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Product Details of [ 108-30-5 ]

CAS No. :108-30-5 MDL No. :MFCD00005525
Formula : C4H4O3 Boiling Point : -
Linear Structure Formula :- InChI Key :RINCXYDBBGOEEQ-UHFFFAOYSA-N
M.W : 100.07 Pubchem ID :7922
Synonyms :
Succinyl Oxide;SA
Chemical Name :Dihydrofuran-2,5-dione

Calculated chemistry of [ 108-30-5 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.5
Num. rotatable bonds : 0
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 20.71
TPSA : 43.37 Ų

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) : -7.24 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.62
Log Po/w (XLOGP3) : -0.46
Log Po/w (WLOGP) : -0.15
Log Po/w (MLOGP) : -0.08
Log Po/w (SILICOS-IT) : 1.07
Consensus Log Po/w : 0.2

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.17
Solubility : 67.6 mg/ml ; 0.675 mol/l
Class : Very soluble
Log S (Ali) : 0.02
Solubility : 104.0 mg/ml ; 1.04 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.43
Solubility : 37.4 mg/ml ; 0.373 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.06

Safety of [ 108-30-5 ]

Signal Word:Danger Class:8
Precautionary Statements:P501-P272-P260-P270-P264-P280-P284-P342+P311-P362+P364-P303+P361+P353-P333+P313-P301+P330+P331-P301+P312+P330-P304+P340+P310-P305+P351+P338+P310-P405 UN#:3261
Hazard Statements:H302-H314-H317-H334 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 108-30-5 ]

* 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 [ 108-30-5 ]
  • Downstream synthetic route of [ 108-30-5 ]

[ 108-30-5 ] Synthesis Path-Upstream   1~60

  • 1
  • [ 110-00-9 ]
  • [ 108-30-5 ]
  • [ 6118-51-0 ]
Reference: [1] Patent: CN103554134, 2016, B, . Location in patent: Paragraph 0020; 0032-0033
  • 2
  • [ 108-30-5 ]
  • [ 1122-12-9 ]
Reference: [1] Tetrahedron, 2008, vol. 64, # 19, p. 4347 - 4353
[2] Journal of the Chemical Society, 1930, p. 1733,1739
  • 3
  • [ 108-30-5 ]
  • [ 7726-95-6 ]
  • [ 5470-44-0 ]
  • [ 1122-12-9 ]
Reference: [1] Journal of the Chemical Society, 1930, p. 1733,1739
  • 4
  • [ 188290-36-0 ]
  • [ 108-30-5 ]
  • [ 4653-08-1 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With aluminum (III) chloride In 1,1-dichloroethane at 20℃; for 1 h; Heating / reflux
Stage #2: With hydrogenchloride In 1,1-dichloroethane; water at 20℃; for 0.166667 h;
Thiophene [(5.] [0GM,] 0.059moles) and succinic anhydride (7.13gm, 0.0713 moles) were taken up in dichloroethane (50 ml). Aluminium chloride (17.43gm, 0.131 moles) was added at room temperature and the resulting mixture heated under reflux for lhr with stirring. The reaction mixture was cooled to room temperature, diluted with 30 ml of 1 : [1] mixture of water and [CONC.] hydrochloric acid. After stirring for 10 min the separated solid was filtered under suction, washed with water and dilute hydrochloric acid (50 ml). The solid was dried at room temp to give 9.8 gm (89percent 0 of the title compound, mp [103-107°] C. [LH NMR] (CDC13, [8)] : 7.69 (dd, [1H),] 7.58 (dd, 1H), 7.07 (dd, lH), 3.9 (bs, 1H), 3.23 (t, 2H), 2.74 (t, 2H).
87% With aluminum (III) chloride In dichloromethane at 20 - 35℃; for 19 h; Inert atmosphere Dihydrofuran-2,5-dione (30 g, 300 mmol) and thiophene (24 ml, 300 mmol) were added to a 250 ml RBF and DCM (120 ml) was added. The mixture was stirred at room temperature under nitrogen until the succinic anhydride was dissolved (colorless solution) following this aluminum trichloride (48 g, 360 mmol) was added to the mixture portion wise over 30 min (the solution became dark red/brown). The reaction mixture was stirred at room temperature under nitrogen for 17 h and then heated to 35°C under nitrogen for 2 h.The reaction mixture was allowed to cool down to room temperature and was poured into a mixture of ice, concentrated HCl (20 ml) was added. The mixture was stirred for 30 minand was then partitioned between DCM (200 ml) and water (100 ml). A solid crashed out in the aqeuous phase and was filtered. The organic phase was washed with water (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo and combined with the solid obtained previously. The combined material was filtered and dried to afford 4-oxo-4-(thiophen-2-yl)butanoic acid (48g, 262 mmol) 87percent yield as a white solid. 1H NMR (METHANOL-d4) d: 7.88 - 8.00 (m, 1 H), 7.79 - 7.88 (m, 1 H), 7.22 (t, J = 4.3 Hz, 1 H), 3.69 (s, 1 H), 3.29 (t, J = 6.4 Hz, 2 H), 2.69 - 2.76 (m, 2 H) ES- 183.
81% With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 17 h; Add 24 ml of thiophene and 30 g of succinic anhydride and 200 ml of dichloromethane in a 500 ml three-necked flask, stir and cool to 0-5 °C, add 36 g of anhydrous aluminum trichloride in batches, stir at room temperature for 17 hours after the addition, and then The reaction solution was poured into 500 ml of crushed ice, stirred for half an hour, and the organic layer was separated. The organic layer was washed with 500 ml of water, then dried over magnesium sulfate and evaporated to dryness. The mixture was dried by blowing at 50-60 °C for 12 hours to obtain a solid 44.7 g, and the yield was 81percent.
77% at 20℃; for 5 h; Example 5.; Preparation of dichloror6,6'-bis(dimethylsilanediyl)di(η5-(7-phenyl-5,6-dihvdro-4/-/- indeno[5,4-.pound.>1thiophene-6-yl)1zirconium.; The preparation is described in the following scheme. KOH 6,7-dihydro-1-benzothiophen-4(5/-/)-one was obtained with an overall yield of 43percent via the acylation of thiophene by succinic anhydride followed by reduction of the ketone formed and by the cyclisation of 4-(2-thienyl)butanoic acid in the presence of the laton's reagent. Next, 4,5,5a,6-tetrahydro-7/-/-indeno[5,4-ιb]thiophen-7-one was synthesised from 6,7-dihydro-1 -benzothiophen-4(5H)-one with an overall yield of 30percent. The latter product was further reacted with one equivalent of PhLi in ether followed by acidification of the reaction medium to give a mixture of 7-phenyl-5,5a- dihydro-4H-indeno[5,4-ib]thiophene and 7-phenyl-5,8-dihydro-4H-indeno[5,4- .pound.>]thiophene as shown in the scheme belowThe lithium salt of this ligand was treated with 0.5 eqv of Me2SiCl2 in THF to form the respective ιb/s(cyclopentadienyl)dimethylsilane. This b/s-cyclopentadienyl ligand was isolated as a mixture of the Me2Si-bhdging ligands involving ca. 70percent of the desired isomers with a yield of 17percent by repeating flash chromatography on Silica Gel 60. It was metallated with 2 eqv of "BuLi in toluene-hexanes, and then with metallic salt ZrCI4(THF)2. This mixture was stirred overnight at room temperature and then filtered through glass frit. Crystals precipitated from the filtrate at a temperature of -3O0C were collected and dried in vacuum. On the evidence of 1H NMR spectroscopy, this product isolated with a yield of 13percent is a mixture of me- and meso-complexes in a ratio of 1 to 5. This 1H NMR spectrum is shown in figure 9. The meso-isomer was characterised by X-ray crystal structure analysis. Figure 10 is the ORTEP representation of the molecular structure of this meso-complex with thermal ellipsoids drawn at the 50percent probability level.The key geometric paramerers of this structure are:- bond lengths Zr-Cp(c) and Zr-Cp(c)' are 2.239(1 ) Angstroms;- angle between two cyclopentadienyl planes is 59.2°.
63%
Stage #1: With aluminum (III) chloride In dichloromethane at 0℃; for 2 h;
Stage #2: at 0 - 20℃; for 5 h;
General procedure: General procedure 6 (GP6) for Friedel Crafts reaction: Representative experimental procedure for the Friedel Crafts using heterocycles with the anhydride. To solution of succinic anhydride (1 eq.) in anhydrous DCM was added anhydrous A1C13 (1.2 eq) at 0 C and the reaction mixture was stirred for 2 h at 0 °C. Then the aromatic heterocycle was added dropwise over a period of 1 h. The reaction mixture was stirred for 4 h at room temperature. 50 ml of ice-cold H20 was added at 0 °C, followed by acidification with 2N HC1 to pH 2. The aqueous phase was extracted with DCM (3 times). The combined organic extracts were dried over Na2S04, filtered and evaporated in vacuo. The crude mixture was purified by recrystallization or flash column chromatography to afford the compounds 9, 10.
38%
Stage #1: With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 8 h;
Stage #2: With hydrogenchloride In dichloromethane; water at 0℃;
EXAMPLE 13; 4-Oxo-4-(thiophen-2-yl)butanoic acidAnhydrous aluminium chloride (15.8 g, 0.12 mol) was added to a solution of succinic anhydride (1 1.9 g, 0.12 mol) in dry CH2CI2 (50 Ml) and the reaction mixture was cooled to 0 °C. A solution of thiophene (10.0 g, 0.12 mol) in CH2CI2 (50 Ml) was then added dropwise maintaining the same temperature. The reaction mixture was allowed to warm up to room temperature and stirred for 8 h. The mixture was then cooled to 0 °C and the Ph was adjusted to ~3 using 6N HCI. The organic product was extracted with CH2CI2. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 5-10percent MeOH in CH2CI2), to get 4- oxo-4-(thiophen-2-yl)butanoic acid (8.3 g, yield 38percent). 1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1 H), 8.00 - 7.98 (m, 2H), 7.26 - 7.23 (m, 1 H), 3.21 - 3.18 (m, 2H), 2.58 - 2.55 (m, 2H). MS (ESI) m/z: Calculated for C8H803S: 184.02; found: 184.9 (M+H)+

Reference: [1] Patent: WO2004/26848, 2004, A1, . Location in patent: Page 33
[2] European Journal of Pharmacology, 2014, vol. 727, # 1, p. 1 - 7
[3] Patent: CN108341797, 2018, A, . Location in patent: Paragraph 0008; 0017
[4] Patent: WO2010/76188, 2010, A1, . Location in patent: Page/Page column 17-19
[5] Archiv der Pharmazie, 1988, vol. 321, # 10, p. 735 - 738
[6] Journal of Medicinal Chemistry, 2016, vol. 59, # 5, p. 2222 - 2243
[7] Patent: WO2017/63910, 2017, A1, . Location in patent: Page/Page column 19
[8] European Journal of Medicinal Chemistry, 1998, vol. 33, # 11, p. 867 - 877
[9] Patent: WO2011/88187, 2011, A1, . Location in patent: Page/Page column 60
[10] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2000, vol. 39, # 8, p. 614 - 619
[11] Journal of the Chemical Society, 1954, p. 4162,4165
[12] Journal of the American Chemical Society, 1935, vol. 57, p. 1611,1614
[13] Bulletin des Societes Chimiques Belges, 1956, vol. 65, p. 874,891
[14] Tetrahedron Letters, 1984, vol. 25, # 47, p. 5439 - 5440
[15] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2000, vol. 39, # 5, p. 334 - 338
[16] European Journal of Medicinal Chemistry, 2009, vol. 44, # 8, p. 3147 - 3157
[17] European Journal of Medicinal Chemistry, 2013, vol. 69, p. 490 - 497
[18] Patent: WO2015/95261, 2015, A1, . Location in patent: Page/Page column 100
[19] Patent: WO2015/89842, 2015, A1, . Location in patent: Page/Page column 98-99
[20] Archiv der Pharmazie, 2017, vol. 350, # 10,
[21] Patent: US2423709, 1945, ,
  • 5
  • [ 108-30-5 ]
  • [ 4653-08-1 ]
Reference: [1] Patent: US4299769, 1981, A,
  • 6
  • [ 96-43-5 ]
  • [ 108-30-5 ]
  • [ 80885-91-2 ]
  • [ 70685-06-2 ]
Reference: [1] Patent: US4299769, 1981, A,
  • 7
  • [ 96-43-5 ]
  • [ 108-30-5 ]
  • [ 70685-06-2 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 1083,1103
  • 8
  • [ 1003-09-4 ]
  • [ 108-30-5 ]
  • [ 52240-28-5 ]
Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 22, p. 7283 - 7286
[2] Organic Syntheses, 2002, vol. 79, p. 204 - 204
[3] Journal of the Chemical Society, 1954, p. 4162,4165
[4] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 1083,1103
[5] Nippon Kagaku Zasshi, 1957, vol. 78, p. 779,783[6] Chem.Abstr., 1960, p. 22559
  • 9
  • [ 1003-09-4 ]
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  • [ 80885-88-7 ]
  • [ 52240-28-5 ]
Reference: [1] Patent: US4299769, 1981, A,
  • 10
  • [ 108-30-5 ]
  • [ 1165952-91-9 ]
  • [ 6708-37-8 ]
Reference: [1] Australian Journal of Chemistry, 1981, vol. 34, # 8, p. 1719 - 1727
  • 11
  • [ 108-30-5 ]
  • [ 72-14-0 ]
  • [ 116-43-8 ]
YieldReaction ConditionsOperation in experiment
67% at 20℃; for 6 h; Compound 27j was synthesized by the method outlined in FIG. 1. Briefly, Compound 27j was synthesized by first complexing succinic anhydride with sulfathiazole by reacting these compounds at room temperature for 6 hours in tetrahydrofuran (THF) in the presence of triethylamine (TEA) to produce succinylsulfathiazole as a white solid (67percent yield). The succinylsulfathiazole was then reacted for 2 hours at room temperature with O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU) in dichloromethane in the presence of TEA to produce the corresponding succinimidyl ester, which was reacted with 1-(4-aminobutyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide in dichloromethane in the presence of TEA at room temperature for 16 hours to produce Compound 27j as a yellow gummy mass (45percent yield). Compound 27j was characterized by NMR, two-dimensional NMR, and mass spectroscopy.
Reference: [1] Pharmaceutical Chemistry Journal, 1997, vol. 31, # 9, p. 471 - 473
[2] Patent: US2007/292352, 2007, A1, . Location in patent: Page/Page column 45
[3] Patent: US2324013, 1941, ,
[4] Journal of the American Chemical Society, 1942, vol. 64, p. 1572,1573, 1574
[5] Patent: US2324014, 1941, ,
[6] Rum. Med. Rev., 1957, vol. 2, p. 96
[7] Patent: US2391853, 1942, ,
[8] Rum. Med. Rev., 1957, vol. 2, p. 96
[9] Patent: CH242247, 1944, ,
[10] Patent: CH242247, 1944, ,
  • 12
  • [ 108-30-5 ]
  • [ 604-75-1 ]
  • [ 4700-56-5 ]
Reference: [1] Pharmazie, 2000, vol. 55, # 1, p. 42 - 48
  • 13
  • [ 108-30-5 ]
  • [ 462-06-6 ]
  • [ 366-77-8 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: at -5 - 20℃; for 18 h;
Stage #2: With hydrogenchloride In water at 0 - 20℃; for 0.5 h;
4-(4-FIuorophenyI)-4-oxobutanoic acid 142. To a stirred mixture of succinic anhydride (1.0Og5 10 mmol) in fluorobenzene (5.6 mL, 60 mmol), cooled to -5°C, was added aluminium chloride (2.66 g, 20 mmol). The reaction temperature was maintained at -5°C for Ih before being allowed to warm slowly to r.t. over 17h. The mixture was poured into a stirred solution of aqueous HCl (30 mL of 18percent) at 0°C and stirring was continued for a further 30 min while the mixture was allowed to warm to r.t. The resulting white powder was collected by filtration and washed with water. Yield 1.67g, 85percent: 1H NMR .pound. (400 MHz, CD3OD) 2.70-2.74 (2H, m), 3.32-3.35 (2H5 m), 6.64 (IH, s), 7.20-7.26 (2H5 m), 8.06-8.10 (2H, m); LC/MS (APCI) m/z 195.17 (M-H)'; HPLC tτ = 1.53 min (>99percent) 80percent MeCN in H2O.
83% With aluminum (III) chloride In dichloromethane for 2 h; Cooling with ice; Reflux Dichloromethane (50 ml) was added to a 250 ml reaction flask, 10.6 g (0.11 mol) of fluorobenzene and 14.7 g (0.11 mol) of anhydrous aluminum trichloride were added. The reaction mixture was stirred evenly in an ice-water bath, and succinic anhydride was slowly added dropwise 10.1. After 100percent of a solution of g (0.1 mol) in methylene chloride was added dropwise, the temperature was gradually raised to reflux and the reaction was carried out for 2 hours. After the reaction is completed, add 150ml of water, cool to 0°C, add 100ml of concentrated hydrochloric acid, stir at room temperature for 1 hour, stand for stratification, wash the organic layer with saturated aqueous sodium bicarbonate solution and saturated brine 150ml, and concentrate to dryness under reduced pressure. HPLC The purity was 98.0percent, and it was purified by recrystallization from toluene to obtain 16.3 g of 4-(4-fluorophenyl)-4-oxobutanoic acid in a yield of 83percent. The purity by HPLC was 99.8percent, and the content of ortho-substitution by-product was 0.03percent.
81.5% at 100℃; for 2 h; In a 500 ml three-necked reaction flask equipped with a mechanical stirrer, a condenser, and a thermometer,17.1 g (0.171 mol) of succinic anhydride and 105 g (1.09 mol) of fluorobenzene were added and dissolved with stirring. 60 g (0.306 mol) of anhydrous aluminum chloride was added in one portion,The mixture was stirred at 100 ° C for 2 hours, and decomposed by adding 165 ml of hydrochloric acid at a concentration of 10percent for 30 minutes.The other product was obtained in the same manner as in Example 1, m.p. 105-107 ° C, the yield of this step was 81.5percent, and the overall yield was 46.7percent
71%
Stage #1: at -9 - 20℃; for 4.5 h;
Stage #2: at 0℃;
4-(4-Fluoro-phenyl)-4-oxo-butyric acid. Succinic anhydride (1.0 g, 0.01 mmol) was dissolved in 4-fluorobenzene (3.75 mL; 0.04 mmol) and cooled to -9 CC under nitrogen. AICI3 (2.67 g, 0.02 mmol) was added, and the temperature was kept between -9 and 0 °C for 4.5 hours. The reaction was allowed to warm to room temperature and left over night. The reaction mixture was poured into aqueous 4 M HCI (10 mL) at 0 0C, filtered and washed with water. The solid was recrystallized from toluene to give 1.40 g of a colorless solid (71 percent). LC/MS (an10n8): Rt 0.26 min, m/z 195 [M-H], 413 [2M-2H+Na]; 1H NMR (CDCI3, 300 MHz) δ 2.84 (t, J = 6.5 Hz, 2H), 3.31 (t, J = 6.5 Hz, 2H), 7.16 (m, 3H), 8.03 (m, 2H).
62% With aluminum (III) chloride In dichloromethane at 20℃; Inert atmosphere General procedure: AlCl3 (1.0 g, 7.5 mmol)was added portion-wise to a solution of succinic anhydride (0.5 g, 5 mmol) and anaromatic compound (6 mmol) in CH2Cl2 (5 mL) at room temperature. The mixture wasstirred at room temperature for overnight, and the mixture was poured into 1N HClsolution (10 mL), extracted with ethyl acetate (15 mL x 3). The organic layer was driedover MgSO4. The solvent was removed under reduced pressure, and the crude productwas purified by recrystallized from ethyl acetate and hexane.
59.6%
Stage #1: With aluminum (III) chloride In dichloromethane at 20℃; for 2 h;
Stage #2: With hydrogenchloride; water In dichloromethane
Fluorobenzene (50 mL, 530 mmol) and aluminum trichloride (156 g, 1.17 mol) were added to 500 mL of methylene chloride, and the reaction mixture was stirred. Succinic anhydride (50 g, 500 mmol) was added to the stirrring reaction mixture all at once, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by cautious addition of 10percent HCl, and the reaction mixture was added to 500 mL of water. The aqueous mixture was extracted twice with 250 mL of methylene chloride, and the combined organic layers were dried (MgSO4), and evaporated under reduced pressure to give 62 g (316 mmol, 59.6percent) of 4-(4-fluoro-phenyl)-4-oxo-butyτic acid as a crude solid. MS: 197 (M+H)+.
59.6%
Stage #1: With aluminum (III) chloride In dichloromethane at 20℃; for 2 h;
Stage #2: With hydrogenchloride; water In dichloromethane
Fluorobenzene (50 mL, 530 mmol) and aluminum trichloride (156 g, 1.17 mol) were added to 500 mL of methylene chloride, and the reaction mixture was stirred. Succinic anhydride (50 g, 500 mmol) was added to the stirrring reaction mixture all at once, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by cautious addition of 10percent HCl, and the reaction mixture was added to 500 mL of water. The aqueous mixture was extracted twice with 250 mL of methylene chloride, and the combined organic layers were dried (MgSO4), and evaporated under reduced pressure to give 62 g (316 mmol, 59.6percent) of 4-(4-fluoro-phenyl)-4-oxo-butyric acid as a crude solid. MS: 197 (M+H)+.
59.6%
Stage #1: With aluminum (III) chloride In dichloromethane at 20℃; for 2 h;
Stage #2: With hydrogenchloride In dichloromethane; water
Step 1: 4-(4-Fluoro-phenyl)-4-oxo-butyric acid Fluor obenzene (50 mL, 530 mmol) and aluminum trichloride (156 g, 1.17 mol) were added to 500 mL of methylene chloride, and the reaction mixture was stirred. Succinic anhydride (50 g, 500 mmol) was added to the stirrring reaction mixture all at once, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by cautious addition of 10percent HCl, and the reaction mixture was added to 500 mL of water. The aqueous mixture was extracted twice with 250 mL of methylene chloride, and the combined organic layers were dried (MgSO4), and evaporated under reduced pressure to give 62 g (316 mmol, 59.6percent) of 4-(4-fluoro-phenyl)-4-oxo-butyric acid as a crude solid. MS: 197 (M+H)+. Step 2: 4-Oxo-4-(4-phenylsulfanyl-ρhenyl') -butyric acid
59.6% With aluminum (III) chloride In dichloromethane at 20℃; for 2 h; Step 1:
4-(4-Fluoro-phenyl)-4-oxo-butyric acid
Fluorobenzene (50 mL, 530 mmol) and aluminum trichloride (156 g, 1.17 mol) were added to 500 mL of methylene chloride, and the reaction mixture was stirred.
Succinic anhydride (50 g, 500 mmol) was added to the stirring reaction mixture all at once, and the reaction mixture was stirred at room temperature for 2 hours.
The reaction was quenched by cautious addition of 10percent HCl, and the reaction mixture was added to 500 mL of water.
The aqueous mixture was extracted twice with 250 mL of methylene chloride, and the combined organic layers were dried (MgSO4), and evaporated under reduced pressure to give 62 g (316 mmol, 59.6percent) of 4-(4-fluoro-phenyl)-4-oxo-butyric acid as a crude solid. MS: 197 (M+H)+.
59.6% With aluminum (III) chloride In dichloromethane at 20℃; for 2 h; Preparation 27-Benzenesulfonγl-3,4-dihγdro-2H-naphthalen-l-oneThe synthetic procedure described in this Preparation was carried out according to the process shown in Scheme E. <n="45"/>SCHEME E4-(4-Fluoro-phenγl)-4-oxo-butγric acid Fluorobenzene (50 niL, 530 nimol) and aluminum trichloride (156 g, 1.17 mol) were added to 500 mL of methylene chloride, and the reaction mixture was stirred. Succinic anhydride (50 g, 500 mmol) was added to the stirrring reaction mixture all at once, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by cautious addition of 10percent HCl, and the reaction mixture was added to 500 mL of water. The aqueous mixture was extracted twice with 250 mL of methylene chloride, and the combined organic layers were dried (MgSCU), and evaporated under reduced pressure to give 62 g (316 mmol, 59.6percent) of 4-(4-fluoro-phenyl)-4-oxo-butyric acid as a crude solid. MS: 197 (M+H)+.

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[2] Patent: WO2007/96647, 2007, A2, . Location in patent: Page/Page column 148-149
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  • 15
  • [ 108-30-5 ]
  • [ 60-32-2 ]
  • [ 55750-53-3 ]
YieldReaction ConditionsOperation in experiment
77.4% at 20℃; for 10 h; Reflux Compound 1 (150 g, 1.53 mol) was added to a stirred solution of Compound 2 (201 g, 1.53 mol) in HOAc (1000 mL). After the mixture was stirred at r.t. for 2 h, it was heated at reflux for 8 h. The organic solvents were removed under reduced pressure and the residue was extracted with EtOAc (500 mL x 3), washed with H20. The combined organic layers was dried over Na2S04 and concentrated to give the crude product. It was washed with petroleum ether to give compound 3 as white solid (250 g, 77.4 percent).
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  • [ 141-52-6 ]
  • [ 4743-99-1 ]
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  • 18
  • [ 108-30-5 ]
  • [ 75-65-0 ]
  • [ 15026-17-2 ]
YieldReaction ConditionsOperation in experiment
100% With dmap; 1-hydroxy-pyrrolidine-2,5-dione In toluene for 48 h; Reflux The monoester of succinate was prepared as described by Srinivasan,Uttamchandani and Yao [42]: Tert-butanol (10 mL) was added to asolution of succinic anhydrate (6.04 g, 60.40 mmol), Nhydroxysuccinimid (2.53g, 22.01 mmol) and DMAP (0.88 g, 7.23 mmol) in toluene (100 mL)and the solution was heated for 48 h under reflux conditions. After cooling down to rt, twolayers formed in the reaction vessel (brown oil and clear, colourless solution). The crudesolution was diluted with EtOAc (50 mL) and washed with citric acid (10 percent, 2 × 50 mL) andbrine. The organic layer was dried over Na2SO4, the solvent evaporated and the crude productwas recrystallized from Et2O/PE (1:3, 25 mL) to yield the title compound in quantitativeyield.
77% With dmap; 1-hydroxy-pyrrolidine-2,5-dione; triethylamine In toluene for 24 h; Inert atmosphere; Reflux Succinic anhydride 7 (10 g, 100 mmol), N-hydroxysuccinimide (3.34 g, 0.30 mmol), and DMAP (1.17 g, 1.00 mmol) were dissolved in toluene (50 mL). tert-Butanol (11.7 mL, 124 mmol) and Et3N (3.03 g, 4.17 mL, 30.0 mmol) were added sequentially. The suspension was heated under reflux for 24 h. The solution was cooled and diluted with EtOAc (50 mL) and was washed with citric acid (10percent w/v, 100 mL) and brine (100 mL), dried over Na2SO4, and concentrated to give a brown solid. The solid was recrystallised with ether and petroleum ether (10:90) at -20 °C to give succinic acid mono-tert-butyl ester 8 (13.3 g, 76.4 mmol, 77percent) as fawn crystals
77% With dmap; 1-hydroxy-pyrrolidine-2,5-dione; triethylamine In toluene Succinic anhydride (10 g, 100 mmol) was reacted with anhydrous t-butyl alcohol (17 mL) in anhydrous toluene (150 mL) in the presence of dimethylaminopyridine (1.8 g, 15 mmol), N-hydroxysuccinamide (3.45 g, 30 mmol), and trimethylamine (4.2 mL, 30 mmol) to yield the ring opened mono-tert-butylsuccinate product (4). The product was purified by ethyl acetate and water extractions followed by recrystallization of the isolated products of the organic phase in 1:3 ether:hexanes (77percent). The pure compound (4) (5.57 g, 31.9 mmol) was then reacted with tert-Butyldimethylchlorosilane (TBDMS) protected diethanolamine (24.6 mmol) in a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (6.60 g, 34.4 mmol) mediated coupling reaction in anhydrous N,N-dimethylformamide (DMF) (30 mL) overnight. The resulting product (5) was purified by removing the DMF via rotovap, performing ethyl acetate and water extractions, and further purifying the product by performing silica gel liquid column chromatography using ethyl acetate and hexanes as the mobile phase (69.8percent). Deprotection of the TBDMS groups was performed by reacting the purified product from the previous step with iodine in methanol (2percent w/v) at reflux for three hours. After reaction, Na2S2O3 was added until the reaction mixture became clear and was concentrated on rotary evaporator. To purify the t-butyl protected carboxylate diol monomer (5), methylene chloride and water extractions were performed followed by silica gel liquid column chromatography using methylene chloride and methanol as the mobile phase to purify the products extracted into the organic phase. The product was dried under reduced pressure to yield pure monomer (6) (61percent). Synthesis of the monomer was confirmed by 1HNMR.
64% With dmap; 1-hydroxy-pyrrolidine-2,5-dione; triethylamine In toluene for 24 h; Inert atmosphere; Reflux Succinic anhydride, 3 (5.0g, 49.96mmol) was suspended in 30mL of toluene under nitrogen atmosphere. N-Hydroxysuccinimide (1.72g, 14.98mmol), 4-(dimethylamino)pyridine (0.610g, 4.9mmol), dry tert-butyl alcohol (15mL, 150mmol), and Et3N (2.10mL, 14.98mmol) were added to the solution. Dissolution occurred upon refluxing it for one day. After cooling, ethyl acetate (20mL) was added, and the organic layer was washed three times with 10percent citric acid and once with brine, and dried over Na2SO4, filtered, and evaporated to afford 5.40g (64percent yield) of brown solid. Recrystallization with ether gave white crystals of 4. The structure was confirmed by 1H NMR. Mp: 49–50°C (lit.22 49–51°C) 1H NMR (500MHz, CDCl3) δ 2.61 (t, J=6.7Hz, 2H), 2.56–2.49 (m, 2H), 1.43 (s, 9H); 13C NMR (125MHz, CDCl3) 178.7, 171.6, 81.2, 30.2, 29.3, 28.2.

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  • 20
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  • [ 100-51-6 ]
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  • [ 35656-89-4 ]
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  • 24
  • [ 108-30-5 ]
  • [ 108-88-3 ]
  • [ 4619-20-9 ]
YieldReaction ConditionsOperation in experiment
99.3% at 50 - 60℃; for 2 h; Dissolve 75.7 g of succinic anhydride in 457.5 ml of toluene.220.5 g of anhydrous AlCl3 are added batchwise. The reaction mixture is controlled at a temperature of 50-60°C.After stirring for 2 hours,The end of the reaction was confirmed by TLC. With vigorous stirring,The reaction solution was slowly added dropwise to 1250 ml of 1 mol/L ice hydrochloric acid.Gradually precipitated milky solids,After the addition was complete, the mixture was stirred for 0.5 hours and filtered.After the filter cake was washed with toluene and ice water,Withdrawing the filter cake with 50 ml of ethyl acetate;Slowly add the solution and add 500ml of petroleum ether to crystallize.After stirring for another 0.5 hours,Filter and dry at 40°C for 2 hours to obtain Compound II144g.Yield 99.3percent.[Compound II intermediate] white solid,
95% With aluminum (III) chloride In dichloromethane at 20℃; General procedure: The general procedure (Scheme 1) for the preparation of compounds (2a, 2b and 2c): succinicanhydride (1 equiv, 10 mmol) was reacted with an appropriate aromatic compound (substitutedbenzene, 1 equiv, 10 mmol) in DCM (20 mL) in the presence of anhydrous aluminium chloride(1.5 equiv, 15 mmol). The reaction mixture was stirred under anhydrous conditions overnight at roomtemperature and then ice-cold diluted hydrochloric acid solution was added dropwise. A solid massseparated out which was filtered and purified by recrystallization to give 2a, 2b and 2c [44].
80% With aluminum (III) chloride In dichloromethane at 20℃; Inert atmosphere General procedure: AlCl3 (1.0 g, 7.5 mmol)was added portion-wise to a solution of succinic anhydride (0.5 g, 5 mmol) and anaromatic compound (6 mmol) in CH2Cl2 (5 mL) at room temperature. The mixture wasstirred at room temperature for overnight, and the mixture was poured into 1N HClsolution (10 mL), extracted with ethyl acetate (15 mL x 3). The organic layer was driedover MgSO4. The solvent was removed under reduced pressure, and the crude productwas purified by recrystallized from ethyl acetate and hexane.
69% at 0 - 20℃; for 3 h; To a suspension of succinic anhydride (1 g, 10.2 mmol, 1 eq)in toluene (4.6 mL, 44.8 mmol, 4.4 eq) kept at 0 C, aluminumchloride (2.7 g, 20.4 mmol, 2 eq) was added in small portions.The resulting suspension was stirred at room temperature for3 h, then poured onto ice and acidified with HCl conc. The aqueoussolution was extracted with EtOAc and the combined organiclayers were dried (Na2SO4) and concentrated under reducedpressure. The residue was triturated with petroleum ether to furnish4 as a white solid (1.35 g, 69percent). Rf = 0.36 (petroleum ether/EtOAc 4:6), mp 125–128 C; 1H NMR (400 MHz, Chloroform-d) d7.88 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 3.29 (t, J = 6.6 Hz,2H), 3.00 (br s, 1H, OH, exch. with D2O), 2.80 (t, J = 6.0 Hz, 2H),2.41 (s, 3H).

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  • 28
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  • [ 108-86-1 ]
  • [ 6340-79-0 ]
YieldReaction ConditionsOperation in experiment
93.4%
Stage #1: at 0 - 20℃; for 100 h; Inert atmosphere
Stage #2: at 0℃; for 1 h; Inert atmosphere
Succinic anhydride 3 (5.0 g, 50 mmol) and bromobenzene 2 (48 g, 300 mmol) were cooled to 0°C. Aluminium chloride (13.3 g, 100 mmol) was added and the mixture was stirred for 4 h at 0°C under nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred for 96 h under nitrogen atmosphere. The reaction was cooled to 0°C and concentrated HCI (125 mL) was added and reaction stirred under nitrogen for a further 1 h. The reaction was filtered and washed with water (1 L) to obtain a pale yellow solid which was recrystallised from toluene to yield 4-(4- bromophenyl)-4-oxobutanoic acid 4 (12 g, 46.68 mmol, 93.4percent). MS (ESI-QUADRUPOLE) m/z: calc. for Ci0H9BrO3: 255.97, 257.97; Found : 258.0 (1 1 ), 257.0 (98), 256.0 (12), 255.0 (100), 213.0 (18), 21 1 .0 (17) (negative ions). HPLC: tr = 24.4 min 1 H NMR (500 MHz, ofe-DMSO) δ: 2.59 (2 H, t, J = 6.5 Hz, CH2), 3.21 (2 H, t, J = 6.5 Hz, CH2), 7.88 (2 H, d, J = 8.8 Hz, ArH), 7.96 (2 H, d, J = 8.8 Hz, ArH), 12.19 (1 H, br s, OH).
82% With hydrogenchloride; aluminum (III) chloride In dichloromethane at 0 - 20℃; for 4 h; Step 1: Synthesis of 4-(4-bromophenyl)-4-oxobutanoic acid (37A, R═Br) (0320) Anhydrous aluminum trichloride (29.1 g, 218 mmol) was suspended in dichloromethane (120 mL) and cooled to 0° C. Bromobenzene (35.1 g, 224 mmol) was added carefully. When the addition was complete, succinic anhydride (10.0 g, 100 mmol) was added in ten portions carefully. Then the mixture was warmed to room temperature and stirred for 4 h. TLC showed the reaction was complete, 6N HCl (50 mL) was added dropwise. The solid was filtered, washed with distilled water (10 mL×2) and dried in vacuo to afford 37A, R═Br as a white solid (22 g, yield 82percent).
60% With aluminum (III) chloride In dichloromethane at 20℃; Inert atmosphere General procedure: AlCl3 (1.0 g, 7.5 mmol)was added portion-wise to a solution of succinic anhydride (0.5 g, 5 mmol) and anaromatic compound (6 mmol) in CH2Cl2 (5 mL) at room temperature. The mixture wasstirred at room temperature for overnight, and the mixture was poured into 1N HClsolution (10 mL), extracted with ethyl acetate (15 mL x 3). The organic layer was driedover MgSO4. The solvent was removed under reduced pressure, and the crude productwas purified by recrystallized from ethyl acetate and hexane.
55% With aluminum (III) chloride In cyclohexane at 80℃; for 2 h; Step A: Bromobenzene (150 ml, 1.42 mol) was added in one portion to a mixture of aluminum chloride (109 g, 0.82 mmol) and succinic anhydride (41 g, 0.41 mol) in cyclohexane (200 ml) at 80° C. and the resulting mixture was stirred at 80° C. for 2 hours. After cooling below 40° C., the mixture was slowly poured into 6 M HCl (200 ml) and ice, and yellow solids precipitated. Methyl tert-butyl ether was added to dissolve the solids and the phases were separated. The organic layer was washed with water three times and was extracted into 2 M NaOH. The aqueous extracts were acidified to pH 1 with 6 M HCl, extracted with methyl tert-butyl ether, dried with magnesium sulfate and concentrated to a residue. This material was recrystallized by dissolving the residue in 50:35:15 cyclohexane/toluene/isopropanol at 70° C. followed by cooling to room temperature, filtering and azeotroping the resulting solids with hexanes to give the desired compound (57 g, 55percent) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.89-7.93 (m, 2H), 7.72-7.77 (m, 2H), 3.23 (t, J=6.0 Hz, 2H), 2.58 (t, J=6.6 Hz, 2H).

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YieldReaction ConditionsOperation in experiment
90% With aluminum (III) chloride In dichloromethane at 20℃; Inert atmosphere General procedure: AlCl3 (1.0 g, 7.5 mmol)was added portion-wise to a solution of succinic anhydride (0.5 g, 5 mmol) and anaromatic compound (6 mmol) in CH2Cl2 (5 mL) at room temperature. The mixture wasstirred at room temperature for overnight, and the mixture was poured into 1N HClsolution (10 mL), extracted with ethyl acetate (15 mL x 3). The organic layer was driedover MgSO4. The solvent was removed under reduced pressure, and the crude productwas purified by recrystallized from ethyl acetate and hexane.
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  • 33
  • [ 108-30-5 ]
  • [ 100-51-6 ]
  • [ 103-40-2 ]
YieldReaction ConditionsOperation in experiment
93.8% With dmap; triethylamine In dichloromethane at 20℃; a)
Succinic acid monobenzyl ester
To the ice-cooled solution of benzyl alcohol (12.96 g, 120 mmol) in methylene chloride (300 mL) was added triethylamine (25 mL, 180 mmol), 4-dimethylaminopyridine (610 mg, 5 mmol) followed by dropwise addition of succinic anhydride (10 g, 100 mmol).
The reaction mixture was stirred at room temperature overnight and washed with 1N HCl (2*100 mL) and brine (100 mL).
The organic layer was dried (Na2SO4) and concentrated.
The residue was dissolved in ethyl acetate (150 mL) and extracted with saturated aqueous NaHCO3 (3*150 mL).
The combined aqueous layers were acidified with concentrated HCl to pH=1-2, and extracted with methylene chloride (4*250 mL).
The combined organic layers were dried (Na2SO4) and concentrated to give the title acid (19.5 g, 93.8percent).
1H NMR (400 MHz, CDCl3) δ: 11.80-10.50 (br, 1H), 7.35 (m, 5H), 5.15 (s, 2H), 2.70 (m, 4H).
89% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; General procedure: To a solution of succinic anhydride (1.0g, 10mmol) in DMF (4mL) was added benzyl alcohol (0.94mL, 9.09mmol) and DIEA (1.93mL, 11mmol) at 0°C. The reaction mixture was stirred at room temperature overnight and was evaporated in Speed-vac. The residue was dissolved in ethyl acetate (50mL) and washed with saturated NaCl (10mL×2). The organic solution was extracted with aqueous NaHCO3 (5M, 5mL×3) and the aqueous extractions were combined, acidified to pH 4 by adding citric acid (5M), extracted with ethyl acetate (30mL×3). The EtOAc extractions were combined, washed with saturated NaCl, and dried over Na2SO4. Solvent was removed by evaporation in vacuo to give a white solid (1.66g, 89percent); 1H NMR (200MHz, CDCl3) δ 7.38 (s, 5H), 5.18 (s, 2H), 2.73–2.71 (m, 4H); LC–MS (ESI−) 207.0 (100percent).
88% With dmap In tetrahydrofuran for 18 h; Reflux A solution of succinic anhydride (1.0 g, 10 mmol), benzyl alcohol (1.14 g,11 mmol), and DMAP (54 mg, 0.44 mmol) in THF (5 mL) was refluxed for 18 h. The mixture was bacified with sat. NaHCO3, and washed with AcOEt. The aqueous layer was then acidified, and the precipiated solid was extracted with AcOEt. The solid was recrystalized to afford succinic acid monobenzyl ester as colorless needles, 1.85 g, 88percent. 1H NMR (400 MHz, CDCl3) d. 2.65–2.73 (m, 4H,CH2CH2), 5.15 (s, 2H, PhCH2), and 7.31–7.38 ppm(s, 5H, aromatic).
85% With dmap; triethylamine In dichloromethane at 20℃; for 18 h; Method B: Succinic anhydride (5 g, 50.0 mmol) was dissolved in anhydrous DCM (40 mL). Benzyl alcohol (5.69 mL, 55.0 mmol), triethylamine (7.50 mL, 55.0 mmol), and a catalytic amount of DMAP were added to this solution. The resulting clear solution was stirred at room temperature for 18h, after which the, all the volatiles were removed under vacuum. The crude residue was taken up in diethyl ether (200 mL) and was extracted with 2N NaOH (2 χ 75 mL). The aqueous extracts were carefully acidified to pH 2 with concentrated HC1 and then extracted with diethyl ether (2 χ 100 mL). The organic layer was dried (Na2S04), filtered and concentrated to give the title compound as a white solid (8.84 g, 85 percent). M.p. 52-54 °C, lit. 56-57 °C; 1H NMR (300 MHz, acetone-tfc): δ 2.68-2.71 (m, 4H, 2 χ CH2), 5.14 (s, 2H, CHiAr), 7.34-7.36 (m, 5H, ArH).
77% With pyridine; dmap In dichloromethane 3-Hydroxyflavone-3-hemisuccinate (15) was produced according to the reaction outlined in Figure 3. Reaction of succinic anhydride (11) and benzyl alcohol (12) in the presence of 4-dimethylaminopyridine (DMAP) and pyridine in dichloromethane produced the succinic acid monobenzyl esteT (13) as white crystalline flakes in 77percent yield. This protected succinic acid derivative was coupled to 3-hydroxyflavone (1) in the presence of DCC and DMAP, forming flavone-3-hemisuccinate monobenzyi ester(14) as yellow or brown oil that solidified upon standing, with yields of up to 96percent produced.The deprotection of the monobenzyl ester to form the corresponding hemisuccinate using a Pd(OAc)2 in the THF:EtOH;acetic acid solvent system, a larger scale reaction was undertaken to yield the requiτed 3-hydrosyflavone-3-hernisuccinate (15).
71% With dmap In dichloromethane at 0 - 25℃; for 96 h; Example 14; 1-(((4-(benzyloxy)-4-oxobutanoyl)oxy)methyl)-1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-1-ium iodide (Compound 14)Synthesis of 4-(benzyloxy)-4-oxobutanoic acidSuccinic anhydride (7 g, 70.0 mmol) and benzyl alcohol (8.7 mL, 83.9 mmol) were combined in dichloromethane (350 mL) at 0° C. and DMAP (0.85 g, 7.0 mmol) was added portion-wise. The reaction was allowed to gradually warm to 25° C. and stirred for 4 days. The reaction mixture was washed with 1M HCl (3.x.200 mL) then water (300 mL). The organic phases were then extracted with aq saturated NaHCO3 (3.x.300 mL). This was then acidified with conc HCl until pH 1 resulting in a solid precipitating which was filtered then dissolved in dichloromethane. The dichloromethane was dried (MgSO4) and concentrated in vacuo to give 4-(benzyloxy)-4-oxobutanoic acid (10.36 g, 71percent).1H-NMR (300 MHz, CDCl3) δ 7.41-7.29 (5H, m), 5.15 (2H, s), 2.74-2.63 (4H, m).
70.47% at 100℃; for 2 h; A mixture of 5.0 g (0.05 mol) of succinic acid anhydride, 5.4 g (0.05 mol) of benzyl alcohol, 16.25 g (0.05 mol) of cesium carbonate, and 50 ml of N,N-dimethylforamide was stirred at 100° C. for 2 hours.
The reaction mixture was cooled to room temperature, and then poured into 200 ml of ethyl acetate.
The mixture was washed with saturated aqueous NaCl containing 0.35 N HCl (3*100 mL).
The ethyl acetate phase, which contains the product, was collected and dried over anhydrous MgSO4.
The MgSO4 was removed via filtration, and the ethyl acetate was removed under reduced pressure.
The crude product was purified by crystallization in diethyl ether and hexane to provide 7.34 g of succinic acid monobenzyl ester, 70.47percent.
63.29% With dmap In tetrahydrofuran at 50℃; for 5 h; Succinic anhydride 1 (5.00 g, 49.96 mmol), benzyl alcohol (5.94 g, 54.96 mmol)And 4-dimethylaminopyridine (DMAP, 61 mg, 0.50 mmol) was added to 50 mL of tetrahydrofuran, and the mixture was heated to 50 ° C and stirred under heating for 5 hours.The solvent was removed under reduced pressure, 100 mL of ethyl acetate was added to the residue, washed with saturated sodium bicarbonate (100 mL) with,Discard the organic layer, adjust the water layer to pH=2 with dilute hydrochloric acid (1 mol/L), and filter.The filter cake was dried to obtain a white solid of 6.58 g, and the yield was 63.29percent.
57%
Stage #1: at 100℃; for 0.5 h; Microwave irradiation
Stage #2: With water In ethyl acetate at 20℃; for 2 h;
Succinic acid anhydride (0.66 g, 6.6 mmol) and benzyl alcohol (0.65 g, 6.0 mmol) were dissolved in CH2Cl2 (5 mL) and the mixture was kept under stirring in a microwave reactor (Biotage Initiator 8) at 100 °C (pressure: ca 7 bar) for 30 min. The solvent was removed under reduced pressure and the residue was taken up in EtOAc (80 mL) and water (10 mL). The mixture was stirred at rt for 2 h, washed with 5percent KHSO4 (2 * 20 mL) and brine (20 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the colorless oil was subjected to column chromatography (eluent: CH2Cl2/EtOAc 10:1 to CH2Cl2/EtOAc 2:1). The volatiles were removed from the eluate under reduced pressure, CH2Cl2 (20 mL) was added, the solvent was evaporated, and the process repeated. Product 10 was obtained as colourless oil, which crystallized during drying in vacuo to give a white compact solid (0.71 g, 57percent) mp 55-56 °C (lit.;31 mp 56-57 °C). Rf = 0.3 (CH2Cl2/EtOAc 5:1). 1H NMR (300 MHz, [D4]MeOH): δ (ppm) 2.57-2.68 (m, 4H), 5.13 (s, 2H), 7.26-7.38 (m, 5H). C11H12O4 (208.21).
57.7% With dmap In tetrahydrofuran at 50℃; for 5 h; The succinic anhydride (10g, 0.1mol), benzyl alcohol (11.88g, 0.11mol), 4- dimethylaminopyridine (DMAP) (120mg) was added to a 100ml flask, THF (50ml) as solvent, the outside temperature 50 ° C reaction 5h. The reaction solution was concentrated, ethyl acetate was added, the organic layer was successively washed with water, saturated NaHCO3 solution, saturated brine, dried over anhydrous Na2SO4, and concentrated to a solid with isopropyl ether / acetone and recrystallized to give a white solid 12g, yield 57.7percent,
48% for 4 h; Reflux Benzyl succinic acid was synthesized by following a known procedure.33 Here, succinic anhydride (30 g, 300 mmol) was dissolved in benzyl alcohol (31.6 mL, 33 g, 300 mmol), and the resulting solutionwas heated at reflux for 4 h. The reaction mixture was dissolvedin ether (100 mL), and the insoluble succinic acid wasremoved by filtration. The filtrate was extracted with saturatedaqueous Na2CO3 (3 100 mL), and the combined aqueous extractswere acidified with 2 M HCl (2.0 L). The precipitate was collectedby filtration and dried under vacuum to give 2 (30 g, 48percent). 1HNMR (CDCl3, 300 MHz) d 7.35 (m, 5H), 5.15 (s, 2H), 2.70 (m, 4H).13C NMR (CDCl3, 75 MHz) d 177.7, 172.1, 135.7, 128.8, 128.5,128.4, 66.9, 29.1, 29.0.
250 g With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene for 5 h; Reflux A solution of Succinic anhydride (184 grams, 1.84 mol), Benzyl alcohol (200 grams, 1.849 mol) and PTSA (1 gram, 5.25 mmol) in Xylene (1200 ml) was stirred at reflux temperature for 5 hours. The reaction mixture was cooled to room temperature, poured onto 10percent Sodium bicarbonate solution (2500 ml), aqueous layer washed with Ethyl acetate (500 ml), pH made acidic with dil HCl, extracted with Chloroform, dried over Sodium sulphate, distilled under reduced pressure, precipitated the residue by using Hexane to give pure Succinic acid mono benzyl ester (250 grams) as white powder with a melting point of 61-63° C. The product was characterized by IH NMR (CDCl3) δ 2.70 (m, 4H, CH2X2), 5.20 (s, 2H, CH2), 7.35 (m, 5H, Ar), 10.25 (bs, 1H, COOH).
18.5 g With pyridine In tetrahydrofuran at 20℃; for 120 h; 10.0 g (100 mmol) of succinic anhydride, 10 ml of THF (tetrahydrofuran), 10.8 g (100 mmol) of benzyl alcohol and 4 ml of pyridine were combined and stirred for 5 days at ambient temperature. The solution was diluted with toluene. The mixture was extracted with a saturated solution of sodium hydrogen carbonate. The water phase was separated, and acidified with hydrochloric acid. The product was extracted with toluene to yield 18.5 g of succinic acid monobenzyl ester.

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  • 34
  • [ 108-30-5 ]
  • [ 121-44-8 ]
  • [ 103-40-2 ]
YieldReaction ConditionsOperation in experiment
83% With hydrogenchloride; benzyl alcohol In tetrahydrofuran; ethyl acetate Butanedioic acid monobenzylester 21
To a solution of 4.13 mL (4.32 g, 40 mmol) of benzyl alcohol and 4.40 g (44 mmol) of succinic anhydride in 100 mL of THF at 0° C. was added at once 12.24 mL (8.90 g, 88 mmol) of Et3 N.
The mixture was allowed to come to room temperature and stirred for 18 h at which time it was concentrated under vacuum to a viscous oil and partitioned between 100 mL of 1 N HCl and 100 mL of EtOAc.
The EtOAc layer was extracted with 84 mL of 5percent NaHCO3 solution.
The aqueous layer was acidified with concentrated HCl solution to pH 1 and extracted with two 50 mL portions of EtOAc.
The EtOAc layers were combined and washed with brine, dried (Mg SO4), filtered, and concentrated to give 6.9 g (83percent) of 21 as a white chunky solid: 1 H NMR (CDCl3) 2.70 (s, 4H), 5.22 (s, 2H), 7.38 (s, 5H).
83% With hydrogenchloride; benzyl alcohol In tetrahydrofuran; ethyl acetate Butanedioic acid monobenzylester 21
To a solution of 4.13 mL (4.32 g, 40 mmol) of benzyl alcohol and 4.40 g (44 mmol) of succinic anhydride in 100 mL of THF at 0° C. was added at once 12.24 mL (8.90 g, 88 mmol) of Et3 N.
The mixture was allowed to come to room temperature and stirred for 18 h at which time it was concentrated under vacuum to a viscous oil and partitioned between 100 mL of 1N HCl and 100 mL of EtOAc.
The EtOAc layer was extracted with 84 mL of 5percent NaHCO3 solution.
The aqueous layer was acidified with concentrated HCl solution to pH 1 and extracted with two 50 mL portions of EtOAc.
The EtOAc layers were combined and washed with brine, dried (Mg SO4), filtered, and concentrated to give 6.9 g (83percent) of 21 as a white chunky solid: 1 H NMR (CDCl3) 2.70
(s, 4H), 5.22 (s, 2H), 7.38 (s, 5H).
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  • 38
  • [ 108-30-5 ]
  • [ 2216-69-5 ]
  • [ 3562-99-0 ]
YieldReaction ConditionsOperation in experiment
86.4% With aluminum (III) chloride In dichloromethane at 33 - 37℃; for 6 h; 15.8 g of 1-methoxynaphthalene and 10.0 g of succinic anhydride were dissolved in 120 mL of dichloromethane,Stir,Cooling to 1 ~ 3 ° C,Divided into three batches of anhydrous aluminum trichloride 15.0 grams,The addition process takes about 20 minutes,The solution was then heated to 35 ± 2 ° C,Insulation reaction 6 hours (5.5 ~ 6.5 hours range),After the reaction is complete,The reaction solution was poured into an ice-water mixture (200 g of ice and 300 g of water) for 30 minutes,Standing, analysiscrystal,Filter,The filtrate was heated and distilled to recover dichloromethane,The cake is the crude of the ketone ketone;And then the crude ketoprofen water as a solvent by 2-3 times recrystallization,Activated carbon decolorization,Demon ketone boutique.The mass of the present product of the chamballone was 22.3 g,Melting point of 176 ~ 179 ° C,The yield was 86.4percent.
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[3] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1936, vol. 5/2, p. 73,75
  • 42
  • [ 108-30-5 ]
  • [ 57-88-5 ]
  • [ 1510-21-0 ]
YieldReaction ConditionsOperation in experiment
96% at 20℃; for 168 h; General procedure: Succinic anhydride (14.7mmol; 1.57equiv) and DMAP (1.584mmol, 0.17equiv) was added to a solution of (3β)-lanosta-8,24-dien-3-ol (1) or (3β)-cholest-5-en-3-ol (11) (9.37mmol) in pyridine (28mL). The reaction mixture was stirred over 7days at r.t. After stopping the reaction, the resulting mixture was poured onto ice, and hydrochloric acid was added to adjust pH=7, extracted with chloroform, and dried over sodium sulfate. Evaporation of the solvent gave a solid which was purified by column chromatography, affording the products (2) or (12) in 79percent or 96percent yield, respectively, and with >99.9percent analytical purity (Schemes 1–2). The analytical data of the products 2 and 12 are presented in the Supplementary material.
95%
Stage #1: at 20℃; for 24 h;
Stage #2: With hydrogenchloride In 1,4-dioxane; water
7.6 grams of cholesterol and 2.36 grams of succinic anhydride were dissolved in 100 ml of 1,4-dioxane in a round-bottomed flask.
A reaction catalyst, 2.9 grams of 4-(dimethylamino)pyridine (DMAP), was added thereto, and the mixture was stirred at room temperature for 24 hours.
The reaction mixture was introduced into an HCl solution in order to precipitate the cholesterol succinate (9.1 g; yield=95percent).
95% With dmap In dichloromethane at 20℃; for 15 h; DMAP (1.58g, 12.9mmol) and succinic anhydride (1.29g, 12.9mmol) were added to a solution of cholesterol (5g, 12.9mmol) in CH2Cl2 (50mL). The solution was stirred at room temperature for 15h. Progress of the reaction was monitored by TLC. After completion of the reaction, solvent was removed in vacuo and the resultant residue was dissolved in chloroform (50mL). The organic layer was subsequently washed with aq. HCl (1N) (2×50mL), saturated NaHCO3 (2×50mL), brine solution (50mL) and dried over anhydrous Na2SO4, followed by solvent evaporation in vacuo. The crude product was purified by column chromatography (SiO2, 20percent EtOAc-hexane) to afford CS [29], as a white amorphous powder. Yield=5.98g (95percent); Rf 0.5 (1:9 MeOH/CHCl3); mp: 178.85°C from DSC trace, second cycle; [α]D20=−36.02 (c 1.00, CHCl3); FT-IR (Neat): ν 2930, 1704, 1434, 1314, 1178, 998cm−1; 1H NMR (400MHz, CDCl3): δ 0.5–2.1 (m, 41H, cholesterol), 2.35 (d, J=7.0Hz, 2H, CH2), 2.60 (t, J=6.0Hz, 2H, CH2), 2.65 (t, J=6.0Hz, 2H, CH2), 4.50 (m, 1H, OCH), 5.37 (m, 1H, CH); 13C NMR (100MHz, CDCl3): δ 177.6, 171.6, 139.5, 122.7, 74.2, 56.7, 56.1, 50.0, 42.2, 39.7, 39.5, 37.9, 36.9, 36.5, 36.2, 35.8, 31.9, 31.9, 29.2, 28.21, 28.0, 27.7, 24.2, 23.8, 22.8, 22.5, 21.0, 19.3, 18.7, 11.8; HRMS: m/z C31H50O4Na calcd. 509.3607, found 509.3608.
93% at 90℃; for 24 h; Inert atmosphere ChMS was synthesized according to a previously reported protocol [33], which is shown in Scheme 1. The cholesterol (2.5 g) was dissolved in 6 mL of pyridine, and succinic anhydride (1.8 g) was added. The reaction was allowed to proceed at 90 °C for 24 h with stirring under a nitrogen atmosphere. After completion of the reaction, the dark brown colored reaction mixture was cooled to room temperature and poured into distilled water. The resulting precipitate was thoroughly washed with distilled water. The obtained product was dried under reduced pressure and purified by recrystallization from acetone. The recrystallized product was dried under vacuum at room temperature (yield = 2.92 g; 93percent). IR (KBr, cm−1): 3200–2500 (−COOH), 2980–2839 (CH2, CH), 1709 (C=O), 1181 (C−O−C).
92% at 80℃; for 3 h; Cholesteryl Hemisuccinate (CHEMS, ):
Succinic anhydride (1.55 gm, 15.5 mmol) was added to a solution of cholesterol (5 gm, 12.9 mmol) in pyridine (10 ml).
After heating at 80° C. for 3 h, the reaction mixture was diluted with DCM and the organic phase was washed with 10percent HCl (50 ml) followed by a water wash (50 ml).
The organic phase was separated, dried over Na2SO4 to obtain cholesterol hemisuccinate as white solid.
The solid was recrystallized from DCM and hexane (5.78 gm, 92percent yield, and melting point 176-178° C.).
1H NMR (300 MHz, CDCl3): δ 5.47 (d, vinylic-H, J=5.0), 4.70-4.60 (m, 1H), 2.75-2.65 (m, 4H), 2.38-2.35 (d, 7H), 2.20-1.80 (m, 12H), 1.60-1.40 (m, 12H), 0.78-0.75 (m, 3H).
89%
Stage #1: With triethylamine In ethyl acetate for 12 h; Heating / reflux
Stage #2: With hydrogenchloride In methanol; water; ethyl acetate
Cholesterylhemisuccinate (2) [0391] Warm a solution of 38.7 g (100 mmol) cholesterol, 20.0 g (200 mmol) succinic acid anhydride, 0.6 g (5 mmol) DMAP and 51.2 ml (400 mmol) triethylamine in 500 ml ethyl acetate for 12 hours with reflux. Add 100 ml ethyl acetate and 100 ml methanol, then extract with 200 ml 2 N HCl. Add an additional 100 ml ethyl acetate, then extract the organic phase twice with 150 ml each time of a mixture (2:1) of 0.2 N HCl and methanol. Concentrate the organic phase to a small volume and take up the residue in 300 ml methanol. Stir the resultant suspension for 15 minutes at room temperature. Add 300 ml water to completely precipitate the product. Siphon off the raw product, wash twice with 200 ml water each time, vacuum-dry, then recrystallize out of 200 ml diisopropyl ether. The yield is 43.4 g 2 as a colorless powder.
85.3% at 90℃; for 24 h; 5 g of cholesterol and 1.55 g of succinic anhydride were dissolved in 90 mL of pyridine,90 reflux 24h,Cool to room temperature,Dilute hydrochloric acid (pH 1.0, 100 mL) Produce a white precipitate,filter,After the filter cake was washed with ethyl acetate dissolved in water,Dichloromethane / methanol column chromatography,A white solid (cholesterol succinate, 5.24 g, 85.3percent) was obtained.100 mg of cholesterol succinate monoester was dissolved in 10 mL of chloroform,Stirred at room temperature,65 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) was added,46 mg of 1-hydroxybenzotriazole (HOBt) and 150 μL of triethylamine,After 1 h 62.5 mg of ADIBO,After stirring at room temperature overnight,After completion of the reaction, wash with water (10 mL × 3)The organic layer was concentrated,Dichloromethane / methanol column chromatography,Obtained as a light yellow solid (azabicyclooctynecholesterol, 64 mg, 40.3percent).
80.1% at 20℃; for 24 h; The Chol-COOH was synthesized successfully according to the method reported by Yu et al. [30]. Briefly, cholesteroland succinic anhydride (SA) were dissolved in pyridine and kept for 24 h with constant stirring at room temperature.Then, deionized water was added to the above solution. The produced precipitate was obtained by filtration and dried.The crude product was recrystallized in acetone to obtain the white powder, Chol-COOH.
72% With triethylamine In acetone at 25℃; for 24 h; Inert atmosphere 3-Cholesteryloxycarbonylpropanoic acid was synthesized by the reported method.30 A solution of cholesterol (3.89 g, 10 mmol), succinic anhydride (1.27 g, 13 mmol) and triethylamine (1.5 mL, 15 mmol) in dry acetone (60 mL) was heated to reflux under nitrogen atmosphere for 24 h. The acetone was then evaporated and resulting precipitate was recrystallized twice from glacial acetic acid, white solid 3.5 g, 72 percent, yield. 1H NMR (500 MHz, CDCl3) δ 5.37 (d, 1H, J = 4.0 Hz), 4.63 (m, 1H), 2.68 (t, 2H, J = 6.0 Hz), 2.61 (t, 2H, J = 7.0 Hz), 2.32 (d, 2H, J = 9.0 Hz), 2.02-0.91 (m, 33H), 0.86 (dd, 6H, J = 4.0 Hz), 0.68 (s, 3H).
71% With dmap In dichloromethane at 20℃; To a solution of cholesterol (l.Og, 2.5 mmoles) in dry dichloromethane was added succinic anhydride (0.25g, 2.5mmoles) and 4-dimethyaminopyridine (0.305g, 2.5mmoles) under nitrogen atmosphere, which was allowed to stir overnight at room temperature. The reaction mixture was extracted with chloroform (5OmL) and washed with ammonium chloride solution (3x25mL) followed by brine solution (3x20 mL). The chloroform extract was dried over sodium sulfate and evaporated on a rotary evaporator. Silica gel column chromatographic purification of the resulting residue using 230-400 mesh silica gel size and 5-6percent methanol in chloroform (v/v) as the eluent afforded the title compound as a white solid (2.0 g, 71percent yield, Rf = 0.5, 10:90, v/v, methanolxhloroform).1H NMR (400 MHz, CDCl3): δ/ppm= 0.6-2.30 [m, 43H, cholesteryl skeleton]; 2.60 [t, Chol-OCO-C/ir]; 2.70 [t, ChOl-OCO-CH2-CH2-COOH]; 4.60 [m, IH5 H30 (Choi)]; 5.40 [m, IH5 H6 (Choi)].
70% With pyridine In n-heptane for 21 h; Reflux A solution of cholesterol (5.80 g, 15 mmol), succinic anhydride (1.50 g, 15 mmol), pyridine (1.00 mL), and dry heptane (150 mL) were heated to reflux for 21 h and cooled to room temperature. The resulting precipitate was recrystallized twice from acetone. Yield: 70percent.
55% With dmap In dichloromethaneReflux Example 6: Preparation of 2-((2-(2,4-difluorophenyl)-l,3-di(lH-l,2,4-triazol-l-yl)propan- 2-yloxy)(ethoxy)phosphoryloxy)ethyl (3S,8R,9S,10R,13S,14S,17R)-10,13,17-trimethyl-17- ((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,ll,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta [a] phenanthren-3-yl succinateScheme 6cholesterol 55percent 6-163percent 6-268percentAs shown in Scheme 6 above, cholesterol was reacted with succinic anhydride in the presence of 4-dimethylaminopyridine in re fluxing dichloromethane to afford in 55percent yield the carboxylic acid 6.1, which was converted into its acid chloride with thionyl chloride in toluene at 65°C and further reacted with ethylene glycol in the presence of triethylamine in dichloromethane at room temperature to give derivative 6.2 in 63percent yield. The reaction of 6.2 with the freshly prepared phosphorylating reagent ethyl Λ/.iV-diisopropylchlorophosphoramidite, in the presence ofN,N- diisopropylethylamine (Hnig's base) in dry tetrahydrofuran at room temperature, subsequent coupling with fluconazole (FLC) in the presence of tetrazole followed by oxidation with 30percent aqueous hydrogen peroxide afforded in a one-pot process the desired fosfluconazole derivative in 68percent yield after chromatography. The resulting product was characterized by proton nuclear magnetic resonance and mass spectrometry as follows:- 1H NMR (400MHz, CDCl3): 58.39 (d, J = 14.9 Hz, 2H), 7.81 (s, 2H), 7.11 (m, IH), 6.88 (m, IH), 6.77 (m, IH), 5.35 (m, IH), 5.18 (m, 4H), 4.59 (m, IH), 4.24 (m, 2H), 4.21-4.01 (m, 4H), 2.61 (m, 4H), 2.30 (m, 2H), 1.98 (m, 2H), 1.83 (m, 2H), 1.62-1.03 (m, 25H), 1.00(s, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.86 and 0.84 (dd, J = 1.8 Hz, 6H), 0.67 (s, 3H)- MS (APCI): 928 (M) White powderA melting point DSC characterization of the product is presented in Figure 2.
31% Reflux General procedure: A solution of cholesterol (38.6 g, 100 mmol) and dicarboxylic acid anhydride (10 mmol) was refluxed in dry pyridine (100 mL) for 8-10 h., The reaction mixture was concentrated under reduced pressure using rotary evaporator to produce a wet residue, which was dissolved in 50 mL of boiling acetone, and on cooling it gave colorless product. The crude compound was purified by two recrystallizations from acetone and one from absolute ethanol. 4-(Cholesteryloxy)-4-oxobutanoic acid (1). Yield 15.1 g, 31percent, mp 175-176°C as reported [15].

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Reference: [1] Journal of the American Pharmaceutical Association (1912-1977), 1944, vol. 33, p. 107[2] Chem.Abstr., 1944, p. 2765
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  • 44
  • [ 108-30-5 ]
  • [ 2216-51-5 ]
  • [ 77341-67-4 ]
YieldReaction ConditionsOperation in experiment
99.9% at 110℃; for 8 h; Autoclave; Inert atmosphere; Neat (no solvent) Synthetic Example 1
Synthesis of l-menthyl-(l-menthoxyethyl)succinic ester
Compound 1
To a 100 ml autoclave, 10.00 g (63.99 mmol) of l-menthol and 6.40 g (63.96 mmol) of succinic anhydride were added, flushed with nitrogen gas, and then stirred at 110° C. for 8 hours.
After cooling to room temperature, 100 ml of hexane was added thereto.
The precipitated crystals were filtered and the filtrate, hexane phase was concentrated to obtain 16.61 g of l-menthylsuccinic acid.
The yield was >99.9percent.
78.6% With dmap In tetrahydrofuran for 12 h; Reflux (-)- Monomenthyl succinate was synthesized using the common method esterification of (-)-methanol and succinic anhydridein THF with the catalyst DMAP. Yield: 78.6percent. M.p. 61–63 °C.FR-IR (KBr, cm−1): 2917–3440, 1727, 1710, 1388, 1285, 1224, 1177, 1037, 1011. 1HNMR (CDCl3, ppm): .4.67–4.74 (m, 1H), 2.67–2.72 9 (t, 2H), 2.58–2.63 (t, 2H),0.72–2.01 (broad, 18H).
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[4] Patent: US2009/28803, 2009, A1,
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  • [ 15356-70-4 ]
  • [ 15356-60-2 ]
  • [ 2216-51-5 ]
  • [ 77341-67-4 ]
  • [ 204326-53-4 ]
YieldReaction ConditionsOperation in experiment
53 % ee With Candida cylindracea lipase In diethyl ether at 20℃; for 24 h; Schlenk technique; Resolution of racemate; Enzymatic reaction A dry Schlenk tube was charged with rac-alcohol (1 equivalent) and succinic anhydride (1 equiv.) dissolved in 2 mL of diethyl ether. The reaction was initiated by the addition of 100 mg of CCL. The reaction mixture was shaken at room temperature for 24 h. After removal of the lipase by filtration, the filtrate was shaken with 1 M Na2CO3 solution, and the remaining alcohol and the produced monoester succinate were separated by liquid–liquid extraction. The remaining enantiomer was obtained from the organic layer and the aqueous phase was washed with an organic solvent and treated by adding 1 M NaOH solution to obtain the other enantiomer. The enantiomeric excesses values were quantified by chiral GC analyses. Chiral GC: Chiralsil-DEX CB: (Tcolumn = 120 °C. flow: 1,2 mL/min); dl-(±)-menthyl acetate: td-(+) = 9.58 min; tl-(-) =10.85 min. dl-(±)-menthol: td-(+) = 13.25 min; tl-(-) = 13.69 min.
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  • [ 34212-59-4 ]
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[2] Patent: US7247743, 2007, B1, . Location in patent: Page/Page column 5-6
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Reference: [1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1924, vol. 179, p. 405[2] Bulletin de la Societe Chimique de France, 1926, vol. &lt;4&gt; 39, p. 672
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  • 49
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  • 50
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  • [ 80-08-0 ]
  • [ 5934-14-5 ]
Reference: [1] Patent: US2268754, 1940, ,
[2] Patent: CN103420879, 2016, B, . Location in patent: Paragraph 0018-0020
  • 51
  • [ 108-30-5 ]
  • [ 135963-42-7 ]
  • [ 135159-51-2 ]
YieldReaction ConditionsOperation in experiment
92.5%
Stage #1: for 6 h; Reflux
Stage #2: With hydrogenchloride In acetone at 0 - 20℃; for 8 h;
1-Dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-2-propanol (29.8 g, 0.090 mol)And succinic anhydride (11.3 g, 0.113 mol)Soluble in acetone (200ml),Heating and refluxing for 6 hours,The ice bath is cooled to 0~5 °C,Passing dry hydrogen chloride gas,To a pH of 1 to 2, a white solid precipitated,Slowly warm to room temperature and continue to stir for 8 hours.filter,The filter cake is dried and recrystallized from acetone.Obtained white solid sarpogrelate hydrochloride (38.8g, yield 92.5percent), purity 99.8percent
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  • [ 135261-74-4 ]
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  • [ 125700-67-6 ]
Reference: [1] Patent: US9290760, 2016, B2,
  • 54
  • [ 108-30-5 ]
  • [ 14949-00-9 ]
  • [ 78851-85-1 ]
YieldReaction ConditionsOperation in experiment
96% at 100℃; for 12 h; To solution of compound 3 (0.40 g, 2.22 mmol) in N,N-dimethylformamide was added succinic anhydride (0.22 g, 2.22 mmol). The reaction mixture was heated at 100 oC for 12 hr. After reaction completion, solvent was evaporated to obtained 0.60 g of compound 4 in 96 percent yields (compound was used without purification). 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 2H), 2.78 (t, J = 6.6 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 174.08, 172.38, 164.52, 162.15, 30.77, 29.08; HRMS (ESI+): m/z Calcd for C6H9N4O5S2 [M+H]+: 281.0014, Found: 281.0009.
33% at 50℃; EC3105 (178 mg, 0.988 mmol) was dissolved in DMF (1.6 mL). To this solution was added succinic anhydride (98.8 mg, 1 eq.) The solution was heated to 50 oC overnight. The reaction was diluted with water and loaded onto a Biotage C18 column (0.1percent TFA/ACN) and purified. After freeze drying, EC3108 (92mg, 33percent yield) was recovered as a white solid. ESI-MS [M+H]+ = 281.1.13C NMR (125 MHz, DMSO-d6): δ 173.5, 171.9, 164.9, 161.2, 30.4, 28.5.
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  • [ 116574-71-1 ]
  • [ 116574-71-1 ]
  • [ 140695-84-7 ]
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  • 56
  • [ 108-30-5 ]
  • [ 63968-64-9 ]
  • [ 88495-63-0 ]
YieldReaction ConditionsOperation in experiment
96%
Stage #1: With sodium tetrahydroborate; cation exchange resin In tetrahydrofuran at 20 - 35℃; for 0.666667 h;
Stage #2: With triethylamine In tetrahydrofuran at 20 - 35℃; for 1 h;
Artemisinin (500MG) and cation exchange resin (LG) are stirred in tetrahydrofuran (10ML) at room temperature for 5 minutes. Sodium borohydride (250mg) is added slowly for 10 minutes and the reaction mixture is stirred for about 30 minutes at room temperature (20- 35 degree C). After completion of the reaction succinic anhydride (250mg) and triethylamine (0. 7ML) are added at room temperature and the reaction mixture is stirred further for 1 hours at room temperature. The resin is filtered. After usual worlcup and column chromatography of the crude product (710MG), 480mg of pure artesunic acid (yield = 96percent W/W) is obtained.
93%
Stage #1: With sodium tetrahydroborate; D-glucose In 1,4-dioxane at 20 - 30℃; for 2 h;
Stage #2: at 20 - 30℃; for 2 h;
Artemisinin (500mg) and polyhydroxy compound (dextrose, 2.5g) are stirred in 1,4-dioxan (15ML) at room temperature for 5 minutes. Sodium borohydride (2.5g) is added slowly for 10 minutes and the reaction mixture is stirred for about 2 hours at room temperature (20- 30° C). After completion of the reaction (Checked by TLC), succinic anhydride (250 mg) and anion exchange (basic) resin (1.5g) are added at room temperature and the reaction mixture is stirred further for 2 hours at room temperature. Cold water (50 ml) is added to the reaction mixture and pH is adjusted between 6-7 with dilute acetic acid and extracted with 40percent ethyl acetate in hexane (3 x 25 ml). The combined extract is washed with water (50 ml). The ethyl acetate n-hexane extract is dried over anhydrous sodium sulphate and evaporation of the solvent yield 655 mg of crude artesunic acid which upon purification over silica gel (1: 5 ratio) with 20-30percent ethyl acetate in hexane, furnish pure artesunic acid in 93percent w/w (465 mg) yield (according to CO-TLC). After drying the pure a-artesunic acid, mp 140-142° C is characterized by spectral analysis
93%
Stage #1: With sodium tetrahydroborate; cation exchange resin In tetrahydrofuran at 20 - 35℃; for 0.75 h;
Stage #2: With sodium hydrogencarbonate In tetrahydrofuran at 20 - 35℃; for 1.25 h;
Artemisinin (500 mg) and cation exchange resin (LG) are stirred in tetrahydrofuran (15 ml) for 5 minutes. Sodium borohydride (2.4gm) is added slowly and the reaction mixture is stirred for 45 minutes at room temperature (20-35 degree C). After completion of the reduction reaction, succinic anhydride (245 mg) and sodium bicarbonate (3.5g) are added and the reaction mixture is further stirred for 1.25 hours. After usual workup and purification of impure reaction product (650 mg), pure artesunic acid in 93percent w/w yield is obtained.
91.2%
Stage #1: With sodium tetrahydroborate; D-glucose In 1,4-dioxane at 20 - 30℃; for 2 h;
Stage #2: With triethylamine In 1,4-dioxane at 20 - 30℃; for 2 h;
Artemisinin (500 mg), polyhydroxy compound (dextrose, 2. 0G) are stirred in 1,4-dixan (10 ml). Sodium borohydride (2.5g) is added slowly for 10 minutes and the reaction mixture is stirred for about 2 hours at room temperature (20-30° C). After completion of the reduction step, succinic anhydride (250 mg) and triethylamine (LML) are added and the reaction mixture is further stirred for 2 hours at room temperature (20-30 degree C). After usual work up and purification of crude product (690mg) through column chromatography (1: 4 ratio) 91.2percent pure artesunic acid is obtained.
89.6%
Stage #1: With sodium tetrahydroborate; D-glucose In 1,4-dioxane at 20 - 30℃; for 2 h;
Stage #2: With sodium hydrogencarbonate In 1,4-dioxane at 20 - 30℃; for 2 h;
Artemisinin (500 mg) and polyhydroxy compound (dextrose, 2g) are stirred in dioxan (15 ml) for 5 minutes. Sodium borohydride (2.4gm) is added slowly and the reaction mixture is stirred for 2 hours at room temperature (20-30 degree C). After completion of the reduction step succinic anhydride (250 mg) and sodium bicarbonate (3. 5G) are added and the reaction mixture is further stirred for 2 hours. After usual workup and purification of impure reaction product (650 mg), 89.6percent w/w pure artesunic acid is obtained.
87.4%
Stage #1: With sodium tetrahydroborate; D-glucose In tetrahydrofuran at 20 - 30℃; for 2 h;
Stage #2: With triethylamine In tetrahydrofuran at 20 - 30℃; for 2 h;
Artemisinin (500 mg), polyhydroxy compound (dextrose, 2. 0G) are stirred in tetrahydrofuran (10 ml). Sodium borohydride (2. 5G) is added slowly for 10 minutes and the reaction mixture is stirred for about 2 hours at room temperature. After completion of the reduction step succinic anhydride (250 mg) and triethylamine (LML) are added and the reaction mixture is further stirred for 2 hours at room temperature. After usual work up and purification of the crude product (615mg) through column chromatography 87.4percent pure artesunic acid is obtained.
85%
Stage #1: With sodium tetrahydroborate; cation exchange resin In 1,4-dioxane at 20 - 35℃; for 0.75 - 0.916667 h;
Stage #2: With triethylamine In 1,4-dioxane at 20 - 35℃; for 1.25 h;
ARTEMISININ (500MG) and cation exchange resin (LG) are stirred in 1,4 dioxan (10ML) at room temperature for 5 minutes. Sodium borohydride (250mg) is added slowly for 10 minutes and the reaction mixture is stirred for about 30 minutes at room temperature (20-35 degree C). After completion of the reaction succinic anhydride (250mg) and triethylamine (0. 7ML) are added slowly at room temperature and the reaction mixture is stirred further for 1.25 hours at room temperature. After usual work up and purification of the crude artesunic acid (680mg) pure product in 91.7percent w/w is obtained.

Reference: [1] Patent: WO2004/50661, 2004, A1, . Location in patent: Page 7
[2] Patent: WO2004/50661, 2004, A1, . Location in patent: Page 6
[3] Patent: WO2004/50661, 2004, A1, . Location in patent: Page 8
[4] Patent: WO2004/50661, 2004, A1, . Location in patent: Page 6-7
[5] Patent: WO2004/50661, 2004, A1, . Location in patent: Page 7
[6] Patent: WO2004/50661, 2004, A1, . Location in patent: Page 7
[7] Patent: WO2004/50661, 2004, A1, . Location in patent: Page 7-8
  • 57
  • [ 108-30-5 ]
  • [ 81496-81-3 ]
  • [ 88495-63-0 ]
YieldReaction ConditionsOperation in experiment
97% With dmap In 1,2-dichloro-ethane at 45℃; for 6 h; Industrial scale Weigh 5 kg of dihydroartemisininIn the jacketed stainless steel reactor R1,Adding 50.0 L dichloroethane,Room temperature stirring dissolved,To prepare a solution; weigh the succinic anhydride 10kg in a jacketed stainless steel reactor R2, add 40.0L dichloroethane, add 50g DMAP, stirring at room temperature, made of solution;The solution in the reactor R1 was added dropwise to the reactor R2 for 4 hours and the mixture was stirred for 2 hours. The pH of the reaction solution was adjusted to 5 with hydrochloric acid and concentrated to a solvent-free solution. 25L dichloroethane and 25L water, stirring extraction, liquid separation, 25L dichloroethane repeated extraction time;The organic phases were combined, dried over anhydrous sodium sulfate, fine filtered, concentrated under reduced pressure,Artesunate 6.56 kg,Yield 97.0percentHPLC detection purity 99.9percent
Reference: [1] Patent: CN106946904, 2017, A, . Location in patent: Paragraph 0030; 0031
  • 58
  • [ 108-30-5 ]
  • [ 102-54-5 ]
  • [ 1273-94-5 ]
Reference: [1] Doklady Akademii Nauk SSSR, 1956, vol. 106/111, p. 675 - 677[2] Doklady Akademii Nauk SSSR, 1956, vol. 111, p. 362 - 364
[3] , Gmelin Handbook: Fe: Org.Verb.A1, 2.5.7.6.5, page 156 - 161,
[4] , Gmelin Handbook: Fe: Org.Verb.A1, 2.5.7.6.5, page 156 - 161,
[5] Journal of the American Chemical Society, [6] Journal of the American Chemical Society, 1957, vol. 79, p. 3416 - 3420
  • 59
  • [ 108-30-5 ]
  • [ 786593-06-4 ]
YieldReaction ConditionsOperation in experiment
93.4% With triethylamine In ethyl acetate for 8 h; Inert atmosphere; Reflux; Large scale Add andrographolide 5kg and 50L reactorSuccinic anhydride 10kg,Triethylamine 7.5kg,Ethyl acetate 20L,First sealed the reactor, pumping negative pressure,Fill it with nitrogen again and repeat it three times under nitrogen protection.Warm up to reflux for 8 hours,TLC analysis, no material andrographolide, that is, after the end of the reaction, stop heating, cooling to 40 ~ 50 °C, vacuum distillation at this temperature,Dehydrated andrographolide disuccinate hemi-ester crude oil;Dehydration of Andrographolide Disuccinic Acid Half-ester:Dissolve the crude dehydrated andrographolide disuccinate hemiester oil with dichloromethane.The dehydrated andrographolide disuccinic acid half ester solution in dichloromethane isWeigh 200 kg of 200-300 mesh silica gel and load the column to load the solution of the dehydrated andrographolide disuccinic acid half ester in dichloromethane.Elution was performed with a mixture of dichloromethane:methanol:formic acid=500:15:0.5, and the sample was subjected to TLC analysis. The purified dehydrated andrographolide disuccinic acid half ester eluent was collected and distilled under reduced pressure.Pure dehydroandrographolide disuccinic acid half ester was obtained in 7.1 kg, and the yield was 93.4percent.
Reference: [1] Patent: CN107857747, 2018, A, . Location in patent: Paragraph 0043-0045; 0048-0050; 0053-0055; 0058-0060
  • 60
  • [ 108-30-5 ]
  • [ 142037-79-4 ]
  • [ 110-15-6 ]
  • [ 786593-06-4 ]
Reference: [1] Synthetic Communications, 2009, vol. 39, # 19, p. 3444 - 3452
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