[ CAS No. 24666-56-6 ] {[proInfo.proName]}

Name: 24666-56-6|3-Aminopiperidine-2,6-dione hydrochloride|97%
Brand: Ambeed
SKU: A476158
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Quality Control of [ 24666-56-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 24666-56-6 ]

Product Details of [ 24666-56-6 ]

CAS No. :	24666-56-6	MDL No. :	MFCD11042437
Formula :	C₅H₉ClN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YCPULGHBTPQLRH-UHFFFAOYSA-N
M.W :	164.59	Pubchem ID :	134548
Synonyms :

Calculated chemistry of [ 24666-56-6 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.6
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	40.82
TPSA :	72.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.79 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	-0.69
Log Po/w (WLOGP) :	-0.83
Log Po/w (MLOGP) :	-0.55
Log Po/w (SILICOS-IT) :	-0.19
Consensus Log Po/w :	-0.45

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.43
Solubility :	61.8 mg/ml ; 0.375 mol/l
Class :	Very soluble
Log S (Ali) :	-0.35
Solubility :	73.3 mg/ml ; 0.445 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.47
Solubility :	55.9 mg/ml ; 0.34 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.71

Safety of [ 24666-56-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 24666-56-6 ]

* 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 [ 24666-56-6 ]
Downstream synthetic route of [ 24666-56-6 ]

[ 24666-56-6 ] Synthesis Path-Upstream 1~17

1
[ 24666-56-6 ]
[ 88-99-3 ]
[ 50-35-1 ]

Yield	Reaction Conditions	Operation in experiment
11.6 g	With 1,1'-carbonyldiimidazole In acetonitrile at 20 - 30℃; Inert atmosphere	Example 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-isoindole-1 -dione(Thalidomide) 1,1-carbonyldiimidazole (21.5 g or 0.13 mole) was added to a stirred mixture of phthalic acid (10.0 g. or 0.06 mole) in acetonitrile (100 ml) maintained under nitrogen at ambient temperature. To this mixture, 3-aminopiperidine 2,6-dione hydrochloride (9.9 g or 0.06 mole) was added, and the reaction mixture was stirred at 25 to 30 °C until the reaction was completed as monitored by TLC. After completion of the reaction, the solvent was distilled out under reduced pressure. Water (100 ml) was added to the reaction mass and the reaction mass was slowly cooled at 0 to 5 °C while stirring. The isolated solid was filtered, washed with water, then by methanol, and suck dried. Finally the isolated sold was dried at 55 to 60 °C under vacuum until constant weight to get thalidomide. Yield: 1 1.6 g, 75.2percent (molar). Purity by HPLC 99.13percent

Reference： [1] Patent: WO2015/75694, 2015, A1, . Location in patent: Page/Page column 8; 9

2
[ 85-44-9 ]
[ 24666-56-6 ]
[ 50-35-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	for 3 h; Reflux	To a stined solution of 150 g (0.91 mol) of 3-amino-piperidine-2, 6-dione hydrochloride in 1500 ml of acetic acid was added 135.0 g (0.91 mol) of phthalic anhydride and 202.6 g (2 mol) of triethyl amine. Reaction mixture was heated to reflux and further stined at reflux for 3 hours. The progress and completion of reaction was monitored by HPLC till 3-amino-piperidine-2, 6-dione hydrochloride absent. Reaction mass was cooled to 25-30°C and further stirred for 1 hour at 25- 30°C. Solid was filtered and washed the wet cake with 750 ml of water. Wet compound was sluned in 2250 ml of water and suspension mass was further stined for 1 hour. Solid was filtered and washed the wet cake with 750 ml of water. Dried under vacuum at 5 5-60°C under vacuum to give 223.5 g (95percent yield) of crude thalidomide with a purity 99.9percent by HPLC.

Reference： [1] Patent: WO2017/81701, 2017, A1, . Location in patent: Page/Page column 7;8;9;10

3
[ 24424-99-5 ]
[ 24666-56-6 ]
[ 31140-42-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: With triethylamine In dichloromethane at 50℃; for 0.5 h; Sealed tube; Microwave irradiation Stage #2: at 0℃; for 0.5 h;	A mixture of 3-aminopiperidine-2,6- dione hydrochloride (500 mg, 3.04 mmol) and triethylamine (931 µL, 6.68 mmol) in DCM (3 mL) was heated in a sealed 20 mL microwave vial at 50 °C for 30 min. The mixture was cooled to 0 °C and di-tert-butyl dicarbonate (663 mg, 3.04 mmol) in DCM (1 mL) was added via syringe, and stirring at 0 °C was continued for a further 30 min. The mixture was concentrated under vacuum and ethyl acetate (200 mL) added. The resulting mixture was washed with NaHCO₃ (100 mL, sat. aq.), brine (50 mL), dried (Na₂SO₄) and concentrated under vacuum. Trituration of the residue with ethyl acetate/hexanes gave pure product (601 mg, 87percent) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.12 (d, J = 8.7 Hz, 1H), 4.20 (ddd, J = 11.5, 8.7, 6.2 Hz, 1H), 2.69 (ddd, J = 17.2, 12.3, 6.5 Hz, 1H), 2.49–2.40 (m, 1H, overlapped with the residual DMSO signal), 1.99–1.81 (m, 2H), 1.38 (s, 9H).

Reference： [1] Patent: WO2017/161119, 2017, A1, . Location in patent: Page/Page column 136

4
[ 641-70-3 ]
[ 24666-56-6 ]
[ 19171-18-7 ]

Yield	Reaction Conditions	Operation in experiment
89.7%	at 25 - 118℃; for 18 h;	A round bottom flask was charged with a solution of glacial acetic acid (75 ml) and α-amino glutarimide hydrochloride (8.5 g). Sodium acetate anhydrous (4.5 g) was added lot-wise to the solution at 25° C. to 30° C. followed by addition of 3-nitro phthalic anhydride (log) at the same temperature. The reaction mixture was stirred at 118° C. for 18 hr. After the completion of reaction, the reaction mass was cooled to 60° C. and the solvent was distilled off under vacuum to get the residue. To the residue obtained, water (100 ml) was added; the mixture was stirred for 1 hr at 25° C. to 30° C. and the mass filtered. The wet cake obtained was slurried with water (100 ml*2), filtered and dried in an air tray dryer until the water content was less than 0.5percent to afford 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (14 g). Yield: 89.7percent, Purity: 98percent.
88.3%	With sodium acetate; acetic acid In water at 116 - 118℃; for 17 h;	In the 2L reaction bottle into the water 60ml, 3-nitrophthalic anhydride 65 g (336.6 mmol), 3-aminopiperidine-2,6-dione hydrochloride 53.5 g (325.0 mmol) Sodium acetate 27 g (329.3 mmol) and acetic acid (1200 ml) The reaction was stirred at 116-118 ° C for 17 h, Cooled to room temperature, filtered, Filter cake water washing, Solid at 50-60 decompression (vacuum ≥ 0.08MPa) dry 5h, That is the target product 87g, silver-gray solid, The yield was 88.3percent and the purity was 99.88percent.

Reference： [1] Patent: US2017/260157, 2017, A1, . Location in patent: Page/Page column 5
[2] Patent: CN104926786, 2017, B, . Location in patent: Paragraph 0044; 0045
[3] Synthetic Communications, 2016, vol. 46, # 16, p. 1343 - 1348
[4] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630
[5] Patent: CN104402863, 2016, B, . Location in patent: Paragraph 0035

5
[ 603-11-2 ]
[ 24666-56-6 ]
[ 19171-18-7 ]

Yield	Reaction Conditions	Operation in experiment
86.2%	With sodium acetate; acetic acid In water at 116 - 118℃; for 16 h;	40 ml of water, 70 g (331.6 mmol) of 3-nitrophthalic acid, 3-aminopiperidine-2,6-dione hydrochloride 53.5 g (325.0 mmol) Sodium acetate 27 g (329.3 mmol) and acetic acid (1200 ml) The reaction was stirred at 116-118 ° C for 16 h, Cooled to room temperature, Filter, filter cake water washing, Solid at 50-55 decompression (vacuum ≥ 0.08MPa) dry 4h, That is the target product 85g, For silver-gray solid, The yield was 86.2percent and the purity was 99.91percent.
28.2 g	With 1,1'-carbonyldiimidazole In acetonitrile at 20 - 80℃; Inert atmosphere	Example 1: Synthesis of l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-nitro-isoindoline- dione (3-nitrophthalidomide) To the stirred mixture of 3-nitrophthalic acid (25.0 g or 0.12 mole) in acetonitrile (175 ml) was added 1 , 1 -carbonyldiimi dazole (CD1) (42,3 g or 0.26 mole) under nitrogen atmosphere at ambient temperature. To this mixture, 3-aminopiperidine 2,6-dione hydrochloride (19.5g or 0.12 mole) was added, and the reaction mixture was heated to 75 to 80 °C until the reaction was completed as monitored by TLC. After completion of the reaction, the solvent was distilled out under reduced pressure. Water (375 ml) was added to the reaction mass, and the reaction mass was slowly cooled at 0 to 5 °C while stirring. The isolated solid was filtered, washed with water, then by methanol, and suck dried. Finally the isolated solid was dried at 55 to 60 °C under vacuum until constant weight to obtain 3-nitrophthalidomide. Yield: 28.2 g, 78.5percent (molar) (HPLC purity -99.5percent)

Reference： [1] Patent: CN104926786, 2017, B, . Location in patent: Paragraph 0039; 0040
[2] Patent: WO2015/75694, 2015, A1, . Location in patent: Page/Page column 2; 4; 8

6
[ 603-62-3 ]
[ 24666-56-6 ]
[ 19171-18-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With 1,1'-carbonyldiimidazole In acetonitrile at 80 - 82℃;	4-Nitro-lH-isoindole-l, 3(2H)-dione (117.3 g; Formula IV) followed by 1,1- carbonyldiimidazole (138.1 g) were added to a slurry of 3-aminopiperidine-2,6-dione hydrochloride (100 g, Formula III; obtained in Example 1) in acetonitrile (800 mL) to obtain a reaction mixture. The reaction mixture was heated to reflux at 80°C to 82°C and then stirred for 2 hours. 1,1-Carbonyldiimidazole (19.8 g) was further added to the reaction mixture twice over an interval of one hour. The reaction mixture was cooled to 25 °C to 30°C and then stirred for 30 minutes. The product obtained was filtered and the wet solid obtained was dried at 50°C to 55°C under reduced pressure to obtain the title compound. (0076) Yield: 162 g (88percent)

Reference： [1] Patent: WO2018/154516, 2018, A1, . Location in patent: Page/Page column 8

7
[ 24666-55-5 ]
[ 24666-56-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; hydrogen In methanol; water for 4 h;	A solution of 15 (4.0Og, 0.015 mol) in methanol (200 ml) and 2N HCl (15 ml) was hydrogenated over 5percent Pd-C (100 mg) at 60 psi for 4 h. The catalyst was filtered off and the filtrate concentrated to dryness to give the title compound 16 as a white solid (2.61 g, 100percent), mp 245 ⁰C (dec) (lit. 235 ⁰C (dec)). ¹H NMR (400 MHz, DMSO-D6) δ ppm 11.22 (br s_? IH), 8.68 (br s, 3H), 4.20 (dd, J=13.0, 5.3 Hz, IH), 2.77-2.65 (m, IH), 2.64- 2.56 (m, IH), 2.27-2.19 (m, IH)₅ 2.09-1.97 (m, IH).
92%	With hydrogenchloride In dimethyl sulfoxide	N-CBZ-L-glutamic acid 2.81 g (0.01 mol),Urea 1.2g (0.2mol) was added to DMSO to dissolve and reflux at 150 ° C. After 2 h, the temperature was lowered.HCl gas, a white solid 1.518 g, a yield of 92percent;
90%	Stage #1: With palladium 10% on activated carbon; hydrogen In methanol; water at 25 - 30℃; Stage #2: With hydrogenchloride In methanol; water at 25 - 30℃;	Benzyl (2,6-dioxopiperidin-3-yl)carbamate (100 g; obtained in Step b) was added to methanol (1000 mL) and the mixture was heated at 50°C to 55°C to obtain a clear solution. The solution was cooled to 25 °C to 30°C and then 10percent Palladium on carbon (10 g; 50percent wet) was added. The solution was hydrogenated with 3.0 kg/cm² to 3.5 kg/cm² hydrogen pressure at 25 °C to 30°C for 2 hours to 3 hours. The catalyst was removed by filtration. Concentrated hydrochloric acid (100 mL) was added to the filtrate and then stirred for 60 minutes to 90 minutes at 25°C to 30°C. The reaction mixture was concentrated at 40°C to 45 °C under reduced pressure. Methanol (100 mL) was added to the residue and then stirred for 60 minutes at 10°C to 15°C to obtain a slurry. The slurry was filtered and the wet solid obtained was dried at 50°C under reduced pressure to obtain the title compound. (0073) Yield: 56 g (90percent)

Reference： [1] Patent: WO2008/7979, 2008, A1, . Location in patent: Page/Page column 13
[2] Patent: CN108218833, 2018, A, . Location in patent: Paragraph 0043; 0044; 0057; 0058; 0063; 0071; 0072
[3] Patent: WO2018/154516, 2018, A1, . Location in patent: Page/Page column 7-8
[4] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630

8
[ 2650-64-8 ]
[ 24666-56-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630

9
[ 6398-06-7 ]
[ 24666-56-6 ]

Reference： [1] Patent: WO2011/50962, 2011, A1,

10
[ 50516-14-8 ]
[ 24666-56-6 ]

Reference： [1] Patent: WO2008/7979, 2008, A1,

11
[ 56-86-0 ]
[ 24666-56-6 ]

Reference： [1] Patent: CN108218833, 2018, A,

12
[ 1155-62-0 ]
[ 24666-56-6 ]

Reference： [1] Patent: CN108218833, 2018, A,

13
[ 24666-56-6 ]
[ 191732-76-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630

14
[ 24666-56-6 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium acetate; acetic acid In acetonitrile at 80 - 85℃; for 8 h;	Acetonitrile (100 mL),Acetic acid (25.41 mL, 444.2 mmol),Anhydrous sodium acetate (18.22 g, 222.1 mmol),Disodium 3-aminophthalate (10 g, 44.4 mmol),Aminopiperidine-2,6-dione hydrochloride (7.68 g, 46.6 mmol)Added to the reaction flask, heated to 80 ~ 85 ° C reflux,The reaction was complete after 8h, the reaction was cooled to 20 ~ 25 ° C, purified water was slowly added, stirred crystallization 2h, filtered, the filter cake was dried under reduced pressure 8 ± 5 ° C for 8h to give 10.2g of a yellow solid, yield 84.0percent Purity 99.4percent.

Reference： [1] Patent: CN107325075, 2017, A, . Location in patent: Paragraph 0019; 0020; 0021; 0022; 0023; 0024-0028

15
[ 24666-56-6 ]
[ 6946-22-1 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: for 0.25 h; Stage #2: With triethylamine In water; acetonitrile at 15 - 87℃; for 49.0833 - 50.8333 h;	Example 14; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; Example 14 was prepared similarly according to the procedure for Example 13 except that there was no acetic acid; the amount of triethylamine was reduced from 4.6 mol to 3.2 mol; and the refluxing time was increased from about 5 to 7 hours to about 47 hours. The amount of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reaction mixture was found to be 94percent.
92%	Stage #1: for 0.25 h; Stage #2: With 1H-imidazole In water; acetonitrile at 15 - 87℃; for 7.08333 - 10.8333 h;	Example 15; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; Example 15 was prepared similarly according to the procedure for Example 13 except that there was no acetic acid and the 4.6 mol of triethylamine was replaced with 9.2 mole of imidazole. The amount of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reaction mixture was found to be 92percent
85%	Stage #1: With acetic acid In acetonitrile for 0.25 h; Stage #2: With 1H-imidazole In water; acetonitrile at 15 - 87℃; for 7.08333 - 10.8333 h;	Example 16; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; Example 16 was prepared similarly according to the procedure for Example 13 except that the 4.6 mol of triethylamine was replaced with 9.2 mole of imidazole. The amount of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reaction mixture was found to be 85percent.

84%	Stage #1: With acetic acid In acetonitrile for 0.25 h; Stage #2: With triethylamine In water; acetonitrile at 15 - 87℃; for 7.08333 - 10.8333 h;	Example 13; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; According to Scheme E A mixture of 3-aminophthalic acid hydrochloride (200 g, 0.92 mol, from Prosynth Ltd., Suffolk, UK), 3-aminoglutarimide hydrochloride (159 g, 0.96 mol, from Evotec OAI, Hamburg, Germany), acetonitrile (2.0 L), and acetic acid (577 g, 9.6 mol, from Fisher Scientifc) was charged into a reaction vessel. After the mixture was stirred for 15 minutes, triethylamine (465.0 g, 4.6 mol, from Aldrich, Milwaukee, Wis.) was added dropwise over 30-35 minutes while the reaction temperature was maintained at 20-25° C. Next, the reaction mixture was stirred further for 10-15 minutes and then refluxed at about 85 to 87° C. for about 5 to 7 hours or until the in-process control, i.e., HPLC AP at 240 nm, indicates that <2percent of the 3-aminophthalic acid remained in the reaction mixture. After the reaction mixture was cooled to about 20 to 25° C. over 1-2 hours, 1.0 L of water was charged over 15-30 minutes at about 20 to 25° C. The resulting mixture was stirred at about 15 to 20° C. for about 20 to 30 minutes to provide a yellow solid precipitate, which was filtered, washed with DI water (3.x.1.0 L) and acetonitrile (2.x.500 mL), and then dried at about 35 to 40° C in vacuo to a constant weight at 210.0 g (84 percent).
68.5%	With acetic acid; triethylamine In acetone at 80 - 85℃; for 6 h;	Acetonitrile (100 mL), acetic acid (26.28 mL, 459.5 mmol),Triethylamine (31.85 mL, 229.8 mmol), 3-aminophthalic acid hydrochloride (10 g, 46.0 mmol),Aminopiperidine-2,6-dione hydrochloride (7.68 g, 46.6 mmol)Added to the reaction flask, heated to 80 ~ 85 ° C reflux, the reaction was complete after 6h,The reaction solution was cooled to 20 ~ 25 ° C, purified water was slowly added, the crystallization was stirred for 2h, filtered, the filter cake was dried under reduced pressure at 60 ± 5 ° C for 8h to obtain 8.6g black solid, yield 68.5percent

Reference： [1] Patent: US2007/4920, 2007, A1, . Location in patent: Page/Page column 13
[2] Patent: US2007/4920, 2007, A1, . Location in patent: Page/Page column 13-14
[3] Patent: US2007/4920, 2007, A1, . Location in patent: Page/Page column 14
[4] Patent: US2007/4920, 2007, A1, . Location in patent: Page/Page column 13
[5] Patent: CN107325075, 2017, A, . Location in patent: Paragraph 0029; 0030; 0031

16
[ 24666-56-6 ]
[ 19171-19-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630
[2] Patent: CN103724323, 2016, B,
[3] Patent: CN103724323, 2016, B,
[4] Patent: CN103724323, 2016, B,
[5] Patent: CN103724323, 2016, B,

17
[ 24666-56-6 ]
[ 1015474-32-4 ]

Reference： [1] Patent: WO2017/197056, 2017, A1,

[ 24666-56-6 ] Synthesis Path-Downstream 1~76

1
[ 5466-84-2 ]
[ 24666-56-6 ]
[ 55003-81-1 ]

Yield	Reaction Conditions	Operation in experiment
1.4 g (54%)	With sodium acetate; In dichloromethane; water; acetic acid;	EXAMPLE 2 A mixture of <strong>[5466-84-2]4-nitrophthalic anhydride</strong> (1.7 g, 8.5 mmol), alpha-aminoglutarimide hydrochloride (1.4 g, 8.5 mmol) and sodium acetate (0.7 g, 8.6 mmol) in glacial acetic acid (30 mL) was heated under reflux for 17 hours. The mixture was concentrated in vacuo and the residue was stirred with methylene chloride (40 mL) and water (30 mL). The aqueous layer was separated, extracted with methylene chloride (2*40 mL). The combined methylene chloride solutions were dried over magnesium sulfate and concentrated in vacuo to give 1.4 g (54%) of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline as a light brown solid. An analytical sample was obtained by recrystallization from methanol: mp 228.5-229.5 C.; 1 H NMR (DMSO-d6) delta 11.18(s, 1 H), 8.69-8.65(d,d J=1.9 and 8.0 Hz, 1H), 8.56(d, J=1.9 Hz, 1H), 8.21(d, H=8.2 Hz, 1H), 5.28(d,d J=5.3 and 12.8 Hz, 1H), 2.93-2.07(m, 4H); 13 C NMR (DMSO-d6) delta 172.66, 169.47, 165.50, 165.23, 151.69, 135.70, 132.50, 130.05, 124.97, 118.34, 49.46, 30.85, 21.79; Anal. Calcd for C13 H9 N3 O6: C, 51.49; H, 2.99; N, 13.86. Found: C, 51.59; H, 3.07; N, 13.73.

Reference： [1]Patent: US6335/349,2002,B1 .Location in patent: Example 2
[2]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630
[3]Patent: US5635517,1997,A

2
[ 641-70-3 ]
[ 24666-56-6 ]
[ 19171-18-7 ]

Yield	Reaction Conditions	Operation in experiment
89.7%	With sodium acetate; acetic acid; at 25 - 118℃; for 18h;	A round bottom flask was charged with a solution of glacial acetic acid (75 ml) and alpha-amino glutarimide hydrochloride (8.5 g). Sodium acetate anhydrous (4.5 g) was added lot-wise to the solution at 25 C. to 30 C. followed by addition of 3-nitro phthalic anhydride (log) at the same temperature. The reaction mixture was stirred at 118 C. for 18 hr. After the completion of reaction, the reaction mass was cooled to 60 C. and the solvent was distilled off under vacuum to get the residue. To the residue obtained, water (100 ml) was added; the mixture was stirred for 1 hr at 25 C. to 30 C. and the mass filtered. The wet cake obtained was slurried with water (100 ml*2), filtered and dried in an air tray dryer until the water content was less than 0.5% to afford 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (14 g). Yield: 89.7%, Purity: 98%.
89%	With formic acid; ammonium formate; at 80℃; for 0.166667h;	(1) Dispose formic acid solution of 3-nitrophthalic anhydride in the first raw material storage tank, the ratio of phthalic anhydride and formic acid is 100g: 250mL;(2) Configure the formic acid solution of 3-amino-2,6-piperidinedione and ammonium formate in the second raw material storage tank, and the ratio of 3-amino-2,6-piperidinedione, ammonium formate and formic acid 100g: 40g: 250mL. The solution in the storage tank waits to be pumped into the microstructure mixer and enters the microstructure reactor for reaction;(3) Combine the first raw material storage tank (3-nitrophthalic anhydride and formic acid solution) and the second raw material storage tank (3-amino-2,6-piperidinedione and ammonium formate formic acid solution) according to The volume flow ratio is 1: 1 pumped into the micro-structured mixer I, and then flowed into the micro-structured reactor I, the first reactor is 1/4 stainless steel pipe, the tube length is 6 meters, the total volume of 100mL at a certain temperature, reserved For a period of time, the reaction liquid from the microstructure reactor I was taken, and the yield was calculated by HPLC detection. See Table 1 for specific examples and temperature and time.
88.3%	With sodium acetate; acetic acid; In water; at 116 - 118℃; for 17h;	In the 2L reaction bottle into the water 60ml, 3-nitrophthalic anhydride 65 g (336.6 mmol), 3-aminopiperidine-2,6-dione hydrochloride 53.5 g (325.0 mmol) Sodium acetate 27 g (329.3 mmol) and acetic acid (1200 ml) The reaction was stirred at 116-118 C for 17 h, Cooled to room temperature, filtered, Filter cake water washing, Solid at 50-60 decompression (vacuum ? 0.08MPa) dry 5h, That is the target product 87g, silver-gray solid, The yield was 88.3% and the purity was 99.88%.

70.6%	With acetic acid; at 130℃; for 16h;Inert atmosphere;	A mixture of 4-nitroisobenzofuran-1,3-dione (70.4 g, 365 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (50.0 g, 304 mmol) in acetic acid (1 L) was stirred at 130 C. for 16 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and the residual solid was washed with ethyl acetate (500 mL) and dried in vacuum to afford 2-(2,6-dioxo-3-piperidyl)-4-nitro-isoindoline-1,3-dione as a gray solid (130 g, 70.6% yield). 1H NMR (400 MHz DMSO-d6) delta ppm 11.15 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.21 (d, J=7.6 Hz, 1H), 8.09 (t, J=7.6 Hz, 1H), 5.20-5.15 (m, 1H), 2.89-2.81 (m, 1H), 2.60-2.47 (m, 2H), 2.04 (t, J=5.6 Hz, 1H).
	With sodium acetate; acetic acid; at 120℃; for 8h;	165 g of 3-aminopiperidine-2,6-dione hydrochloride was added,90 g of sodium acetate,2500ml acetic acid,120 heating reflux 8h after cooling to 75 ± 2 .
	With potassium acetate; acetic acid; at 120℃;	4-Nitroisobenzofuran-l,3-dione (2.0 g, 10 mmol, 1.0 eq.) was added to a mixture of 3- aminopiperidine-2,6-dione.HCl (1.9 g, 11 mmol, 1.1 eq.) and potassium acetate (2.9 g, 30 mmol, 3.0 eq.) in acetic acid (30 mL) and the mixture was stirred at 120 C overnight. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The amorphous solid that formed was stirred in H2O (ca. 30 mL) for 1 hour, to give a brown solid which was filtered and dried under high vacuum at 60 C for 1 hour. The solid was used without further purification (2.4 g, 73%). NMR (500 MHz, DMSO-rfc) d 11.18 (s, 1H), 8.36 (dd, 7 = 8.1, 0.9 Hz, 1H), 8.25 (dd, 7 = 7.6, 0.9 Hz, 1H), 8.13 (t, 7 = 7.8 Hz, 1H), 5.21 (dd, 7 = 13.0, 5.4 Hz, 1H), 2.85-2.80 (m, 1H), 2.67-2.58 (m, 1H), 2.58-2.51 (m, 1H), 2.13-2.06 (m, 1H); HPLC- MS (ESI+): m/z 304.2 [100%, (M+H)+] (See US 9365640.)

Reference： [1]Patent: US2017/260157,2017,A1 .Location in patent: Page/Page column 5
[2]Patent: CN110790746,2020,A .Location in patent: Paragraph 0055-0063
[3]Patent: CN104926786,2017,B .Location in patent: Paragraph 0044; 0045
[4]Synthetic Communications,2016,vol. 46,p. 1343 - 1348
[5]Patent: US2019/322647,2019,A1 .Location in patent: Paragraph 0188; 0189
[6]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630
[7]Patent: CN104402863,2016,B .Location in patent: Paragraph 0035
[8]Patent: WO2020/14489,2020,A2 .Location in patent: Page/Page column 123

3
[ 61940-22-5 ]
[ 24666-56-6 ]
[ 1063995-54-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630

4
[ 90725-68-1 ]
[ 24666-56-6 ]
[ 1063995-49-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate; In acetonitrile; at 20℃; for 0.25h;	To a solution of <strong>[90725-68-1]methyl 2-(bromomethyl)-5-nitrobenzoate</strong> (24-1) (5 g, 18.2 mmol) in ACN (50 mL ) , 3-aminopiperidine-2,6-dione hydrochloride (1-2) (2.99 g, 18.2 mmol) was added to the reaction mixture. The reaction mixture was stirred for 15 minutes at RT. Then DIEA (11.7 g, 91.0 mmol) was added. the reaction mixture was heated and stirred for 18 hours at 90C.RM was monitored by TLC. Dark violet solid was filtered through sintered and washed it with water (300ml) and DCM (100ml) and dried under high vaccum to get 3-(6-nitro-1-oxoisoindolin-2- yl)piperidine-2,6-dione (24-2) (4.00 g, 13.8 mmol, 76.0 %) as dark gray solid. LC/MS (ES+): m/z 290 [M + H]+
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃;	3-Aminopiperidine-2,6-dione.HCl (420 mg, 2.6 mmol, 1.4 eq.) was added to a solution of <strong>[90725-68-1]methyl 2-(bromomethyl)-5-nitrobenzoate</strong> EC2-053 (500 mg, 1.8 mmol, 1.0 eq.) in DMF (5 mL), DIPEA (0.8 mL, 4.6 mmol, 2.5 eq.) was then added and the suspension was stirred at 50 C for 2 hours. The mixture was cooled to room temperature, the solvent evaporated under reduced pressure. The residue was triturated with MeOH (50 mL), filtered and washed further with MeOH (50 mL) to give 3-(6-nitro-l-oxoisoindolin-2-yl)piperidine-2,6-dione (EC2-046) as a purple solid (340 mg, 65%) which was used to the next step without further purification. 1 H NMR (500 MHz, DMSO-ifc) d 11.04 (s, 1H), 8.51 (dd, 7 = 8.3, 2.2 Hz, 1H), 8.42 (d, 7 = 2.2 Hz, 1H), 7.93 (d, 7 = 8.4 Hz, 1H), 5.18 (dd, 7 = 13.3, 5.2 Hz, 1H), 4.66 (d, 7 = 18.6 Hz, 1H), 4.53 (d, 7 = 18.6 Hz, 1H), 2.99-2.87 (m, 1H), 2.67-2.59 (m, 1H), 2.48-2.36 (m, 1H), 2.10-2.03 (m, 1H); HPLC-MS (ESI+) and (ESI-): m/z 290.0 [100%, (M+H)+], 601.2 [100%, (2M+Na)+], 288.1 [100%, (M- H)+]. (See WO2017/197056.)

Reference： [1]Patent: WO2017/197056,2017,A1 .Location in patent: Page/Page column 371
[2]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630
[3]Patent: US6335/349,2002,B1 .Location in patent: Example 2
[4]Patent: WO2020/14489,2020,A2 .Location in patent: Page/Page column 139

5
[ 24666-56-6 ]
[ 133446-99-8 ]
3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With triethylamine; In N,N-dimethyl-formamide; at 75℃; for 12h;	To a solution of 3-aminopiperidine-2,6-dione (2.00 g, 12.2 mmol, HCl) and <strong>[133446-99-8]methyl 2-(bromomethyl)-4-nitro-benzoate</strong> (4.21 g, 15.4 mmol) in DMF (10.0 mL) was added TEA (3.07 g, 30.4 mmol). The reaction mixture was stirred at 75 C. for 12 hrs. On completion, the reaction mixture was diluted with water (200 mL), filtered. The filtered cake was collected. The reaction mixture was concentrated in vacuo. The residue was triturated EA:H2O=1:1 (50 mL) to give the title compound (1.7 g, 48% yield) as a blue solid. 1H NMR (400 MHz, DMSO-d6) delta 11.04 (s, 1H), 8.53 (d, J=1.2 Hz, 1H), 8.36 (dd, J=2.0, 8.4 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 5.17 (dd, J=5.2, 13.2 Hz, 1H), 4.69-4.45 (m, 1H), 3.01-2.86 (m, 1H), 2.68-2.59 (m, 1H), 2.48-2.35 (m, 1H), 2.13-2.02 (m, 1H).
1.50 g	With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 45℃; for 6h;	Preparation of <strong>[133446-99-8]methyl <strong>[133446-99-8]2-(bromomethyl)-4-nitrobenzoate</strong></strong> (23-1) (2.5 g, 9.12 mmol) and 3- aminopiperidine-2,6-dione (1-2) (1.74 g, 13.6 mmol) were added to DMF (12.5 ml) at 25C. Potassium carbonate (3.15 g, 22.8 mmol) was added to the reaction mixture at 25C and the temperature was raised to 42C. The reaction mixture was stirred for 6 hours at 42C and cooled to 20C to 25C. De-ionized water (12.5 ml) was added to the reaction mixture at 20C and stirred for 20 minutes. The solid obtained was filtered, washed with de-ionized water (2 x 25 ml) and dried under vacuum at 40C to 45C for 20 hours to obtain the title compound.Then the crude material was slurried with PE/EA(1/1) 20 mL to give 3-(5-nitro-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (23-2) (1.50 g, 5.18 mmol, ) as gray-green solid. LC/MS (ES+): m/z 290 [M + H]+

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 3416; 3418
[2]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630
[3]Patent: US6335/349,2002,B1 .Location in patent: Example 2
[4]Patent: WO2017/197056,2017,A1 .Location in patent: Page/Page column 370

6
[ 24666-56-6 ]
[ 98475-07-1 ]
[ 827026-45-9 ]

Yield	Reaction Conditions	Operation in experiment
99.73%		3-aminopiperidine-2,6-dione hydrochloride (III) (25 g, 0.15 mol) and dimethyl sulfoxide (150 mL) were charged into 500 mL 3N RBF. Triethylamine (62 g, 0.61 mol) was added slowly to the above reaction mixture under nitrogen over a period of 10 min. Methyl 2-(bromomethyl)-3-nitrobenzoate (II) (45.8 g, 0.16 mol) of example 3 dissolved in dimethyl sulfoxide (50 mL) was added to the reaction mixture under nitrogen over a period of 20 min and heated to 50-55 C. for 12 hrs. Progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mixture was cooled to room temperature and water (250 mL) was added and heated to 55 C. for 1 hr. Then cooled to room temperature and filtered to get 42 g of crude. Methanol (125 mL) was added to the crude and stirred at 50 C. for 30 min, cooled to room temperature and filtered. The solid bed was washed with methanol (2*5 mL) to obtain the product. Results: Quantity of the product obtained: 34 gYield: 77.00%Purity (by HPEC): 99.73% Nature: grey colored solid
98.5%	With sodium carbonate; at 100℃; for 0.75h;Inert atmosphere;	108.8 g of methyl 2- (bromomethyl) -3-nitrobenzoate, 66.3 g of 3-aminopiperidine-2,6-dione hydrochloride,A mixture of 596.3 g of sodium carbonate was stirred at 100 C for 45 minutes under a nitrogen atmosphere.After the reaction was completed, the mixture was cooled to room temperature, 400 mL of ethanol was added, and stirred for 5 minutes.The precipitate was then collected by filtration and dried to give the product.Off-white solid, 118.4 g, yield 98.5%.
92%	With sodium carbonate; In tetrahydrofuran;Reflux;	To 500 ml of tetrahydrofuran was added 99.9 g of methyl 2-bromomethyl-3-nitrobenzoate, 3-amino-2,6-piperidinedione hydrochloride (50.0 g) and sodium carbonate (96.6 g)Heating reflux reaction, HPLC detection of 3-amino-2,6-piperidinedione hydrochloride is less than or equal to 0.5% stop reaction, The reaction solution was cooled to room temperature, The reaction solution was poured into 2 L of purified water, stirred at room temperature for 1 hour, filtered and filteredThe cake was dispersed in a 1 L mixture of ethanol and 1 L of purified water, stirred at room temperature for 1 hour, filtered, the cake was dispersed in 1 L of ethanol, The mixture was stirred for 1 hour, filtered, and the filter cake was washed once with 200 ml of ethanol. The filter cake was dried at 50 C for 10 hours under reduced pressure to give a white solidBody 80.8 g, yield 92.0%.

91.7%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 45℃;Product distribution / selectivity;	Example 1 : Preparation of 3-(4-nitro-l-oxo-l,3-dihvdro-2H-isoindol-2-yl piperidine-2,6- dioneMethyl-2-bromomethyl-3-nitrobenzoate (25 g) and 3-aminopiperidine-2,6-dione hydrochloride (18 g) were added to N,N-dimethylformamide (125 ml) at 20C to 25C. Potassium carbonate (31.52 g) was added to the reaction mixture at 25C to 30C and the temperature was raised to 40C to 45C. The reaction mixture was stirred for 6 hours at 40C to 45C and cooled to 20C to 25C. De-ionized water (125 ml) was added to the reaction mixture at 20C to 25C and stirred for 15 minutes to 20 minutes. The solid obtained was filtered, washed with de-ionized water (2 x 25 ml) and dried under vacuum at 40C to 45C for 20 hours to obtain the title compound.Yield: 91.7%HPLC purity: 99.86%
89%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20 - 55℃; for 19h;Green chemistry;	In a 4 l reactor, equipped with areflux condenser and a mechanical stirrer, 3-aminopiperidine-1,6-dione hydrochloride (6) (150 g, 0.91 mol,1.0 equiv), methyl 2-(bromomethyl)-3-nitrobenzoate (4a)(300 g, 1.09 mol, 1.2 equiv), and K2CO3 (315 g, 2.28 mol,2.5 equiv) were placed. Then N-methylpyrrolidone (1.50 l)was added and the resulted suspension was stirred at250 rpm without heating for 30 min, while the reactiontemperature rose to 30-33C. Then the external heatingwas turned on and the reaction mixture was stirred at 35Cfor another 30 min. During this period more intensivestirring (350 rpm) was applied, because the reactionmixture became thick. The color of the mixture turned toblue-gray. Then the reaction mixture was heated to 55Cand stirred at this temperature at 350 rpm for another 18 h.The resulted yellowish-beige mixture was cooled to 5C,methyl tert-butyl ether (300 ml) and H2O (1.5 l) wereadded, and stirring was continued at 400 rpm for 30 min.The precipitate was filtered off, washed with H2O (4×250 ml),MeOH (2×150 ml), and dried in vacuo (15-20 mbar) at 60Cfor 6 h. Yield 211 g (89%), off-white solid, mp 273-275C(mp 274-276C)19. HPLC purity 99.8%. 1H NMR spectrum,delta, ppm (J, Hz): 1.97-2.07 (1H, m), 2.51-2.65 (2H, m) and2.84-2.98 (1H, m, 4,5-CH2); 4.80 (1H, d,J = 19.3) and 4.91 (1H, d, J = 19.3, 3-CH2 isoindole); 5.18(1H, dd, J = 13.1, J = 5.2, 3-CH); 7.84 (1H t, J = 7.8, H-6isoindole); 8.19 (1H, d, J = 7.5, H-7 isoindole); 8.47 (2H,dd, J = 8.2, J = 0.8, H-5 isoindole); 11.03 (1H, s, NH).13C NMR spectrum, delta, ppm: 22.2 (C-4); 31.2 (C-5); 48.5(C-3 isoindole); 51.8 (C-3); 127.1, 129.6, 130.1, 134.7,137.4 (C isoindole); 143.4 (C-4 isoindole); 165.9 (C=O);170.7 (C=O); 172.8 (C=O). Mass-spectrum, m/z (Irel, %):291 (16), 290 [M+H]+ (100).
88%	With triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 50 - 55℃; for 10h;Inert atmosphere;	Tiiethylamine (140.8 g, 2.29 mol) was added at 25-300C to a solution of 3-amino- piperidine-2,6-dione hydrochloride (100 g, 0.61 mol) in N,N-dimethylformamide (800 ml). A solution of methyl 2-bromomethyl-3-nitro-benzoate (186.0 g, 1.13 mol) in acetonitrile (200 ml) was then added under stirring and a nitrogen atmosphere and the reaction mixture was heated to 50-550C for 8-10 hours. After completion of the reaction approximately 60% solvent was removed by distillation at 50-600C under reduced pressure (100 mbar). Water (1000 ml) was added to the residual mixture at 50-550C and stirred for 1 hour at this temperature. The resultant solid product was cooled to 25-300C and filtered. The solid was washed with water (500 ml) at 50-550C, cooled at ambient temperature and filtered again. Finally the solid was washed with methanol (500 ml) at 50-550C, cooled at 25-300C and filtered. The filtered solid product was dried at 50-550C under low pressure (200 mmHg) for 4 hours to give 3-(l-oxo-4-nitro-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as a purple to ash coloured solid.Yield: 145-155 g (83-88%)HPLC purity: 99.8% (by area normalisation)
88%		Example 1Preparation of 3-(1-oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneTriethylamine (140.8 g, 2.29 mol) was added at 25-30 C. to a solution of 3-amino-piperidine-2,6-dione hydrochloride (100 g, 0.61 mol) in N,N-dimethylformamide (800 ml). A solution of methyl 2-bromomethyl-3-nitro-benzoate (186.0 g, 1.13 mol) in acetonitrile (200 ml) was then added under stirring and a nitrogen atmosphere and the reaction mixture was heated to 50-55 C. for 8-10 hours. After completion of the reaction approximately 60% solvent was removed by distillation at 50-60 C. under reduced pressure (100 mbar). Water (1000 ml) was added to the residual mixture at 50-55 C. and stirred for 1 hour at this temperature. The resultant solid product was cooled to 25-30 C. and filtered. The solid was washed with water (500 ml) at 50-55 C., cooled at ambient temperature and filtered again. Finally the solid was washed with methanol (500 ml) at 50-55 C., cooled at 25-30 C. and filtered. The filtered solid product was dried at 50-55 C. under low pressure (200 mmHg) for 4 hours to give 3-(1-oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as a purple to ash coloured solid.Yield: 145-155 g (83-88%)HPLC purity: 99.8% (by area normalisation)
87.8%	With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 50 - 60℃;Large scale;	Add 7.0L of N, N dimethylformamide to a 20L reactor,Add methyl 2-bromomethyl-3-nitrobenzoate (1.5 kg, 5.47 mol) and 3-amino-2,6-piperidinedione hydrochloride (1.0 kg, 6.07 mol) with stirring.Additional sodium bicarbonate (1.5 kg, 14.1 mol) was added.Heat to 50 C to 60 C and stir for 2 to 3 hours, then lower the temperature to 30 to 40 C.In another 30-L reaction kettle, 18 L of purified water was added, and the reaction solution was added in portions, cooled to 15 C-20 C, stirred, left to stand, and filtered.In a 30-L reaction kettle, 22 L of purified water was added, and the filter cake was stirred, stirred at 15 C to 25 C for 0.5 hours, filtered, and the filter cake was washed with 7.5 L of purified water and dried.Add 15L of ethyl acetate to a 20L reaction kettle, stir and add the filter cake,Stir for 0.5 hours at 15 25 , filter,Wash the filter cake with 2.5L of ethyl acetate and pump dry.Vacuum drying (45 C to 55 C, -0.01MPa to -0.1MPa) for 8 to 12 hours,1.39 kg of lenalidomide intermediate II was obtained as a white solid,The yield was 87.8%, and the HPLC purity was 99.84%.
82%	With triethylamine; In acetonitrile; for 3h;Reflux;	2.74 g (0.01 mol) of methyl 2-bromomethyl-3-nitrobenzoate,2-amino-2,6-piperidinone hydrochloride 2.46 g (0.015 mol) was dissolved in 10 ml of acetonitrile.Add 3.5 g of triethylamine,Reflux for 3h,After cooling, it was distilled under reduced pressure, and ice water was added to precipitate a yellow solid, which was filtered and washed with water twice.The product was dried to give 2.35g, 82% yield;
81.5%	With potassium carbonate; In acetone; at 20 - 60℃;Product distribution / selectivity;	Comparative Example 5: Preparation of 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dioneMethyl-2-bromomethyl-3-nitrobenzoate (8.38 g) and 3-aminopiperidine-2,6-dione hydrochloride (5 g) were added to acetone (50 ml) at 20C to 25C. Potassium carbonate (10.5 g) was added into the reaction mixture at 20C to 25C and the temperature was raised to 55C to 60C. The reaction was stirred for 32 hours at 55C to 60C. Acetone was recovered under vacuum at 55C to 60C and the residue was cooled to 20C to 25C. De-ionized water (100 ml) was added to the residue and stirred for 2 hours at 20C to 25C. The reaction mixture was filtered, and the solid obtained was washed with de- ionized water (2 x 10 ml) and dried under vacuum at 50C to 55C for 18 hours to obtain the title compound. Yield: 81.5%HPLC purity: 94.02%
79.5%	With triethylamine; In acetonitrile; at 20 - 55℃; for 54.6667h;Product distribution / selectivity;	Comparative Example 3: Preparation of 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dioneA mixture of 3-aminopiperidine-2,6-dione hydrochloride (50 g) and acetonitrile (650 ml) were stirred for 10 minutes at 20C to 25C. Methyl-2-bromomethyl-3- nitrobenzoate (83.28 g) was added to the reaction mixture and stirred for 30 minutes. The temperature of the reaction was raised to 55C. Triethylamine (15.37 g) was added slowly over 30 minutes at 50C to 55C and stirred for 2 hours. The above step of adding of triethylamine and stirring was repeated for three more times with same quantity, temperature and duration except that the final stirring is carried out for 40 hours at 50C to 55C. The reaction mixture was cooled to 20C to 25C. De-ionized water (250 ml) was added to the reaction mixture and stirred for 1 hour at 20C to 25C. The reaction mixture was filtered, and the solid obtained was washed with chilled de-ionized water (100 ml) and dried under vacuum at 45C to 50C to obtain the title compound.Yield: 79.5%HPLC purity: 92.28%
75%		D. 3-(4-nitro- l -oxo-l ,3-dihydro-isoindol-2-yl)piperidine-2,6-dione rac-a-Amino-glutarimide hydrochloride (41 .2 g, 0.25 mole), and methyl 2- bromomethyl-3-nitrobenzoate (69.0 g , 0.25 mole) were charged to the dry 3- necked RBF and dry acetonitrile (300 ml, 252. 1 g) was added. The homogeneous suspension was stirred at room temperature for about 15 min. In the meantime diisopropyl-ethyl-amine (DIPEA, 71 g, 94 ml) was diluted with dry acetonitrile (300 ml, 241 .6 g) and the solution was filled into the dropping funnel (500 ml), from which it was added drop-wise to the suspension over 40 min.After 3 h stirring the mixture was slowly heated. The temperature of the oil bath was set to 85 C, shortly above the boiling point of acetonitrile (80 C). Reflux started after 20 min. and was maintained for further 3 hours.The mixture was allowed to come to RT, while further stirred over night at RT. After this, the dark blue-violet suspension was filtered on a Buchner filter, the colored residual was suspended in water (200mL) for 15 min to remove ionic species (Amine salts). Then it was suspended in dichloromethane ( 100 ml) for 30 min, followed by thorough washing with this solvent (800 ml) on the filter after filtration.A light lilac to light mauve colored solid remained, which had 54.5 g (75 % from theory 72.3 g) in 97.6 % purity by HPLC after drying.
74%	With triethylamine; In isopropyl alcohol; at 20 - 55℃;Product distribution / selectivity;	Comparative Example 2: Preparation of 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dioneMethyl-2-bromomethyl-3-nitrobenzoate (16.65 g) and 3-aminopiperidine-2,6- dione hydrochloride (10 g) were added to 2-propanol (130 ml) at 20C to 25C.Triethylamine (12.3 g) was added to the reaction mixture slowly over 30 minutes at 20C to 25C. The temperature of the reaction mixture was raised to 55C and stirred for 41 hours at 50C to 55C. The reaction mixture was cooled to 20C to 25C and de-ionized water (50 ml) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was filtered and the solid obtained was washed with de-ionized water (50 ml) and dried under vacuum at 45C to 50C to obtain the title compound.Yield: 74%
71%	With triethylamine; In N,N-dimethyl-formamide; at 20 - 25℃; for 8.66667h;Product distribution / selectivity;	Example 2: Preparation of 3-(4-nitro-l-oxo-l,3-dihvdro-2H-isoindol-2-yl)piperidine-2,6- dione 3-Aminopiperidine-2,6-dione hydrochloride (25 g) and methyl-2-bromomethyl-3- nitrobenzoate (41.5 g) were added to N,N-dimethylformamide (375 ml) at 20C to 25C and stirred for 20 minutes at 20C to 25C. Triethylamine (10.58 ml) was added to the reaction mixture at 20C to 25C over 5 minutes and the reaction mixture was stirred for 2 hours at 20C to 25C. The above step of adding of triethylamine and stirring was repeated for three more times with same quantity, temperature and duration. The reaction mixture was filtered, and the solid obtained was washed with de-ionized water (250 ml). The solid was stirred for 15 minutes in de-ionized water (500 ml), filtered and dried under vacuum at 45C to 50C to obtain the title compound.Yield: 71% HPLC purity: 99.44 %
41.5%	With triethylamine; In ethanol; at 0 - 55℃;Product distribution / selectivity;	Comparative Example 1 : Preparation of 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dioneMethyl-2-bromomethyl-3-nitrobenzoate (8.36 g) and 3-aminopiperidine-2,6-dione hydrochloride (5 g) were added to ethanol (50 ml) at 20C to 25C. The temperature was raised to 50C to 55C. Triethylamine (7.8 g) was added to the reaction mixture slowly over 30 minutes at 50C to 55C. The reaction mixture was stirred for 32 hours at 50C to 55C, cooled to 0C to 5C and stirred for 30 minutes at 0C to 5C. The reaction mixture was filtered and the solid obtained was added into a mixture of dichloromethane and de- ionized water (1 :2 ratio; 100 ml) at 20C to 25C. The mixture was stirred for 30 minutes at 20C to 25C, filtered and dried under vacuum at 50C to 55C for 17 hours to obtain the title compound.Yield: 41.5%HPLC purity: 99.63%
26%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃;Product distribution / selectivity;	Comparative Example 4: Preparation of 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dioneMethyl-2-bromomethyl-3-nitrobenzoate (8.38 g) and 3-aminopiperidine-2,6-dione hydrochloride (5 g) were added to N,N-dimethylformamide (50 ml) at 20C to 25C. Potassium carbonate (10.5 g) was added to the reaction mixture at 20C to 25C and the temperature was raised to 55C to 60C. The reaction mixture was stirred for 33 hours at 55C to 60C. Approximately 20 ml of Nu,Nu-dimethylformamide was recovered under vacuum at 60C to 65C. De-ionized water (50 ml) was added to the reaction mixture at 20C to 25C and stirred for 1 hour at 15C to 20C. The reaction mixture was filtered, washed with de-ionized water (2 x 10 ml) and dried under vacuum at 50C to 55C for 18 hours to obtain the title compound.Yield: 26%HPLC purity: 97.97%
		Methyl 2-bromomethyl-3-nitrobenzoate (2.2 Kg) is dissolved in acetonitrile (22 L) and placed into a glass container. alpha-Amino glutarimide hydrochloride (1.32 Kg) is added to the solution at 280C and stirred for 10 minutes. Triethylamine <n="21"/>(0.56 L) is added under a nitrogen atmosphere and the mixture heated to a temperature of 550C, and then the mixture stirred for 2 hours. The thethylamine addition, heating, and stirring are repeated 3 times and then the reaction mixture is stirred for 18 hours at 5O0C. After completion of the reaction, the reaction mixture is cooled to 280C. Demineralized water (7 L) is charged to the reaction mixture and then stirred for 2 hours at 280C. The reaction mixture is filtered and the solid is dried at 450C under a vacuum of 600 mm Hg for 8-9 hours to afford 2 Kg of the title compound, with a purity by HPLC of 99.07%.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	Methyl 2- (bromomethyl)-3-nitrobenzoate (4.0 g, 14.6 mmol, 1.0 eq.) was added to a solution of 3- aminopiperidine-2,6-dione.HCl (3.4 g, 20.4 mmol, 1.4 eq.) and DIPEA (6.4 mL, 2.5 eq.) in dry DMF (37 mL) and the solution was stirred under Argon at 50 C overnight. The purple suspension that formed was cooled to room temperature and the solvent was removed under reduced pressure. The residue was triturated with MeOH ( ca . 20 mL), filtered and washed further with MeOH (3 x 10 mL) to give 3-(4-nitro-l-oxoisoindolin-2-yl)piperidine-2,6-dione (EC1-134) as a grey solid (3.7 g, 88%) and was used in the next step without further purification. NMR (500 MHz, DMSO-ifc) d 11.04 (s, 1H), 8.48 (dd, J = 8.2, 1.0 Hz, 1H), 8.20 (dd, J = 7.5, 1.0 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 5.19 (dd, J = 13.3, 5.2 Hz, 1H), 4.92 (d, J = 19.2 Hz, 1H), 4.81 (d, J = 19.2 Hz, 1H), 2.98-2.86 (m, 1H), 2.67-2.53 (m, 2H), 2.07-1.99 (m, 1H); HPLC-MS (ESI-): m/z 288.2 [100%, (M-H)+], 576.1 [20%, (2M-2H)2+] (See WO2013/126394.).

Reference： [1]Patent: US2018/334443,2018,A1 .Location in patent: Paragraph 0060; 0061; 0062
[2]Patent: CN110642834,2020,A .Location in patent: Paragraph 0024-0025; 0027-0028; 0030-0031
[3]Patent: CN106957299,2017,A .Location in patent: Paragraph 0013
[4]Patent: WO2011/27326,2011,A1 .Location in patent: Page/Page column 11
[5]Chemistry of Heterocyclic Compounds,2015,vol. 51,p. 133 - 138
Khim. Geterotsikl. Soedin.,2015,vol. 51,p. 133 - 138,6
[6]Patent: WO2010/100476,2010,A2 .Location in patent: Page/Page column 22-23
[7]Patent: US2012/71509,2012,A1 .Location in patent: Page/Page column 7-8
[8]Patent: CN110551100,2019,A .Location in patent: Paragraph 0038; 0039
[9]Patent: CN111196800,2020,A .Location in patent: Paragraph 0083; 0084
[10]Patent: CN108218833,2018,A .Location in patent: Paragraph 0045; 0046; 0049; 0059; 0060; 0073; 0074
[11]Patent: WO2011/27326,2011,A1 .Location in patent: Page/Page column 10
[12]Patent: WO2011/27326,2011,A1 .Location in patent: Page/Page column 9
[13]Patent: WO2011/50962,2011,A1 .Location in patent: Page/Page column 31
[14]Patent: WO2011/27326,2011,A1 .Location in patent: Page/Page column 9
[15]Patent: WO2011/27326,2011,A1 .Location in patent: Page/Page column 11
[16]Patent: WO2011/27326,2011,A1 .Location in patent: Page/Page column 8
[17]Patent: WO2011/27326,2011,A1 .Location in patent: Page/Page column 10
[18]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630
[19]Patent: US6335/349,2002,B1 .Location in patent: Example 2
[20]Patent: WO2009/114601,2009,A2 .Location in patent: Page/Page column 19-20
[21]Patent: WO2018/140809,2018,A1 .Location in patent: Paragraph 00392
[22]Patent: WO2020/14489,2020,A2 .Location in patent: Page/Page column 112

7
[ 24666-55-5 ]
[ 24666-56-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; hydrogen In methanol; water for 4h;	1 A solution of 15 (4.0Og, 0.015 mol) in methanol (200 ml) and 2N HCl (15 ml) was hydrogenated over 5% Pd-C (100 mg) at 60 psi for 4 h. The catalyst was filtered off and the filtrate concentrated to dryness to give the title compound 16 as a white solid (2.61 g, 100%), mp 245 0C (dec) (lit. 235 0C (dec)). 1H NMR (400 MHz, DMSO-D6) δ ppm 11.22 (br s? IH), 8.68 (br s, 3H), 4.20 (dd, J=13.0, 5.3 Hz, IH), 2.77-2.65 (m, IH), 2.64- 2.56 (m, IH), 2.27-2.19 (m, IH)5 2.09-1.97 (m, IH).
92%	With hydrogenchloride In dimethyl sulfoxide	3.4 (4) Preparation of 3-aminopiperidine-2,6-dione hydrochloride N-CBZ-L-glutamic acid 2.81 g (0.01 mol),Urea 1.2g (0.2mol) was added to DMSO to dissolve and reflux at 150 ° C. After 2 h, the temperature was lowered.HCl gas, a white solid 1.518 g, a yield of 92%;
90%	Stage #1: 3-(benzyloxycarbonyl)-amino-2,6-dioxopiperidine With palladium 10% on activated carbon; hydrogen In methanol; water at 25 - 30℃; Stage #2: With hydrogenchloride In methanol; water at 25 - 30℃;	1.c Step c: Preparation of 3-aminopiperidine-2,6-dione hydrochloride Benzyl (2,6-dioxopiperidin-3-yl)carbamate (100 g; obtained in Step b) was added to methanol (1000 mL) and the mixture was heated at 50°C to 55°C to obtain a clear solution. The solution was cooled to 25 °C to 30°C and then 10% Palladium on carbon (10 g; 50% wet) was added. The solution was hydrogenated with 3.0 kg/cm2 to 3.5 kg/cm2 hydrogen pressure at 25 °C to 30°C for 2 hours to 3 hours. The catalyst was removed by filtration. Concentrated hydrochloric acid (100 mL) was added to the filtrate and then stirred for 60 minutes to 90 minutes at 25°C to 30°C. The reaction mixture was concentrated at 40°C to 45 °C under reduced pressure. Methanol (100 mL) was added to the residue and then stirred for 60 minutes at 10°C to 15°C to obtain a slurry. The slurry was filtered and the wet solid obtained was dried at 50°C under reduced pressure to obtain the title compound. (0073) Yield: 56 g (90%)

90.5%	With hydrogenchloride; palladium 10% on activated carbon; hydrogen In methanol at 25℃; for 5h;	Synthesis of 3-Amino-2,6-piperidinone hydrochloride (VIa) 3-N-benzyloxycarbonylamino-2,6-dioxopiperidine 40 g (0.153 mol) was sequentially added to the hydrogenation vessel.10% Pd/C 4g, methanol 2L, 2mol/L hydrochloric acid 1.5L, a certain H2 pressure, kept at 25 ° C for 5 h, filtered after pressure relief, the filtrate was evaporated to dryness, and then 500 ml of methanol was added.After stirring for 0.5 h, it was filtered to give a white solid.The yield was 90.5%.
	With hydrogenchloride; hydrogen In ethyl acetate

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF AUCKLAND - WO2008/7979, 2008, A1 Location in patent: Page/Page column 13
[2]Current Patent Assignee: Wang Yanping; Yang Yi; Zhang Xiaoling; Zhou Qinghe; Xu Congying - CN108218833, 2018, A Location in patent: Paragraph 0043; 0044; 0057; 0058; 0063; 0071; 0072
[3]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2018/154516, 2018, A1 Location in patent: Page/Page column 7-8
[4]Current Patent Assignee: SHIJIAZHUANG DUEN MEDICAL TECH - CN109776493, 2019, A Location in patent: Paragraph 0037-0038
[5]Muller, George W.; Chen, Roger; Huang, Shaei-Yun; Corral, Laura G.; Wong, Lu Min; Patterson, Rebecca T.; Chen, Yuxi; Kaplan, Gilla; Stirling, David I. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630]

8
[ 86-90-8 ]
[ 24666-56-6 ]
[ 26166-92-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium acetate; acetic acid;Heating / reflux;	5.52 l-f2-CHLQRO-PHENYLV3-r2-(2.6-DIOXO-PIPERIDIN-3-YLV1.3- DIOXO-2.3-DIHYDRO- 1H-ISOINDOL-5-YLMETHYL1-UREAStep .: A mixture of <strong>[86-90-8]4-bromophthalic anhydride</strong> (10.0 g, 44.1 mmol), rac-a- aminoglutarimide hydrochloride (7.25 g, 44.0 mmol) and sodium acetate (3.61 g, 44.0 mmol) in acetic acid (150 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The residue was stirred in water (170 mL) for 3 hours, and the resulting solid was filtered, washed with additional water (80 mL), and dried under vacuum, to afford 13.8 g of 5-bromo-2-(2,6-dioxo-piperidin-3-yl)-isoindole-l ,3-dione, in 93% yield; 1H NMR (DMSO-(Z6) delta 2.03-2.10 (m, IH), 2.43-2.63 (m, 2H), 2.82-2.97 (m, IH), 5.17 (dd, J = 12.8 Hz, J = 5.3 Hz, IH), 7.85-7.88 (d, J = 7.9 Hz, IH), 8.10 (dd, J = 7.9 Hz, J = 1.7 Hz, IH), 8.16 (d, J = 1.7 Hz, IH), 1 1.15 (s, IH); 13C NMR (DMSCW6) delta 21.9, 30.9, 49.2, 125.3, 126.4, 128.5, 130.1, 133.2, 137.6, 165.9, 166.4, 169.7, 172.7; Anal. Calcd for C13H9N2O4Br: C, 46.32; H, 2.69; N, 8.31. Found: C, 46.23; H, 2.47; N, 8.41.
92%	With sodium acetate; In acetic acid; at 20 - 80℃; for 16h;	To a solution of <strong>[86-90-8]4-bromophthalic anhydride</strong> (15.0 g, 66.1 mmol, CAS86-90-8) in acetic acid (225 mL) was added 2,6-dioxopiperidin-3-amine hydrochloride (10.87 g, 66.1 mmol, CAS24666-56-6) and sodium acetate (5.42 g, 66.07 mmol) at rt. The reaction mixture was heated to 80 C. and stirred for 16 h. The resulting reaction mixture was cooled to rt and concentrated on a rotary evaporator. The obtained residue was suspended in water (255 mL) and the resulting mixture was cooled to 0 C. The resulting slurry was stirred at 0 C. for 1 h. The resulting precipitate was filtered, washed with water (60 mL) and dried under vacuum to give the title compound (20.44 g, 92%) as a purple solid. LC-MS (ESI+) m/z 336.9 (M+H)+.
60%	With potassium acetate; acetic acid; at 90℃; for 12h;	To a solution of 3-aminopiperidine-2,6-dione (7.98 g, 48.4 mmol, HCl salt, CAS24666-56-6), KOAc (13.4 g, 136 mmol) in HOAc (200 mL) was added 5-bromoisobenzofuran-1,3-dione (10.0 g, 44.0 mmol, CAS282-73-5). The mixture was then heated to 90 C. and stirred for 12 hours. On completion, the mixture was cooled down to 25 C. and diluted with water (800 mL), and then filtered to give a filter cake. The filter cake was stirred in DCM (20 mL) for 1 hour and filtered to give a filter cake. The filter cake was dried in vacuo to give the title compound (9.00 g, 60% yield) as a blue solid. 1H NMR (400 MHz, DMSO-d6) delta 11.15 (s, 1H), 8.15 (d, J=1.2 Hz, 1H), 8.10 (dd, J=1.6, 8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 5.17 (dd, J=5.6, 12.8 Hz, 1H), 2.95-2.83 (m, 1H), 2.65-2.52 (m, 2H), 2.11-2.00 (m, 1H).

Reference： [1]Patent: WO2008/27542,2008,A2 .Location in patent: Page/Page column 75
[2]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2384; 2385
[3]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2736; 2737
[4]Patent: WO2018/140809,2018,A1 .Location in patent: Paragraph 00423

9
[ 24666-56-6 ]
[ 78471-43-9 ]
[ 1010100-26-1 ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 16h;	1 To a stirred solution of methyl 4-bromo-2-(bromomethyl)benzoate (1a, 15 g, 48.7 mmol) in DMF (150 mL) was added 3-aminopiperidine-2,6-dione-HCl (Ib, 6.9 g, 53.6 mmol) and K2CO3 (20.2 g, 146.1 mmol). The resulting mixture was heated at 70° C. for 16 h after which time the reaction mixture was cooled to rt and then concentrated to dryness. To the resulting residue, water was added and the mixture stirred at rt for 30 min. The resultant solid was filtered and washed with ether and ethyl acetate. The solid was dried under vacuum filtration to afford 1c (10.6 g, 32.9 mmol, 67% yield). MS [M+H]+=323.0. 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.91-7.88 (m, 1H), 7.72 (dd, J=8.1, 1.6 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.7 Hz, 1H), 4.34 (d, J=17.7 Hz, 1H), 2.98-2.83 (m, 1H), 2.65-2.55 (m, 1H), 2.45-2.29 (m, 1H), 2.01 (dtd, J 12.7, 5.3, 2.3 Hz, 1H).
67%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 16h;	1.1 Step 1.3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1c) To a stirred solution of methyl 4-bromo-2-(bromomethyl)benzoate (1a, 15 g, 48.7 mmol) in DMF (150 mL) was added 3-aminopiperidine-2,6-dioneHCl salt (1b, 6.9 g, 53.6 mmol) and K2CO3 (20.2 g, 146.1 mmol). The resulting mixture was stirred at 70 °C for 16 h after which time the reaction mixture was cooled to rt and then concentrated to dryness. To the resulting residue, water was added and the mixture stirred at rt for 30 min. The resultant solid was filtered and washed with ether and ethyl acetate. The solid was dried under vacuum filtration to afford 1c (10.6 g, 32.9 mmol, 67% yield). MS [M+H]+ = 323.0. 1H NMR (400 MHz, DMSO-d6) ^ 10.99 (s, 1H), 7.91-7.88 (m, 1H), 7.72 (dd, J = 8.1, 1.6 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 4.34 (d, J = 17.7 Hz, 1H), 2.98-2.83 (m, 1H), 2.65-2.55 (m, 1H), 2.45-2.29 (m, 1H), 2.01 (dtd, J = 12.7, 5.3, 2.3 Hz, 1H).
67%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 16h;	1 Example 1: 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (INT-1) Intermediate 1a was prepared as described in U.S. Patent Application US 2009/0142297. To a stirred solution of methyl 4-bromo-2-(bromomethyl)benzoate (1a, 15 g, 48.7 mmol) in DMF (150 mL) was added 3-aminopiperidine-2,6-dione HCl salt (1b, 6.9 g, 53.6 mmol) and K2CO3 (20.2 g, 146.1 mmol) and the obtained reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to r.t. and concentrated to dryness. Water was added and the mixture was stirred at r.t. for 30 min. The obtained solid was filtered, washed with ethyl acetate, and dried under vacuum filtration to afford 3- (5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione INT-1 (10.6 g, 32.9 mmol, 67% yield). MS [M+H]+ = 323.0.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.91-7.88 (m, 1H), 7.72 (dd, J = 8.1, 1.6 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 4.34 (d, J = 17.7 Hz, 1H), 2.98-2.83 (m, 1H), 2.65-2.55 (m, 1H), 2.45-2.29 (m, 1H), 2.01 (dtd, J = 12.7, 5.3, 2.3 Hz, 1H).

65%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 20h;	Intermediate 5: 3-(6-bromo-3-oxo-LH-isoindol-2-yI)piperidine-2, 6-dione (Int-5) To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (3.08 g, 10 mmol) in DMF (30 mL) was added 3-aminopiperidine-2, 6-dione, HC1 (Accela, catalog : SY030429, 1.81 g, 11 mmol) and potassium carbonate (4.15 g, 30 mmol). The reaction mixture was heated at 70 °C for 20 h. The reaction was cooled to RT and concentrated to dryness under reduced pressure. Water (50 mL) was added to the residue and the mixture was stirred at RT for 30 min then filtered. The resulting solid was washed with EtOAc to give 3-(6-bromo-3-oxo-1H-isoindol-2-yl)piperidine-2, 6-dione (2.1 g, 65% yield) as a pale-grey solid. LCMS m/z calcd for C13H12BrN2O3 [M+H]+: 323.0; found: 323.1.
65%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 20h;	Intermediate 5: 3-(6-bromo-3-oxo-LH-isoindol-2-yI)piperidine-2, 6-dione (Int-5) To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (3.08 g, 10 mmol) in DMF (30 mL) was added 3-aminopiperidine-2, 6-dione, HC1 (Accela, catalog : SY030429, 1.81 g, 11 mmol) and potassium carbonate (4.15 g, 30 mmol). The reaction mixture was heated at 70 °C for 20 h. The reaction was cooled to RT and concentrated to dryness under reduced pressure. Water (50 mL) was added to the residue and the mixture was stirred at RT for 30 min then filtered. The resulting solid was washed with EtOAc to give 3-(6-bromo-3-oxo-1H-isoindol-2-yl)piperidine-2, 6-dione (2.1 g, 65% yield) as a pale-grey solid. LCMS m/z calcd for C13H12BrN2O3 [M+H]+: 323.0; found: 323.1.
57%	With triethylamine	Preparation of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C192-1) Preparation of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C192-1) Methyl 4-bromo-2-(bromomethyl)benzoate (300mg, 0.974mmol), 3-aminopiperidine-2,6-dione hydrochloride (208mg, 1.266mmol), and triethylamine (128mg, 1.266mmol) were dissolved in 5mL of acetonitrile, and the mixture was stirred at 80°C under nitrogen protection overnight. The mixture was cooled to room temperature. The solvent was removed under reduced pressure, and the crude product was purified by Flash to afford white solid compound C192-1(180mg, yield 57.0%). LCMS: [M + H]+ = 323, 325.
57%	With triethylamine In acetonitrile at 80℃; Inert atmosphere;	Preparation of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C192-1) Methyl 4-bromo-2-(bromomethyl)benzoate (300 mg, 0.974mmol), 3-aminopiperidine-2,6-dione hydrochloride (208 mg, 1.266mmol), and triethylamine (128 mg, 1.266mmol) were dissolved in 5mL of acetonitrile, and the mixture was stirred at 80°C under nitrogen protection overnight. The mixture was cooled to room temperature. The solvent was removed under reduced pressure, and the crude product was purified by Flash to afford white solid compound C192-1(180 mg, yield 57.0%). LCMS: [M + H]+ = 323, 325.
44%	With triethylamine at 20℃; for 25h; Inert atmosphere;
44%	With triethylamine at 20℃; for 25h;
43.8%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;	1.C; 2.C C. 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Methyl-4-bromo-2-(bromomethyl) benzoate (100 g, 324.70 mmol), 3-Aminopiperidine-2,6-dione.hydrochloride (53.2 g, 324.70 mmol), triethylamine (113.29 mL, 811.75 mmol), and dry dimethylformamide (400 mL) were combined and stirred at room temperature under inert atmosphere for 18 hours. The reaction was cooled to 5°C and diluted with water (400 mL), acetic acid (115 mL), diethylether (300 mL) with continued stirring at room temperature for 2 hours. The resultant solid was filtered, washed with ether (100 mL) and further dried under high vacuum to give 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (46 g, 142.35 mmol, 43.8 % yield) as a light blue solid. MS(ESI) m/z 325.0 [M+1].
43%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 18h;
42%	With triethylamine In N,N-dimethyl-formamide at 25℃; for 16h; Inert atmosphere;	2.1 To a stirred mixture of methyl 4-bromo-2-(bromomethyl)benzoate (Compound 10, 20.0 g, 64.8 mmol, 1.00 equiv) and 3-aminopiperidine-2,6-dione hydrochloride (10.64 g, 83.0 mmol, 1.28 equiv) in DMF (80 ml) was added TEA (22.4mL, 162.2 mmol, 2.50 equiv) dropwise at 25 °C under nitrogen atmosphere. The mixture was stirred at 25 °C for 16 h. This was followed by addition of H20 (60 mL), AcOH (23 mL) and Et20 (60 mL) in sequence at 25 °C. The mixture was stirred at 25 °C for 2 h. The precipitated solids were collected by filtration and washed with Et20 (60 mL). This resulted in 3-(5-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (9.0 g, 42%) as a light blue solid. LCMS (ESI): 323.32 (M+H)+
39%	With triethylamine In N,N-dimethyl-formamide at 75℃; for 12h;	2 Step 2-3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione To a solution of 3-aminopiperidine-2,6-dione (2.00 g, 12.1 mmol, HCl) and methyl 4-bromo-2-(bromomethyl)benzoate (5.10 g, 16.5 mmol) in DMF (50.0 mL) was added TEA (4.92 g, 48.6 mmol). The reaction mixture was stirred at 75° C. for 12 hrs. On completion, the reaction mixture was diluted with water (200 mL) and filtered. The filtered cake was collected. The reaction mixture was concentrated in vacuo. The residue was triturated with EA:H2O=1:1 (50 mL) to give the title compound (1.70 g, 39% yield) as blue solid. 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.90 (s, 1H), 7.74-7.66 (m, 2H), 5.14-5.09 (m, 1H), 4.50-4.33 (m, 2H), 2.95-2.86 (m, 1H), 2.70-2.61 (m, 1H), 2.42-2.36 (m, 1H), 2.04-2.01 (m, 1H).
20%	With triethylamine In N,N-dimethyl-formamide at 20℃;	5.5.76.3 Step 3: A mechanically stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF (400 mL) was treated dropwise with triethylamine (98.5 g, 980 mmol) over 75 minutes. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The mixture was quenched sequentially with acetic acid (5OmL), water (250OmL) and a 1:1 mixture of ethyl acetate and hexanes (600 mL). After stirring the mixture for 20 minutes, the solid was filtered, washed with water and air dried overnight. The solid was stirred in acetic acid (200 mL) and refiuxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid was washed with additional acetic acid, hexanes and air dried overnight to give 25.4 g of 3-(5-bromo-l- oxo-l,3-dihydro-isoindol~2-yl)-piperidine-2,6-dione as a grey solid, in 20% yield; 1H NMR (DMSCM;) δ 1.97-2.04 (m, I H), 2.32-2.46 (m, IH), 2.56-2.63 (m, IH), 2.85-2.97 (m, IH), 4.34 (d, J = 17.7 Hz, IH), 4.47 (d, J = 17.7 Hz, IH), 5.1 1 (dd, J = 13.2 Hz, J = 5.1 Hz, IH), 7.67 (d, J = 8.1 Hz, IH), 7.72 (dd, J = 8.1 Hz, J = 1.5 Hz, IH), 7.89 (d, J = 0.9 Hz, IH), 11.00 (s, I H).
20%	Stage #1: 3-amino-piperidine-2,6-dione hydrochloride; methyl 4-bromo-2-(bromomethyl)benzoate With triethylamine In N,N-dimethyl-formamide for 1.25h; Stage #2: With glacial acetic acid for 2h; Reflux;	6.6.3 A mechanically stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF (400 mL) was treated dropwise with triethylamine (98.5 g, 980 mmol) over 75 minutes. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The mixture was quenched sequentially with acetic acid (50mL), water (2500mL) and a 1:1 mixture of ethyl acetate and hexanes (600 mL). After stirring the mixture for 20 minutes, the solid was filtered, washed with water and air dried overnight. The solid was stirred in acetic acid (200 mL) and refluxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid was washed with additional acetic acid, hexanes and air dried overnight to give 25.4 g of 3-(5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as a grey solid, in 20% yield; 1H NMR (DMSO-d6) 1.97-2.04 (m, 1H), 2.32-2.46 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.97 (m, 1H), 4.34 (d, J = 17.7 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 5.11 (dd, J = 13.2 Hz, J = 5.1 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.72 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 11.00 (s, 1H).
20%	Stage #1: 3-amino-piperidine-2,6-dione hydrochloride; methyl 4-bromo-2-(bromomethyl)benzoate With triethylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With glacial acetic acid for 2h; Reflux;	3 [00409j Step 3: A mechanically stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF (400 mL) was treated dropwise with triethylamine (98.5 g, 980 mmol) over75 minutes. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The mixture was quenched sequentially with acetic acid (50 mL), water (2500 mL) and a 1:1 mixture of ethyl acetate and hexanes (600 mL). After stirring the mixture for 20 minutes, the solid was filtered, washed with water, and air dried overnight. The solid was stirred in acetic acid (200 mL) and refluxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid was washed with additional acetic acid, hexanes, and air dried overnight to give 25.4 g of 3 -(5-bromo- 1 -oxo- 1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6- dione as a grey solid, in 20% yield; 1H NMR (DMSO-d6) ö 1.97-2.04 (m, 1H), 2.32-2.46 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.97 (m, 1H), 4.34 (d, J = 17.7 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H),5.11 (dd,J= 13.2Hz,J5.1 Hz, 1H),7.67(d,J8.1 Hz, 1H),7.72(dd,J=8.1 Hz,J= 1.5Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 11.00 (s, 1H).
20%	Stage #1: 3-amino-piperidine-2,6-dione hydrochloride; methyl 4-bromo-2-(bromomethyl)benzoate With triethylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With glacial acetic acid for 2h; Reflux;	6.6.3 A mechanically stirred mixture of 4-bromo-2-bromomethyl -benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF (400 mL) was treated dropwise with triethylamine (98.5 g, 980 mmol) over 75 minutes. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The mixture was quenched sequentially with acetic acid (50mL), water (2500mL) and a 1 : 1 mixture of ethyl acetate and hexanes (600 mL). After stirring the mixture for 20 minutes, the solid was filtered, washed with water and air dried overnight. The solid was stirred in acetic acid (200 mL) and refluxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid was washed with additional acetic acid, hexanes and air dried overnight to give 25.4 g of 3-(5-bromo-l-oxo-l,3-dihydro-isoindol-2-yl)-piperidine-2,6- dione as a grey solid, in 20% yield; 1H MR (DMSO-i) δ 1.97-2.04 (m, 1H), 2.32-2.46 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.97 (m, 1H), 4.34 (d, J = 17.7 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 5.11 (dd, J = 13.2 Hz, J = 5.1 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.72 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 11.00 (s, 1H).
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 16h;
	In acetonitrile at 80℃; Alkaline conditions;

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2019/62309, 2019, A1 Location in patent: Paragraph 0732; 0734
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2020/165833, 2020, A1 Location in patent: Page/Page column 296-297
[3]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2022/29573, 2022, A1 Location in patent: Page/Page column 311
[4]Current Patent Assignee: PRELUDE THERAPEUTICS INCORPORATED - WO2022/99117, 2022, A1 Location in patent: Paragraph 393
[5]Current Patent Assignee: PRELUDE THERAPEUTICS INCORPORATED - WO2022/99117, 2022, A1 Location in patent: Paragraph 393
[6]Current Patent Assignee: BEIJING TIDE PHARMACEUTICAL CO LTD; SINO BIOPHARMACEUTICAL LIMITED; BEIJING TEDE PHARMACEUTICAL - EP4019021, 2022, A1
[7]Current Patent Assignee: BEIJING TIDE PHARMACEUTICAL CO LTD; SINO BIOPHARMACEUTICAL LIMITED; BEIJING TEDE PHARMACEUTICAL - EP4019021, 2022, A1 Location in patent: Paragraph 0176-0177
[8]Hansen, Joshua D.; Condroski, Kevin; Correa, Matthew; Muller, George; Man, Hon-Wah; Ruchelman, Alexander; Zhang, Weihong; Vocanson, Fan; Crea, Tim; Liu, Wei; Lu, Gang; Baculi, Frans; Lebrun, Laurie; Mahmoudi, Afshin; Carmel, Gilles; Hickman, Matt; Lu, Chin-Chun [Journal of Medicinal Chemistry, 2018, vol. 61, # 2, p. 492 - 503]
[9]Hansen, Joshua D.; Correa, Matthew; Alexander, Matt; Nagy, Mark; Huang, Dehua; Sapienza, John; Lu, Gang; Lebrun, Laurie A.; Cathers, Brian E.; Zhang, Weihong; Tang, Yang; Ammirante, Massimo; Narla, Rama K.; Piccotti, Joseph R.; Pourdehnad, Michael; Lopez-Girona, Antonia [Journal of Medicinal Chemistry, 2021, vol. 64, # 4, p. 1835 - 1843]
[10]Current Patent Assignee: SIEMENS ENERGY AG; BRISTOL-MYERS SQUIBB CO - WO2017/120422, 2017, A1 Location in patent: Paragraph 00377; 00389
[11]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2021/171493, 2021, A1 Location in patent: Paragraph 0191
[12]Current Patent Assignee: ORUM THERAPEUTICS INC. - WO2021/198965, 2021, A1 Location in patent: Paragraph 0508
[13]Current Patent Assignee: KYMERA THERAPEUTICS INC - US2019/192668, 2019, A1 Location in patent: Paragraph 3097; 3099
[14]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2008/27542, 2008, A2 Location in patent: Page/Page column 90
[15]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2015/200795, 2015, A1 Location in patent: Paragraph 00390
[16]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2016/57503, 2016, A1 Location in patent: Paragraph 00409
[17]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/117118, 2017, A1 Location in patent: Paragraph 00473
[18]Current Patent Assignee: ARVINAS - WO2018/140809, 2018, A1 Location in patent: Paragraph 00391
[19]Zhang, Jingyu; Che, Jinxin; Luo, Xiaomin; Wu, Mingfei; Kan, Weijuan; Jin, Yuheng; Wang, Hanlin; Pang, Ao; Li, Cong; Huang, Wenhai; Zeng, Shenxin; Zhuang, Weihao; Wu, Yizhe; Xu, Yongjin; Zhou, Yubo; Li, Jia; Dong, Xiaowu [Journal of Medicinal Chemistry, 2022]

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[ 191732-76-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630

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[ 24666-56-6 ]
[ 19171-19-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630
[2]Patent: CN103724323,2016,B
[3]Patent: CN103724323,2016,B
[4]Patent: CN103724323,2016,B
[5]Patent: CN103724323,2016,B
[6]Patent: WO2019/191112,2019,A1

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[ 24666-56-6 ]
[ 61940-21-4 ]
[ 1063995-54-9 ]

Reference： [1]Patent: US6335/349,2002,B1 .Location in patent: Example 2

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[ 6946-22-1 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
94%		Example 14; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; Example 14 was prepared similarly according to the procedure for Example 13 except that there was no acetic acid; the amount of triethylamine was reduced from 4.6 mol to 3.2 mol; and the refluxing time was increased from about 5 to 7 hours to about 47 hours. The amount of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reaction mixture was found to be 94percent.
92%		Example 15; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; Example 15 was prepared similarly according to the procedure for Example 13 except that there was no acetic acid and the 4.6 mol of triethylamine was replaced with 9.2 mole of imidazole. The amount of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reaction mixture was found to be 92percent
85%		Example 16; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; Example 16 was prepared similarly according to the procedure for Example 13 except that the 4.6 mol of triethylamine was replaced with 9.2 mole of imidazole. The amount of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reaction mixture was found to be 85percent.

84%		Example 13; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; According to Scheme E A mixture of 3-aminophthalic acid hydrochloride (200 g, 0.92 mol, from Prosynth Ltd., Suffolk, UK), 3-aminoglutarimide hydrochloride (159 g, 0.96 mol, from Evotec OAI, Hamburg, Germany), acetonitrile (2.0 L), and acetic acid (577 g, 9.6 mol, from Fisher Scientifc) was charged into a reaction vessel. After the mixture was stirred for 15 minutes, triethylamine (465.0 g, 4.6 mol, from Aldrich, Milwaukee, Wis.) was added dropwise over 30-35 minutes while the reaction temperature was maintained at 20-25° C. Next, the reaction mixture was stirred further for 10-15 minutes and then refluxed at about 85 to 87° C. for about 5 to 7 hours or until the in-process control, i.e., HPLC AP at 240 nm, indicates that <2percent of the 3-aminophthalic acid remained in the reaction mixture. After the reaction mixture was cooled to about 20 to 25° C. over 1-2 hours, 1.0 L of water was charged over 15-30 minutes at about 20 to 25° C. The resulting mixture was stirred at about 15 to 20° C. for about 20 to 30 minutes to provide a yellow solid precipitate, which was filtered, washed with DI water (3.x.1.0 L) and acetonitrile (2.x.500 mL), and then dried at about 35 to 40° C in vacuo to a constant weight at 210.0 g (84 percent).
68.5%	With acetic acid; triethylamine; In acetone; at 80 - 85℃; for 6h;	Acetonitrile (100 mL), acetic acid (26.28 mL, 459.5 mmol),Triethylamine (31.85 mL, 229.8 mmol), 3-aminophthalic acid hydrochloride (10 g, 46.0 mmol),Aminopiperidine-2,6-dione hydrochloride (7.68 g, 46.6 mmol)Added to the reaction flask, heated to 80 ~ 85 ° C reflux, the reaction was complete after 6h,The reaction solution was cooled to 20 ~ 25 ° C, purified water was slowly added, the crystallization was stirred for 2h, filtered, the filter cake was dried under reduced pressure at 60 ± 5 ° C for 8h to obtain 8.6g black solid, yield 68.5percent

Reference： [1]Patent: US2007/4920,2007,A1 .Location in patent: Page/Page column 13
[2]Patent: US2007/4920,2007,A1 .Location in patent: Page/Page column 13-14
[3]Patent: US2007/4920,2007,A1 .Location in patent: Page/Page column 14
[4]Patent: US2007/4920,2007,A1 .Location in patent: Page/Page column 13
[5]Patent: CN107325075,2017,A .Location in patent: Paragraph 0029; 0030; 0031

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[ 24666-56-6 ]
[ 5054-59-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In toluene; for 12h;Reflux; Dean-Stark;	EXAMPLE 1 Synthesis of (3'R,4'S,5'R)-6"-chloro-4'-(3-chloro-2-fluorophenyl)-N-(4-((4-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)butyl)carbamoyl)phenyl)- 2"-oxodispiro[cyclohexane-l,2'-pyrrolidine-3',3"-indoline]-5'-carboxamide Ste 1 : Synthesis of S 1 To a round-bottom flask, 3-hydroxyphthalic anhydride (1 g, 6.09 mmol) and 3-aminoperidine-2,6-dione hydrochloride (1.0 g, 6.09 mmol) were mixed in 50 mL of toluene. Triethyl amine (0.93 mL, 6.7 mmol) was added. The resulting reaction mixture was heated to reflux for 12 h with Dean-Stark Trap equipment. After cooling to ambient temperature, evaporation of most of the solvent to give a crude product, which was purified by flash column chromatography with DCM:EA to get the desired product as a slightly yellow solid S I (1.5g, 90% yield). 1H NMR (400 MHz, DMSO-d6) delta (ppm) 11.16 (s, 1H), 11.08 (s, 1H), 7.65 (t, = 7.6 Hz, 1H), 7.32 (d, = 7.2 Hz, 1H), 7.25 (d, = 8.4 Hz, 1H), 5.07 (dd, = 12.8 Hz, = 5.2 Hz, 1H), 2.93-2.84 (m, 1H), 2.61-2.46 (m, 1H), 2.05-2.01 (m, 1H).
90%	With triethylamine; In toluene; for 12h;Reflux; Dean-Stark;	To a round-bottom flask, 3-hydroxyphthalic anhydride (1 g, 6.09 mmol) and 3- aminoperidine-2,6-dione hydrochloride (1.0 g, 6.09 mmol) were mixed in 50 mL of toluene. Triethyl amine (0.93 mL, 6.7 mmol) was added. The resulting reaction mixture was heated to reflux for 12 h with Dean-Stark trap equipment. After cooling to ambient temperature, evaporation of most of the solvent to give a crude product, which was purified by flash column chromatography with DCM: ethyl acetate to get the desired product as a slightly yellow solid S26 (1.5g, 90% yield). ?H NMR (400 MHz, DMSO-d6) (ppm) 11.16 (s, 1H), 11.08 (s, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.25 (d, J= 8.4 Hz, 1H), 5.07 (dd, J= 12.8 Hz, J= 5.2 Hz, 1H), 2.93-2.84 (m, 1H), 2.61-2.46 (m, 1H), 2.05-2.0 1 (m, 1H).
88%	With pyridine; at 110℃; for 14h;	3-Hydroxyphthalic anhydride (1.641 g, 10 mmol, 1 eq) and 3-aminopiperidine-2,6- dione hydrochloride (1.646 g, 10 mmol, 1 eq) were dissolved in pyridine (40 mL, 0.25 M) and heated to 110 C. After 14 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. Purification by column chromatography (ISCO, 24 g silica column, 0-10% MeOH/DCM) afforded the desired product as a tan solid (2.424 g, 8.84 mmol, 88%).

88%	With pyridine; at 110℃; for 16h;	4-hydroxyisobenzofuran-1,3-dione (0.773 g, 4.71 mmol, 1 eq) and 3-aminopiperidine-2,6-dione hydrochloride (0.775 g, 4.71 mmol, 1 eq) were dissolved in pyridine (19 mL) and heated to 110 C. for 16 hours. The mixture was concentrated under reduced pressure and purified by column chromatography (ISCO, 12 g silica column, 0-10% MeOH/DCM, 25 minute gradient) to give an off white solid (1.14 g, 4.16 mmol, 88%). 1H NMR (400 MHz, DMSO-d6) delta 11.19 (s, 1H), 11.07 (s, 1H), 7.65 (dd, J=8.3, 7.3 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 5.07 (dd, J=12.8, 5.4 Hz, 1H), 2.88 (ddd, J=17.7, 14.2, 5.4 Hz, 1H), 2.63-2.50 (m, 2H), 2.11-1.95 (m, 1H). LCMS 275.11 (M+H).
88%	With pyridine; at 110℃; for 14h;	3-Hydroxyphthalic anhydride (1.641 g, 10 mmol, 1 eq.) and 3-aminopiperidine-2,6- dione hydrochloride (1.646 g, 10 mmol, 1 eq.) were dissolved in pyridine (40 mL, 0.25 M) and heated to 110 C. After 14 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. Purification by column chromatography (ISCO, 24 g silica column, 0- 10% MeOH/DCM) gave the desired product as a tan solid (2.424 g, 8.84 mmol, 88%).NMR (400 MHz, DMSO-d6) delta 11.08 (s, 2H), 7.65 (dd, J = 8.4, 7.2 Hz, 1H), 7.36 - 7.28 (m, 1H), 7.25 (dd, J= 8.4, 0.6 Hz, 1H), 5.07 (dd, J= 12.8, 5.4 Hz, 1H), 2.88 (ddd, J =- 2.50 (m, 2H), 2.08 - 1.95 (m, 1H).
88%	With pyridine; at 110℃; for 14h;	3-Hydroxyphthalic anhydride (3-7, 1.64 g, 10 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (3-8, 1.65 g, 10 mmol) were dissolved in pyridine (40 mL, 0.25 M) and heated to 1 10 C. After 14 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-10% MeOH/DCM) to give 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (3-9) as a grey solid (2.41 g, 88%). LC-MS: m/z 275 [M+l]
74%	With potassium acetate; acetic acid; at 90℃;	In a 20 mL glass vial, a mixture of 3-hydroxyphthalic anhydride (500 mg, 3.05 mmol, 1 equiv), potassium acetate (927 mg, 9.44 mmol, 3.1 equiv) and 3-aminopiperidine-2,6-dionehydrochloride (552 mg, 3.35 mmol, 1.1 equiv) in acetic acid (10.2 mL, 0.3 M) was heated to 90C overnight. The black reaction mixture was cooled to room temperature and diluted to 20 mLwith water, and subsequently cooled on ice for 30 mm. The resulting slurry was transferred to a50 mL Falcon tube, which was centrifuged at 3500 rpm for 5 mm. The supernatant was discardedand the black solid was transferred to a 250 mL RBF with methanol and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (CH2C12:MeOH (9:1)) to afford the title compound as a white solid (619 mg, 74%). 1H NMR (400 MHz, DMSO-d6) 11.07 (s, 1H), 7.65 (dd,J=8.4, 6.8Hz, 1H), 7.31 (d,J=6.8Hz, 1H), 7.24(d,J=8.4Hz, 1H), 5.06(dd, J= 12.8, 5.4 Hz, 1H), 2.94-2.82 (m, 1H), 2.64-2.43 (m, 2H), 2.08 - 1.97 (m, 1H); MS (ESI)calcd for C13H11N205 [M+H] 275.07, found 275.26.
74%	With potassium acetate; acetic acid; at 90℃;	In a 20 mL glass vial, a mixture of 3-hydroxyphthalic anhydride (500 mg, 3.05 mmol, 1 equiv), potassium acetate (927 mg, 9.44 mmol, 3.1 equiv) and 3-aminopiperidine-2,6-dione hydrochloride (552 mg, 3.35 mmol, 1.1 equiv) in acetic acid (10.2 mL, 0.3 M) was heated to 90 oC overnight. The black reaction mixture was cooled to room temperature and diluted to 20 mL with water, and subsequently cooled on ice for 30 min. The resulting slurry was transferred to a 50 mL Falcon tube, which was centrifuged at 3500 rpm for 5 min. The supernatant was discarded and the black solid was transferred to a 250 mL RBF with methanol and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (CH2Cl2:MeOH (9:1)) to afford the title compound as a white solid (619 mg, 74%).1H NMR (400 MHz, DMSO-d6) delta 11.07 (s, 1H), 7.65 (dd, J = 8.4, 6.8 Hz, 1H), 7.31 (d, J = 6.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 2.94- 2.82 (m, 1H), 2.64- 2.43 (m, 2H), 2.08- 1.97 (m, 1H); MS (ESI) calcd for C13H11N2O5 [M+H]+ 275.07, found 275.26.
74%	With pyridine; at 110℃; for 16h;	To a solution of 4-hydroxyisobenzofuran-1,3-dione (20.0 g, 122 mmol) in pyridine (100 mL) was added 3-aminopiperidine-2,6-dione (20.0 g, 122 mmol, HCl salt). The reaction mixture was stirred at 110 C. for 16 h. On completion, the mixture was concentrated in vacuo. The residue was diluted with water (500 mL) and stirred for 16 h. The mixture was then filtered and the filter cake was dried in vacuo to give the title compound (24.8 g, 74% yield) as a white solid. LC-MS (ESI+) m/z 297.0 (M+Na)+.
64%	With pyridine; at 110℃; for 16h;	The 3-hydroxyphthalic anhydride (SMI-175) (2.00 g, 12.19 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (2.01 g, 12.19 mmol) were dissolved in pyridine (19 mL) and heated to 110 C for 16 h. The mixture was concentrated and purified by SiCh chromatography eluting with 5% MeOH in DCM followed by trituration from MeOH to give the title compound SMI-175 as an off-white solid (2.15 g, 64%). 1 H NMR (500 MHz, DMSO-de) d 11.18 (s, 1H), 11.09 (s, 1H), 7.68 - 7.62 (m, 1H), 7.32 (d, 7 = 7.1 Hz, 1H), 7.25 (d, 7 = 8.4 Hz, 1H), 5.07 (dd, 7 = 5.4, 12.8 Hz, 1H), 2.88 (ddd, 7 = 5.4, 13.8, 16.9 Hz, 1H), 2.63 - 2.51 (m, 2H), 2.00-2.03 (m, 7 = 3.2, 10.5 Hz, 1H). HPLC-MS (ESI+): m/z 571.1 [100%, (2M+Na)+], 297.1 [50%, (M+Na)+], 275.2 [30%, (M+H)+] HRMS (ESI ): m/z calcd. for C13H10N2O5 (M-H) 273.0517, found 273.0516.
60%	With potassium acetate; acetic acid; at 120℃;	In a three-neck round bottom flask, 3-hydroxyphthalic anhydride (2 g, 12.18 mmol), 3-aminopiperidine-2,6-dione hydrochloride (2.21 g, 13.42 mmol) and potassium acetate (3.59 g, 36.57 mmol) were dissolved in acetic acid (35.5 mL, 0.3 M). After heating to reflux (120 C) overnight, the solvent was evaporated under reduced pressure to give a grey solid which was washed with water (45 mL). The solid was then subjected to column chromatography (silica gel; (0219) MeOEl/CEhCh, 0 to 1 :9) to give a bright yellow powder which was further washed with activated charcoal to afford 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-l,3-dione as a pale yellow solid (1.9 g, 60%). NMR (400 MHz, DMSO-de): d 10.72 (s, 1H), 10.63 (s, 1H), 7.23 - 7.17 (m, 1H), 6.89 - 6.84 (m, 1H), 6.80 (dd, J= 5.6, 8.0 Hz, 1H), 4.65 - 4.58 (m, 1H), 2.49 - 2.37 (m, 1H), 2.19 - 2.10 (m, 2H)? 1.61 - 1.52 (m, 1H).
56%	With triethylamine; In N,N-dimethyl-formamide; at 90℃;	Example 6 4-(3,4-Dichloro-benzyloxy)-2-(2,6-d-oxo-piperid-n-3-yl)-isoindole-l,3-d-oneStep 1 :[179] Triethylamine (2.70 mL, 19.4 mmol) was added to a mixture of 3- hydroxyphthalic anhydride (3.00 g, 18.3 mmol) and ralphac-alpha-aminoglutarimide hydrochloride <n="57"/>(3.01 g, 18.3 mmol) in DMF (60 mL). The reaction mixture was heated to 90 0C overnight, then cooled to room temperature and the solvent was evaporated under vacuum. The residue was stirred in CH2Cl2 (100 mL) for 30 min and the solvent was removed under vacuum. The residue was stirred in water (120 mL) for 2 h and the resulting solid was filtered, washed with water (50 mL) and dried. 1 ,4-Dioxane (200 mL) was added, and the resulting suspension was stirred for 16 h and filtered; the insoluble material was reserved. The filtrate was treated with decolorizing carbon (2 g) and heated to reflux for 1 h. After cooling to 50 0C, the reaction mixture was filtered through Celite and the filter was washed with additional 1,4-dioxane (50 mL). The filtrate was combined with the insoluble precipitate and evaporated to dryness. The resulting solid was triturated with ethyl acetate (100 mL), filtered and dried to give 2-(2,6-dioxo-piperidin-3-yl)-4-hydroxy-isoindole-l,3-dione, 4.18 g, in 56% yield; 1H NMR (DMSO-J6) delta 1.99-2.06 (m, IH), 2.45-2.61 (m, 2H), 2.82-2.96 (m, IH), 5.08 (dd, J = 12.6 Hz, J = 5.3 Hz, IH), 7.23-7.33 (m, 2H), 7.66 (dd, J = 8.2 Hz, J = 7.2 Hz, IH), 11.10 (s, IH), 11.19 (s, IH).
	With potassium acetate; acetic acid; at 120℃;	A mixture of 3-hydroxyphthalic anhydride (1 equiv.), 3-aminopiperidine-2,6-dione HCl salt (1 equiv.), and potassium acetate (2.5 equiv.) in acetic acid is stirred at 120 C overnight. The dark mixture is cooled and filtered. The filter cake is dissolved in DCM and washed with saturated NaHCO3 and brine. The organic layer is dried (Na2SO4) and concentrated to provide 4- hydroxythalidomide.
	With pyridine; at 110℃; for 9h;Schlenk technique;	4-Hydroxyisobenzofuran-1,3-dione (13, 0.5 g, 3.05 mmoL) and3-amino- pidperidine-2,6-dione hydrochlorides (14, 0.47 g, 3.66mmoL) were taken up in 19 mL of pyridine and heated to 110 C,and the reaction mixture was stirred for 9 h at the same temperature.The mixture was concentrated under reduced pressure andthen purified by silica gel column chromatography with MeOH/DCM (1/70, V/V) as an eluent to give 0.71 g of an off-white solid 15.Yield, 80.1%; TLC Rf 0.41 (MeOH: DCM 1:15, V/V); 1H NMR(400 MHz, DMSO) d 11.20 (s, 1H),11.11 (s, 1H), 7.68 (t, 1H, J 8.0 Hz),7.33 (d, 1H, J 4.0 Hz), 7.27 (d, 1H, J 12.0 Hz), 5.10 (m, 1H),2.89e2.86 (m, 1H), 2.57e2.50 (m, 2H), 2.04e2.01 (m, 1H). 13C NMR(100 MHz, DMSO) d 173.29, 170.50, 167.50, 166.29, 155.94, 136.86,133.62, 124.03, 114.83, 114.76, 49.10, 31.43, 22.50; ESI-HRMS, m/z:[M Na], Calcd. for C13H10N2NaO5 297.0482, Found, 297.0481.
	With sodium acetate; acetic acid; at 90℃;	3-hydroxyphthalic anhydride (2 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (2 mmol) were added to the acetic acid solution, and then sodium acetate (2.4 mmol) was added. The reaction mixture was stirred at 90C overnight. The reaction solution was extracted with dichloromethane (3×50 mL), and the combined organic phase was washed with water, dried over anhydrous MgSO 4, and then evaporated under reduced pressure. The mixture was purified by flash column chromatography to obtain intermediate 7.

Reference： [1]Chemical Communications,2017,vol. 53,p. 7577 - 7580
[2]Patent: WO2017/176958,2017,A1 .Location in patent: Paragraph 0822-0823
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 462 - 481
[4]Patent: WO2018/52949,2018,A1 .Location in patent: Paragraph 0488
[5]ACS Medicinal Chemistry Letters,2020
[6]Journal of the American Chemical Society,2020,vol. 142,p. 11734 - 11742
[7]Angewandte Chemie - International Edition,2017,vol. 56,p. 5738 - 5743
Angew. Chem.,2017,vol. 129,p. 5832 - 5837,6
[8]Patent: WO2017/223452,2017,A1 .Location in patent: Page/Page column 129; 130
[9]Patent: US2016/176916,2016,A1 .Location in patent: Paragraph 0747-0749
[10]Cell Chemical Biology,2019,vol. 26,p. 300 - 9,306
[11]Patent: WO2019/79701,2019,A1 .Location in patent: Paragraph 0259-0262; 0550-0554
[12]Patent: WO2020/23480,2020,A1 .Location in patent: Page/Page column 105
[13]Journal of Medicinal Chemistry,2018,vol. 61,p. 453 - 461
[14]Journal of Medicinal Chemistry,2018,vol. 61,p. 918 - 933
[15]Patent: US2020/239430,2020,A1 .Location in patent: Paragraph 0100
[16]Journal of Medicinal Chemistry,2019,vol. 62,p. 5522 - 5540
[17]Patent: WO2018/148440,2018,A1 .Location in patent: Page/Page column 297; 298; 397; 398
[18]Patent: WO2018/148443,2018,A1 .Location in patent: Page/Page column 278-279
[19]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2317; 2318
[20]Patent: WO2020/113233,2020,A1 .Location in patent: Paragraph 00962; 00994-00996
[21]Patent: WO2020/14489,2020,A2 .Location in patent: Page/Page column 66-67
[22]Chemical Communications,2020,vol. 56,p. 2881 - 2884
[23]Patent: WO2019/241231,2019,A1 .Location in patent: Paragraph 0089
[24]Patent: WO2008/115516,2008,A2 .Location in patent: Page/Page column 55-56
[25]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365
[26]Patent: WO2017/197056,2017,A1 .Location in patent: Page/Page column 248-249
[27]Patent: WO2019/241766,2019,A1 .Location in patent: Paragraph 0427; 0431
[28]European Journal of Medicinal Chemistry,2020,vol. 189
[29]Patent: WO2020/92662,2020,A1 .Location in patent: Paragraph 00131; 00135
[30]Patent: CN111171025,2020,A .Location in patent: Paragraph 0039
[31]European Journal of Medicinal Chemistry,2020,vol. 204

15
[ 24666-56-6 ]
[ 75-36-5 ]
[ 5653-40-7 ]
[ 1135009-12-9 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: acetyl chloride; 2-Amino-4,5-dimethoxybenzoic acid With 1H-imidazole In acetonitrile at 20℃; Stage #2: rac-α-aminoglutarimide hydrochloride With 1H-imidazole; triphenyl phosphite In acetonitrile for 22h; Heating / reflux;	5.45 5.45 3-(6,7-DIMETHOXY-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE To a stirred mixture of 2-amino-4,5-dimethoxybenzoic acid (5.0 g, 25 mmol) and imidazole (2.1 g, 30 mmol) in acetonitrile (50 mL), was added acetyl chloride (2.2 mL, 30 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (4.2 g, 25 mmol), imidazole (3.8 g, 56 mmol) and triphenyl phosphite (7.3 mL, 28 mmol) and heated to reflux for 22 hours. The suspension was filtered and washed with acetonitrile (50 mL) and water (250 mL) to give a solid. The solid was stirred in sodium hydrogen carbonate (sat, 50 mL), and water (50 mL) for 1 hour. The suspension was filtered and washed with water (250 mL) and ethyl acetate (30 mL) to give 3-(6,7-dimethoxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (5.7 g, 68% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9*150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 3.26 min (99.8%); mp: 325° C. (decomp); 1H NMR (DMSO-d6) δ 2.15-2.19 (m, 1H, CHH), 2.56-2.88 (m, 6H, CH3, CH2, CHH), 3.85 (s, 3H, CH3), 3.90 (s, 3H, CH3), 5.22 (dd, J=5, 11 Hz, 1H, NCH), 7.09 (s, 1H, Ar), 7.35 (s, 1H, Ar), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.12, 23.21, 30.62, 55.63, 55.97, 56.38, 104.98, 107.31, 113.27, 143.09, 148.40, 153.24, 154.83, 159.76, 169.61, 172.64; LCMS: MH=332; Anal Calcd for C16H17N3O5: C, 58.00; H, 5.17; N, 12.68. Found: C, 57.88; H, 5.06; N, 12.77.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/93504, 2009, A1 Location in patent: Page/Page column 39-40

16
[ 24666-56-6 ]
[ 75-36-5 ]
[ 619-17-0 ]
[ 1135009-44-7 ]

Yield	Reaction Conditions	Operation in experiment
55%		Step 1: To a stirred mixture of 2-amino-4-nitrobenzoic acid (5.0 g, 28 mmol) and imidazole (2.2 g, 33 mmol) in acetonitrile (50 mL), was added acetyl chloride (2.3 mL, 33 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (4.5 g, 28 mmol), imidazole (4.1 g, 60 mmol) and triphenyl phosphite (8.7 mL, 33 mmol), and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (250 mL), ethyl acetate (250 mL), and water (50 mL) to give 342-methyl-7-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (4.8 g, 55% yield): HPLC: Waters Symmetry C18, 5 mum, 3.9*150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, 5.69 min (95.4%); 1H NMR (DMSO-d6) delta 2.15-2.25 (m, 1H, CHH), 2.59-2.69 (m, 2H, 2CHH), 2.70 (s, 3H, CH3), 2.79-2.87 (m, 1H, CHH), 5.35 (dd, J=6, 12 Hz, 1H, NCH), 8.20-8.29 (m, 2H, Ar), 8.34 (d, J=2 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) delta 20.60, 23.53, 30.49, 56.85, 120.26, 121.58, 124.35, 128.30, 147.08, 151.30, 157.61, 159.52, 160.09, 172.48; LCMS: MH=317.
49.4%		Step 1: Preparation of 21-2 21-2 To a stirred mixture of 2-amino-4-nitrobenzoic acid (2.0 g, 10.9 mmol) and imidazole (0.88 g, 12.84 mmol) in acetonitrile (40 mL), was added Acetyl chloride (1.02 g, 13.0 mmol) at room temperature.The mixture was stirred at room temperature overnight. To the mixture, was added 3- amino-piperidine-2,6-dione hydrogen chloride (1.78 g, 10.9 mmol) , imidazole (1.60 g, 23.24 mmol) and Phosphorous acid, triphenyl ester (4.03 g, 13.0 mmol) , and heated to reflux overnight. Water (200 mL) was added to the mixture.The suspension was filtered and the solid was stirred for 20min in CH3CN(25 mL). The mixture was filtrated to give 3-(2-methyl-7-nitro-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione 21-2 (1.70 g, 5.37 mmol, 49.4 %) as an off-white solid. LC/MS (ES+): m/z 317.2 [M+H]+
49.4%		To a stirred mixture of 2-amino-4-nitrobenzoic acid (28-1) (2.0 g, 10.9 mmol) and imidazole (0.88 g, 12.84 mmol) in acetonitrile (40 mL), was added Acetyl chloride (25-2) (1.02 g, 13.0 mmol) at room temperature.The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (1-2) (1.78 g, 10.9 mmol) , imidazole (1.60 g, 23.24 mmol) and Phosphorous acid, triphenyl ester (4.03 g, 13.0 mmol) , and heated to reflux overnight. Water (200 mL) was added to the mixture. The suspension was filtered and the solid was stirred for 20min in CH3CN(25 mL). The mixture was filtrated to give 3-(2- methyl-7-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (28-2) (1.70 g, 5.37 mmol, 49.4 %) as an off-white solid. LC/MS (ES+): m/z 317 [M + H]+

Reference： [1]Patent: US2009/93504,2009,A1 .Location in patent: Page/Page column 35
[2]Patent: WO2017/197051,2017,A1 .Location in patent: Page/Page column 328-329
[3]Patent: WO2017/197056,2017,A1 .Location in patent: Page/Page column 375

17
[ 394-31-0 ]
[ 24666-56-6 ]
[ 75-36-5 ]
[ 1135008-26-2 ]

Yield	Reaction Conditions	Operation in experiment
31%		5.6 3-(6-HYDROXY-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE To a stirred mixture of <strong>[394-31-0]2-amino-5-hydroxybenzoic acid</strong> (5.1 g, 33 mmol) and imidazole (5.0 g, 73 mmol) in acetonitrile (60 mL), was added acetyl chloride (5.2 mL, 73 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (6.0 g, 37 mmol), imidazole (5.0 g, 73 mmol) and triphenyl phosphite (10.5 mL, 40 mmol) and heated to reflux for 22 hours. To the mixture, was added water (100 mL) and conc HCl until pH ~1. The solvent was removed in vacuo. To the residue, was added water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). To the aqueous layer, was added ethyl acetate (50 mL), and the mixture was stirred at room temperature to give a suspension. The suspension was filtered to give a solid, which was stirred in methanol (50 mL) overnight. The suspension was filtered and washed with methanol (230 mL) and water to give 3-(6-hydroxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (2.97 g, 31% yield): HPLC: Waters Symmetry C18, 5 mum, 3.9150 mm, 1 mL/min, 240 nm, 5/95 grad 95/5 in 5 min CH3CN/0.1% H3PO4, 4.50 min (96.8%); mp: 315-317 C.; 1H NMR (DMSO-d6) delta 2.13-2.18 (m, 1H, CH-H), 2.58 (s, 3H, CH3), 2.62-2.71 (m, 2H, 2CH-H), 2.78-2.91 (m, 1H, CH-H), 5.22 (dd, J=6, 11 Hz, 1H, NCH), 7.24-7.32 (m, 2H, Ar), 7.49 (d, J=9 Hz, 1H, Ar), 10.07 (s, 1H, OH), 11.00 (s, 1H, NH); 13C NMR (DMSO-d6) delta 20.97, 23.10, 30.59, 56.36, 108.59, 121.24, 124.13, 128.19, 140.14, 151.39, 155.89, 160.24, 169.58, 172.63; LCMS: MH=288; Anal Calcd for C14H13N3O4+1H2O: C, 55.08; H, 4.95; N, 13.76. Found: C, 54.82; H, 4.74; N, 13.54.

Reference： [1]Patent: US2009/93504,2009,A1 .Location in patent: Page/Page column 25

18
[ 4389-45-1 ]
[ 24666-56-6 ]
[ 75-36-5 ]
[ 1135008-96-6 ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: 3-methylantranilic acid; acetyl chloride With 1H-imidazole In acetonitrile at 20℃; Stage #2: rac-α-aminoglutarimide hydrochloride With 1H-imidazole; triphenyl phosphite In acetonitrile for 22h; Heating / reflux;	5.38 5.38 3-(2,8-DIMETHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE To a stirred mixture of 2-amino-3-methylbenzoic acid (3.0 g, 20 mmol) and imidazole (1.6 g, 24 mmol) in acetonitrile (30 mL), was added acetyl chloride (1.7 mL, 24 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (3.3 g, 20 mmol), imidazole (3.0 g, 68 mmol) and triphenyl phosphite (6.2 mL, 24 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2100 mL), ethyl acetate (2100 mL), sodium hydrogen carbonate (sat, 100 mL) and water (100 mL) to give a white solid, which was stirred in DMSO (20 mL) at 65° C. The mixture was polished filtered and washed with DMSO (10 mL). To the filtrate, was added water (100 mL) to give a suspension. The suspension was filtered and washed with water (250 mL) to give 3-(2,8-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (3.2 g, 56% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 5.85 min (99.6%); mp: 296-298° C.; 1H NMR (DMSO-d6) δ 2.12-2.24 (m, 1H, CHH), 2.51 (s, 3H, CH3), 2.48-2.74 (m, 2H, 2CHH), 2.66 (s, 3H, CH3), 2.76-2.91 (m, 1H, CHH), 5.27 (dd, J=6, 11 Hz, 1H, NCH), 7.38 (t, J=8 Hz, 1H, Ar), 7.67 (d, J=7 Hz, 1H, Ar), 7.86 (dd, J=0.6, 8 Hz, 1H, Ar), 11.02 (s, 1H, N); 13C NMR (DMSO-d6) δ 16.91, 20.91, 23.80, 30.60, 56.51, 120.23, 123.59, 126.05, 134.72, 134.94, 145.25, 153.82, 160.71, 169.51, 172.62; LCMS: MH=286; Anal Calcd for C15H15N3O3+0.2H2O: C, 62.36; H, 5.37; N, 14.54. Found: C, 62.21; H, 5.31; N, 14.43.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/93504, 2009, A1 Location in patent: Page/Page column 37

19
[ 6388-47-2 ]
[ 24666-56-6 ]
[ 75-36-5 ]
[ 1135009-01-6 ]

Yield	Reaction Conditions	Operation in experiment
38%		5.40 3-(8-CHLORO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE To a stirred mixture of <strong>[6388-47-2]2-amino-3-chlorobenzoic acid</strong> (2.2 g, 13 mmol) and imidazole (1.1 g, 16 mmol) in acetonitrile (30 mL), was added acetyl chloride (1.1 mL, 16 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.3 g, 14 mmol), imidazole (1.9 g, 28 mmol) and triphenyl phosphite (4.0 mL, 15 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (250 mL), ethyl acetate (250 mL), and water (50 mL) to give a white solid, which was stirred in methanol (50 mL) overnight. The suspension was filtered and washed with methanol (30 mL) and water (30 mL) to give 3-(8-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (1.5 g, 38% yield): HPLC: Waters Symmetry C18, 5 mum, 3.9*150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 6.51 min (99.6%); mp: 290-292 C.; 1H NMR (DMSO-d6) delta 2.16-2.23 (m, 1H, CHH), 2.59-2.69 (m, 5H, C/A, 2CHH), 2.79-2.87 (m, 1H, CH h, 5.32 (dd, J=5, 11 Hz, 1H, NCH), 7.48 (t, J=8 Hz, 1H, Ar), 7.96-8.02 (m, 2H, Ar), 11.07 (s, 1H, NH); 13C NMR (DMSO-d6) delta 20.68, 23.75, 30.51, 56.68, 121.87, 125.08, 126.91, 130.03, 134.69, 143.14, 156.14, 159.88, 169.23, 172.51; LCMS: MH=306, 308; Anal Calcd for C14H12N3O3Cl: C, 55.00; H, 3.96; N, 13.74; Cl, 11.60. Found: C, 54.73; H, 3.96; N, 13.58; Cl, 11.03.

Reference： [1]Patent: US2009/93504,2009,A1 .Location in patent: Page/Page column 38

20
[ 24666-56-6 ]
[ 75-36-5 ]
[ 2789-92-6 ]
[ 1135009-14-1 ]

Yield	Reaction Conditions	Operation in experiment
58%		5.46 3-(6,8-DICHLORO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE To a stirred mixture of <strong>[2789-92-6]2-amino-3,5-dichlorobenzoic acid</strong> (5.0 g, 24 mmol) and imidazole (1.9 g, 28 mmol) in acetonitrile (60 mL), was added acetyl chloride (2.0 mL, 28 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (3.9 g, 24 mmol), imidazole (3.5 g, 52 mmol) and triphenyl phosphite (6.8 mL, 26 mmol) and heated to reflux for 22 hours. The suspension was filtered and washed with acetonitrile (30 mL), water (230 mL), and ethyl acetate (30 mL) to give 3-(6,8-dichloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (4.65 g, 58% yield): HPLC: Waters Symmetry C18, 5 mum, 3.9150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.78 min (100%); mp: 238-240 C.; 1H NMR (DMSO-d6) delta 2.15-2.22 (m, 1H, CHH), 2.55-2.69 (m, 5H, CH3, 2CHH), 2.78-2.91 (m, 1H, CHH), 5.33 (dd, J=6, 11 Hz, 1H, NCH), 7.96 (d, J=2 Hz, 1H, Ar), 8.15 (d, J=2 Hz, 1H, Ar), 11.09 (s, 1H, NH); 13C NMR (DMSO-d6) delta 20.63, 23.85, 30.54, 56.92, 122.55, 24.24, 130.51, 131.72, 134.38, 142.25, 156.80, 159.07, 169.12, 172.53; LCMS: MH=340, 342; Anal Calcd for C14H11N3O3Cl2: C, 49.43; H, 3.26; N, 12.35; Cl, 20.84. Found: C, 49.21; H, 3.11; N, 12.30; Cl, 19.43.

Reference： [1]Patent: US2009/93504,2009,A1 .Location in patent: Page/Page column 40

21
[ 402-13-1 ]
[ 24666-56-6 ]
[ 75-36-5 ]
[ 1135008-83-1 ]

Yield	Reaction Conditions	Operation in experiment
24%		5.32 3-(2-METHYL-4-OXO-7-TRIFLUOROMETHYL-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE To a stirred mixture of <strong>[402-13-1]2-amino-4-(trifluoromethyl)benzoic acid</strong> (3.0 g, 15 mmol) and imidazole (1.2 g, 18 mmol) in acetonitrile (30 mL), was added acetyl chloride (1.3 mL, 18 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.4 g, 15 mmol), imidazole (2.2 g, 32 mmol) and triphenyl phosphite (4.6 mL, 18 mmol) and heated to reflux for 22 hours. To the mixture, was added water (100 mL). The suspension was filtered and washed with water (250 mL), ethyl acetate (250 mL), sodium hydrogen carbonate (sat, 50 mL) and water (50 mL) to give a white solid, which was dissolved in DMSO (10 mL). To the solution, was added water (3 mL) to give a suspension. The suspension was filtered and washed with DMSO (2 mL) to give a white solid. The solid was stirred in water (50 mL) at 60 C. for 2 hours, then at room temperature overnight. The suspension was filtered and washed with water (250 mL) to give 3-(2-methyl-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (1.17 g, 24% yield): HPLC: Waters Symmetry C18, 5 mum, 3.9150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 8.14 min (99.9%); mp: 277-279 C.; 1H NMR (DMSO-d6) delta 2.18-2.25 (m, 1H, CHH), 2.59-2.74 (m, 5H, CH3, 2CH-H), 2.81-2.88 (m, 1H, CHH), 5.34 (dd, J=6, 11 Hz, 1H, NCH), 7.80 (dd, J=2, 8 Hz, 1H, Ar), 7.96 (s, 1H, Ar), 8.24 (d, J=8 Hz, 1H, Ar), 11.09 (s, 1H, NH); 13C NMR (DMSO-d6) delta 20.73, 23.54, 30.57, 56.82, 122.30 (q, JC-F=3 Hz), 122.99, 123.45 (q, JC-F=273 Hz), 123.74 (q, JC-F=4 Hz), 127.85, 134.22 (q, JC-F=32 Hz), 146.84, 156.98, 159.80, 169.24, 172.56; LCMS: MH=340; Anal Calcd for C15H12N3O3F3: C, 53.10; H, 3.57; N, 12.39; F, 16.80. Found: C, 52.55; H, 3.42; N, 12.21; F, 17.18.

Reference： [1]Patent: US2009/93504,2009,A1 .Location in patent: Page/Page column 34

22
[ 313-12-2 ]
[ 24666-56-6 ]
[ 75-36-5 ]
[ 1135009-09-4 ]

Yield	Reaction Conditions	Operation in experiment
10%		5.43 3-(2-METHYL-4-OXO-8-TRIFLUOROMETHYL-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE To a stirred mixture of <strong>[313-12-2]2-amino-3-(trifluoromethyl)benzoic acid</strong> (2.0 g, 9.8 mmol) and imidazole (0.8 g, 12 mmol) in acetonitrile (20 mL), was added acetyl chloride (0.83 mL, 12 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (1.6 g, 9.8 mmol), imidazole (1.5 g, 22 mmol) and triphenyl phosphite (3.1 mL, 12 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (250 mL), ethyl acetate (250 mL), sodium hydrogen carbonate (sat, 50 mL) and water (50 mL) to give 3-(2-methyl-4-oxo-8-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white so id (0.32 g, 10percent yield): HPLC: Waters Symmetry C18, 5 mum, 3.9*150 mm, 1 mL/min, 240 nm, 35/65 CH3CN/0.1percent H3PO4, 7.57 min (99.8percent); mp: 351-353° C.; 1H NMR (DMSO-d6) delta 2.19-2.26 (m, 1H, CHH), 2.59-2.70 (m, 5H, CH3, 2CHH), 2.81-2.93 (m, 1H, CHH), 5.34 (dd, J=5, 11 Hz, 1H, NCH), 7.64 (t, J=8 Hz, 1H, Ar), 8.20 (d, J=8 Hz 1H, Ar), 8.31 (d, J=8 Hz, 1H, Ar), 11.09 (s, 1H, NH); 13C NMR (DMSO-d6) delta 20.67, 24.05, 30.57, 56.84, 121.48, 123.52 (q, JC-F=274 Hz), 124.77 (q, JC-F=30 Hz), 125.98, 130.74, 132.29 (q, JC-F=5 Hz), 144.20, 156.71, 159.68, 169.28, 172.58; LCMS: MH=340; Anal Calcd for C15H12N3O3F3+0.3H2O+0.1 CH3CN: C, 52.34; H. 3.72; N, 12.45; F, 16.34. Found: C, 52.71; H, 3.52; N, 12.31; F, 15.99.

Reference： [1]Patent: US2009/93504,2009,A1 .Location in patent: Page/Page column 39

23
[ 20776-50-5 ]
[ 24666-56-6 ]
[ 75-36-5 ]
[ 1135008-81-9 ]

Yield	Reaction Conditions	Operation in experiment
75%		5.31 3-(7-BROMO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE To a stirred mixture of <strong>[20776-50-5]2-<strong>[20776-50-5]amino-4-bromobenzoic acid</strong></strong> (2.0 g, 9.3 mmol) and imidazole (0.8 g, 11 mmol) in acetonitrile (20 mL), was added acetyl chloride (0.8 mL, 11 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (1.5 g, 9.3 mmol), imidazole (1.4 g, 20 mmol) and triphenyl phosphite (2.9 mL, 11 mmol) and heated to reflux for 22 hours. To the mixture, was added water (30 mL). The suspension was filtered and washed with water (250 mL), ethyl acetate (250 mL), and water (50 mL) to give 3-(7-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (2.4 g, 75% yield): HPLC: Waters Symmetry C18, 5 mum, 3.9*150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 18.65 min (98.9%); mp: 315-317 C.; 1H NMR (DMSO-d6) delta 2.08-2.22 (m, 1H, CHH), 2.62-2.79 (m, 5H, CH3, 2CHH), 2.80-2.91 (m, 1H, CHH), 5.28 (dd, J=6, 11 Hz, 1H, NCH), 7.66 (dd, J=2, 8 Hz, 1H, Ar), 7.84 (d, J=2 Hz 2H, Ar), 7.95 (d, J=8 Hz, 1H, Ar), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) delta 20.83, 23.53, 24.02, 30.58, 56.67, 119.36, 128.06, 128.29, 128.80, 129.67, 147.93, 156.69, 160.02, 169.33, 172.57; LCMS: MH=350, 352; Anal Calcd for C14H12N3O3Br: C, 48.02; H, 3.45; N, 12.00; Br, 22.82. Found: C, 47.94; H, 3.17; N, 11.85; Br, 20.65.

Reference： [1]Patent: US2009/93504,2009,A1 .Location in patent: Page/Page column 34

24
[ 4389-45-1 ]
[ 24666-56-6 ]
[ 1135009-51-6 ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: 3-methylantranilic acid With 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 5h; Stage #2: rac-α-aminoglutarimide hydrochloride With acetic acid; triethylamine In acetonitrile for 16h; Heating / reflux;	5.44.1 Step 1: A mixture of 2-amino-3-methylbenzoic acid (2.1 g, 14 mmol) and CDI (1.9 g, 12 mmol) in acetonitrile (25 mL) was stirred at room temperature for 5 hours. To the suspension, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.3 g, 14 mmol), triethylamine (7.2 mL, 66 mmol) and acetic acid (8 mL, 132 mmol), and the mixture was heated to reflux for 16 hours. To the mixture, was added water (75 mL) and stirred at room temperature for 2 hours. The suspension was filtered and washed with water (50 mL) and ethyl acetate (20 mL) to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-3-methyl-benzamide as a white solid (1.9 g, 61% yield): 1H NMR (DMSO-d6) δ 1.92-1.99 (m, 1H, CHH), 2.06 (s, 3H, CH3), 2.04-2.14 (m, 1H, CHH), 2.51-2.56 (m, 1H, CHH), 2.73-2.85 (m, 1H, CHH), 4.69-4.78 (m, 1H, NCH), 6.22 (brs, 2H, NH2), 6.50 (t, J=8 Hz, 1H, Ar), 7.10 (d, J=8 Hz, 1H, Ar), 7.40 (d, J=8 Hz, 1H, Ar), 8.47 (d, J=8 Hz, 1H, NH), 10.83 (s, 1H, NH); LCMS: MH=262.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/93504, 2009, A1 Location in patent: Page/Page column 39

25
[ 4692-98-2 ]
[ 24666-56-6 ]
[ 1135009-20-9 ]

Yield	Reaction Conditions	Operation in experiment
72%	With acetic acid; triethylamine; In acetonitrile; at 90℃; for 18h;	Step 1: A stirred mixture of 5-bromo-isatoic anhydride (6.0 g, 25 mmol), 3-amino-piperidine-2,6-dione hydrogen chloride (4.1 g, 25 mmol), triethylamine (18 mL, 129 mmol), and acetic acid (15 mL, 262 mmol) in acetonitrile (60 mL) was heated at 90 C. for 18 hours. The suspension was filtered and washed with acetonitrile (280 mL), water (280 mL) and ethyl acetate (2*80 mL) to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide as a white solid (5.8 g, 72% yield): LCMS: MH=326, 328. The sample was used in the next step without further purification. Step 1: A stirred mixture of 5-bromo-isatoic anhydride (6.0 g, 25 mmol), 3-amino-piperidine-2,6-dione hydrogen chloride (4.1 g, 25 mmol), triethylamine (18 mL, 129 mmol), and acetic acid (15 mL, 262 mmol) in acetonitrile (60 mL) was heated at 90 C. for 18 hours. The suspension was filtered and washed with acetonitrile (2×80 mL), water (2×80 mL) and ethyl acetate (2×80 mL) to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide as a white solid (5.8 g, 72% yield): LCMS: MH=326, 328. The sample was used in the next step without further purification.

Reference： [1]Patent: US2009/93504,2009,A1 .Location in patent: Page/Page column 24-25; 26

26
[ 652-12-0 ]
[ 24666-56-6 ]
2-[(2,6-dioxo-3-piperidinyl)amino]carbonyI}-3,4,5,6-tetrafluorobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		Triethylamine (0.65 mi, 4.54 mmol) was added to a suspension of 16 (0.37 g, 2.27 mmol) in dry tetrahydrofuran (40 ml) and the mixture was stirred at room temperature for 10 min. Tetrafluorophthalic anhydride (17) (0.50 g, 2.27 mmol) was added and stirring was continued at room temperature for 48 h. The reaction mixture was partitioned between ethyl acetate and water and the aqueous portion was acidified with 2N HCl and extracted with ethyl acetate (5 times). The combined extracts were worked up to give an oil which was dried well in vacuo and then triturated with diethyl ether until crystallization began. The solid was filtered off and further triturated with cold diethyl ether (5 times) to give the title compound 2 as a white powder (0.54 g, 62%), mp 254-258 0C. 1H NMR (400 MHz, DMSO-D6) δ ppm 14.00 (br, IH), 10.85 (s, IH, exch. with D2O), 9.08 (d, J=8.0 Hz, IH, exch. with D2O), 4.75-4.69 (m, IH), 2.79-2.69 (m, <n="15"/>IH), 2.58-2.48 (m, IH), 2.08-2.00 (m, IH)5 1.99-1.90 (m, IH). Found: C, 44.71; H, 2.43; N3 7.82. C13H8F4N2O5 requires C, 44.84; H, 2.32; N, 8.05%.

Reference： [1]Patent: WO2008/7979,2008,A1 .Location in patent: Page/Page column 13; 14

27
[ 20320-43-8 ]
[ 24666-56-6 ]
N-(2,6-dioxo-3-piperidinyl)-2-(1-pyrroIidinylcarbonyI)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: 2-(pyrrolidin-1-ylcarbonyl)benzoic acid With pivaloyl chloride; triethylamine In dichloromethane at 5℃; for 1h; Stage #2: rac-α-aminoglutarimide hydrochloride With triethylamine In dichloromethane at 20℃; for 16h;	3 Pivaloyl chloride (0.62 ml, 5.01 mmol) was added dropwise at 5 0C to a solution of (20) (1.0Og, 4.56 mmol) and triethylamine (0.70 ml, 5.02 mmol) in dichloromethane (20 ml) and the solution was stirred at this temperature for 1 h. Triethylamine (1.40 ml, 0.01 mol) was added, followed by the powdered salt (16) (0.79 g, 4.79 mmol). The solution was stirred at room temperature for 16 h and the crude product was adsorbed directly onto silica by removal of the solvent, and chromatographed. Ethyl acetate eluted fore fractions, while 5-10% methanol/ethyl acetate eluted crude (21), which was triturated with diethyl ether to leave the title compound (21) as a hygroscopic white powder (0.53 g, 35%), mp 106-109 0C. 1H NMR (400 MHz, DMSO-D6) δ ppm 10.81 (br s, IH), 8.59 (d, J=8.3 Hz, IH), 7.68 (dd, J=7.5, 1.0 Hz, IH), 7.55 (ddd, J=7.4, 7.4, 1.1 Hz, IH)5 7.49 (ddd, J=7.5, 7.4, 1.1 Hz, IH), 7.32 (dd, J=7.5, 1.1 Hz, IH), 4.75-4.69 (m, IH), 3.42-3.36 (m, 2H), 3.15-3.06 (m, 2H), 2.82-2.73 (m, IH), 2.57-2.50 (m, IH), 2.06-1.92 (m, 2H), 1.88-1.74 (m, 4H). Found: C, 61.84; H, 6.10; N, 12.07. C17Hi9N3O4.1/4Et2O requires C, 62.15; H, 6.23; N, 12.08%.

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF AUCKLAND - WO2008/7979, 2008, A1 Location in patent: Page/Page column 15; 16

28
[ 53600-33-2 ]
[ 24666-56-6 ]
[ 75-36-5 ]
3-(5-methoxy-2-methyl-4-oxoquinazolin-3-yl)piperidin-2,6-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%		5.8 3-(5-METHOXY-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-To a stirred mixture of 2-amino-6-methoxybenzoic acid (2.0 g, 12 mmol) and imidazole (1.0 g, 14 mmol) in acetonitrile (20 mL), was added acetyl chloride (1.0 mL, 14 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.0 g, 12 mmol), imidazole (1.8 g, 26 mmol) and triphenyl phosphite (3.8 mL, 14 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2 X 50 mL), ethyl acetate (2 X 50 mL), sodium hydrogen carbonate (sat, 50 mL) and water (50 mL) to give 3-(5-methoxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (1.3 g, 35% yield): HPLC: Waters Symmetry Ci8, 5μm, 3.9 x 150 mm, 1 mL/min, 240 nm, 15/85 CH3CN/0.1 % H3PO4, 3.37 min (99.4 %); mp: 274-276 0C; 1H NMR (DMSO-d6) δ 2.09-2.16 (m, IH, CHH), 2.51- 2.63 (m, 5η, CH3, 2CηH), 2.72-2.89 (m, 1 η, CηH), 3.83 (s, 3η, CH3), 5.14 (dd, J = 6, 1 1 Hz, I H, NCH), 6.98 (d, J = 8 Hz, IH, Ar), 7.12 (d, J = 8 Hz, IH, Ar), 7.69 (t, J = 8 Hz, IH, Ar), 10.96 (s, IH, NH); 13C NMR (DMSO-d6) δ 20.84, 23.36, 30.55, 55.85, 56.16, 107.96, 109.91, 118.26, 134.98, 149.24, 155.30, 158.13, 159.42, 169.63, 172.63; LCMS: MH = 302; Anal Calcd for C15H15N3O4 + 1.6 H2O: C, 54.57; H, 5.56; N, 12.73. Found: C, 54.19; H, 5.42; N, 12.55

Reference： [1]Patent: WO2008/39489,2008,A2 .Location in patent: Page/Page column 45

29
[ 434-76-4 ]
[ 24666-56-6 ]
[ 75-36-5 ]
3-(5-fluoro-2-methyl-4-oxoquinazolin-3⁽⁴¹¹⁾-yl)piperidine-2,6-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		5.9 S-fS-FLUORO-Z-METHYL^-OXO^H-OUINAZOLIN-S-YLVPIPERIDINE- 2.6-DIONETo a stirred mixture of <strong>[434-76-4]2-amino-6-fluorobenzoic acid</strong> (5.3 g, 34 mmol) and imidazole (2.8 g, 41 mmol) in acetonitrile (60 mL), was added acetyl chloride (2.9 mL, 41 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (6.1 g, 37 mmol), imidazole (5.1 g, 75 mmol) and triphenyl phosphite (10.6 mL, 41 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2 X 50 mL), ethyl acetate (2 X 50 mL), and water (50 mL) to give a white solid, which was stirred in methanol (50 mL) overnight. The suspension was washed with methanol (30 mL) and water (30 mL) to give 3-(5-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid <n="47"/>(7.6 g, 78% yield): HPLC: Waters Symmetry C18, 5mum, 3.9 x 150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 3.8 min (99.6 %); mp: 275-277 0C; 1H NMR (DMSO-d6) delta 2.13-2.20 (m, I H, CHH), 2.57-2.69 (m, 5eta, CH3, 2CetaH), 2.77-2.90 (m, 1eta, CetaH), 5.25 (dd, J = 6, 1 1 Hz, I H, NCH), 7.26 (ddd, J = 0.6, 8, 1 1 Hz, IH, Ar), 7.44 (d, J = 8 Hz, IH, Ar), 7.80 (dt, J = 5, 8 Hz IH, Ar), 1 1.04 (s, I H, NH); 13C NMR (DMSOd6) delta 20.73, 23.45, 30.57, 56.45, 109.79 (d, JC.F = 6 Hz), 1 12.89 (d, Jc-F = 21 Hz), 122.64 (d, Jc-F = 4 Hz), 135.39 (d, Jc-F = 11 Hz), 148.86, 156.22, 157.46, 160.15 (d, Jc. F = 264 Hz), 169.38, 172.57; LCMS: MH = 290; Anal Calcd for C14H12N3O3F: C, 58.13; H, 4.18; N, 14.53; F, 6.57. Found: C, 57.98; H, 4.00; N, 14.45; F, 6.73

Reference： [1]Patent: WO2008/39489,2008,A2 .Location in patent: Page/Page column 45-46

30
[ 188187-03-3 ]
[ 24666-56-6 ]
[ 1198299-48-7 ]