[ CAS No. 17564-64-6 ] {[proInfo.proName]}

Name: 17564-64-6|2-(Chloromethyl)isoindoline-1,3-dione|95%
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SKU: A464485
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Quality Control of [ 17564-64-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 17564-64-6 ]

CAS No. :	17564-64-6	MDL No. :	MFCD00005898
Formula :	C₉H₆ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JKGLRGGCGUQNEX-UHFFFAOYSA-N
M.W :	195.60	Pubchem ID :	87154
Synonyms :

Calculated chemistry of [ 17564-64-6 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.11
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	51.52
TPSA :	37.38 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.95 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.63
Log Po/w (XLOGP3) :	2.17
Log Po/w (WLOGP) :	1.1
Log Po/w (MLOGP) :	1.87
Log Po/w (SILICOS-IT) :	1.89
Consensus Log Po/w :	1.73

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.7
Solubility :	0.394 mg/ml ; 0.00202 mol/l
Class :	Soluble
Log S (Ali) :	-2.59
Solubility :	0.505 mg/ml ; 0.00258 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.09
Solubility :	0.16 mg/ml ; 0.000818 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.32

Safety of [ 17564-64-6 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P261-P273-P280-P301+P310-P305+P351+P338	UN#:	2811
Hazard Statements:	H301-H315-H317-H319-H335-H412	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 17564-64-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 17564-64-6 ]
Downstream synthetic route of [ 17564-64-6 ]

[ 17564-64-6 ] Synthesis Path-Upstream 1~3

1
[ 17564-64-6 ]
[ 118-29-6 ]

Reference： [1] Chemistry - A European Journal, 2012, vol. 18, # 11, p. 3241 - 3247

2
[ 17564-64-6 ]
[ 550-44-7 ]
[ 118-29-6 ]
[ 1380112-97-9 ]

Reference： [1] Chemistry - A European Journal, 2012, vol. 18, # 11, p. 3241 - 3247

3
[ 17564-64-6 ]
[ 696-60-6 ]

Reference： [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 15, p. 1701
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 15, p. 1700

[ 17564-64-6 ] Synthesis Path-Downstream 1~74

1
[ 17564-64-6 ]
[ 91-20-3 ]
[ 6968-09-8 ]

Reference： [1]Synthetic Communications,2001,vol. 31,p. 3309 - 3313
[2]Patent: DE442774,
Fortschr. Teerfarbenfabr. Verw. Industriezweige,vol. 15,p. 1700

2
[ 118-29-6 ]
[ 17564-64-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2.5h;	A mixture of phthalimide (41.14 g, 0.30 mol) and distilled water (100 mL) was stirred for 10 min at room temperature. After addition of formaldehyde solution (40%, 27 mL, 0.36 mol), the resulting solution was refluxed for 1.5 h. After cooling to 0-5 C, the resulting precipitate was collected by filtration, washed with cold water (0-5 C, 200 mL) and dried in air to give the corresponding N-hydroxymethylphthalimide (51.01 g, 96% yield).(0010)A solution of thionyl chloride (23.0 mL, 37.7 g, 0.32 mol) in dichloromethane (50 mL) was slowly added to a mixture of the resulting N-hydroxymethylphthalimide and dichloromethane (550 mL) and N,N-dimethylformamide (350 mL) during 30 min at room temperature with stirring. The resulting mixture was further stirred for 2 h at room temperature. After cooling to 0 C, water (200 mL) was added slowly. And the solution was neutralized to pH 6.7-7.0 by using saturated aqueous NaHCO3 solution. The organic layer was separated and then was dried over anhydrous magnesium sulfate. After evaporation of the solvent under the reduced pressure, the residue was washed with n-hexane (100 mL) to give N-chloromethylphthalimide (51.4 g, 93% yield).(0011) N-Chloromethylphthalimide (51.0 g, 0.26 mol) was dissolved in acetone (500 mL) and potassium O-ethyl xanthate (43.9 g, 274 mmol) was added portionwise in an ice water bath under stirring. The resulting solution was further stirred for 10 h at room temperature. After removal of the solvent, the residue was dissolved in dichloromethane. The resulting solution was washed with water and dried over sodium sulfate. After removal of the solvent under the reduced pressure, pale yellow solid was obtained and recrystallized from ethyl acetate to afford the xanthate 1 as colorless crystals 67.2 g, 92% yield, mp: 99-100 C. Lit.20 mp: 94-95 C. 1H NMR (CDCl3, 400 MHz) (delta, ppm) 1.47 (t, J=7.1 Hz, 3H, CH3), 4.68 (q, J=7.1 Hz, 2H, CH2), 5.34 (s, 2H, CH2), 7.75 (dd, J=5.5, 3.1 Hz, 2H, ArH), 7.88 (dd, J=5.5, 3.1 Hz, 2H, ArH). 13C NMR (CDCl3, 100 MHz) (delta, ppm) 13.7, 41.2, 70.5, 123.6, 131.8, 134.4, 166.6, 210.2.

Reference： [1]Tetrahedron,2013,vol. 69,p. 1050 - 1056
[2]Chemische Berichte,1898,vol. 31,p. 1229
[3]Chemische Berichte,1908,vol. 41,p. 248
[4]Chemische Berichte,1959,vol. 92,p. 1258,1261
[5]Journal of Organic Chemistry,1993,vol. 58,p. 4913 - 4918
[6]Journal of general chemistry of the USSR,1991,vol. 61,p. 1875 - 1881
Zhurnal Obshchei Khimii,1991,vol. 61,p. 2024 - 2031
[7]Russian Journal of Organic Chemistry,2009,vol. 45,p. 1644 - 1650
[8]Journal of Organic Chemistry,2010,vol. 75,p. 6468 - 6476
[9]Revue Roumaine de Chimie,2010,vol. 55,p. 559 - 564
[10]Chemistry - A European Journal,2012,vol. 18,p. 3241 - 3247
[11]MedChemComm,2017,vol. 8,p. 1477 - 1484

3
[ 17564-64-6 ]
[ 83-31-8 ]
<i>N</i>-(2,2-dioxo-2λ⁶-naphth[1,8-<i>cd</i>][1,2]oxathiol-6-ylmethyl)-phthalimide [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1948,vol. 31,p. 1229,1233

4
[ 17564-64-6 ]
[ 34231-78-2 ]
N-<2-(3-acetoxyphenyl)-2-hydroxyethyl>phthalimide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1993,vol. 58,p. 588 - 599

5
[ 17564-64-6 ]
[ 100-52-7 ]
[ 35645-98-8 ]

Reference： [1]Journal of Organic Chemistry,1993,vol. 58,p. 588 - 599

6
[ 17564-64-6 ]
[ 66-25-1 ]
N-(2-hydroxyheptyl)phthalimide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1993,vol. 58,p. 588 - 599

7
[ 17564-64-6 ]
[ 2043-61-0 ]
N-(2-cyclohexyl-2-hydroxyethyl)phthalimide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1993,vol. 58,p. 588 - 599

8
[ 17564-64-6 ]
[ 108-95-2 ]
[ 92498-03-8 ]

Reference： [1]Revue Roumaine de Chimie,1999,vol. 44,p. 261 - 264
[2]Journal of Organic Chemistry,1993,vol. 58,p. 4913 - 4918
[3]Journal of Heterocyclic Chemistry,1998,vol. 35,p. 1477 - 1483
[4]Advanced Synthesis and Catalysis,2014,vol. 356,p. 2627 - 2642

9
[ 17564-64-6 ]
[ 100-53-8 ]
[ 52096-57-8 ]

Reference： [1]Chemistry Letters,1994,p. 2139 - 2142
[2]European Journal of Organic Chemistry,2005,p. 2758 - 2770

10
[ 17564-64-6 ]
[ 88-97-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 955 - 958

11
[ 17564-64-6 ]
[ 2050-16-0 ]
C₃₀H₂₀N₄O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate In ethanol for 0.166667h; Heating;

Reference： [1]Bratulescu, George; Le Bigot, Yves; Delmas, Michel [Revue Roumaine de Chimie, 1998, vol. 43, # 6, p. 525 - 530]

12
[ 67-56-1 ]
[ 17564-64-6 ]
[ 23244-58-8 ]

Yield	Reaction Conditions	Operation in experiment
	With iodine; triphenylphosphine 1.) ether, THF, -18 deg C to r.t., 12 h, 2.) THF, r.t., 48 h; Yield given. Multistep reaction;

Reference： [1]Petri, Wolfgang; Beck, Wolfgang [Chemische Berichte, 1984, vol. 117, # 11, p. 3265 - 3269]

13
[ 17564-64-6 ]
[ 6320-02-1 ]
[ 269742-90-7 ]

Reference： [1]Heterocycles,2004,vol. 64,p. 33 - 39
[2]European Journal of Organic Chemistry,2005,p. 2758 - 2770
[3]Organic Letters,2000,vol. 2,p. 1201 - 1204

14
[ 17564-64-6 ]
[ 108-98-5 ]
[ 32637-30-2 ]

Reference： [1]Heterocycles,2004,vol. 64,p. 33 - 39
[2]European Journal of Organic Chemistry,2005,p. 2758 - 2770
[3]Organic Letters,2000,vol. 2,p. 1201 - 1204
[4]Journal of Organic Chemistry,2001,vol. 66,p. 4695 - 4703

15
[ 17564-64-6 ]
[ 91-60-1 ]
[ 71858-48-5 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 2758 - 2770
[2]Organic Letters,2000,vol. 2,p. 1201 - 1204

16
[ 17564-64-6 ]
[ 79-10-7 ]
[ 40459-70-9 ]

Reference： [1]Journal of Organic Chemistry,2001,vol. 66,p. 2966 - 2977

17
[ 17564-64-6 ]
phenylmagnesium bromide [ No CAS ]
[ 2142-01-0 ]

Reference： [1]Journal of Organometallic Chemistry,2003,vol. 687,p. 403 - 409

18
[ 17564-64-6 ]
[ 7217-59-6 ]
[ 849363-80-0 ]

Reference： [1]Heterocycles,2004,vol. 64,p. 33 - 39

19
[ 505-48-6 ]
[ 17564-64-6 ]
suberic acid methylphthalimidomonoester [ No CAS ]

Reference： [1]Organic letters,2001,vol. 3,p. 4239 - 4242

20
[ 17564-64-6 ]
[ 4410-99-5 ]
[ 53497-64-6 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 2758 - 2770

21
[ 17564-64-6 ]
[ 696-63-9 ]
[ 863393-49-1 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 2758 - 2770
[2]Advanced Synthesis and Catalysis,2014,vol. 356,p. 2627 - 2642

22
[ 17564-64-6 ]
[ 2037-31-2 ]
[ 19378-61-1 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 2758 - 2770

23
[ 17564-64-6 ]
[ 15570-12-4 ]
[ 863393-48-0 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 2758 - 2770

24
[ 17564-64-6 ]
[ 645-96-5 ]
[ 93378-90-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium acetate; In N,N-dimethyl-formamide; at 20℃; for 13h;Inert atmosphere;	General procedure: Conditions A: aqueous 37% hydrochloric acid (0.17 mL, 2 mmol) was added to a solution of 1 (258 mg, 1.0 mmol) in 8 mL of degassed ethanol. The mixture was heated at 95 C under Argon atmosphere until the selenocarbonate 1 disappeared (2,5-3 h). After cooling to room temperature sodium bicarbonate (0.34 g, 4 mmol) and alkylhalide (1.5 mmol, see Table 3) were added and the resulting mixture was stirred until the end of the reaction (TLC analysis). After the addition of water (10 mL) the mixture was extracted three times with 10 mL of EtOAc. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified on a silica gel column with a mixture of petroleum ether and ethyl ether as eluant to give the corresponding selenide 5. Conditions B: trifluoroacetic acid (0.15 mL, 2 mmol) was added to a solution of 1 (258 mg, 1.0 mmol) in 8 mL of degassed DMF. The mixture was heated at 95 C under Argon atmosphere until the selenocarbonate 1 disappeared (2,5-3 h). After cooling to room temperature sodium acetate (0.33 g, 4 mmol) and alkyl or aryl halide (1.5 mmol, see Table 3) were added and the resulting mixture was stirred until the end of the reaction (TLC analysis). After the addition of water (10 mL) the mixture was extracted three times with 10 mL of EtOAc. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The corresponding selenide 5 was isolated after column chromatographyon SiO2 utilizing a mixture of diethyl ether and petroleum ether as eluant. Characterisation data for selenides 5b-5c [26], 5d, [27] 5e, [28] 5f [29], 5g [30], 5h [31], and 5i [32] matched the ones previously reported in literature for these compounds.

Reference： [1]European Journal of Organic Chemistry,2005,p. 2758 - 2770
[2]Tetrahedron,2020,vol. 76

25
[ 17564-64-6 ]
[ 4892-02-8 ]
[ 863393-50-4 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 2758 - 2770

26
[ 17564-64-6 ]
[ 6065-59-4 ]
[ 339195-95-8 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1217 - 1230

27
[ 136918-14-4 ]
[ 50-00-0 ]
[ 17564-64-6 ]

Reference： [1]Journal of Heterocyclic Chemistry,2007,vol. 44,p. 951 - 960

28
[ 17564-64-6 ]
[ 154447-36-6 ]
[ 778643-65-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; In acetonitrile; at 55℃; for 96.0h;	[0214] In order to preparation the phthalimidomethyl quarternary salt of Compound 1101, a mixture of 100 mg Compound 1101 and 100 mg sodium iodide (2.0 equivalents) were dissolved in 3.0 ml dry acetonitrile. To the mixture was added 128 mg of chloromethylphthalimide and the vial was heated in an oil bath at 55 C for four days. The product was identified by LCMS as a new peak with RF= 3.984, M+ = 467

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 89

29
[ 17564-64-6 ]
[ 950-59-4 ]
N-(3,5-di-tert-butyl-4-hydroxyphenylthiomethyl)phthalimide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In water; acetone;	EXAMPLE 1 N-(3,5-di-tert-butyl-4-hydroxyphenylthiomethyl)phthalimide A vessel was charged with 12.19 grams of 3,5-di-tert-butyl-4-hydroxybenzene thiol and 3.30 grams of potassium hydroxide dissolved in 50 ml of acetone and 2 ml of water at 0 C. which was mixed with 10.0 grams of <strong>[17564-64-6]N-(chloromethyl)phthalimide</strong>. After stirring for one hour, the precipitated product was removed by filtration and then recrystallized from ethyl acetate-hexane to give 14.9 grams of produt, m.p. 151-53 C. Anal. Calc'd for C23 H27 NO3 S: C, 69.5; H, 6.9; N, 3.5. Found: C, 69.5, H, 7.0, N, 3.6.

Reference： [1]Patent: US4692532,1987,A

30
[ 75-15-0 ]
[ 17564-64-6 ]
[ 15143-34-7 ]

Yield	Reaction Conditions	Operation in experiment
7.46%	With sodium hydroxide; In water; acetone;	EXAMPLE 42 To a stirred solution containing 15 grams (0.12 mole) of amine, 19.2 grams (0.12 mole) of 25% sodium hydroxide and 250 ml. of acetone there was added dropwise at 5-15 C., 9.2 grams (0.12 mole) of carbon bisulfide. After stirring at 25-30 C. for an hour, 19.6 grams (0.1 mole) of phthalimidomethyl chloride was added in one portion and stirring continued at 25-30 C. for another hour. Thereupon there was added 700 ml. of water and the reaction mixture stirred and cooled to 5 C. The product was isolated as described in Example 41. Phthalimidomethyl 3-azabicyclo[3.2.2]nonane-3- carbodithioate was obtained in 99% yield as a grey solid melting at 139-140 C. after recrystallization from ethyl alcohol/benzene. Analysis gave 7.46% nitrogen and 18.09% sulfur compared to 7.77% nitrogen and 17.79% sulfur calculated for C18 H20 N2 O2 S2.

Reference： [1]Patent: US4013638,1977,A

31
[ 17564-64-6 ]
[ 65600-74-0 ]
[ 1075800-16-6 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 8987 - 8991

32
[ 17564-64-6 ]
[ 122085-76-1 ]
[ 935473-45-3 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 8987 - 8991

33
[ 17564-64-6 ]
[ 40637-56-7 ]
2-allyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-malonic acid dimethyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 17638 - 17639
[2]Chemistry - A European Journal,2014,vol. 20,p. 9910 - 9913
[3]Green Chemistry,2017,vol. 19,p. 4515 - 4519

34
[ 17564-64-6 ]
[ 1232884-73-9 ]
[ 1232886-20-2 ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium carbonate;sodium iodide; at 20℃;Darkness;	Example 17: (E)-3-[3'-Adamantan-l-yl-4'-(l,3-dioxo-l,3-dihydroisoindol-2- ylmethoxy)-biphenyl-4-yl] -acrylic acid ST5632AA1; STEP 1: A solution of (E)-3-(3'-adamantan-l-yl-4'-hydroxybiphenyl-4-yl)acrylic acid tert-hutyl ester (200 mg, 0.464 mmol), N-chloromethylphthalimide (91 mg, 0.464 mmol), K2CO3 (70 mg, 0.464 mmol) and NaI (70 mg, 0.464 mmol) was stirred overnight at RT in the dark. The solvent was evaporated and the residue was taken up in EtOAc. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. 3-[3'- Adamantan-l-yl-4'-(l,3-dioxo-l,3-dihydroisoindol-2-ylmethoxy)-biphenyl-4- yl] acrylic acid tert-hutyl ester was obtained after purification on silica gel (EtOAc/hexane 15:85) in 55%yield (150 mg).1H NMR (DMSO-ds) delta: 7.30-8.05 (m, 12H); 6.55 (d, J = 16 Hz, IH); 5.70 (s, 2H); 2.05 (s, 6H); 1.95 (s, 3H); 1.60 (s, 6H); 1.50 (s, 9H).

Reference： [1]Patent: WO2010/72727,2010,A1 .Location in patent: Page/Page column 30

35
[ 17564-64-6 ]
[ 39520-24-6 ]
[ 1196887-89-4 ]

Yield	Reaction Conditions	Operation in experiment
85%		To a stirred suspension of sodium hydride (60% in mineral oil, 2.4 g, 60.0 mmol) in anhydrous ether (170 mL) was added dropwise <strong>[39520-24-6]dimethyl isobutylmalonate</strong> (10.0 mL, 53.8 mmol) over 10 min. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h, and was then chilled in an ice-bath. To the stirred cold solution was added N-(chloromethyl)phthalimide (10.1 g, 51.6 mmol) in one portion. The mixture was allowed to warm to room temperature slowly, and was stirred at room temperature for 18 h, followed by refluxing for 1 h. The reaction mixture was cooled to room temperature, and cold 1 N HCl (215 mL) was added. The organic phase was separated, and the aqueous phase was extracted with ether (40 mL). The combined organic phase was washed with brine (40 mL x 2), dried over MgSO4, and then concentrated on a rotary evaporator to dryness. The residue was triturated with hexanes (60 mL). The product was collected by filtration, washed with hexanes (30 mL x 2), and dried in vacuo to afford dimethyl 2-((l,3-dioxoisoindolin-2- yl)methyl)-2-isobutylmalonate as a white solid (15.3 g, yield 85%).1H NMR (CDCl3) delta (ppm) 7.84 (2H, q, J = 2.8 Hz), 7.72 (2H, q, J = 2.8 Hz), 4.30 (2H, s), 3.78 (6H, s), 2.02 (IH, m), 1.80 (2H, d, J = 6.4 Hz), 0.86 (6H, d, J = 6.8 Hz).
		To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.997 g, 24.9 mmol) in diethyl ether (100 mL) was added dimethyl 2- isobutylmalonate (3.13 g, 16.6 mmol) dropwise. The resulting mixture was stirred at RT for 3 h. The reaction mixture was cooled to 0 C. N-chloromethyl phthalimide (3.24 g, 16.6 mmol) was added in one portion. The reaction mixture was stirred at RT overnight followed by heating to reflux for 1 h. The reaction mixture was cooled to RT and cold 1.5 N HC1 (100 mL) was added. The organic layer was separated. The aqueous layer was extracted with diethyl ether (2 x 50 mL). The combined ether layers were dried over Na2S04, filtered and concentrated under reduced pressure to afford the title compound (5.3 g, 15.2 mmol, 92 % yield). The crude product was taken to next step without further purification. LCMS (ESI) m/e 347.9 [(M+H)+, calcd for Ci8H22N06, 348.1]; LC/MS retention time (method C): tR = 1.95 min.

Reference： [1]Patent: WO2009/139834,2009,A1 .Location in patent: Page/Page column 191
[2]Patent: WO2016/22312,2016,A1 .Location in patent: Page/Page column 121

36
[ 17564-64-6 ]
[ 172527-71-8 ]
2-(2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.17 h / 0 °C 1.2: 0 - 20 °C 2.1: hydrogen bromide; acetic acid / 3.5 h / 110 °C

Reference： [1]Fodor, Elena; Maftei, Catalin-Vasile; Mangalagiu, Ionel; Jones, Peter G.; Daniliuc, Constantin-Gabriel; Franz, M. Heiko; Neda, Ion [Revue Roumaine de Chimie, 2010, vol. 55, # 9, p. 559 - 564]

37
[ 17564-64-6 ]
[ 172527-71-8 ]
diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((1,3-dioxoisoindolin-2-yl)methyl)malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 3-chloro-5-trifluoromethyl-2-pyridylmalonic acid diethyl ester With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: N-(chloromethyl)phthalimide In N,N-dimethyl-formamide at 0 - 20℃;

Reference： [1]Location in patent: experimental part Fodor, Elena; Maftei, Catalin-Vasile; Mangalagiu, Ionel; Jones, Peter G.; Daniliuc, Constantin-Gabriel; Franz, M. Heiko; Neda, Ion [Revue Roumaine de Chimie, 2010, vol. 55, # 9, p. 559 - 564]

38
[ 5355-68-0 ]
[ 17564-64-6 ]
[ 1336910-24-7 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 14; 2-(l-lsopropyl-4-oxopiperidiii-3~ylmethyi)isomdole-l,3~dioj5e To a solution of diisopropylamine (3mL, 21.2mmol) in THF (15mL) at -78C under Ar was added w-butyl lithium (2.5M in hexanes, 8.5mL, 21.2mmol) before 0,25h later 1- isopropylpiperidin-4-one (2.5g, 17.7mmol) in THF (15mL) was added dropwise to the mixture. After stirring for a further Ih at -78C 2-chloromethylisoindole-l,3-dione (5.2g, 26.6mmol) in THF (30mL) was added dropwise. After Ih at -78? the mixture was warmed to ri, stirred for 16h before sat. NFLjCl solution (50mL) was added and the mixture extracted with EtOAc. The combined organic phase was washed with brine, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (1 :199 NEt3:DCM to 1 :20: 179 NEt3:MeOH:DCM) to give, after removal of the solvent in vacuo, the title compound: RT=== 2.00mm; m/z (ES+) = 301.1 [M ? H]+.

Reference： [1]Patent: WO2011/117254,2011,A1 .Location in patent: Page/Page column 32

39
[ 17564-64-6 ]
[ 75265-67-7 ]
[ 1362387-24-3 ]

Reference： [1]Chemistry - A European Journal,2011,vol. 17,p. 14199 - 14223
[2]Organic Letters,2015,vol. 17,p. 5160 - 5163

40
[ 4702-13-0 ]
[ 17564-64-6 ]

Reference： [1]Journal of the American Chemical Society,2012,vol. 134,p. 4258 - 4263

41
[ 17564-64-6 ]
[ 203255-55-4 ]

Reference： [1]Angewandte Chemie - International Edition,2017,vol. 56,p. 14212 - 14216
Angew. Chem.,2017,vol. 129,p. 14400 - 14404,5
[2]Chemistry - A European Journal,2012,vol. 18,p. 3241 - 3247

42
[ 17564-64-6 ]
[ 1666-13-3 ]
[ 93378-90-6 ]

Yield	Reaction Conditions	Operation in experiment
82%		The N,Se acetal 5 was prepared by a slight and safer modification of the original procedure4 where, the required phenylselenol intermediate was replaced by sodium phenylselenolate. In a 50 mL three-neck flask equipped with a reflux condenser were placed diphenyl diselenide (0.63 g, 2 mmol) and 16 mL of dry DMF. The solution was heated at 60 C and stirred rapidly under nitrogen while NaBH4 (0.15 g, 4 mmol) was added portionwise. Hydrogen was evolved and the reaction mixture turned colorless and homogeneous upon complete reduction of the selenide. The reaction was heated at 110 C for 1 h and then cooled to room temperature. Solid N-chloromethylphthalimide (0.78 g, 4 mmol) was added to the orange solution. After stirring at room temperature for 12 h, 2 N aqueous hydrochloric acid (10 mL) was added carefully to the white suspension. The entire product mixture was poured into 50 mL of water and 40 mL of diethyl ether, mixed, and separated. The aqueous phase was extracted with 20 mL of diethyl ether and the combined organic phases were washed with H2O (4 × 10 mL), 10 mL of brine, dried over sodium sulfate and concentrated. The solid residue was washed with light petroleum (2 × 10 mL) and dried over P2O5 to afford 5 in 82% yield and with spectral data in good agreement with those reported in the literature.4

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 2709 - 2711

43
[ 17564-64-6 ]
[ 140-89-6 ]
[ 19194-55-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	In acetone; at 20℃; for 10h;Cooling with ice;	A mixture of phthalimide (41.14 g, 0.30 mol) and distilled water (100 mL) was stirred for 10 min at room temperature. After addition of formaldehyde solution (40%, 27 mL, 0.36 mol), the resulting solution was refluxed for 1.5 h. After cooling to 0-5 C, the resulting precipitate was collected by filtration, washed with cold water (0-5 C, 200 mL) and dried in air to give the corresponding N-hydroxymethylphthalimide (51.01 g, 96% yield).(0010)A solution of thionyl chloride (23.0 mL, 37.7 g, 0.32 mol) in dichloromethane (50 mL) was slowly added to a mixture of the resulting N-hydroxymethylphthalimide and dichloromethane (550 mL) and N,N-dimethylformamide (350 mL) during 30 min at room temperature with stirring. The resulting mixture was further stirred for 2 h at room temperature. After cooling to 0 C, water (200 mL) was added slowly. And the solution was neutralized to pH 6.7-7.0 by using saturated aqueous NaHCO3 solution. The organic layer was separated and then was dried over anhydrous magnesium sulfate. After evaporation of the solvent under the reduced pressure, the residue was washed with n-hexane (100 mL) to give N-chloromethylphthalimide (51.4 g, 93% yield).(0011) N-Chloromethylphthalimide (51.0 g, 0.26 mol) was dissolved in acetone (500 mL) and potassium O-ethyl xanthate (43.9 g, 274 mmol) was added portionwise in an ice water bath under stirring. The resulting solution was further stirred for 10 h at room temperature. After removal of the solvent, the residue was dissolved in dichloromethane. The resulting solution was washed with water and dried over sodium sulfate. After removal of the solvent under the reduced pressure, pale yellow solid was obtained and recrystallized from ethyl acetate to afford the xanthate 1 as colorless crystals 67.2 g, 92% yield, mp: 99-100 C. Lit.20 mp: 94-95 C. 1H NMR (CDCl3, 400 MHz) (delta, ppm) 1.47 (t, J=7.1 Hz, 3H, CH3), 4.68 (q, J=7.1 Hz, 2H, CH2), 5.34 (s, 2H, CH2), 7.75 (dd, J=5.5, 3.1 Hz, 2H, ArH), 7.88 (dd, J=5.5, 3.1 Hz, 2H, ArH). 13C NMR (CDCl3, 100 MHz) (delta, ppm) 13.7, 41.2, 70.5, 123.6, 131.8, 134.4, 166.6, 210.2.
74%	In acetone; at 0℃; for 0.5h;	To a cold (0 C.) solution of <strong>[17564-64-6]N-(chloromethyl)phthalimide</strong> (40.0 g, 205.0 mmol) in acetone (400 mL) there is added, in successive portions, potassium O-ethylxanthate (36.1 g, 225.0 mmol). The reaction mixture is stirred at 0 C. for 30 minutes and then the solvent is evaporated off. The residue thereby obtained is taken up in water. The aqueous phase is extracted with dichloromethane, whilst the organic phases are dried over MgSO4 and concentrated under reduced pressure. The residue thereby obtained is recrystallised from a mixture of ethyl acetate and petroleum ether to yield the title product in a yield of 74%. 1H NMR (delta, ppm) 7.90-7.84 (m, 2H, CH-2), 7.77-7.72 (m, 2H, CH-1), 5.33 (s, 2H, (CDCl3, 400 MHz) CH2-5), 4.68 (q, 2H, J=7.1 Hz, CH2-7), 1.46 (t, 3H, J=7.1 Hz, CH3-8).

Reference： [1]Tetrahedron,2013,vol. 69,p. 1050 - 1056
[2]Patent: US2013/289308,2013,A1 .Location in patent: Paragraph 0064; 0065; 0066
[3]Organic Letters,2015,vol. 17,p. 3058 - 3061

44
[ 17564-64-6 ]
2-(azidomethyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium azide; In dimethyl sulfoxide; at 20℃; for 24h;	2.5 g (38.4 mmol) of sodium azide was added to a solution of a commercially available N-(Chloromethyl)phthalimide (25.6 mmol, 5 g) in 50 mL of DMSO. The resulting suspension was stirred at room temperature for 24 h. After adding ice water, the mixture was extracted several times with diethyl ether. The combined organic phases were dried over MgSO4 and the solvent was removed by evaporation under vacuum. Azide 5 was sufficiently pure to be used thereafter (4.810 g, 93% yield).

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 3485 - 3489
Angew. Chem.,2013,vol. 125,p. 3569 - 3573,5
[2]Steroids,2018,vol. 138,p. 102 - 107

45
[ 17564-64-6 ]
[ 6078-17-7 ]
[ 1361117-16-9 ]

Yield	Reaction Conditions	Operation in experiment
5%		Under a protective nitrogen atmosphere, sodium hydride (NaH, 48 mg, 1.2 mmol) is added into a solution of berbamine dihydrochloride (205 mg, 0.3 mmol) in N,N-dimethyl formamide (5 ml) at 0 C., after being stirred for 1 hour, <strong>[17564-64-6]2-chloromethyl-isoindoline-1,3-dione</strong> (88 mg, 0.45 mmol) is added therein. The reaction solution is heated to 80 C. overnight. Then the reaction mixture is evaporated under vacuum, and purified by a preparative thin layer chromatography to give white or pale yellow compound (BS-BE-001) (11.5 mg, 5.0%). [0105] LC/MS m/z: M+1 768.3 100% (purity). [0106] 1H NMR (CDCl3) delta:7.887.865 (dd, 2H, J=6.0 Hz, 5.5 Hz), 7.747.732 (dd, 2H, J=5.5 Hz, 6.0 Hz), 7.264 (s, 1H), 7.0196.998 (dd, 1H, J=8.5 Hz, 8.0 Hz) , 6.9196.903 (d, 1H, J=7.5 Hz), 6.716.698 (d, 1H, J=7.5 Hz), 6.626.614 (m, 1H), 6.527 (s, 1H), 6.4206.385 (m, 1H), 6.266 (s, 1H), 5.954 (s, 1H), 5.7665.717 (m, 2H), 3.850 (s, 2H), 3.750 (s, 3H), 3.610 (s, 3H), 3.4873.473 (m, 1H), 3.396 (s, 1H), 3.2413.203 (m, 2H), 3.113 (s, 3H), 3.0122.768 (m, 6H), 2.566 (s, 3H), 2.532 (s, 1H), 2.3832.271 (m, 1H), 2.216 (s, 1H), 1.7951.725 (m, 2H).

Reference： [1]Patent: US2013/158068,2013,A1 .Location in patent: Paragraph 0103; 0104; 0105; 0106

46
[ 75-15-0 ]
[ 17564-64-6 ]
[ 109-79-5 ]
[ 19194-21-9 ]

Yield	Reaction Conditions	Operation in experiment
88%		Butanethiol (902 mg, 10 mmol), carbon disulfide (761 mg, 10 mmol), and THF (5 mL) were placed in 25 mL round-bottomed flask. A solution of KOH (561 mg, 10 mol) in 3 mL of water was added dropwise under stirring at room temperature. The resulting solution was stirred at room temperature for a further 15 min. Then the solution was added slowly into a solution of <strong>[17564-64-6]N-(chloromethyl)phthalimide</strong> (1.96 g, 10 mmol) in acetone (10 mL). The reaction mixture was stirred for 30 min. After removal of the solvent, the residue was diluted with ethyl acetate (100 mL). The solution was washed sequentially with water (250 mL) and saturated brine (250 mL), dried over anhydrous Na2SO4, and the solvent was removed by rotary evaporation, the residue was recrystallized from a mixture of petroleum ether and ethyl acetate to give S-[(1-tert-butoxycarbonylamino-4-phthalimido)butan-2-yl] S'-butyl trithiocarbonate (1k) as yellow crystals 2.86 g, 88% yield, mp: 89-91 C. Lit. 17 89-91 C. 1H NMR (CDCl3, 400 MHz) (delta, ppm) 0.93 (t, J=7.2 Hz, 3H, CH3), 1.42 (hextet, J=7.2 Hz, 2H, CH2), 1.64-1.72 (m, 2H, CH2), 3.37 (t, J=7.2 Hz, 2H, CH2), 5.65 (s, 2H, CH2), 7.75 (dd, J=5.2, 3.0 Hz, 2H, ArH), 7.87 (dd, J=5.2, 3.0 Hz, 2H, ArH). 13C NMR (CDCl3, 101 MHz) (delta, ppm) 13.5, 22.0, 29.8, 36.9, 41.9, 123.7, 131.8, 134.4, 166.6, 220.8.

Reference： [1]Tetrahedron,2013,vol. 69,p. 10272 - 10278

47
[ 17564-64-6 ]
[ 141-96-8 ]
C₁₄H₁₅NO₃S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	In acetone Inert atmosphere;

Reference： [1]Quiclet-Sire, Beatrice; Zard, Samir Z. [Organic Letters, 2013, vol. 15, # 22, p. 5886 - 5889]

48
[ 17564-64-6 ]
(S,Z)-1-hydroxy-3-(1-hydroxypropan-2-yl)-3-methyltriaz-1-ene 2-oxide sodium salt [ No CAS ]
[ 1538566-08-3 ]

Yield	Reaction Conditions	Operation in experiment
3%	With sodium iodide; In acetonitrile; at 25℃;	NONOate salt N001 (0.270 g, 1.58 mmol) suspended in acetonitrile (3.0 mL) was treated with a solution of <strong>[17564-64-6]N-(chloromethyl)phthalimide</strong> (0.280 g, 1.43 mmol) in acetonitrile (3.0 mL) and then sodium iodide (0.215 g, 1.43 mmol) was added. The resulting mixture was stirred at 25 C overnight. N,N-dimethylformamide (1.0 mL) was added to the reaction mixture which was then heated to 60 C for 1 hour. The acetonitrile was removed under reduced pressure. The residue was suspended in ethyl acetate and then washed with a 0.2 N solution of sodium thiosulfate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was subjected to prep-chromatography using ethyl acetate in hexane to provide a tan oily solid (14 mg, 3.0% yield). 1H NMR (400 MHz, CDC13) delta 7.92-7.87 (m, 2H), 7.78-7.73 (m, 2H), 5.67 (s, 2H), 2.97 (s, 1H), 2.19 (s, 2H), 1.59 (s, 6H). LC tr=2.65 minutes (C- 18 column, 5 to 95% acetonitrile/water over 6 minutes at 1.7 mL/min with detection 254 nm, at 23 C). ES(pos)MS m/z 331 (M+Na calcd for C13Hi6N405 requires 331).
3.0%		NONOate salt NS-01 (0.270 g, 1.58 mmol) suspended in acetonitrile (3.0 mL) was treated with a solution of <strong>[17564-64-6]N-(chloromethyl)phthalimide</strong> (0.280 g, 1.43 mmol) in acetonitrile (3.0 mL) and then sodium iodide (0.215 g, 1.43 mmol) was added. The resulting mixture was stirred at 25 C overnight. N,N-dimethylformamide (1.0 mL) was added to the reaction mixture which was then heated to 60 C for 1 hour. The acetonitrile was removed under reduced pressure. The residue was suspended in ethyl acetate and then washed with a 0.2 N solution of sodium thiosulfate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was subjected to prep-chromatography using ethyl acetate in hexane to provide a tan oily solid (14 mg, 3.0% yield). 1H NMR (400 MHz, CDCI3) delta 7.92-7.87 (m, 2H), 7.78-7.73 (m, 2H), 5.67 (s, 2H), 2.97 (s, 1H), 2.19 (s, 2H), 1.59 (s, 6H). LC tr=2.65 minutes (C-18 column, 5 to 95% acetonitrile/water over 6 minutes at 1.7 mL/min with detection 254 nm, at 23 C). ES(pos)MS m/z 331 (M+Na calcd for C13H16N4O5 requires 331).

Reference： [1]Patent: WO2014/12074,2014,A2 .Location in patent: Paragraph 00105; 00106
[2]Patent: WO2015/108835,2015,A1 .Location in patent: Paragraph 0071

49
[ 17564-64-6 ]
[ 81-07-2 ]
[ 16417-22-4 ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 72h;	0.45 g of potassium carbonate (1.1equiv) were added to a stirring solution of saccharin (500mg, 1.0equiv) in 20mL of N,N-dimethylformamide at room temperature. N-(Chloromethyl)phthalimide (0.54g, 1.0equiv) was added and the reaction stirred at 80C for 72h. The reaction was poured on ice. The aqueous phase was extracted with ethyl acetate (3×50mL), the organics were reunited, dried over sodium sulfate and evaporated in vacuo. Purification via column chromatography on silica gel (ethyl acetate-n-hexane 2:1) gave title compound as a white solid (0.61mg, 66% yield); mp 284-287C; IR numax 1725 (nu C=O), 1337 (nuas S=O), 1252 (nu C-N), 1166 (nus S=O), 727 (delta Csp2-H), 677 (delta Csp2-H) cm-1; 1H NMR (400MHz, DMSO-d6) delta 5.66 (2H, s, CH2), 7.90 (2H, m, 2×CHAr), 7.97 (m, 2H, 2×CHAr), 8.02 (1H, t, J=7.6Hz, CHAr), 8.07 (1H, t, J=7.6Hz, CHAr), 8.19 (1H, d, J=7.6Hz, CHAr), 8.28 (1H, d, J=7.6Hz, CHAr); 13C NMR (101MHz, DMSO-d6) delta 41.8 (CH2), 122.0 (Ar),124.1 (Ar), 126.0 (Ar), 126.15 (Ar), 131.6 (Ar), 135.6 (Ar), 135.9 (Ar), 136.7 (Ar), 137.1 (Ar), 157.75 (C=O), 166.9 (C=O).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1821 - 1831

50
[ 38825-66-0 ]
[ 17564-64-6 ]
2-((2-(2-(propan-2-ylidene)hydrazono)-4-oxothiazolidin-3-yl)methyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone;Reflux;	General procedure: The initial carbonyl compound (50 mmol) was dissolved/suspended in ethanol (50 mL) and magnetically stirred with thiosemicarbazide (50 mmol) and catalytic amounts of acetic acid for 8-24 h at room temperature. The obtained thiosemicarbazone was filtered, washed with appropriate solvent (n-hexane, petroleumether or diethyl ether) and dried under vacuum. The intermediate thiosemicarbazone (50 mmol) reacted with ethyl bromoacetate (50 mmol), in methanol (50 mL) and sodium acetate (50 mmol) at room temperature under magnetic stirring for 24 h. The resulting 4-thiazolidinone was poured on ice, filtered or extracted with chloroform (3 x 100 mL) and purified by column chromatography (SiO2, ethyl acetate/n-hexane). Then, the obtained thiazolidinone (50 mmol) was dissolved/suspended in 50 mL of anhydrous acetone in the presence of anhydrous potassium carbonate (50 mmol), and reacted with equimolar amounts of 4-nitrobenzyl bromide, 1-(chloromethyl)naphthalene and <strong>[17564-64-6]N-(chloromethyl)phthalimide</strong> for 24-48 h. The product was poured on ice, filtered or extracted with chloroform (3 x 50 mL) and purified by column chromatography (SiO2, ethyl acetate/n-hexane) in order to obtain the title compoundsin high yields. 7.1.53 2-((2-(2-(Propan-2-ylidene)hydrazono)-4-oxothiazolidin-3-yl)methyl)isoindoline-1,3-dione (1C) Yellow powder, mp 119-124 C, 99% yield; 1H NMR (400 MHz, DMSO-d6): delta 1.79 (s, 3H, CH3), 1.88 (s, 3H, CH3), 3.95 (s, 2H, CH2, thiazolidinone), 5.52 (s, 2H, ArCH2), 7.73-8.31 (m, 4H, Ar).