[ CAS No. 41340-25-4 ] {[proInfo.proName]}

Name: 41340-25-4|2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid|99+%
Brand: Ambeed
SKU: A128494
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Quality Control of [ 41340-25-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 41340-25-4 ]

Product Details of [ 41340-25-4 ]

CAS No. :	41340-25-4	MDL No. :	MFCD00133313
Formula :	C₁₇H₂₁NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NNYBQONXHNTVIJ-UHFFFAOYSA-N
M.W :	287.35	Pubchem ID :	3308
Synonyms :	AY-24236;NIH 9918;NSC 282126;(±)-Etodolac	Chemical Name :	2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid

Calculated chemistry of [ 41340-25-4 ]

Physicochemical Properties

Num. heavy atoms :	21
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.47
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	82.66
TPSA :	62.32 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.23
Log Po/w (XLOGP3) :	2.81
Log Po/w (WLOGP) :	3.27
Log Po/w (MLOGP) :	2.12
Log Po/w (SILICOS-IT) :	4.31
Consensus Log Po/w :	2.95

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.45
Solubility :	0.103 mg/ml ; 0.000359 mol/l
Class :	Soluble
Log S (Ali) :	-3.78
Solubility :	0.0481 mg/ml ; 0.000168 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.2
Solubility :	0.00181 mg/ml ; 0.00000631 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.47

Safety of [ 41340-25-4 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P264-P270-P280-P301+P310+P330-P305+P351+P338-P337+P313-P405-P501	UN#:	2811
Hazard Statements:	H301-H319-H350-H360	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 41340-25-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 41340-25-4 ]
Downstream synthetic route of [ 41340-25-4 ]

[ 41340-25-4 ] Synthesis Path-Upstream 1~5

1
[ 87226-41-3 ]
[ 87249-11-4 ]
[ 41340-25-4 ]

Reference： [1] Patent: US2005/14953, 2005, A1, . Location in patent: Page 2
[2] Patent: US2005/14953, 2005, A1, . Location in patent: Page column 2

2
[ 87226-41-3 ]
[ 41340-25-4 ]

Reference： [1] Patent: US2005/14953, 2005, A1, . Location in patent: Page column 2
[2] Patent: US2006/167259, 2006, A1, . Location in patent: Page/Page column 10

3
[ 87249-11-4 ]
[ 41340-25-4 ]

Reference： [1] Patent: US2006/167259, 2006, A1, . Location in patent: Page/Page column 9
[2] Patent: US2006/167259, 2006, A1, . Location in patent: Page/Page column 9

4
[ 41340-36-7 ]
[ 30414-53-0 ]
[ 41340-25-4 ]

Reference： [1] Croatica Chemica Acta, 2016, vol. 89, # 4,

5
[ 41340-36-7 ]
[ 4949-44-4 ]
[ 41340-25-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1976, vol. 19, p. 391 - 395

[ 41340-25-4 ] Synthesis Path-Downstream 1~88

1
[ 41340-36-7 ]
[ 4949-44-4 ]
[ 41340-25-4 ]

Reference： [1]Journal of Medicinal Chemistry,1976,vol. 19,p. 391 - 395

2
[ 41340-25-4 ]
[ 74-88-4 ]
[ 114737-77-8 ]
[ 114720-05-7 ]

Reference： [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 1712 - 1719

3
[ 41340-25-4 ]
[ 41340-36-7 ]
7-ethyl-2-(1-methyl-1-propenyl)-1H-indole-3-ethanol [ No CAS ]
7-ethyl-2-(1-methylenepropyl)-1H-indole-3-ethanol [ No CAS ]
1,8-diethyl-1-methyl-1,3,4,9-tetrahydropyrano-<3,4-b>indole [ No CAS ]

Reference： [1]Journal of Pharmaceutical Sciences,1988,vol. 77,p. 81 - 86

4
[ 41340-25-4 ]
[ 87249-11-4 ]

Reference： [1]Journal of Medicinal Chemistry,1983,vol. 26,p. 1778 - 1780

5
[ 41340-25-4 ]
[ 87226-41-3 ]

Reference： [1]Journal of Medicinal Chemistry,1983,vol. 26,p. 1778 - 1780

6
[ 41340-25-4 ]
7-ethyl-2-(1-methylenepropyl)-1H-indole-3-ethanol [ No CAS ]

Reference： [1]Journal of Pharmaceutical Sciences,1988,vol. 77,p. 81 - 86

7
[ 67217-55-4 ]
[ 41340-25-4 ]
[ 957229-37-7 ]
[ 957229-36-6 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 100℃; for 30h;	EXAMPLE; Synthesis of 6-O-[1,8-diethyl-1,3,4,9.tetrahydropyrano(3,4-b)indole-1-acetyl]-beta-cyclodextrin; 6-O-tosyl-beta-cyclodextrin (12 g) (R.P. Bonomo et al., Inorg. Chem., 1991, 30, 2708) was added to an <strong>[41340-25-4]etodolac</strong> solution in 100 ml of DMF (in stoichiometric amounts). The reaction was carried out at 100C under stirring. After 30h the solvent was evaporated off under vacuo. The reaction mixture was purified by Rp8 column chromatography, using water-MeOH as the eluent. The product was eluted at a MeOH concentration of 70%. TLC: Propanol-AcOEt-H2O-NH3 5:2:3:3 Rf= 0.61. The recovered product consists of two diastereomers: the conjugate with S(+)-<strong>[41340-25-4]etodolac</strong> and that with R(-) <strong>[41340-25-4]etodolac</strong>. Yield in diastereomer mixture: 35%. The two diastereomers were separated by preparative HPLC with Econosphere ODS column (Alltech, 22x250 mm), eluent H2O-MeOH 40 ? 70 (40', flow rate 10 ml/min). The conjugate with S-<strong>[41340-25-4]etodolac</strong> eluted first. The configuration of cyclodextrin-conjugated <strong>[41340-25-4]etodolac</strong> was assigned by hydrolysing one of the diastereomeric products, namely the one eluted first from the preparative HPLC column and then measuring the optical rotary power of the <strong>[41340-25-4]etodolac</strong> released. This product was hydrolyzed by suspending it in 1% NaOH aqueous solution for 2h at room temperature. After completion of the reaction, the mixture was acidified and <strong>[41340-25-4]etodolac</strong> was extracted by CH2Cl2, dried, dissolved in EtOH and the measured [alpha]D20 optical rotary power = 31.2 (c=0.2, ethanol) indicated that the product was <strong>[41340-25-4]etodolac</strong> S(+)-enantiomer. The two diastereomers were characterized singularly. 6-O-[1(S)1,8-diethyl-1,3,4,9.tetrahydropyrano(3,4-b)indole-1-acetyl]-beta-cyclodextrin: ES-MS 1404 m/e; 1H NMR (CD3OD) in ppm 0.76 (3H, t, CH3 of the ethylene chain bound to tetrahydropyran), 1.35 (3H, t, CH3 of the ethylene chain of the benzene residue), 2.07 (2H, m, CH2 of the ethylene chain bound to the tetrahydropyran ring), 2.76 (2H, m, H-3 of the tetrahydropyran); 2.89 (3H, m, CH2 of ethylene chain bound to the benzene and a CH2 proton in alpha to the carboxyl group); 3.16 (1H, d, other CH2 proton in alpha to carboxyl group); 321 (1H, dd, 2A); 3.25 (1H, t, 4-A); 3.28-3.53 (12H, m, 2-H and 4-H of CD); 3.54-3.99 (26H, m, 5-,6,-3-H of CD); 4.03 (2H, m, H-2 of tetrahydropyran); 4.77 (d, 1A, with HOD peak), 4.83 (1H, d, 1G); 4.98 (5H, d, other H-1 of CD); 6.91 (1H,d, proton in ortho to the ethylene chain of the benzene ring), 6.96 (1H, t, proton in metha to the ethylene chain); 7.27 (1H, d, proton in para to the ethylene chain). Circular dichroism: 205 nm Deltaepsilon = 3; 233 nm Deltaepsilon = -16.6-O-[1(R)1,8-diethyl-1,3,4,9. tetrahydropyran (3,4-b) indole-1-acetyl]-beta-cyclodextrin ES-MS 1404 m/e; 1H NMR (D2O): in ppm 0.65 (3H, t, CH3 of ethylene chain bound to tetrahydropyran), 1.25 (3H, t, CH3 of ethylene chain of benzene), 1.91 (1H, m, H of CH2 bound to tetrahydropyran), 2.03 (1H, m, H of CH2 bound to tetrahydropyran); 2.69 (2H, m, H-3 of tetrahydropyran); 2.72 (2H, m, CH2 of ethylene chain of benzene); 2.98 (2H, s, CH2 in a to the carboxyl group); 3.15 (1H, t, 4-A); 3.20-4.00 (33H, m, 5-,6,-3-,2-,4-H of CD and H-2 of tetrahydropyran); 4.60 (1H, d, 6A); 4.75 (1H, d, H-1), 4.83 (2H, m, H-1 and 1A); 4.99 (1H, d, H-1 of CD); 4.97 (3H, m, H-1); 6.96 (1H,d, proton in ortho to the ethylene chain of benzene), 7.03 (1H, t, proton in metha to the ethylene chain); 7.30 (1H, d, proton in para to the ethylene chain). Circular Dichroism: 205 nm Deltaepsilon = -4; 233 nm Deltaepsilon = 16.

Reference： [1]Patent: EP1860110,2007,A1 .Location in patent: Page/Page column 4-5

8
[ 41340-25-4 ]
[ 200880-25-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With LiAlH4; In tetrahydrofuran; hexane; ethyl acetate;	EXAMPLE 1 2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)-ethanol (1) A solution of <strong>[41340-25-4]etodolac</strong> (2.0 g, 6.97 mmol) in dry THF (5 mL) was added dropwise to 1M LiAlH4 in THF (10.5 mL, 10.5 mmol, 1.5 eq) over five minutes and stirred at room temperature overnight under argon. The resulting mixture was then slowly quenched with EtOAc and poured over water to form an emulsion. The emulsion was filtered, and the aqueous layer was separated and extracted twice with EtOAc. The three organic phases were combined, washed with brine, dried with Na2SO4, concentrated, and purified by column chromatography using 50:50:EtOAc:Hexane to give a yellow oil (1.87 g, 98%): 1H-NMR (CDCl3, 6 TMS): 0.95 (t, 3H), 1.36 (t, 3H), 1.96 (m, 2H), 2.14 (m, 2H), 2.68 (br, OH), 2.81 (m, 2H), 2.83 (q, 2H), 3.70 (m, 2H), 4.07 (m, 2H), 7.02-7.39 (m, 3H, Ar-H), 7.74 (br, 1H, NH). MS+: m/z 296 (MNa+). MS-: m/z 308 (MCl-), 272 ([M-H]-).

Reference： [1]Patent: US2005/239752,2005,A1
[2]RSC Advances,2017,vol. 7,p. 23680 - 23686

9
[ 1336-21-6 ]
[ 79-37-8 ]
[ 41340-25-4 ]
[ 591752-31-7 ]

Yield	Reaction Conditions	Operation in experiment
35%	N,N-dimethyl-formamide; In tetrahydrofuran; hexane; dichloromethane; ethyl acetate;	EXAMPLE 6 2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)-acetamide (6) To a stirred solution of <strong>[41340-25-4]etodolac</strong> (287 mg, 1.0 mmol) in CH2Cl2 (5 mL) at room temperature, oxalyl chloride (105 muL, 1.2 mmol, 1.2 eq) was added dropwise, followed by a catalytic amount of DMF (2 drops). The mixture was stirred for one hour and then concentrated. The resulting orange solid was dissolved in dry THF (2 mL) and added dropwise to a stirred solution of ice-cold concentrated NH4OH (5 mL). The mixture was allowed to warm to room temperature, stirred for two days, diluted with brine, and extracted three times with EtOAc. The combined organic phases were dried with Na2SO4, concentrated, and purified by column chromatography using 50:50:EtOAc:Hexane to give a yellow-white solid (100 mg, 35%): mp 189-190 C. 1H-NMR (CDCl3, 6 TMS): 0.87 (t, 3H), 1.32 (t, 3H), 2.08 (m, 2H), 2.83 (m, 4H), 2.91 (q, 2H), 4.07 (m, 2H), 5.48 (br, 1H, CONH2), 6.33 (br, 1H, CONH2), 6.99-7.36 (m, 3H, Ar-H), 9.26 (br, 1H, NH). MS+: m/z 309 (MNa+). MS-: m/z 321 (MCl-), 286 (M-). Anal. (C17H22N2O2.0.125H2O): C, H, N.

Reference： [1]Patent: US2005/239752,2005,A1

10
[ 64-19-7 ]
[ 41340-25-4 ]
2-(dimethylamino)ethyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.4%		Preparation of N-dimethylaminoethyl l,8-diethyl-l,3,4,9-tetrahydropyrano-[3,4-b]indole-l-acetamide.AcOH[42] 28.9 g (0.1 mol) of l,8-diethyl-l,3,4,9-tetrahydropyrano-[3,4-b]indole-l-acetic acid was dissolved in 100 ml of acetonitrile. 32.1 g of O-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 30 ml of tri- ethylamine were added into the reaction mixture. 11.7 g of dimethylaminoethylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 250 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 40 g of the <n="27"/>desired product (89.4%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H N O ; MW: 447.61. Calculated % C: 67.08; H: 9.23; N:J J 25 41 3 A ' '9.39; O: 14.30; Found % C: 67.05; H: 9.25; N: 9.38; O: 14.32. 1H-NMR (400 MHz, D 2 O): delta: 0.95 (t, 3H), 1.20 (t, 3H), 1.24 (t, 3H), 1.40 (m, 2H), 1.50 (s, 6H), 1.87 (m, 2H), 2.21 (s, 3H), 2.25 (s, 2H), 2.56 (m, 2H), 3.08 (m, IH), 3.11 (m, IH), 3.28 (m, 4H), 3.50 (m, 2H), 3.64 (m, 2H), 7.0 (b, IH), 6.43 (m, IH), 6.70 (m, IH), 6.72 (m, IH), 7.6 (b, IH).

Reference： [1]Patent: WO2008/17903,2008,A1 .Location in patent: Page/Page column 24-25

11
[ 41340-25-4 ]
2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetonitrile [ No CAS ]

Reference： [1]Heterocycles,2003,vol. 60,p. 1095 - 1110

12
[ 41340-25-4 ]
C₁₈H₁₇⁽²⁾H₆NO₃ [ No CAS ]

Reference： [1]Journal of the Chinese Chemical Society,2001,vol. 48,p. 229 - 234

13
[ 41340-25-4 ]
C₁₈H₁₆⁽²⁾H₇NO₃ [ No CAS ]

Reference： [1]Journal of the Chinese Chemical Society,2001,vol. 48,p. 229 - 234

14
[ 92594-46-2 ]
[ 41340-25-4 ]
compound 18 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 24h;	To a solution of <strong>[41340-25-4]etodolac</strong> (D8) (83 mg; 0.29 mmole) in dry [CH2CI2] (5 [ML)] under argon, 0.380 [ML] (2.73 mmole) of triethylamine, 80 mg (0.59 mmole) of 1- hydroxybenzotriazole, 230 mg (0.29 mmole) of [ML2] and 235 mg (1.23 mmole) of [1-] [(3-DIMETHYLAMINOPROPYL)-3-ETHYL-CARBODIIMIDE] hydrochloride were added. The reaction mixture was stirred for 24 hours at room temperature in a flow of argon, then evaporated to a smaller volume under reduced pressure and purified on a silica gel column (eluant: [CHCL3] : MeOH: NH40H = 6: 1: 0.1). 78 mg of compound 18 was obtained. MS [(M/Z)] : 1061.4 [MH] [+.]

Reference： [1]Patent: WO2004/5309,2004,A2 .Location in patent: Page 54

15
[ 2627-86-3 ]
[ 41340-25-4 ]
[ 87226-41-3 ]
[ 87249-11-4 ]

Yield	Reaction Conditions	Operation in experiment
		1) Resolution of the Racemic Mixture and Recovery of the S-(+)-Etodolic Acid from the Mother Liquors of the Resolution Process [0029] 1 kg of R,S-etodolic acid (3.48 moles) was dissolved in 5 litres of acetone. 445 ml of S-(-)-phenylethylamine (3.48 moles) was added dropwise and slight exothermy from 23 C. to 28 C. was observed; after the dropwise addition, the solution was heated to 35 C. and stirring was continued until precipitation was observed. The solution was cooled to 20 C. and stirring was continued for 20 hours. The solid was filtered out, taken up in 4 litres of ethyl acetate, and whisked with two 1500 ml portions of 4% hydrochloric acid, the organic phase was concentrated to a volume of 550 ml and taken up with 420 ml of heptane to bring about crystallization. 248 g of R-(-)-etodolic acid was obtained. [0030] The solution was concentrated to a residual volume of 1.8 litres and was then taken up with 5.4 litres of heptane, causing the formation of abundant precipitate. The mixture was left for 3 hours with stirring at 20 C., the precipitate was filtered out and 880 g of etodolic acid salt was recovered. The solid was dissolved in 8 litres of AcOEt and two washings with 3 litres of 4% HCl and one with 3 litres of H2O were performed. [0031] The organic phase was evaporated to a residual volume of 1.15 litres, 1.26 litres of heptane was added, the mixture was left at 20 C. for 3 hours with stirring, and the precipitate was filtered out. 545 g of S-(+)-etodolic acid was recovered by this method, with a 42% enantiomeric excess.

Reference： [1]Patent: US2005/14953,2005,A1 .Location in patent: Page column 2

16
[ 87226-41-3 ]
[ 41340-25-4 ]

Yield	Reaction Conditions	Operation in experiment
	With tin(IV) chloride; In tetrahydrofuran; dichloromethane; for 4h;Heating / reflux;	c) 2 g (6.96 mmoles) of R-(-)-etodolic acid (98% enantiomeric excess) was dissolved in 18 ml of CH2Cl2 and 2 ml of THF at 20 C. 160 ml (1.39 mmoles) of SnCl4 was added and was left under reflux for 4 hours with stirring. Two washings with 18 ml of H2O were performed, the organic phase was separated and was concentrated to a residual volume of 3 ml, 5 ml of heptane was added and the mixture was left at 20 C. for 3 hours. The precipitate was filtered out and 1.5 g of racemic etodolic acid was thus recovered
	sulfuric acid; In isopropyl alcohol; at 20℃; for 23h;Product distribution / selectivity;	Racemization of (R)-etodolac by BF3-Et2O and concentrated H2SO4a results reaction time ratio of R:S of percentage of entry acid (h) Etodolacside products (%)b 1c BF3-Et2O 22 1.3:1.0 12d H2SO4 23 1.0:1.0 5 aRacemization reaction conditions unless otherwise indicated: 20 C., 0.37 mmol of (R)-etodolac, and 5.0 ml of dry 2-propanol. For HPLC analysis, a portion of reaction mixture was taken out after about 16-18 hours and concentrated under reduced pressure. The residue was extracted from water with dichloromethane twice. The combined organic phases were dried over MgSO4, filtered, and concentrated. No. The resulting residue was dried in vacuo and then subjected to HPLC analysis by using Chiral-AGP column at 225 nm. bRatio of HPLC peak areas at 225 nm. c1.5 equivalents of BF3-Et2O. dOne equivalent of H2SO4.

Reference： [1]Patent: US2005/14953,2005,A1 .Location in patent: Page column 2
[2]Patent: US2006/167259,2006,A1 .Location in patent: Page/Page column 10

17
[ 87226-41-3 ]
[ 87249-11-4 ]
[ 41340-25-4 ]

Yield	Reaction Conditions	Operation in experiment
	With tin(IV) chloride; In dichloromethane; at 20℃; for 2h;	a) 10 g (34.8 mmoles) of S-(+)-etodolic acid (42% enantiomeric excess) was dissolved in 100 ml of CH2Cl2 at 20 C. 60 ml (0.52 mmoles) of SnCl4 was added and the mixture was left for 2 hours with stirring. Two washings with 100 ml of H2O were performed, the organic phase was separated and was concentrated to a residual volume of 15 ml, 20 ml of heptane was added, and the mixture was left at 20 C. for 3 hours with stirring. The precipitate was filtered out and 8.1 g of racemic etodolic acid was thus recovered.
		10 g (34.8 mmoles) of S-(+)-etodolic acid (42% enantiomeric excess) was dissolved in 100 ml of CH2Cl2 at 20 C. [0035] 60 ml (0.52 mmoles) of SnCl4 was added and the mixture was left for 2 hours with stirring. Two washings with 100 ml of H2O were performed and the organic phase was extracted with 40 ml of 6% NaOH. The aqueous phase was separated, diluted with 10 ml of MeOH and acidified to pH=5 with formic acid. The mixture was left at 0 C. for 1 hour with stirring and was filtered and 7.6 g of racemic etodolic acid was recovered

Reference： [1]Patent: US2005/14953,2005,A1 .Location in patent: Page 2
[2]Patent: US2005/14953,2005,A1 .Location in patent: Page column 2

18
[ 100-39-0 ]
[ 41340-25-4 ]
2-(9-benzyl-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With sodium hydride; In tetrahydrofuran; at 50℃; for 2h;	COMPOUND 49 : 2-(9-BENZYL-1,8-DIETHYL-1,3, 4, 9-TETRAHYDRO-PYRANO [3, 4-B] INDOL-1- YL)-ETHANOL Compound 49 was synthesized according to the following scheme: 49. A. Synthesis of (9-Benzyl-1, 8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1- yl)-acetic acid To a solution of (1, 8-diethyl-1, 3,4, 9-tetrahydro-pyrano [3,4-b] indol-1-yl)-acetic acid (0.51 g, 1.8 mmol) in tetrahydrofuran at room temperature was added sodium hydride (60% dispersion in mineral oil, 0.4 g). After being heated at 50 C for 2 hours, benzyl bromide (0.6 g, 3.5 mmol) was added and the solution was stirred for another 2 hours. It was quenched with ethyl acetate and washed with water. The ethyl acetate layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.486 g (73%) of the title compound as a SOLID. 1H NMR (500 MHz, CDC13) 8 7.13 (m, 3H), 6.97 (d, 1H), 6.74 (d, 1H), 6.68 (t, 1H), 6.21 (d, 1H), 3.90 (s, 1H), 3.63 (m, 1H), 3.35 (td, 1H), 3. 18 (d, 1H), 3.00 (d, 1H), 2.67 (q, 2H), 2.44 (q, 2H), 2.10 (m, 1H), 1.85 (d, 1H), 1.52 (m, 1H), 1.41 (m, 1H), 1.16 (t, 3H), 0.75 (t, 3H); ESI (+) MS m/e=278 (MH+).

Reference： [1]Patent: WO2005/33112,2005,A2 .Location in patent: Page/Page column 101

19
[ 1867-66-9 ]
[ 41340-25-4 ]
rac-ketamine etodolate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol; water; for 1h;	rac-Ketamine etodolate may be prepared using the following synthetic scheme. Etodolac (0.2874 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic etodolate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.

Reference： [1]Patent: US2005/203115,2005,A1 .Location in patent: Page/Page column 22

20
[ 64-31-3 ]
[ 41340-25-4 ]
5R,6S,9R,13S,14R-morphine etodolate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol; water; for 1h;	5R,6S,9R,13S,14R-Morphine etodolate may be prepared using the following synthetic scheme. Etodolac (0.2874 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Morphine sulfate pentahydrate (0.3794 g, 0.50 mmol) is dissolved in a minimal volume of water and combined with the ethanolic etodolate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation.

Reference： [1]Patent: US2005/203115,2005,A1 .Location in patent: Page/Page column 34

21
[ 29485-83-4 ]
[ 41340-25-4 ]
5R,6S,9R,13S,14R-codeine etodolate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol; water; for 1h;	5R,6S,9R,13S,14R-Codeine etodolate may be prepared using the following synthetic scheme. Etodolac (0.2874 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Codeine sulfate (0.3484 g, 0.50 mmol) is dissolved in a minimal volume of water and combined with the ethanolic etodolate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.

Reference： [1]Patent: US2005/203115,2005,A1 .Location in patent: Page/Page column 31

22
[ 1639-60-7 ]
[ 41340-25-4 ]
d-propoxyphene etodolate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol; water; for 1h;	d-Propoxyphene etodolate may be prepared using the following synthetic scheme. A solution of 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (herein referred to as <strong>[41340-25-4]etodolac</strong>) (0.2874 g, 1.00 mmol) in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol (20 mL) and stirred for 1 hour. d-Propoxyphene hydrochloride (0.3759 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic etodolate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.

Reference： [1]Patent: US2005/203115,2005,A1 .Location in patent: Page/Page column 20

23
[ 33643-47-9 ]
[ 41340-25-4 ]
(S)-ketamine etodolate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol; water; for 1h;	(S)-Ketamine etodolate may be prepared using the following synthetic scheme. Etodolac (0.2874 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic etodolate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.

Reference： [1]Patent: US2005/203115,2005,A1 .Location in patent: Page/Page column 24-25

24
[ 125-72-4 ]
[ 41340-25-4 ]
levorphanol etodolate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol; water; for 1h;	Levorphanol etodolate may be prepared using the following synthetic scheme. Etodolac (0.2874 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Levorphanol tartrate dihydrate (0.4435 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic etodolate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.

Reference： [1]Patent: US2005/203115,2005,A1 .Location in patent: Page/Page column 36

25
5R,9R,13S,14R-hydrocodone bitartrate [ No CAS ]
[ 41340-25-4 ]
5R,9R,13S,14R-hydrocodone etodolate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol; water; for 1h;	5R,9R,13S,14R-Hydrocodone etodolate may be prepared using the following synthetic scheme. Etodolac (0.2874 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. 5R,9R,13S,14R-Hydrocodone bitartrate hemipentahydrate (0.4945 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic etodolate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.

Reference： [1]Patent: US2005/203115,2005,A1 .Location in patent: Page/Page column 29

26
[ 1095-90-5 ]
[ 41340-25-4 ]
rac-methadone etodolate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol; water; for 1h;	rac-Methadone etodolate may be prepared using the following synthetic scheme. Etodolac (0.2874 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic etodolate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.

Reference： [1]Patent: US2005/203115,2005,A1 .Location in patent: Page/Page column 27

27
[ 87249-11-4 ]
[ 41340-25-4 ]

Yield	Reaction Conditions	Operation in experiment
	sulfuric acid; In isopropyl alcohol; at 20℃; for 4 - 18h;Product distribution / selectivity;	Effects of Br°nsted acid and Lewis acid onRacemization of (S)-Etodolaca conditions results reaction ratio of R:S of percentage of entry acid time Etodolacside products (%)b 1SOCl2 18 hless than 0.06:1.0c less than 4c 2SnCl4 18 h 0.39:1.0 nod 3TiCl4 18 hless than 0.06:1.0c less than 4c 4AlCl3 24 hless than 0.37:1.0c less than 27c 5La(CF3SO3)3 24 hless than 0.01:1.0c nod 6 HCl 21 h 0.30:1.0 3 7BF3-Et2O 15 h 1:1 6% 8H2SO4 4 h 1:1 2 aRacemization reaction conditions unless otherwise indicated: 20 C., 0.37 mmol of (S)-etodolac, and 1-1.5 equivalents of acid in 5 ml of organic solvent. For HPLC analysis, a portion of reaction mixture was taken out after certain hours and concentrated under reduced pressure. The residue was extracted from water with dichloromethane twice. The combined organic phases were dried over MgSO4, filtered, and concentrated. No. The resulting residue was dried in vacuo and then subjected to HPLC analysis by using Chiral-AGP column at 225 nm. bRatio of HPLC peak areas at 225 nm. In some cases, the data are inaccurate because the HPLC peak of side products overlapped with that of either (S)-etodolac or (R)-etodolac. cThe data are skewed because the peaks of side products overlapped with that of (R)-etodolac. dNot detectable by HPLC at 254 nm. Effect of Solvent on Racemization of (S)-etodolaca results percentage of entry solvent ratio of R:S of Etodolacside products (%)b 1 MeOH-c -c 2CH3CN 0.10:1.0 87 3 1,4-dioxane 0.22:1.0 11 4 THF no racemation - 5 2-propanol 1:1 5 aracemization reaction conditions unless otherwise indicated: 20 C., 0.37 mmol of (S)-etodolac, and 1.5 equivalent of acid in 5-10 ml of organic solvent. For HPLC analysis, a portion of reaction mixture was taken out after about 16-18 hours and concentrated under reduced pressure. The residue was extracted from water with dichloromethane twice. The combined organic phases were dried over MgSO4, filtered, and concentrated. No. The resulting residue was dried in vacuo and then subjected to HPLC analysis by using Chiral-AGP column at 225 nm. bRatio of HPLC peak areas at 225 nm. In some cases, the data as to the side products are skewed because the HPLC peaks of the side products overlapped with that of either (S)-etodolac or (R)-etodolac. cTLC indicated no desired product but only methyl ester of etodolac was generated.
	boron trifluoride diethyl etherate; In isopropyl alcohol; at 20℃; for 15h;Product distribution / selectivity;	Effects of Br°nsted acid and Lewis acid onRacemization of (S)-Etodolaca conditions results reaction ratio of R:S of percentage of entry acid time Etodolacside products (%)b 1SOCl2 18 hless than 0.06:1.0c less than 4c 2SnCl4 18 h 0.39:1.0 nod 3TiCl4 18 hless than 0.06:1.0c less than 4c 4AlCl3 24 hless than 0.37:1.0c less than 27c 5La(CF3SO3)3 24 hless than 0.01:1.0c nod 6 HCl 21 h 0.30:1.0 3 7BF3-Et2O 15 h 1:1 6% 8H2SO4 4 h 1:1 2 aRacemization reaction conditions unless otherwise indicated: 20 C., 0.37 mmol of (S)-etodolac, and 1-1.5 equivalents of acid in 5 ml of organic solvent. For HPLC analysis, a portion of reaction mixture was taken out after certain hours and concentrated under reduced pressure. The residue was extracted from water with dichloromethane twice. The combined organic phases were dried over MgSO4, filtered, and concentrated. No. The resulting residue was dried in vacuo and then subjected to HPLC analysis by using Chiral-AGP column at 225 nm. bRatio of HPLC peak areas at 225 nm. In some cases, the data are inaccurate because the HPLC peak of side products overlapped with that of either (S)-etodolac or (R)-etodolac. cThe data are skewed because the peaks of side products overlapped with that of (R)-etodolac. dNot detectable by HPLC at 254 nm.

Reference： [1]Patent: US2006/167259,2006,A1 .Location in patent: Page/Page column 9
[2]Patent: US2006/167259,2006,A1 .Location in patent: Page/Page column 9

28
[ 530-62-1 ]
[ 41340-25-4 ]
C₂₀H₂₃N₃O₃ [ No CAS ]

Reference： [1]Acta poloniae pharmaceutica,2009,vol. 66,p. 201 - 206

29
[ 139175-50-1 ]
[ 41340-25-4 ]
C₂₈H₂₇F₁₇N₂O₂ [ No CAS ]

Reference： [1]Analytical Chemistry,2009,vol. 81,p. 5039 - 5045

30
[ 19408-84-5 ]
[ 41340-25-4 ]
[ 1224429-03-1 ]

Reference： [1]Letters in drug design and discovery,2010,vol. 7,p. 122 - 127

31
[ 404-86-4 ]
[ 41340-25-4 ]
[ 1224429-01-9 ]

Reference： [1]Letters in drug design and discovery,2010,vol. 7,p. 122 - 127

32
heptakis(6-(2-hydroxypropyl))-β-cyclodextrin [ No CAS ]
[ 41340-25-4 ]
C₁₇H₂₁NO₃*C₆₃H₁₁₂O₄₂ [ No CAS ]

Reference： [1]Central European Journal of Chemistry,2010,vol. 8,p. 953 - 962

33
heptakis(6-(2-hydroxypropyl))-β-cyclodextrin [ No CAS ]
[ 41340-25-4 ]
C₁₇H₂₁NO₃*2C₆₃H₁₁₂O₄₂ [ No CAS ]

Reference： [1]Central European Journal of Chemistry,2010,vol. 8,p. 953 - 962

34
[ 7585-39-9 ]
[ 41340-25-4 ]
[ 1179324-46-9 ]

Reference： [1]Journal of Inclusion Phenomena and Macrocyclic Chemistry,2010,vol. 66,p. 381 - 392
[2]Journal of Carbohydrate Chemistry,2016,vol. 35,p. 118 - 130

35
[ 7585-39-9 ]
[ 41340-25-4 ]
β-cyclodextrin 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indolyl-acetic acid inclusion complex 2:1 [ No CAS ]

Reference： [1]Journal of Inclusion Phenomena and Macrocyclic Chemistry,2010,vol. 66,p. 381 - 392
[2]Journal of Inclusion Phenomena and Macrocyclic Chemistry,2013,vol. 77,p. 121 - 134

36
[ 41340-25-4 ]
((R)-1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid methyl ester [ No CAS ]
((S)-1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid methyl ester [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 418 - 426

37
[ 41340-25-4 ]
C₁₉H₂₅NO₃ [ No CAS ]
C₁₉H₂₅NO₃ [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 418 - 426

38
[ 62-53-3 ]
[ 41340-25-4 ]
C₂₃H₂₆N₂O₂ [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 418 - 426

39
[ 62-53-3 ]
[ 41340-25-4 ]
C₂₃H₂₆N₂O₂ [ No CAS ]
C₂₃H₂₆N₂O₂ [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 418 - 426

40
[ 1445-45-0 ]
[ 41340-25-4 ]
methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano(3,4-b)-indole-1-acetate [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 418 - 426

41
[ 78-39-7 ]
[ 41340-25-4 ]
[ 200880-23-5 ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 418 - 426

42
[ 6284-40-8 ]
[ 41340-25-4 ]
(S)-(+)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid D-(-)-meglumine salt [ No CAS ]
(R)-(-)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid D-(-)-meglumine salt [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 418 - 426

43
[ 67-56-1 ]
[ 41340-25-4 ]
methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano(3,4-b)-indole-1-acetate [ No CAS ]
1,8-diethyl-1-methyl-1,3,4,9-tetrahydropyrano-<3,4-b>indole [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 418 - 426

44
[ 41340-25-4 ]
5-[(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)methyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione [ No CAS ]

Reference： [1]Patent: WO2014/3694,2014,A1
[2]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785
[3]Archiv der Pharmazie,2018,vol. 351

45
[ 41340-25-4 ]
[ 946848-58-4 ]

Reference： [1]Patent: WO2014/3694,2014,A1
[2]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785
[3]Archiv der Pharmazie,2018,vol. 351

46
[ 41340-25-4 ]
1-[2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]-4-methyl thiosemicarbazide [ No CAS ]

Reference： [1]Patent: WO2014/3694,2014,A1
[2]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785
[3]Archiv der Pharmazie,2018,vol. 351

47
[ 67-56-1 ]
[ 41340-25-4 ]
methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano(3,4-b)-indole-1-acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With sulfuric acid; for 3h;Reflux;	Etodolac (0.01 mol) and methanol (16 niL) refluxed for 3 h in a few drops of concentrated sulfuric acid. The contents of the flask were subsequently cooled and neutralized by using NaHC03 (5%). The resulting precipitate was filtered, dried and recrystallized twice from ethanol.Compound [SGK 196]: Yield 66%, m.p. 127-130 C (rap. 128-130 C [13, 14] ). IR ( maks, cm"1): 3379 (NH), 1705 (C=0). *H NMR (400 MHz, DMSO-d6) delta ppm: 0.83 (3H, t, - CH2-CH3 at Ci); 1.37 (3H, t, -CH2-CH3at C8); 1.98-2.18 (2H, m, -CH2-CH3 at Ci); 2.73-3.04 (6H, m, -CH2-CH3 at C8, -CH2-COOCH3at Ci and -CH2at C4); 3.72 (3H, s, -COOCH3); 3.94-4.06 (2H, m, -CH2at C3); 7.01 (1H, d, C7-H, J=6.8 Hz); 7.06 (1H, t, C6-H); 7.36 (1H, d, C5-H, J=7.2 Hz); 9.06 (s, 1H, indole N-H).13C NMR (100 MHz) (DMSO-d TMS) delta ppm: 8.26 (C-12); 14.92 (C-10); 22.34 (C-9); 24.18 (C-4); 31.18 (C-l l); 42.93 (C-13); 5 L68 (- COOCH3); 60.43 (C-3); 75.82 (C-l); 107.83 (C-4a); 115.88 (C-5); 119.32 (C-6); 120.15 (C- 7); 126.47 (C-5a); 127.03 (C-8); 135.01 (C-la); 136.28 (C-8a); 170.52 (C=0). Analysis for C18H23NO3 (301.380). Calcd: C, 71.73; H, 7.69; N, 4.65%. Found: C, 70.85; H, 7.24; N, 4.75%.

Reference： [1]Patent: WO2014/3694,2014,A1 .Location in patent: Page/Page column 3, 4
[2]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785
[3]Archiv der Pharmazie,2018,vol. 351

48
0.75Mg⁽²⁺⁾*0.25Al⁽³⁺⁾*0.125CO₃^(2-)*2HO^(1-)*0.52H₂O [ No CAS ]
[ 41340-25-4 ]
0.75Mg⁽²⁺⁾*0.25Al⁽³⁺⁾*2HO^(1-)*0.78H₂O*0.125C₁₇H₂₁NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 50℃; for 24h;	The ion-exchange reaction was performed by stirring (500 rpm) 0.05 g of LDH and 20mL of solvent in a closed flask under an air atmosphere. The solvents used were alcohol [methanol (MeOH) or ethanol (EtOH)], decarbonated water, or a mixture of decarbonated water and an equal volume of MeOH or EtOH. Reactions were conducted at different <strong>[41340-25-4]etodolac</strong> concentrations (10-160 mM), reaction temperatures (30-60C), and reaction times (1-72 h). The suspension was centrifuged (3500 rpm), and the solid (complex)obtained was washed with the solvent used in the reaction and dried under vacuum for 3 h at room temperature.

Reference： [1]Bulletin of the Chemical Society of Japan,2013,vol. 86,p. 1256 - 1260

49
0.66Mg⁽²⁺⁾*0.33Al⁽³⁺⁾*0.02CO₃^(2-)*2HO^(1-)*0.32H₂O*0.27NO₃^(1-) [ No CAS ]
[ 7732-18-5 ]
[ 41340-25-4 ]
0.66Mg⁽²⁺⁾*0.33Al⁽³⁺⁾*0.02CO₃^(2-)*2HO^(1-)*0.62H₂O*0.13NO₃^(1-)*0.14C₁₇H₂₁NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 50℃;	The ion-exchange reaction was performed by stirring (500 rpm) 0.05 g of LDH and 20mL of solvent in a closed flask under an air atmosphere. The solvents used were alcohol [methanol (MeOH) or ethanol (EtOH)], decarbonated water, or a mixture of decarbonated water and an equal volume of MeOH or EtOH. Reactions were conducted at different <strong>[41340-25-4]etodolac</strong> concentrations (10-160 mM), reaction temperatures (30-60C), and reaction times (1-72 h). The suspension was centrifuged (3500 rpm), and the solid (complex)obtained was washed with the solvent used in the reaction and dried under vacuum for 3 h at room temperature.

Reference： [1]Bulletin of the Chemical Society of Japan,2013,vol. 86,p. 1256 - 1260

50
0.66Mg⁽²⁺⁾*0.33Al⁽³⁺⁾*0.02CO₃^(2-)*2HO^(1-)*0.32H₂O*0.27NO₃^(1-) [ No CAS ]
[ 7732-18-5 ]
[ 41340-25-4 ]
0.66Mg⁽²⁺⁾*0.33Al⁽³⁺⁾*0.02CO₃^(2-)*2HO^(1-)*0.53H₂O*0.16NO₃^(1-)*0.11C₁₇H₂₁NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 60℃;	The ion-exchange reaction was performed by stirring (500 rpm) 0.05 g of LDH and 20mL of solvent in a closed flask under an air atmosphere. The solvents used were alcohol [methanol (MeOH) or ethanol (EtOH)], decarbonated water, or a mixture of decarbonated water and an equal volume of MeOH or EtOH. Reactions were conducted at different <strong>[41340-25-4]etodolac</strong> concentrations (10-160 mM), reaction temperatures (30-60C), and reaction times (1-72 h). The suspension was centrifuged (3500 rpm), and the solid (complex)obtained was washed with the solvent used in the reaction and dried under vacuum for 3 h at room temperature.

Reference： [1]Bulletin of the Chemical Society of Japan,2013,vol. 86,p. 1256 - 1260

51
[ 88192-19-2 ]
[ 41340-25-4 ]
C₂₀H₂₇N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,1'-carbonyldiimidazole; In dichloromethane;	To facilitate the conjugation of these small molecules to the polyacrylic acid-coated iron oxide nanoparticles, the small molecules were coupled to an azide linker (3-azide propylamine) through their respective carboxylic acid groups using carbonyldiimidazole chemistry yielding a series of 30 azide-conjugated small molecules (Table 3).

Reference： [1]Patent: US2015/87605,2015,A1 .Location in patent: Paragraph 0122

52
[ 41340-25-4 ]
C₁₇H₂₁NO₄ [ No CAS ]
C₁₇H₂₁NO₅ [ No CAS ]

Reference： [1]Science of the Total Environment,2015,vol. 518-519,p. 258 - 265

53
[ 458-37-7 ]
[ 41340-25-4 ]
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1h;	General procedure: A solution of Curcumin (1.2mmol), NSAID (1.0 mmol), EDCI (1.0 mmol) and DMAP (0.1mmol) in CH2Cl2 (30 mL), the mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with satd. aqueous NaHCO3, extracted with CH2Cl2 (3 x 30 mL), dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3044 - 3051

54
[ 458-37-7 ]
[ 41340-25-4 ]
((1E,6E)-3,5-dioxohepta-1,6-diene-1,7-diyl)bis(2-methoxy-4,1-phenylene) bis(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1h;	General procedure: Curcumin (1.2 mmol), NSAID (2.0 mmol), EDCI (1.0 mmol) and DMAP (0.1 mmol) were dissolved in CH2Cl2 (30 mL), and the mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with satd. aqueous NaHCO3, extracted with CH2Cl2 (3 x 30 mL), dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography. All crude products were recrystallized in petroleumether/diethyl ether (v/v 1:1) to give the pure products.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3044 - 3051

55
[ 41340-25-4 ]
1-[2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]-4-phenyl thiosemicarbazide [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785
[2]Archiv der Pharmazie,2018,vol. 351

56
[ 41340-25-4 ]
1-[2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]-4-cyclohexyl thiosemicarbazide [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785

57
[ 41340-25-4 ]
5-[(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)methyl]-4-ethyl-2,4-dihydro-3H-1,2,4-triazole-3-thione [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785
[2]Archiv der Pharmazie,2018,vol. 351

58
[ 41340-25-4 ]
5-[(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)methyl]-4-propyl-2,4-dihydro-3H-1,2,4-triazole-3-thione [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785

59
[ 41340-25-4 ]
5-[(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)methyl]-4-butyl-2,4-dihydro-3H-1,2,4-triazole-3-thione [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785

60
[ 41340-25-4 ]
5-[(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)methyl]-4-benzyl-2,4-dihydro-3H-1,2,4-triazole-3-thione [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785

61
[ 41340-25-4 ]
5-[(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)methyl]-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785
[2]Archiv der Pharmazie,2018,vol. 351

62
[ 41340-25-4 ]
5-[(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)methyl]-4-cyclohexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785

63
[ 41340-25-4 ]
1-[2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]-4-ethyl thiosemicarbazide [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785
[2]Archiv der Pharmazie,2018,vol. 351

64
[ 41340-25-4 ]
1-[2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]-4-propyl thiosemicarbazide [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785

65
[ 41340-25-4 ]
1-[2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]-4-butyl thiosemicarbazide [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785

66
[ 41340-25-4 ]
1-[2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetyl]-4-benzyl thiosemicarbazide [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2015,vol. 30,p. 778 - 785

67
[ 528-43-8 ]
[ 41340-25-4 ]
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl-2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; In dichloromethane; at 25 - 30℃;	General procedure: 1.2 mmol of magnolol and 1.0 mmol to 2.0 mmol of etodolic acid were placed in a round bottom flask,Plus 50 mL of dichloromethane and a catalytic amount of DMAP (N, N-4-dimethylaminopyridine)A solution of 2 to 4 mmol of EDCI (1-ethyl- (3-dimethylaminopropyl) phthalimide hydrochloride) or DCC (dicyclohexylcarbodiimide) in methylene chloride was slowly added dropwise The reaction was stirred at room temperature (25 ~ 30 ) for 1 ~ 4h,The product was isolated by column chromatography.Column chromatography separation and purification of the eluent ethyl acetate: petroleum ether = 1:10 ~ 1: 2, spin dry solvent,And dried in vacuo to give the title compound, compound 19 and compound 20, respectively.The yields were 90% and 78%, respectively.

Reference： [1]MedChemComm,2015,vol. 6,p. 2129 - 2139
[2]Patent: CN105884614,2016,A .Location in patent: Paragraph 0070-0072

68
[ 528-43-8 ]
[ 41340-25-4 ]
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl-bis(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With dmap; In dichloromethane; at 25 - 30℃;	General procedure: 1.2 mmol of magnolol and 1.0 mmol to 2.0 mmol of etodolic acid were placed in a round bottom flask,Plus 50 mL of dichloromethane and a catalytic amount of DMAP (N, N-4-dimethylaminopyridine)A solution of 2 to 4 mmol of EDCI (1-ethyl- (3-dimethylaminopropyl) phthalimide hydrochloride) or DCC (dicyclohexylcarbodiimide) in methylene chloride was slowly added dropwise The reaction was stirred at room temperature (25 ~ 30 ) for 1 ~ 4h,The product was isolated by column chromatography.Column chromatography separation and purification of the eluent ethyl acetate: petroleum ether = 1:10 ~ 1: 2, spin dry solvent,And dried in vacuo to give the title compound, compound 19 and compound 20, respectively.The yields were 90% and 78%, respectively.

Reference： [1]MedChemComm,2015,vol. 6,p. 2129 - 2139
[2]Patent: CN105884614,2016,A .Location in patent: Paragraph 0070-0072

69
[ 458-37-7 ]
[ 41340-25-4 ]
C₃₆H₃₅NO₈ [ No CAS ]
C₅₁H₅₀N₂O₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%; 80%	With dmap; In dichloromethane; at 25 - 30℃;	1.2 mmol of curcumin and 1-2 mmol of Etodolac were placed in a round bottom flask then added 50 mL of dichloromethane and catalytic amount of 0.01mmol of DMAP (N, N-4-dimethylaminopyridine) solution , then again dichloromethane containing 2 - 3 mmol of EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or DCC (dicyclohexylcarbodiimide) was slowly added dropwise and the reaction was stirred at room temperature (25 to 30 C) for 1 to 4 h . the product was separated and purified by column chromatography. The eluent for column chromatography separation was ethyl acetate: cyclohexane = 1: 10: 1: 2. The solvent was dried to give the crude product which was recrystallized from acetone or ethanol and dried in vacuo to give compound 19 and compound 20. The yields were 56% and 80%, respectively.

Reference： [1]Patent: CN105884615,2016,A .Location in patent: Paragraph 0081-0084

70
[ 38780-40-4 ]
[ 41340-25-4 ]
C₂₃H₃₄ClN₃O₃Pt [ No CAS ]