1059630-08-8|(4aS,9bR)-Ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate| Ambeed

Structure of 1059630-08-8

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Quality Control of [ 1059630-08-8 ] Purity: 97% SDS Specification

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Product Details of [ 1059630-08-8 ]

CAS No. :	1059630-08-8
Formula :	C₁₄H₁₇BrN₂O₂
M.W :	325.20
SMILES Code :	O=C(N1CC[C@]2([H])NC3=C(C=CC=C3Br)[C@]2([H])C1)OCC
MDL No. :	MFCD29923604
InChI Key :	YKRFDXKYULKKPS-JQWIXIFHSA-N
Pubchem ID :	59317960

Safety of [ 1059630-08-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1059630-08-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	19
Num. arom. heavy atoms	6
Fraction Csp3	0.5
Num. rotatable bonds	3
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	84.45
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	41.57 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.13
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.89
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.24
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.59
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.1
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.59

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.71
Solubility	0.063 mg/ml ; 0.000194 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.42
Solubility	0.123 mg/ml ; 0.000377 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.01
Solubility	0.0314 mg/ml ; 0.0000966 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	Yes
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	Yes
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.23 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.22

Application In Synthesis of [ 1059630-08-8 ]

* 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 [ 1059630-08-8 ]
Downstream synthetic route of [ 1059630-08-8 ]

[ 1059630-08-8 ] Synthesis Path-Upstream 1~6

1
[ 1059630-13-5 ]
[ 541-41-3 ]
[ 1059630-08-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium carbonate In tetrahydrofuran at 25℃; for 1.33333 h;	Example 3: Production of (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH- pyrido[4,3-b]indoIe-2(9bH)-carboxylate; (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- 1 H-pyrido[4,3-b]indole-2(9bH)-carboxylate may be prepared by first optaining [4aS, 9bR]-6-bromo- 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-Z>]indole (36.0 g, 0.142mol)) as a free base by using 50percent aqueous sodium hydroxide solution and extracting the product into MTBE. The conversion to (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lη-pyrido[4,3- b]indole-2(9bH)-carboxylate may then be done by cooling a suspension of compounds of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-*]indole (36.0 g, 0.142mol)) in THF (300 ml) and triethylamine (24 ml) in an ice- water bath. Ethyl chloroformate is added dropwise (13.5 ml, 0.142mol) via a syringe pump over 1 hour. The ice-water bath is removed and the reaction mixture is stirred at room temperature for another hour. The reaction mixture is passed through a pad of celite and the solvent is evaporated to give (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH-pyrido[4,3- b]indole-2(9bH)-carboxylate). ¹H NMR (CDCl₃, 300 MHz): 1.20-1.35 (m,3H), 1.73- 1.85 (m, IH), 1.85-1.99 (m, IH), 3.22-3.52 (m, 3H), 3.52-3.66 (m, IH), 3.66-3.95 (Br, IH), 3.95-4.21 (m, 4H), 6.60 (t, J = 7.7 Hz, IH), 7.04 (d, J = 7.2 Hz, IH), 7.20 (d, J = 8.1 Hz, IH).[0084] Alternative to the use of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro- lH-pyrido[4,3-Z>]indole (Compound of Formual 1C) free base, the reaction may also be done by starting with the (S)-mandelate salt of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- <n="87"/>hexahydro-lH-pyrido[4,3-6]indole. A 100 mL round-bottomed flask is equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, and a N₂ inlet on top of the addition funnel. The flask is charged with the S-mandelate starting material (5 g, 12.35 mmol), Na₂CO₃ (2.88 g, 27.17 mmol), and 25 mL of TηF. To the yellow reaction mixture at 25 ⁰C (heating block temperature) is added a solution of ethyl chloroformate (1.64 g, 15.11 mmol) in 5 mL of TηF dropwise over ca 70 minutes. The batch is stirred at 25 ⁰C for another 10 min, and is checked by ηPLC. Less than 2percent of the starting material is observed by ηPLC, and the desired product is registered at ca. 98percent. To the batch is added 12.5 mL of EtOH, and the batch is concentrated under reduced pressure to remove ca. 30 mL of solvent (mostly TηF). To the batch is then added 37.5 mL ofη₂O, and the resultant mixture shows pH >9 by pH paper. The yellow mixture is then stirred at rt for ca. 1 h, and is filtered. The solid is rinsed with 25 mL of H₂O. After drying in a vacuum oven at 58 ⁰C for ca. 16 h, 3.9442 g of a yellow solid is obtained (98percent yield). ¹H NMR of the solid conformed, and showed no (s)-mandelic acid. HPLC analysis of the product shows the desired product at >99percent purity. LC-MS showed a peak with M/e = 326 (M+ 1).

References: [1] Patent: WO2008/112280, 2008, A1, . Location in patent: Page/Page column 85-86.

2
[ 1059630-07-7 ]
[ 541-41-3 ]
[ 1059630-08-8 ]

References: [1] Patent: WO2008/112280, 2008, A1, . Location in patent: Page/Page column 85-86.
[2] Drugs of the Future, 2015, vol. 40, # 10, p. 643 - 650.

3
[ 50709-33-6 ]
[ 1059630-08-8 ]

References: [1] Drugs of the Future, 2015, vol. 40, # 10, p. 643 - 650.

4
[ 40064-34-4 ]
[ 1059630-08-8 ]

References: [1] Drugs of the Future, 2015, vol. 40, # 10, p. 643 - 650.

5
[ 1059630-11-3 ]
[ 1059630-08-8 ]

References: [1] Drugs of the Future, 2015, vol. 40, # 10, p. 643 - 650.

6
[ 1059630-12-4 ]
[ 1059630-08-8 ]

References: [1] Drugs of the Future, 2015, vol. 40, # 10, p. 643 - 650.

[ 1059630-08-8 ] Synthesis Path-Downstream 1~27

1
[ 1059630-13-5 ]
[ 541-41-3 ]
[ 1059630-08-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium carbonate; In tetrahydrofuran; at 25℃; for 1.33333h;Product distribution / selectivity;	Example 3: Production of (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH- pyrido[4,3-b]indoIe-2(9bH)-carboxylate; (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- 1 H-pyrido[4,3-b]indole-2(9bH)-carboxylate may be prepared by first optaining [4aS, 9bR]-6-bromo- 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-Z>]indole (36.0 g, 0.142mol)) as a free base by using 50% aqueous sodium hydroxide solution and extracting the product into MTBE. The conversion to (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-leta-pyrido[4,3- b]indole-2(9bH)-carboxylate may then be done by cooling a suspension of compounds of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-*]indole (36.0 g, 0.142mol)) in THF (300 ml) and triethylamine (24 ml) in an ice- water bath. Ethyl chloroformate is added dropwise (13.5 ml, 0.142mol) via a syringe pump over 1 hour. The ice-water bath is removed and the reaction mixture is stirred at room temperature for another hour. The reaction mixture is passed through a pad of celite and the solvent is evaporated to give (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH-pyrido[4,3- b]indole-2(9bH)-carboxylate). 1H NMR (CDCl3, 300 MHz): 1.20-1.35 (m,3H), 1.73- 1.85 (m, IH), 1.85-1.99 (m, IH), 3.22-3.52 (m, 3H), 3.52-3.66 (m, IH), 3.66-3.95 (Br, IH), 3.95-4.21 (m, 4H), 6.60 (t, J = 7.7 Hz, IH), 7.04 (d, J = 7.2 Hz, IH), 7.20 (d, J = 8.1 Hz, IH).[0084] Alternative to the use of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro- lH-pyrido[4,3-Z>]indole (Compound of Formual 1C) free base, the reaction may also be done by starting with the (S)-mandelate salt of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- <n="87"/>hexahydro-lH-pyrido[4,3-6]indole. A 100 mL round-bottomed flask is equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, and a N2 inlet on top of the addition funnel. The flask is charged with the S-mandelate starting material (5 g, 12.35 mmol), Na2CO3 (2.88 g, 27.17 mmol), and 25 mL of TetaF. To the yellow reaction mixture at 25 0C (heating block temperature) is added a solution of ethyl chloroformate (1.64 g, 15.11 mmol) in 5 mL of TetaF dropwise over ca 70 minutes. The batch is stirred at 25 0C for another 10 min, and is checked by etaPLC. Less than 2% of the starting material is observed by etaPLC, and the desired product is registered at ca. 98%. To the batch is added 12.5 mL of EtOH, and the batch is concentrated under reduced pressure to remove ca. 30 mL of solvent (mostly TetaF). To the batch is then added 37.5 mL ofeta2O, and the resultant mixture shows pH >9 by pH paper. The yellow mixture is then stirred at rt for ca. 1 h, and is filtered. The solid is rinsed with 25 mL of H2O. After drying in a vacuum oven at 58 0C for ca. 16 h, 3.9442 g of a yellow solid is obtained (98% yield). 1H NMR of the solid conformed, and showed no (s)-mandelic acid. HPLC analysis of the product shows the desired product at >99% purity. LC-MS showed a peak with M/e = 326 (M+ 1).

References: [1]Patent: WO2008/112280,2008,A1 .Location in patent: Page/Page column 85-86.

2
[ 1059630-07-7 ]
[ 541-41-3 ]
[ 1059630-08-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2.0h;Product distribution / selectivity;	Example 3: Production of (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH- pyrido[4,3-b]indoIe-2(9bH)-carboxylate; (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- 1 H-pyrido[4,3-b]indole-2(9bH)-carboxylate may be prepared by first optaining [4aS, 9bR]-6-bromo- 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-Z>]indole (36.0 g, 0.142mol)) as a free base by using 50% aqueous sodium hydroxide solution and extracting the product into MTBE. The conversion to (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-leta-pyrido[4,3- b]indole-2(9bH)-carboxylate may then be done by cooling a suspension of compounds of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-*]indole (36.0 g, 0.142mol)) in THF (300 ml) and triethylamine (24 ml) in an ice- water bath. Ethyl chloroformate is added dropwise (13.5 ml, 0.142mol) via a syringe pump over 1 hour. The ice-water bath is removed and the reaction mixture is stirred at room temperature for another hour. The reaction mixture is passed through a pad of celite and the solvent is evaporated to give (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH-pyrido[4,3- b]indole-2(9bH)-carboxylate). 1H NMR (CDCl3, 300 MHz): 1.20-1.35 (m,3H), 1.73- 1.85 (m, IH), 1.85-1.99 (m, IH), 3.22-3.52 (m, 3H), 3.52-3.66 (m, IH), 3.66-3.95 (Br, IH), 3.95-4.21 (m, 4H), 6.60 (t, J = 7.7 Hz, IH), 7.04 (d, J = 7.2 Hz, IH), 7.20 (d, J = 8.1 Hz, IH).[0084] Alternative to the use of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro- lH-pyrido[4,3-Z>]indole (Compound of Formual 1C) free base, the reaction may also be done by starting with the (S)-mandelate salt of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- <n="87"/>hexahydro-lH-pyrido[4,3-6]indole. A 100 mL round-bottomed flask is equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, and a N2 inlet on top of the addition funnel. The flask is charged with the S-mandelate starting material (5 g, 12.35 mmol), Na2CO3 (2.88 g, 27.17 mmol), and 25 mL of TetaF. To the yellow reaction mixture at 25 0C (heating block temperature) is added a solution of ethyl chloroformate (1.64 g, 15.11 mmol) in 5 mL of TetaF dropwise over ca 70 minutes. The batch is stirred at 25 0C for another 10 min, and is checked by etaPLC. Less than 2% of the starting material is observed by etaPLC, and the desired product is registered at ca. 98%. To the batch is added 12.5 mL of EtOH, and the batch is concentrated under reduced pressure to remove ca. 30 mL of solvent (mostly TetaF). To the batch is then added 37.5 mL ofeta2O, and the resultant mixture shows pH >9 by pH paper. The yellow mixture is then stirred at rt for ca. 1 h, and is filtered. The solid is rinsed with 25 mL of H2O. After drying in a vacuum oven at 58 0C for ca. 16 h, 3.9442 g of a yellow solid is obtained (98% yield). 1H NMR of the solid conformed, and showed no (s)-mandelic acid. HPLC analysis of the product shows the desired product at >99% purity. LC-MS showed a peak with M/e = 326 (M+ 1).
	With triethylamine; In tetrahydrofuran; at 20℃; for 2.0h;Cooling with ice;	(4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH-pyrido[4,3-b]indole- 2(9bH)-carboxylate may be prepared by first obtaining [4aS, 9bR]-6-bromo- 2,3,4,4a,5,9b-hexahydro-17/-pyrido[4,3-h]indole (36.0 g, 0.142mol)) as a free base by using 50% aqueous sodium hydroxide solution and extracting the product into MTBE. The conversion to (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH-pyrido[4,3- b]indole-2(9bH)-carboxylate may then be done by cooling a suspension of [4aS, 9bR]- 6-bromo-2,3,4,4a,5,9b-hexahydro-17/-pyrido[4,3-h]indole (36.0 g, 0.142mol)) in THF (300 ml) and triethylamine (24 ml) in an ice-water bath. Ethyl chloroformate is added dropwise (13.5 ml, O.l42mol) via a syringe pump over 1 hour. The ice-water bath is removed and the reaction mixture is stirred at room temperature for another hour. The reaction mixture is passed through a pad of Celite and the solvent is evaporated to give (4aS,9bR) -ethyl 6-bromo-3,4,4a,5-tetrahydro-lH-pyrido[4,3-b]indole-2(9bH)- carboxylate). 1H NMR (CDCb, 300 MHz): 1.20-1.35 (m,3H), 1.73-1.85 (m, 1H), 1.85-1.99 (m, 1H), 3.22-3.52 (m, 3H), 3.52-3.66 (m, 1H), 3.66-3.95 (Br, 1H), 3.95-4.21 (m, 4H), 6.60 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H).

References: [1]Patent: WO2008/112280,2008,A1 .Location in patent: Page/Page column 85-86.
[2]Drugs of the Future,2015,vol. 40,p. 643 - 650.
[3]Patent: WO2019/241278,2019,A1 .Location in patent: Paragraph 000114.

3
[ 1059630-08-8 ]
[ 79-07-2 ]
[ 1059630-09-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; potassium iodide; In acetonitrile; for 27.0h;Heating / reflux;	Example 4: Production of [4aS,9bR] -ethyl 5-(2-amino-2-oxoethyl)-6-bromo- 3,4,4a,5-tetrahydro-lH-pyrido[4,3-b]indole-2(9bH)-carboxylate; (4aS,9bR)-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro- lH-pyrido[4,3-b]indole-2(9bH)-carboxylate may be prepared by heating to a reflux a suspension of (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- 1 H-pyrido[4,3-b]indole- 2(9bH)-carboxylate (5.648g, 17.4mmol), 2-chloroacetamide (7.32g, 78.2mmol), potassium iodide (19.2g, 77.7mol) and diisopropylethylamine (19mL, 115mmol) in acetonitrile (8OmL) for 27 hours. The solvent is removed in a vacuo and water <n="88"/>(20OmL) is added to the residue and stirred for 1 hour. The resulting white solid is filtered off, washed with ethanol and dried.
	With N-ethyl-N,N-diisopropylamine; potassium iodide; In acetonitrile; for 27.0h;Reflux;	(4aS,9bR)-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro-lH- pyrido[4,3-b]indole-2(9bH)-carboxylate may be prepared by heating to a reflux a suspension of (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH-pyrido[4,3-b]indole- 2(9bH)-carboxylate (5.648g, l7.4mmol), 2-chloroacetamide (7.32g, 78.2mmol), potassium iodide (19.2g, 77.7mol) and diisopropylethylamine (l9mL, H5mmol) in acetonitrile (80mL) for 27 hours. The solvent is removed in a vacuo and water (200mL) is added to the residue and stirred for 1 hour. The resulting white solid is filtered off, washed with ethanol and dried.

References: [1]Patent: WO2008/112280,2008,A1 .Location in patent: Page/Page column 86-87.
[2]Drugs of the Future,2015,vol. 40,p. 643 - 650.
[3]Patent: WO2019/241278,2019,A1 .Location in patent: Paragraph 000116.

4
[ 96-30-0 ]
[ 1059630-08-8 ]
(4aS,9bR)-ethyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; potassium iodide; In 1,4-dioxane; at 103℃; for 48.0h;	Example 5-A: Production of (6bR,10aS)-ethyI 2,3,6b,9,10,10a-hexahydro-2-oxo-lH- pyrido [3 ',4' :4,5]-py rrolo [1 ,2,3-de] quinoxaline-8-carboxy late; Alternative to Example 5 above, (6bR, 1 OaS)-ethyl 3,6b,9, 10, 1 Oa- hexahydro-3 -methyl-2-oxo- 1 H-pyrido [3 ' ,4 ' :4,5]-pyrrolo [ 1 ,2,3 -de]quinoxaline-8- carboxylate may also be made in a one pot method starting from Compound of Formula ID. A 2 liter 4 neck round bottom flask is equipped with a mechanical stirrer, reflux condenser, N2 inlet, teflon covered K-type temperature probe with a controller, and a heating mantle. To the flask is charged (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- lH-pyrido[4,3-b]indole-2(9bH)-carboxylate (250 g, 769 mmol), chloroacetamide (124 g, 1153 mmol, 1.5 equiv), potassium iodide (191.5 g, 1160 mmol, 1.5 equiv), diisopropyl ethylamine (266 mL, 1531 mmol, 2.0 equiv), and dioxane (625 mL). The reaction is heated to reflux temperature of about 103 0C until less than 3% of the starting substrate is observed by HPLC (about 48 hours). Additional charge of N- methyl chloroacetamide and diisopropyl ethylamine maybe necessary. The reaction is then cooled to ca. 80 0C, and at this temperature copper iodide (29.2 g, 153.8 mmol, 0.2 equiv), potassium carbonate (232.5 g, 1682 mmol, 2.2 equiv), dimethylethylene diamine (49.6 mL, 461 mmol, 0.6 equiv), and additional dioxane (375 mL) is added. The reaction is then re-heated to reflux and is monitored by HPLC. Reflux occurs at ca. 103 0C. The reaction is monitored by HPLC.; Example 6-A: Production of (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-3-methyl- 2-oxo-lH-pyrido[3%4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8-carboxylate; Alternative to Example 6 above, (6bR, 1 OaS)-ethyl 3,6b,9, 10, 1 Oa- hexahydro-3-methyl-2-oxo-lH-pyrido[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8- carboxylate may also be made in a one pot method starting from Compound of Formula ID. A 2 liter 4 neck round bottom flask is equipped with a mechanical stirrer, reflux condenser, N2 inlet, teflon covered K-type temperature probe with a controller, and a heating mantle. To the flask is charged (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- lH-pyrido[4,3-b]indole-2(9bH)-carboxylate (250 g, 769 mmol), N-methyl chloroacetamide (124 g, 1153 mmol, 1.5 equiv), potassium iodide (191.5 g, 1160 mmol, 1.5 equiv), diisopropyl ethylamine (266 mL, 1531 mmol, 2.0 equiv), and dioxane (625 mL). The reaction is heated to reflux temperature of about 103 0C until less than 3% of the starting substrate is observed by HPLC (about 48 hours). Additional charge of N- methyl chloroacetamide and diisopropyl ethylamine maybe necessary. The reaction is then cooled to ca. 80 0C, and at this temperature copper iodide (29.2 g, 153.8 mmol, 0.2 equiv), potassium carbonate (232.5 g, 1682 mmol, 2.2 equiv), dimethylethylene diamine (49.6 mL, 461 mmol, 0.6 equiv), and additional dioxane (375 mL) is added. The reaction is then re-heated to reflux and is monitored by HPLC. Reflux occurs at ca. 103 0C. The reaction is monitored by HPLC.[0090] When complete, the reaction is cooled to ca. 40 0C and poured onto a plug of flash-grade silica gel (625 g, 2.5 g/g). It is eluted (under vacuum) with 6.25 L of ethyl acetate. The eluent is concentrated to a solid residue (320 gm), and then is <n="91"/>dissolved in hot ethanol (800 ml). This mixture is allowed to cool to ambient temperature and stirred overnight. The next day it is cooled to 0-50C, aged for Ih and filtered. The cake is washed with cold ethanol (150 ml) and allowed to air dry to afford 170 grams (70%) of product as a white solid which is >99A% pure by HPLC. HPLC 10:90 to 90:10 CH3CN:H2O over 15 min. Hold at 90:10 for 2 min, 0.025% TFA Buffer, 1.5 mL/min, UV at 220 run, Phenomenex Jupiter Cl 8 column 4.6 mm x 250 mm. The product is 75A% pure by LC/MS in the total ion chromatogram. 1H-NMR (300MHz, CDCl3) 1.28(t, J= 6.9Hz, 3H), 1.86-1.96(m, 2H), 2.72(br, IH), 3.09-3.48(m, 7H), 3.86- 4.21(m, 5H), 6.75(dd, J= 1.2, 7.8Hz, IH), 6.82(t, J= 7.8Hz, IH), 6.90(dd, J= 1.2, 7.2Hz, IH).
	With N-ethyl-N,N-diisopropylamine; potassium iodide; In N,N-dimethyl acetamide; at 20 - 102℃;	1.000 equivalents of ethyl (4aS,9bR)-6-bromo-l,3,4,4a,5,9b-hexahydro-2H- pyrido[4,3-b]indole-2-carboxylate is charged into a reactor with 0.50 volumes of dimethylacetamide solvent at 20 C. A solution of 1.500 equivalents of N-methyl chloroacetamide in 0.30 volumes of dimethylacetamide is added, followed by 1.000 equivalents of potassium iodide, and 1.700 equivalents of diisopropylethylamine. The resulting suspension is heated at 102 C for 15 to 18 hours. After cooling to 45 C, 5.00 volumes of water are added. After further cooling and agitation, the product is isolated as a solid filter cake and is washed with additional water and dried under vacuum.

References: [1]Patent: WO2008/112280,2008,A1 .Location in patent: Page/Page column 87-90.
[2]Drugs of the Future,2015,vol. 40,p. 643 - 650.
[3]Patent: WO2019/241278,2019,A1 .Location in patent: Paragraph 000117; 000119.

5
[ 50709-33-6 ]
[ 1059630-08-8 ]

References: [1]Drugs of the Future,2015,vol. 40,p. 643 - 650.

6
[ 40064-34-4 ]
[ 1059630-08-8 ]

References: [1]Drugs of the Future,2015,vol. 40,p. 643 - 650.

7
[ 1059630-11-3 ]
[ 1059630-08-8 ]

References: [1]Drugs of the Future,2015,vol. 40,p. 643 - 650.

8
[ 1059630-12-4 ]
[ 1059630-08-8 ]

References: [1]Drugs of the Future,2015,vol. 40,p. 643 - 650.

9
[ 1059630-08-8 ]
[ 313369-16-3 ]

References: [1]Drugs of the Future,2015,vol. 40,p. 643 - 650.

10
[ 1059630-08-8 ]
[ 313369-25-4 ]

References: [1]Drugs of the Future,2015,vol. 40,p. 643 - 650.
[2]Drugs of the Future,2015,vol. 40,p. 643 - 650.
[3]Patent: WO2019/241278,2019,A1 .
[4]Patent: WO2019/241278,2019,A1 .

11
[ 1059630-08-8 ]
[ 313369-26-5 ]

References: [1]Drugs of the Future,2015,vol. 40,p. 643 - 650.
[2]Patent: WO2019/241278,2019,A1 .
[3]Patent: WO2019/241278,2019,A1 .

12
[ 1059630-08-8 ]
[ 313368-85-3 ]

References: [1]Drugs of the Future,2015,vol. 40,p. 643 - 650.
[2]Patent: WO2019/241278,2019,A1 .
[3]Patent: WO2019/241278,2019,A1 .

13
[ 1059630-08-8 ]
(6bR,10aS)-ethyl 1,1-dideuterio-3-methyl-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(9H)-carboxylate [ No CAS ]