[ CAS No. 912999-49-6 ] {[proInfo.proName]}

Name: 912999-49-6|(2,4-Dihydroxy-5-isopropylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone|98%
Brand: Ambeed
SKU: A389427
Price: 66.0 USD
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2D 3D

Structure of 912999-49-6 * Storage: {[proInfo.prStorage]}

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Quality Control of [ 912999-49-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 912999-49-6 ]

SDS Specification

Alternatived Products of [ 912999-49-6 ]

Product Details of [ 912999-49-6 ]

CAS No. :	912999-49-6	MDL No. :	MFCD18633198
Formula :	C₂₄H₃₁N₃O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IFRGXKKQHBVPCQ-UHFFFAOYSA-N
M.W :	409.52	Pubchem ID :	11955716
Synonyms :	AT13387	Chemical Name :	(2,4-Dihydroxy-5-isopropylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

Calculated chemistry of [ 912999-49-6 ]

Physicochemical Properties

Num. heavy atoms :	30
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.46
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	129.92
TPSA :	67.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.63 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.71
Log Po/w (XLOGP3) :	3.06
Log Po/w (WLOGP) :	1.53
Log Po/w (MLOGP) :	2.09
Log Po/w (SILICOS-IT) :	3.09
Consensus Log Po/w :	2.7

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.27
Solubility :	0.0218 mg/ml ; 0.0000534 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.14
Solubility :	0.0297 mg/ml ; 0.0000726 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.91
Solubility :	0.00503 mg/ml ; 0.0000123 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.01

Safety of [ 912999-49-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 912999-49-6 ]

* 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 [ 912999-49-6 ]
Downstream synthetic route of [ 912999-49-6 ]

[ 912999-49-6 ] Synthesis Path-Upstream 1~10

1
[ 1019890-18-6 ]
[ 912999-49-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With hydrogen; potassium carbonate In water; isopropyl alcohol for 1 - 1.16667 h;	The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with N₂ 10percent Pd/C (9Og) and K₂CO₃ (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H₂. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCI (30percent hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60 ⁰C under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued (until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06L) and netralised to pH 7.5- 8.5 by addition of cone ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2 x 0.8 L) and dried at 40 ⁰C to constant weight to give the title compound 588 g (94 percent yield).
94%	With hydrogen; potassium carbonate In water; isopropyl alcohol for 1 - 1.16667 h;	The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with N₂ 10percent Pd/C (9Og) and K₂CO₃ (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr <n="105"/>pressure of H₂. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCI (30percent hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60 ⁰C under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued (until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06L) and netralised to pH 7.5- 8.5 by addition of cone ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2 x 0.8 L) and dried at 40 ⁰C to constant weight to give the title compound 588 g (94 percent yield).
94%	With hydrogen; potassium carbonate In water; isopropyl alcohol for 1 - 1.16667 h;	The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with N₂ 10percent Pd/C (9Og) and K₂CO₃ (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H₂. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCI (30percent hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60 ⁰C under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued <n="297"/>296(until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06L) and netralised to pH 7.5- 8.5 by addition of cone ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2 x 0.8 L) and dried at 40 ⁰C to constant weight to give the title compound 588 g (94 percent yield).

94%	With hydrogen; potassium carbonate In water; isopropyl alcohol for 1 - 1.16667 h;	The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with N₂ 10percent Pd/C (9Og) and K₂CO₃ (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H₂. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCI (30percent hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60 ⁰C under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued <n="350"/>(until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06L) and netralised to pH 7.5- 8.5 by addition of cone ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2 x 0.8 L) and dried at 40 ⁰C to constant weight to give the title compound 588 g (94 percent yield).
94%	Stage #1: With hydrogen; potassium carbonate In water; isopropyl alcohol for 1 - 1.16667 h; Stage #2: With hydrogenchloride In water at 60℃;	The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with N₂ 10percent Pd/C (9Og) and K₂CO₃ (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H₂. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCI (30percent hydrochloric acid, <n="194"/>0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60 ⁰C under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued (until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06L) and netralised to pH 7.5- 8.5 by addition of cone ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2 x 0.8 L) and dried at 40 ⁰C to constant weight to give the title compound 588 g (94 percent yield).
94%	With hydrogen; potassium carbonate In water; isopropyl alcohol for 1 - 1.16667 h; Inert atmosphere	The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol (6.8 L) and water (1.04 L) and after purging with N₂10percent Pd/C (90 g) and K₂CO₃(0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H₂. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCl (30percent hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60° C. under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued (until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06 L) and netralised to pH 7.5-8.5 by addition of conc ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2.x.0.8 L) and dried at 40° C. to constant weight to give the title compound 588 g (94percent yield).

Reference： [1] Patent: WO2008/44029, 2008, A1, . Location in patent: Page/Page column 274
[2] Patent: WO2008/44034, 2008, A1, . Location in patent: Page/Page column 103-104
[3] Patent: WO2008/44041, 2008, A1, . Location in patent: Page/Page column 295-296
[4] Patent: WO2008/44045, 2008, A1, . Location in patent: Page/Page column 348-349
[5] Patent: WO2008/44054, 2008, A2, . Location in patent: Page/Page column 191-192
[6] Patent: US2010/152184, 2010, A1, . Location in patent: Page/Page column 122
[7] Patent: WO2008/44029, 2008, A1, . Location in patent: Page/Page column 269
[8] Patent: WO2008/44041, 2008, A1, . Location in patent: Page/Page column 290-291
[9] Patent: WO2008/44045, 2008, A1, . Location in patent: Page/Page column 343-344
[10] Patent: WO2008/44054, 2008, A2, . Location in patent: Page/Page column 186-187
[11] Journal of Medicinal Chemistry, 2010, vol. 53, # 16, p. 5956 - 5969

2
[ 1019890-25-5 ]
[ 912999-49-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: With acetic anhydride In toluene at 100℃; for 16 h; Stage #2: With hydrogenchloride In methanol; water for 5 h; Heating / reflux Stage #3: With potassium carbonate In water	In some batches of product, the title compound (X = H in the formula) can contain small amounts of the impurity 2,4-Dihydroxy-5-(2-hydroxyprop-2-yl)-phenyl)-[5-(4-methyl- piperazin-1-ylmethyl)-1 ,3-dihydro-isoindol-2-yl]-methanone (X = OH in the formula). The impurities can be removed by the following method.X = H and OHAcetic anhydride (1.04 ml, 11.0 mmol) was added to a stirred suspension of impure 2-(2,4- dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1 -ylmethyl)-1 ,3-dihydroisoindole (2.05 g, 5.0 mmol) in toluene (20 ml) and the resulting mixture was stirred and held at 100 ⁰C for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford a brown oil which was dissolved in methanol (20 ml). Concentrated hydrochloric acid (1 ml) was added and the mixture was stirred and held at reflux for 5 hours. Upon cooling to room temperature, the organic solvent and volatile material were removed in vacuo and the <n="100"/>aqueous residue was diluted with water (25 ml) and basified to pH 8 with vigourous stirring by the careful addition of 10percent aqueous potassium carbonate solution. 50percent Ethyl acetate in heptane (50 ml) was added and the mixture was stirred vigourously at room temperature for 16 hours. The solid material was collected by suction filtration, rinsed with 50percent ethyl acetate in heptane (50 ml), sucked dry under reduced pressure and dried overnight in a vacuum oven at 50 ⁰C to afford 2-(2,4-dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin- 1-yimethyl)-1,3-dihydroisoindole (1.85 g, 90percent) as an off-white solid. ¹H NMR (DMSO-d₆) 10.07 (1H, br s), 9.60 (1H, br s), 7.24 (3H, m), 7.06 (1 H, s), 6.40 (1 H, s), 4.76 (4H, br s), 3.44 (2H, s), 3.10 (1 H, m), 2.32 (8H, m), 2.14 (3H, s), 1.15 (6H, d). MS: [M+H]⁺ 410.
90%	Stage #1: With acetic anhydride In toluene at 100℃; for 16 h; Stage #2: With hydrogenchloride In methanol for 5 h; Reflux	Acetic anhydride (1.04 ml, 11.0 mmol) was added to a stirred suspension of impure 2-(2,4-dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindole (2.05 g, 5.0 mmol) in toluene (20 ml) and the resulting mixture was stirred and held at 100° C. for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford a brown oil which was dissolved in methanol (20 ml). Concentrated hydrochloric acid (1 ml) was added and the mixture was stirred and held at reflux for 5 hours. Upon cooling to room temperature, the organic solvent and volatile material were removed in vacuo and the aqueous residue was diluted with water (25 ml) and basified to pH 8 with vigorous stirring by the careful addition of 10percent aqueous potassium carbonate solution. 50percent Ethyl acetate in heptane (50 ml) was added and the mixture was stirred vigourously at room temperature for 16 hours. The solid material was collected by suction filtration, rinsed with 50percent ethyl acetate in heptane (50 ml), sucked dry under reduced pressure and dried overnight in a vacuum oven at 50° C. to afford 2-(2,4-dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindole (1.85 g, 90percent) as an off-white solid. ¹H NMR (DMSO-d₆) 10.07 (1H, br s), 9.60 (1H, br s), 7.24 (3H, m), 7.06 (1H, s), 6.40 (1H, s), 4.76 (4H, br s), 3.44 (2H, s), 3.10 (1H, m), 2.32 (8H, m), 2.14 (3H, s), 1.15 (6H, d). MS: [M+H]⁺410.

Reference： [1] Patent: WO2008/44034, 2008, A1, . Location in patent: Page/Page column 98-99
[2] Patent: US2010/152184, 2010, A1, . Location in patent: Page/Page column 119; 120
[3] Patent: WO2008/44045, 2008, A1, . Location in patent: Page/Page column 344-345

3
[ 1415742-78-7 ]
[ 912999-49-6 ]

Reference： [1] Journal of Organic Chemistry, 2012, vol. 77, # 24, p. 11296 - 11301

4
[ 913000-35-8 ]
[ 912999-49-6 ]

Reference： [1] Patent: WO2008/44045, 2008, A1, . Location in patent: Page/Page column 319

5
[ 1019890-18-6 ]
[ 912999-49-6 ]
[ 1019890-25-5 ]

Reference： [1] Patent: WO2008/44034, 2008, A1, . Location in patent: Page/Page column 97-98

6
[ 127168-84-7 ]
[ 912999-49-6 ]

Reference： [1] Journal of Organic Chemistry, 2012, vol. 77, # 24, p. 11296 - 11301

7
[ 6941-75-9 ]
[ 912999-49-6 ]

Reference： [1] Journal of Organic Chemistry, 2012, vol. 77, # 24, p. 11296 - 11301

8
[ 201940-08-1 ]
[ 912999-49-6 ]

Reference： [1] Journal of Organic Chemistry, 2012, vol. 77, # 24, p. 11296 - 11301

9
[ 1015484-22-6 ]
[ 912999-49-6 ]

Reference： [1] Journal of Organic Chemistry, 2012, vol. 77, # 24, p. 11296 - 11301

10
[ 109-01-3 ]
[ 912999-49-6 ]

Reference： [1] Journal of Organic Chemistry, 2012, vol. 77, # 24, p. 11296 - 11301

[ 912999-49-6 ] Synthesis Path-Downstream 1~29

2
[ 1019890-18-6 ]
[ 912999-49-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With hydrogen; potassium carbonate;palladium 10% on activated carbon; In water; isopropyl alcohol; under 2250.23 Torr; for 1 - 1.16667h;	The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with N2 10% Pd/C (9Og) and K2CO3 (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H2. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCI (30% hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60 0C under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued (until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06L) and netralised to pH 7.5- 8.5 by addition of cone ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2 x 0.8 L) and dried at 40 0C to constant weight to give the title compound 588 g (94 % yield).
94%	With hydrogen; potassium carbonate;palladium 10% on activated carbon; In water; isopropyl alcohol; under 2250.23 Torr; for 1 - 1.16667h;Product distribution / selectivity;	The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with N2 10% Pd/C (9Og) and K2CO3 (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr <n="105"/>pressure of H2. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCI (30% hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60 0C under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued (until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06L) and netralised to pH 7.5- 8.5 by addition of cone ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2 x 0.8 L) and dried at 40 0C to constant weight to give the title compound 588 g (94 % yield).
94%	With hydrogen; potassium carbonate;palladium 10% on activated carbon; In water; isopropyl alcohol; under 2250.23 Torr; for 1 - 1.16667h;Product distribution / selectivity;	The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with N2 10% Pd/C (9Og) and K2CO3 (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H2. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCI (30% hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60 0C under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued <n="297"/>??296(until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06L) and netralised to pH 7.5- 8.5 by addition of cone ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2 x 0.8 L) and dried at 40 0C to constant weight to give the title compound 588 g (94 % yield).

94%	With hydrogen; potassium carbonate;palladium 10% on activated carbon; In water; isopropyl alcohol; under 2250.23 Torr; for 1 - 1.16667h;Product distribution / selectivity;	The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with N2 10% Pd/C (9Og) and K2CO3 (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H2. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCI (30% hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60 0C under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued <n="350"/>(until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06L) and netralised to pH 7.5- 8.5 by addition of cone ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2 x 0.8 L) and dried at 40 0C to constant weight to give the title compound 588 g (94 % yield).
94%		The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with N2 10% Pd/C (9Og) and K2CO3 (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H2. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCI (30% hydrochloric acid, <n="194"/>0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60 0C under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued (until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06L) and netralised to pH 7.5- 8.5 by addition of cone ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2 x 0.8 L) and dried at 40 0C to constant weight to give the title compound 588 g (94 % yield).
94%	With hydrogen; potassium carbonate;palladium 10% on activated carbon; In water; isopropyl alcohol; under 2250.23 Torr; for 1 - 1.16667h;Inert atmosphere;Product distribution / selectivity;	The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol (6.8 L) and water (1.04 L) and after purging with N2 10% Pd/C (90 g) and K2CO3 (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H2. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCl (30% hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60 C. under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued (until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06 L) and netralised to pH 7.5-8.5 by addition of conc ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2×0.8 L) and dried at 40 C. to constant weight to give the title compound 588 g (94% yield).
81%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 12h;	Palladium on carbon (10%) (214.6 mg, 2.01 mmol, 0.3 eq.) was added to a solution of (2,4-Bis(benzyloxy)-5-(prop-1-en-2-yl)phenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (3.95 g, 6.72 mmol, 1 eq.) in methanol (30 mL). The reaction mixture was then stirred under a hydrogen atmosphere for 12 h. The mixture was filtered through a pad of celite, eluted with ethyl acetate and the eluent was concentrated. The resulting residue was purified by silica chromatography (0-10% MeOH: DCM) to afford (2,4-dihydroxy-5-isopropylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone as a colorless solid (2.2 g, 81%): 1H NMR (400 MHz, CDCl3) delta 7.38 (s, 1H), 7.23-7.18 (br m, 3H), 6.33 (s, 1H), 5.01 (s, 2H), 4.98 (s, 2H), 3.55 (s, 2H), 3.26-3.19 (m, 1H), 2.89-2.68 (br m, 8H), 2.57 (s, 3H), 1.24 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) delta 171.22, 159.93, 158.76, 136.71, 136.46, 135.72, 128.97, 126.20, 126.07, 123.47, 122.53, 108.48, 103.62, 62.10, 54.12 (2C), 53.69 (2C), 50.92 (2C), 44.43, 26.58, 22.87 (2C); HRMS (ESI+): m/z [M+H+]calcd. for C24H31N3O3, 410.2438; found: 410.2438.
		The product from Step 12 (4.7 g) was dissolved in 1 :1 MeOH/water (98 mL) and after purging with N2 10% Pd/C and K2CO3 (2.38g, 17.2 mmol) were added and the suspension was hydrogenated for 16 h under an atmosphere of H2. The solution was filtered and the solvent evaporated. To the residue was added aqueous 2M-HCI (40 mL) and the solution was washed with 1 :1 EtOAc/petrol (40 mL x 2) and then the pH adjusted to pH 8.5 by addition of NaOH and EtOAc (50 mL) added. The solution was heated to 60 0C and the aqueous phase removed. The hot organic phase was washed with water (30 mL) and then evaporated to a small volume (ca. 5 mL) and allowed to stand at RT 16h with seeding. To the crystalline material was added 1 :1 EtOAc/ petrol (10 mL) and the mixture was filtered and dried to give the title compound as the free base 1.76 g . 1 H NMR (400 MHz, Me- d3-OD): 7.29 (S1 3H), 7.19 (s, 1 H), 6.39 (s, 1 H), 4.91 (s, 4H), 3.56 (S1 2H), 3.28-3.15 (m, 1 H), 2.53 (s, 8H)1 2.31 (S, 3H), 1.23 (d, J = 6.9 Hz1 7H).
	With hydrogen; potassium carbonate;palladium 10% on activated carbon; In methanol; water; for 16h;Product distribution / selectivity;	The product from Step 12 (4.7 g) was dissolved in 1:1 MeOH/water (98 mL) and after purging with N2 10% Pd/C and K2CO3 (2.38g, 17.2 mmol) were added and the suspension was hydrogenated for 16 h under an atmosphere of H2. The solution was filtered and the solvent evaporated. To the residue was added aqueous 2M-HCI (40 mL) and the solution was washed with 1 :1 EtOAc/petrol (4O mL x 2) and then the pH adjusted to pH 8.5 by addition of NaOH and EtOAc (50 mL) added. The solution was heated to 60 0C and the aqueous phase removed. The hot organic phase was washed with water (30 mL) and then evaporated to a small volume (ca. 5 mL) and allowed to stand at RT 16h with seeding. To the crystalline material was added 1 :1 EtOAc/ petrol (10 mL) and the mixture was filtered and dried to give the title compound as the free base 1.76 g . 1 H NMR (400 MHz, Me- d3-OD): 7.29 (s, 3H), 7.19 (s, 1 H), 6.39 (s, 1 H), 4.91 (s, 4H), 3.56 (s, 2H), 3.28-3.15 (m, 1H), 2.53 (s, 8H), 2.31 (s, 3H), 1.23 (d, J = 6.9 Hz, 7H).
	With hydrogen; potassium carbonate;palladium 10% on activated carbon; In methanol; water; for 16h;Product distribution / selectivity;	The product from Step 12 (4.7 g) was dissolved in 1:1 MeOH/water (98 mL) and after purging with N2 10% Pd/C and K2CO3 (2.38g, 17.2 mmol) were added and the suspension was hydrogenated for 16 h under an atmosphere of H2. The solution was filtered and the solvent evaporated. To the residue was added aqueous 2M-HCI (40 mL) and the solution was washed with 1:1 EtOAc/petrol (40 mL x 2) and then the pH adjusted to pH 8.5 by addition of NaOH and EtOAc (50 mL) added. The solution was heated to 60 0C and the aqueous phase removed. The hot organic phase was washed with water (30 mL) and then evaporated to a small volume (ca. 5 mL) and allowed to stand at RT 16h with seeding. To the crystalline material was added 1:1 EtOAc/ petrol (10 mL) and the mixture was filtered and dried to give the title compound as the free base 1.76 g . 1 H NMR (400 MHz, Me- d3-OD): 7.29 (s, 3H), 7.19 (s, 1 H), 6.39 (s, 1H)1 4.91 (s, 4H), 3.56 (s, 2H), 3.28-3.15 (m, 1 H), 2.53 (S1 8H), 2.31 (s, 3H), 1.23 (d, J = 6.9 Hz, 7H).
		The product from Step 12 (4.7 g) was dissolved in 1:1 MeOH/water (98 mL) and after purging with N2 10% Pd/C and K2CO3 (2.38g, 17.2 mmol) were added and the suspension was hydrogenated for 16 h under an atmosphere of H2. The solution was filtered and the solvent evaporated. To the residue was added aqueous 2M-HCI (40 mL) and the solution was washed with 1 :1 EtOAc/petrol (40 mL x 2) and then the pH adjusted to pH 8.5 by addition of NaOH and EtOAc (50 mL) added. The solution was heated to 60 0C and the aqueous phase removed. The hot organic phase was washed with water (30 mL) and then evaporated to a small volume (ca. 5 mL) and allowed to stand at RT 16h with seeding. To the crystalline material was added 1 :1 EtOAc/ petrol (10 mL) and the mixture <n="189"/>was filtered and dried to give the title compound as the free base 1.76 g . 1 H NMR (400 MHz, Me- d3-OD): 7.29 (s, 3H), 7.19 (s, 1 H), 6.39 (s, 1H), 4.91 (s, 4H), 3.56 (s, 2H), 3.28-3.15 (m, 1 H), 2.53 (S, 8H), 2.31 (s, 3H), 1.23 (d, J = 6.9 Hz, 7H).

Reference： [1]Patent: WO2008/44029,2008,A1 .Location in patent: Page/Page column 274
[2]Patent: WO2008/44034,2008,A1 .Location in patent: Page/Page column 103-104
[3]Patent: WO2008/44041,2008,A1 .Location in patent: Page/Page column 295-296
[4]Patent: WO2008/44045,2008,A1 .Location in patent: Page/Page column 348-349
[5]Patent: WO2008/44054,2008,A2 .Location in patent: Page/Page column 191-192
[6]Patent: US2010/152184,2010,A1 .Location in patent: Page/Page column 122
[7]Synthetic Communications,2019,vol. 49,p. 1436 - 1443
[8]Patent: WO2008/44029,2008,A1 .Location in patent: Page/Page column 269
[9]Patent: WO2008/44041,2008,A1 .Location in patent: Page/Page column 290-291
[10]Patent: WO2008/44045,2008,A1 .Location in patent: Page/Page column 343-344
[11]Patent: WO2008/44054,2008,A2 .Location in patent: Page/Page column 186-187
[12]Journal of Medicinal Chemistry,2010,vol. 53,p. 5956 - 5969
[13]Patent: WO2019/14600,2019,A1 .Location in patent: Page/Page column 63; 77

Yield	Reaction Conditions	Operation in experiment
		Acetic anhydride (1.04 ml, 11.0 mmol) was added to a stirred suspension of impure 2-(2,4- dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1 ,3-dihydroisoindole (2.05 g, 5.0 mmol) in toluene (20 ml) and the resulting mixture was stirred and held at 100 0C for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford a brown oil which was dissolved in methanol (20 ml). Concentrated hydrochloric acid (1 ml) was added and the mixture was stirred and held at reflux for 5 hours. Upon cooling to room temperature, the organic solvent and volatile material were removed in vacuo and the aqueous residue was diluted with water (25 ml) and basified to pH 8 with vigourous stirring by the careful addition of 10% aqueous potassium carbonate solution. 50% Ethyl acetate in heptane (50 ml) was added and the mixture was stirred vigourously at room temperature for 16 hours. The solid material was collected by suction filtration, rinsed with 50% ethyl acetate in heptane (50 ml), sucked dry under reduced pressure and dried overnight in a vacuum oven at 50 0C to afford 2-(2,4-dihydroxy-5- isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1 ,3-dihydroisoindole (1.85 g, 90%) as an off- white solid. 1H NMR (DMSOd6) 10.07 (1 H, br s), 9.60 (1H, br s), 7.24 (3H, m), 7.06 (1H, s), 6.40 (1H, s), 4.76 (4H, br s), 3.44 (2H, s), 3.10 (1H, m), 2.32 (8H, m), 2.14 (3H, s), 1.15 (6H, d). MS: [M+H]+ 410.
		Acetic anhydride (1.04 ml, 11.0 mmol) was added to a stirred suspension of impure 2-(2,4- dihydroxy-5-isopropyIbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1 ,3-dihydroisoindole (2.05 g, 5.0 mmol) in toluene (20 ml) and the resulting mixture was stirred and held at 100 0C for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford a brown oil which was dissolved in methanol (20 ml). Concentrated hydrochloric acid (1 ml) was added and the mixture was stirred and held at reflux for 5 hours. Upon cooling to room temperature, the organic solvent and volatile material were removed in vacuo and the aqueous residue was diluted with water (25 ml) and basified to pH 8 with vigourous stirring by the careful addition of 10% aqueous potassium carbonate solution. 50% Ethyl acetate in heptane (50 ml) was added and the mixture was stirred vigourously at room temperature for 16 hours. The solid material was collected by <n="293"/>suction filtration, rinsed with 50% ethyl acetate in heptane (50 ml), sucked dry under reduced pressure and dried overnight in a vacuum oven at 50 0C to afford 2-(2,4-dihydroxy-5- isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindo.e (1.85 g, 90%) as an off- white solid. 1H NMR (DMSO-ds) 10.07 (1H, br s), 9.60 (1H, br s), 7.24 (3H, m), 7.06 (1 H, s), 6.40 (1 H, s), 4.76 (4H, br s), 3.44 (2H, s), 3.10 (1H, m), 2.32 (8H, m), 2.14 (3H, s), 1.15 (6H, d). MS: [M+H]+ 410.
		Acetic anhydride (1.04 ml, 11.0 mmol) was added to a stirred suspension of impure 2-(2,4- dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1 -ylmethyl)-1 ,3-dihydroisoindole (2.05 g, 5.0 mmol) in toluene (20 ml) and the resulting mixture was stirred and held at 100 0C for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford a brown oil which was dissolved in methanol (20 ml). Concentrated hydrochloric acid (1 ml) was added and the mixture was stirred and held at reflux for 5 hours. Upon cooling to room temperature, the organic solvent and volatile material were removed in vacuo and the aqueous residue was diluted with water (25 ml) and basified to pH 8 with vigourous stirring by the careful addition of 10% aqueous potassium carbonate solution. 50% Ethyl acetate in heptane (50 ml) was added and the mixture was stirred vigourously at room temperature for 16 hours. The solid material was collected by suction filtration, rinsed with 50% ethyl acetate in heptane (50 ml), sucked dry under reduced pressure and dried overnight in a vacuum oven at 50 0C to afford 2-(2,4-dihydroxy-5- isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1 ,3-dihydroisoindole (1.85 g, 90%) as an off- white solid. 1H NMR (DMSO-d6) 10.07 (1H, br s), 9.60 (1H, br s), 7.24 (3H, m), 7.06 (1 H, s), 6.40 (1H, s), 4.76 (4H, br s), 3.44 (2H, s), 3.10 (1 H, m), 2.32 (8H, m), 2.14 (3H, s), 1.15 (6H, d). MS: [M+H]+ 410.

4
[ 1019890-18-6 ]
[ 912999-49-6 ]
[ 1019890-25-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen; potassium carbonate;palladium 10% on activated carbon; In methanol; water; for 16h;Product distribution / selectivity;	The product from Step 12 (4.7 g) was dissolved in 1 :1 MeOH/water (98 m._) and after purging with N2 10% Pd/C and K2CO3 (2.38g, 17.2 mmol) were added and the suspension was hydrogenated for 16 h under an atmosphere of H2. The solution was filtered and the solvent evaporated. To the residue was added aqueous 2M-HCI (40 ml_) and the solution was washed with 1 :1 EtOAc/petrol (40 mL x 2) and then the pH adjusted to pH 8.5 by addition of NaOH and EtOAc (50 mL) added. The solution was heated to 60 0C and the aqueous phase removed. The hot organic phase was washed with water (30 mL) and then evaporated to a small volume (ca. 5 mL) and allowed to stand at RT 16h with seeding. To the crystalline material was added 1 :1 EtOAc/ petrol (10 mL) and the mixture was filtered and dried to give the title compound as the free base 1.76 g . 1 H NMR (400 MHz, Me-d3- OD): 7.29 (s, 3H), 7.19 (s, 1 H), 6.39 (s, 1 H), 4.91 (s, 4H), 3.56 (s, 2H), 3.28-3.15 (m, 1 H), 2.53 (s, 8H), 2.31 (s, 3H), 1.23 (d, J = 6.9 Hz, 7H).

Reference： [1]Patent: WO2008/44034,2008,A1 .Location in patent: Page/Page column 97-98

5
[ 912999-49-6 ]
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; ethanol;	The product of Example 1 (0.49 g, 1 mmol) was dissolved in ethanol (10 mL) and 4M HCI in dioxane (0.5 mL, 2 mmol) was dissolved with warming and then the solution was evaporated to dryness. The residue was dissolved with warming ethanol : water (9:1 ; 5 mL). The solution was stirred for16 h with seeding and the solid which formed was removed by filtration and was dried in vacuo to give the title compound. 1H NMR (400 MHz, Me-d3-OD): 7.63-7.52 (m, 2H), 7.47 (s, 1H), 7.17 (s, 1 H), 6.40 (s, 1 H), 4.96 (d, J = 7.0 Hz, 4H), 4.47 (s, 2H), 3.87-3.40 (m, 8H), 3.30-3.16 (m, 1 H), 3.02 (s, 3H), 1.23 (d, J = 6.9 Hz, 6H).

Reference： [1]Patent: WO2008/44034,2008,A1 .Location in patent: Page/Page column 104

6
[ 1019890-25-5 ]
[ 912999-49-6 ]

Yield	Reaction Conditions	Operation in experiment
90%		In some batches of product, the title compound (X = H in the formula) can contain small amounts of the impurity 2,4-Dihydroxy-5-(2-hydroxyprop-2-yl)-phenyl)-[5-(4-methyl- piperazin-1-ylmethyl)-1 ,3-dihydro-isoindol-2-yl]-methanone (X = OH in the formula). The impurities can be removed by the following method.X = H and OHAcetic anhydride (1.04 ml, 11.0 mmol) was added to a stirred suspension of impure 2-(2,4- dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1 -ylmethyl)-1 ,3-dihydroisoindole (2.05 g, 5.0 mmol) in toluene (20 ml) and the resulting mixture was stirred and held at 100 0C for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford a brown oil which was dissolved in methanol (20 ml). Concentrated hydrochloric acid (1 ml) was added and the mixture was stirred and held at reflux for 5 hours. Upon cooling to room temperature, the organic solvent and volatile material were removed in vacuo and the <n="100"/>aqueous residue was diluted with water (25 ml) and basified to pH 8 with vigourous stirring by the careful addition of 10% aqueous potassium carbonate solution. 50% Ethyl acetate in heptane (50 ml) was added and the mixture was stirred vigourously at room temperature for 16 hours. The solid material was collected by suction filtration, rinsed with 50% ethyl acetate in heptane (50 ml), sucked dry under reduced pressure and dried overnight in a vacuum oven at 50 0C to afford 2-(2,4-dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin- 1-yimethyl)-1,3-dihydroisoindole (1.85 g, 90%) as an off-white solid. 1H NMR (DMSO-d6) 10.07 (1H, br s), 9.60 (1H, br s), 7.24 (3H, m), 7.06 (1 H, s), 6.40 (1 H, s), 4.76 (4H, br s), 3.44 (2H, s), 3.10 (1 H, m), 2.32 (8H, m), 2.14 (3H, s), 1.15 (6H, d). MS: [M+H]+ 410.
90%		Acetic anhydride (1.04 ml, 11.0 mmol) was added to a stirred suspension of impure 2-(2,4-dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindole (2.05 g, 5.0 mmol) in toluene (20 ml) and the resulting mixture was stirred and held at 100 C. for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford a brown oil which was dissolved in methanol (20 ml). Concentrated hydrochloric acid (1 ml) was added and the mixture was stirred and held at reflux for 5 hours. Upon cooling to room temperature, the organic solvent and volatile material were removed in vacuo and the aqueous residue was diluted with water (25 ml) and basified to pH 8 with vigorous stirring by the careful addition of 10% aqueous potassium carbonate solution. 50% Ethyl acetate in heptane (50 ml) was added and the mixture was stirred vigourously at room temperature for 16 hours. The solid material was collected by suction filtration, rinsed with 50% ethyl acetate in heptane (50 ml), sucked dry under reduced pressure and dried overnight in a vacuum oven at 50 C. to afford 2-(2,4-dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindole (1.85 g, 90%) as an off-white solid. 1H NMR (DMSO-d6) 10.07 (1H, br s), 9.60 (1H, br s), 7.24 (3H, m), 7.06 (1H, s), 6.40 (1H, s), 4.76 (4H, br s), 3.44 (2H, s), 3.10 (1H, m), 2.32 (8H, m), 2.14 (3H, s), 1.15 (6H, d). MS: [M+H]+ 410.
		Acetic anhydride (1.04 ml, 11.0 mmol) was added to a stirred suspension of impure 2-(2,4- dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1 ,3-dihydroisoindole (2.05 g, 5.0 mmol) in toluene (20 ml) and the resulting mixture was stirred and held at 100 0C for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford a brown oil which was dissolved in methanol (20 ml). Concentrated hydrochloric acid (1 ml) was added and the mixture was stirred and held at reflux for 5 hours. Upon cooling to room temperature, the organic solvent and volatile material were removed in vacuo and the aqueous residue was diluted with water (25 ml) and basified to pH 8 with vigourous stirring by the careful addition of 10% aqueous potassium carbonate solution. 50% Ethyl acetate in heptane (50 ml) was added and the mixture was stirred vigourously at room temperature for 16 hours. The solid material was collected by <n="346"/>suction filtration, rinsed with 50% ethyl acetate in heptane (50 ml), sucked dry under reduced pressure and dried overnight in a vacuum oven at 50 0C to afford 2-(2,4-dihydroxy-5- isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindole (1.85 g, 90%) as an off- white solid. 1H NMR (DMSO-d6) 10.07 (1H, br s), 9.60 (1H, br s), 7.24 (3H, m), 7.06 (1H, s), 6.40 (1 H, s), 4.76 (4H, br s), 3.44 (2H, s), 3.10 (1H, m), 2.32 (8H, m), 2.14 (3H, s), 1.15 (6H, d). MS: [M+H]+ 410.

Reference： [1]Patent: WO2008/44034,2008,A1 .Location in patent: Page/Page column 98-99
[2]Patent: US2010/152184,2010,A1 .Location in patent: Page/Page column 119; 120
[3]Patent: WO2008/44045,2008,A1 .Location in patent: Page/Page column 344-345

7
[ 913000-35-8 ]
[ 912999-49-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen; potassium carbonate;palladium 10% on activated carbon; In methanol; water;Product distribution / selectivity;	Hydrogenation was carried out using Method A5 but with the addition of K2CO3 (2 equiv.) in a MeOH/H2O [9.1]. After evaporation of methanol the reaction was diluted with water, neutralised using 1M HCI and extracted with CH2CI2 (x2). Organics dried (MgSO4), filtered and evaporated under vacuum then purified by preparative HPLC to give 21 mg of (2,4-dihydroxy-5-isopropyl- phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone. MS: [M+H] + 410.1H NMR (Me-d3-OD) 7.37-7.23 (3H, br s), 7.19 (1H, s), 6.39 (1H, s), 4.94-4.87 (4H, br s), 3.57 (2H, s), 3.27-3.16 (1H, m), 2.67-2.39 (8H, m), 2.31 (3H, s), 1.23 (6H, d).

Reference： [1]Patent: WO2008/44045,2008,A1 .Location in patent: Page/Page column 319

8
[ 79-33-4 ]
[ 912999-49-6 ]
[ 1019889-35-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	In ethanol;Product distribution / selectivity;	The product of Step 12 (646 g, 1.58 mol) was dissolved in ethanol (5.17 L) and the solution filtered. A solution of L-lactic acid (142 g, 1.58 mol) dissolved in ethanol (2.59 L) was filtered and added to the solution of the filtered solution (above) and then to the mixture was added EtOAc (7.75 L). The suspension was stirred at RT for 12 h and then cooled to 5 0C for a further 2h. The solid which had formed was removed by filtration, washed with EtOAc (2 x 2.58 L) and heptane (2 x 1.94 L) and dried to constant weight at 35 0C giving the title compound (581 g, 74 % yield).
	In ethanol; ethyl acetate;	The product of Example 1 (1.24 g, 3.303 mmol) was suspended in ethanol (3 mL) and EtOAc (5 mL) and a solution of L-lactic acid (0.285 g, 3.13 mmol) dissolved in ethanol (3 mL) was added. The solution was heated until clear and then was filtered. EtOAc (5 mL) was used to wash the filter and the combined filtrates were stirred at RT for 2 h with seeding. The crystalline mass which formed was removed by filtration, was washed with EtOAc and then dried in vacuum at 5O0C to give the title compound 1.29 g.1 H NMR (400 MHz, Me-d3-OD): 7.30 (s, 3H), 7.18 (s, 1H), 6.39 (s, 1 H), 4.91 (s,4H), 4.08 (q, J = 6.8 Hz, 1H), 3.70-3.63 (m, 2H), 3.28-3.15 (m, 1H), 3.01 (s, 4H), 2.68 (m, 7H), 1.36 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 6.9 Hz, 6H).

Reference： [1]Patent: WO2008/44054,2008,A2 .Location in patent: Page/Page column 192
[2]Patent: WO2008/44054,2008,A2 .Location in patent: Page/Page column 188

9
[ 912999-49-6 ]
[ 88-10-8 ]
[ 1191108-29-8 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of diethyl-carbamic acid 5-diethylcarbamoyloxy-2-isopropyl-4-[5-(4-methyl- piperazin-1 -ylmethyl)-1 ^-dihydro-isoindole^-carbonyli-cvclohexa-i ,3-dienyl esterTo a solution of (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1 ,3- dihydro-isoindol-2-yl]-methanone (1.Og, 2.44 mmol) in THF (25 ml.) containing Et3N (0.68 ml_, 4.88 mmol) and N,N-4-dimethylaminopyridine (5 mg, 0.41 mmol) was added N,N- diethylcarbamoyl chloride (1.5 ml_, 1 1.62 mmol). The solution was heated to 60 0C for 18 h when EtOAc (50 mL) and 10% aq K2CO3 (50 mL) were added. The organic phase was washed with saturated brine (30 mL) and the organic phase was separated andevaporated to a small volume. A solution of the residue in DCM was applied to a column containing silica gel and the product eluted successively with DCM followed by 0.2% aqueous ammonia in 5%MeOH in DCM. The fractions containing product were evaporated from DCM followed by diethyl ether to give the title compound as a foam 1.07 g. 1 H NMR (400 MHz, DMSO-d6): 7.44 (1 H, d), 7.37-7.30 (1 H, m), 7.30-7.15 (2H, m), 7.01 (1 H, s), 4.75 (2H, s), 4.61 (2H, d), 3.56-3.40 (4H, m), 3.33 (4H, d), 3.24 (3H, d), 3.19-3.09 (2H, m), 3.09-2.95 (2H, m), 2.85-2.56 (4H, m), 2.42 (3H, s), 1.38-0.76 (18H, m); m/z 608 (MH).

Reference： [1]Patent: WO2009/125230,2009,A1 .Location in patent: Page/Page column 119-120

10
[ 912999-49-6 ]
[ 3282-30-2 ]
2,2-dimethyl-propionic acid 5-(2,2-dimethyl-propionyloxy)-2-isopropyl-4-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindole-2-carbonyl]-phenyl ester dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 24 2,2-Dimethyl-propionic acid 5-(2,2-dimethyl-propionyloxy)-2-isopropyl-4-[5-(4-methyl- piperazin-1-ylmethyl)-1 ,3-dihydro-isoindole-2-carbonyl1-phenyl ester dihydrochlorideTo a solution of (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1 ,3- dihydro-isoindol-2-yl]-methanone (0.546 g, 1.33 mmol) in THF (10 mL) was added Et3N (0.464 mL), pivaloyl chloride (0.492 mL, 3.99 mmol) and N,N-4-dimethylaminopyridine (15 mg, 0.123 mmol). The solution was stirred at RT for 5 h then the solvent was removed by evaporation. The residue was partitioned between EtOAc and saturated NaHCC>3 and the organic phase was washed with saturated brine and dried (Na2SO4). The solvent was evaporated to give an oil which was dissolved in diethyl ether and EtOAc and to this solution was added 4M HCI in dioxan (0.67 mL, 2.68 mmol). The suspension was evaporated and dried under vacuum to give the title compound as a foam (0.835 g). 1 H NMR (400 MHz, DMSO-d6): 7.64-7.42 (3H, m), 7.39 (1 H, d), 7.06 (1 H, s), 4.78 (2H, s), 4.61 (2H, s), 3.44 (10H, s), 3.07-2.95 (1 H, m), 2.79 (3H, s), 1.35 (9H, s), 1.20 (6H, d), 1.18-1.15 (9H, m); m/z 578 (MH).

Reference： [1]Patent: WO2009/125230,2009,A1 .Location in patent: Page/Page column 127-128

11
[ 912999-49-6 ]
[ 24424-99-5 ]
[ 1191108-43-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In tetrahydrofuran; at 60℃; for 3h;	EXAMPLE 23Carbonic acid 5-tert-butoxycarbonyloxy-4-isopropyl-2-[5-(4-methyl-piperazin-1 -ylmethyl)- 1 ,3-dihvdro-isoindole-2-carbonyll-phenyl ester tert-butyl esterTo a solution of (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1 ,3- dihydro-isoindol-2-yl]-methanone (1 g, 2.44 mmol) in THF (25 ml.) was added di-t-butyl- dicarbonate (1.17 g, 5.5 mmol) and N,N-4-dimethylaminopyridine (45 mg, 0.37 mmol).The solution was heated to 60 0C for 3 h then cooled to RT and evaporated to dryness.The residue was purified on silica gel eluting with DCM followed by 0.2% aqueous ammonia in 5% MeOH in DCM. The fractions containing product were evaporated to a foam to give the title compound (1.52 g). 1 H NMR (400 MHz, DMSO-d6): 7.58 (1 H, d),7.38-7.28 (1 H, m), 7.28-7.15 (3H, m), 4.77 (2H, s), 4.61 (2H, d), 3.44 (2H, d), 3.09-2.96(1 H, m), 2.47-2.17 (8H, m), 2.15 (3H, d), 1.52 (9H, s), 1.34 (9H, s), 1.21 (6H, dd); m/z 610(MH)

Reference： [1]Patent: WO2009/125230,2009,A1 .Location in patent: Page/Page column 127

12
[ 912999-49-6 ]
acetic acid 5-acetoxy-4-isopropyl-2-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindole-2-carbonyl]-phenyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; acetic anhydride; at 120℃; for 0.333333h;	A mixture of (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone (100 mg) and acetic anhydride (350 mul) in pyridine (1 ml) was heated at 120 C. for 20 minutes in a CEM discover microwave synthesiser then evaporated and re-evaporated with toluene (×3). The crude material was purified by flash column chromatography (Biotage SP4), eluting with DCM then DMAW240 then DMAW120. Product containing fractions were evaporated then partitioned between DCM and saturated NaHCO3 solution, the DCM layer was separated, dried (MgSO4) filtered and evaporated to give the title compound.

Reference： [1]Patent: US2010/152184,2010,A1 .Location in patent: Page/Page column 125

13
[ 912999-49-6 ]
Sulphuric acid mono-{5-hydroxy-4-isopropyl-2-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindole-2-carbonyl]-phenyl} ester [ No CAS ]
Sulphuric acid mono-{5-hydroxy-2-isopropyl-4-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindole-2-carbonyl]-phenyl} ester [ No CAS ]
sulphuric acid mono-{4-isopropyl-2-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindole-2-carbonyl]-5-sulphoxy-phenyl} ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With chlorosulfonic acid; In N,N-dimethyl-aniline; for 2h;	A solution of (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone (104 mg; 0.25 mmol) in N,N-dimethylaniline (2 ml) was cooled in an ice bath then treated dropwise with chlorosulphonic acid (0.1 ml; 1.5 mmol) and stirred for 2 hours. The reaction mixture was basified with 50% KOH (0.3 ml) then partitioned between water and Et2O. The aqueous layer was separated washed with Et2O, then pH adjusted to 10 with the addition of 1M HCl. The resulting solution was evaporated to dryness. Purification by preparative LC/MS gave the three title compounds with the data shown below.Compound A. LC/MS: Rt=2.13; [M+H]+ 490.Compound B. LC/MS: Rt=2.24; [M+H]+ 490 (compound appears to rearrange to give compound A or decompose).Compound C. LC/MS: Rt=1.96; [M+H]+ 570 (disulphate).

Reference： [1]Patent: US2010/152184,2010,A1 .Location in patent: Page/Page column 126; 127

14
[ 127168-84-7 ]
[ 912999-49-6 ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 11296 - 11301

15
[ 6941-75-9 ]
[ 912999-49-6 ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 11296 - 11301

16
[ 201940-08-1 ]
[ 912999-49-6 ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 11296 - 11301

17
[ 1015484-22-6 ]
[ 912999-49-6 ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 11296 - 11301

18
[ 109-01-3 ]
[ 912999-49-6 ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 11296 - 11301

19
5-((4-methylpiperazin-1-yl)methyl)iso-indoline trihydrochloride [ No CAS ]
[ 1415742-78-7 ]
[ 912999-49-6 ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 11296 - 11301

20
[ 912999-49-6 ]
C₂₄H₂₉F₂N₃O₇S₂ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 2919 - 2925

21
[ 912999-49-6 ]
[ 88-10-8 ]
[ 1191108-34-5 ]
[ 1191108-35-6 ]

Reference： [1]Patent: WO2009/125230,2009,A1

22
[ 912999-49-6 ]
4-nitrophenyl 3-methyl-4-oxo-3,4-dihydroimidazo [5,1-d][1,2,3,5] tetrazine-8-carboxylate [ No CAS ]
C₃₀H₃₄N₈O₅ [ No CAS ]
C₃₀H₃₄N₈O₅ [ No CAS ]

Reference： [1]Patent: WO2019/14600,2019,A1 .Location in patent: Page/Page column 63; 66; 77

23
[ 912999-93-0 ]
[ 912999-49-6 ]

Reference： [1]Patent: WO2019/14600,2019,A1

24
[ 912545-09-6 ]
[ 912999-49-6 ]

Reference： [1]Patent: WO2019/14600,2019,A1
[2]Synthetic Communications,2019,vol. 49,p. 1436 - 1443

25
[ 912545-15-4 ]
[ 912999-49-6 ]

Reference： [1]Synthetic Communications,2019,vol. 49,p. 1436 - 1443

26
[ 89-86-1 ]
[ 912999-49-6 ]

Reference： [1]Synthetic Communications,2019,vol. 49,p. 1436 - 1443

27
[ 121903-70-6 ]
[ 912999-49-6 ]

Reference： [1]Synthetic Communications,2019,vol. 49,p. 1436 - 1443

28
[ 912545-14-3 ]
[ 912999-49-6 ]

Reference： [1]Synthetic Communications,2019,vol. 49,p. 1436 - 1443

29
[ 2021-84-3 ]
[ 912999-49-6 ]
(2-hydroxy-5-isopropyl-4-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone [ No CAS ]
(4-hydroxy-5-isopropyl-2-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34 mg; 22 mg	With calcium hydroxide; In dimethyl sulfoxide; at 20℃; for 8h;	To a solution of <strong>[912999-49-6]AT13387</strong> (36) (90 mg, 0.22 mmol) and a-D-galactopyranosyl fluoride (1.2 g, 6.6 mmol) in water (7 mL) and DMSO (7 mL) was added Ca(OH)2(488 mg, 6.6 mmol) and the resulting mixture was stirred at room temperature for 8h. LC/MS indicated significant conversion to the desired compounds (46) and (47). The reaction mixture was quenched by the addition of aqueous 1M HC1 to adjust to pH 8 and the resulting mixture was concentrated in vacuo to remove water. A DMSO solution of the residue was directly purified by reversed phase HPLC and two regioisomeric products were isolated. The regiochemical identity of the products was inferred by correlation the retention time on reversed phase LC/MS with the calculated LogP values (the isomer calculated to be less lipophilic being assigned to the earlier eluting peak on HPLC). The earlier eluting peak yielded 34 mg of (2-hydroxy-5-isopropyl-4- (((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)oxy)phenyl)(5-((4-methylpiperazin-l-yl)methyl)isoindolin-2-yl)methanone (46) as a white solid (cLogP = 1.8). LC/MS: R T= 1.13 min; m/z = 572.5 [M+H]+. NMR (500 MHz, Methanol-^): d 7.41 - 7.35 (br s, 2H), 7.33 (s, 1H), 7.30 (s, 2H), 5.01 - 4.90 (m, 6H), 4.10 - 4.00 (m, 2H), 3.83 - 3.63 (m, 9H), 3.29 (m, 4H), 2.88 (s, 3H), 1.25 (d, J= 6.9 Hz, 3H) 1.24 (d, J= 6.9 Hz, 3H). The later eluting peak yielded 22 mg of (4-hydroxy-5-isopropyl-2- (((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)oxy)phenyl)(5-((4-methylpiperazin-l-yl)methyl)isoindolin-2-yl)methanone (47) as a white solid (cLogP = 2.0). LC/MS: RT = 1.20 min; m/z = 572.5 [M+H]+. NMR (500 MHz, Methanol-i): d 7.42 - 7.35 (m, 1H), 7.35 - 7.27 (m, 1H), 7.25 - 7.18 (m, 1H), 7.12 (d, J = 1.7 Hz, 1H), 6.78 (s, 1H), 4.98 - 4.78 (m, 6H), 4.71 (m, 1H), 3.92 - 3.86 (m, 1H), 3.85 - 3.62 (m, 6H), 3.55 (m, 1H), 3.30 - 3.22 (m, 7H), 2.88 (d, J= 8.8 Hz, 3H), 1.24 (d, J= 6.8 Hz,3H), 1.22 (d, J= 6.8 Hz, 3H).

Reference： [1]Patent: WO2020/14409,2020,A1 .Location in patent: Paragraph 0345; 0349-0351

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A1492840[ 1019889-35-0 ]

(2,4-Dihydroxy-5-isopropylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (S)-2-hydroxypropanoate

Reason: Free-Salt

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