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[ CAS No. 24666-56-6 ]

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Chemical Structure| 24666-56-6
Chemical Structure| 24666-56-6
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CAS No. :24666-56-6 MDL No. :MFCD11042437
Formula : C5H9ClN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :N/A
M.W :164.59 g/mol Pubchem ID :134548
Synonyms :

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 ]

  • 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 ]
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
  • 2
  • [ 85-44-9 ]
  • [ 24666-56-6 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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,
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