[ CAS No. 104618-31-7 ] {[proInfo.proName]}

Name: 104618-31-7|2-(4-Hydroxycyclohexyl)isoindoline-1,3-dione|97%
Brand: Ambeed
SKU: A103424
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2D 3D

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Quality Control of [ 104618-31-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 104618-31-7 ]

SDS Specification

Alternatived Products of [ 104618-31-7 ]

Product Details of [ 104618-31-7 ]

CAS No. :	104618-31-7	MDL No. :	MFCD09842279
Formula :	C₁₄H₁₅NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YLHCMDNAKVPTIO-UHFFFAOYSA-N
M.W :	245.27	Pubchem ID :	288726
Synonyms :

Calculated chemistry of [ 104618-31-7 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.43
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	69.8
TPSA :	57.61 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.4 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.29
Log Po/w (XLOGP3) :	1.96
Log Po/w (WLOGP) :	1.21
Log Po/w (MLOGP) :	2.13
Log Po/w (SILICOS-IT) :	1.7
Consensus Log Po/w :	1.85

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.78
Solubility :	0.411 mg/ml ; 0.00167 mol/l
Class :	Soluble
Log S (Ali) :	-2.79
Solubility :	0.393 mg/ml ; 0.0016 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.7
Solubility :	0.491 mg/ml ; 0.002 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.41

Safety of [ 104618-31-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 104618-31-7 ]

* 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 [ 104618-31-7 ]
Downstream synthetic route of [ 104618-31-7 ]

[ 104618-31-7 ] Synthesis Path-Upstream 1~7

1
[ 104618-31-7 ]
[ 104618-32-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium bromide In ethyl acetate at 5 - 20℃;	EXAMPLE 1: 4- (Phthalimido) -cyclohexanone [0034] 4- (Phthalimido) -cyclohexanol (146 g) was mixed with AcOEt (1000 mL) , after which and NaBr (8 g) and TEMPO(0.5 g) was added. 1000 mL of NaClO (10 percent) was added in portions and the reaction mixture was adjusted using NaHCψ3 to pH 7- 8 to maintain the temperature between 5 and 20 ⁰C. After the reaction was completed, the aqueous layer was separated and the organic layer was washed with brine (400 mL) and dried over Na2SO₄. The solvent was removed under reduced pressure to give the product as white solid (95 percent yield) .
92.4%	With potassium dichromate; sulfuric acid In chloroform; water at 25℃; for 4 h;	190gms(0.7755mole) 4-phthalimido cyclohexanol are dissolve in 1480ml chloroform.Add solution of H₂SO₄ (435.87gm, 4.4476mole cone. H₂SO₄ was added in 900 mlwater). Cool mass to 25°C,add lot wise 180.5gm(0.6139mole) potassium dichromate inone hour. Stir mass for three hours, add 900 ml water and separate organic phase.Organic phase was washed with water and 2percent NaHCO3 solution, after drying andconcentration of extracts product was isolated by adding methanol and water mixture.YIELD: 175g(92.4percent)PURITY: 96.01percent.
88%	With pyridinium chlorochromate In dichloromethane at 20℃; for 26 h;	The title compound from Step A above (28 g, 114 mmol) was dissolved in dichloromethane (990 mL) and pyridinium chlorochromate (33.6 g, 157 mmol) was added in portions. The reaction mixture was stirred at room temperature for 8 h. Then another batch of pyridinium chlorochromate (10.4 g, 48.6 mmol) was added in portions and stirring at room temperature was continued for 18 h. The reaction mixture was filtered through a pad of Celite and the Celite pad was washed with dichlormethane (400 mL). The combined filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica using ethyl acetate/n-heptane (60/40) as a mobile phase to afford the title compound as a white solid (24.62 g, 88percent)¹H-NMR (400 MHz, CDCl₃): δ=2.17-2.24 (m, 2H), 2.60-2.71 (m, 4H), 2.80-2.90 (m, 2H), 4.78 (tt, 1H), 7.84-7.88 (m, 2H), 7.97-8.02 (m, 2H)

65%

With pyridinium chlorochromate In dichloromethane

Step 2
A solution of 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (3.10 g, 12.6 mmol) in CH₂Cl₂ (25.0 mL) was added to a slurry of PCC (4.10 g, 19.0 mmol) in CH₂Cl₂ (15.0 mL) and stirred at room temperature for 3.5 hours.
The reaction was diluted with Et₂O (60.0 mL), decanted and the residue swirled with Et₂O (2*40.0 mL).
The combined ether layers were filtered through florisil and concentrated in vacuo to dryness, and the residue was recrystallized from ethyl acetate/hexane to give 2.01 g (65percent) of 2-(4-oxocyclohexyl)-1H-isoindole-1,3(2H)-dione as colorless needles: mp 140.3-142.1° C.; ¹H NMR (400 MHz, CDCl₃) δ7.84, 7.74, 4.64, 2.72, 2.54, 2.09; ¹³C NMR (100 MHz, CDCl₃) δ208.9, 168.1, 134.1, 131.9, 123.3, 48.4, 39.9, 28.6; IR (mull) 3062, 3031, 2958, 2949, 2919, 2885, 1775, 1762, 1721, 1708, 1611, 1465, 1436, 1419, 1393, 1379, 719 cm^-1; HRMS (FAB) calcd for C₁₄H₁₄NO₃: 244.0974, found 244.0976; Anal. Calcd for C-₁₄H₁₄NO₃: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.87; H, 5.47; N, 5.73.

Reference： [1] Patent: WO2010/78250, 2010, A1, . Location in patent: Page/Page column 12
[2] Patent: WO2006/3677, 2006, A1, . Location in patent: Page/Page column 10; 16
[3] Patent: US2011/280808, 2011, A1, . Location in patent: Page/Page column 62
[4] Journal of medicinal chemistry, 1993, vol. 36, # 13, p. 1918 - 1919
[5] Patent: US2003/100596, 2003, A1,
[6] Patent: US5827871, 1998, A,
[7] Patent: US5464864, 1995, A,
[8] Patent: EP603432, 1994, A1,
[9] Patent: US4731374, 1988, A,
[10] Patent: WO2008/41240, 2008, A1, . Location in patent: Page/Page column 16-17

2
[ 22509-74-6 ]
[ 104618-31-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium carbonate In tetrahydrofuran; water at 20℃; for 72 h;	Commercially available 4-aminocyclohexanol hydrogen chloride salt (25 g, 164 mmol) was dissolved in water (350 mL). Then potassium carbonate (72 g, 328 mmol) was added, followed by a solution of commercially available N-carbethoxyphthalimide in tetrahydrofurane (300 mL). The reaction mixture was then vigorously stirred at room temperature for 3 days. Tetrahydrofurane was evaporated under reduced pressure and the remaining aqueous phase was extracted with dichloromethane (2.x.300 mL) until the aqueous phase was clear. The combined organic phase was dried over Na₂SO₄, filtered and the solvents were evaporated under reduced pressure to afford the title compound as a white solid (28 g, 69percent).¹H-NMR (400 MHz, CDCl₃): δ=1.32-1.43 (m, 2H), 1.70-1.75 (m, 2H), 2.04-2.09 (m, 2H), 2.25-2.38 (m, 2H), 3.67-3.77 (m, 1H), 4.05-4.13 (m, 1H), 7.63-7.7.68 (m, 2H), 7.76-7.7.80 (m, 2H)
76%	With sodium carbonate In water; ethyl acetate	Step 1 A solution of 4-aminocyclohexanol hydrochloride (2.52 g, 16.6 mmol) in water (20.0 mL) was treated with N-carbethoxyphthalimide (3.82 g, 17.4 mmol) and Na₂CO₃ (3.77 g, 35.6 mmol). The reaction was stirred at room temperature for 15.6 hours. The reaction was cooled to 0° C. and quenched with 10percent HCl, filtered, and washed with water to give a white solid. The solid was dissolved in ethyl acetate washed with water, brine, dried over MgSO4 and concentrated in vacuo to give 3.10 g (76percent) of 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione as a colorless solid: mp 176.9-177.0° C.; ¹H NMR (400 MHz, Acetone-d₆) δ7.82 4.09, 3.74, 3.62, 2.28, 2.04, 1.76, 1.39; ¹³C NMR (100 MHz, acetone-d₆) δ168.7, 135.1, 133.0, 123.6, 69.5, 50.8, 35.7, 28.3; IR (mull) 3389, 3318, 2953, 2930, 2876, 2861, 1767, 1703, 1463, 1393, 1377, 1088, 1075, 1061, 720 cm^-1; HRMS (FAB) calcd for C₁₄H₁₆NO₃: 246.1130, found 246.1128; Anal. Calcd for C₁₄H₁₅NO₃: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.39; H, 6.21; N, 5.70.

Reference： [1] Patent: US2011/280808, 2011, A1, . Location in patent: Page/Page column 62
[2] Patent: US2003/100596, 2003, A1,
[3] Patent: US5464864, 1995, A,
[4] Patent: EP603432, 1994, A1,
[5] Patent: US5827871, 1998, A,

3
[ 22509-74-6 ]
[ 6850-65-3 ]
[ 104618-31-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	for 0.0833333 h; Heating	4-Amino-cyclohexanol (2.627 g, 22.81 mmol) and 1,3-Dioxo-1,3-dihydro-isoindole-2-carboxylic acid ethyl ester (5 g, 22.81 mmol) were placed in a large test-tube and heated with a heat gun until both had melted and then for an additional 5 minutes. The resulting solution was allowed to cool and a solid formed. This solid was transferred to a flask, taken up in CH₂Cl₂and purified via chromatography (75percent EtOAc/Hex) to give 4.57 g of 2-(4-Hydroxy-cyclohexyl)-isoindole-1,3-dione (81percent yield). LCMS (m/z): M+H+MeCN=287.1.
56.82%	With potassium carbonate In water at 20℃; for 2 h;	[00486] To a solution of ethyl 1 ,3-dioxoisoindoline-2-carboxylate (1 .67 g, 7.19 mmol) in water (16 mL) was added 4-aminocyclohexanol (1 .31 g, 8.63 mmol), followed by K2CO3 (1 .59 g, 1 1 .5 mmol). The mixture was stirred at room temperature for 2 h. TLC (PE: EA = 1 :1 ) showed the reaction was complete. The mixture was filtered and the solid was dried under vacuum to give 2-(4- hydroxycyclohexyl)isoindoline-1 ,3-dione (1 g, 56.82percent) as a brown solid.
56.82%	at 20℃; for 2 h;	To a solution of ethyl 1,3-dioxoisoindoline-2-carboxylate (1.67 g, 7.19 mmol) in water (16 mL) was added 4-aminocyclohexanol (1.31 g, 8.63 mmol), followed by K₂CO₃(1.59 g, 11.5 mmol). The mixture was stirred at room temperature for 2 h. TLC (PE:EA=1:1) showed the reaction was complete. The mixture was filtered and the solid was dried under vacuum to give 2-(4-hydroxycyclohexyl)isoindoline-1,3-dione (1 g, 56.82percent) as a brown solid.

Reference： [1] Patent: US2008/269193, 2008, A1, . Location in patent: Page/Page column 33
[2] Patent: WO2013/13188, 2013, A1, . Location in patent: Paragraph 00486
[3] Patent: US9416132, 2016, B2, . Location in patent: Page/Page column 183; 184
[4] Journal of medicinal chemistry, 1993, vol. 36, # 13, p. 1918 - 1919

4
[ 22509-74-6 ]
[ 104618-31-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate In water at 20℃; for 1 h;	2-(4-Hydroxy-cyclohexyl)-isoindole-1,3-dione; K₂CO₃ (19.4 g, 140.6 mmol) was added to a solution of trans-4-aminocyclohexanol hydrochloride (9.0 g, 59.35 mmol) in water (150 ml.) followed by N-carbethoxy phthalimide (18.8 g, 85.96 mmol). A white precipitate was formed immediately. Stirring continued at RT for 1 h. The precipitate was filtered off, washed with water and dried to afford 12 g (84 percent) of 2-(4-hydroxy-cyclohexyl)-isoindole-1 ,3-dione. ¹H-NMR (300 MHz, DMSO-d₆) δ 1.18 - 1.40 (m, 3H), 1.60 - 1.76 (m, 2H), 1.80 - 2.00 (m, 2H), 2.04 - 2.23 (dq, 2H), 3.40 - 3.50 (m, 1 H), 3.89 - 4.03 (tt,1 H), 4.6 (br.s, 1 H,), 7.15 - 7.39 (m,1 H), 7.80 (m, 3H). m/z: 246 (M+1 )+

Reference： [1] Patent: WO2007/115935, 2007, A1, . Location in patent: Page/Page column 61

5
[ 85-44-9 ]
[ 27489-62-9 ]
[ 104618-31-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	With pyridinium p-toluenesulfonate In N,N-dimethyl-formamide; toluene for 15 - 17 h; Heating / reflux	A) SOOgms (2.608mole) of Trans-4-aminocyclohexanol was dissolve in 1500mlDimethyl formamide and 1500ml of Toluene. Add 386gms(2.608mole) of Phthalicanhydride and 3gm(0.012mole) pyridinium p-toluene sulphonate. The reaction mixtureis refluxed and remove water continuously from water separator, maintain this conditionfor 15-17 hrs. Evaporate solvent under reduced pressure. Add chloroform (3000ml).Wash organic part with 1000ml of 5percentNaHCO3, then wash with 1000ml of brine solution.After concentration of reaction mass, crystallize residue in Isopropyl alcohol.YIELD :503gms(79percent)PURITY: 99.66percent
77%	With toluene-4-sulfonic acid In N,N-dimethyl-formamide; toluene at 130 - 135℃; for 10 h; Heating / reflux	(C) 25gms (0.2123mole) Trans-4-aminocyclohexanol was dissolved in 125ml of tolueneand 125ml of DMF. Add 32.17gm(0.2123mole) phthalic anhydride and 0.25gm (0.0066mole ) of p-toluene sulphonic acid. Reflux mass at 130°-135°C for lOhrs. Removecontinuously water from water separator. Cool mass to 40°C.remove solvent underreduced pressure. Dissolve mass in 250ml chloroform, washed chloroform layer with5percentNaHCO3 solution and brine solution. Evaporate chloroform and residue wascrystallizing in isopropyl alcohol.YIELD: 41gms(77percent)
71%	With pyridinium p-toluenesulfonate In cyclohexane; N,N-dimethyl-formamide at 90 - 95℃; for 19 h; Heating / reflux	B) 25gms(0.2123mole) Trans-4-aminocyclohexanol was dissolve in 100ml cyclohexaneand 100ml DMF. Add 128.6gm(0.8689mole) phthalic anhydride and 0.25gm(0.001mole)pyridinium p-toluene sulphonate. Reflux mass at 90-95°C for 19 hrs. Removecontinuously water from water separator. Cool mass to 40°C, remove solvent underreduced pressure. Dissolve mass in 250ml chloroform, washed chloroform layer with5percentNaHCC>3 solution and brine solution. Evaporate chloroform and residue wascrystallizing in isopropyl alcohol.YIELD: 38ems(71percent)

69.4%

With Pyridine hydrobromide In N,N-dimethyl-formamide; toluene at 130 - 135℃; for 15 - 17 h; Heating / reflux

(D) 25gms(0.2123mole) Trans-4-aminocyclohexanol was dissolve in 125ml of tolueneand 125ml of DMF. Add 32.17gm(0.2123mole) phthalic anhydride and 0.25gm(0.0074mole) of pyridine hydrobromide. Reflux mass at 130°-135°C for 15-17 hrs. Removecontinuously water from water separator. Cool mass to 40°C.remove solvent underreduced pressure. Dissolve mass in 250ml chloroform., washed chloroform layer with5percentNaHCO3 solution and brine solution. Evaporate chloroform and residue wascrystallizing hi isopropyl alcohol.YIELD: 37gms(69.4percent)

Reference： [1] Patent: WO2006/3677, 2006, A1, . Location in patent: Page/Page column 10; 15
[2] Patent: WO2006/3677, 2006, A1, . Location in patent: Page/Page column 10; 16
[3] Patent: WO2006/3677, 2006, A1, . Location in patent: Page/Page column 10; 15
[4] Patent: WO2006/3677, 2006, A1, . Location in patent: Page/Page column 10; 16

6
[ 85-44-9 ]
[ 104618-31-7 ]

Reference： [1] Patent: US4731374, 1988, A,

7
[ 136918-14-4 ]
[ 104618-31-7 ]

Reference： [1] Patent: WO2013/13188, 2013, A1,
[2] Patent: US9416132, 2016, B2,

[ 104618-31-7 ] Synthesis Path-Downstream 1~57

1
[ 22509-74-6 ]
[ 6850-65-3 ]
[ 104618-31-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	for 0.0833333h;Heating;	4-Amino-cyclohexanol (2.627 g, 22.81 mmol) and 1,3-Dioxo-1,3-dihydro-isoindole-2-carboxylic acid ethyl ester (5 g, 22.81 mmol) were placed in a large test-tube and heated with a heat gun until both had melted and then for an additional 5 minutes. The resulting solution was allowed to cool and a solid formed. This solid was transferred to a flask, taken up in CH2Cl2 and purified via chromatography (75% EtOAc/Hex) to give 4.57 g of 2-(4-Hydroxy-cyclohexyl)-isoindole-1,3-dione (81% yield). LCMS (m/z): M+H+MeCN=287.1.
56.82%	With potassium carbonate; In water; at 20℃; for 2h;	[00486] To a solution of ethyl 1 ,3-dioxoisoindoline-2-carboxylate (1 .67 g, 7.19 mmol) in water (16 mL) was added 4-aminocyclohexanol (1 .31 g, 8.63 mmol), followed by K2CO3 (1 .59 g, 1 1 .5 mmol). The mixture was stirred at room temperature for 2 h. TLC (PE: EA = 1 :1 ) showed the reaction was complete. The mixture was filtered and the solid was dried under vacuum to give 2-(4- hydroxycyclohexyl)isoindoline-1 ,3-dione (1 g, 56.82%) as a brown solid.
56.82%	With potassium carbonate; at 20℃; for 2h;	To a solution of ethyl 1,3-dioxoisoindoline-2-carboxylate (1.67 g, 7.19 mmol) in water (16 mL) was added 4-aminocyclohexanol (1.31 g, 8.63 mmol), followed by K2CO3 (1.59 g, 11.5 mmol). The mixture was stirred at room temperature for 2 h. TLC (PE:EA=1:1) showed the reaction was complete. The mixture was filtered and the solid was dried under vacuum to give 2-(4-hydroxycyclohexyl)isoindoline-1,3-dione (1 g, 56.82%) as a brown solid.

Reference： [1]ACS Medicinal Chemistry Letters,2020
[2]Patent: US2008/269193,2008,A1 .Location in patent: Page/Page column 33
[3]Patent: WO2013/13188,2013,A1 .Location in patent: Paragraph 00486
[4]Patent: US9416132,2016,B2 .Location in patent: Page/Page column 183; 184
[5]Journal of medicinal chemistry,1993,vol. 36,p. 1918 - 1919

2
[ 104618-31-7 ]
[ 104618-32-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium bromide; In ethyl acetate; at 5 - 20℃;pH 7 - 8;	EXAMPLE 1: 4- (Phthalimido) -cyclohexanone [0034] 4- (Phthalimido) -cyclohexanol (146 g) was mixed with AcOEt (1000 mL) , after which and NaBr (8 g) and TEMPO(0.5 g) was added. 1000 mL of NaClO (10 %) was added in portions and the reaction mixture was adjusted using NaHCtheta3 to pH 7- 8 to maintain the temperature between 5 and 20 0C. After the reaction was completed, the aqueous layer was separated and the organic layer was washed with brine (400 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to give the product as white solid (95 % yield) .
92.4%	With potassium dichromate; sulfuric acid; In chloroform; water; at 25℃; for 4h;	190gms(0.7755mole) 4-phthalimido cyclohexanol are dissolve in 1480ml chloroform.Add solution of H2SO4 (435.87gm, 4.4476mole cone. H2SO4 was added in 900 mlwater). Cool mass to 25C,add lot wise 180.5gm(0.6139mole) potassium dichromate inone hour. Stir mass for three hours, add 900 ml water and separate organic phase.Organic phase was washed with water and 2% NaHCO3 solution, after drying andconcentration of extracts product was isolated by adding methanol and water mixture.YIELD: 175g(92.4%)PURITY: 96.01%.
88%	With pyridinium chlorochromate; In dichloromethane; at 20℃; for 26h;	The title compound from Step A above (28 g, 114 mmol) was dissolved in dichloromethane (990 mL) and pyridinium chlorochromate (33.6 g, 157 mmol) was added in portions. The reaction mixture was stirred at room temperature for 8 h. Then another batch of pyridinium chlorochromate (10.4 g, 48.6 mmol) was added in portions and stirring at room temperature was continued for 18 h. The reaction mixture was filtered through a pad of Celite and the Celite pad was washed with dichlormethane (400 mL). The combined filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica using ethyl acetate/n-heptane (60/40) as a mobile phase to afford the title compound as a white solid (24.62 g, 88%)1H-NMR (400 MHz, CDCl3): delta=2.17-2.24 (m, 2H), 2.60-2.71 (m, 4H), 2.80-2.90 (m, 2H), 4.78 (tt, 1H), 7.84-7.88 (m, 2H), 7.97-8.02 (m, 2H)

2.01 g (65%)	With pyridinium chlorochromate; In dichloromethane;	Step 2 A solution of <strong>[104618-31-7]2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione</strong> (3.10 g, 12.6 mmol) in CH2Cl2 (25.0 mL) was added to a slurry of PCC (4.10 g, 19.0 mmol) in CH2Cl2 (15.0 mL) and stirred at room temperature for 3.5 hours. The reaction was diluted with Et2O (60.0 mL), decanted and the residue swirled with Et2O (2*40.0 mL). The combined ether layers were filtered through florisil and concentrated in vacuo to dryness, and the residue was recrystallized from ethyl acetate/hexane to give 2.01 g (65%) of 2-(4-oxocyclohexyl)-1H-isoindole-1,3(2H)-dione as colorless needles: mp 140.3-142.1 C.; 1H NMR (400 MHz, CDCl3) delta7.84, 7.74, 4.64, 2.72, 2.54, 2.09; 13C NMR (100 MHz, CDCl3) delta208.9, 168.1, 134.1, 131.9, 123.3, 48.4, 39.9, 28.6; IR (mull) 3062, 3031, 2958, 2949, 2919, 2885, 1775, 1762, 1721, 1708, 1611, 1465, 1436, 1419, 1393, 1379, 719 cm-1; HRMS (FAB) calcd for C14H14NO3: 244.0974, found 244.0976; Anal. Calcd for C-14H14NO3: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.87; H, 5.47; N, 5.73.
	With pyridinium chlorochromate; In diethyl ether; dichloromethane;	A solution of 4-phthalimido cyclohexanol (7.1 g, 0.029 mole) in dichloromethane (250 ml) was treated with pyridinium chlorochromate (8.6 g, 0.04 mole) and the resulting dark mixture was stirred at room temperature overnight. Diethyl ether (50 ml) was added and the mixture filtered through keiselguhr. The filtrate was concentrated in vacuo and the residue purified by column chromatography (SiO2; CHCl3 /EtOAc) to give 4-phthalimido cyclohexanone as a white solid (6.4 g).
	With pyridinium chlorochromate; In diethyl ether; dichloromethane;	A solution of 4-phthalimido cyclohexanol (7.1 g, 0.029 mole) in dichloromethane (250 ml) was treated with pyridinium chlorochromate (8.6 g, 0.04 mole) and the resulting dark mixture was stirred at room temperature overnight. Diethyl ether (50 ml) was added and the mixture filtered through keiselguhr. The filtrate was concentrated in vacuo and the residue purified by column chromatography (SiO2; CHCl3/EtOAc) to give 4-phthalimido cyclohexanone as a white solid (6.4 g).
	With potassium dichromate; sulfuric acid; In chloroform; water;	(b) 4-(Phthalimido)-cyclohexanone 95 g (0.388 Mol) of 4-(phthalimido)cyclohexanol are dissolved in 600 ml of chloroform and, after the addition of 450 ml of water and 120 ml of sulfuric acid, 90 g (0.3 Mol) of potassium dichromate are added in batches. The internal temperature of the mixture is maintained at between 25 and 30 C. by slight cooling. The mixture is stirred for a further 3 hours, then the chloroform phase is separated of and the mixture extracted twice more with chloroform. After drying and concentration of the extracts 82 g (86.9% of theory) are obtained.
	With chromic acid; In acetone; at 5 - 10℃;	Preparation of 2-amino-6-phthalimido-4,5,6,7-tetrahydrobenzothiazole via 4-(phthalimido)-cyclohexanone; 1.0 Kg of <strong>[104618-31-7]4-(phthalimido)-cyclohexanol</strong> was added in 20.0 L of acetone at 250C to 350C. The reaction mixture was cooled to 50C to 100C and treated with chromic acid solution. 0.2 L of isopropanol was added and stirred for 30 min. The reaction mixture was filtered and washed with acetone (1.0 L). The filtrate was treated with 0.4 kg sodium bicarbonate at 250C to 350C and stirred for 1 h. The reaction mass was again filtered, washed with acetone (1.0 L). Excess of acetone was distilled under vacuum. The residue was treated with 0.5 L ethanol followed by distillation of ethanol under vacuum. The reaction mass was cooled and treated with 3.36 L ethanol at 450C to 250C while gradual cooling. The reaction mixture was further cooled to 150C to 200C and treated with 0.22 L of bromine and 0.43 Kg of thiourea under stirring for 1 h. The reaction mixture was heated to reflux at 750C to 780C for 6 hrs. The reaction mixture was cooled and stirred for 1 hr at 50C to 100C. The product was isolated by centrifuge, washing with ethanol 0.66 L and drying under vacuum at 500C to 550C. (yield: 0.70 Kg).

Reference： [1]Patent: WO2010/78250,2010,A1 .Location in patent: Page/Page column 12
[2]Patent: WO2006/3677,2006,A1 .Location in patent: Page/Page column 10; 16
[3]Patent: US2011/280808,2011,A1 .Location in patent: Page/Page column 62
[4]Journal of medicinal chemistry,1993,vol. 36,p. 1918 - 1919
[5]Patent: US2003/100596,2003,A1
[6]Patent: US5827871,1998,A
[7]Patent: EP603432,1994,A1
[8]Patent: US4731374,1988,A
[9]Patent: WO2008/41240,2008,A1 .Location in patent: Page/Page column 16-17

3
trans-4-hydroxycyclohexylamine hydrochloride [ No CAS ]
[ 22509-74-6 ]
[ 104618-31-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; In water; at 20℃; for 1h;	2-(4-Hydroxy-cyclohexyl)-isoindole-1,3-dione; K2CO3 (19.4 g, 140.6 mmol) was added to a solution of trans-4-aminocyclohexanol hydrochloride (9.0 g, 59.35 mmol) in water (150 ml.) followed by N-carbethoxy phthalimide (18.8 g, 85.96 mmol). A white precipitate was formed immediately. Stirring continued at RT for 1 h. The precipitate was filtered off, washed with water and dried to afford 12 g (84 %) of 2-(4-hydroxy-cyclohexyl)-isoindole-1 ,3-dione. 1H-NMR (300 MHz, DMSO-d6) delta 1.18 - 1.40 (m, 3H), 1.60 - 1.76 (m, 2H), 1.80 - 2.00 (m, 2H), 2.04 - 2.23 (dq, 2H), 3.40 - 3.50 (m, 1 H), 3.89 - 4.03 (tt,1 H), 4.6 (br.s, 1 H,), 7.15 - 7.39 (m,1 H), 7.80 (m, 3H). m/z: 246 (M+1 )+

Reference： [1]Patent: WO2007/115935,2007,A1 .Location in patent: Page/Page column 61

4
[ 120-47-8 ]
[ 104618-31-7 ]
[ 952589-02-5 ]

Yield	Reaction Conditions	Operation in experiment
42%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 6h;	4-[4-(1,3-Dioxo-1 , 3-dihydro-isoindol-2-yl)-cyclohexyloxy]-benzoic acid ethyl ester; <n="63"/>To a stirred solution of 2-(4-hydroxycyclohexyl)isoindole-1 ,3-dione (8.0 g, 32.6 mmol) in dry THF (100 ml.) was added triphenyl phosphine (12.8 g, 48.8 mmol) and 4- hydroxy benzoic acid ethyl ester (5.44 g, 32.7 mmol). The reaction mixture was cooled to 0 0C and DIAD (9.6 g, 47.4 mmol) was added dropwise from an addition funnel over a period of 3 h. The reaction was gradually brought to room temperature and stirring continued for 3 h. The solvent was removed under vacuum and ether (100 ml.) was added and cooled to 0 0C. The solid formed was filtered and the clear filtrate concentrated and purified by column chromatography over neutral alumina (8 % AcOEt in hexane) to give 5.13 g (42 %) of 4-[4- (I .S-dioxo-I .S-dihydro-isoindol^-ylJ-cyclohexyloxyJ-benzoic acid ethyl ester. 1H-NMR (300 MHz, CDCI3); delta 1.24 - 1.36 (m, 2H), 1.40 (t, 3H), 1.63 - 1.77 (m, 3H), 2.19 - 2.29 (m, 2H), 2.62 - 2.79 (dq, 2H), 4.15 - 4.72 (m, 1 H), 4.35 (q, 2H), 7.01 (d, 2H), 7.71 (m, 2H), 7.82 (m, 2H), 8.0 (d, 2H). m/z: 394.1 (M+1 )+

Reference： [1]Patent: WO2007/115935,2007,A1 .Location in patent: Page/Page column 61-62

5
[ 104618-31-7 ]
[ 147008-87-5 ]

Reference： [1]Journal of medicinal chemistry,1993,vol. 36,p. 1918 - 1919

6
[ 104618-31-7 ]
[ 147009-19-6 ]

Reference： [1]Journal of medicinal chemistry,1993,vol. 36,p. 1918 - 1919

7
[ 104618-31-7 ]
[ 147009-20-9 ]

Reference： [1]Journal of medicinal chemistry,1993,vol. 36,p. 1918 - 1919

8
[ 104618-31-7 ]
[ 147009-18-5 ]

Reference： [1]Journal of medicinal chemistry,1993,vol. 36,p. 1918 - 1919

9
[ 104618-31-7 ]
BRL 56905 hydrochloride [ No CAS ]

Reference： [1]Journal of medicinal chemistry,1993,vol. 36,p. 1918 - 1919

10
[ 85-44-9 ]
[ 27489-62-9 ]
[ 104618-31-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	With pyridinium p-toluenesulfonate; In N,N-dimethyl-formamide; toluene; for 15 - 17h;Heating / reflux;Product distribution / selectivity;	A) SOOgms (2.608mole) of Trans-4-aminocyclohexanol was dissolve in 1500mlDimethyl formamide and 1500ml of Toluene. Add 386gms(2.608mole) of Phthalicanhydride and 3gm(0.012mole) pyridinium p-toluene sulphonate. The reaction mixtureis refluxed and remove water continuously from water separator, maintain this conditionfor 15-17 hrs. Evaporate solvent under reduced pressure. Add chloroform (3000ml).Wash organic part with 1000ml of 5%NaHCO3, then wash with 1000ml of brine solution.After concentration of reaction mass, crystallize residue in Isopropyl alcohol.YIELD :503gms(79%)PURITY: 99.66%
77%	With toluene-4-sulfonic acid; In N,N-dimethyl-formamide; toluene; at 130 - 135℃; for 10h;Heating / reflux;Product distribution / selectivity;	(C) 25gms (0.2123mole) Trans-4-aminocyclohexanol was dissolved in 125ml of tolueneand 125ml of DMF. Add 32.17gm(0.2123mole) phthalic anhydride and 0.25gm (0.0066mole ) of p-toluene sulphonic acid. Reflux mass at 130-135C for lOhrs. Removecontinuously water from water separator. Cool mass to 40C.remove solvent underreduced pressure. Dissolve mass in 250ml chloroform, washed chloroform layer with5%NaHCO3 solution and brine solution. Evaporate chloroform and residue wascrystallizing in isopropyl alcohol.YIELD: 41gms(77%)
71%	With pyridinium p-toluenesulfonate; In cyclohexane; N,N-dimethyl-formamide; at 90 - 95℃; for 19h;Heating / reflux;Product distribution / selectivity;	B) 25gms(0.2123mole) Trans-4-aminocyclohexanol was dissolve in 100ml cyclohexaneand 100ml DMF. Add 128.6gm(0.8689mole) phthalic anhydride and 0.25gm(0.001mole)pyridinium p-toluene sulphonate. Reflux mass at 90-95C for 19 hrs. Removecontinuously water from water separator. Cool mass to 40C, remove solvent underreduced pressure. Dissolve mass in 250ml chloroform, washed chloroform layer with5%NaHCC>3 solution and brine solution. Evaporate chloroform and residue wascrystallizing in isopropyl alcohol.YIELD: 38ems(71%)

69.4%

With Pyridine hydrobromide; In N,N-dimethyl-formamide; toluene; at 130 - 135℃; for 15 - 17h;Heating / reflux;Product distribution / selectivity;

(D) 25gms(0.2123mole) Trans-4-aminocyclohexanol was dissolve in 125ml of tolueneand 125ml of DMF. Add 32.17gm(0.2123mole) phthalic anhydride and 0.25gm(0.0074mole) of pyridine hydrobromide. Reflux mass at 130-135C for 15-17 hrs. Removecontinuously water from water separator. Cool mass to 40C.remove solvent underreduced pressure. Dissolve mass in 250ml chloroform., washed chloroform layer with5%NaHCO3 solution and brine solution. Evaporate chloroform and residue wascrystallizing hi isopropyl alcohol.YIELD: 37gms(69.4%)

Reference： [1]Patent: WO2006/3677,2006,A1 .Location in patent: Page/Page column 10; 15
[2]Patent: WO2006/3677,2006,A1 .Location in patent: Page/Page column 10; 16
[3]Patent: WO2006/3677,2006,A1 .Location in patent: Page/Page column 10; 15
[4]Patent: WO2006/3677,2006,A1 .Location in patent: Page/Page column 10; 16

11
[ 22509-74-6 ]
trans-4-hydroxycyclohexylamine hydrochloride [ No CAS ]
[ 104618-31-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium carbonate; In tetrahydrofuran; water; at 20℃; for 72h;	Commercially available 4-aminocyclohexanol hydrogen chloride salt (25 g, 164 mmol) was dissolved in water (350 mL). Then potassium carbonate (72 g, 328 mmol) was added, followed by a solution of commercially available N-carbethoxyphthalimide in tetrahydrofurane (300 mL). The reaction mixture was then vigorously stirred at room temperature for 3 days. Tetrahydrofurane was evaporated under reduced pressure and the remaining aqueous phase was extracted with dichloromethane (2×300 mL) until the aqueous phase was clear. The combined organic phase was dried over Na2SO4, filtered and the solvents were evaporated under reduced pressure to afford the title compound as a white solid (28 g, 69%).1H-NMR (400 MHz, CDCl3): delta=1.32-1.43 (m, 2H), 1.70-1.75 (m, 2H), 2.04-2.09 (m, 2H), 2.25-2.38 (m, 2H), 3.67-3.77 (m, 1H), 4.05-4.13 (m, 1H), 7.63-7.7.68 (m, 2H), 7.76-7.7.80 (m, 2H)
3.10 g (76%)	With sodium carbonate; In water; ethyl acetate;	Step 1 A solution of 4-aminocyclohexanol hydrochloride (2.52 g, 16.6 mmol) in water (20.0 mL) was treated with N-carbethoxyphthalimide (3.82 g, 17.4 mmol) and Na2CO3 (3.77 g, 35.6 mmol). The reaction was stirred at room temperature for 15.6 hours. The reaction was cooled to 0 C. and quenched with 10% HCl, filtered, and washed with water to give a white solid. The solid was dissolved in ethyl acetate washed with water, brine, dried over MgSO4 and concentrated in vacuo to give 3.10 g (76%) of 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione as a colorless solid: mp 176.9-177.0 C.; 1H NMR (400 MHz, Acetone-d6) delta7.82 4.09, 3.74, 3.62, 2.28, 2.04, 1.76, 1.39; 13C NMR (100 MHz, acetone-d6) delta168.7, 135.1, 133.0, 123.6, 69.5, 50.8, 35.7, 28.3; IR (mull) 3389, 3318, 2953, 2930, 2876, 2861, 1767, 1703, 1463, 1393, 1377, 1088, 1075, 1061, 720 cm-1; HRMS (FAB) calcd for C14H16NO3: 246.1130, found 246.1128; Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.39; H, 6.21; N, 5.70.
	In tetrahydrofuran; water;	EXAMPLE 1 3-Amino-6-cyano-1,2,3,4-tetrahydrocarbazole hydrochloride A solution of 4-aminocyclohexanol hydrochloride (6.08 g, 0.04 mole) in water (60 ml) was brought to pH 8 with aqueous sodium bicarbonate solution. N-carbethoxy-phthalimide (8.76 g, 0.04 mole) was added followed by tetrahydrofuran (until homogenous solution was obtained). The clear solution was stirred at room temperature overnight. During this time a white solid was precipitated. The tetrahydrofuran was removed in vacuo and the remaining aqueous solution was extracted with ethyl acetate until the solution was clear. The ethyl acetate extracts were combined, washed with water, dried (MgSO4) and concentrated to give 4-phthalimido cyclohexanol as a white solid (7.1 g).

In tetrahydrofuran; water;

Example 1 3-Amino-6-cyano-1,2,3,4-tetrahydrocarbazole hydrochloride A solution of 4-aminocyclohexanol hydrochloride (6.08 g, 0.04 mole) in water (60 ml) was brought to pH 8 with aqueous sodium bicarbonate solution. N-carbethoxy-phthalimide (8.76 g, 0.04 mole) was added followed by tetrahydrofuran (until homogenous solution was obtained). The clear solution was stirred at room temperature overnight. During this time a white solid was precipitated. The tetrahydrofuran was removed in vacuo and the remaining aqueous solution was extracted with ethyl acetate until the solution was clear. The ethyl acetate extracts were combined, washed with water, dried (MgSO4) and concentrated to give 4-phthalimido cyclohexanol as a white solid (7.1 g).

Reference： [1]Patent: US2011/280808,2011,A1 .Location in patent: Page/Page column 62
[2]Patent: US2003/100596,2003,A1
[3]Patent: US5464864,1995,A
[4]Patent: EP603432,1994,A1

12
[ 85-44-9 ]
trans-4-hydroxycyclohexylamine hydrochloride [ No CAS ]
[ 104618-31-7 ]

Yield	Reaction Conditions	Operation in experiment
	In water; toluene;	(a) (4-(Phthalimido)-cyclohexanol 75.5 g (0.5 Mol) of 4-aminocyclohexanolhydrochloride and 74.0 g (0.5 Mol) of phthalic acid anhydride are mixed with 65 g (0.5 Mol) of ethyl-diisopropyl-amine and 1000 ml of toluene and boiled for 36 hours with a water separator. Then water is added, the toluene phase is separated off and the aqueous phase is extracted several times with chloroform. The organic phases are combined, dried and concentrated. The concentration residue is recrystallized from isopropanol. Yield: 95 g (77.8% of theory), M.p.: 175-176 C.

Reference： [1]Patent: US4731374,1988,A

13
[ 104618-31-7 ]
[ 74-88-4 ]
[ 1073973-07-5 ]