[ CAS No. 50-35-1 ]

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Product Details

CAS No. :50-35-1MDL No. :MFCD00153873
Formula :C13H10N2O4InChI Key :UEJJHQNACJXSKW-UHFFFAOYSA-N
M.W :258.23Pubchem ID :5426
Boiling Point :509.7°C at 760 mmHg
Synonyms :

Computed Properties

TPSA : 83.6 H-Bond Acceptor Count : 4
XLogP3 : - H-Bond Donor Count : 1
SP3 : 0.23 Rotatable Bond Count : 1

Safety

Signal Word:WarningClassN/A
Precautionary Statements:P261-P305+P351+P338UN#:N/A
Hazard Statements:H302-H315-H319-H335Packing Group:N/A
GHS Pictogram:

Application In Synthesis

  • Upstream synthesis route

[ 50-35-1 ] Synthesis Path-Upstream   1~29

  • 1
  • [ 3343-28-0 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation in experiment
50% With urea In tetralin at 180℃; In a manner analogue to that of Example 4, a reaction was performed using tetraline as the solvent.
The reaction temperature was 180° C.
Thalidomide was isolated in a yield of 50percent.
49% With urea In diethylene glycol diethylether at 180℃; for 1.00 h; 50 g (0.193 mol) of phthaloyl glutamic anhydride were heated to 180° C. in 75 g of diethyleneglycol diethylether.
After the reaction temperature was reached 16.5 g (0.275 mol) of urea were spread in under constant flushing with N2 (exothermal).
Afterwards, further stirring was carried out for 1 hour at the reaction temperature while constant flushing with N2 was performed.
At the end of the reaction period, the reaction was diluted with dimethylsulfoxide (DMSO), cooled and then added with ethanol.
Following filtering, washing and drying 24.9 g (49percent of the theoretical yield) of thalidomide were obtained.
49% With urea In N,N-diethylaniline at 180℃; In a manner analogue to that of Example 14, N,N-diethylaniline was used as solvent at 180° C.
Thalidomide was isolated in a yield of 49percent.
48% With urea In sulfolane at 175 - 180℃; for 2.00 h; 75 g of sulfolane were heated to 175° C.
At this temperature, a mixture of 50 g (0.193 mol) of phthaloyl glutamic anhydride and 16.5 g (0.275 mol) of urea was spread in under constant flushing with N2.
Afterwards, the stirring was continued for approx.
2 hours at about 180° C. under constant flushing with N2.
At the end of the reaction period, cooling was performed and then 285 g ethanol were added.
After filtering, washing and drying 24.3 g (48percent of the theoretical yield) of thalidomide were obtained.
Reactions of adipic anhydride with urea
48% With urea In sulfolane at 180℃; In a manner analogue to that of Example 14, sulfolane was used as solvent at 180° C.
Thalidomide was isolated in a yield of 48percent.
48% With urea In decalin at 180℃; In a manner analogue to that of Example 4, a reaction was performed using decaline as the solvent.
The reaction temperature was 180° C.
Thalidomide was isolated in a yield of 48percent.
46% With urea In decaethylene glycol at 185℃; In a manner analogue to that of Example 14, polyethylene glycol 400 was used as solvent at 185° C.
Thalidomide was isolated in a yield of 46percent.
40% With urea In 1,3-dimethyl-2-imidazolidinone at 185℃; In a manner analogue to that of Example 14, 1,3-dimethyl-2-imidazolidinone (DMI) was used as solvent at 185°.
Thalidomide could be isolated in a yield of 40percent.
39% With urea In ortho-diethylbenzene at 170℃; In a manner analogue to that of Example 4, a reaction was performed using diethylbenzene as the solvent.
The reaction temperature was 1700C. Thalidomide was isolated in a yield of 39percent.
38% With urea In diphenylether at 185℃; In a manner analogue to that of Example 4, a reaction was performed using diphenylether as the solvent.
The reaction temperature was 185° C.
Thalidomide could be isolated in a yield of 38percent.
38% With urea In 1-methyl-pyrrolidin-2-one at 180℃; for 1.00 h; 50 g (0.193 mol) of phthaloyl glutamic anhydride were heated to 180° C. in 75 g of NMP.
After the reaction temperature was achieved 16.5 g (0.275 mol) of urea were spread in under constant flushing with N2 (exothermal).
Afterwards, the stirring was continued for 1 hour at the reaction temperature under constant flushing with N2.
At the end of the reaction period cooling was performed and then ethanol was added.
Following filtering, washing and drying, 19.3 g (38percent of the theoretical yield) of thalidomide were obtained.
35% With urea In formamide at 185℃; In a manner analogue to that of Example 14, formamide was used as solvent at 185° C.
Thalidomide could be isolated in a yield of 35percent.
34% With urea In 1-ethyl-3-methyl imidazolium tosylate at 185℃; In a manner analogue to that of Example 4, a reaction was performed using 1-ethyl-3-methyl imidazolium tosylate as the solvent.
The reaction temperature was 185° C.
Thalidomide was isolated in a yield of 34percent.
30% With urea In 1,2-propylene cyclic carbonate at 180℃; In a manner analogue to that of Example 14, propylene carbonate was used as solvent at 180° C.
Thalidomide could be isolated in a yield of 30percent.
25% With urea In 1,2,4-Trimethylbenzene at 160℃; In a manner analogue to that of Example 4, a reaction was performed using pseudocumene as the solvent.
The reaction temperature was 160° C.
Thalidomide was isolated in a yield of 25percent.
23% With urea In 1,3,5-trimethyl-benzene at 160℃; In a manner analogue to that of Example 4, a reaction was performed using mesitylene as the solvent.
The reaction temperature was 160° C.
Thalidomide was isolated in a yield of 23percent.
20% With urea In decamethylcyclopentasiloxane at 180℃; In a manner analogue to that of Example 4, a reaction was performed using decamethylcyclopentasiloxane as the solvent.
The reaction temperature was 180° C.
Thalidomide could be isolated in a yield of 20percent.
11% With urea In Isopropylbenzene at 150℃; In a manner analogue to that of Example 4, a reaction was performed using cumene as the solvent.
The reaction temperature was 150° C.
Thalidomide was isolated in a yield of 11percent.

Reference: [1] Pharmaceutical Research, 2002, vol. 19, # 1, p. 13 - 19
[2] Arzneimittel-Forschung/Drug Research, 1981, vol. 31, # 6, p. 941 - 949
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2010, vol. 53, # 2, p. 53 - 57
[4] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[5] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 2
[6] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[7] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 1; 3
[8] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 1; 3
[9] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[10] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[11] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[12] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[13] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[14] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[15] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[16] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[17] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[18] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 2
[19] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[20] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 3
[21] Patent: US2007/173647, 2007, A1. Location in patent: Page/Page column 2
[22] Patent: US2830991, 1955,
[23] Patent: GB768821, 1955,
  • 2
  • [ 85-44-9 ]
  • [ 617-65-2 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation in experiment
86% at 150℃; for 0.17 h; Microwave irradiation; Sealed tube; Green chemistry 2-(2,6-Dioxopiperidin-3-yl)isoindole-1,3-dione. (1): phthalicanhydride (0.10 g, 0.68mmol), glutamic acid (0.10 g,0.68mmol), DMAP (0.02 g, 0.16mmol), and NH4Cl (0.04 g,0.75mmol) were mixed thoroughly in a CEM-sealed vialwith a magnetic stirrer.The sample was heated for 10min at150C in a CEM Discover microwave powered at 150W. Itwas then cooled rapidly to 50C.When at room temperatureit was dissolved in 15mL of (1 : 1) ethyl acetate : acetone. Theorganic layer was washed with 2x (10 mL) distilled water andthen dried over sodium sulfate (anhydrous). The organiclayer was concentrated under vacuum. The residue wastreated with hexanes (30mL) affording a white solid (0.14 g,80percent). mp 268–270∘C. 1H NMR (400MHz, DMSO-d6) δ 11.14 (s, 1 H, NH), 7.94 (m, 4 H, Ar), 5.17 (dd, 1H, 12.5, 5.5Hz),2.92 (m, 1 H), 2.57 (m, 2), 2.09 (m, 1H); 13C NMR (100MHz,DMSO-d6) 172.7, 169.8, 167.1, 134.9, 131.2,123.4, 49.0, 30.9,22.0; MS m/z 258 (M+); 230, 213, 202, 173, 148, 111, 76,50.
Reference: [1] Journal of Chemistry, 2017, vol. 2017,
  • 3
  • [ 85-44-9 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation in experiment
54% With triethylamine In tetrahydrofuran for 48.00 h; Heating / reflux Thalidomide (1) was prepared and isolated as follows. A mixture of 4, phthalic anhydride and Et3N in THF was refluxed for two days. The reaction mixture was concentrated and purification by column chromatography (eluent CH2CL2/ETOAC=6 : 1) gave thalidomide (104 mg, 54percent) as white crystals.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 21, p. 5819 - 5824
[2] Patent: WO2005/28436, 2005, A2. Location in patent: Page/Page column 31; 54
  • 4
  • [ 85-44-9 ]
  • [ 56-85-9 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation in experiment
71%
Stage #1: at 20 - 80℃; for 6.00 h;
Stage #2: With 1,1'-carbonyldiimidazole In ISOPROPYLAMIDE at 20 - 90℃; for 4.00 h;
Example 6; 10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of dimethyl-acetamide in a 250 ml 5-neck round-bottom flask at room temperature, followed by 10 g (67.6 mmoles) of phthalic anhydride and the mixture is heated to T=80° C. After 6 h the solution is cooled to 30° C. and dropped in a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole dissolved in 20 ml of dimethyl-acetamide at room temperature. The resulting solution is heated to 85-90° C. and kept under stirring at this temperature for 4 h, then the solution is poured into a conical flask containing 500 ml of cold water. The precipitated solid is filtered, washed twice with 250 ml of water and taken up in 100 ml of (4/1) water/ethanol. After filtering and drying overnight under vacuum at 40° C. a crystalline white solid is obtained (12.5 g; Y=71percent).
65%
Stage #1: at 20 - 80℃; for 6.00 h;
Stage #2: With 1,1'-carbonyldiimidazole In 1-methyl-pyrrolidin-2-one at 20 - 90℃; for 4.00 h;
Example 5; 10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of N-methyl-2-pyrrolidone in a 250 ml 5-neck round-bottom flask at room temperature, followed by 10 g (67.60 mmoles) of phthalic anhydride and heated to T=80° C. After 6 h the solution is cooled to 30° C. and poured into a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole dissolved in 30 ml of N-methyl-2-pyrrolidone at room temperature. The solution is heated at 85-90° C. and kept under stirring at this temperature for 4 h. The solution is then poured into a conical flask containing 500 ml of cold water. The precipitated solid is filtered, washed twice with 250 ml of water and taken up in 100 ml of (4/1) water/ethanol. After filtration and drying overnight under vacuum at 40° C. a crystalline white solid is obtained (11.5 g; 24 mmoles; Y=65percent).
63%
Stage #1: at 20 - 80℃; for 6.00 h;
Stage #2: With 1,1'-carbonyldiimidazole In DMF (N,N-dimethyl-formamide) at 20 - 90℃; for 4.00 h;
Example 7; Following the procedure of example 6 using dimethyl-formamide instead of dimethyl-acetamide thalidomide is obtained in 63percent yield.
62%
Stage #1: at 20 - 80℃; for 6.00 h;
Stage #2: With 1,1'-carbonyldiimidazole In dimethyl sulfoxide at 20 - 90℃; for 4.00 h;
Example 4; 10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of DMSO in a 250 ml 5-neck round-bottom flask at room temperature, added with 10 g (67.60 mmoles) of phthalic anhydride and heated to T=80° C. After 6 h the solution is cooled to 20° C., filtered and poured into a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole in 20 ml of DMSO at 20° C. The resulting solution is heated to 85-90° C. and stirred at this temperature for 4 h. The solution is then poured into a conical flask containing 500 ml of cold water (about 5° C.) and left under stirring for 2 h at room temperature. The precipitated solid is filtered and washed twice with 250 ml of water. The filtered solid is then suspended in 200 ml of (4/1) water/methanol at 60° C., filtered and dried overnight under vacuum at 40° C., to give a crystalline white product (10.9 g, yield 62percent).
60%
Stage #1: at 20 - 85℃; for 6.00 h;
Stage #2: at 40℃; for 2.00 h;
Stage #3: With hydrogenchloride In ethanol; water at 5 - 25℃; for 4.00 h;
EXAMPLES; Example 1; L-glutamine (10 g; 68.42 mmoles) is suspended in pyridine (50 ml) at room temperature. Phthalic anhydride (14 g, 94.5 mmoles) is added and the mixture is gradually heated to T=80-85° C. After 6 h, an aliquot of the reaction mixture is distilled off under vacuum and the mixture is cooled to 40° C. Carbonyl-diimidazole (12 g, 74 mmoles) is added in portions, keeping under stirring for 2 h, thereafter the mixture is concentrated under vacuum to about one fifth of the starting volume, cooled to 25° C., then diluted with a cold (approx. 5° C.) 4:1 water-ethanol mixture (100 ml). Aqueous hydrochloric acid (37percent) is dropped to adjust the pH to 7.0+/-0.5. The mixture is left under stirring for 4 h until it warms up to room temperature, then the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40° C., to give a white crystalline product (10.6 g; yield: 60percent on glutamine).
45%
Stage #1: at 20 - 85℃; for 6.00 h;
Stage #2: at 40℃;
Example 2; 5 g (34.21 mmoles) of L-glutamine are suspended in 25 ml of pyridine in a 100 ml 5-neck round-bottom flask at room temperature, followed by addition of 5 g (33.80 mmoles) of phthalic anhydride and the mixture is heated to T=80-85° C. 6 hrs later an aliquot of the reaction mixture is distilled under vacuum, then cooled to 40° C. 3.1 g (45.5 mmoles) of imidazole are loaded in the flask, which is then cooled to 5-10° C., then 1.6 ml (22 mmoles) of thionyl chloride are dropped in with caution. The mixture is stirred at room temperature for 1 h, heated to 85° C. and kept under stirring at this temperature for 3 h, then distilled to one fifth of the starting volume. The residue is cooled to 25° C. and 100 ml of a cold (ca. 5° C.) (4/1) water/absolute ethanol mixture are added. The mixture is acidified with 37percent HCl to pH=7.0-0.5 and left under stirring for 4 h until room temperature, then the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40° C. to give a white crystalline product (3.9 g, yield 45percent).
41%
Stage #1: at 20 - 80℃; for 6.00 h;
Stage #2: at 5 - 20℃; for 3.00 h;
Stage #3: With hydrogenchloride In ethanol; water at 8 - 35℃; for 4.00 h;
Example 3; 5 g (34.21 mmoles) of L-glutamine are suspended in 25 ml of pyridine in a 100 ml 5-neck round-bottom flask at room temperature, followed by 5 g (33.80 mmoles) of phthalic anhydride. The mixture is heated to T=80° C. for 6 hrs, then the solution is cooled to 5-10° C. 2.60 ml (4.2 g; 35.3 mmoles) of thionyl chloride are dropped with caution in the reaction flask, then the mixture is cooled to room temperature. After 3 h a pyridine volume of about 80-85percent of the starting volume is distilled off and the residue is cooled to 30-35° C., then 100 ml of a (4/1) water/absolute ethanol mixture are added. The mixture is cooled to 8-10° C. with an ice bath and acidified with 37percent HCl 37percent to pH=7-5. The mixture is left under stirring for 4 h until room temperature; the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40° C. to give a crystalline white solid (3.6 g, yield 41percent).

Reference: [1] Patent: US2005/272934, 2005, A1. Location in patent: Page/Page column 3
[2] Patent: US2005/272934, 2005, A1. Location in patent: Page/Page column 3
[3] Patent: US2005/272934, 2005, A1. Location in patent: Page/Page column 3
[4] Patent: US2005/272934, 2005, A1. Location in patent: Page/Page column 3
[5] Patent: US2005/272934, 2005, A1. Location in patent: Page/Page column 2-3
[6] Patent: US2005/272934, 2005, A1. Location in patent: Page/Page column 3
[7] Patent: US2005/272934, 2005, A1. Location in patent: Page/Page column 3
[8] , 2018, vol. 19, # 10,
  • 5
  • [ 7607-72-9 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation in experiment
71% With 1,1'-carbonyldiimidazole In ISOPROPYLAMIDE at 20 - 90℃; for 4.00 h; 10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of dimethyl-acetamide in a 250 ml 5-neck round-bottom flask at room temperature, followed by 10 g (67.6 mmoles) of phthalic anhydride and the mixture is heated to T=80°C. After 6 h the solution is cooled to 30°C and dropped in a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole dissolved in 20 ml of dimethyl-acetamide at room temperature. The resulting solution is heated to 85-90°C and kept under stirring at this temperature for 4 h, then the solution is poured into a conical flask containing 500 ml of cold water. The precipitated solid is filtered, washed twice with 250 ml of water and taken up in 100 ml of (4/1) water/ethanol. After filtering and drying overnight under vacuum at 40°C a crystalline white solid is obtained (12.5 g; Y=71 percent).
65% With 1,1'-carbonyldiimidazole In 1-methyl-pyrrolidin-2-one at 20 - 90℃; for 4.00 h; 10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of N-methyl-2-pyrrolidone in a 250 ml 5-neck round-bottom flask at room temperature, followed by 10 g (67.60 mmoles) of phthalic anhydride and heated to T=80°C. After 6 h the solution is cooled to 30°C and poured into a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole dissolved in 30 ml of N-methyl-2-pyrrolidone at room temperature. The solution is heated at 85-90°C and kept under stirring at this temperature for 4 h. The solution is then poured into a conical flask containing 500 ml of cold water. The precipitated solid is filtered, washed twice with 250 ml of water and taken up in 100 ml of (4/1) water/ethanol. After filtration and drying overnight under vacuum at 40°C a crystalline white solid is obtained (11.5 g; 24 mmoles; Y=65percent).
62% With 1,1'-carbonyldiimidazole In dimethyl sulfoxide at 20 - 90℃; for 4.00 h; 10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of DMSO in a 250 ml 5-neck round-bottom flask at room temperature, added with 10 g (67.60 mmoles) of phthalic anhydride and heated to T=80°C. After 6 h the solution is cooled to 20°C, filtered and poured into a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole in 20 ml of DMSO at 20°C. The resulting solution is heated to 85-90°C and stirred at this temperature for 4 h. The solution is then poured into a conical flask containing 500 ml of cold water (about 5°C) and left under stirring for 2 h at room temperature. The precipitated solid is filtered and washed twice with 250 ml of water. The filtered solid is then suspended in 200 ml of (4/1) water/methanol at 60°C, filtered and dried overnight under vacuum at 40°C, to give a crystalline white product (10.9 g, yield 62percent).
60% With 1,1'-carbonyldiimidazole In pyridine at 40℃; for 2.00 h; L-glutamine (10 g; 68.42 mmoles) is suspended in pyridine (50 ml) at room temperature. Phthalic anhydride (14 g, 94.5 mmoles) is added and the mixture is gradually heated to T=80-85°C. After 6 h, an aliquot of the reaction mixture is distilled off under vacuum and the mixture is cooled to 40°C. Carbonyl-diimidazole (12 g, 74 mmoles) is added in portions, keeping under stirring for 2 h, thereafter the mixture is concentrated under vacuum to about one fifth of the starting volume, cooled to 25°C, then diluted with a cold (approx. 5°C) 4:1 water-ethanol mixture (100 ml). Aqueous hydrochloric acid (37percent) is dropped to adjust the pH to 7.0 +/- 0.5. The mixture is left under stirring for 4 h until it warms up to room temperature, then the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40°C, to give a white crystalline product (10.6 g; yield: 60percent on glutamine).
58% With 1,1'-carbonyldiimidazole In pyridine at 20℃; for 4.00 h; L-glutamine (10 g; 68.42 mmoles) is suspended in pyridine (50 ml) at 10°C and added with phthaloyl-dichloride (27.8 g; 136.84 mmoles), keeping the temperature below 15°C. After 4 h carbonyl-diimidazole (12 g) is added in portions, keeping under stirring for 4 h at room temperature, then the mixture is concentrated under vacuum and poured in cold water (100 ml; 5°C).
(37percent) Aqueous hydrochloric acid is dropped adjusting the pH to 7.0 +- 0.5 and the mixture is left under stirring for 4 h, until room temperature.
The precipitate is filtered by suction, washed twice with 25 ml of water and dried overnight under vacuum at 40°C to give thalidomide in 58percent yield.
45% With 1H-imidazole; thionyl chloride In pyridine at 5 - 85℃; for 4.00 h; 5 g (34.21 mmoles) of L-glutamine are suspended in 25 ml of pyridine in a 100 ml 5-neck round-bottom flask at room temperature, followed by addition of 5 g (33.80 mmoles) of phthalic anhydride and the mixture is heated to T=80-85°C. 6 hrs later an aliquot of the reaction mixture is distilled under vacuum, then cooled to 40°C. 3.1 g (45.5 mmoles) of imidazole are loaded in the flask, which is then cooled to 5-10°C, then 1.6 ml (22 mmoles) of thionyl chloride are dropped in with caution. The mixture is stirred at room temperature for 1 h, heated to 85°C and kept under stirring at this temperature for 3 h, then distilled to one fifth of the starting volume. The residue is cooled to 25°C and 100 ml of a cold (ca. 5°C) (4/1) water/absolute ethanol mixture are added. The mixture is acidified with 37percent HCl to pH=7.0 +/- 0.5 and left under stirring for 4 h until room temperature, then the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40°C to give a white crystalline product (3.9 g, yield 45percent).
41% at 5 - 20℃; for 3.00 h; 5 g (34.21 mmoles) of L-glutamine are suspended in 25 ml of pyridine in a 100 ml 5-neck round-bottom flask at room temperature, followed by 5 g (33.80 mmoles) of phthalic anhydride. The mixture is heated to T=80°C for 6 hrs, then the solution is cooled to 5-10°C. 2.60 ml (4.2 g; 35.3 mmoles) of thionyl chloride are dropped with caution in the reaction flask, then the mixture is cooled to room temperature. After 3 h a pyridine volume of about 80-85percent of the starting volume is distilled off and the residue is cooled to 30-35°C, then 100 ml of a (4/1) water/absolute ethanol mixture are added. The mixture is cooled to 8-10°C with an ice bath and acidified with 37percent HCl 37percent to pH=7-5. The mixture is left under stirring for 4 h until room temperature; the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40°C to give a crystalline white solid (3.6 g, yield 41 percent).

Reference: [1] Patent: EP1602654, 2005, A1. Location in patent: Page/Page column 5/7
[2] Patent: EP1602654, 2005, A1. Location in patent: Page/Page column 4-5/6-7
[3] Patent: EP1602654, 2005, A1. Location in patent: Page/Page column 4/6
[4] Patent: EP1602654, 2005, A1. Location in patent: Page/Page column 4/5
[5] Patent: EP1602654, 2005, A1. Location in patent: Page/Page column 5/7
[6] Patent: EP1602654, 2005, A1. Location in patent: Page/Page column 4/5
[7] Patent: EP1602654, 2005, A1. Location in patent: Page/Page column 4/6
  • 6
  • [ 201230-82-2 ]
  • [ 2353-44-8 ]
  • [ 583-53-9 ]
  • [ 50-35-1 ]
Reference: [1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5578 - 5581
  • 7
  • [ 24666-56-6 ]
  • [ 88-99-3 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation 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
  • 8
  • [ 85-44-9 ]
  • [ 24666-56-6 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation in experiment
95% for 3.00 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
  • 9
  • [ 56-85-9 ]
  • [ 131-11-3 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation in experiment
72%
Stage #1: at 20 - 85℃; for 6.00 h;
Stage #2: at 40℃; for 2.00 h;
Stage #3: With hydrogenchloride In ethanol; water at 5 - 25℃; for 4.00 h;
Example 8; Following the procedure of example 1 using dimethyl-phthalate instead of phthalic anhydride thalidomide is obtained in 72percent yield.
Reference: [1] Patent: US2005/272934, 2005, A1. Location in patent: Page/Page column 3
  • 10
  • [ 56-85-9 ]
  • [ 88-95-9 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation in experiment
58%
Stage #1: at 10 - 15℃; for 4.00 h;
Stage #2: at 20℃; for 4.00 h;
Stage #3: With hydrogenchloride In water at 5 - 20℃; for 4.00 h;
Example 9; L-glutamine (10 g; 68.42 mmoles) is suspended in pyridine (50 ml) at 10° C. and added with phthaloyl-dichloride (27.8 g; 136.84 mmoles), keeping the temperature below 15° C. After 4 h carbonyl-diimidazole (12 g) is added in portions, keeping under stirring for 4 h at room temperature, then the mixture is concentrated under vacuum and poured in cold water (100 ml; 5° C). (37percent) Aqueous hydrochloric acid is dropped adjusting the pH to 7.0+/-0.5 and the mixture is left under stirring for 4 h, until room temperature. The precipitate is filtered by suction, washed twice with 25 ml of water and dried overnight under vacuum at 40° C. to give thalidomide in 58percent yield.
Reference: [1] Patent: US2005/272934, 2005, A1. Location in patent: Page/Page column 3
  • 11
  • [ 3343-29-1 ]
  • [ 50-35-1 ]
Reference: [1] Organic Process Research and Development, 1999, vol. 3, # 2, p. 139 - 140
  • 12
  • [ 85-44-9 ]
  • [ 31140-42-8 ]
  • [ 50-35-1 ]
Reference: [1] ChemMedChem, 2018, vol. 13, # 15, p. 1508 - 1512
[2] ACS Chemical Biology, 2018, vol. 13, # 9, p. 2771 - 2782
  • 13
  • [ 85-44-9 ]
  • [ 2353-44-8 ]
  • [ 50-35-1 ]
Reference: [1] European Journal of Pharmaceutical Sciences, 2016, vol. 83, p. 114 - 119
  • 14
  • [ 671787-01-2 ]
  • [ 50-35-1 ]
Reference: [1] Journal of the Chinese Chemical Society, 2003, vol. 50, # 4, p. 795 - 797
  • 15
  • [ 340-90-9 ]
  • [ 50-35-1 ]
Reference: [1] Synthesis, 2001, # 7, p. 999 - 1000
  • 16
  • [ 222713-07-7 ]
  • [ 50-35-1 ]
Reference: [1] Journal of the Chinese Chemical Society, 2002, vol. 49, # 3, p. 383 - 385
[2] Synthetic Communications, 2003, vol. 33, # 8, p. 1375 - 1382
  • 17
  • [ 31140-42-8 ]
  • [ 88-99-3 ]
  • [ 50-35-1 ]
Reference: [1] ChemMedChem, 2018, vol. 13, # 15, p. 1508 - 1512
  • 18
  • [ 6139-18-0 ]
  • [ 50-35-1 ]
Reference: [1] Patent: US2008/167272, 2008, A1. Location in patent: Page/Page column 3-5; sheet 8
  • 19
  • [ 485817-55-8 ]
  • [ 50-35-1 ]
Reference: [1] Synthetic Communications, 2003, vol. 33, # 8, p. 1375 - 1382
[2] Journal of the Chinese Chemical Society, 2002, vol. 49, # 3, p. 383 - 385
  • 20
  • [ 136918-14-4 ]
  • [ 50-35-1 ]
Reference: [1] Synthetic Communications, 2003, vol. 33, # 8, p. 1375 - 1382
  • 21
  • [ 26878-24-0 ]
  • [ 50-35-1 ]
Reference: [1] Synthetic Communications, 2003, vol. 33, # 8, p. 1375 - 1382
  • 22
  • [ 85-44-9 ]
  • [ 136918-14-4 ]
  • [ 50-35-1 ]
Reference: [1] Journal of Chemistry, 2017, vol. 2017,
  • 23
  • [ 85535-45-1 ]
  • [ 50-35-1 ]
Reference: [1] ChemMedChem, 2018, vol. 13, # 15, p. 1508 - 1512
[2] ChemMedChem, 2018, vol. 13, # 15, p. 1508 - 1512
  • 24
  • [ 485817-54-7 ]
  • [ 50-35-1 ]
Reference: [1] Journal of the Chinese Chemical Society, 2002, vol. 49, # 3, p. 383 - 385
  • 25
  • [ 485817-52-5 ]
  • [ 50-35-1 ]
Reference: [1] Journal of the Chinese Chemical Society, 2002, vol. 49, # 3, p. 383 - 385
  • 26
  • [ 57-13-6 ]
  • [ 3343-28-0 ]
  • [ 50-35-1 ]
Reference: [1] Patent: US2830991, 1955,
[2] Patent: GB768821, 1955,
[3] Pharmaceutical Research, 2002, vol. 19, # 8, p. 1232 - 1235
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Reference: [1] Journal of the Chinese Chemical Society, 2003, vol. 50, # 4, p. 795 - 797
  • 28
  • [ 85-44-9 ]
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  • [ 50-35-1 ]
  • [ 149-87-1 ]
Reference: [1] Synthesis, 2001, # 7, p. 999 - 1000
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Reference: [1] Journal of the Chemical Society, 1957, p. 873,879
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