[ CAS No. 103816-19-9 ] {[proInfo.proName]}

Name: 103816-19-9|[1,4'-Bipiperidine]-1'-carbonyl chloride|98%
Brand: Ambeed
SKU: A441189
Rating: 99 (30 reviews)

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

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Quality Control of [ 103816-19-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 103816-19-9 ]

SDS Specification

Alternatived Products of [ 103816-19-9 ]

Product Details of [ 103816-19-9 ]

CAS No. :	103816-19-9	MDL No. :	MFCD08445612
Formula :	C₁₁H₁₉ClN₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YDNSNQRKIINKPV-UHFFFAOYSA-N
M.W :	230.73	Pubchem ID :	9813375
Synonyms :

Calculated chemistry of [ 103816-19-9 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.91
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	69.77
TPSA :	23.55 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.13 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.74
Log Po/w (XLOGP3) :	2.22
Log Po/w (WLOGP) :	1.53
Log Po/w (MLOGP) :	1.88
Log Po/w (SILICOS-IT) :	1.64
Consensus Log Po/w :	2.0

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.54
Solubility :	0.67 mg/ml ; 0.0029 mol/l
Class :	Soluble
Log S (Ali) :	-2.35
Solubility :	1.03 mg/ml ; 0.00447 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.67
Solubility :	4.92 mg/ml ; 0.0213 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.95

Safety of [ 103816-19-9 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	3261
Hazard Statements:	H302-H312-H314-H332	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 103816-19-9 ]

* 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 [ 103816-19-9 ]
Downstream synthetic route of [ 103816-19-9 ]

[ 103816-19-9 ] Synthesis Path-Upstream 1~5

1
[ 4897-50-1 ]
[ 32315-10-9 ]
[ 103816-19-9 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	Stage #1: at 20 - 70℃; Stage #2: With potassium carbonate In dichloromethane at 20℃;	Example 1 [1,4']bipiperidinyl-1'-carbonyl chloride (II) In a solution of Triphosgene (16.48 gm) in methylene chloride (200 ml) was added a solution of 4-piperidinopiperidine (20 g) in methylene chloride (200 ml) at 20-25° C. within 1-2 hours. Part of the methylene chloride was distilled off and acetonitrile was added. Further, methylene chloride and acetonitrile was distilled off completely until the temperature rises to 70° C. At room temperature fresh methylene chloride was added to the reaction mixture to make homogenous slurry followed by potassium carbonate (30-35 gm) and reaction mixture was stirred for 1-2 hours. The reaction mixture was filtered and subsequently the filtrate was concentrated. Hexane was added slowly into the reaction mixture under stirring. Solid compound so obtained was filtered, washed with hexane and dried under reduced pressure at about 40° C. Yield-27 g (98.5percent); GC purity: 99.80percent; Dimeric Impurity: Not Detected
98.5%	Stage #1: at 20 - 25℃; Stage #2: With potassium carbonate In dichloromethane at 20℃;	Example 1 [1,4']bipiperidinyl-1'-carbonyl chloride (II) In a solution of Triphosgene (16.48gm) in methylene chloride (200ml) was added a solution of 4-piperidinopiperidine (20 g) in methylene chloride (200ml) at 20-25 °C within 1-2 hours. Part of the methylene chloride was distilled off and acetonitrile was added. Further, methylene chloride and acetonitrile was distilled off completely until the temperature rises to 70 °C. At room temperature fresh methylene chloride was added to the reaction mixture to make homogenous slurry followed by potassium carbonate (30-35 gm) and reaction mixture was stirred for 1-2 hours. The reaction mixture was filtered and subsequently the filtrate was concentrated. Hexane was added slowly into the reaction mixture under stirring. Solid compound so obtained was filtered, washed with hexane and dried under reduced pressure at about 40 °C. Yield- 27 g (98.5percent); GC purity: 99.80percent; Dimeric Impurity: Not Detected

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: US2007/208050, 2007, A1, . Location in patent: Page/Page column 7
[4] Patent: WO2009/97695, 2009, A1, . Location in patent: Page/Page column 114-115
[5] Patent: WO2006/16203, 2006, A1, . Location in patent: Page/Page column 8-9
[6] European Journal of Medicinal Chemistry, 2011, vol. 46, # 6, p. 2490 - 2502
[7] MedChemComm, 2016, vol. 7, # 4, p. 658 - 666
[8] Patent: WO2017/74325, 2017, A1, . Location in patent: Paragraph 0104-0105
[9] Patent: US2017/114076, 2017, A1, . Location in patent: Paragraph 0116
[10] Patent: WO2017/123809, 2017, A1, . Location in patent: Paragraph 0078

2
[ 4897-50-1 ]
[ 503-38-8 ]
[ 103816-19-9 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 6, p. 1446 - 1454

3
[ 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

4
[ 103816-19-9 ]
[ 100286-90-6 ]

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

5
[ 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

[ 103816-19-9 ] Synthesis Path-Downstream 1~60

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
[ 4897-50-1 ]
[ 503-38-8 ]
[ 103816-19-9 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1446 - 1454

3
[ 103816-19-9 ]
[ 156055-46-8 ]
1-[(2-Dimethylaminoethyl)aminocarbonyl]-5,6-dimethyl-9-(4-piperidinopiperidinocarbonyloxy)-6H-pyrido[4,3-b]carbazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 2191 - 2203

4
2-acetamido-5-hydroxy-propiophenone [ No CAS ]
[ 103816-19-9 ]
4-acetamido-3-propionylphenyl-1,4'-bipiperidine-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; dmap; at 20℃; for 48 - 60h;	Step II: Preparation of ^acetimidoS-propionylphenyl-l^'-bipiperidine-l'-carboxylate (Ia; R=-C0CH3 and R1=C2 H5)Dissolve Step- I product (1Og) in dry pyridine (160ml). Add 4-Dimethylamino pyridine (23.3g), followed by 4-piperidino piperidine carbomylchloride (25.3g) to it. Stirred the mixture at room temperature for 48h-60h. Monitor the reaction mixture by HPLC. Work up the reaction mixture when step- 1 product is NMT 3.0% by adding water (60ml).Extract with ethylacetate (200ml) .Separate layers, evaporate ethyl acetate layer to dryness.Dissolve the residue in chloroform 215ml), washed with 10% aqueous sodium bicarbonate solution (6x 215ml), followed by water (6x 215ml). Dry the washed chloroform over anhydrous sodium sulphate, filterand evaporate to dryness to yield step- II product (11.5g), HPLC purity not less than 95.00%.

Reference： [1]Patent: WO2008/35377,2008,A2 .Location in patent: Page/Page column 7

5
2-propionamido-5-hydroxy-propiophenone [ No CAS ]
[ 103816-19-9 ]
4-propionamido-3-propionylphenyl-1,4'-bipiperidine-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; dmap; at 20℃; for 48 - 60h;	Step II: Preparation of 4- propionimido -3-propionylphenyl-l,4'-bipiperiditie-l'- carboxylate (Ia; R= COCH2 CH3and R1=C2 H5Dissolve Step- 1 product (12g) in dry pyridine (192ml). Add 4-Dimethylamino pyridine (24), followed by 4rpiperidino piperidine carbomylchloride (26.4g) to it. Stirred the mixture at room temperature for 48h-60h. Monitor the reaction mixture by etaPLC. Work up the reaction mixture when step- 1 product is NMT 3.0% by adding water (72ml). Extract with ethylacetate (240ml) .Separate layers, evaporate ethyl acetate layer to dryness. Dissolve the residue in chloroform 260ml), washed with 10% aqueous sodium bicarbonate solution (6x 260ml), followed by water (6x 260ml).Dry the washed chloroform over anhydrous sodium sulphate, filterand evaporate to dryness to yield step- II product (11.5g), etaPLC purity not less than 94.00%.

Reference： [1]Patent: WO2008/35377,2008,A2 .Location in patent: Page/Page column 8

6
2-chloroacetamido-5-hydroxy-propiophenone [ No CAS ]
[ 103816-19-9 ]
4-chloroacetamido-3-propionylphenyl-1,4'-bipiperidine-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; dmap; at 20℃; for 48 - 60h;	Step II: Preparation of 4-chloroacetimido-3-propionylphenyl-l,4'-bipiperidine-l'~ carboxylate (Ia; R=-COCH2Cl and R1=C2 H5) Step- I product (1Og) in dry pyridine (160ml). Add 4-Dimethylamino pyridine (18.3g), followed by 4-piperidino piperidine carbomylchloride (20.Og) to it. Stirred the mixture at room temperature for 48h-60h. Monitor the reaction mixture by HPLC. Work up the reaction mixture when step- 1 product is NMT 3.0% by adding water (60ml). Extract with ethylacetate (200ml) .Separate layers, evaporate ethyl acetate layer to dryness. Dissolve the residue in chloroform 215ml), washed with 10% aqueous sodium bicarbonate solution (6x 215ml), <n="11"/>followed by water (6x 215ml).Dry the washed chloroform over anhydrous sodium sulphate, filterand evaporate to dryness to yield step- II product (11. Og), HPLC purity not less than95.00%.

Reference： [1]Patent: WO2008/35377,2008,A2 .Location in patent: Page/Page column 9; 10

7
C₁₆H₁₂ClN₅O₄ [ No CAS ]
[ 103816-19-9 ]
C₂₇H₃₀ClN₇O₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6593 - 6601

8
[ 1000807-33-9 ]
[ 103816-19-9 ]
C₂₇H₃₂ClN₇O₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6593 - 6601

9
[ 760992-17-4 ]
[ 103816-19-9 ]
[ 760992-18-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	With pyridine; for 72h;	Example 171A (150 mg, 0.25 mmol) in pyridine (4 mL) was treated with [1, 4 ] BIPIPERIDINYL-1 -CARBONYL chloride (190 mg, 3 mmol) and stirred for 3 days. Reaction mixture was poured into water and extracted with dichloromethane and ethyl acetate. The organic layer was dried over MGS04, and evaporated. The residue was purified by flash chromatography eluting with ethyl acetate: MeOH: NH40H (100: 5: 0.5). The title compound (160 mg) was obtained at 81% yield.

Reference： [1]Patent: WO2004/80973,2004,A1 .Location in patent: Page 148-149

10
[ 741737-80-4 ]
[ 103816-19-9 ]
4-[(Z)-2-cyano-2-(3,4-dimethoxy-phenyl)-vinyl]-phenyl [1,4']bipiperidinyl-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With pyridine;	Production of 4-[(Z)-2-cyano-2-(3,4-dimethoxy-phenyl)-vinyl]-phenyl [1,4']bipiperidinyl-1'-carboxylate (compound 2) (Z)-2-(3,4-dimethoxyphenyl)-3-(4-hydroxyphenyl)acrylonitrile (compound 1) (0.28 g) and 4-piperidinopiperidinocarbonyl chloride (0.23 g) were dissolved in pyridine (5 ml), and the resultant solution was stirred for a whole day and night. After completion of reaction, the resultant reaction mixture was added to water (200 ml), and the thus-precipitated product was purified by means of silica gel chromatography employing a chloroform/methanol system, to thereby produce the target product (0.38 g, yield: 79%). Pale yellow crystals, MS (APCI, m/z): 476 (MH+), 1H-NMR (DMSO-d6) delta 1.47(3H, m), 1.75(2H, m), 2.49(5H, m), 2.85(1H, br.t), 3.01(1H, br.t), 3.71 (1H, m), 3.79 (3H, s), 3.84 (3H, s), 4.03(1H, br.d), 4.17(1H, br.d), 6.89(2H, d, J=9Hz), 7.07 (1H, d, J=8Hz), 7.26(1H, dd, J=2Hz, 8Hz), 7.27(2H, d, J=8Hz), 7.33(1H, d, J=2Hz), 7.91(2H, d, J=8Hz), 7.95(1H, s)

Reference： [1]Patent: EP1591117,2005,A1 .Location in patent: Page/Page column 13

11
4-piperidinopiperidine-1-carbonyl chloride hydrochloride [ No CAS ]
[ 103816-19-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dichloromethane; for 1h;	[l,4']bipiperidinyl-l'-carbonyl chloride hydrochloride (9.7 g), methylene chloride (150 ml) and K2CO3 (10.5 g, 2.1 ekv) were charged. The mixture was stirred for about 1 hour. The solution was filtered and the cake washed with 10 ml of methylene chloride. The solution (containing 8.4 g of [l,4']bipiperidinyl-l'-carbonyl chloride) can be used as such for the preparation of Irinotecan

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

12
[ 38838-26-5 ]
[ 103816-19-9 ]
N-[3-(4-(1-piperidinyl)piperidinylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; for 1h;Heating / reflux;	Example 3 N-[3-(4-(1-piperidinyl)piperidinylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a ,c ]cyclohepten-5yl]acetamide A solution of N-acetyl-colchinol (300mg, 0.84mmol), (J. Cech F. Santacy Collect. Czech Comm 1949, 4, 532-539), in pyridine (5ml) was treated with 4-piperidinopiperidine carbamoyl chloride (346mg, 1.5mmol), (K.H.Henegar et al. J.Org. Chem., 1997, 62, 6588-6597) and the solution heated at reflux for 1 hour. The cooled mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified on silica gel eluding with methanol to give the title compound (180mg) as a white solid. m.p. 168-175C m/e 551

Reference： [1]Patent: EP1140745,2003,B1 .Location in patent: Page/Page column 32

Yield	Reaction Conditions	Operation in experiment
		Under ice cooling, the filtrate was added to 330 ml of a 10% aqueous solution of sodium hydroxide. Then the organic layer obtained by separation was washed with water, dried over anhydrous magnesium sulfate and then concentrated under a low pressure. Isopropyl ether (50 ml) was added to the concentrate to dissolve the latter in the former, followed by cooling at 0 C. for 2 hours. The precipitate was then removed by filtration and the residue was concentrated under reduced pressure. The concentrate so obtained was recrystallized from 50 ml of n-hexane, whereby 15 g of the title compound (1-5) were obtained. The compound so obtained has the following physical properties: Melting point:63.8 C. HCl titration:96.46% IR cm-1:1725, 1409 NMR delta:1.0-2.1 (10H,m), 2.1-3.4(7H,m), 4.1-4.6(2H,m).

14
[ 4897-50-1 ]
[ 32315-10-9 ]
[ 103816-19-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In dichloromethane; at -10 - 20℃; for 4h;	Dissolve triphosgene (882mg, 2.97mmol) in 30mL of dichloromethane, and then dropwiseadd 1,4'-bipiperidine (500mg, 2.97mmol) and triethylamine (900mg, 8.91mmol)at -10 C.Dichloromethane solution (20 mL). After the dropwise addition was continued, the reaction was stirred at -10 C for 2 hours, and then transferredto room temperature for 2 hours.It was concentrated under reduced pressure, 20 mL of tetrahydrofuran was added to the residue, and the mother liquid was concentrated under reduced pressure to obtain the white title compound(680 mg, yield: 99%).
98.5%		Example 1 [1,4']bipiperidinyl-1'-carbonyl chloride (II) In a solution of Triphosgene (16.48 gm) in methylene chloride (200 ml) was added a solution of 4-piperidinopiperidine (20 g) in methylene chloride (200 ml) at 20-25 C. within 1-2 hours. Part of the methylene chloride was distilled off and acetonitrile was added. Further, methylene chloride and acetonitrile was distilled off completely until the temperature rises to 70 C. At room temperature fresh methylene chloride was added to the reaction mixture to make homogenous slurry followed by potassium carbonate (30-35 gm) and reaction mixture was stirred for 1-2 hours. The reaction mixture was filtered and subsequently the filtrate was concentrated. Hexane was added slowly into the reaction mixture under stirring. Solid compound so obtained was filtered, washed with hexane and dried under reduced pressure at about 40 C. Yield-27 g (98.5%); GC purity: 99.80%; Dimeric Impurity: Not Detected
98.5%		Example 1 [1,4']bipiperidinyl-1'-carbonyl chloride (II) In a solution of Triphosgene (16.48gm) in methylene chloride (200ml) was added a solution of 4-piperidinopiperidine (20 g) in methylene chloride (200ml) at 20-25 C within 1-2 hours. Part of the methylene chloride was distilled off and acetonitrile was added. Further, methylene chloride and acetonitrile was distilled off completely until the temperature rises to 70 C. At room temperature fresh methylene chloride was added to the reaction mixture to make homogenous slurry followed by potassium carbonate (30-35 gm) and reaction mixture was stirred for 1-2 hours. The reaction mixture was filtered and subsequently the filtrate was concentrated. Hexane was added slowly into the reaction mixture under stirring. Solid compound so obtained was filtered, washed with hexane and dried under reduced pressure at about 40 C. Yield- 27 g (98.5%); GC purity: 99.80%; Dimeric Impurity: Not Detected

98%	With triethylamine; In dichloromethane; at -15 - 20℃; for 1h;Inert atmosphere;	(D) In equipped with a thermometer, a dropping funnel, 250ml reaction flask three drying tube, was added triphosgene 1.8g (6mmol), dry dichloromethane 50ml, stirred to dissolution, the reaction was cooled to -15 deg.] C, stirred was added dropwise 4-piperidinyl piperidine 2g (11.9mmol), 50ml dichloromethane solution was dried 5.3ml of triethylamine was added dropwise while the reaction temperature was controlled at -15 ~ -10 , dropwise, warmed to room temperature stirring continued for 1 h, TLC determined reaction end point detection plate.Completion of the reaction, saturated sodium bicarbonate solution was added to the chilled reaction flask PH = 8, separation and extraction, the organic phase was washed with saturated brine precooled to neutral, dried over anhydrous magnesium sulfate, filtered, 35 water bath and concentrated under reduced pressure to an oil, yielding intermediate 4-piperidinyl piperidine carboxylic acid chloride (2.7 g, 98% yield).
		EXAMPLE 3 PREPARATION OF 4-PIPERIDINOPIPERIDINE CARBAMOYL CHLORIDE 150 g of 4-piperidinopiperidine was dissolved in 10.5 L of dichloromethane and the solution was cooled to about 0 C. A solution of triphosgene (94.8 g of triphosgene in 1.2 L of dichloromethane) was added slowly to the solution at about 5 C. over a period of 45 minutes under a nitrogen atmosphere with simultaneous stirring. The resultant reaction mixture was stirred at 27 C. for 12 hours. The reaction mixture was filtered and then the filtrate was washed with 1.2 L of 7% sodium bicarbonate solution. The organic layer was separated and concentrated completely at about 40 C. under a vacuum of 580 mm Hg to afford title compound. Purity: 97.2% by GC.
	In dichloromethane; at 0 - 20℃;	Example 101: 2-[(5E)-2-(l,2-diazinan-l-yl)-4-oxo-4,5-dihydro-l,3-thiazol-5- ylidene]methyl}-5-fluorophenyl 4-(piperidin-l-yl)piperidine-l-carboxylate dihydrochloride; To a solution of 4-piperidinepiperidine (2.O g, 11.9 mmol) in anhydrous CH2Cl2 (50 mL) at 0 0C was added a triphosgene solution (1.3 g, 4.3 mmol) in anhydrous CH2Cl2 (10 mL)by syringe pump addition (1 hour). The mixture was stirred at room temperature overnight. The solid material was removed by filtration. The mixture was extracted with 10% NaHCO3 (2 x 50 mL) and brine (1 x 50 mL). The organic phase was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording the 4-piperidinopiperidinecarbonyl chloride (1.6 g, 59%). The product was used without further purification.To a mixture of (5Z)-2-(l,2-diazinan-l-yl)-5-[(4-fluoro-2-hydroxyphenyl)methylidene]- 4,5-dihydro-l,3-thiazol-4-one (1.0 g, 3.3 mmol) in anhydrous acetonitrile (15 mL) was added potassium carbonate (900 mg, 6.6 mmol), followed by a solution of 4- piperidinopiperidinecarbonyl chloride (1.07 g, 4.6 mmol) in anhydrous acetonitrile (5 mL). The reaction mixture was stirred at reflux for 60 hours. After cooling the mixture to room temperature, the solid material was removed by filtration. The filtrate was recovered and evaporated under reduced pressure. The crude product was purified by flash chromatography (Combiflash Rf, 0-20% MeOH/CH2Cl2). The residue was triturated with diethyl ether (50 mL x 2). The solid material was recovered by filtration and dried in vacuo, affording 2-[(5E)-2-(l,2- diazinan-l-yl)-4-oxo-4,5-dihydro-l,3-thiazol-5-ylidene]methyl}-5-fluorophenyl 4-(piperidin-l- yl)piperidine-l-carboxylate (954 mg, 57%).To a mixture of 2-[(5E)-2-(l,2-diazinan-l-yl)-4-oxo-4,5-dihydro-l,3-thiazol-5- ylidene]methyl}-5-fluorophenyl 4-(piperidin-l-yl)piperidine-l-carboxylate (954 mg, 1.9 mmol) in methanol (5 mL) was added a solution of 4M HCl/ dioxane (3 mL, 12.0 mmol). The resultant solution was filtered, and the filtrate was recovered and evaporated. The solid was triturated with diethyl ether (50 mL). The solid material was recovered by filtration and dried in vacuo, affording the final compound (931mg, 91%). 1H NMR (400 MHz, DMSO-J6) 1-45 (m, IH), <n="116"/>1.81 (m, HH), 2.16 (m, 2H), 2.96 (m, 5H), 3.15 (m, IH), 3.44 (m, 3H), 3.88 (m, 2H), 4.11 (m, IH), 4.35 (m,lH) 6.17 (t, IH, J= 6.7 Hz), 7.32 (m, 2H), 7.47 (s, IH), 7.67 (t, IH, J= 6.3 Hz); M+ 502. HPLC purity: 99.1%.
		Example 1.; Preparation of 1-chlorocarbonyl-4-piperidinopiperidine base (IRT-4):; Dissolving 4-piperdinoperidine (100g) in benzene (1580ml) under stirring for 15 to 30 minutes at room temperature, adding a solution of triphosgene (150g) in benzene (660 ml) over a period of 1 to 3 hours at a temperature of 20- 25C. Filtering the solid, washing it with benzene and drying, then dissolve the dried solid in chloroform (5900 ml) by stirring at room temperature for about 30 minutes. Charging aqueous sodium bicarbonate solution (400 ml), stirring and separating chloroform layer, washing the chloroform layer with water (1800 ml), separating chloroform layer anddistilling off chloroform under vacuum at a temperature up to below 45C to obtain 1-chlorocorbonyl-4-piperidopiperidine base (60 g).
	With triethylamine; In dichloromethane; at -7 - 20℃;	To a solution of triphosgene (8 g, 26.9 mmol) in dry dichloromethane (40 mL) at -7 C were added dry triethylamine (1 mL, 7.1 mmol) and dropwise a solution of 1,4'-dipiperidine (5 g, 29.7 mmol) in dry dichloromethane (35 mL) over a period of 50 min. Then the solution was stirred at room temperature for 8 h, at which time the reaction was completed, the solution was filtered, the filtrate was concentrated, the residue was reacted with 23-hydroxybetulinic acid directly without further purification.
	In dichloromethane; at 0 - 20℃; for 17h;	The 4- piperidinopiperidinecarbamyl chloride reagent was prepared according to the literature condition (US patent 6,121,451. Briefly, To a solution of 4-piperidinopiperidine (35g, 208 mmol) in DCM (2.6L) at OoC was added a solution of triphosgene (22. lg, 83.2 mmol) in DCM (300 mL) slowly. The mixture was stirred from 0C to rt for 17 hr. Celite was added and the solution was filtered. The filtrate was washed with 7%> wt/v NaHC03 solution and dried over MgS04 (100g). The mixture was filtered and the solvent evaporated. The remaining residue was dissolved in anhydrous DCM (208 mL) to make 1M solution. The solution was used as is without further purification.
	In dichloromethane; at 0 - 20℃; for 17h;	The 4-piperidinopiperidinecarbamyl chloride reagent was prepared according to the literature condition (U.S. Pat. No. 6,121,451. Briefly, To a solution of 4-piperidinopiperidine (35 g, 208 mmol) in DCM (2.6 L) at 0 C. was added a solution of triphosgene (22.1 g, 83.2 mmol) in DCM (300 mL) slowly. The mixture was stirred from 0 C. to rt for 17 hr. Celite was added and the solution was filtered. The filtrate was washed with 7% wt/v NaHCO3 solution and dried over MgSO4(100 g). The mixture was filtered and the solvent evaporated. The remaining residue was dissolved in anhydrous DCM (208 mL) to make 1M solution. The solution was used as is without further purification.
	In dichloromethane; at 0 - 20℃;	A solution 4-piperidinopiperidine (2.00 g, 11.88 mmol) in anhydrous DCM (50 mL) at 0 C was added a solution of triphosgene (1.30 g, 4.38 mmol) in anhydrous DCM (10 mL). The mixture was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was concentrated in vacuo to afford a white solid (1.35 g). The solid (1.35 g) was added to a suspension of niclosamide (22) (1.94 g, 5.93 mmol), DMAP (0.15 g, 1.23 mmol) in pyridine (15 mL) at room temperature, and stirred at 80 C. After the reaction had completed, the solution was cooled to room temperature and neutralized to pH 7. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel with EtOAc/w-Hexane to afford compound 34 (0.87 g, 14%, two steps) as a pale white solid: mp 216.3-217.9 C; -NMR (300 MHz, CDCh) delta 1.54-1.84 (m, 8H), 2.02-2.17 (m, 4H), 2.72-3.06 (m, 8H), 4.28-4.40 (m, 2H), 5.30 (s, 1H), 7.14 (d, J = 8.7 Hz, 1H), 7.53 (dd, J= 2.4, 8.7 Hz, 1H), 7.82 (d, J= 2.7 Hz, 1H), 8.20 (dd, J= 2.4, 9.0 Hz, 1H), 8.33 (d, J= 2.4 Hz, 1H), 8.50-8.80 (m, 2H); 13C-NMR (75 MHz, DMSO-c e) delta 22.2, 23.2, 25.5, 43.0, 43.3, 48.9, 61.8, 123.1, 125.1, 125.5, 126.2, 127.4, 128.9, 129.5, 130.3, 131.8, 140.9, 144.5, 147.6, 152.1, 163.5; HRMS (ESI) for C24H25CI2N4O5 (M-H+) calcd 519.1202, found 519.1206; HPLC purity of 100.00% (retention time = 25.09)

Reference： [1]Patent: CN104387358,2016,B .Location in patent: Paragraph 0161-0164
[2]Patent: US2011/144342,2011,A1 .Location in patent: Page/Page column 7
[3]Patent: EP2341046,2011,A2 .Location in patent: Page/Page column 9
[4]Patent: CN110041318,2019,A .Location in patent: Paragraph 0104-0106; 0112-0113
[5]Patent: US2007/208050,2007,A1 .Location in patent: Page/Page column 7
[6]Patent: WO2009/97695,2009,A1 .Location in patent: Page/Page column 114-115
[7]Patent: WO2006/16203,2006,A1 .Location in patent: Page/Page column 8-9
[8]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2490 - 2502
[9]MedChemComm,2016,vol. 7,p. 658 - 666
[10]Patent: WO2017/74325,2017,A1 .Location in patent: Paragraph 0104-0105
[11]Patent: US2017/114076,2017,A1 .Location in patent: Paragraph 0116
[12]Patent: WO2017/123809,2017,A1 .Location in patent: Paragraph 0078

15
9-allyl-10-hydroxycamptothecin [ No CAS ]
[ 103816-19-9 ]
[ 951290-31-6 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane;	Embodiment of the Invention Preparation Examples Preparation Example 1; Preparation of 10-((4'-piperidylpiperidine)carbonyloxy)-9-allylcamptothecin(CPT-4); One gram (1.25 equivalent weight) of piperidylpiperidine chloroformic acid amide (compound 8) was dissolved in 70mL of dichloromethane, 10-hydroxy-9-allylcamptothecin (1g, 1 equivalent weight) was dissolved in 70mL of anhydrous pyridine, and then the above dichloromethane solution was added into the anhydrous pyridine solution under cooling condition. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and 1.25g of CPT-4 yellow solid was obtained. 1HNMR (DMSO-d6) (ppm) : 1.01 (3H, t), 1.58?1.90 (10H, m), 1.80?1.99 (2H, m), 2.89 (4H, b), 3.09 (1H, b), 3.71 (2H, d), 4.45 (2H, dd), 4.94 (1H, dd), 5.11 (1H, dd), 5.14 (2H, s), 5.15 (1H, d), 5.66 (1H, d), 6.00 (1H, m), 7.47 (1H, d), 7.65 (1H, s), 8.11 (1H, d), 8.51 (1H, s).
	With pyridine; In dichloromethane;Cooling;	Preparation Example 1Preparation of 10-((4'-piperidylpiperidine)carbonyloxy)-9-allylcamptothecin(CPT-4)One gram (1.25 equivalent weight) of piperidylpiperidine chloroformic acid amide (compound 8) was dissolved in 70 mL of dichloromethane, 10-hydroxy-9-allylcamptothecin (1 g, 1 equivalent weight) was dissolved in 70 mL of anhydrous pyridine, and then the above dichloromethane solution was added into the anhydrous pyridine solution under cooling condition. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and 1.25 g of CPT-4 yellow solid was obtained. 1HNMR (DMSO-d6) (ppm): 1.01 (3H, t), 1.58~1.90 (10H, m), 1.80~1.99 (2H, m), 2.89 (4H, b), 3.09 (1H, b), 3.71 (2H, d), 4.45 (2H, dd), 4.94 (1H, dd), 5.11 (1H, dd), 5.14 (2H, s), 5.15 (1H, d), 5.66 (1H, d), 6.00 (1H, m), 7.47 (1H, d), 7.65 (1H, s), 8.11 (1H, d), 8.51 (1H, s).

Reference： [1]Patent: EP1995249,2008,A1 .Location in patent: Page/Page column 5
[2]Patent: US2009/325996,2009,A1 .Location in patent: Page/Page column 3

16
[ 103816-19-9 ]
SN-38 [ No CAS ]
irinotecan [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane;	Preparation Example 2; Preparation of 10-((4'-piperidylpiperidine)carbonyloxy)-9-ethylcamptothecin(CPT-2); Zero point nine five gram (1.25 equivalent weight) of piperidylpiperidine chloroformic acid amide (compound 8) was dissolved in 70mL of dichloromethane, 10-hydroxy-9-ethylcamptothecin (1g, 1 equivalent weight) was dissolved in 70mL of anhydrous pyridine, and the above dichloromethane solution was added into the anhydrous pyridine solution under cooling condition. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and 1.24g of CPT-2 yellow solid was obained. 1HNMR (DMSO-d6) (ppm) : 1.01 (3H, t), 1.20 (3H, t), 1.58?1.90 (2H, m), 1.80?1.99 (2H, m), 2.89 (4H, b), 3.09 (1H, b), 3.21 (2H, q), 4.45 (2H, dd), 5.14 (2H, s), 5.15 (1H, d), 5.66 (1H, d), 6.00 (1H, m), 7.47 (1H, d), 7.65 (1H, s), 8.11 (1H, d), 8.67 (1H, s),
	With pyridine; In dichloromethane;Cooling;	Preparation Example 2Preparation of 10-((4'-piperidylpiperidine)carbonyloxy)-9-ethylcamptothecin(CPT-2)Zero point nine five gram (1.25 equivalent weight) of piperidylpiperidine chloroformic acid amide (compound 8) was dissolved in 70 mL of dichloromethane, 10-hydroxy-9-ethylcamptothecin (1 g, 1 equivalent weight) was dissolved in 70 mL of anhydrous pyridine, and the above dichloromethane solution was added into the anhydrous pyridine solution under cooling condition. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and 1.24 g of CPT-2 yellow solid was obtained. 1HNMR (DMSO-d6) (ppm): 1.01 (3H, t), 1.20 (3H, t), 1.58~1.90 (2H, m), 1.80~1.99 (2H, m), 2.89 (4H, b), 3.09 (1H, b), 3.21 (2H, q), 4.45 (2H, dd), 5.14 (2H, s), 5.15 (1H, d), 5.66 (1H, d), 6.00 (1H, m), 7.47 (1H, d), 7.65 (1H, s), 8.11 (1H, d), 8.67 (1H, s).

Reference： [1]Patent: EP1995249,2008,A1 .Location in patent: Page/Page column 5
[2]Patent: US2009/325996,2009,A1 .Location in patent: Page/Page column 3-4

17
[ 850940-45-3 ]
[ 103816-19-9 ]
[ 951290-30-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane;	Preparation Example 3; Preparation of 10-((4'-piperidylpiperidine)carbonyloxy)-9-propylcamptothecin(CPT-3); One gram (1.25 equivalent weight) of piperidylpiperidine chloroformic acid amide (compound 8) was dissolved in 70mL of dichloromethane, 10-hydroxy-9-propylcamptothecin (1g, 1 equivalent weight) was dissolved in 70mL of anhydrous pyridine, and the above dichloromethane solution was added into the anhydrous pyridine solution under cooling condition. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and 1.17g of CPT-3 yellow solid was obtained. 1HNMR (DMSO-d6) (ppm) : 1.01 (3H, t), 1.12 (3H, t), 1.59 ( 2H, m), 1.82?1.90 (2H, m), 1.80?1.99 (2H, m), 2.89 (4H, b), 3.09, 3.22 (2H, t), (1H, b), 4.45 (2H, dd), 5.14 (2H, s), 5.15 (1H, d), 5.66 (1H, d), 6.00 (1H, m), 7.47 (1H, d), 7.65 (1H, s), 8.11 (1H, d), 8.51 (1H, s).
	With pyridine; In dichloromethane;Cooling;	Preparation Example 3Preparation of 10-((4'-piperidylpiperidine)carbonyloxy)-9-propylcamptothecin(CPT-3)One gram (1.25 equivalent weight) of piperidylpiperidine chloroformic acid amide (compound 8) was dissolved in 70 mL of dichloromethane, 10-hydroxy-9-propylcamptothecin (1 g, 1 equivalent weight) was dissolved in 70 mL of anhydrous pyridine, and the above dichloromethane solution was added into the anhydrous pyridine solution under cooling condition. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and 1.17 g of CPT-3 yellow solid was obtained. 1HNMR (DMSO-d6) (ppm): 1.01 (3H, t), 1.12 (3H, t), 1.59 (2H, m), 1.82~1.90 (2H, m), 1.80~1.99 (2H, m), 2.89 (4H, b), 3.09, 3.22 (2H, t), (1H, b), 4.45 (2H, dd), 5.14 (2H, s), 5.15 (1H, d), 5.66 (1H, d), 6.00 (1H, m), 7.47 (1H, d), 7.65 (1H, s), 8.11 (1H, d), 8.51 (1H, s).

Reference： [1]Patent: EP1995249,2008,A1 .Location in patent: Page/Page column 5
[2]Patent: US2009/325996,2009,A1 .Location in patent: Page/Page column 4

18
[ 1181081-93-5 ]
[ 103816-19-9 ]
[ 1181081-94-6 ]

Yield	Reaction Conditions	Operation in experiment
4%	With potassium carbonate; In acetonitrile;Reflux;	Example 62: 2-[(5Z)-2-(l,2-Diazinan-l-yl)-4-sulfanylidene-4,5-dihydro-l,3-thiazol-5- ylidene]methyl}-5-fluorophenyl 4-(piperidin-l-yl)piperidine-l-carboxylate; To a mixture of (5Z)-5-(4-fluoro-2-hydroxybenzylidene)-2-(tetrahydropyridazin-l(2H)- yl)-l,3-thiazole-4(5H)-thione (783 mg, 2.4 mmol) in anhydrous acetonitrile (15 mL) was added potassium carbonate (663 mg, 4.8 mmol), followed by a solution of 4- piperidinopiperidinecarbonyl chloride (3.9 mmol) in anhydrous acetonitrile (5 mL). The reaction mixture was stirred at reflux overnight. After cooling the mixture to room temperature, the solid material was removed by filtration. The filtrate was recovered and evaporated under reduced pressure. The crude product was purified by flash chromatography (Combiflash Rf, 0-30% MeOeta/Ceta2Cl2), affording the title compound (43 mg, 4%). 1H NMR (400 MHz, DMSO-J6) delta 1.65 (m, 14H), 2.83 (m, 7H), 4.02 (m, 5H), 4.25 (m, IH), 6.39 (t, IH, J= 7.0 Hz), 7.31 (m, 2H), 7.69 (t, IH, J= 6.5 Hz), 7.98 (s, IH); M+ 518.

Reference： [1]Patent: WO2009/97695,2009,A1 .Location in patent: Page/Page column 93

19
[ 1181081-71-9 ]
[ 103816-19-9 ]
2-[(5E)-2-(1,2-diazinan-1-yl)-4-oxo-4,5-dihydro-1,3-thiazol-5-ylidene]methyl}-5-fluorophenyl 4-(piperidin-1-yl)piperidine-1-carboxylate dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 101: 2-[(5E)-2-(l,2-diazinan-l-yl)-4-oxo-4,5-dihydro-l,3-thiazol-5- ylidene]methyl}-5-fluorophenyl 4-(piperidin-l-yl)piperidine-l-carboxylate dihydrochloride; To a solution of 4-piperidinepiperidine (2.O g, 11.9 mmol) in anhydrous CH2Cl2 (50 mL) at 0 0C was added a triphosgene solution (1.3 g, 4.3 mmol) in anhydrous CH2Cl2 (10 mL)by syringe pump addition (1 hour). The mixture was stirred at room temperature overnight. The solid material was removed by filtration. The mixture was extracted with 10% NaHCO3 (2 x 50 mL) and brine (1 x 50 mL). The organic phase was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording the 4-piperidinopiperidinecarbonyl chloride (1.6 g, 59%). The product was used without further purification.To a mixture of (5Z)-2-(l,2-diazinan-l-yl)-5-[(4-fluoro-2-hydroxyphenyl)methylidene]- 4,5-dihydro-l,3-thiazol-4-one (1.0 g, 3.3 mmol) in anhydrous acetonitrile (15 mL) was added potassium carbonate (900 mg, 6.6 mmol), followed by a solution of 4- piperidinopiperidinecarbonyl chloride (1.07 g, 4.6 mmol) in anhydrous acetonitrile (5 mL). The reaction mixture was stirred at reflux for 60 hours. After cooling the mixture to room temperature, the solid material was removed by filtration. The filtrate was recovered and evaporated under reduced pressure. The crude product was purified by flash chromatography (Combiflash Rf, 0-20% MeOH/CH2Cl2). The residue was triturated with diethyl ether (50 mL x 2). The solid material was recovered by filtration and dried in vacuo, affording 2-[(5E)-2-(l,2- diazinan-l-yl)-4-oxo-4,5-dihydro-l,3-thiazol-5-ylidene]methyl}-5-fluorophenyl 4-(piperidin-l- yl)piperidine-l-carboxylate (954 mg, 57%).To a mixture of 2-[(5E)-2-(l,2-diazinan-l-yl)-4-oxo-4,5-dihydro-l,3-thiazol-5- ylidene]methyl}-5-fluorophenyl 4-(piperidin-l-yl)piperidine-l-carboxylate (954 mg, 1.9 mmol) in methanol (5 mL) was added a solution of 4M HCl/ dioxane (3 mL, 12.0 mmol). The resultant solution was filtered, and the filtrate was recovered and evaporated. The solid was triturated with diethyl ether (50 mL). The solid material was recovered by filtration and dried in vacuo, affording the final compound (931mg, 91%). 1H NMR (400 MHz, DMSO-J6) 1-45 (m, IH), <n="116"/>1.81 (m, HH), 2.16 (m, 2H), 2.96 (m, 5H), 3.15 (m, IH), 3.44 (m, 3H), 3.88 (m, 2H), 4.11 (m, IH), 4.35 (m,lH) 6.17 (t, IH, J= 6.7 Hz), 7.32 (m, 2H), 7.47 (s, IH), 7.67 (t, IH, J= 6.3 Hz); M+ 502. HPLC purity: 99.1%.

Reference： [1]Patent: WO2009/97695,2009,A1 .Location in patent: Page/Page column 114-115

20
[ 103816-19-9 ]
[ 85999-40-2 ]
[ 1309982-12-4 ]

Yield	Reaction Conditions	Operation in experiment
85.7%	With pyridine; at 20℃; for 16h;	To a solution of 1,4'-dipiperidine-1-carbonyl chloride mixture obtained from previous reaction in dry pyridine (120 mL) was added 23-hydroxybetulinic acid (1.0 g, 2.1 mmol). The solution was stirred at room temperature for 16 h. At which time the reaction was completed, ethyl acetate (100 mL) was added, the pH of the solution was adjusted to 4-5 by 10% HCl, the organic layer was separated and washed by brine (100 mL), dried with anhydrous Na2SO4. Filtered, the filtrate was concentrated, the residue was dissolved in methanol and purified on a silica gel column (200 g, chloroform-methanol 5:1) to give 53 (1.2 g, 85.7%) as white foam. MS (ESI): m/z 667.5 [M + H]+, 665.9 [M - H]-; HR-ESI-MS: m/z 667.5056 [M + H]+ (calcd: 667.5044); 1H NMR (DMSO-d6, 400 MHz) delta: 0.51, 0.78, 0.86, 0.94 (each 3H, s, Me-24, -25, -26, and -27), 1.36 (6H, H-3,4,5), 1.46 (4H, H-3', 5'), 1.66 (3H, s, Me-30), 1.92 (1H, m, H-18), 2.12 (1H, m, H-19), 2.42 (2H, t, H-2), 2.50 (2H, t, H-6), 2.86 (2H, t, H-2'), 3.02 (2H, t, H-6'), 3.06 (1H, m, H-3), 3.84 (1H, d, J = 11.6 Hz, H-23alpha), 4.01 (1H, d, J = 11.6 Hz, H-23beta), 4.58 (1H, s, H-29alpha), 4.71 (1H, s, H-29beta); 13C NMR (DMSO-d6, 100 MHz) delta: 12.3, 13.4, 14.2, 18.5, 18.8, 24.4, 26.0, 29.9, 36.3, 38.8, 39.2, 39.5, 39.7, 39.9, 40.1, 41.8, 42.0, 46.6, 49.5, 56.4, 60.7, 64.9, 70.2, 109.9, 149.6, 166.8, 171.6.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2490 - 2502

21
[ 103816-19-9 ]
[ 97682-44-5 ]
[ 1310903-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; acetamide; triethylamine; In dichloromethane; at 30 - 35℃; for 48h;	Example 6(S)-4,11-diethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-4,9-diyl bis([1,4'-bipiperidine]-1'-carboxylate)Compound of Formula-XCharged 1 gm (1.7 mmol) of Irinotecan free base, 10 mL of MDC, 3 ml of pyridine and 150 mg of Acetamide in a flask. Prepared a solution of 0.56 gm (2.27 mmol) [1,4']bipiperidinyl-1'-carbonyl chloride (II) in 15 mL of MDC and 1 mL of TEA in another flask and added in above reaction mass. The temperature of reaction mass was raised to 30-35° C. and maintained for 48 hrs. The reaction mass was washed with 5 mL of 5percent NaHCO3 and evaporated in vacuum. To the reaction mass toluene was added and again evaporated completely. Added 10 mL of n-Hexane and stirred for 30 min, filtered and washed with n-Hexane to get the product which was purified by column chromatography by eluting with MDC:Methanol (95:5percent) to afford 208 mg of title compound having 99percent purity by HPLC.M.P.=227° C.
	With pyridine; triethylamine; In acetamide; dichloromethane; at 30 - 35℃;	Example 6 (S)-4,11-diethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-4,9-diyl bis([1,4'-bipiperidine]-1'-carboxylate) [Compound of formula-X] Charged 1 gm (1.7 mmol) of Irinotecan free base, 10 mL of MDC, 3 ml of pyridine and 150 mg of Acetamide in a flask. Prepared a solution of 0.56gm (2.27 mmol) [1,4']bipiperidinyl-1'-carbonyl chloride (II) in 15 mL of MDC and 1 mL of TEA in another flask and added in above reaction mass. The temperature of reaction mass was raised to 30-35°C and maintained for 48 hrs. The reaction mass was washed with 5 mL of 5percent NaHCO3 and evaporated in vacuum. To the reaction mass toluene was added and again evaporated completely. Added 10 mL of n-Hexane and stirred for 30 min, filtered and washed with n-Hexane to get the product which was purified by column chromatography by eluting with MDC:Methanol (95:5percent) to afford 208 mg of title compound having 99 percent purity by HPLC. M.P. =227 °C

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 10

22
[ 103816-19-9 ]
[ 100286-90-6 ]

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

23
[ 1443411-25-3 ]
[ 103816-19-9 ]
[ 76-05-1 ]
3-(2-([1,4'-bipiperidine]-1'-carbonyl)-9-fluoro-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-(benzofuran-3-yl)-1H-pyrrole-2,5-dione trifluoroacetate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5115 - 5129

24
[ 34170-23-5 ]
[ 103816-19-9 ]
[ 1542436-59-8 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; dmap; at 60℃; for 2h;Inert atmosphere; Schlenk technique;	General procedure: Chartarin- 1,10 bis- 1 ,4'-bipiperidine- 1 '-carboxylate Chartarin (1.0 eq.) l,4'-bipiperidine-r-carbonyl chloride (4.0 eq.), N,N-dimethylpyridin-4- amine was placed in a Schlenk tube and flushed with argon 3 times. Then pyridin was added and the solution was stirred for 2 days at 60 C. After cooling the solvent was removed and the resulting brownish solid was dissolved in Methanol/THF. The solution was suspected to preparative HPLC using a Phenomenex Kinetix XB-C18 column with a gradient from 10 to 83% acetonitrile in water with 0.1% formic acid. HRMS (ESI+) calc. for C43H4708N4 [M+H]+: 723.3402, found. 723.3395 amu.

Reference： [1]Patent: WO2014/19685,2014,A1 .Location in patent: Page/Page column 65; 66

25
[ 1401735-76-9 ]
[ 103816-19-9 ]
[ 1401735-67-8 ]

Yield	Reaction Conditions	Operation in experiment
70.1%	With pyridine; In pyridine; dichloromethane; at 20℃; for 16h;Cooling with ice;	1.5 g (6.5 mmol) of piperidinylpiperidinyl-chlorocarbonylamide was dissolved in 30 ml of dichloromethane. 2.1 g (4.4 mmol) of 2-(10-hydroxycamptothecin-9-)t-butylamine-oxime was dissolved in 30 ml of anhydrous pyridine, which was cooled in an ice bath while the aforementioned dichloromethane solution was added. The mixture was stirred for 16 hours at room temperature and, after the reaction was completed, the solvent was distilled off under reduced pressure. The residue was then purified by silica gel column chromatography to obtain 2.1 g of yellow solid, at a yield of 70.1%. 1H NMR (CDCl3): delta 8.78 (s, E), 8.61 (s, Z), 8.13 (d, 1H), 7.66 (d, 1H), 7.58 (dd, 1H), 7.37 (t, E), 6.68 (t, Z), 5.74 (d, 1H), 5.29 (d, 1H), 5.26 (s, 2H), 4.43 (br, 1H), 4.32 (d, 1H), 4.11 (d, Z), 3.93 (d, E), 3.1 (t, 1H), 2.95 (t, 1H), 2.57 (br, 4H), 1.95 (br, 2H) 1.83 (m, 2H), 1.63 (br, 4H), 1.47 (br, 2H), 1.27 (s, E), 1.25 (s, Z), 1.03 (t, 3H).

Reference： [1]Patent: US2014/11833,2014,A1 .Location in patent: Paragraph 0042; 0043

26
[ 103816-19-9 ]
N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]-3-chloro-4-fluorobenzamide [ No CAS ]
(3S,4S)-6-acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-3-yl 4-(piperidin-1-yl)piperidine-1-carboxylate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.3%		N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-di methyl-3,4-di hydro-2H- 1 -benzopyran-4-yl]-3-chloro-4- fluorobenzamide (784mg, 2.OOmmol) was dissolved in THF (25mL) and the reaction mixture was cooled to 0CC. NaH (100mg, 60% dispersion in mineral oil, 2.5Ommol) was added and the reaction mixture was stirred at 000 for 20mm. 4-Piperidinopiperidine-1-carbonyl chloride (461mg, 2.OOmmol) was added portion-wise and the reaction mixture was stirred overnight and concentrated in vacuo. The residue was partitioned between 15% aq NH4CI and EtOAc and the organic fraction was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on normal phase silica eluting with DCM/MeOH/NH4OH (100/2.5/0.5) and dissolved in Et20 and 2M HCI in Et20 was added. The resulting precipitate was collected by filtration and washed with Et20 to give the title compound (900mg, 72.3%) as a white solid. HPLC: Rt 5.41mm, 99.8% purity. HRMS (ESI+) calcd for 031 H37C1FN305 586.248 found 586.250.
72.3%		Example 18 (3S,4S)-6-Acetyl-4-[(3-chloro-4-fluorobenzene)amido]-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-3-yl 4-(piperidin-1-yl)piperidine-1-carboxylate hydrochloride N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]-3-chloro-4-fluorobenzamide (784 mg, 2.00 mmol) was dissolved in THF (25 mL) and the reaction mixture was cooled to 0 C. NaH (100 mg, 60% dispersion in mineral oil, 2.50 mmol) was added and the reaction mixture was stirred at 0 C. for 20 min. 4-Piperidinopiperidine-1-carbonyl chloride (461 mg, 2.00 mmol) was added portion-wise and the reaction mixture was stirred overnight and concentrated in vacuo. The residue was partitioned between 15% aq NH4Cl and EtOAc and the organic fraction was washed with brine, dried (MgSO4) and concentrated hi vacuo. The residue was purified by column chromatography on normal phase silica eluting with DCM/MeOH/NH4OH (100/2.5/0.5) and dissolved in Et2O and 2M HCl in Et2O was added. The resulting precipitate was collected by filtration and washed with Et2O to give the title compound (900 mg, 72.3%) as a white solid. LCMS (ES+): 586.2 [MH]+. HPLC: Rt 5.41 min, 99.8% purity.

Reference： [1]Patent: WO2014/140510,2014,A1 .Location in patent: Page/Page column 40; 41
[2]Patent: US2014/275068,2014,A1 .Location in patent: Paragraph 0234; 0235

27
[ 20004-62-0 ]
[ 103816-19-9 ]
resistomycin-10-1,4'-bipiperidine-1'-carboxylate [ No CAS ]