (100 mg, 0.255mmol) in CH2Cl2 (13 mL, 0.02 M) was added cholesterol hydrogen succinate (126 mg, 0.259mmol), EDC-HCl (104 mg, 0.544mmol), and DMAP (3.1 mg, 0.0255mmol). After stirring for 18 h at room temperature, the reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous solution of NH4Cl, water, and brine. The organic layer was then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH = 100:1) to give <strong>[86639-52-3]SN-38</strong>-cholesterol (11) (171 mg, 78%) as a pale yellow solid. 1HNMR (400 MHz, CDCl3) = 0.67 (3H, s), 0.852.02 (48H, m), 2.35 (2H, d, J = 8.0 Hz), 2.772.80 (2H, m), 2.952.99 (2H, m), 3.14 (1H, q, J = 3.6 Hz), 3.87 (1H, brs), 4.614.72 (1H, m), 5.25 (1H, s), 5.30 (1H, d, J = 16.4 Hz), 5.37 (1H, d, J = 4.0 Hz), 5.74 (1H, d, J = 16.4 Hz), 7.56 (1H, dd, J = 9.2, 2.4 Hz), 7.66 (1H, s), 7.82 (1H, brs), 8.23 (1H, d, J = 9.2 Hz) ppm. 13CNMR (100 MHz, CDCl3) delta = 8.0, 12.0, 14.1, 18.9, 19.5, 21.2, 22.7, 23.0, 23.3, 24.0, 24.4, 27.9, 28.2, 28.4, 29.5, 29.6, 31.8, 31.98, 32.04, 35.9, 36.3, 36.7, 37.1, 38.2, 39.7, 39.9, 42.5, 49.5, 50.2, 56.3, 56.8, 66.5, 72.9, 74.9, 98.3, 114.7, 118.8, 123.0, 125.6, 127.4, 127.6, 132.1, 139.6, 146.9, 147.4, 149.8, 150.3, 151.9, 157.8, 171.1, 171.6, 174.0 ppm. HR-MS (ESI-TOF): m/z calcd for C53H69N2O8 ([M + H]+) 861.5048, found 861.5048.
70%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-(dimethylamino)pyridinium tosylate; In dichloromethane; at 20℃; for 2.5h;	Example 3. Preparation of the conjugate (ic)A mixture of <strong>[86639-52-3]SN-38</strong> (20 mg, 0.050 mmol), 3-cholesteryl hemisuccinate (27 mg, 0.055 mmol) and DPTS catalyst (26 mg, 0.088 mmol) in DMAc (0.65 mL) and dichloromethane (0.2 mL) was stirred at room temperature, and EDC (11 mg, 0.056mmol) was added. The stirring was continued for 2.5 h, and the second portion of EDC (22.mg, 0.11 mmol) followed by dichloromethane (1 mL) were introduced. The stirringroom temperature was continued for 8 h. The resulting thick suspension was diluted with aqueous 5% solution of sodium dihydrophosphate (20 mL, acidified with phosphoric acid to pH = 3), extracted with ethyl acetate (25 mL), the organic phase was washed withwater (3x10 mL), with SM aqueous sodium chloride (3x25 mL), and dried. The crude product was purified by flash chromatography (silica-gel, chloroform - ethyl acetate, 100:0 to 3:2). Yield of ic: 30 mg (70%), the structure and purity were confirmed by TLC and 1H NMR.

Reference： [1]Bulletin of the Chemical Society of Japan,2019,vol. 92,p. 1305 - 1313
[2]Angewandte Chemie - International Edition,2014,vol. 53,p. 11532 - 11537
Angew. Chem.,2014,vol. 126,p. 11716 - 11721,6
[3]Patent: WO2013/188727,2013,A2 .Location in patent: Page/Page column 9

22
[ 100286-90-6 ]
[ 86639-52-3 ]

Yield	Reaction Conditions	Operation in experiment
	With Bis(p-nitrophenyl) phosphate; In aq. buffer; at 37℃;pH 7.5;Enzymatic reaction;	PNPA (1 mM), clopidogrel, and CPT-11 (10 muM each) were incubated in 50 mM Tris-HCl buffer (pH 7.5) with 5% (v/v) conditioned media from human CES1- or CES2-overexpressed cell culture as an enzyme source under the conditions with or without 1 mM bis-p-nitrophenylphosphate (BNPP). PNPA-hydrolase activity at 30 Cwas determined by monitoring the absorbance at 405 nm. Clopidogrel- and CPT-11-hydrolase activities at 37 C were determined by measuring formed metabolites, clopidogrel carboxylic acid and SN-38, respectively, by LC-MS/MS. Data represent the means ± SD of triplicate determinations.

Reference： [1]Drug Metabolism and Disposition,2013,vol. 41,p. 1888 - 1895

23
[ 110-91-8 ]
[ 50-00-0 ]
[ 86639-52-3 ]
[ 1605283-03-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With acetic acid In water; acetonitrile at 80℃; for 10h;	I Production of 7-ethyl-9-(N-morpholinyl)methyl-10-hydroxycamptothecin SN38 (7-ethyl-l O-hydroxycamptothecin) (3,3 mg; 8 x 10"3 mmol) was suspended in 2,4 ml CCN, and then supplemented with acetic acid (103 μL· ), 37 % aqueous CH20 (8μΤ,; 0.0986 mmol), 8,5 μ morpholine (0.098 mmol). The resulting mixture was mixed at a temperature of 80°C. After 10 h the solvent was evaporated off under a vacuum (at 40°C) and rinsed with diethyl ether (3 x lmL). The resulting residue was lyophilized using 2 ml H20 and dissolved in deuterated DMSO. On the basis of NMR spectra, we detected the presence of two substances: SN38 and 7-ethyl-9-(N-morpholinyl)methyl-l O-hydroxycamptothecin (efficiency: 33% ). LR-MS (ESI): m/z 393 [ M+H]+, 492 [M+H]+ . The deuteriated DMSO was evaporated off under a vacuum. The residue was extracted using 0.5% HC1 (3x 1 ml) in order to extract water-soluble derivatives of morpholinylcamptothecin. The insoluble 7-ethyl- 1 O-hydroxycamptothecin was removed through filtration. Next, this was purified using HPLC on an RP-C18 LPH column (150 mm x 10 mm) using the following liquid phase system: 20% CH3CN / 80% aqueous 0.1% HCOOH at a flow rate of 3ml/min. The course of the chromatography was monitored using UV detection at a wavelength of 260 nm. Fractions were collected (retention time: 8,5 min) and were lyophilized yielding a pure product (> 98%). Spectral data: 7-ethyl-9-(N-morpholinyl)methyl-l O-hydroxycamptothecin LR-MS (ESI): m/z 492 [M+H]+ NMR δ (D20, TSPA) 500 MHz: 1.01 (t, J=7.3 Hz, 3H), 1.45 (t, J=7.3Hz, 3H), 2.00 (m, 2H), 3.13 (m, 1H), 3.22 (m, 1H), 3.32 (m, 4H), 3.97 (m, 4H), 4.87 (d, J=15.0Hz, 1H), 4.88 (d, J=15.0Hz, 1H), 4.93 (d, J=18.7 Hz, 1H), 4.96 (d, J=18.7 Hz, 1H), 5.41 (J=16.14 Hz, 1H), 5.55 (J=16.14 Hz , 1H), 7,25 (d, J=9.17 Hz ,1H), 7.26 (s, 1H), 7.59 (d, J=9.17 Hz, 1H). 13C NMR 6 (D20, TSPA); HSQC 6.1, 13.4, 24.6, 30.5, 42.9, 49.8, 55.0. 63.4, 65.8, 97.8, 121.5, 130.7; HMBC 73.2, 1 17.5, 146.0. 146.9, 150.5, 174.30 UV nm: 378, 366, 329, 268, 224, 202. IR (KBr) cm"1 : 1038, 1056, 1108, 1162, 1261 , 1303, 1383, 1423, 1463, 1513, 1593, 1656, 1744, 2853, 2922, 2958, 3401
24%	With acetic acid In acetonitrile at 80℃; for 10h;

Reference： [1]Current Patent Assignee: NARODOWY INSTYTUT LEKOW - WO2014/64654, 2014, A1 Location in patent: Page/Page column 7; 8; 9
[2]Naumczuk, Beata; Wiktorska, Katarzyna; Lubelska, Katarzyna; Kawȩcki, Robert; Bocian, Wojciech; Bednarek, Elzbieta; Sitkowski, Jerzy; Chilmonczyk, Zdzisław; Kozerski, Lech [New Journal of Chemistry, 2016, vol. 40, # 9, p. 7978 - 7985]

24
C₃₄H₅₃ClO₆ [ No CAS ]
[ 86639-52-3 ]
7-ethyl-10-hydroxycamptothecin R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester-6-succinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.2%	With triethylamine; In N,N-dimethyl acetamide; at 20℃; for 4h;Inert atmosphere;	Under stirring, to a 50 mL reaction flask <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (196 mg, 0.5 mmol), anhydrous triethylamine (61 mg, 0.6 mmol) and anhydrous N,N-dimethylacetamide (20 mL) were added, and then thereto the solution A (6 mL) was slowly added. The reaction mixture was reacted for 4 h at room temperature under the protection of nitrogen gas with stirring, and monitored by thin layer chromatography. If there was a small amount of un-reacted <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong>, suitable amounts of the solution A and triethylamine were additionally added until the reaction was completed. The reaction solution was added into ethyl acetate (100 mL). The mixed solution was washed with water (50 mL×3) and the organic phase was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration. The filtrate was then concentrated to 10 mL, and then isolated by column chromatography (the stationary phase was 230-400 mesh silica gel, and the eluent was a mixture of hexane and acetone), to obtain 7-ethyl-10-hyroxycamptothecin R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester-6-succinate (340 mg, yield 76.2%). The mass spectrum and hydrogen nuclear magnetic resonance spectrum of the synthesized compound are shown in FIGS. 5 and 6. MS (Positive ESI): m/z=949.7 (M+H)+, 971.7 (M+Na)+. 1H NMR (400 MHz, CDCl3): delta ppm: 8.223-8.200 (d, J=9.2 Hz, 1H), 7.796 (s, 1H), 7.624 (s, 1H), 7.554-7.532 (d, J=8.8 Hz, 1H), 5.757-5.717 (d, J=16 Hz, 1H), 5.312-5.271 (d, J=16.4 Hz, 1H), 5.240 (s, 2H), 4.092-4.021 (m, 2H), 3.714 (s, 1H), 3.142-3.081 (m, 6H), 2.632-2.389 (m, 3H), 2.146 (s, 3H), 2.020 (s, 3H), 1.929 (s, 3H), 1.903-1.802 (m, 1H), 1.589-1.545 (m, 7H), 1.374-1.335 (t, J=7.8 Hz, 3H), 1.229 (m, 26H), 1.042-1.005 (t, J=7.4 Hz, 3H), 0.869-0.836 (t, J=6.6 Hz, 3H).
340 mg	With triethylamine; In chloroform; N,N-dimethyl acetamide; at 20℃; for 4h;Inert atmosphere;	3) Synthesis of 7-ethyl-10-hydmxycamptothecin R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester-6-succinate The reaction scheme is shown as follows: Procedure: To a 50 mL reaction flask R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester-6-monosuccinate (519 mg, mmol), thionyl chloride (238 mg, 2 mmol), N,N-dimethylformamide (10 muL) and anhydrous toluene (20 mL) were added under electromagnetic stirring. The reaction mixture was reacted for 4 h at room temperature under the protection of nitrogen gas and electromagnetic stirring. Toluene and the excessive amount of thionyl chloride were removed by distillation under reduced pressure to obtain a viscous liquid, and thereto anhydrous chloroform (10 mL) was added, to obtain solution A. Under stirring, to a 50 mL reaction flask <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (196 mg, 0.5 mmol), anhydrous triethylamine (61 mg, 0.6 mmol) and anhydrous N,N-dimethylacetamide (20 mL) were added, and then thereto the solution A (6 mL) was slowly added. The reaction mixture was reacted for 4 h at room temperature under the protection of nitrogen gas with stirring, and monitored by thin layer chromatography. If there was a small amount of un-reacted <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong>, suitable amounts of the solution A and triethylamine were additionally added until the reaction was completed. The reaction solution was added into ethyl acetate (100 mL). The mixed solution was washed with water (50 mL×3) and the organic phase was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration. The filtrate was then concentrated to 10 mL, and then isolated by column chromatography (the stationary phase was 230-400 mesh silica gel, and the eluent was a mixture of hexane and acetone), to obtain 7-ethyl-10-hyroxycamptothecin R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester-6-succinate (340 mg, yield 76.2 %). The mass spectrum and hydrogen nuclear magnetic resonance spectrum of the synthesized compound are shown in Figs. 5 and 6. MS(Positive ESI): m/z = 949.7(M+H)+, 971.7(M+Na)+. 1H NMR (400 MHz, CDCl3): delta ppm: 8.223-8.200 (d, J = 9.2 Hz, 1H), 7.796 (s, 1H), 7.624 (s, 1H), 7.554-7.532 (d, J = 8.8 Hz, 1H), 5.757-5.717 (d, J = 16 Hz, 1H), 5.312-5.271 (d, J = 16.4 Hz, 1H), 5.240 (s, 2H), 4.092-4.021 (m, 2H), 3.714 (s, 1H), 3.142-3.081 (m, 6H), 2.632-2.389 (m, 3H), 2.146 (s, 3H), 2.020 (s, 3H), 1.929 (s, 3H), 1.903-1.802 (m, 1H), 1.589-1.545 (m, 7H), 1.374-1.335 (t, J = 7.8 Hz, 3H), 1.229 (m, 26H), 1 042-1.005 (t, J = 7.4 Hz, 3H), 0.869-0 836 (t, J = 6.6 Hz, 3H).
	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere;	General procedure: A solution of appropriate 2-(alkyloxycarbonyl)-2,5,7,8-tetramethylchroman-6-yloxy acid derivative (3, 1 mmol),thionyl chloride (2 mmol), 10 muL DMF in 20 mL toluenewas stirring at room temperature under the atmosphere ofnitrogen for 4 h and the completion of reaction was monitoredby TLC. After evaporation, 10 mL chloroform wasadded to the reaction, and the resulted solution was addedslowly to the stirring solution of <strong>[86639-52-3]SN-38</strong> (5, 0.5 mmol) andtriethylamine (0.6 mmol) in 20 mL DMF in a 100 mL flask.The stirring was continued at room temperature under theatmosphere of nitrogen for 4 h and the completion ofreaction was monitored by TLC. The reaction on completionwas poured onto ethyl acetate (100 mL), and washed 3times with water (50 mL each). The organic phase wasevaporated and the residue was separated by chromatography(silica gel, 230-400 mesh) eluted by hexane/acetone.

Reference： [1]Patent: US2014/343088,2014,A1 .Location in patent: Paragraph 0151; 0154; 0156; 0157
[2]Patent: EP2799438,2014,A1 .Location in patent: Paragraph 0077-0080
[3]Medicinal Chemistry Research,2017,vol. 26,p. 3395 - 3406

25
C₂₄H₃₃ClO₆ [ No CAS ]
[ 86639-52-3 ]
7-ethyl-10-hyroxycamptothecin R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid n-hexyl ester-6-succinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In N,N-dimethyl acetamide; at 20℃; for 4h;Inert atmosphere;	Under stirring, to a 50 mL reaction flask 7-ethyl-10-hyroxycamptothecin (196 mg, 0.5 mmol), anhydrous triethylamine (61 mg, 0.6 mmol) and anhydrous N,N-dimethylacetamide (20 mL) were added, and then thereto the solution A (6 mL) was slowly added. The reaction mixture was reacted for 4 h at room temperature under the protection of nitrogen gas with stirring and monitored by thin layer chromatography. If there was a small amount of un-reacted <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong>, suitable amounts of the solution A and triethylamine were additionally added until the reaction was completed. The reaction solution was added into ethyl acetate (100 mL). The mixed solution was washed with water (50 mL×3) and the organic phase was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated to 10 mL, and then isolated by column chromatography (the stationary phase was 230-400 mesh silica gel, and the eluent was a mixture of hexane and acetone), to obtain 7-ethyl-10-hyroxycamptothecin R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid n-hexyl ester-6-succinate (358 mg, yield 90.0%). The mass spectrum and hydrogen nuclear magnetic resonance spectrum of the synthesized fat-soluble anti-cancer pharmaceutical compound are shown in FIGS. 7 and 8. MS (Positive ESI): m/z=809.5 (M+H)+, 831.5 (M+Na)+. 1H NMR (400 MHz, CDCl3) delta ppm: 8.223-8.200 (d, J=9.2 Hz, 1H), 7.795 (s, 1H), 7.625 (s, 1H), 7.555-7.532 (d, J=9.2 Hz, 1H), 5.759-5.718 (d, J=16.4 Hz, 1H), 5.313-5.273 (d, J=16 Hz, 1H), 5.241 (s, 2H), 4.066-4.020 (m, 2H), 3.705 (s, 1H), 3.142-3.083 (6H), 2.632-2.382 (m, 3H), 2.144 (s, 3H), 2.018 (s, 3H), 1.927 (s, 3H), 1.901-1.799 (m, 1H), 1.590-1.512 (m, 7H), 1.372-1.334 (t, J=7.6 Hz, 3H), 1.232-1.170 (m, 6H), 1.041-1.005 (t, J=7.2 Hz, 3H), 0.857-0.822 (t, J=7 Hz, 3H).
358 mg	With triethylamine; In chloroform; N,N-dimethyl acetamide; at 20℃; for 4h;Inert atmosphere;	3) Synthesis of <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> R-(+)-6-hydroxy-2,5,7,8 -tetramethylchroman-2-carboxylic acid n-hexyl ester-6-succinate Procedure: To a 50 mL reaction flask R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid n-hexyl ester-6-monosuccinate (439 mg, 1 mmol), thionyl chloride (238 mg, 2 mmol), N,N-dimethylformamide (10 muL) and anhydrous toluene (20 mL) were added under electromagnetic stirring. The reaction mixture was reacted for 4 h at room temperature under the protection of nitrogen gas and electromagnetic stirring. Toluene and an excessive amount of thionyl chloride were removed by distillation under reduced pressure to obtain a viscous liquid, and thereto anhydrous chloroform (10 mL) was added to obtain solution A. Under stirring, to a 50 mL reaction flask 7-ethyl-10-hyroxycamptothecin (196 mg, 0.5 mmol), anhydrous triethylamine (61 mg, 0.6 mmol) and anhydrous N,N-dimethylacetamide (20 mL) were added, and then thereto the solution A (6 mL) was slowly added. The reaction mixture was reacted for 4 h at room temperature under the protection of nitrogen gas with stirring and monitored by thin layer chromatography. If there was a small amount of un-reacted <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong>, suitable amounts of the solution A and triethylamine were additionally added until the reaction was completed. The reaction solution was added into ethyl acetate (100 mL). The mixed solution was washed with water (50 mL*3) and the organic phase was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated to 10 mL, and then isolated by column chromatography (the stationary phase was 230-400 mesh silica gel, and the eluent was a mixture of hexane and acetone), to obtain 7-ethyl-10-hyroxycamptothecin R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid n-hexyl ester-6-succinate (358 mg, yield 90.0 %). The mass spectrum and hydrogen nuclear magnetic resonance spectrum of the synthesized fat-soluble anti-cancer pharmaceutical compound are shown in and . MS(Positive ESI): m/z = 809.5(M+H)+, 831.5(M+Na)+. 1H NMR (400 MHz, CDCl3) delta ppm: 8.223-8.200 (d, J = 9.2 Hz, 1H), 7.795 (s, 1H), 7.625 (s, 1H), 7.555-7.532 (d, J = 9.2 Hz, 1H), 5.759-5.718 (d, J = 16.4 Hz, 1 H), 5.313-5.273 (d, J = 16 Hz, 1H), 5.241 (s, 2H), 4.066-4.020 (m, 2H), 3.705 (s, 1H), 3.142-3.083 (6H), 2.632-2.382 (m, 3H), 2.144 (s, 3H), 2.018 (s, 3H), 1.927 (s, 3H), 1.901-1.799 (m, 1H), 1.590-1.512 (m, 7H), 1.372-1.334 (t, J = 7.6 Hz, 3H), 1.232-1.170 (m, 6H), 1.041-1.005 (t, J = 7.2 Hz, 3H), 0.857-0.822 (t, J = 7Hz, 3H).
	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere;	General procedure: A solution of appropriate 2-(alkyloxycarbonyl)-2,5,7,8-tetramethylchroman-6-yloxy acid derivative (3, 1 mmol),thionyl chloride (2 mmol), 10 muL DMF in 20 mL toluenewas stirring at room temperature under the atmosphere ofnitrogen for 4 h and the completion of reaction was monitoredby TLC. After evaporation, 10 mL chloroform wasadded to the reaction, and the resulted solution was addedslowly to the stirring solution of <strong>[86639-52-3]SN-38</strong> (5, 0.5 mmol) andtriethylamine (0.6 mmol) in 20 mL DMF in a 100 mL flask.The stirring was continued at room temperature under theatmosphere of nitrogen for 4 h and the completion ofreaction was monitored by TLC. The reaction on completionwas poured onto ethyl acetate (100 mL), and washed 3times with water (50 mL each). The organic phase wasevaporated and the residue was separated by chromatography(silica gel, 230-400 mesh) eluted by hexane/acetone.

Reference： [1]Patent: US2014/343088,2014,A1 .Location in patent: Paragraph 0169; 0172; 0174; 0175
[2]Patent: EP2799438,2014,A1 .Location in patent: Paragraph 0086-0089
[3]Medicinal Chemistry Research,2017,vol. 26,p. 3395 - 3406

26
C₃₀H₄₅ClO₆ [ No CAS ]
[ 86639-52-3 ]
7-ethyl-10-hydroxycamptothecin R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid dodecyl ester-6-succinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.2%	With triethylamine; In N,N-dimethyl acetamide; at 20℃; for 4h;Inert atmosphere;	Under stirring, to a 50 mL reaction flask <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (196 mg, 0.5 mmol), anhydrous triethylamine (61 mg, 0.6 mmol) and anhydrous N,N-dimethylacetamide (20 mL) were added, and then thereto the solution A (6 mL) was slowly added. The reaction mixture was reacted for 4 h at room temperature under the protection of nitrogen gas with stirring, and monitored by thin layer chromatography. If there was a small amount of un-reacted <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong>, suitable amounts of the solution A and triethylamine were additionally added until the reaction was completed. The reaction solution was added into ethyl acetate (100 mL). The mixed solution was washed with water (50 mL×3) and the organic phase was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated to 10 mL, and then isolated by column chromatography (the stationary phase was 230-400 mesh silica gel, and the eluent was a mixture of hexane and acetone), to obtain 7-ethyl-10-hyroxycamptothecin R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid dodecyl ester-6-succinate (340 mg, yield 76.2%). The mass spectrum and hydrogen nuclear magnetic resonance spectrum of the synthesized fat-soluble anti-cancer pharmaceutical compound are shown in FIGS. 9 and 10. MS (Positive ESI): m/z=893.7 (M+H)+, 915.7 (M+Na)+. 1H NMR (400 MHz, CDCl3): delta ppm: 8.220-8.197 (d, J=9.2 Hz, 1H), 7.794 (s, 1H), 7.623 (s, 1H), 7.552-7.529 (d, J=9.2 Hz, 1H), 5.755-5.714 (d, J=16.4 Hz, 1H), 5.310-5.269 (d, J=16.4 Hz, 1H), 5.238 (s, 2H), 4.075-4.108 (m, 2H), 3.739 (s, 1H), 3.140-3.081 (m, 6H), 2.633-2.397 (t, 3H), 2.145 (s, 3H), 2.020 (s, 3H), 1.929 (s, 3H), 1.902-1.801 (m, 1H), 1.589-1.506 (s, 7H), 1.373-1.335 (t, J=7.6 Hz, 3H), 1.272-1.223 (m, 18), 1.041-1.004 (t, J=7.4 Hz, 3H), 0.869-0.835 (t, J=6.8 Hz, 3H).
340 mg	With triethylamine; In chloroform; N,N-dimethyl acetamide; at 20℃; for 4h;Inert atmosphere;	3) Synthesis of <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> R-(+)-6-hydroxy 2,5,7,8-tetramethylchroman-2-carboxylic acid dodecyl ester-6-succinate Procedure: To a 50 mL reaction flask R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid dodecyl ester-6-monosuccinate (519 mg, 1 mmol), thionyl chloride (238 mg, 2 mmol), N,N-dimethylformamide (10 muL) and anhydrous toluene (20 mL) were added under electromagnetic stirring. The reaction mixture was reacted for 4 h at room temperature under the protection of nitrogen gas and electromagnetic stirring. Toluene and an excessive amount of thionyl chloride were removed by distillation under reduced pressure to obtain a viscous liquid, and thereto anhydrous chloroform (10 mL) was added to obtain solution A. Under stirring, to a 50 mL reaction flask <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong> (196 mg, 0.5 mmol), anhydrous triethylamine (61 mg, 0.6 mmol) and anhydrous N,N-dimethylacetamide (20 mL) were added, and then thereto the solution A (6 mL) was slowly added. The reaction mixture was reacted for 4 h at room temperature under the protection of nitrogen gas with strring, and monitored by thin layer chromatography. If there was a small amount of un-reacted <strong>[86639-52-3]7-ethyl-10-hydroxycamptothecin</strong>, suitable amounts of the solution A and triethylamine were additionally added until the reaction was completed. The reaction solution was added into ethyl acetate (100 mL). The mixed solution was washed with water (50 mL*3) and the organic phase was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated to 10 mL, and then isolated by column chromatography (the stationary phase was 230-400 mesh silica gel, and the eluent was a mixture of hexane and acetone), to obtain 7-ethyl-10-hyroxycamptothecin R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid dodecyl ester-6-succinate (340 mg, yield 76.2%). The mass spectrum and hydrogen nuclear magnetic resonance spectrum of the synthesized fat-soluble anti-cancer pharmaceutical compound are shown in and . MS(Positive ESI): m/z = 893.7(M+H)+, 915.7(M+Na)+. 1H NMR (400 MHz, CDCl3): delta ppm: 8.220-8.197 (d, J = 9.2 Hz, 1H), 7.794 (s, 1H), 7.623 (s, 1H), 7.552-7.529 (d, J = 9.2 Hz, 1H), 5.755-5.714 (d, J = 16.4 Hz, 1H), 5.310-5.269 (d, J = 16.4 Hz, 1H), 5.238 (s, 2H), 4.075-4.108 (m, 2H), 3.739 (s, 1H), 3.140-3.081 (m, 6H), 2.633-2.397 (t, 3H), 2.145 (s, 3H), 2.020 (s, 3H), 1.929 (s, 3H), 1.902-1.801 (m, 1H), 1.589-1.506 (s, 7H), 1.373-1.335 (t, J = 7.6 Hz, 3H), 1.272-1.223 (m, 18), 1.041-1.004 (t, J = 7.4 Hz, 3H), 0.869-0.835 (t, J = 6.8 Hz, 3H).

Reference： [1]Patent: US2014/343088,2014,A1 .Location in patent: Paragraph 0187; 0190; 0192; 0193
[2]Patent: EP2799438,2014,A1 .Location in patent: Paragraph 0095-0098
[3]Medicinal Chemistry Research,2017,vol. 26,p. 3395 - 3406

27
[ 1383936-95-5 ]
[ 86639-52-3 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine In N,N-dimethyl acetamide at 20℃; for 4h; Inert atmosphere;	7.3 3) Synthesis of 7-ethyl-10-hydroxycamptothecin (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester-6-oxyacetate Under electromagnetic stirring, to a 50 mL reaction flask 7-ethyl-10-hydroxycamptothecin (196 mg, 0.5 mmol), anhydrous triethylamine (61 mg, 0.6 mmol) and anhydrous N,N-dimethylacetamide (20 mL) were added, and then thereto the solution A (6 mL) was slowly added. The reaction mixture was reacted for 4 h at room temperature under the protection of nitrogen gas and electromagnetic stirring, and monitored by thin layer chromatography. If there was a small amount of un-reacted 7-ethyl-10-hydroxycamptothecin, suitable amounts of the solution A and triethylamine were additionally added until the reaction was completed. The reaction solution was added into ethyl acetate (100 mL), and the solid substances were removed by filtration. The filtrate was concentrated to 10 mL, and then isolated by column chromatography (the stationary phase was 230-400 mesh silica gel, and the eluent was a mixture of hexane and actone), to obtain 7-ethyl-10-hydroxycamptothecin (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester-6-oxyacetate (259 mg, yield 57.0%).
259 mg	With triethylamine In chloroform; N,N-dimethyl acetamide at 20℃; for 4h; Inert atmosphere;	7.3 3) Synthesis of 7-ethyl-10-hydroxycamptothecin (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester-6-oxyacetate 3) Synthesis of 7-ethyl-10-hydroxycamptothecin (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester-6-oxyacetate The reaction scheme is shown as follows: Procedure: To a 50 mL reaction flask (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester-6-oxyacetic acid (533 mg, 1 mmol), thionyl chloride (238 mg, 2 mmol), N,N-dimethylformamide (10 µL) and anhydrous toluene (20 mL) were added under electromagnetic stirring. The reaction mixture was reacted for 4 h at room temperature under the protection of nitrogen gas and electromagnetic stirring. Toluene and an excessive amount of thionyl chloride were removed by distillation under reduced pressure to obtain a viscous liquid, and thereto anhydrous chloroform (10 mL) was added to obtain solution A. Under electromagnetic stirring, to a 50 mL reaction flask 7-ethyl-10-hydroxycamptothecin (196 mg, 0.5 mmol), anhydrous triethylamine (61 mg, 0.6 mmol) and anhydrous N,N-dimethylacetamide (20 mL) were added, and then thereto the solution A (6 mL) was slowly added. The reaction mixture was reacted for 4 h at room temperature under the protection of nitrogen gas and electromagnetic stirring, and monitored by thin layer chromatography. If there was a small amount of un-reacted 7-ethyl-10-hydroxycamptothecin, suitable amounts of the solution A and triethylamine were additionally added until the reaction was completed. The reaction solution was added into ethyl acetate (100 mL), and the solid substances were removed by filtration. The filtrate was concentrated to 10 mL, and then isolated by column chromatography (the stationary phase was 230-400 mesh silica gel, and the eluent was a mixture of hexane and actone), to obtain 7-ethyl-10-hydroxycamptothecin (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester-6-oxyacetate (259 mg, yield 57.0%).
	With triethylamine In N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere;	The synthesis of 2-(alkyloxycarbonyl)-tocopherol-6-yl 7-ethyl-camptothecin-10-yl ester derivatives (7) General procedure: A solution of appropriate 2-(alkyloxycarbonyl)-2,5,7,8-tetramethylchroman-6-yloxy acid derivative (3, 1 mmol),thionyl chloride (2 mmol), 10 μL DMF in 20 mL toluenewas stirring at room temperature under the atmosphere ofnitrogen for 4 h and the completion of reaction was monitoredby TLC. After evaporation, 10 mL chloroform wasadded to the reaction, and the resulted solution was addedslowly to the stirring solution of SN-38 (5, 0.5 mmol) andtriethylamine (0.6 mmol) in 20 mL DMF in a 100 mL flask.The stirring was continued at room temperature under theatmosphere of nitrogen for 4 h and the completion ofreaction was monitored by TLC. The reaction on completionwas poured onto ethyl acetate (100 mL), and washed 3times with water (50 mL each). The organic phase wasevaporated and the residue was separated by chromatography(silica gel, 230-400 mesh) eluted by hexane/acetone.

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - US2014/343088, 2014, A1 Location in patent: Paragraph 0232; 0235
[2]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - EP2799438, 2014, A1 Location in patent: Paragraph 0122-0124
[3]Zhang, Xiquan; Cao, Meng; Xing, Jing; Liu, Fei; Dong, Ping; Tian, Xin; Xu, Hongjiang; Zhang, Laifang; Gu, Hongmei; Yang, Ling; Li, Rui; Zheng, Ming; Ji, Min; Gu, Ning [Medicinal Chemistry Research, 2017, vol. 26, # 12, p. 3395 - 3406]

28
[ 37595-74-7 ]
[ 86639-52-3 ]
7-ethyl-10-(trifluoromethylsulfonyloxy)camptothecin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine; In N,N-dimethyl-formamide; at 60℃;	S1. Add to the reaction vessel7-Ethyl-10-hydroxycamptothecin (2.0 g, 5.09 mmol),N-phenylbis(trifluoromethanesulfonimide) 2.18 g (6.11 mmol) and 30 mL DMF,1.5 g (15 mmol) of TEA was added dropwise with stirring.S2. The reaction system is heated to 60 C for 2 to 3 hours.TLC dot plate detection material disappears,Drop to room temperature.S3. Pour the reaction solution in S2100mL ice water,a pale yellow solid precipitated,Stir for 10 to 30 minutes and filter.S4. The filter cake is washed twice with 20 mL of water.Then, it was dried at 40 to 50 C to obtain a sulfonate intermediate 1a (2.2 g, yield: 85%).
2.1 g	With diethylamine; In N,N-dimethyl-formamide; at 50℃; for 3h;	Stepl: To the solution of <strong>[86639-52-3]SN-38</strong> (1.2 g, 3.05 mmol) in DMF (30 mL), was added diethyl amine (0.85 mL, 6.12 mmol) and l,l,l-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl) methanesulfonamide (1.64 g, 4.58 mmol). The resultant mixture was stirred at 50 C for 3h. The reaction mixture was diluted with DCM and quenched with water. The organic layer was dried over Na2S04 and concentrated. The crude was purified by flash column to afford solid the triflate product (2.1 g).
1.27 g	With triethylamine; In N,N-dimethyl-formamide; for 3h;Inert atmosphere;	To a solution of <strong>[86639-52-3]SN-38</strong> (1.0 g, 2.5 mmol) and N, N-bis(trifluoromethylsulfonyl)aniline (1.3 g, 3.6 mmol) in anhydrous dimethyl formamide (5 mL) was added triethylamine (1.0 mL, 7.5 mmol) and the reaction mixture was stirred under argon at 60 C for 3 h. The reaction mixture was cooled and concentrated under reduced pressure to remove the solvents. The crude product was purified by flash chromatography to give compound 10 (1.27 g, 95%). White solid, m.p. 242-244C; 1H NMR (400MHz, CDCl3) delta 8.34 (d, J=9.3Hz, 1H), 7.97 (d, J=2.2Hz, 1H), 7.72 (s, 1H), 7.65 (dd, J=9.3, 2.2Hz, 1H), 5.72 (d, J=16.4Hz, 1H), 5.48-5.09 (m, 3H), 4.27 (s, 1H), 3.19 (q, J=7.5Hz, 2H), 2.00-1.80 (m, 2H), 1.42 (t, J=7.6Hz, 3H), 1.01 (t, J=7.3Hz, 3H). 13C NMR (101MHz, CDCl3) delta 173.77, 157.62, 153.52, 150.27, 148.27, 148.01, 146.27, 146.16, 133.57, 128.27, 127.38, 123.74, 120.51, 119.54, 117.32, 115.74, 98.79, 72.93, 66.34, 49.48, 31.81, 23.37, 14.12, 7.94.

134 mg

With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;

The <strong>[86639-52-3]SN-38</strong> (0.1g, 0.255mmol) under nitrogen and suspended in dry N, N- dimethylformamide (2.5ml) inThe resulting suspension was added triethylamine (52mg, 0.51mmol).Stirring,Subsequently thereto was added N- phenyl-bis (trifluoromethanesulfonyl) imide (137mg, 0.383mmol),Room temperature for 16 hours (TLC control of the main raw material reaction was complete).After completion of the reaction was added methylene chloride (5ml),Water (2 × 10ml),Stirred wash,Collect the organic phase,Dried over anhydrous sodium sulfate,Filtered, and concentrated in vacuo to give an off-white solid (134mg, 0.255mmol).

Reference： [1]Patent: CN108690036,2018,A .Location in patent: Paragraph 0043; 0044; 0045; 0046; 0047; 0048; 0049; 0050
[2]Patent: WO2016/4166,2016,A1 .Location in patent: Paragraph 0047; 0096
[3]European Journal of Medicinal Chemistry,2016,vol. 116,p. 84 - 89
[4]Patent: CN103848856,2016,B .Location in patent: Paragraph 0078; 0079
[5]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4694 - 4697

29
[ 112-80-1 ]
7-ethyl-10-hydroxycamptothecin [ No CAS ]
C₄₀H₅₂N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 4h; Inert atmosphere;	General Method for Synthesis of SN38-C6, -C10, -C14,-C18, and -C18:1. General procedure: SN-38 (100 mg, 0.255 mmol) was dissolved in CH2Cl2 (12.7 mL, 0.02 M), and then fatty acid (0.281 mmol),EDC (97.4 mg, 0.510 mmol), and DMAP (3.1 mg, 0.0255 mmol) were added sequentially at 25 °C. After stirring for 4 hat 25 °C, the reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous solution of NH4Cl, water, and brine. The organic layer was then dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography with CHCl3 to give SN-38 fatty acid ester.
52%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃;

Reference： [1]Koseki, Yoshitaka; Ikuta, Yoshikazu; Kamishima, Takaaki; Onodera, Tsunenobu; Oikawa, Hidetoshi; Kasai, Hitoshi [Bulletin of the Chemical Society of Japan, 2016, vol. 89, # 5, p. 540 - 545]
[2]Wang, Hangxiang; Xie, Haiyang; Wu, Jiaping; Wei, Xuyong; Zhou, Lin; Xu, Xiao; Zheng, Shusen [Angewandte Chemie - International Edition, 2014, vol. 53, # 43, p. 11532 - 11537][Angew. Chem., 2014, vol. 126, # 43, p. 11716 - 11721,6]

30
[ 86639-52-3 ]
[ 88495-63-0 ]
C₄₁H₄₆N₂O₁₂ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11532 - 11537
Angew. Chem.,2014,vol. 126,p. 11716 - 11721,6

31
[ 86639-52-3 ]
[ 142-62-1 ]
[ 905564-85-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 4h; Inert atmosphere;	General Method for Synthesis of SN38-C6, -C10, -C14,-C18, and -C18:1. SN-38 (100 mg, 0.255 mmol) was dissolved in CH2Cl2 (12.7 mL, 0.02 M), and then fatty acid (0.281 mmol),EDC (97.4 mg, 0.510 mmol), and DMAP (3.1 mg, 0.0255 mmol) were added sequentially at 25 °C. After stirring for 4 hat 25 °C, the reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous solution of NH4Cl, water, and brine. The organic layer was then dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography with CHCl3 to give SN-38 fatty acid ester. SN-38-C6: SN-38 (98.2 mg, 0.250 mmol), caproic acid (35 μL, 0.280 mmol), EDC (105.5 mg, 0.550 mmol), and DMAP (4.2 mg, 0.0344 mmol) afford SN-38-C6 (116.6 mg,0.238 mmol, 95%) as a pale-yellow solid. IR: νmax 1756, 1661,1599, 1225, 1213, 1179, 1164, 1135, 1106 cm1. 1HNMR(CDCl3, 400 MHz): 0.96 (3H, t, J = 7.2 Hz), 1.04 (3H, t,J = 7.2 Hz), 1.381.45(7H, m), 1.781.96(4H, m), 2.66 (2H, t,J = 7.6 Hz), 3.16 (2H, q, J = 7.6 Hz), 3.72 (1H, s), 5.27 (2H,s), 5.31 (1H, d, J = 16.4 Hz), 5.76 (1H, d, J = 16.4 Hz), 7.56(1H, dd, J = 9.2, 2.4 Hz), 7.65 (1H, s), 7.83 (1H, d, J = 2.4Hz), 8.24 (1H, d, J = 9.2 Hz). 13CNMR (CDCl3, 100 MHz): 8.0, 14.1, 22.4, 23.2, 24.6, 31.4, 31.7, 34.5, 49.5, 66.3, 73.0,98.2, 114.5, 118.7, 125.5, 127.4, 127.5, 132.1, 145.4, 146.8,147.3, 149.8, 150.3, 151.8, 157.7, 172.3, 173.9. HR-MS (ESITOF):m/z calcd for C28H31N2O6 ([M + H]+) 491.2177, found491.2175.
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane

Reference： [1]Koseki, Yoshitaka; Ikuta, Yoshikazu; Kamishima, Takaaki; Onodera, Tsunenobu; Oikawa, Hidetoshi; Kasai, Hitoshi [Bulletin of the Chemical Society of Japan, 2016, vol. 89, # 5, p. 540 - 545]
[2]Koseki, Yoshitaka; Ikuta, Yoshikazu; Cong, Liman; Takano-Kasuya, Mayumi; Tada, Hiroshi; Watanabe, Mika; Gonda, Kohsuke; Ishida, Takanori; Ohuchi, Noriaki; Tanita, Keita; Taemaitree, Farsai; Dao, Anh Thi Ngoc; Onodera, Tsunenobu; Oikawa, Hidetoshi; Kasai, Hitoshi [Bulletin of the Chemical Society of Japan, 2019, vol. 92, # 8, p. 1305 - 1313]

32
[ 334-48-5 ]
7-ethyl-10-hydroxycamptothecin [ No CAS ]
SN₃₈-undecanoate-C₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 4h; Inert atmosphere;	General Method for Synthesis of SN38-C6, -C10, -C14,-C18, and -C18:1. General procedure: SN-38 (100 mg, 0.255 mmol) was dissolved in CH2Cl2 (12.7 mL, 0.02 M), and then fatty acid (0.281 mmol),EDC (97.4 mg, 0.510 mmol), and DMAP (3.1 mg, 0.0255 mmol) were added sequentially at 25 °C. After stirring for 4 hat 25 °C, the reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous solution of NH4Cl, water, and brine. The organic layer was then dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography with CHCl3 to give SN-38 fatty acid ester.
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane

Reference： [1]Koseki, Yoshitaka; Ikuta, Yoshikazu; Kamishima, Takaaki; Onodera, Tsunenobu; Oikawa, Hidetoshi; Kasai, Hitoshi [Bulletin of the Chemical Society of Japan, 2016, vol. 89, # 5, p. 540 - 545]
[2]Koseki, Yoshitaka; Ikuta, Yoshikazu; Cong, Liman; Takano-Kasuya, Mayumi; Tada, Hiroshi; Watanabe, Mika; Gonda, Kohsuke; Ishida, Takanori; Ohuchi, Noriaki; Tanita, Keita; Taemaitree, Farsai; Dao, Anh Thi Ngoc; Onodera, Tsunenobu; Oikawa, Hidetoshi; Kasai, Hitoshi [Bulletin of the Chemical Society of Japan, 2019, vol. 92, # 8, p. 1305 - 1313]

33
7-ethyl-10-hydroxycamptothecin [ No CAS ]
[ 57-11-4 ]
7-ethyl-10-hydroxycamptothecin-10-stearate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 4h; Inert atmosphere;	General Method for Synthesis of SN38-C6, -C10, -C14,-C18, and -C18:1. General procedure: SN-38 (100 mg, 0.255 mmol) was dissolved in CH2Cl2 (12.7 mL, 0.02 M), and then fatty acid (0.281 mmol),EDC (97.4 mg, 0.510 mmol), and DMAP (3.1 mg, 0.0255 mmol) were added sequentially at 25 °C. After stirring for 4 hat 25 °C, the reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous solution of NH4Cl, water, and brine. The organic layer was then dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography with CHCl3 to give SN-38 fatty acid ester.
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane

Reference： [1]Koseki, Yoshitaka; Ikuta, Yoshikazu; Kamishima, Takaaki; Onodera, Tsunenobu; Oikawa, Hidetoshi; Kasai, Hitoshi [Bulletin of the Chemical Society of Japan, 2016, vol. 89, # 5, p. 540 - 545]
[2]Koseki, Yoshitaka; Ikuta, Yoshikazu; Cong, Liman; Takano-Kasuya, Mayumi; Tada, Hiroshi; Watanabe, Mika; Gonda, Kohsuke; Ishida, Takanori; Ohuchi, Noriaki; Tanita, Keita; Taemaitree, Farsai; Dao, Anh Thi Ngoc; Onodera, Tsunenobu; Oikawa, Hidetoshi; Kasai, Hitoshi [Bulletin of the Chemical Society of Japan, 2019, vol. 92, # 8, p. 1305 - 1313]

34
[ 86639-52-3 ]
[ 7693-46-1 ]
(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinolin-9-yl (4-nitrophenyl) carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 4h;Large scale;	<strong>[86639-52-3]SN-38</strong> (2.1 kg), THF (140.0 kg) and 4-nitrophenyl chloroformate (2.3 kg) were charged to a reactor and stirred. N,N-diisopropylethylamine (1.05 kg) was added to the reactor and the resulting mixture was stirred at ambient temperature for about 4 hours. A sample was pulled to monitor the completion of reaction by HPLC, ethyl acetate (48.0 kg) was added to the suspension, and stirring continued for about 4 hours. The solid was isolated by filtration, rinsed with ethyl acetate (25.3 kg) and dried under vacuum at ajacket temperature of about 50C to give STA-31-0222 (2.4 kg, 86% yield).
64%	With dmap; In dichloromethane; at 0℃; for 8h;	SN38 (1.0 g, 2.55 mmol) and 4-dimethylaminopyridine DMAP (140 mg, 1.3 mmol) were dissolved in 50 mL of dichloromethane, and p-nitrophenyl chloroformate (510 mg, 2.55 mmol) was added dropwise at 0 C. After a DCM solution (20 mL), the reaction was incubated at 0 C for 8 hours.The organic phase was washed with a 0.1M HCl solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 0.9 g of a white solid with a yield of 64%.
1.16 g		Nitrophenyl chloroformate (771 mg, 3.82 mmol) and DIPEA (1.25 mL, 7.50 mmol) were dissolved in DMF (20 mL) at 0 C and the reaction mixture was reacted 1 Hour. Then, N-triphenyl-N, N'-dimethylethylenediamine (2.65 mg, 7.98 mmol) was added to the system, and the mixture was reacted at room temperature for 16 hours.The reaction mixture was extracted with methylene chloride and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.The crude product was purified by column chromatography (PE: DCM = 1: 1 - DCM: MeOH = 30: 1) to afford 1 as a yellow foamy solid (1.16 g).

	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;	<strong>[86639-52-3]SN-38</strong> (94 mg, 0.24 mmol) was dissolved in N, N-dimethylformamide (2 mL),N, N-Diisopropylethylamine (39 mg, 0.3 mmol), p-nitrophenyl chloroformate (48 mg, 0.24 mmol)After stirring for 4 hours at room temperature, after the reaction was completed, a solution of compound 12 in dichloromethane was added and stirring continued overnight at room temperature.After concentration of the organic phase, a yellow solid (80 mg, 50%) was isolated by column chromatography (methylene chloride: methanol = 50: 1).
1.45 g	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere;	<strong>[86639-52-3]SN-38</strong> (0.5 g, 1.3 mmol) and 4-nitrophenyl chloroformate (313 mg,1.6 mmol) was dispersed in 30 mL anhydrous THF, and then DIEA(0.33 mL, 2.0 mmol) was added to the solution slowly at 0 C undernitrogen. The mixture was stirred for 2 h, and it turned to a clear solution.The solvent was removed under vacuum to give the crude productwhich was washed by the Et2O to afford a pale yellow power(1.45 g). Then the crude product was dissolved in DCM, and N-Bocpiperazine(520 mg, 2.6 mmol), DMAP (158 mg, 1.3 mmol) were addedto the solution. The mixture was stirred at room temperature for 1 h.The organic layer was washed by water followed by NH4Cl (aq), brine,and dried over Na2SO4. The final product was purified by silicagelcolumn to afford a pale yellow powder (674 mg, 83.9%).
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 2h;Cooling with ice;	Disperse SN38 (1.0 g, 2.55 mmol) and p-nitrophenyl chloroformate (617 mg, 3.06 mmol) in 30 mL of anhydrousIn a THF solution, DIEA (0.66 mL, 3.82 mmol) was slowly added thereto under ice-water bath, and reacted at room temperature for 2 h.After the reaction was completed, the solvent was spun and the obtained solid compound was washed with diethyl ether.1.77 g of a pale yellow solid, crude compound 22 was obtained.After compound 22 (1.0 g, 1.80 mmol) was dissolved in DCM, 4-Boc aminomethylpiperazine was added thereto.(502 mg, 2.34 mmol) and DMAP (240 mg, 1.96 mmol) were reacted at room temperature for 2 h.After the reaction is completed, it is washed with water, extracted with DCM, and the organic phase is washed successively with saturated ammonium chloride solution and saturated aqueous sodium chloride solution.Dry over anhydrous sodium sulfate and separate by column chromatography.0.8 g of a pale yellow solid was obtained in a yield of 70.8%.
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 12h;	To a cooled (0 C), stirred solution of <strong>[86639-52-3]SN-38</strong> (5.0 g, 12.8 mmol) inanhydrous THF (100 mL) was added 4-nitrophenyl chloroformate(3.1 g, 15.4 mmol) and DIPEA (3.2 mL, 19.2 mmol). The reactionmixture was stirred at room temperature for 12 h. The resulting mixturewas concentrated in vacuo to give a light yellow solid, which was useddirectly to the next step.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.5h;	Weigh 490mg of SN38 in 30mL of DMF, cool to 0 C, add 320mg of DIPEA and 330mg of p-nitrophenyl chloroformate, continue the reaction at this temperature for half an hour, and react at room temperature for 3 hours to obtain intermediate 64. Add to this 320 mg of DIPEA and 253 mg of compound 63. After the addition was completed, the reaction was allowed to proceed at room temperature overnight, and DMF was concentrated. The reaction was monitored by TLC. Column chromatography gave 420 mg of crude product 65.
	With N-ethyl-N,N-diisopropylamine;	DIEA (40 m, 1 .5 equiv., 0.23 mmol) was added drop-wise to a stirred dispersion of SN- 38 (60 mg, 1 equiv., 0.15 mmol) and 4-nitrophenyl carbonochloridate (37 mg, 1 .2 equiv., 0.18 mmol) in TFIF (5 mL) at 0C under nitrogen. The reaction was stirred for 2 hours. Solution was concentrated to yield (S)-4,1 1 -diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1 H-pyrano[3',4':6,7]indolizino[1 ,2- b]quinolin-9-yl (4-nitrophenyl) carbonate as a crude light yellow residue

Reference： [1]Angewandte Chemie - International Edition,2020,vol. 59,p. 4176 - 4181
Angew. Chem.,2020,vol. 132,p. 4205 - 4210,6
[2]Journal of Medicinal Chemistry,2020,vol. 63,p. 5421 - 5441
[3]Patent: WO2018/236781,2018,A2 .Location in patent: Paragraph 0153; 0154
[4]Patent: CN110314238,2019,A .Location in patent: Paragraph 0061; 0065-0066; 0072
[5]Bioconjugate Chemistry,2016,vol. 27,p. 1267 - 1275
[6]Patent: CN104587487,2018,B .Location in patent: Paragraph 0093-0096
[7]Patent: CN107382872,2017,A .Location in patent: Paragraph 0026; 0090-0093
[8]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 4706 - 4715
[9]Patent: CN109758587,2019,A .Location in patent: Paragraph 0074; 0081-0083
[10]Bioorganic and medicinal chemistry,2020
[11]Patent: CN110845559,2020,A .Location in patent: Page/Page column 25; 26-29
[12]Patent: WO2020/37009,2020,A1 .Location in patent: Page/Page column 124-127

35
[ 463-40-1 ]
[ 86639-52-3 ]
7-ethyl-cis-9,12,15-octadecaacryloyloxycamptothecin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With benzotriazol-1-ol; diisopropyl-carbodiimide; In chloroform; for 18h;	1mol7-ethyl -10-hydroxy camptothecin, 1.1mol cis 9, 12, 15-eighteen carbon trienic acid and 1.2molN, N '-diisopropyl carbodiimide dissolved in the 2L in chloroform, 2.1mol1-hydroxy benzotriazole added after dissolving a small amount of chloroform is added to the constant pressure titration funnel in dissolved drug solution, sample reaction after 18 hours, turns on lathe does solvent, the obtained drug powder washed twice with ethyl ether, dissolved in the chloroform after drying, recrystallization to obtain pure target product. Yield: 93%.

Reference： [1]Patent: CN105777769,2016,A .Location in patent: Paragraph 0076; 0077

36
[ 3386-33-2 ]
[ 86639-52-3 ]
7-ethyl-10-hydroxycamptothecin-10-stearate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.75%		1 mmol of 7-ethyl-10-hydroxycamptothecin was added to the reaction vessel,After adding 0.7 L of dry methylene chloride,Then 1.5 mmol of pyridine was added,The mixture was stirred under ice-cooling for 20 minutes,1.5 mmolOf stearyl chloride,The reaction was continued for 30 minutes under ice-cooling,The reaction was further carried out at room temperature for 12 hours,The reaction was recrystallized from acetone,7-ethyl-10-hydroxycamptothecin-10-stearate was isolated,Yield 98.75%.

Reference： [1]Patent: CN105777770,2016,A .Location in patent: Paragraph 0081; 0082; 0083; 0084; 0085

37
[ 103816-19-9 ]
[ 86639-52-3 ]
[ 100286-90-6 ]

Yield	Reaction Conditions	Operation in experiment
14.1 g		7-ethyl-10-hydroxycamptothecin (10. 0 g) was added to dichloromethane (250 mL), and triethylamine (3 mL), 4-dimethylaminopyridine (0.5 g) (7.0 g) was added and the reaction stirred at room temperature overnight(20 C) and filtered to remove insolubles. The organic layer was separated, dried over anhydrous magnesium sulphate (5 g) for 0.5 h, and filtered to remove magnesium sulphate, bis (2-ethoxybenzoic acid), and sodium bisulfate (100 mL) The filter cake was rinsed twice with methylene chloride (50 mL) and the organic layers were combined. The solvent was distilled off under reduced pressure at 30 C to obtain crude irinotecan (14 g).The crude product of irinotecan obtained in step 1) was added to methanol (100 mL), and methanol solution of hydrogen chloride(20%), to pH = 1 ~ 2, vacuum removal of excess hydrogen chloride and methanol solution, in hydrochloric acid irinotecan crude about16gThe crude irinotecan hydrochloride obtained in Step 2) was added to a mixed solution of purified water (100 mL) and acetone (300 mL)Liquid, heating dissolved, filtered hot, stirring crystallization at room temperature for 24 hours to obtain refined products 14. lg, purity 99. 9%

Reference： [1]Patent: CN102260272,2016,B .Location in patent: Paragraph 0045; 0046; 0047; 0048; 0049; 0050; 0051

38
[ 38075-11-5 ]
[ 39825-33-7 ]
[ 86639-52-3 ]
isopropyl (S)-2-[[[[(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl]oxy](methoxymethyl)phosphoryl]amino]propanoate [ No CAS ]
isopropyl (S)-2-[[[[(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl]oxy](methoxymethyl)phosphoryl]amino]propanoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 8580 - 8590

39
[ 86639-52-3 ]
[ 3958-60-9 ]
[ 1403812-29-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 22℃; for 6h; Sonication; Inert atmosphere;	4.2. Synthesis and Characterization of 2-Nitrobenzyl-C₁₀-SN-38 (2) SN-38 (1) (0.0941 g, 0.24 mmol) was added into a round bottom flask (10 mL) with a magneticstirring bar. Dimethylformamide (DMF, 2.0 mL, anhydrous, Sigma-Aldrich) and DBU (80 μL, 0.54mmol) were then added, and the mixture was sonicated until SN-38 was dissolved. The dissolvedSN-38 was then stirred on a stirring plate and purged with argon flow for 20 min. 2-Nitrobenzylbromide (0.1149 g, 0.53 mmol) was dissolved in 0.75 mL anhydrous DMF and then added slowly(over 30 min) into SN-38 with a syringe. The mixture was allowed to stir at room temperature (22 °C)for 6 h. The resulted yellow solid was separated by centrifuging and washed with acetone (2 mL × 5).Residual acetone was then evaporated under vacuum to give 2-nitrobenzyl SN-38 as a yellow powder(0.0986 g, 78%). 1H-NMR (400 MHz, DMSO) δ 8.21-8.06 (m, 2H), 7.89 (d, J = 7.5 Hz, 1H), 7.81 (t, J = 7.3Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.59 (d, J = 7.7 Hz, 2H), 7.28 (s, 1H), 6.52 (s, 1H), 5.72 (s, 2H), 5.43 (s,2H), 5.31 (s, 2H), 3.17 (q, J = 7.4 Hz, 2H), 1.87 (m, J = 14.2, 6.9 Hz, 2H), 1.23 (t, J =7.5 Hz, 3H), 0.88 (t, J= 7.3 Hz, 3H). 13C-NMR (101 MHz, DMSO) δ 173.00, 157.31, 157.14, 150.53, 150.44, 148.31, 146.70,145.10, 144.48, 134.41, 132.14, 130.25, 129.92, 129.00, 128.19, 125.34, 122.73, 118.84, 104.64, 99.98, 96.56,72.86, 67.32, 65.71, 50.02, 30.68, 22.67, 13.86, 8.23. ESI-MS(+) m/z (% relative intensity, [ion]): 528.20(100, [M + H]+), 569.25 (57.55, [M + H + CH3CN]+).

Reference： [1]Liang, Dinghua; Wu, Xing; Hasinoff, Brian B.; Herbert, David E.; Tranmer, Geoffrey K. [Molecules, 2018, vol. 23, # 8]

40
[ 86639-52-3 ]
[ 3958-57-4 ]
C₂₉H₂₅N₃O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; at 66℃; under 15514.9 Torr; for 0.333333h;Molecular sieve; Sealed tube; Microwave irradiation;	The synthesis was conducted in a microwave synthesizer (DiscoverSP W/Activent, CEM,Matthews, NC, USA). To a microwave reaction vessel (10 mL) were added <strong>[86639-52-3]SN-38</strong> (1) (0.0241 g, 0.061mmol), dry dichloromethane (DCM, 4 mL, dried over molecular sieves overnight), DBU (36 muL, 0.24mmol) and 3-nitrobenzyl bromide (0.0375 g, 0.17 mmol). The reaction vessel was then sealed andplaced in the microwave synthesizer. The reaction was conducted under dynamic mode, 66 C,PowerMax mode (simultaneous air cooling, model of microwave synthesizer: DiscoverSPW/Activent, CEM, USA), max power 200 W, max pressure 300 psi, for 10 min. The reaction mixturewas then purified with silica gel column chromatography on a CombiFlash Rf 200 purificationsystem, Teledyne Isco, Lincoln, NE, USA, with ethyl acetate in hexane from 0% to 100% (3-nitrobenzyl<strong>[86639-52-3]SN-38</strong> was eluted out with 100% ethyl acetate). Residual solvent was evaporated under vacuum togive 3-nitrobenzyl <strong>[86639-52-3]SN-38</strong> as a yellow powder (0.0216 g, 67%). 1H-NMR (400 MHz, DMSO) delta 8.46 (s,1H), 8.24 (dd, J = 8.2, 1.5 Hz, 1H), 8.17-8.08 (m, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H),7.64 (dd, J = 6.7, 3.1 Hz, 2H), 7.28 (s, 1H), 6.53 (s, 1H), 5.55 (s, 2H), 5.43 (s, 2H), 5.31 (s, 2H), 3.20 (q, J =7.3 Hz, 2H), 1.96-1.77 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H). 13C-NMR (101 MHz,DMSO) delta 173.00, 157.27, 157.19, 150.50, 150.27, 148.33, 146.67, 145.00, 144.40, 139.54, 134.75, 132.05,130.66, 128.89, 128.15, 123.37, 122.96, 122.79, 118.78, 104.35, 96.54, 72.86, 68.88, 65.71, 49.97, 30.69, 22.67,13.85, 8.23. ESI-MS(+) m/z (% relative intensity, [ion]): 528.20 (100, [M + H]+), 569.30 (69.21, [M + H +CH3CN]+).

Reference： [1]Molecules,2018,vol. 23

41
[ 86639-52-3 ]
[ 100-11-8 ]
[ 1403812-27-0 ]

Yield	Reaction Conditions	Operation in experiment
75.9%	Stage #1: SN-38 With potassium carbonate In N,N-dimethyl-formamide at 0℃; Inert atmosphere; Stage #2: 1-bromomethyl-4-nitro-benzene In N,N-dimethyl-formamide at 80℃; for 12h;	2 Dissolve 0.5 g (1.27 mmol) of hydroxycamptothecin in 20 ml of N,N-dimethylformamide, add 0.35 g (2.57 mmol) of potassium carbonate, cool to 0°C, and protect with nitrogen. 0.28 g (1.27 mmol) of p-nitrobenzyl bromide dissolved in 5 mL of N,N-dimethylformamide was slowly dropped with a syringe. After the addition, the temperature was slowly raised to 80° C. and refluxed for 12 hours. After the reaction, potassium carbonate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography, and eluted with dichloromethane: methanol (2:1) to obtain 0.51 g of white solid (I-2) with a yield of 75.9 %.
68%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 22℃; for 6h; Sonication; Inert atmosphere;	4.4. Synthesis and Characterization of 4-Nitrobenzyl-C10-SN-38 (4) SN-38 (1) (0.0936 g, 0.24 mmol) was added into a round bottom flask (10 mL) with a magneticstirring bar. Dimethylformamide (DMF, 2.0 mL, anhydrous, Sigma-Aldrich) and DBU (80 μL, 0.54mmol) were then added, and the mixture was sonicated until SN-38 was dissolved. The dissolvedSN-38 was then stirred on a stirring plate and purged with argon flow for 20 min. 4-Nitrobenzylbromide (0.1187 g, 0.55 mmol) was dissolved in 0.75 mL anhydrous DMF and then added slowly(over 30 min) into SN-38 with a syringe. The mixture was allowed to stir at room temperature (22 °C)for 6 h. The resulted yellow solid was separated by centrifuging and washed with acetone (2 mL × 5).Residual acetone was then evaporated under vacuum to give 4-nitrobenzyl SN-38 as a yellow powder(0.0864 g, 68%). 1H-NMR (400 MHz, DMSO) δ 8.35-8.26 (m, 2H), 8.13 (d, J = 9.1 Hz, 1H), 7.85 (d, J =8.8 Hz, 2H), 7.63 (dt, J = 5.7, 2.6 Hz, 2H), 7.28 (s, 1H), 6.53 (s, 1H), 5.56 (s, 2H), 5.43 (s, 2H), 5.31 (s, 2H),3.18 (q, J = 7.4 Hz, 2H), 1.87 (m, J = 14.0, 7.1 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H). 13CNMR(101 MHz, DMSO) δ 172.98, 157.33, 157.25, 150.54, 150.39, 147.61, 146.72, 145.10, 145.08, 144.49,132.12, 128.98, 128.23, 124.16, 122.94, 118.84, 104.55, 96.56, 72.87, 71.45, 69.07, 65.74, 50.00, 30.76, 22.68,13.89, 8.21. ESI-MS(+) m/z (% relative intensity, [ion]): 528.25 (100, [M + H]+), 569.30 (92.39, [M + H +CH3CN]+).

Reference： [1]Current Patent Assignee: LIAOCHENG UNIVERSITY - CN113968867, 2022, A Location in patent: Paragraph 0085-0091
[2]Liang, Dinghua; Wu, Xing; Hasinoff, Brian B.; Herbert, David E.; Tranmer, Geoffrey K. [Molecules, 2018, vol. 23, # 8]

42
[ 86639-52-3 ]
[ 72040-64-3 ]
6-biotinylaminocaproic acid-(20s)-7-ethyl-20-hydroxy-camptothecin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With dmap; diisopropyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃; for 48h;Inert atmosphere;	General procedure: To a mixture of Biotin or 6-biotinylaminocaproic acid (0.3 mmol), camptothecin analogues (0.1 mmol) and DMF (2.5 mL) was added, 4-Dimethylaminopyridine (DMAP) (0.01 mmol) was added and N, N'-Diisopropylcarbodiimide) (DIC) (0.6 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 days under N2. Solvent were removed under a reduced. The residue was purified on a silica gel chromatography (CHCl3:CH3OH = 15:1?9:1) to afford the product Biotin-(20s)-camptothecin (11). Yellow amorphous powder, yield 60percent;

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 234 - 237

43
7-ethyl-10-hydroxycamptothecin [ No CAS ]
[ 148579-94-6 ]
C₄₂H₄₁N₃O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46 mg	With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In N,N-dimethyl-formamide; toluene at 60℃; Inert atmosphere;
	With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In toluene at 60℃;

Reference： [1]Walther, Raoul; Jarlstad Olesen, Morten T.; Zelikin, Alexander N. [Organic and Biomolecular Chemistry, 2019, vol. 17, # 29, p. 6970 - 6974]
[2]Huang, Ying; Wang, Lei; Cheng, Zhiyang; Yang, Biyu; Yu, Jiahui; Chen, Yi; Lu, Wei [Journal of Controlled Release, 2021, vol. 339, p. 297 - 306]

44
4-piperidylpiperidine methyl carbonate [ No CAS ]
[ 86639-52-3 ]
[ 97682-44-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	In dichloromethane; at 45 - 50℃; for 6h;	In a reaction bottle equipped with a stirring, thermometer, and condensing unit,Add 4-piperidylpiperidine methyl carbonate (0.83 g, 3.4 mmol) obtained in the previous step.30 mL of dichloromethane, 7-ethyl-10-hydroxycamptothecin (0.75 g, 1.87 mmol), stirredAfter homogenization, the temperature of the reaction solution is controlled to be stirred at 45 C to 50 C for 6 hours. After the reaction is completed,Add 50 mL of water, separate the dichloromethane layer, and extract the aqueous layer with 20 mL of dichloromethane.Combine the methylene chloride layer,After concentration under reduced pressure to dryness, 1500 mL of anhydrous ethanol, (E/Z)-Southwest Polygalaceae D 0.1 g was recrystallized, and dried at 45 C to obtain irinotecan monomer (0.89 g, 1.52 mmol).Yield: 95%.

Reference： [1]Patent: CN109796462,2019,A .Location in patent: Paragraph 0027; 0032; 0034-0039; 0041; 0046

45
[ 77341-67-4 ]
[ 86639-52-3 ]
C₃₆H₄₂N₂O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20.0h;	To a suspension of SN-38 (74.8 mg, 0.191mmol) in CH2Cl2 (10 mL, 0.02 M) was added ()-menthyl succinate (52.2 mg, 0.204mmol), EDC-HCl (82 mg, 0.425mmol), and DMAP (9.1 mg, 0.0745mmol). After stirring for 20 h at room temperature, the reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous solution of NH4Cl, water, and brine. The organic layer was then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH = 100:1) to give SN-38-menthol (10) (86 mg, 68%) as a pale yellow solid. 1HNMR (400 MHz, CDCl3) = 0.75 (3H, d, J = 6.8 Hz), 0.871.10 (12H, m), 1.371.50 (5H, m), 1.661.69 (2H, m), 1.871.91 (5H, m), 1.992.02 (4H, m), 2.762.80 (2H, m), 2.962.99 (2H, m), 3.13 (2H, q, J = 3.6 Hz), 4.00 (1H, s), 4.75 (1H, ddd, 6.8, 6.8, 4.4 Hz), 5.24 (1H, s), 5.29 (1H, d, J = 16.4 Hz), 5.73 (1H, d, J = 16.4 Hz), 7.54 (1H, dd, J = 9.2, 2.4 Hz), 7.65 (1H, s), 7.81 (1H, d, J = 2.4 Hz), 8.21 (1H, d, J = 9.2 Hz) ppm. 13CNMR (100 MHz, CDCl3) delta = 8.0, 14.1, 16.5, 20.9, 22.1, 23.3, 23.6, 26.4, 29.5, 29.6, 31.5, 31.7, 34.3, 41.0, 47.2, 49.5, 66.4, 72.9, 75.1, 98.2, 114.6, 118.7, 125.5, 127.4, 127.5, 132.2, 145.4, 147.0, 147.5, 149.7, 150.3, 152.0, 157.7, 171.0, 171.8, 174.0 ppm. HR-MS (ESI-TOF): m/z calcd for C36H43N2O8 ([M + H]+) 631.3014, found 631.3018.

Reference： [1]Bulletin of the Chemical Society of Japan,2019,vol. 92,p. 1305 - 1313

46
[ 874302-76-8 ]
[ 86639-52-3 ]
SN-38 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.7%	With triethylamine; In dichloromethane; for 5h;Reflux;	4-Nitrophenyl-2-(2-pyridyldithio)ethyl carbonate (2.21 g, 6.28 mmol) and SN-38 (3.69 g, 9.41 mmol) were dissolved in 200 mL dichloromethane. 2 ml of triethylamine was then warmed to reflux for 5 hours. After the reaction is completed, the temperature is lowered to room temperature, and the organic phase is washed with dilute hydrochloric acid, separated, dried, concentrated, purified by silica gel column, and concentrated.Vacuum drying gave 2.8 g of a pale yellow solid in a yield of 73.7%. 1H NMR of the product was determined to give the structure of formula c2-(2-Pyridyldithio)ethyl carbonate conjugated with SN-38 (Py-SS(O)-SN38).

Reference： [1]Patent: CN110025574,2019,A .Location in patent: Paragraph 0042; 0052; 0052; 0056

47
[ 103816-19-9 ]
[ 86639-52-3 ]
[ 136572-09-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 4-piperidinopiperidine-1-carbonyl chloride; 7-ethyl-10-hydroxycamptothecin With potassium carbonate In pyridine; dichloromethane at 20℃; for 6h; Stage #2: With hydrogenchloride In pyridine; dichloromethane; water	1 Example 1 Add 45 mL of dichloromethane, 3.9 g of 7-ethyl-10-hydroxycamptothecin (SN38), and 4.0 g of 4-piperidinyl piperidinecarboxylic acid chloride to a three-necked flask, and stir thoroughly at room temperature. Add 18 ml of pyridine and 2.8 g of potassium carbonate. Continue to stir the reaction at room temperature for 6 hours; add 50 mL of 5% sodium bicarbonate solution, neutralize the reaction mixture, extract and separate the layers; separate the organic phase, add 25 mL of water to the organic phase, shake and wash for 20 min; separate layers to obtain the organic phase Add 190mL of n-hexane to the organic phase; stir for 2h to crystallize, filter, add the filter cake to a three-necked flask, add 70mL of dichloromethane, reflux and stir to dissolve, add dropwise 1mL of concentrated hydrochloric acid (6mol/L) solution under stirring; Concentrate the dichloromethane to dryness, add 15 mL of purified water and stir to dissolve, add 45 mL of acetone while stirring, and stir to crystallize at 3°C for 20 hours. After filtering, the filter cake was washed with an appropriate amount of acetone and dried under vacuum at 35°C for 2 hours to obtain a light yellow solid with a yield of 90%.

Reference： [1]Current Patent Assignee: HUBEI DEXINCHEN TECH - CN113121554, 2021, A Location in patent: Paragraph 0026-0028

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[ CAS No. 86639-52-3 ] {[proInfo.proName]}

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