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Product Details of [ 1074-82-4 ]

CAS No. :1074-82-4 MDL No. :MFCD00005887
Formula : C8H4KNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :FYRHIOVKTDQVFC-UHFFFAOYSA-M
M.W : 185.22 Pubchem ID :3356745
Synonyms :

Calculated chemistry of [ 1074-82-4 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 40.86
TPSA : 34.14 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.61 cm/s

Lipophilicity

Log Po/w (iLOGP) : -8.96
Log Po/w (XLOGP3) : 1.15
Log Po/w (WLOGP) : 0.97
Log Po/w (MLOGP) : 1.65
Log Po/w (SILICOS-IT) : 1.55
Consensus Log Po/w : -0.73

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.08
Solubility : 1.53 mg/ml ; 0.00826 mol/l
Class : Soluble
Log S (Ali) : -1.46
Solubility : 6.4 mg/ml ; 0.0346 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.76
Solubility : 0.325 mg/ml ; 0.00175 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.1

Safety of [ 1074-82-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330 UN#:N/A
Hazard Statements:H302-H315-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1074-82-4 ]

* 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 [ 1074-82-4 ]
  • Downstream synthetic route of [ 1074-82-4 ]

[ 1074-82-4 ] Synthesis Path-Upstream   1~56

  • 1
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Reference: [1] Farmaco, Edizione Scientifica, 1958, vol. 13, p. 261,282
  • 2
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  • [ 1074-82-4 ]
  • [ 109-11-5 ]
Reference: [1] Suomen Kemistilehti B, 1945, vol. 18, p. 40,42
  • 3
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  • [ 3481-09-2 ]
YieldReaction ConditionsOperation in experiment
94% With chlorine In tetrachloromethane; water A.
To 100 ml. of carbon tetrachloride saturated with chlorine at 0° C. to 5° C. were added 5 grams (27 mmoles) of potassium phthalimide.
The resulting yellow-green suspension was allowed to warm to room temperature and then was stirred for 60-90 minutes.
The solvent then was removed in vacuo, and about 100 ml. of water were added to the resulting white solid.
The mixture was filtered, and the collected solid was washed with water and vacuum dried to obtain 4.6 grams (94percent yield) of N-chlorophthalimide.
92.5% With acetic acid In water EXAMPLE 6
The procedure of Example 5 was repeated using 48 grams of potassium phthalimide.
The workup was modified to use dilute acetic acid (15.5 ml. glacial acetic acid in 500. m. of water) followed by a water wash.
Heptane was not employed. N-chlorophthalimide (42.0 grams; 92.5percent yield) was recovered.
Reference: [1] Patent: US4082766, 1978, A,
[2] Patent: US4082766, 1978, A,
[3] Advanced Synthesis and Catalysis, 1998, vol. 340, # 2, p. 129 - 134
  • 4
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YieldReaction ConditionsOperation in experiment
46.4 grams (95.% yield) With chlorine In dichloromethane; water EXAMPLE 5
Chlorine gas was added to one liter of methylene chloride for 20 minutes at 0° C. during which time saturation was achieved.
Potassium phthalimide (50 grams; 270 mmoles) was added to the chlorine-saturated methylene chloride.
Cooling was discontinued, and the mixture was stirred for two hours during which time the mixture warmed to 20° C.
The resulting slightly greenish-yellow mixture was evaporated to a slush without filtering, and water was added to the mixture to dissolve the resulting potassium chloride.
The total mixture was filtered, and the solid which was collected was washed with water and then with heptane.
The solid was vacuum-dried overnight to obtain 46.4 grams (95.percent yield) of N-chlorophthalimide.
Reference: [1] Patent: US4082766, 1978, A,
  • 5
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  • [ 3481-09-2 ]
Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 9, p. 1383 - 1387
  • 6
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  • [ 2439-85-2 ]
Reference: [1] Journal of Organic Chemistry, 1986, vol. 51, # 25, p. 4959 - 4963
[2] Synthesis, 1983, # 3, p. 207 - 208
  • 7
  • [ 1074-82-4 ]
  • [ 74-95-3 ]
  • [ 5332-26-3 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 7, p. 1678 - 1684
  • 8
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  • [ 106-96-7 ]
  • [ 7223-50-9 ]
YieldReaction ConditionsOperation in experiment
96.7% With manganese(IV) oxide In N,N-dimethyl-formamide at 28℃; for 2 h; 8.4 mmol of bromopropyne and 8.4 mmol of phthalimide potassium salt were added to 10 mL of N,N-dimethylformamide. Further, 0.2 g of manganese dioxide solid was added. The reaction at a temperature of 28°C for 2h; After adding 100 mL of ethyl acetate, the organic layer was collected by washing with water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and separated by a column. The eluent was selected by petroleum ether-ethyl acetate 5: 1 (v: v) to seperate and purify to obtain pure B.
90% at 80℃; for 8 h; Preparation 2:; 2-Prop-2-ynyl-isoindole-1, 3-dione; A mixture of potassium phthalimide (10 grams, 54 mmol) and propargyl bromide (7.65 grams, 65 mmol) was heated in dimethyl formamide (DMF) (50 mL) at 80 °C for 8 hours. The reaction mixture was then poured into ice cold water. White solid obtained was filtered on a Buchner funnel and washed with water and dried (yield is 8.95 grams, 90percent). Melting Point : 138°C. 'H NMR (CDC13) : 6 7.95-7. 85 (m, 2H), 7.75-7. 68 (m, 2H), 4.46 (d, J = 2.5 Hz, 2H), 2.23 (t, J= 2. 5 Hz, 1H). IR (KBr, cm-1): 3294,2925, 1771,1725, 1397. CI-MS (m/z) : 186 (M++1), 148.
80% at 0 - 20℃; Step 2: Preparation of acetylene 4: To an ice cold mixture of propargyl bromide (50 g of an 80percent solution in toluene, 336 mmol) in DMF (200 mL) under argon was added potassium phthalimide (64.7 g, 350 mmol) via a funnel. The runnel was rinsed with additional DMF (50 mL). The reaction mixture was allowed to warm to room temperature and then stirred overnight. After solids were removed from the mixture by filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and water and the combined organics were washed with water and saturated aqueous NaHCO3 and dried over MgSO4. The solution was concentrated under reduced pressure to give <n="148"/>an off-white solid. The product was suspended in water, sonicated and the resulting solid was collected by filtration. After drying under vacuum, the solid was triturated with hexanes, collected by filtration and dried to give acetylene 4 as a slightly off-white solid. Yield (49.7 g, 80percent): 1H NMR (400 MHz, DMSO- d6) δ 7.85-7.93 (m, 4H), 4.38 (d, J= 6.0 Hz, 2H), 3.26-3.34 (m, IH).
72% at 0 - 70℃; for 8 h; 32.3 g (271 mmol) 3-bromopropine are dissolved in 150 ml DMF and 50.3 g (271 mmol) phthalimide potassium salt are added under ice cooling. The suspension is warmed at 70° C. for eight hours. The mixture is concentrated under a vacuum and the residue is distributed between acetic acid ethyl ester and water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is crystallized from acetic acid ethyl ester: Yield 36.4 g (72percent) colorless crystals.
3.15 g for 5 h; Reflux Propargyl bromide (1.3 mL, 17.4 mmol) is dissolved in DMF (30 mL) and potassium phtalimide (3.4 g; 18.4 mmol) is added. The mixture is refluxed for 5 h. After cooling at room temperature the mixture is diluted with diethyl ether, washed with water (3x50 mL), dried over Na2SO4 and evaporated under vacuum to give N-propargyl phtalimide as white solid (3.15 g; 17 mmol).

Reference: [1] Patent: CN105669525, 2016, A, . Location in patent: Paragraph 0062; 0063; 0082
[2] Molecular Crystals and Liquid Crystals Science and Technology Section A: Molecular Crystals and Liquid Crystals, 2002, vol. 377, p. 13 - 18
[3] Phosphorus, Sulfur and Silicon and the Related Elements, 2004, vol. 179, # 8, p. 1611 - 1614
[4] Patent: WO2005/82892, 2005, A2, . Location in patent: Page/Page column 58-59
[5] European Journal of Organic Chemistry, 2017, vol. 2017, # 27, p. 3941 - 3946
[6] Patent: WO2009/45479, 2009, A1, . Location in patent: Page/Page column 145-146
[7] Patent: US6903118, 2005, B1, . Location in patent: Page/Page column 165
[8] Angewandte Chemie - International Edition, 2011, vol. 50, # 32, p. 7354 - 7358
[9] Tetrahedron Asymmetry, 1998, vol. 9, # 24, p. 4419 - 4428
[10] Heterocycles, 2010, vol. 80, # 2, p. 989 - 1002
[11] Journal of the American Chemical Society, 2018, vol. 140, # 27, p. 8448 - 8455
[12] Nippon Kagaku Zasshi, 1955, vol. 76, p. 1404[13] Chem.Abstr., 1957, p. 17760
[14] Annales de Chimie (Cachan, France), 1956, vol. &lt;13&gt;1, p. 161,184,186
[15] Patent: EP1366018, 2016, B1, . Location in patent: Paragraph 0096
[16] Synthetic Communications, 2017, vol. 47, # 7, p. 722 - 733
  • 9
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  • [ 7223-50-9 ]
Reference: [1] Australian Journal of Chemistry, 1988, vol. 41, # 8, p. 1201 - 1208
[2] Tetrahedron Letters, 1988, vol. 29, # 16, p. 1983 - 1984
  • 10
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YieldReaction ConditionsOperation in experiment
89.6% for 15 h; Inert atmosphere To a well-stirred solution of potassium phthalimide 13 (5.00 g, 27.0mmol) in DMF (10 ml) was added 1, 2-dibromoethane (6.91 ml, 81.0 mmol) and thereaction mixture was stirred 15 h under nitrogen. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (200 ml) andextracted with water (2 × 100 ml). The organic layer was washed successively withsaturated aqueous NH4Cl and NaCl, dried over Na2SO4, filtered, and concentratedunder reduced pressure to afford 14 (6.15 g, 89.6 percent) as a white crystalline solid. 1HNMR (400 MHz, CDCl3) δ: 7.85 (m, 2H, ArH), 7.72 (m, 2H, ArH), 4.10 (t, 2H, NCH2),3.58 (t, 2H, CH2Br).
88.9% at 20℃; for 24 h; To phthalimide potassium (10.00 g, 54.00 mmol) in DMF (50 mL), 1,2-dibromoethane (30.45 g, 14 mL, 162.00 mmol) was added. After stirred at room temperature for 24 h, H2O (300 mL) and CH2Cl2 (100 mL) were added. The aqueous phase was separated and extracted with CH2Cl2 (150 mL2). The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and eluted with petroleum ether (60-90 °C) and ethyl acetate to give M-2 as a white solid (12.20 g, 48.02 mmol). Yield: 88.9percent; 1H NMR (300 MHz, CDCl3) δ 7.92–7.84 (m, 1H), 7.79–7.70 (m, 1H), 4.12 (t,J= 6.7 Hz, 1H), 3.62(t,J= 6.7 Hz, 1H).
81.8% With potassium carbonate In acetone for 8 h; Reflux A 500 mL round-bottom flask was charged with4.63 g (0.025 mol) Phthalimide potassium salt, dissolve in 120 mL Anhydrousacetone. 6.9 g (0.05 mol) potassium carbonate and 11.75 g (0.0625 mol) 1,2-Dibromoethanewas added. The solution was heated to reflux for 8 h. The stirring mixture wasallowed to cool, and then was filtered. The solids were washed with 50 mL ofacetone, followed by 50 mL of EtOAc. The filtrate and the washer liquid werepooled and concentrated in a rotary evaporator, then purified by flashchromatography on SiO2 (gradient, 1:6 to 1:4 petroleum ether:EtOAc)to obtain 5.2 g (81.8percent) of N-(2-Bromoethyl) phthalimideas a white solid. The NMR data of compound (6I): 1H NMR (300 MHz) δ: 7.81-7.87(m, 2H), 7.69-7.74 (m, 2H), 3.80 (t, 2H,J=6.8Hz), 2.63 (t, 2H,J=6.6Hz).
80.5% With tetrabutylammomium bromide In N,N-dimethyl-formamide at 70℃; for 2 h; 50 mL DMF,0.025 mol potassium salt of phthalimide,0.10 mol 1,2-dibromoethane,0.5g TBAB,70 reaction 2.0h,Cool to room temperature,Pour ice waterEthyl acetate extraction,Washed,dry,De-soluble,Stand overnight,5.11 g of colorless solid N- (2-bromoethyl) phthalimide was precipitated,m.p. 80-83 ° C,Yield 80.5percent.
80.5% With tetrabutylammomium bromide In N,N-dimethyl-formamide at 70℃; for 2 h; 50 mL of DMF, 0.025 mol of the potassium salt of phthalimide, 0.1 mL of 1,2-dibromoethane, 0.5 g of TBAB, 2.00 h at 70°C, cooled to room temperature, poured into ice water, ethyl acetate Extraction, washing with water, drying, desolvation, standing overnight, precipitation of colorless solid 1 (2-bromoethyl) phthalimide
79.7% With potassium carbonate In acetone for 8 h; Reflux 0.04 mol (7.52 g) of potassium phthalimide and 0.15 mol (28.17 g)1,2-dibromoethane was dissolved in 150 mL of acetone, Join 0.04mol (5.52g) of potassium carbonate reflux 8h; The reaction mixture was then suction filtered, The filtrate was concentrated over the column, There was obtained 8.1 g of N- (2-bromoethyl) phthalimide, Yield 79.7percent.
70.7% With potassium carbonate In acetone at 60 - 65℃; Inert atmosphere General procedure: The appropriate dibromoalkane derivative 2a-2e (11.9 mmol) was added slowly to a mixture of the starting material phthalimide potassium salt (1) (1g, 5.4 mmol) and anhydrous K2CO3 (0.82 g, 5.94 mmol) in acetone (15 mL). The reaction mixture was heated to 60-65 °C and stirred for 6-10 h under an argon atmosphere. After complete reaction, the solvent was evaporated under reduced pressure. Water (50 mL) was added to the residue and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated aqueous NaCl, dried over Na2SO4, and filtered. The solvent was evaporated to dryness under reduced pressure. The crude product was purified on a silica gel chromatography using dichloromethane/acetone (50:1) as eluent to give the intermediates 3a-3e. 4.1.1.1 2-(2-Bromoethyl)-1H-isoindole-1,3(2H)-dione (3a). White solid, yield 70.7percent, mp: 151.3-152.5 °C (lit.1 150-153 °C).
65.6%
Stage #1: at 20℃; for 23 h;
Stage #2: Inert atmosphere
One g phthalimide potassium (5.4 mmol) was dissolved in 5 mL DMF and then 3 g of 1,2-dibromoethane 11a (1.4 mL, 16.2 mmol) was added to the mixture and stirred at room temperature.After 23 hours, 30 mL H2O and 10 mL DCM were added to the mixture and then the aqueousphase was separated and extracted with DCM. The organic layer was washed with brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedwith column chromatography on silica gel and eluted with n-hexane and ethyl acetate to give 1-bromo-2-phthalimidoethane 12a as a white solid (0.9 g, 3.54 mmol). Yield: 65.6percent
57% at 60℃; Into a 500-mL round- bottom flask, was placed a solution of 1,2-dibromoethane (30 g, 159 57 mmol, 2 95 equiv) in N.N-dimethylformamide (200 mL) This was followed by the addition of potassium phthalimide (10 g, 54 05 mmol, 1 00 equiv) in several batches The resulting solution was stirred for 24 h at 6O0C The reaction was then quenched by the addition of20 500 mL of water The resulting solution was extracted with 2x200 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 10) This resulted in 8 g (57percent) of 2-(2- bromoethyl)isomdolme-l,3-dione as a white solid .
45% at 30℃; Potassium phthalimide (0.93 g, 5 mmol) was added to a solution of 1,2-dibromoethane (1.3 mL, 15 mmol) in DMF (8 mL). The mixture was stirred at room temperature overnight and evaporated the solvent in vacuo, the residue dissolved in H2O and extracted with ethyl acetate. The organic layer was washed by brine and dried by MgSO4. Filtered and the solvent evaporated in vacuo, recrystallized from ethyl acetate to give white solid (566 mg, 45 percent).

Reference: [1] Phosphorus, Sulfur and Silicon and Related Elements, 2000, vol. 161, p. 97 - 113
[2] Beilstein Journal of Organic Chemistry, 2014, vol. 10, p. 2406 - 2413
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 3, p. 474 - 483
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 4, p. 391 - 394
[5] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2380 - 2382
[6] Patent: CN107382980, 2017, A, . Location in patent: Paragraph 0027; 0028; 0029; 0031
[7] Patent: CN107540647, 2018, A, . Location in patent: Paragraph 0025
[8] Arzneimittel-Forschung/Drug Research, 1985, vol. 35, # 12, p. 1763 - 1768
[9] Patent: CN104447498, 2017, B, . Location in patent: Paragraph 0040
[10] Journal of the Chemical Society. Perkin Transactions 1, 2002, vol. 2, # 2, p. 197 - 206
[11] Journal of Organic Chemistry, 1985, vol. 50, # 23, p. 4499 - 4504
[12] Organic Letters, 2011, vol. 13, # 4, p. 764 - 767
[13] Organic and Biomolecular Chemistry, 2011, vol. 9, # 12, p. 4498 - 4506
[14] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 22, p. 5053 - 5059
[15] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 7, p. 1223 - 1227
[16] Patent: WO2010/78449, 2010, A2, . Location in patent: Page/Page column 147
[17] Chinese Chemical Letters, 2016, vol. 27, # 2, p. 185 - 189
[18] Coll.Vol.1&lt;New York 1932&gt;,S.115,
[19] Journal of Organic Chemistry, 1981, vol. 46, # 13, p. 2767 - 2771
[20] Journal of the American Chemical Society, 1981, vol. 103, # 26, p. 7773 - 7779
[21] Monatshefte fuer Chemie, 1981, vol. 112, p. 825 - 840
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[23] Helvetica Chimica Acta, 1994, vol. 77, # 6, p. 1570 - 1576
[24] Journal of Medicinal Chemistry, 2002, vol. 45, # 5, p. 1128 - 1141
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[26] Chemical Biology and Drug Design, 2014, vol. 83, # 2, p. 183 - 190
[27] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 17 - 26
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  • [ 106-93-4 ]
  • [ 574-98-1 ]
  • [ 607-26-1 ]
Reference: [1] Chemistry of Heterocyclic Compounds, 2004, vol. 40, # 3, p. 343 - 350
[2] Bulletin of the Chemical Society of Japan, 1982, vol. 55, # 5, p. 1671 - 1672
  • 12
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  • [ 5460-83-3 ]
Reference: [1] Chemistry Letters, 1986, p. 369 - 372
  • 13
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  • [ 2913-97-5 ]
Reference: [1] Journal of Pharmacy and Pharmacology, 1952, vol. 4, p. 693,705
[2] Journal of Chemistry, 2015, vol. 2015,
[3] Patent: CN103864754, 2016, B,
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YieldReaction ConditionsOperation in experiment
88.3% With tetrabutylammomium bromide In N,N-dimethyl-formamide at 70℃; for 2 h; 50mLDMF,0.025 mol potassium salt of phthalimide,0.10 mol 1,3-dibromopropane and 0.5 g TBAB,70 reaction 2.0h;Cool to room temperature,Pour ice waterEthyl acetate extraction,Washed,dry,De-soluble,Stand overnight,5.91 g of N- (3-bromopropyl) phthalimide was precipitated as a white solid,m.p. 70-73 ° C,Yield 88.3percent.
88.3% With tetrabutylammomium bromide In N,N-dimethyl-formamide at 70℃; for 2 h; 50 mL DMF, 0.025 mol potassium salt of phthalimide, 0.10 mol 1,3-dibromopropane and 0.5 g TBAB, reacted at 70°C for 2.0 h; cooled to room temperature, poured into ice water, extracted with ethyl acetate, washed with water , Drying, desolvation, standing overnight, precipitation of a white solid N-(3-bromopropyl) phthalimide 5.91g, mp 70 ~ 73 ° C, the yield of 88.3percent.
87% for 24 h; Reflux General procedure: A mixture of phthalimide10(6.8 mmol) dissolved in EtOH (20 mL) was gently boiled for about 1h. The hot solution was decanted from any solid into 1.25 mL of a specially prepared solution of KOH (15.25 g KOH dissolved in 15 mL of H2O and 45 mL of EtOH). A precipitate of potassium phthalimide separates at once. The mixture was stirred and cooled quickly to room temperature, and the precipitate was filtered under vacuum. To the alcoholic mother liquors a second 1 g portion of phthalimide was added, and the entire process was repeated. The two crops of crystals were united and washed with acetone to remove any unchanged phthalimide. After air-dried pure potassium phthalimidewas obtained as white crystals (yield 30percent). In a second step, a mixture of potassium phthalimide (2.2 mmol),the appropriate dibromoalkane derivative (2.9 mmol) and 2.5 mL of acetone was stirred and refluxed for 24h, and then cooled to 15 °C. After filtering off the precipitated potassium bromide, the cake was washed with acetone and the solvent evaporated to give pure compound.
75%
Stage #1: at 20℃; for 23 h;
Stage #2: Inert atmosphere
One g phthalimide potassium (5.4 mmol) was dissolved in 5 mL DMF and then 3 g of 1,2-dibromoethane 11a (1.4 mL, 16.2 mmol) was added to the mixture and stirred at room temperature.After 23 hours, 30 mL H2O and 10 mL DCM were added to the mixture and then the aqueousphase was separated and extracted with DCM. The organic layer was washed with brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedwith column chromatography on silica gel and eluted with n-hexane and ethyl acetate to give 1-bromo-2-phthalimidoethane 12a as a white solid (0.9 g, 3.54 mmol). Yield: 65.6percent
74.8% With potassium carbonate In acetone at 60 - 65℃; Inert atmosphere General procedure: The appropriate dibromoalkane derivative 2a-2e (11.9 mmol) was added slowly to a mixture of the starting material phthalimide potassium salt (1) (1g, 5.4 mmol) and anhydrous K2CO3 (0.82 g, 5.94 mmol) in acetone (15 mL). The reaction mixture was heated to 60-65 °C and stirred for 6-10 h under an argon atmosphere. After complete reaction, the solvent was evaporated under reduced pressure. Water (50 mL) was added to the residue and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated aqueous NaCl, dried over Na2SO4, and filtered. The solvent was evaporated to dryness under reduced pressure. The crude product was purified on a silica gel chromatography using dichloromethane/acetone (50:1) as eluent to give the intermediates 3a-3e.
68% for 10.25 h; Reflux General procedure: Acetone (150mL) and dibromoalkyl (30mol) were added to a 250mL three-necked round-bottom flask fitted with a mechanical stirrer and reflux condenser. Potassium phthalimide (11.85g, 10 mol) was added slowly over a 15-min period, and then the reaction mixture was heated under reflux for 10h. The reaction mixture was filtered via suction, and the acetone was removed via rotary evaporation. The crude product was purified by flash chromatography on silica gel (EtOAc:petroleum ether=1:14) to afford 2–5 as white solid.
64.7% With potassium carbonate In acetoneReflux General procedure: A mixture of dibromoalkane (23 mmol) and potassium carbonate (12 mmol)was added in acetone (30 mL), and potassium phthalimide (10 mmol) was added slowly over a 15-min period, and then the reaction was heated under reflux for 8-10 h. The reaction mixture was filtered,and the acetone was evaporated in vacuo. The crude product was purified by column chromatography on silica gel using mixtures of petroleum/acetone as eluent) to obtain the white solid compounds 2-4. 2-(3-Bromopropyl)-1H-isoindoline-1,3(2H)-dione (2). Potassium phthalimide was treated with 1,3-dibromopropane according to the general procedure to give the desired product 2 as white solid, yield 64.7percent, mp: 71.0-72.5 °C.1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J1 = 5.6 Hz, J2 = 2.8 Hz, 2H), 7.73 (dd, J1 = 5.6 Hz, J2 = 2.8 Hz, 2H), 3.84 (t, J = 7.2 Hz, 2H), 3.42 (t, J = 6.8 Hz, 2H), 2.29-2.26 (m, 2H).
59.7% at 18℃; for 20 h; Inert atmosphere Preparation of Compound 62A: (0449) A solution of 1,3-dibromopropane (16.4 g, 81.0 mmol) and potassium phthalimide (5.0 g, 27.0 mmol) in DMF (100 mL) was stirred under N2 at 18° C. for 20 hours. The reaction mixture was concentrated, and the residue was diluted with EtOAc (30 mL). The organic phase was washed with water (20 mL), brine (20 mL×2), dried by anhydrous Na2SO4 and concentrated. The residue was triturated with PE (30 mL), filtered to give 2-(3-bromopropyl)isoindoline-1,3-dione (compound 62A, 4.3 g, 59.7percent) as a white solid. MS: calc'd 268 (M+H)+, measured 268 (M+H)+.

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  • 15
  • [ 598-17-4 ]
  • [ 1074-82-4 ]
  • [ 5460-29-7 ]
YieldReaction ConditionsOperation in experiment
49% With sodium hydroxide In N,N-dimethyl-formamide EXAMPLE 7
COMPOUND 7: meso-2'β,6'β-[3-(3,3"-dimethyl-3',4',5',6'-tetrahydro-2'H-cis-[2,2';6',2"]terpyridin-1'-yl)-propylamine]
To a solution of dibromopropane (0.61 mL, 6.0 mmol) in DMF (8 mL) was added potassium phthalimide (0.2756 g, 1.5 mmol), and was stirred at 90° C. for 17 hours.
The mixture was concentrated, 1N NaOH (10 mL) was added, and extracted with CH2Cl2 (2*30 mL).
The combined organic extracts were washed with water (1*15 mL), dried (Na2SO4), and concentrated.
Purification of the crude material by column chromatography on silica gel (4:1 hexanes-EtOAc) provided 0.1977 g (49percent) of 2-(3-bromo-propyl)-isoindole-1,3-dione as a white solid. 1H NMR (CDCl3) δ 2.21-2.30 (m, 2H), 3.41 (t, 2H, J=6.0 Hz), 3.83 (t, 2H, J=6.0 Hz), 7.69-7.75 (m, 2H), 7.82-7.86 (m, 2H).
Reference: [1] Patent: US2005/154201, 2005, A1,
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YieldReaction ConditionsOperation in experiment
92% at 115℃; for 15 h; Into a Sovirel type reactor mechanically stirred, provided with a condenser, an opening for introduction of solids, a system for inerting with nitrogen, and a temperature probe, are loaded 5 mol (1081 g) of 1,4-dibromobutane and 1 mol (188 g; 98.5percent pure) of potassium phthalimide. The reaction medium is brought under stirring to 115° C. and then kept at this temperature for 15 h. It is verified that the conversion is complete by a measurement of the potassium bromide in the reaction medium. [0048] After cooling of the reaction medium to 80° C., 200 g of water are added. After 15 min of stirring and then decantation, the aqueous phase containing the potassium bromide is removed and then a second washing is carried out (still at 80° C.) with 50 g of water. [0049] The ascending condenser is then replaced by a distillation column and then the excess 1,4-dibromobutane is distilled under reduced pressure (8-10 mbar) with a bottom temperature from 80 to 120° C. Thus, 815 g of 1,4-dibromobutane are recovered corresponding to a recovery rate of 1,4-dibromobutane of 94percent. This latter with a purity greater than 99.8percent may be directly recycled into a later operation. [0050] At the end of the distillation, the reaction medium is left to cool to 75-80° C. and then 325 g of ethanol are added. After homogenization and obtention of a clear organic solution at reflux of ethanol, the reaction medium is left to cool under stirring to room temperature (20° C.). [0051] After crystallization of the N-(4-bromobutyl)phthalimide, the ethanolic suspension of the product is filtered on frit at room temperature. The moist cake is washed with 35 g of ethanol and then dried at 50° C. under reduced pressure (20 mmHg). Thus, 268 g of N-(4-bromobutyl)phthalimide are obtained that correspond to a molar yield of 92percent compared with the potassium phthalimide provided.
92.4% at 20℃; for 26 h; The phthalimide potassium salt (2.0g, 10 . 7mmol) with 1, 4 - dibromo butane (2.8g, 12 . 9mmol) dissolved in 25 ml dry N,N-dimethylformamide in, for pH 10, room temperature stirring 26h. Dichloromethane is used for extraction three times (100 ml × 3), washed with distilled water, combined with the organic layer, drying by anhydrous magnesium sulphate, concentrated, dichloromethane/distilled water recrystallization, filtering, drying to obtain the white solid, yield of 92.4percent.
85% at 30℃; General procedure: Potassium phthalimide (0.93 g, 5 mmol) was added to a solution of 1,2-dibromoethane (1.3 mL, 15 mmol) in DMF (8 mL). The mixture was stirred at room temperature overnight and evaporated the solvent in vacuo, the residue dissolved in H2O and extracted with ethyl acetate. The organic layer was washed by brine and dried by MgSO4. Filtered and the solvent evaporated in vacuo, recrystallized from ethyl acetate to give white solid (566 mg, 45 percent).
84% With tetrabutylammomium bromide In N,N-dimethyl-formamide at 78℃; for 6 h; Potassium phthalimide (18.62 g, 0.10 mol) and tetrabutylammoniumbromide (TBAB, 5.00 g) were added to a solutionof 1,4-dibromobutane (35.5 mL, 0.30mol) in N, N-Dimethylformamide (DMF, 240 mL) at room temperature and then the mixture was stirred at 78 °C for 6 h. After the completion of the reaction (monitored by TLC analysis), the mixture was filtered, and washed with DMF (20 mL × 2).The filtrate was evaporated under vacuum to removed DMF,the residual liquid was poured into ice-water bath, immediately a large amount of white solid generated. The white solid was collected by filtration, washed on the filter withwater and dried in vacuum. The crude residue was purifiedby recrystallization from methanol to afford pure N-(4-Bromobutyl) phthalimide 2 (23.60 g, 84percent, m.p. 79-81oC aswhite solid. 1H NMR (CDCl3, 400 MHz), δ: 1.82-1.95 (m,4H, C13H, C14H), 3.45 (t, J=6.3 Hz, 2H, C15H), 3.73 (t,J=6.6 Hz, 2H, C16H), 7.27-7.74 (m, 2H, C3H, C6H), 7.83-7.86 (m, 2H, C1H, C2H); 13C NMR (CDCl3, 100 MHz), δ:27.3 (C13), 29.9 (C14), 32.8 (C15), 37.0 (C12), 123.3 (C3,C6), 132.1 (C4, C5), 134.0 (C1, C2), 168.4 (C7, C9). KunHu has reported the same compound in 2013 [17], the NMRcharacterization in the literature is described as follows: 1HNMR (CDCl 3, 500 MHz): d 1.84-1.94 (m, 4H), 3.45 (t,2H, J = 6.0 Hz), 3.73 (t, 2H, J = 6.5 Hz), 7.73 (dd, 2H, J =3.0, 5.5 Hz), 7.85 (dd, 2H, J = 3.0, 5.0 Hz); 13 C NMR(CDCl 3, 125 MHz): d 27.27, 29.89, 32.73, 36.99, 123.27,132.11, 133.99, 168.36.
82.5% With tetrabutylammomium bromide In N,N-dimethyl-formamide at 70℃; for 2 h; 50 mL DMF, 0.025 mol potassium salt of phthalimide,0.10 mol 1,4-dibromobutane and 0.5 g TBAB,70 reaction 2.0h;Cool to room temperature,Pour ice waterEthyl acetate extraction,Washed,dry,De-soluble,Stand overnight,5.82 g of N- (4-bromobutyl) phthalimide precipitated as a white solid,m.p. 78-81 ° C, yield 82.5percent.
82% for 24 h; Reflux General procedure: A mixture of phthalimide10(6.8 mmol) dissolved in EtOH (20 mL) was gently boiled for about 1h. The hot solution was decanted from any solid into 1.25 mL of a specially prepared solution of KOH (15.25 g KOH dissolved in 15 mL of H2O and 45 mL of EtOH). A precipitate of potassium phthalimide separates at once. The mixture was stirred and cooled quickly to room temperature, and the precipitate was filtered under vacuum. To the alcoholic mother liquors a second 1 g portion of phthalimide was added, and the entire process was repeated. The two crops of crystals were united and washed with acetone to remove any unchanged phthalimide. After air-dried pure potassium phthalimidewas obtained as white crystals (yield 30percent). In a second step, a mixture of potassium phthalimide (2.2 mmol),the appropriate dibromoalkane derivative (2.9 mmol) and 2.5 mL of acetone was stirred and refluxed for 24h, and then cooled to 15 °C. After filtering off the precipitated potassium bromide, the cake was washed with acetone and the solvent evaporated to give pure compound.
82.5% With tetrabutylammomium bromide In N,N-dimethyl-formamide at 70℃; for 2 h; 50 mL of DMF, 0.025 mol of the potassium salt of phthalimide, 0.10 mol of 1,4-dibromobutane and 0.5 g of TBAB, reaction at 70° C. for 2.0 h; cooling to room temperature, pouring into ice water, extraction with ethyl acetate, After washing with water, drying and desolvation, the mixture was allowed to stand overnight to precipitate 5.82 g of N-(4-bromobutyl)phthalimide as a white solid, mp 78-81°C, yield 82.5percent.
78.2% With potassium carbonate In acetone at 60 - 65℃; Inert atmosphere General procedure: The appropriate dibromoalkane derivative 2a-2e (11.9 mmol) was added slowly to a mixture of the starting material phthalimide potassium salt (1) (1g, 5.4 mmol) and anhydrous K2CO3 (0.82 g, 5.94 mmol) in acetone (15 mL). The reaction mixture was heated to 60-65 °C and stirred for 6-10 h under an argon atmosphere. After complete reaction, the solvent was evaporated under reduced pressure. Water (50 mL) was added to the residue and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated aqueous NaCl, dried over Na2SO4, and filtered. The solvent was evaporated to dryness under reduced pressure. The crude product was purified on a silica gel chromatography using dichloromethane/acetone (50:1) as eluent to give the intermediates 3a-3e.
76% With potassium carbonate; potassium iodide In acetone at 100℃; for 6 h; General procedure: To a solution of 1.6g (10.0mmol) of (R,S) 4-phenyloxazolin-2-one (13), 3.4g (25.0mmol) of K2CO3 and a catalytic amount of KI in acetonitrile, 5.4g (25.0mmol) of 1,4-dibromobutane were slowly added drop by drop stirring at rt. The mixture was then heated under reflux for 6–12h, monitored by TLC (CH2Cl2/EtOH 9:1). The hot solution was filtered and evaporated under reduced pressure. The yellow oil residue of (R,S) 3-(4-bromobutyl)-4-phenyloxazolidin-2-one 23 was used without further purification. (0045) Yield: 96percent;
75% for 10.25 h; Reflux General procedure: Acetone (150mL) and dibromoalkyl (30mol) were added to a 250mL three-necked round-bottom flask fitted with a mechanical stirrer and reflux condenser. Potassium phthalimide (11.85g, 10 mol) was added slowly over a 15-min period, and then the reaction mixture was heated under reflux for 10h. The reaction mixture was filtered via suction, and the acetone was removed via rotary evaporation. The crude product was purified by flash chromatography on silica gel (EtOAc:petroleum ether=1:14) to afford 2–5 as white solid.
72.3% at 90℃; for 18.5 h; To a stirred solution of 1,4-dibromobutane (2j) (9,7 mL, 27,0 mmoi) (100 mL), was added potassIum phthaiate (i—) (5.0 g, 27,0 mrnol) portion—wise over 30 mm at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 rnL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 rnL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5.40percent EtOAc / hexanes to afford 3j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 2.3.9(M+1)
72.3% at 20 - 90℃; for 18.5 h; To a stirred solution of 1,4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 min at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).
72.3% at 20 - 90℃; for 18.5 h; To a stirred solution of 1,4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 mm at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).
72.3% at 90℃; for 18 h; To a stirred solution of 1,4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 min at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).
72.3% at 20 - 90℃; for 18.5 h; To a stirred solution of 1,4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 mm at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).
72.3% at 20 - 90℃; Production Example 25a: Synthesis of (R)-N-(1-(3-(cyclopropylmethoxy)-4- fluorophenyl) ethyl)-4-(2,4-dioxoimidazolidin-1-yl)butane-1-sulfonamideScheme 11. [0697] Step 1: Synthesis of 2-(4-bromobutyl)isoindoline-1,3-dione (3-j) To a stirred solution of 1,4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 min at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).
68.3% With potassium carbonate In acetoneReflux General procedure: A mixture of dibromoalkane (23 mmol) and potassium carbonate (12 mmol)was added in acetone (30 mL), and potassium phthalimide (10 mmol) was added slowly over a 15-min period, and then the reaction was heated under reflux for 8-10 h. The reaction mixture was filtered,and the acetone was evaporated in vacuo. The crude product was purified by column chromatography on silica gel using mixtures of petroleum/acetone as eluent) to obtain the white solid compounds 2-4.
66% at 0 - 20℃; for 18 h; Syntheses of D,L-Sulforaphane and Erysolin; Compound 9; 2-(4-bromobutyl)isoindoline-l,3-dione; The following procedure was adapted from that previously reported by Vermeulen, et al (25) 1 ,4-Dibromobutane (4 400 mL, 36 457 mmols) was dissolved in anhydrous DMF (52 mL) and the resulting solution was chilled to 0°C under argon After 15 min, potassium phthahmide (3 459 g, 18 672 mmols) was slowly added to the stirring solution and the reaction was allowed to warm to ambient temperature under argon over 18 h The reaction was concentrated in vacuo and co-stπpped with anhydrous THF several times Products were dissolved in 1 1 H2O EtOAc (200 mL) and the aqueous phase was extracted with EtOAc (3 x 100 mL) Combined organics were washed with brine, dried over Na2SO4, and filtered through a celite plug prior to concentration in vacuo Silica gel chromatography (3 1 Hexane EtOAc) and subsequent concentration afforded 3 466 g 9 as a white solid (66percent yield) 1H NMR (CDCl3) 5 7 85 (dd, J = 5 4, 3 1 Hz, 2H), 7 73 (dd, J = 5 4, 3 0 Hz, 2H), 3 73 (t, J = 6 7 Hz, 2H), 3 45 (t, J = 6 4 Hz, 2H), 1 89 (m, 4H) 13C NMR (CDCl3) δ 168 5, 134 1, 132 2, 123 4, 37 1, 32 9, 30 0, 27 4 HRMS (ESI-EMM) calc'd for [M + Na]+ m/z 303 9949, found 303 9936
66% at 0 - 20℃; for 18 h; Inert atmosphere Compound 9: 2-(4-bromobutyl)isoindoline-1,3-dione. The following procedure was adapted from that previously reported by Vermeulen, et al. (25). 1,4-Dibromobutane (4.400 mL, 36.457 mmols) was dissolved in anhydrous DMF (52 mL) and the resulting solution was chilled to 0° C. under argon. After 15 min, potassium phthalimide (3.459 g, 18.672 mmols) was slowly added to the stirring solution and the reaction was allowed to warm to ambient temperature under argon over 18 h. The reaction was concentrated in vacuo and co-stripped with anhydrous THF several times. Products were dissolved in 1:1 H2O:EtOAc (200 mL) and the aqueous phase was extracted with EtOAc (3×100 mL). Combined organics were washed with brine, dried over Na2SO4, and filtered through a celite plug prior to concentration in vacuo. Silica gel chromatography (3:1 Hexane:EtOAc) and subsequent concentration afforded 3.466 g 9 as a white solid (66percent yield). 1H NMR (CDCl3) δ 7.85 (dd, J=5.4, 3.1 Hz, 2H), 7.73 (dd, J=5.4, 3.0 Hz, 2H), 3.73 (t, J=6.7 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 1.89 (m, 4H). 13C NMR (CDCl3) δ 168.5, 134.1, 132.2, 123.4, 37.1, 32.9, 30.0, 27.4. HRMS (ESI-EMM) calc'd for [M+Na]+m/z 303.9949. found 303.9936.
61% at 115 - 120℃; for 12 h; Into a Sovirel type reactor mechanically stirred, provided with a condenser, an opening for introduction of solids, a system inerting with nitrogen, and a temperature probe, are loaded 655 g of 1,4-dibromobutane at 99percent purity (3 mol) and 187 g of potassium phthalimide at 99percent purity (1 mol). The reaction medium is brought under stirring between 115° C. and 120° C. and then kept at this temperature for 12 h. It is verified that the transformation of potassium phthalimide is completed by a measurement of the KBr in the reaction medium and then the excess 1,4-dibromobutane is evaporated under reduced pressure (10 to 18 mmHg). The recovery rate of the 1,4-dibromobutane is near 90percent and this latter may be recycled directly into a later operation. [0052] At the end of the distillation, the heterogeneous reaction medium is 120° C.-130° C. Its temperature is lowered to 70° C. and then 320 g of ethanol are introduced. The medium is kept at 70° C. [0053] The contents of the reactor are filtered at 70° C. on a frit kept at this temperature. The moist cake is dried. It essentially contains KBr and diphthalimidobutane. [0054] The ethanolic filtrate is left to cool to 20° C., which causes crystallization of the N-(4-bromobutyl)phthalimide. The ethanolic suspension of the product is filtered on the frit. The moist cake is washed with 2 ethanol fractions and then dried at 50° C. under reduced pressure (20 to 30 mmHg). Thus, 173 g of N-(4-bromobutyl)phthalimide are obtained or an isolated yield of 61percent compared with the potassium phthalimide provided.
61% for 12 h; Heating / reflux Potassium phthalimide (65 g, 350 mmol, 1.00 eq.) and tetramethylene dibromide (200 g, 930 mmol, 2.66 eq.) were combined (neat) and heated for 12 hours. The excess tetramethylene dibromide was removed via rotary-evaporation (rotovap). The resulting residue was digested with ethanol and filtered. The material that crystallized on standing was filtered, washed with ethanol, and dried in vacuo. A second crop was obtained by concentration of combined filtrate and washings. The combined mass of crops was 60.5 g (61percent yield).
48.6% With tetra-(n-butyl)ammonium iodide In acetone for 18 h; Reflux (3)
N-(4-bromobutyl)phthalimide
93.6g (0.43mol) 1,4-dibromobutane was weighed, and added to 380mL acetone.
The mixture was added with 72.5g (0.39mol) phthalimide potassium salt and 2.1g tetrabutylammonium iodide under stirring, subjected to refluxing for 18h, cooled, filtrated to remove solid, and washed with acetone.
All acetone solutions are combined, subjected to recovering the solvent under a reduced pressure, and added with petroleum ether for crystallization while the reaction mixture was hot.
A solid was filtered out, washed with with petroleum ether and dried to obtain a product 48.0g(43.6percent),mp 75∼78°C.
The mother liquor was concentraed to precipitate crystal, cooled in an ice-bath to obtain a solid 5.5g (5.0percent), mp 73∼76°C.
48.6% With tetra-(n-butyl)ammonium iodide In acetone for 18 h; Reflux (3)
N-(4-bromobutyl)phthalimide
93.6 g (0.43 mol) 1,4-dibromobutane was weighed, and added to 380 mL acetone.
The mixture was added with 72.5 g (0.39 mol) phthalimide potassium salt and 2.1 g tetrabutylammonium iodide under stirring, subjected to refluxing for 18 h, cooled, filtrated to remove solid, and washed with acetone.
All acetone solutions are combined, subjected to recovering the solvent under a reduced pressure, and added with petroleum ether for crystallization while the reaction mixture was hot.
A solid was filtered out, washed with petroleum ether and dried to obtain a product 48.0 g (43.6percent), mp 75~78° C.
The mother liquor was concentrated to precipitate crystal, cooled in an ice-bath to obtain a solid 5.5 g (5.0percent), mp 73~76° C.
17.3 g at 20℃; for 48 h; A mixture of 1,4-dibromobutane (22 mL, 185 mmol) and potassium phthalimide (11.35 g, 61.4 mmol) in 60 mL of DMF was mixed at room temperature for 1 day. Then, the reaction mixture was extracted with hexane (3x150 mL). The hexane fractions were dried over MgS04, filtered, and concentrated to give 30 g of a 1:2.2 molar mixture of recovered 1,4-dibromobutane and DMF. This mixture was diluted with 30 mL of DMF and retreated with potassium phthalimide (4.80 g, 26 mmol) at room temperature for 1 day. The two reaction mixtures in DMF were partitioned between 1: 1 EA/Hex (3x150 mL) and H20 (2x100 mL), 0.1M HCl (100 mL), and brine (100 mL).The organic phases were dried over MgS04 and concentrated. SPE, eluting with 0percent and 10percent EA/Hex, gave 17.3 g of colorless solid. R 0.55 (40percent EA/Hex); 1H NMR (CDC13) δ 7.86-7.81 (m, 2H), 7.73-7.69 (m, 2H), 3.71 (t, 2H), 3.43 (t, 2H), 1.94-1.80 (m, 4H); 13C NMR (CDC13) δ 168.5, 134.2, 132.3, 123.5, 37.2, 32.9, 30.1, 27.4.
5.6 g at 20℃; for 15 h; 7.8ml (6. 5 X 10 2 mol) of 1,4-dibromobutane with 6 g (3. 2 X 10 2 moles) Phthalimide potassium salt dissolved in 100ml of N, N- dimethylformamide andunder room temperatureit was stirred for 15hours.The solvent was distilled off under reduced pressure The residue usingn-hexane: ethyl acetate with a volumeratio of 10: 1 eluent to carry out column chromatography, gradually increasingthe polarity to hexane: ethyl acetate with a volume ratio of 5: 1 to give aproduct of 5.6g (2.0X102mole) a bromo group substituted by Phthalimide. The product with 5. 0g (5. 0X 10 2 mol) ofsodium sulfite, 140ml water and 85ml95percent ethanol mixed reaction was heated to 95° C for 18h, the remaining solvent was drained, and the resulting residue was mixed with 73ml ofconcentrated hydrochloric acid then was heated to 110 ° C the for 18H, itwas drained, with water - 95percent ethanol on the residue to carry out recrystallization to give 2. 5g of4-amino-1-Butanesulfonic acid (total yield 50percent).

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  • [ 1074-82-4 ]
  • [ 5394-18-3 ]
YieldReaction ConditionsOperation in experiment
58% With sodium hydrogencarbonate In <i>N</i>-methyl-acetamide; hexane; water EXAMPLE 81
2-(4-Bromo-butyl)-isoindole-1,3-dione
To a hot solution (90° C.) of dibromobutane (1.50 kg, 6.95 mol) in dimethylformamide (1.7 L) was added potassium phthalimide (329 g, 1.74 mol).
The solution was stirred at 90° C. for 5 hours.
The solution was cooled to room temperature prior to the addition of water (900 mL).
The layers were separated and the aqueous layer was extracted with CH2Cl2 (2*500 mL).
The combined organic portions were washed with a saturated aqueous solution of NaHCO3 (1.0 L).
The organic layer was dried (MgSO4) and concentrated under reduced pressure.
Hexane (3.0 L) was added to the residue and the solid (mostly diphthalimide side product) was filtered.
Hexane (1.0 L) was added to the filtrate and the resulting mixture was placed at -20° C. for 1.5 hours. the precipitate was filtered and dried under vacuum to afford 285 g (58percent) of 2-(4-bromo-butyl)-isoindole-1,3-dione as white solid. 1H NMR (CDCl3) δ 1.75-7.95 (m, 4H), 3.44 (t, 2H, J=6.5 Hz), 3.71 (t, 2H, J=6.5 Hz), 7.65-7.75 (m, 2H), 7.80-7.90 (m, 2H).
13C NMR (CDCl3) δ 27.64, 30.22, 33.26, 37.35, 123.68, 132.42, 134.42, 168.79.
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YieldReaction ConditionsOperation in experiment
73.5% With potassium carbonate In acetone at 60 - 65℃; Inert atmosphere General procedure: The appropriate dibromoalkane derivative 2a-2e (11.9 mmol) was added slowly to a mixture of the starting material phthalimide potassium salt (1) (1g, 5.4 mmol) and anhydrous K2CO3 (0.82 g, 5.94 mmol) in acetone (15 mL). The reaction mixture was heated to 60-65 °C and stirred for 6-10 h under an argon atmosphere. After complete reaction, the solvent was evaporated under reduced pressure. Water (50 mL) was added to the residue and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated aqueous NaCl, dried over Na2SO4, and filtered. The solvent was evaporated to dryness under reduced pressure. The crude product was purified on a silica gel chromatography using dichloromethane/acetone (50:1) as eluent to give the intermediates 3a-3e.
73% for 24 h; Reflux General procedure: A mixture of phthalimide10(6.8 mmol) dissolved in EtOH (20 mL) was gently boiled for about 1h. The hot solution was decanted from any solid into 1.25 mL of a specially prepared solution of KOH (15.25 g KOH dissolved in 15 mL of H2O and 45 mL of EtOH). A precipitate of potassium phthalimide separates at once. The mixture was stirred and cooled quickly to room temperature, and the precipitate was filtered under vacuum. To the alcoholic mother liquors a second 1 g portion of phthalimide was added, and the entire process was repeated. The two crops of crystals were united and washed with acetone to remove any unchanged phthalimide. After air-dried pure potassium phthalimidewas obtained as white crystals (yield 30percent). In a second step, a mixture of potassium phthalimide (2.2 mmol),the appropriate dibromoalkane derivative (2.9 mmol) and 2.5 mL of acetone was stirred and refluxed for 24h, and then cooled to 15 °C. After filtering off the precipitated potassium bromide, the cake was washed with acetone and the solvent evaporated to give pure compound.
72% for 10.25 h; Reflux General procedure: Acetone (150mL) and dibromoalkyl (30mol) were added to a 250mL three-necked round-bottom flask fitted with a mechanical stirrer and reflux condenser. Potassium phthalimide (11.85g, 10 mol) was added slowly over a 15-min period, and then the reaction mixture was heated under reflux for 10h. The reaction mixture was filtered via suction, and the acetone was removed via rotary evaporation. The crude product was purified by flash chromatography on silica gel (EtOAc:petroleum ether=1:14) to afford 2–5 as white solid.
65% at 20 - 90℃; for 18.5 h; To a stirred solution of 1,5-dibromopentane (13-k) (170.58 mL, 1.26 mol) in DMF (1.5 L) was added potassium phthalate (12-k) (78.0 g, 0.42 mol) portion-wise over 30 mm at room temperature. After complete addition, the reaction mixture was stirred at 90°C for 1 8 h, then quenched with water (3 L) and extracted with diethyl ether (500 mL x 4). The combined organic extracts were washed with water (500 mL x 2), followed by brine (500 mL x 2) and dried over anhydrous sodium sulfate, filtered anad concentrated under reduced pressure to obtain the crude. The residue was purified by silica gel column chromatography (60-120 mesh) using 5-10percent EtOAc / hexanes to afford 14-k as an off-white solid (81 g, 65percent yield).H NMR (400 MHz, CDCI3): d 7.82 (dd,J= 5.5, 3.1 Hz, 2H), 7.69 (dd,J= 5.5, 3.0 Hz, 2H),3.68 (t, J= 7.2 Hz, 2H), 3..38 (t, J= 6.8 i-iz, 2Ff). 1.93-1.85 (n:i, 2H), 1.70 (p, J= 7,5 Hz, 2H),1.53-1.43 (m, 2H).
65% at 20 - 90℃; o a stirred solution of 1,5-dibromopentane (13-k) (170.58 mL, 1.26 mol) in DMF (1.5 L) was added potassium phthalate (12-k) (78.0 g, 0.42 mol) portion-wise over 30 min at room temperature. After complete addition, the reaction mixture was stirred at 90°C for 18 h, then quenched with water (3 L) and extracted with diethyl ether (500 mL x 4). The combined organic extracts were washed with water (500 mL x 2), followed by brine (500 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The residue was purified by silica gel column chromatography (60-120 mesh) using 5-10percent EtOAc / hexanes to afford 14-k as an off-white solid (81 g, 65percent yield).1H NMR (400 MHz, CDC13): δ 7.82 (dd, J= 5.5, 3.1 Hz, 2H), 7.69 (dd, J= 5.5, 3.0 Hz, 2H), 3.68 (t, J= 7.2 Hz, 2H), 3.38 (t, J= 6.8 Hz, 2H), 1.93-1.85 (m, 2H), 1.70 (p, J= 7.5 Hz, 2H), 1.53-1.43 (m, 2H).
65% at 20 - 90℃; for 18.5 h; To a stirred solution of 1,5-dibromopentane (13-k) (170.58 mL, 1.26 mol) in DMF (1.5 L) was added potassium phthalate (12-k) (78.0 g, 0.42 mol) portion-wise over 30 mm at room temperature. After complete addition, the reaction mixture was stirred at 90°C for 18 h, then quenched with water (3 L) and extracted with diethyl ether (500 mL x 4). The combined organic extracts were washed with water (500 mL x 2), followed by brine (500 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The residue was purified by silica gel column chromatography (60-120 mesh) using 5-10percent EtOAc / hexanes to afford 14-k as an off-white solid (81 g, 65percent yield). ‘HNMR (400 IVIFIz, CDC13): 7.82 (dd, J= 5.5, 3.1 Hz, 2H), 7.69 (dd, J 5.5, 3.0 Hz, 2H), 3.68 (t, J 7.2 Hz, 2H), 3.38 (t, J 6.8 Hz, 2H), 1.93-1.85 (m, 2H), 1.70 (p, J= 7.5 Hz, 2H),1.53-1.43 (m, 2H).
65% at 20 - 90℃; for 18.5 h; To a stirred solution of 1,5-dibromopentane (13-k) (170.58 mL, 1.26 mol) in DMF (1.5 L) was added potassium phthalate (12-k) (78.0 g, 0.42 mol) portion-wise over 30 min at room temperature. After complete addition, the reaction mixture was stirred at 90°C for 18 h, then quenched with water (3 L) and extracted with diethyl ether (500 mL x 4). The combined organic extracts were washed with water (500 mL x 2), followed by brine (500 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The residue was purified by silica gel column chromatography (60-120 mesh) using 5-10percent EtOAc / hexanes to afford 14-k as an off-white solid (81 g, 65percent yield). 1H NMR (400 MHz, CDC13): δ 7.82 (dd, J= 5.5, 3.1 Hz, 2H), 7.69 (dd, J= 5.5, 3.0 Hz, 2H), 3.68 (t, J= 7.2 Hz, 2H), 3.38 (t, J= 6.8 Hz, 2H), 1.93-1.85 (m, 2H), 1.70 (p, J= 7.5 Hz, 2H), 1.53-1.43 (m, 2H).
65% at 20 - 90℃; for 18.5 h; To a stirred solution of 1,5-dibromopentane (13-k) (170.58 mL, 1.26 mol) in DMF (1.5 L) was added potassium phthalate (12-k) (78.0 g, 0.42 mol) portion-wise over 30 mm at room temperature. After complete addition, the reaction mixture was stirred at 90°C for 18 h, then quenched with water (3 L) and extracted with diethyl ether (500 mL x 4). The combined organic extracts were washed with water (500 mL x 2), followed by brine (500 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The residue was purified by silica gel column chromatography (60-120 mesh) using 5-10percent EtOAc / hexanes to afford 14-k as an off-white solid (81 g, 65percent yield).‘H NMR (400 MHz, CDC13): 7.82 (dd,J= 5.5, 3.1 Hz, 2H), 7.69 (dd,J= 5.5, 3.0 Hz, 2H), 3.68 (t, J 7.2 Hz, 2H), 3.38 (t, J 6.8 Hz, 2H), 1.93-1.85 (m, 2H), 1.70 (p, J= 7.5 Hz, 2H),1.53-1.43 (m, 2H).
65% at 20 - 90℃; [0714] Step 11: Synthesis of 2-(5-bromopentyl) isoindoline-1,3-dione (14-k) To a stirred solution of 1,5-dibromopentane (13-k) (170.58 mL, 1.26 mol) in DMF (1.5 L) was added potassium phthalate (12-k) (78.0 g, 0.42 mol) portion-wise over 30 min at room temperature. After complete addition, the reaction mixture was stirred at 90°C for 18 h, then quenched with water (3 L) and extracted with diethyl ether (500 mL x 4). The combined organic extracts were washed with water (500 mL x 2), followed by brine (500 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The residue was purified by silica gel column chromatography (60-120 mesh) using 5-10percent EtOAc / hexanes to afford 14-k as an off-white solid (81 g, 65percent yield). 1H NMR (400 MHz, CDCl3): δ 7.82 (dd, J = 5.5, 3.1Hz, 2H), 7.69 (dd, J = 5.5, 3.0 Hz, 2H), 3.68 (t, J = 7.2 Hz, 2H), 3.38 (t, J = 6.8 Hz, 2H), 1.93-1.85 (m, 2H), 1.70 (p, J = 7.5 Hz, 2H), 1.53-1.43 (m, 2H).
55% at 20℃; for 24 h; [65] To a solution of 1,5-dibromopentane (9.00 ml, 65.22 mmol) dissolved in DMF (100 ml) was added potassium phthalimide (12.08 g, 65.22 mmol) at room temperature, and the reaction mixture was stirred for 24 hours. After the reaction was completed, distilled water was added, and the resulting reaction mixture was stirred for 10 minutes and extracted with ethyl acetate three times. Then, the organic phase was washed with a saline solution, dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: ethyl acetate:hexane = 1:3) to give the target compound (10.6 g, 55 percent).[66] 1H-NMR (400 MHz, CDCl3) δ 7.85-7.70 (m, 4H, aromatic), 3.71-3.67 (t, 2H, -CH2 -CH2-CH2-CH2-CH2-Br), 3.4-3.38 (t, 2H, -CH^-CH2-CH2-CH2-Qi2-Br), 1.94-1.87 (m, 2H, -CH2-CIl2-CH2-CH2-CH2-Br), 1.73-1.67 (m, 2H, -CH2-CH2-CH2-CH2-CH2-Br), 1.53-1.47 (m, 2H, -CH2-CH2-CH2-CH2-CH2-Br).[67]
6.9 g at 20℃; for 15 h; 8.7ml (6 · 5 X 102 moles) 1,5-dibromopentane with6 g (3. 2 X 10 2 moles) Phthalimide potassium salt dissolved in 100ml of N, N- dimethylformamide andunder room temperatureit was stirred for 15hours.The solvent was distilled off under reduced pressure, The residue usingn-hexane: ethyl acetate with a volumeratio of 10: 1 eluent to carry out column chromatography, gradually increasingthe polarity to hexane: ethyl acetate with a volume ratio of 5: 1 to give a product of 6.9g(2.3X102 mol) a bromogroup substituted by Phthalimide. The product with 5. 9g (4. 7X 102 mol) of sodium sulfite, 140ml water and 85ml95percent ethanol mixed reactionwas heated to 95 ° C for18h, the remainingsolvent was drained, and the resulting residue was mixed with 73ml ofconcentrated hydrochloric acidthen was heated to 110 ° C thefor 18H, it was drained, with water - 95percent ethanol on the residue to carry out recrystallization to give 5-amino-1-pentylSulfonic acid 2. 7g (total yield 50percent).

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  • [ 78902-09-7 ]
YieldReaction ConditionsOperation in experiment
70% With cetyltributylphosphonium bromide In toluene at 111℃; for 24 h; Inert atmosphere Potassium phthalimide (5 g,26.5mmol), bromoacetal (4.1 mL, 26.5mmol), and hexadecyltributylphosphoniumbromide (13.8 g, 26.5mmol) wereheated together in toluene (200mL) for 24 h at 111 °C under N2 atmosphere.The product was then filtered, and the filtratewas concentrated on a rotary evaporator to give yellow oil.Column chromatography using hexane : ether (1 : 1) allowedobtaining the desired compound. Yield 70percent; Elementalanalysis calculated for C14H17NO4 (263.29): C 63.8, H 6.4, N 5.3; found: C 64.6, H 6.5, N 5.3. 1H NMR (300MHz,CDCl3): δ7.8–7.6 (m, 4H), 4.79 (t, 1H), 3.75 (d, 2H), 3.62–3.42 (m, 4H), 1.06 (t, 6H). ES-MS: m/z 264. IR: ν(C-O-C)2800, ](C=O) 1721 cm−1.
64% at 150℃; for 4 h; intermediate 395 H-Isoindole- l ,3(2H)-dionc, potassium salt (1 : 1) (50 g, 221.9 mmol ) and 2-bromo- 1 , 1 - diethoxy-ethane (54.7 g, 277.4 mmol ) in DMF were stirred at 1 50 °C for 4 hours. The DMF was removed under reduced pressure. The residue was purified by column chromatography (elution: petroleum ether/ ethyl acetate ratio 5/ 1 ) to afford intermediate 395 (40 g, yield: 64percent) as a white solid.
Reference: [1] Russian Journal of General Chemistry, 2007, vol. 77, # 1, p. 98 - 102
[2] Journal of Chemistry, 2015, vol. 2015,
[3] Patent: WO2017/32840, 2017, A1, . Location in patent: Page/Page column 264; 265
[4] Journal of Pharmacy and Pharmacology, 1952, vol. 4, p. 693,705
  • 32
  • [ 5292-43-3 ]
  • [ 1074-82-4 ]
  • [ 6297-93-4 ]
YieldReaction ConditionsOperation in experiment
78.4% With tetrabutylammomium bromide In acetone at 45℃; for 15 h; Inert atmosphere tert-Butyl bromoacetate (10 g, 51 mmol) was charged to a 250 mL 3-neck flask fitted with a thermocouple, nitrogen inlet tube and magnetic stirrer. The flask was charged with acetone (100 mL) and tetrabutylammonium bromide (0.8 g, 2.5 mmol) was added. Potassium phthalimide was next added in one portion and the flask was heated to 45 °C for 15 h. After this time the reaction mixture was cooled to 21 C and the acetone was removed by concentration on a rotovap. EtOAc (100 mL) and water (30 mL) were added. The biphasic mixture was allowed to stir at 21 C for 20 min then the layers were separated. The organic layer was washed with saturated Na2CO3 (3 × 30 mL), then with brine. The volatiles were concentrated. The crude residue was suspended in ethanol (30 mL), and water (30 mL) was slowly added over 30 min. The suspension was allowed to stir at 21 C overnight then the solid was collected by filtration and washed with water to provide the title compound in 78.4percent isolated yield, 99.29 HPLC areapercent purity.
Reference: [1] Heterocycles, 2010, vol. 80, # 2, p. 989 - 1002
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 23, p. 6209 - 6217
  • 33
  • [ 107-59-5 ]
  • [ 1074-82-4 ]
  • [ 6297-93-4 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 4, p. 515 - 525
  • 34
  • [ 1074-82-4 ]
  • [ 589-15-1 ]
  • [ 153171-22-3 ]
YieldReaction ConditionsOperation in experiment
100% at 100℃; for 6 h; (a) The reaction mixture of p-bromobenzyl bromide (corresponding to 50) (4.00g, 16.004mmol) and phthalimide potassium salt (3.26g, 17.61mmol) in DMF (10ml) was stirred for 6h at 100°C with a CaCl2 tube. After cooling, H2O (100ml) was added, and the resulting mixture was extracted with AcOEt (100ml×3). The combined organic layer was washed with H2O (100ml×1) and then brine (100ml×1), dried over Na2SO4 (anhyd), filtered, and concentrated under reduced pressure to afford 2-(4-bromobenzyl)isoindole-1,3-dione (5.28g, quant. y.) as a colorless solid. Colorless cotton-like crystal (n-hexane/AcOEt). Mp 126–129°C. 1H NMR (300MHz/CDCl3) δ 4.80 (2H, s, CH2), 7.32 (2H, d, J=7.8Hz, ArH), 7.44 (2H, d, J=8.1Hz, ArH), 7.71–7.73 (2H, m, ArH), 7.84–7.85 (2H, m, ArH).
Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 14, p. 3720 - 3731
[2] Chemistry - A European Journal, 2010, vol. 16, # 33, p. 10171 - 10177
[3] Journal of the Chemical Society, 1931, p. 1225,1232
[4] Tetrahedron, 1993, vol. 49, # 43, p. 9855 - 9866
[5] Patent: WO2015/103317, 2015, A1, . Location in patent: Page/Page column 271
  • 35
  • [ 136918-14-4 ]
  • [ 1074-82-4 ]
YieldReaction ConditionsOperation in experiment
98% With potassium methanolate In ethanol; water at 60 - 65℃; for 13 h; To the reactor was added phthalimide,Quality than 3 times the absolute ethanol, heating 60 ° C,A pre-formulated 30percent aqueous solution of potassium methoxide in anhydrous ethanol was added dropwise from the dropper,The molar ratio of potassium methoxide to phthalimide is 1.2: 1,Control the dropping time is 3 hours,The temperature rises slightly (up to 65 ° C)After 10 hours of reaction, the mixture was filtered off, washed once with anhydrous ethanol,Dried to obtain a high purity potassium phthalimide potassium salt.Purity 99.3percent, molar yield 98percent.
91.5% With potassium hydroxide In ethanol for 2 h; 3.0 g (20.4 mmol) of phthalimide and 30 mL of ethanol, stirred,30.6 mmol of KOH dissolved in 10 mL of ethanol was added dropwise,Drip, reflux, TLC monitoring, reaction 2.0h,Cooling, suction filtration, drying,The yield of the white solid o-phenyl dipotassium imide potassium salt was 3.43 g, the yield was 91.5percent.
90.3% With potassium hydroxide In ethanol for 2 h; Reflux 3.0 g phthalimide and 30 mL ethanol,Magnetic stirring,Slowly added dropwise 10mL 1.71g KOH ethanol, the drop was completed, reflux,TLC detection until the reaction of the raw material is complete,Reaction 2.0h,cool down,Suction filtration,Drying gives a white solidPotassium salt of phthalimide,Yield 90.3percent.
90.3% With potassium hydroxide In ethanol for 2 h; Reflux 3.0g of phthalimide and 30mL of ethanol were stirred magnetically and slowly added dropwise to 10mL of ethanol containing 1.7lg of KOH. After completion of the dropwise addition, the mixture was refluxed. The reaction of TLC was complete until the reaction of the raw materials was complete. The reaction was 2.Oh, cooled, and suction filtered. Dry to give the potassium salt of phthalimide as a white solid, yield 90.3 percent
82% With potassium hydroxide In methanol; water at 20℃; Phthalimide (20g, 0.136mol) added to anhydrous methanol (400 ml) in, heating the low boiling, the supernatant is poured into the potassium hydroxide (7.6g, 0 . 136mol) of water (7.5 ml) and methanol (23 ml) solution. Rapid cooling to room temperature, the mixed solution, Buchner for filtering the precipitate. The filter cake is washed with methanol (12 ml) washing twice. Vacuum drying, obtain 18.6g compound 4 (colorless solid), yield 82percent.
71% With potassium hydroxide In ethanol; water at 0℃; Reflux Phthalimide (2.00 g, 13.6 mmol, 1.00 eq.) was heated to reflux in ethanol (50 mL)and poured into a solution of potassium hydroxide (0.76 g, 13.6 mmol, 1.00 eq.) in 0.75 mL waterand 2.30 ml ethanol. The resulting suspension was cooled to 0 °C and filtered via Buchner funnel.After washing the greenish residuum with ethanol (1 x 25 mL) and aceton (2x 25 mL), the remainingsolvent was evaporated under reduced pressure to obtain the product as greenish crystals (1.96 g,10.6 mmol, 71percent). 1H NMR (400 MHz, D2O, 292 K): d [ppm] = 7.58–7.31 (m, 4 H).
30% With potassium hydroxide In ethanol; waterReflux A mixture of phthalimide10(6.8 mmol) dissolved in EtOH (20 mL) was gently boiled for about 1h. The hot solution was decanted from any solid into 1.25 mL of a specially prepared solution of KOH (15.25 g KOH dissolved in 15 mL of H2O and 45 mL of EtOH). A precipitate of potassium phthalimide separates at once. The mixture was stirred and cooled quickly to room temperature, and the precipitate was filtered under vacuum. To the alcoholic mother liquors a second 1 g portion of phthalimide was added, and the entire process was repeated. The two crops of crystals were united and washed with acetone to remove any unchanged phthalimide. After air-dried pure potassium phthalimidewas obtained as white crystals (yield 30percent).

Reference: [1] Patent: CN104447497, 2017, B, . Location in patent: Paragraph 0018-0019; 0021; 0023
[2] Patent: CN106699682, 2017, A, . Location in patent: Paragraph 0051; 0052
[3] Patent: CN107382980, 2017, A, . Location in patent: Paragraph 0027; 0028; 0029; 0030
[4] Patent: CN107540647, 2018, A, . Location in patent: Paragraph 0020-0024
[5] Journal of the American Chemical Society, 2011, vol. 133, # 41, p. 16410 - 16413
[6] Patent: CN105461628, 2016, A, . Location in patent: Paragraph 0078; 0079; 0080
[7] Molecules, 2018, vol. 23, # 9,
[8] European Journal of Medicinal Chemistry, 2018, vol. 149, p. 69 - 78
[9] Organic Letters, 2011, vol. 13, # 4, p. 764 - 767
[10] Patent: EP2510926, 2012, A1,
[11] Research on Chemical Intermediates, 2015, vol. 41, # 6, p. 3375 - 3388
[12] Patent: CN103833623, 2016, B, . Location in patent: Paragraph 0027; 0058; 0060
[13] Zeitschrift fur Anorganische und Allgemeine Chemie, 2017, vol. 643, # 5, p. 379 - 386
[14] Patent: CN104447498, 2017, B, . Location in patent: Paragraph 0039
[15] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 7, p. 1678 - 1684
  • 36
  • [ 40794-76-1 ]
  • [ 124-38-9 ]
  • [ 1074-82-4 ]
Reference: [1] ChemSusChem, 2014, vol. 7, # 5, p. 1484 - 1489
  • 37
  • [ 1074-82-4 ]
  • [ 99142-40-2 ]
  • [ 67455-96-3 ]
  • [ 52667-89-7 ]
Reference: [1] Chemistry Letters, 1986, p. 369 - 372
  • 38
  • [ 19752-21-7 ]
  • [ 1074-82-4 ]
  • [ 89282-70-2 ]
YieldReaction ConditionsOperation in experiment
78% With hydrogenchloride; sodium hydroxide; hydrazine In <i>N</i>-methyl-acetamide; methanol; chloroform; water EXAMPLE 3
Synthesis of 2-methoxyisobutylamine
Potassium phthalimide(3.70 g, 0.02 mol) was added to a solution of 2-methoxyisobutylbromide(3.34 g, 0.02 mol) in 100 ml of dimethylformamide.
Stirring and reflux were continued for 4 hours, and the temperature dropped slowly to 25° C.
After the addition of 200 ml of chloroform, the mixture was poured into 500 ml of cold water.
The aqueous phase was separated and extracted with two 50 ml portions of chloroform.
The combined chloroform extractants were washed with 100 ml of 0.2N sodium hydroxide and 100 ml of water.
After drying the chloroform was removed.
The residue was added to hydrazine (2 g, 0.04 mol) in 100 ml of methanol and was heated under reflux for an hour.
The methanol was removed by concentration under reduced pressure.
Concentrated hydrochloric acid was added to the residual aqueous solution and the mixture was heated under reflux for an hour.
The solution was then concentrated under reduced pressure to remove most of the hydrochloric acid.
The moist residue was adjusted pH=14 using sodium hydroxide and was poured into separatory funnel containing saturated K2 CO3 solution.
The resulting solution was distilled at atmospheric pressure and the product collected at 125° C. (1.6 g, 78percent yield).
IR(neat/ν cm-1):3280, 3065, 2960, 2920, 1640, 1430, 1365, 1075.
Reference: [1] Patent: US5210270, 1993, A,
  • 39
  • [ 1074-82-4 ]
  • [ 111-44-4 ]
  • [ 2752-17-2 ]
YieldReaction ConditionsOperation in experiment
30% With potassium hydroxide In water EXAMPLE 38
Preparation of 1,5-diamino-3-oxapentane
1,5-Dichloro-3-oxapentane is treated with potassium phthalimid, followed by hydrazinolysis of the resulting diphthalimido-derivative and consecutive acidification whereby the bis-hydrochloride of the title compound is obtained.
The bis-hydrochloride is treated with a very concentrated (approx. 10N) solution of potassium hydroxide in water and continuously extracted with benzene in a liquid-liquid extractor for several (three to five) days.
The solvent is evaporated and the liquid residue is distilled under reduced pressure giving the desire compound.
b.p.: 48° - 50° /1mm Hg
Yield 30percent (from the initial 1,5-dichloro-3-oxapentane).
PMR (CDCl3): --NH2: 1.30 ppm (singlet: 4H); --CH2 --N: 2.90 ppm (triplet: 4H); --CH2 --O: 3.50 ppm (triplet: 4H).
30% With potassium hydroxide In water EXAMPLE 38
Preparation of 1,5-diamino-3-oxapentane
1,5-Dichloro-3-oxapentane is treated with potassium phthalimid, followed by hydrazinolysis of the resulting diphthalimido-derivative and consecutive acidification whereby the bis-hydrochloride of the title compound is obtained.
The bis-hydrochloride is treated with a very concentrated (approx. 10N) solution of potassium hydroxide in water and continuously extracted with benzene in a liquid-liquid extractor for several (three to five) days.
The solvent is evaporated and the liquid residue is distilled under reduced pressure giving the desire compound.
b.p.: 48° - 50°11mm Hg:
Yield 30percent (from the initial 1,5-dichloro-3-oxapentane); PMR (CDCl3): --NH2: 1.30 ppm (singlet: 4H); --CH2 --N: 2.90 ppm (triplet: 4H); --CH2 --O: 3.50 ppm (triplet: 4H).
Reference: [1] Patent: US4156683, 1979, A,
[2] Patent: US3966766, 1976, A,
  • 40
  • [ 64473-35-4 ]
  • [ 96042-30-7 ]
  • [ 1074-82-4 ]
  • [ 18655-50-0 ]
Reference: [1] Patent: US2002/58659, 2002, A1,
  • 41
  • [ 1074-82-4 ]
  • [ 120740-09-2 ]
  • [ 105827-91-6 ]
Reference: [1] Patent: US5180833, 1993, A,
  • 42
  • [ 1074-82-4 ]
  • [ 105310-75-6 ]
Reference: [1] Patent: WO2011/158249, 2011, A1, . Location in patent: Page/Page column 24-25
[2] Patent: WO2012/46247, 2012, A2, . Location in patent: Page/Page column 26
[3] Journal of the Chinese Chemical Society, 2013, vol. 60, # 6, p. 639 - 644
  • 43
  • [ 1074-82-4 ]
  • [ 105310-90-5 ]
  • [ 105310-75-6 ]
Reference: [1] Journal of Medicinal Chemistry, 1987, vol. 30, # 2, p. 318 - 325
  • 44
  • [ 67843-74-7 ]
  • [ 1074-82-4 ]
  • [ 181140-34-1 ]
YieldReaction ConditionsOperation in experiment
72% With benzyltrimethylammonium chloride In <i>tert</i>-butyl alcohol at 20℃; for 24 h; Into a reaction vessel were put potassium phthalimide (5.00g, 27.0mmol), benzyltrimethylammonium chloride (0.50g, 2.70mmol) and tert -buyl alcohol (50ml) and then thereto was added (S)-epichlorohydrin (6.53g, 54.0mmol). The mixture was stirred at 20C for 24 hours and the solvent was removed. To the residue was added ethyl acetate (30ml), the mixture was washed with water (20ml), and then ethyl acetate was removed to give crude (S)-glycidylphthalimide (3.95g, yield: 72percent, optical purity: 97percente.e.) as a white solid.
Reference: [1] Patent: EP1403267, 2004, A1, . Location in patent: Page 5
  • 45
  • [ 51594-55-9 ]
  • [ 1074-82-4 ]
  • [ 181140-34-1 ]
  • [ 161596-47-0 ]
Reference: [1] Patent: EP1403267, 2004, A1, . Location in patent: Page 6
  • 46
  • [ 51594-55-9 ]
  • [ 1074-82-4 ]
  • [ 161596-47-0 ]
YieldReaction ConditionsOperation in experiment
83% With benzyltrimethylammonium chloride In isopropyl alcohol at 10℃; for 46 h; Into a reaction vessel were put potassium phthalimide (50.0g, 0.27mol), benzyltrimethylammonium chloride 5.00g, 0.02.7mol) and isopropanol (500ml), and the mixture was cooled to 10C. Thereto was added (R)-epichlorohydrin (74.9g, 0.81mol) and the mixture was stirred for 46 hours while being cooled. The solvent was removed and to the residue was added ethyl acetate (250ml). The mixture was washed with water (250ml) and then ethyl acetate was removed to give crude (R)-glycidylphthalimide (optical purity: 97percent e.e.). The crude product was crystallized from ethyl acetate-hexane to give the object (R)-glycidylphthalimide (45.6g, yield: 83percent, optical purity: 98percente.e.) as white crystals. mp 100-102C Specific rotation [a]D?25-9.7 (c2.0. CHCl3)1HNMR (CDCl3, 270MHz) d 2.70 (dd, 1H), 2.81(dd, 1H) , 3.21-3.28 (m, 1H), 3.81 (dd, 1H), 3.97 (dd, 1H), 7.27-7.91 (m, 4H) The optical purity was calculated using HPLC and by its area ratio. Condition: Column: CHIRALPAC AD (0.46cmF x 25cm L (Daicel Co., Ltd.) Mobile phase: n-hexane/isopropanol (90/10(v/v) Velocity:1.0ml/min. Detection: UV220nm Retention: (S)isomer=17.9min., (R)isomer=25.5min.
74% With benzyltrimethylammonium chloride In tetrahydrofuran at 50℃; for 44 h; Comparative examples 2-4 were shown in the following Table 1, which were conducted by changing the solvent according to the method of Comparative example 1.[Table 1] Solvent Reaction temp/hr Yield Optical purity (percent ee) Comp. ex.2 THF 50C/44hr 74 87 Comp. ex.3 Toluene 50C/20hr n.d n.d. Comp. ex.4 Dichloroethane 30C/16hr n.d. n.d.
68% With benzyltrimethylammonium chloride In methanol at 20℃; for 15 h; Into a reaction vessel were put potassium phthalimide (5.00g, 27.0mmol), benzyltrimethylammonium chloride (0.50g, 2.70mmol) and methanol (50ml) and then thereto was added (R)-epichlorohydrin (9.99g, 81.0mmol). The mixture was stirred at 20C for 15 hours and the solvent was removed. To the residue was added ethyl acetate (30ml), the mixture was washed with water (20ml) and ethyl acetate was removed to give crude (R)-glycidylphthalimide (3.74g, yield: 68percent, optical purity: 99percente.e.) as a white solid.
Reference: [1] Patent: EP1403267, 2004, A1, . Location in patent: Page 5
[2] Patent: EP1403267, 2004, A1, . Location in patent: Page 6
[3] Patent: EP1403267, 2004, A1, . Location in patent: Page 5-6
[4] Synlett, 2006, # 13, p. 2151 - 2153
[5] Patent: EP1403267, 2004, A1, . Location in patent: Page 6
[6] Patent: EP1403267, 2004, A1, . Location in patent: Page 6
  • 47
  • [ 67843-74-7 ]
  • [ 1074-82-4 ]
  • [ 161596-47-0 ]
YieldReaction ConditionsOperation in experiment
88.1 g With N-benzyl-N,N,N-triethylammonium chloride; potassium iodide In isopropyl alcohol at 28℃; for 72 h; To a 1 L single-necked flask was added 85 g (0.46 mol) of potassium phthalimide,Benzyltriethylammonium chloride 10. 5 g (0.04 mol)Potassium iodide 0.76 g (0.0046 mol), isopropyl alcohol 382.5 ml,Stir evenly,At 28 ° C,(S) epichlorohydrin 85. 6 g (0.9 mol) was added to the reaction system in the presence of stirring,System from white turbidity into pale yellow turbidity,The reaction was carried out at a temperature of 28 ° C for 72 hours,Filter,Washed,dry,And finally the solid 88. lg,Yield 94. 5percentPurity 92percent.
Reference: [1] Patent: CN103382200, 2016, B, . Location in patent: Paragraph 0034; 0035
  • 48
  • [ 51594-55-9 ]
  • [ 1074-82-4 ]
  • [ 181140-34-1 ]
  • [ 161596-47-0 ]
Reference: [1] Patent: EP1403267, 2004, A1, . Location in patent: Page 6
  • 49
  • [ 1074-82-4 ]
  • [ 161596-47-0 ]
Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 1, p. 18 - 22
[2] Organic Process Research and Development, 2017, vol. 21, # 1, p. 18 - 22
  • 50
  • [ 1074-82-4 ]
  • [ 105827-91-6 ]
  • [ 120740-08-1 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 9, p. 2061 - 2068
  • 51
  • [ 1252018-10-2 ]
  • [ 1074-82-4 ]
  • [ 446292-07-5 ]
YieldReaction ConditionsOperation in experiment
93% at 20 - 100℃; for 3 h; Example 3:Preparation of 2-((2R)-2-Hydroxy-3-[4-(3-oxomorpholin-4-yl)- phenyl]amino}proply)-1 /-/-isoindole-1 ,3(2H)-dione (7a): Potassium phthalimide (7.16 g, 38.632 mmoL) was added in one portion to a mechanically stirred mixture of 4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl]morpholin-3- one (10 g, 35.119 mmoL) in DMF (60 mL). The suspension was stirred at room temperature and was heated to 100 °C, stirred at that temperature for 3 h and then cooled to room temperature. Water (60 mL) was charged and the suspension stirred for another 15 min. The suspension was filtered through a Buchner funnel. The solid was washed with water (2 x 40 mL) and dried under vacuum at 50°C for 10 h to yield 2-((2f?)-2-Hydroxy-3-[4-(3-oxomorpholin-4- yl)-phenyl]amino}proply)-1 7-isoindole-1 ,3(2/-/)-dione (12.55 g, 93percent) as a crystalline white solid.1HNMR (400MHz, DMSO-d6) δ 2.99-3.05 (m, 1 H), 3.14-3.2 (m, 1 H), 3.59-3.69 (m, 4H), 3.91-3.94 (m, 2H), 3.97-4.05 (m, 1 H), 4.14 (s, 2H), 5.16 (d, J=5.2 Hz, 1 H), 5.66 (t, J=6.0 Hz, 1 H), 6.61 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.82-7.88 (m, 4H).
92%
Stage #1: With sodium hydroxide In dichloromethane; water at 20℃; for 8 h;
Stage #2: at 100℃; for 3 h;
The above 57.6 g of intermediate 4 and 400 mL of dichloromethane were charged into a 1 L three-necked flask,A solution of 17.8 g of Na0H and 60 mL of water was added dropwise at room temperature,After stirring at room temperature for 6 h, the organic layer was washed with 120 mL of water and then with 60 mL of saturated brine,The organic layer was dried over anhydrous sodium sulfate,Filtered, concentrated to 180mL of liquid, by adding 360mL n-hexane heated reflux 30min,System cooling to room temperature and then stirring 2h,The filter cake was washed with dichloromethane and n-hexane (1: 3)The filter cake was dried in vacuo for 12 h to give 48.2 g of white crystals.48 g (0.17 mol) of the above solid and 240 mL of the 4-dioxane were charged into a 500 mL three-necked flask,34.4 g (0.19 mol) of potassium phthalimide potassium salt was added with stirring,System gradually heated to 100 ° C, stirring 3h, cooling to room temperature, add 60mL water stirring 15min,Filter, filter cake washed with 2X1 OOmL,White crystals were obtained at 50 ° C in vacuum and dried 1 Oh to give 60.2 g of compound 6 (92percent) mp. = 211.7-211.9 ° C.
87.8% for 10 h; Reflux The reaction flask, and the resulting 32.7g (0.115mol) of intermediate V with 300ml of anhydrous methanol was dissolved, followed by addition of 29.1g (0.157mol) of potassium phthalimide and heated at reflux for 9 hours, TLC in the control (ethyl acetate: methanol = 10: 1, volume ratio) to complete the reaction, filtered hot, the filtrate was lowered to room temperature (about 25 ) was stirred for 2 hours, filtered, the filter cake was rinsed with 75ml of anhydrous methanol, and drying under reduced pressure, intermediate VI to give an off-white about 39.9g (0.101mol), intermediate V molar yield intermediate VI is prepared from about 87.8percent.
87.8% for 9 h; Reflux In the reaction flask, the obtained 32.7 g (0.115 mol) of the intermediate V was dissolved with 300 ml of anhydrous methanol,Then, 29.1 g (0.157 mol) of potassium phthalimide was added and the mixture was heated to reflux for 9 hours.The reaction was completed by TLC (ethyl acetate:methanol=10:1, volume ratio) and the reaction was complete. The filtrate was cooled to room temperature (about 25° C.) and stirred for 2 hours. The mixture was filtered, and the filter cake was rinsed with 75 ml of anhydrous methanol. drying,About 39.9 g (0.101 mol) of the off-white intermediate VI was obtained, and about 87.8percent of the intermediate V was produced in the molar yield of the intermediate VI.
51.4 g for 10 h; Reflux In the reaction flask, the obtained 42.6 g (0.15 mol)Intermediate V was dissolved with 400 ml anhydrous methanol.Then 38.8 g (0.21 mol) of potassium phthalimide was added,The mixture was heated at reflux for 10 hours, and the reaction was completed by TLC (ethyl acetate: methanol = 10:1, volume ratio).Heat filtered, the filtrate was cooled to room temperature (about 25°C) and stirred for 2 hours, filtered,The filter cake was rinsed with 100 ml of anhydrous methanol and dried under reduced pressure to obtain about 51.4 g (0.13 mol) of the off-white intermediate VI. The intermediate V produced the intermediate VI in a molar yield of about 86.7percent.

Reference: [1] Patent: WO2012/51692, 2012, A1, . Location in patent: Page/Page column 42-43
[2] Patent: CN103951661, 2017, B, . Location in patent: Paragraph 0043-0044
[3] Patent: CN104974105, 2017, B, . Location in patent: Paragraph 0073
[4] Patent: CN104974149, 2018, B, . Location in patent: Paragraph 0074; 0075; 0077; 0081; 0083
[5] Patent: WO2012/32533, 2012, A2, . Location in patent: Page/Page column 15
[6] Patent: CN104974148, 2017, B, . Location in patent: Paragraph 0073; 0074; 0076; 0082
  • 52
  • [ 51594-55-9 ]
  • [ 1074-82-4 ]
  • [ 79-22-1 ]
  • [ 438056-69-0 ]
  • [ 446292-08-6 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: at 20℃; Cooling
Stage #2: With sodium hydrogencarbonate In butan-1-ol at 0 - 5℃;
Stage #3: at 95 - 100℃; for 3 h;
4-(4-Aminophenyl)morpholin-3-one (100 gm) was added in n-butanol (300 ml) and charged Alumia sulfonic acid at ambient temperature. Cool the mass, added (R)-Epichlorohydrin (72 gm) and maintain the reaction mass at below 20°C. Confirmed the completion of reaction, separated the catalyst. Added sodiumbicarbonate, cool the mass temperature to Q-5°C and added methylchloroformate (56 gm) . After completion of reaction, evaporated the n- butanol and charged N,N-dimethylformamide (500 mi), potassium phthalimide (122 gm). The reaction temperature maintained at 95- 100°C for 3 hours. Cool the mass temperature to ambient temperature, quenched the mass into water. Filtered the mass and washed the product with water. Dried the material up to get constant weight. The obtained 2-({(5Sj-2-Qxo-3-[4-(3-Gxo-4- morpholmyl]phenyl ]-- 1 ,3--oxazol.idm-5--yl}methyl)-- 1 H--isoindole-- 1 ,3(2H)--d.ione was 186 gm (85percent yield) .
Reference: [1] Patent: WO2018/55499, 2018, A1, . Location in patent: Page/Page column 12
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  • [ 446292-08-6 ]
Reference: [1] Patent: WO2012/32533, 2012, A2, . Location in patent: Page/Page column 14
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  • [ 446292-08-6 ]
Reference: [1] Patent: CN105801572, 2016, A,
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  • [ 111992-61-1 ]
YieldReaction ConditionsOperation in experiment
63% at 90℃; for 10 h; A solution of 2 (1.0 g, 4.4 mmol), potassium phthalimide (0.4 g, 2.2 mmol) in DMF (10 mL) was stirred at 90 °C for 10 h. The mixture was poured into H2O (30 mL) and the suspension was extracted with EtOAc (2 .x. 30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (hexane:EtOAc, 20:1) gave 3 (0.41 g, 63percent) as a white solid: mp 75-76.5 °C; 1H NMR (300 MHz, CDCl3) δ 1.11 (s, 6H), 3.38 (s, 2H), 3.70 (s, 2H), 7.72-7.88 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 24.6, 37.6, 44.5, 46.2, 123.3, 131.9, 134.1, 168.7; MS (ESI) m/z 318.0 [M+Na]+.
Reference: [1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 14, p. 4238 - 4249
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Reference: [1] Journal of Agricultural and Food Chemistry, 2008, vol. 56, # 1, p. 204 - 212
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