There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 928-51-8 * Storage: {[proInfo.prStorage]}
* 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.
Stage #1: With sodium iodide In 1,4-dioxane for 48 h; Heating / reflux Stage #2: With sodium hydroxide In water
EXAMPLE 3; l -(4-Hydroxybutyl)morpholine was prepared as follows. In a 250 mL flask was mixed morpholine (65.5 g, 750 mmol), 4-chlorobutanol (27.2 g, 250 mmol), sodium iodide (3.8 g, 25 mmol) and 75 mL of dioxane. The reaction was heated to reflux. <n="76"/>After 2 days the reaction was allowed to cool to ambient temperature. Solvent was removed by rotary evaporation leaving a brown oil. The oil was dissolved in 100 mL of 2N NaOH, extracted with EtOAc and dried over Na2SO4. After filtration of the drying agent solvent was removed in vacuo leaving an orange oil. The oil was distilled (90 0C, 1 mm Hg), leaving 1 - (4-hydroxylbutyl)morpholine ( 13.9 g, 87 mmol, 35 percent yield) as a colorless oil.
Reference：
[1] Patent: WO2008/66874, 2008, A1, . Location in patent: Page/Page column 74-75
[2] Journal of the American Chemical Society, 1939, vol. 61, p. 3439
[3] Journal of the American Chemical Society, 1942, vol. 64, p. 970,972
2
[ 928-51-8 ]
[ 6940-78-9 ]
Reference：
[1] Journal of Physical Chemistry, 1995, vol. 99, # 32, p. 12195 - 12203
[2] Journal of Organic Chemistry, 1957, vol. 22, p. 834
[3] Patent: US2868850, 1956, ,
[4] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1955, vol. 241, p. 963
[5] Journal of Organic Chemistry, 1957, vol. 22, p. 834
[6] Journal of the American Chemical Society, 1949, vol. 71, p. 1294
[7] Journal of the American Chemical Society, 1934, vol. 56, p. 1596
[8] Helvetica Chimica Acta, 1956, vol. 39, p. 682,684
[9] Patent: DE961087, 1954, ,
[10] Patent: US2839574, 1954, ,
3
[ 928-51-8 ]
[ 10297-05-9 ]
Reference：
[1] Tetrahedron Letters, 1977, p. 2659 - 2662
[2] Chemical Physics Letters, 1999, vol. 300, # 3-4, p. 493 - 498
4
[ 928-51-8 ]
[ 2009-83-8 ]
Reference：
[1] Patent: US5362725, 1994, A,
[2] Patent: US5476848, 1995, A,
5
[ 928-51-8 ]
[ 627-00-9 ]
Reference：
[1] Journal of the Chemical Society, 1952, p. 4492,4495
[2] Journal of the American Chemical Society, 1956, vol. 78, p. 2255,2256[3] Journal of Organic Chemistry, 1956, vol. 21, p. 883,885
[4] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1981, vol. <B> 20, # 4, p. 340 - 342
6
[ 928-51-8 ]
[ 13325-10-5 ]
Reference：
[1] DRP/DRBP Org.Chem.,
[2] Journal of Organic Chemistry, 1965, vol. 30, p. 491 - 495
7
[ 928-51-8 ]
[ 13325-10-5 ]
[ 79448-06-9 ]
Reference：
[1] DRP/DRBP Org.Chem.,
8
[ 928-51-8 ]
[ 7664-41-7 ]
[ 13325-10-5 ]
[ 79448-06-9 ]
Reference：
[1] DRP/DRBP Org.Chem.,
9
[ 928-51-8 ]
[ 74-89-5 ]
[ 42042-68-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 25, p. 4475 - 4480
[2] Chemical and Pharmaceutical Bulletin, 1978, vol. 26, # 12, p. 3891 - 3896
[3] J. Gen. Chem. USSR (Engl. Transl.), 1961, vol. 31, p. 2133 - 2139[4] Zhurnal Obshchei Khimii, 1961, vol. 31, p. 2289 - 2297
[5] Tetrahedron Letters, 1976, vol. No. 8, p. 593 - 596
Reference：
[1] Farmaco, Edizione Scientifica, 1987, vol. 42, # 12, p. 921 - 930
[2] Phosphorus and Sulfur and the Related Elements, 1982, vol. 13, p. 97 - 106
[3] Journal of pharmaceutical sciences, 1962, vol. 51, p. 348 - 351
12
[ 928-51-8 ]
[ 13325-10-5 ]
[ 79448-06-9 ]
Reference：
[1] DRP/DRBP Org.Chem.,
13
[ 928-51-8 ]
[ 7664-41-7 ]
[ 13325-10-5 ]
[ 79448-06-9 ]
Reference：
[1] DRP/DRBP Org.Chem.,
14
[ 928-51-8 ]
[ 75-31-0 ]
[ 42042-71-7 ]
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1961, vol. 31, p. 2133 - 2139[2] Zhurnal Obshchei Khimii, 1961, vol. 31, p. 2289 - 2297
15
[ 928-51-8 ]
[ 30453-20-4 ]
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 9, p. 2580 - 2586
EXAMPLE 3; l -(4-Hydroxybutyl)morpholine was prepared as follows. In a 250 mL flask was mixed morpholine (65.5 g, 750 mmol), 4-chlorobutanol (27.2 g, 250 mmol), sodium iodide (3.8 g, 25 mmol) and 75 mL of dioxane. The reaction was heated to reflux. <n="76"/>After 2 days the reaction was allowed to cool to ambient temperature. Solvent was removed by rotary evaporation leaving a brown oil. The oil was dissolved in 100 mL of 2N NaOH, extracted with EtOAc and dried over Na2SO4. After filtration of the drying agent solvent was removed in vacuo leaving an orange oil. The oil was distilled (90 0C, 1 mm Hg), leaving 1 - (4-hydroxylbutyl)morpholine ( 13.9 g, 87 mmol, 35 % yield) as a colorless oil.
Step A: Preparation of 4-(Chlorobutoxy)-3,4,5,6-2H-tetrahydropyran A solution of 4-chlorobutanol (23.2 g, 0.2140 mol) and 2 drops of concentrated hydrochloric acid at 0 C. is treated with 3,4-dihydro-2H-pyran (15 g, 0.1783 mol). The reaction is allowed to warm to room temperature over 3 hours. The reaction mixture is purified by distillation (130 C., 20 mm) to give 18.07 g of 2-(4-chlorobutoxy)-3,4,5,6-2H-tetrahydropyran as a colorless oil.
7.99 g
With pyridinium p-toluenesulfonate; In dichloromethane;Cooling with ice;
To the reaction vessel, 5.00 g of 4-chlorobutanol,0.58 g of pyridinium p-toluenesulfonate,50 mL of dichloromethane was added.4.65 g of 3,4-dihydro-2H-pyran was added dropwise while cooling with ice.After stirring, it was washed with sodium bicarbonate water and brine.Purification by column chromatography gave 7.99 g of a compound represented by the formula (I-7-1).
With trichlorophosphate;
EXAMPLE 204 Preparation of 4-chloro-1-tetrahydropyranyloxybutane To 9.25 g. (0.11 mole) of dihydropyran containing 3 drops of phosphorus oxychloride is added 10 g. (0.092 mole) of 4-chlorobutanol-1 dropwise over a period of 2 hours with stirring. The reaction mixture is then allowed to stir overnight at room temperature. The reaction mixture is concentrated, the residue is placed on a Florisil column and the product is eluted with benzene to give 14.4 g. (81%) of the subject compound as an oil.
Weigh 2.71 g (25 mmol) of <strong>[928-51-8]4-chloro-1-butanol</strong> into a 250 mL round bottom flask,Add 50 mL of ethanol to dissolve, then add 0.18 g (1.25 mmol) of sodium iodide and 1.92 g (27.5 mmol) of sodium methanethiolate at room temperature,The reaction was continued at room temperature for 12 hours, then washed with water,Extract with dichloromethane (30 mL X 3), combine the organic phases and dry over anhydrous sodium sulfate,After filtration, the solvent was distilled off under reduced pressure to give 2.85 g (95%) of the oily product (Compound 1).
72%
In water; at 25℃; for 48h;
4-Chlorobutan-l-ol 7-a (180 g, 1658 mmol, CAS 928-51-8) was added to sodium thiomethoxide (656 g, 1965 mmol, 21% solution in water) at 0-5C. After addition, the mixture was allowed to warm to 25C and stirred for 48 h. The mixture was extracted with CHCI3. The separated organic layer was dried over Na2C03, filtered and evaporated under vacuum. The residue was distilled to afford the alcohol 9-a as an oil (144.2 g, 72%).
A method for preparing 1,4-butane sultone, comprising the steps of: S1: 4-chlorobutanol and sodium sulfite solution (concentration: 10wt%) were put into the reaction vessel and mixed thoroughly. The ratio of the amount of 4-chlorobutanol to sodium sulfite was 1:1.5, the control temperature was 25 C, and the reaction was carried out for 24 hours. Then decompression-dehydration at a vacuum degree of -0.08 MPa and 90 C, After decompression and dehydration the reaction was completed; S2: Acidification was carried out by adding concentrated hydrochloric acid (concentration: 36.5 wt%) to the material after completion of decompression and dehydration, the ratio of the amount of HCl in the concentrated hydrochloric acid to the amount of 4-chlorobutanol in S1 was 1:1, and the temperature was controlled at 25 C and stirred for 12 h. Then cooled to room temperature, filtered, and the filtrate was concentrated to obtain a concentrated solution containing 4-hydroxybutanesulfonic acid;
80 g of pyridine was added to 100 g of 4-chlorobutanol, And the mixture was stirred under cooling in a nitrogen atmosphere. Thereto, 113 g of acetic anhydride was added dropwise. After dropwise addition, the mixture was stirred at room temperature for 4 hours. 500 ml of water and toluene 500 ml was added to separate the organic layer. The obtained organic layer was washed with water, And dried over anhydrous magnesium sulfate. Toluene was distilled off under reduced pressure, The residue was distilled to obtain 116 g of compound (ex-17).
<strong>[928-51-8]4-Chloro-1-butanol</strong> (4.3 g, 40 mmol) and triethylamine (10.1 g, 100 mmol) were dissolvedin DCM (80 mL) in an ice bath. Acryloyl chloride (5 mL, 55 mmol) in 40 mL DCM wasadded dropwise into the solution with stirring.After acryloyl chloride was added, the reactionwas carried out overnight. Triethylamine salt was filtered and the filtrate was washed water(100 mL), 5% HCl solution (100 mL) and water (100 mL) and dried overMgSO4. After evaporationof the solvent, the residue was subjected to column chromatography on silica gel withDCM as eluting solvent to yield white powder (95%). 1H NMR (300 MHz, CDCl3) delta (ppm):6.36, 6.08, 5.81 (3m, 3H, CH2=CH), 4.16 (t, 2H, -CH2-COO), 3.54 (t, 2H, -CH2-Br), 1.82(m, 4H, -CH2-CH2-CH2-). 13C NMR (75 MHz, d6-DMSO) delta (ppm): 166.0, 131.9, 128.9,63.9, 45.5, 29.3, 26.2.
With sodium hydride In tetrahydrofuran at 20℃; Inert atmosphere; Cooling with ice;
Structural Unit E-3; 1-Chloro-4-methoxy-butaneSodium hydride (24.0 g, 1.0 mol) and iodomethane (142 g, 1.0 mol) were placed in abs. THF (350 ml). Under argon and while cooling with ice, a solution of 4-chlorobutan-1-ol (54 g, 0.5 mol) in abs. THF (50 ml) was added dropwise in the course of 1.5 h, whereupon slight gas formation occurred. The mixture was stirred for 24 h at room temperature. 20% NH4Cl solution (130 ml) was added dropwise to the reaction solution. The organic phase was separated and dried over Na2SO4, and the drying agent was filtered out. The organic phase was distilled under normal pressure.Boiling point: 150-162° C.Yield: 10.4 g (17%)1H-NMR (DMSO-d6): 1.93 (2H, m); 3.23 (3H; s); 3.44 (2H, t); 3.66 (2H, t).
With sodium azide; In dimethyl sulfoxide; at 20 - 85℃; for 16h;
To a solution of 4-chlorobutan-1 -ol (500 mg, 4.61 mmol, 1 eq.) in DMSO (5 mL) was added sodium azide (599 mg, 9.21 mmol, 2 eq.) in one portion at room temperature. The reaction mixture was then heated at 85C for 16 h and monitored by LCMS until completion. After full conversion of 4-chlorobutan-1 -ol into the corresponding azide, the reaction mixture was poured into water and extracted with EtOAc (2x 100 mL). The organic layers were combined, washed successively with water (1 x 100 mL) and saturated NaCI (1 x 100 mL), dried over MgS04, filtered and evaporated under reduced pressure. Compound 1. was recovered as a colorless oil (385 mg, 72% yield). The analytic data were consistent with the structure of the expected product. Rf 0.35 (EtOAc/hexane, 2:1 ); 1 HNMR (400 MHz, CDCI3) delta 3.70 (t, J = 5 Hz, 2H), 3.35 (t, J = 6.5 Hz, 2H), 1 .72-1 .67 (m, 4H), 1 .54 (s, 1 H); 13C NMR (75 MHz, CDCI3) delta 62.2, 51 .3, 29.8, 25.4.
With sodium azide; In N,N-dimethyl-formamide; at 50℃;
Example 1A 4-azidobutan-1-ol 4-Chlorobutanol (0.46 mL, 4.6 mmol) was dissolved in DMF (10 mL), followed by the addition of NaN3 (0.75 g, 12 mmol). The solution was stirred overnight at 50 C. before cooling down to rt. EtOAc (50 mL) was added into the reaction mixture, and the white precipitate was removed by filtration. The solution was washed with H2O (30 mL) and saturated NH4Cl solution (3*30 mL) sequentially. The organic portion was dried over anhydrous Na2SO4 before solvent was evaporated under reduced pressure to give the crude product, which was used directly in the next reaction without purification.
With sodium azide; In N,N-dimethyl-formamide; at 50℃; for 15h;Inert atmosphere;
General procedure: A solution of alcohol (1) (where, n = 3 and 5 g, 36.0 mmol) and NaN3 (4.67 g, 71.9 mmol) in DMF (50 mL)under a nitrogen atmosphere was stirred well at 50C for 15h. The progress of reaction was monitored by TLC. Ther eaction mixture was filtered after 15 h and the solvent was evaporated. The product obtained was washed with water and extracted with ethyl acetate (3 × 50 m). The collected organic layer was dried over NaSO4 and filtered. The product was isolated after evaporating the solvent using a rotary evaporator as a slightly brown colored liquid with 90%yield.
Solid fe/f-butyldimethylsilyl chloride (137 g, 909 mmol) was dissolved in dichloromethane (800 mL) and stirred with a magnetic stir bar at 0 C. 85% 4-chlorobutanol (100 mL, 852 mmol) was added as a solution in dichloromethane (100 mL). The mixture was stirred at 0 C for 30 minutes, followed by the addition of solid imidazole (71.3 g, 1048 mmol) in a single portion. This mixture was stirred at 0 C until TLC indicated the alcohol was consumed, typically 1.5 hours. The reaction mixture was filtered through a medium glass frit, and the glassware was rinsed with dichloromethane. The filtrate was concentrated in vacuo, and the resulting translucent oil was stored at -20 C for 12 hours. A colorless precipitate formed at this temperature. Hexanes (300 mL) was added, the suspension was passed through a Celite/MgS04 plug over a fine frit, and more hexanes (2x200 mL) was passed through the filter. The filtrate was concentrated in vacuo to give a colorless, transparent oil which weighed 189 g (848 mmol, 99%).
50%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 4h;
The alcohol 6-a (100 g, 920 mmol) was dissolved in CH2C12 (1000 ml) at room temperature. The mixture was cooled to 0C then Imidazole (81.5, 1200 mmol) and TBDMS-C1 (152 g, 1010 mmol) were added. The resulting mixture was stirred for 4h at room temperature then filtered off. The filtrate was washed successively with 10% HCl and brine. The resulting solution was dried over MgS04, filtered then concentrated to yield the title compounds 6-b (100 g, 50%) as a colorless oil.
50%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 4h;
Step 1: Synthesis of terf-butyl(4-chlorobutoxy)dimethylsilane (7-c)Compound 7-a, 4-chloro-l-butanol, (CAS 928-51-8) (100 g, 920 mmol) was dissolved in CH2C12 (1000 mL) at room temperature. Imidazole (CAS 288-32-4) (81.5, 1200 mmol) and TBDMS-C1 (CAS 18162-48-6) (152 g, 1010 mmol) was added at 0C. The mixture was stirred for 4 h at rt. The mixture was filtered off. The filtrate was washed with 10%) aqueous HCl-solution and brine. After evaporation of the filtrate, we get the product 7-c as a clear oil (100 g, 50%>).
50%
With 1H-imidazole; In dichloromethane; at 20℃; for 4h;
4-Chlorobutan-l-ol 7-a (100 g, 920 mmol, CAS 928-51-8) was dissolved in CH2C12 (1000 mL) at room temperature. The mixture was cooled to 0C then Imidazole (81.5, 1200 mmol) and TBDMS-C1 (152 g, 1010 mmol) were added. The resulting mixture was stirred for 4 hours at room temperature then filtered off. The filtrate was washed successively with an aqueous solution 10% of HC1 and with brine. The resulting solution was dried over MgS04, filtered then concentrated to yield the title compounds 7-b as a colorless oil (100 g, 50%).
50%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 4h;
The alcohol 6-a (100 g, 920 mmol) was dissolved in CH2Cl2 (1000 ml) at room temperature. The mixture was cooled to 0 C. then Imidazole (81.5, 1200 mmol) and TBDMS-Cl (152 g, 1010 mmol) were added. The resulting mixture was stirred for 4 h at room temperature then filtered off. The filtrate was washed successively with 10% HCl and brine. The resulting solution was dried over MgSO4, filtered then concentrated to yield the title compounds 6-b (100 g, 50%) as a colorless oil.
With pyridine; silver nitrate; In tetrahydrofuran;
REFERENCE EXAMPLE 2 5,5,5-triphenylpentanol t-Butylchlorodimethylsilane (8.3 g, 55 mmol) was added to a stirred mixture of 4-chlorobutanol (5.0 mL, 50 mmol), silver nitrate (12.8 g, 75.1 mmol), and pyridine (4.0 mL, 50 mmol) in 40 mL of dry THF. After 4 hr, the reaction mixture was filtered through Celite and evaporated to give a yellow oil. The material was purified by distillation to provide 4-chlorobutyl t-butyldimethylsilyl ether as a colorless oil (11 g, quantitative).
With dmap; triethylamine; In dichloromethane; at 20℃; for 1.5h;
Step 6: [4-chlorobutyl 4-methylbenzenesulfonate] A mixture of 4-chlorobutan-1-ol (5 g, 46.05 mmol), triethylamine (9.3 g, 92.1 mmol), N,N-dimethylpyridin-4-amine (562 mg, 4.61 mmol) and 4-methylbenzene-1-sulfonyl chloride (9.63 g, 50.66 mmol) in dichloromethane (40 ml) was stirred at room temperature for 1.5 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with 20% ethyl acetate in hexane) to afford 4-chlorobutyl 4-methylbenzenesulfonate (12.0 g, yield 99%) as colorless oil. 1H NMR (400 MHz, CDCl3): delta 1.80-1.84 (m, 4H), 2.46 (s, 3H), 3.49-3.53 (m, 2H), 4.04-4.08 (m, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H).
79%
With pyridine; at 0℃; for 2h;Inert atmosphere;
To a solution of2b(6.52 g, 50.90 mmol) in pyridine (20 mL) was successively added toluene-4-sulfonylchloride (TsCl, 9.72 g, 50.90 mmol) under nitrogen atmosphere, the mixture was stirred at 0 C for 2 h. The resulting mixture was poured into water (110 mL), extracted with ethyl acetate (EA, 2 × 70 mL), The combined organic layers were washed with hydrochloric acid (2 M, 50 mL) and brine, dried over anhydrous Na2SO4and concentrated under vacuum to give3b(10.54 g, 79%) as a colorless oil, Rf(PE /EA, 5:1) = 0.21.1H NMR (CDCl3, 400 MHz) delta = 7.79 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 4.07 (t, J=5.6 Hz, 2H), 3.50 (t, J=5.7 Hz, 2H), 2.46 (s, 3H), 1.86-1.79(m, 2H).
With triethylamine; In dichloromethane; at 0℃; for 2h;
Example 6 Synthesis of 4-(nitrooxy)butyl 4-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa- 1 ,4-dienyl)butanoate (Compound 6) Step 1 : Synthesis of 4-chlorobutyl 4-nitrobenzoate To a solution of 4-Chlorobutanol (1.09 g; 10.04 mmol) and TEA (1.7 ml; 12.05 mmol) in CH2C12 (25 ml) cooled at 0C, 4-Nitrobenzoyl chloride (2.23 g; 12.05 mmol) was added portionwise. The mixture was stirred 2 hours at room temperature then was washed with NaH2P04 (25 ml), H20 and brine. The residue was purified by flash chromatography (Biotage SPl instrument, SNAP cartridge silica 100 g, n-Hexane/EtOAc 9: 1, 10 CV) affording the title compound (2.48 g; Yield: 96%) 1H NMR (300 MHz, CDC13) delta 8.38-8.25 (m, 2H), 8.25-8.14 (m, 2H), 4.55-4.33 (m, 2H), 3.73-3.53 (m, 2H), 2.13-1.85 (m, 4H).
96%
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
Example 6 Synthesis of 4-(nitrooxy)butyl 4-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa- 1 ,4-dienyl)butanoate (Compound 6) Step 1 : Synthesis of 4-chlorobutyl 4-nitrobenzoate To a solution of 4-Chlorobutanol (1.09 g; 10.04 mmol) and TEA (1.7 ml; 12.05 mmol) in CH2C12 (25 ml) cooled at 0C, 4-Nitrobenzoyl chloride (2.23 g; 12.05 mmol) was added portionwise. The mixture was stirred 2 hours at room temperature then was washed with NaH2P04 (25 ml), H20 and brine. The residue was purified by flash chromatography (Biotage SPl instrument, SNAP cartridge silica 100 g, n-Hexane/EtOAc 9: 1, 10 CV) affording the title compound (2.48 g; Yield: 96%) 1H NMR (300 MHz, CDC13) delta 8.38-8.25 (m, 2H), 8.25-8.14 (m, 2H), 4.55-4.33 (m, 2H), 3.73-3.53 (m, 2H), 2.13-1.85 (m, 4H).
96%
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
Methanesulfonic acid (20 mL) was heated at 70C. In parallel, 2,3,5-trimethylbenzene-l,4-diol (2.0 g, 13.14 mmol) and methyl 3-methylbut-2-enoate (1.94 mL, 13.14 mmol, 1 eq) were added quickly and the reaction was heated for 2 h at this temperature. The reaction was then poured in water and, after cooling, was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed successively with water, saturated NaHC03, water and brine, dried (Na2S04), filtered and evaporated. The residue was crystallized from 30% CHC13 in n-Hexane to give the title compound as a pale grey solid (1.86 g, Yield: 60%). Melting point: 185C. 1H NMR (300 MHz, CDC13) delta 4.63 (s, 1H), 2.54 (s, 2H), 2.36 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H), 1.45 (s, 6H).
With hexadecyldimethylammonium bromide; In dimethyl sulfoxide; at 80℃; for 8.5h;
To a 1-L volume three-necked flask, 74.08 g of phthalimide potassium salt, 500 ml of dimethyl sulfoxide, 0.7 g of cetyldimethylammonium bromide, and uniformly stirred to obtain a mixture were added. Then, 56.47 g of 4-chlorobutanol was added dropwise to the mixture at room temperature (when stirring was added dropwise, 0.5 h was added), and after completion of the dropwise addition, the reaction was stirred at 80 C for 8 h to complete the reaction, and the intermediate was obtained. mixture.Then, the mixed solution of the intermediate is subjected to rotary evaporation treatment under the action of a water pump, and the dimethyl sulfoxide is removed by evaporation. After the evaporation is completed, 300 ml of dichloromethane is added to the remaining product, and the mixture is uniformly stirred to obtain an intermediate. Dichloromethane solution; then firstly wash and extract twice with a solution of 2% by mass of sodium hydroxide solution in dichloromethane (100 ml each time), and then wash and extract once with 100 ml of saturated sodium chloride solution. After washing and extracting the organic phase, the organic phase is dried with anhydrous sodium sulfate, and after drying, the dried organic phase is subjected to rotary evaporation concentration treatment under the action of a water pump (the temperature at the time of rotary evaporation is 50 C) The organic phase was concentrated to 100 ml, cooled to room temperature, and the cooled mixture was placed in a refrigerator, placed at 3 to 5 C for 4 hours, and a large amount of white precipitate was precipitated, and then filtered at 0 C to obtain an intermediate N-(8-hydroxybutyl)phthalimide. The mass of the intermediate is 73.43 g, the yield is 83.8%, and the melting point is 53.5-55.2 C;
With potassium carbonate; sodium iodide; In butan-1-ol; at 95℃; for 36h;
To a solution of 1-methyl-[1,4]diazepane (21.3 g, 185 mmol, 2.0 equiv) and 4-chloro-butan-1-ol (10.0 g, 92.6 mmol, 1.0 equiv) in 1-butanol (200 mL) were added K2CO3 (38.0 g, 278 mmol, 3.0 equiv) and NaI (13.9 g, 92.6 mmol, 1.0 equiv). The mixture was warmed to 95 C. and stirred for 36 h. The mixture was then cooled to rt, diluted with water, and extracted with chloroform (3×100 mL). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. Purification by Method 2 afforded 9.3 g of 4-(4-methyl-[1,4]diazepan-1-yl)-butan-1-ol with a small unidentified impurity. A portion of the impure alcohol (5.0 g) was dissolved in DMF (50 mL) and cooled to 0 C. Sodium hydride (60% dispersion in oil, 1.29 g, 32.2 mmol, 1.2 equiv) was added. The mixture was warmed to rt, stirred for 1 h, and then re-cooled to 0 C. A solution of 2-chloro-isonicotinonitrile (3.72 g, 26.8 mmol, 1.0 equiv) in DMF (25 mL) was added dropwise. The mixture was stirred at rt for 18 h, then was diluted with water (25 mL) and satd. aq. NaHCO3 (100 mL), and was extracted with chloroform (3×100 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by Method 2 afforded the title compound (1.0 g). MS (electrospray): mass calculated for C16H24N4O, 288.20; m/z found, 289.4 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.28 (dd, J=4.4 Hz, 0.8 Hz, 1H), 7.05 (dd, J=3.9, 1.1 Hz, 1H) 6.96 (s, 1H), 4.33 (t, J=6.6 Hz, 2H), 2.75-2.68 (m, 4H), 2.65-2.57 (m, 4H), 2.56-2.49 (m, 2H), 2.35 (s, 3H), 1.84-1.74 (m, 4H), 1.66-1.55 (m, 2H).
With hydrogenchloride; In tetrahydrofuran; tetrahydrofuran, ethyl bromide;
EXAMPLE 17 1'-[4-[1-(4-Fluorophenyl)-5-trifluoromethylindazol-3-yl]-1-butyl]spiro]isobenzofuran-1(3H),4'-piperidine], 17a. To a suspension of magnesium turnings (135 g) in 300 ml of dry tetrahydrofuran, ethyl bromide (140 g) dissolved in 500 ml of dry tetrahydrofuran was slowly added followed by reflux for 20 min. A solution of 4-chloro-1-butanol (274 g) in 500 ml of tetrahydrofuran was added dropwise at reflux temperature. After stirring for 20 min, the Grignard solution was filtered and added portionwise to a solution of <strong>[1813-33-8]2-chloro-4-trifluoromethyl-benzonitril</strong> (200 g) in 600 ml of dry tetrahydrofuran. The reaction mixture was stirred for 16 h at room temperature followed by addition af 2N hydrochloric acid and ice. Extraction with ether, drying of the ether phase over magnesium sulfate and removal of solvent in vacuo left a viscous oil which was applied to a silica gel column (eluent:dichloromethane/ether=3:1) giving 4-(2-chloro-5-trifluoromethylbenzoyl)-1-butanol (101 g) as an oil.
With sodium hydroxide; potassium bromide In tetralin; dichloromethane; water
2 EXAMPLE 2
A further 250 ml of dichloromethane, 1,000 ml of water, 542.5 g (5.0 moles) of 4-chlorobutanol, 29.8 g (0.25 mole) of potassium bromide and 89.0 g (0.5 mole) of disodium hydrogen phosphate dihydrate were then added to this solution at room temperature. Thereafter, the pH of the aqueous phase was brought to 6.7 by adding sodium hydroxide solution. 2,660.7 g (5.0 moles) of a 14% strength by weight aqueuous sodium hydrochlorite solution were then slowly added dropwise with through stirring, likewise at room temperature. After the addition, stirring was continued for a further 15 minutes at room temperature. The 4-chlorobutanal-containing organic phase was separated off, the aqueous phase was extracted with dichloromethane and the combined organic phases were slowly added dropwise to a mixture heated to 110° C. and consisting of a solution of 533 g of sodium hydroxide in 1,750 ml of water, 40.0 g of methyltrioctylammonium chloride and 500 ml of tetralin, the reaction mixture being stirred vigorously. During the addition itself, an azeotropic mixture consisting of the components dichloromethane, tetrahydrofuran (formed by cyclization of unconverted 4-chloro-1butanol), water, tetralin and formylcyclopropane was distilled off. During the dropwise addition of the 4-chlorobutanal solution, an additional 750 ml of water were added to the reaction mixture in order to replace the water distilled off in the course of the azeotropic distillation. After the end of the addition and after the distillation temperature of the azeotropic mixture had reached 100° C., distillation was continued for a further 15 minutes. The resulting azeotropic distillate was freed from water and subjected to fractional distillation to isolate the formylcyclopropane. Yield (based on 4-chlorobutanol): 65%.
With sodium hydroxide; potassium bromide; m-chloroperoxybenzoic acid In tetralin; water
3 EXAMPLE 3
EXAMPLE 3 23.3 g (0.15 of triacetoneamine were dissolved in 150 ml of A solution of 0.3 mole of m-chloroperoxybenzoic acid in 450 ml of tetralin was added to this solution while cooling, and stirring was continued for a further half hour after the addition. 600 ml of water, 325.5 g (3.0 moles) of 4-chlorobutanol, 17.9 g (0.15 mole) of potassium bromide and 53.4 g (0.3 mole) of disodium hydrogen phosphate dihydrate were then added to this solution at room temperature. By adding sodium hydroxide solution, the pH of the aqueous phase was brought to 7.0. 1,650 g (3.1 moles) of a 14% strength by weight aqueous sodium hypochlorite solution were then slowly added dropwise with thorough stirring. After the addition, stirring was continued for a further 15 minutes at room temperature. The 4-chlorobutanal-containing organic phase was separated off, the aguecus phase was extracted twice with tetralin and the combined organic phases were slowly added dropwise to a mixture heated to 106° C. and consisting of 636 g 6.0 moles) of sodium carbonate, 3 1 of water, 60.6 g (0.15 mole) of methyltrioctylammonium chloride and 400 ml of tetralin, the reaction mixture being stirred vigorously. During the addition itself, an azeotropic mixture consisting of the components formylcyclopropane, water, tetralin and tetrahydrofuran was distilled off. During the dropwise addition of the 4-chlorobutanal solution an additional 750 ml of water were added to the reaction mixture. After the end of the addition, distillation was continued for a further 15 minutes. The resulting distillate was freed from water and the formylcyclopropane was isolated by fractional distillation. Yield (based on 4-chlorobutanol): 56%.
11 EXAMPLE 11
EXAMPLE 11 0.01 mole of butylene chlorohydrin was added to a suspension of 0.012 moles of tetramethylammonium bicarbonate in 25 cm3 of acetonitrile, whereupon the procedure was as in Example 6. 1.13 g of butylene carbonate were thus obtained. The yield was about 97% (gas-liquid chromatographic analysis).
1.v
Preparation: 30 g of Naproxen chloride are dissolved in 120 g of dichloromethane . This solution is cooled at 00C and a solution of 14.5 g of l-chloro-3-buthanol in 100 g of dichloromethane is added dropwise in 2 hours. After a completion time of 3 hours at 00C, 60 g of water are added and the mixture is stirred for 10 hours. After phase separation, 60 g of water are added to organic phase and the mixture is stirred for 10 hours. After phase separation, the organic phase is concentrated to 120 mL and 4.5 g of potassium carbonate are added. The mixture is refluxed at about 400C for 4 hours. After filtration and vacuum concentration, an oil is obtained (HPLC purity 90%) .
With sodium hydrogencarbonate;sodium iodide; In acetonitrile; at 90℃; for 18h;Heating / reflux;
NaI (450 mg, 3.00 mmol) and anhydrous NaHCO3 (1.512 g, 24.0 mmol) were added to a solution of the amine Int-m2 (1.468 g, 6.00 mmol) and 4-chlorobutan-l-ol (1.299 g, 12.0 mmol) in dry acetonitrile (12 mL). After being stirred overnight at 900C for 18 h. The mixture was cooled to RT, and diluted with EA, washed with water and brine. The organic phase was dried (Na2SO4), filtered and concentrated. Purified by flash chromatograpy give a yellowish oil Int-n2 (1.104 g, 58%).
Cyclobut-1-enecarboxylic acid 4-chloro-butyl ester, (21)
Cyclobut-1-enecarboxylic acid 4-chloro-butyl ester, (21) Cyclobut-1-enecarboxylic acid (2.04 mmol, 200 mg) was dissolved in 1.5 mL dry CH2Cl2. The solution was cooled to 0° C. and oxalyl dichloride (4.08 mmol, 345 μL) was added. The temperature of the solution was raised to rt, and the mixture was allowed to react for 1 h. The solvent was evaporated to generate a viscous oil. 4-chlorobutanol (1.36 mmol, 148 mg) and triethylamine (2.72 mmol, 379 μL) were dissolved in 1.0 mL dry CH2Cl2, and the solution was stirred at 0° C. for 45 min before being added to a vial containing cyclobut-1-enecarboxylic chloride. The reaction mixture was stirred for 16 h at rt. The CH2Cl2 solution was concentrated by rotary evaporation, and then purified by flash column chromatography (60% CH2Cl2/pentane) to yield 21 as a colorless oil (98 mg, 38%). 1H-NMR (500 MHz, CDCl3) δ 6.73 (s, 1H), 4.11 (t, J=6.0 Hz, 2H), 3.54 (t, J=6.0 Hz, 2H), 2.68 (t, J=6.0 Hz, 2H), 2.43 (m, 2H), 1.81 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 162.27, 146.69, 138.71, 63.31, 44.58, 29.31, 29.20, 27.20, 26.20.
General procedure: To a solution of DMSO (10ml) taken in a round bottom flask was added KOH (2equiv) and the solution was stirred at room temperature for 15min. The indole derivative 2 or 7 (1equiv) was then added and the mixture was further stirred for 1h, after which 4-chlorobutan-1-ol or 3-chloropropan-1-ol (1.5equiv) was added dropwise to the reaction mixture. The reaction was monitored by TLC to completion within 5h. The reaction mixture was then quenched by adding water and was extracted with ethyl acetate. Evaporation of the solvent under reduced pressure followed by column chromatography gave the required N-alkylated compounds, 3/8/12/16.
1-(4-hydroxybutyl)-1H-indole-3-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
General procedure: To a solution of DMSO (10ml) taken in a round bottom flask was added KOH (2equiv) and the solution was stirred at room temperature for 15min. The indole derivative 2 or 7 (1equiv) was then added and the mixture was further stirred for 1h, after which 4-chlorobutan-1-ol or 3-chloropropan-1-ol (1.5equiv) was added dropwise to the reaction mixture. The reaction was monitored by TLC to completion within 5h. The reaction mixture was then quenched by adding water and was extracted with ethyl acetate. Evaporation of the solvent under reduced pressure followed by column chromatography gave the required N-alkylated compounds, 3/8/12/16.
85%
General procedure: To a solution of DMSO (10ml) taken in a round bottom flask was added KOH (2equiv) and the solution was stirred at room temperature for 15min. The indole derivative 2 or 20 (1equiv) was then added and the mixture was further stirred for 1h, after which 4-chlorobutan-1-ol or 3-chloropropan-1-ol (1.5equiv) was added dropwise to the reaction mixture. The reaction was monitored by TLC to completion within 5h. The reaction mixture was then quenched by adding water and was extracted with ethyl acetate. Evaporation of the solvent under reduced pressure followed by column chromatography gave the required N-alkylated compounds, 3/13/21. 4.3.1 1-(4-Hydroxybutyl)-1H-indole-3-carbaldehyde (3) White solid (85%); mp 12 75-77 C.
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 5h;
Methyl 4-hydroxy-3-methoxycinnamate (20.8 g) and potassium carbonate (30 g) were suspended in dimethyl formamide (150 ml), and the suspension was heated to 90C. Next, 4-chloro-1-butanol (21.6 g) was added dropwise thereto over 2 hours, and the mixture was stirred at 90C for 3 hours. Further, potassium carbonate (60 g) and 4-chloro-1-butanol (44 g) were added thereto. After confirming the completion of the reaction, dimethylformamide was evaporated under reduced pressure. The remaining solid was dissolved in dichloromethane, and the solution was washed with 5% hydrochloric acid and water. The solvent was evaporated under reduced pressure, and the obtained solid was purified by column chromatography to obtain methyl 4-hydroxy-3-methoxycinnamate (24 g) as a yellow liquid. [0155] 1H NMR (400 MHz, CDCl3) delta: 1.75-1.79 (p, 2H), 1.95-1.99 (p, 2H), 3.71-3.74 (t, 2H), 3.80 (m, 3H), 3.89 (t, 3H), 4.07-4.10 (t, 2H), 6.29-6.33 (d, 1H), 6.85-6.87 (d, 2H), 7.04 (m, 1H), 7.07-7.09 (d, 2H), 7.61-7.65 (d, 2H).
1-[(hexadecyloxycarbonyl)oxybutyl]pyridinium chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: pyridine; 4-Chloro-1-butanol; cetyl chloroformate In toluene at 20℃; for 3h;
Stage #2: In toluene for 10h;
23 1-[(Hexadecyloxycarbonyl)oxy]butyl]pyridinium chloride
2.81 g (1.0 times mol/chlorobutanol) of hexadecyl chloroformate was added to 1 g (9.2 mmol) of 4-chlorobutanol, 7.4 ml of pyridine and 10 ml of toluene and reacted at room temperature for 3 hours. The precipitated pyridine hydrochloride was separated by filtration using a small amount of toluene, whereby 37 g of a mixed solution of 4-chlorobutyl hexadecyl carbonate, pyridine and toluene. A 1 g portion of the obtained solution was reacted for 10 hours while additionally adding 2 ml of pyridine halfway therethrough. After confirming by NMR analysis of the reaction solution that hexadecyl chloroformate disappeared, pyridine was distilled off, and hexane was added to the resulting residue to obtain a crystal. This crystal was dissolved in ethanol and after filtering insoluble matters, the resulting solution was concentrated to obtain 0.11 g of 1-[(hexadecyloxycarbonyl)oxy]butyl]pyridinium chloride (hereinafter, referred to as Onium Salt [10]). Yield: 95% or more. Purity: 90% or more (NMR). [0483] The NMR data of Onium Salt [10] obtained are as follows.0.88 (3H, dd, -CH3), 1.2-1.4 (26H, m, -CH2-), 1.66 (2H, m, -CH2-), 1.85 (2H, m, -CH2-), 2.20 (2H, m, -CH2-), 4.11 (2H, dd, -CH2-), 4.20 (2H, dd, -CH2-), 5.20 (2H, dd, N-CH2-), 8.09 (2H, dd, Py), 8.46 (1H, dd, Py), 9.53 (2H, dd, Py).
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h;
Into 2 mL of DMF were dissolved 75 mg (0.2 mmol) of <strong>[26687-82-1]arctigenin</strong> and 130.3 mg (1.2 mmol) of 4-chloro-1-butanol. Thereto was further added 165.9 mg (1.2 mmol) of potassium carbonate to cause the reactive components to react with each other at 100 C. for 3 hours. The reaction liquid was filtrated, and then the filtrate was distilled off under a reduced pressure. To the residue were added ethyl acetate and water, and this system was stirred. The organic layer was then distilled off under a reduced pressure to yield hydroxybutoxy<strong>[26687-82-1]arctigenin</strong>.
at 100℃; for 0.333333h;Sealed tube; Microwave irradiation;
General procedure: The 4-substituted methyl (phenylsulfonyl)carbamate was dissolved in the chosen alcohol (2 mL) in a microwave vial, which was closed using an aluminum open-top seal with PTFE-faced septum. The reaction mixture was heated under microwave irradiation at 100-120 oC for 20-60 min. The crude reaction mixture was concentrated under reduced pressure and the residue was purified using silica gel column chromatography to yield the desired (aryl)carbamate.
1.A A.
A. Synthesis of 4-chlorobutanal A solution of oxalyl chloride (22.54 ml, 263 mmol) in DCM (400 ml) was cooled in an iPrOH/CO2 bath. DMSO (37.3 ml, 525 mmol) was slowly via syringe and stirred cold for 1 hour. A solution of 4-chlorobutan-1-ol (19 g, 175 mmol) in 50 mL DCM was added dropwise. The col mixture was stirred for one hour, then, triethylamine (110 ml, 788 mmol) was slowly added. The suspension was stirred cold for 30 minutes, then allowed to warm to room temperature. The reaction was quenched with water, acidified and organics separated. Solvent removal followed by distillation yielded the product as a colorless oil, 8 g.
Stage #1: (5,6-diphenyl-pyrazin-2-yl)-isopropyl-amine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 80℃; for 0.583333h;
Stage #2: 4-Chloro-1-butanol In N,N-dimethyl-formamide; mineral oil at 15 - 20℃;
2 EXAMPLE-2: Preparation of 4-[(5,6-diphenyl-pyrazin-2-yl)-isoprdpyl- amino]-butan-1-ol
To a suspension of NaH (60% dispersion in oil, 1.2 g, 50 mmol) in DMF (100 ml) was added the (5,6-diphenyl-pyrazin-2-yl)-isopropyl-amine (10 g, 34 mmol) at room temperature, and the mixture was stirred at 80 °C for 35 min. The mixture was ice cooled to 15-20 °C and a solution of 1-chloro-4-butanol (11.25 g, 100 mmol) in DMF (21 ml) was added dropwise. The mixture was stirred at room temperature for 2-3 hrs, diluted with ice water, and extracted with EtOAc. The extract was washed with brine and dried over MgSC . After the solvent was evaporated, the crude product of 4-[(5,6-diphenyl-pyrazin-2- yl)-isopropyl -amino]-butan-1-ol (8 gm, 64%) as pale yellow solid. [Yield= 8g]
4-chloro-1-butyl 2,3,4,5,6-pentafluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.2%
With sulfuric acid In tetrachloromethane for 20h; Reflux;
2
Pentafluorobenzoic acid (4.24 g, 20 mmol) was mixed with 4-chloro-1-butanol (3.26 g, 0.03 mol) in 20 mL of CCl4, 6 drops of concentrated sulfuric acid was added and the reaction was refluxed for 20 hours.After completion of the reaction, 20 mL of 5% NaHCO was sequentially added3Solution, 20 mL of saturated NaCl solution, and anhydrous MgSO was added4dry.The solution was concentrated on silica gel column chromatography and ethyl acetate / petroleum ether (v: v = 1: 9) as eluant to give chlorobutanol pentafluorobenzoate (4.31 g, 71.2%).
With caesium carbonate; sodium iodide; In acetonitrile; at 50℃; for 12h;
EXAMPLE 21 Synthesis of 3-(4-((4-(4-ethynyl- lH-pyrazol- l-yl)butyl)amino)- l-oxoisoindolin-2- -2,6-dione Step 1 : To a solution of 4-iodo-lH-pyrazole (3.88 g, 20 mmol) in CH3CN (140 mL) was added 4-chlorobutan- l-ol (3.3 g, 1.3eq), Cs2C03 (16.4 g, 60 mmol), and Nal (600 mg). The reaction mixture was heated at 50 C for 12 hour. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography (EtOAc/Hexanes: 1: 1 to EtOAc) to afford 4-(4-iodo-lH-pyrazol-l- yl)butan-l-ol (4 g, 75%).
75%
With caesium carbonate; sodium iodide; In acetonitrile; at 50℃; for 12h;
To a solution of 4-iodo-lH-pyrazole (3.88 g, 20 mmol) in CH3CN (0943) (140 mL) was added 4-chlorobutan-l-ol (3.3 g, 1.3eq), Cs2C03 (16.4 g, 60 mmol), and Nal (600 mg). The reaction mixture was heated at 50 C for 12 hour. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography (EtOAc/Hexanes: 1:1 to EtOAc) to afford 4-(4-iodo-lH-pyrazol-l- yl)butan-l-ol (4 g, 75%).
With potassium carbonate; potassium iodide; In acetonitrile; at 85℃; for 6h;Inert atmosphere;
EXAMPLE 36 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-ethynyl- lH-pyrazol-l- l)butoxy)isoindoline- l,3-dione Step 1 : To a suspension of 4-ethynyl-lH-pyrazole (920 mg, 10 mmol) and 4-chlorobutan- l-ol (216 mg, 20 mmol) in acetonitrile (25 mL) was added K2C03 (4.1 g, 30 mmol, 3 eq) and KI (166 mg, 1 mmol, 0.1 eq). The mixture was stirred for 6 hours at 85 C under N2 protection. The reaction mixture was quenched with water and extracted with EtOAc. The residue was purified by chromatography (DCM:MeOH 10: 1) to afford to afford 1.3 g of 4-(4-ethynyl- lH-pyrazol-l-yl)butan-l-ol with 80% yield. ESI-MS m/z 165.02 [M+H]+.
80%
With potassium carbonate; potassium iodide; In acetonitrile; at 85℃; for 6h;Inert atmosphere;
To a suspension of 4-ethynyl-1H-pyrazole (920 mg, 10 mmol) and4-chlorobutan- 1-ol (216 mg, 20 mmol) in acetonitrile (25 mL) was added K2C03 (4.1 g,30 mmol, 3 eq) and KI (166 mg, 1 mmol, 0.1 eq). The mixture was stirred for 6 hours at85 C under N2 protection. The readion mixture was quenched with water and extractedwith EtOAc. The residue was purified by chromatography (DCM:MeOH 10:1) to afford to afford 1.3 g of 4-(4-ethynyl-1H-pyrazol-1-yl)butan-1-ol with 80% yield. ESI-MS mlz 165.02 [M+Hjt
In a round bottom flask, 5.0 g of <strong>[70500-72-0]7-hydroxyquinolin-2(1H)-one</strong>, 7.5 g K2CO3 and 25 ml DMF were taken at 25-35 C. The reaction mixture was stirred for 30 minutes at 25-35 C. 3.70 g of 4-chloro butane-1-ol was added and the reaction mixture was stirred at 70-75 C. for 9-10 hours. After completion of the reaction, the reaction mixture was cooled to 25-35 C. and added into water and stirred for 10-15 minutes. The solid was filtered and washed with water and dried in a hot air oven at 45-50 C. to obtain 7-(4-hydroxybutoxy) quinolm-2(1H)-one. Yield: 80%.
With toluene-4-sulfonic acid; In toluene; at 90℃; for 5.0h;Dean-Stark;
In the reaction (R-3), the compound (A-1) and the compound (B-1) were reacted to obtain a compound (C-1). Hereinafter, the compound (A-1) is sometimes described as the first raw material of the reaction (R-3) and the compound (B-1) is described as the second raw material of the reaction (R-3). 2.24 g (0.01 mol) of the compound (A-1), 3.26 g (0.03 mol) of the compound (B-1) and toluene (100 mL) were added to the flask, The contents of the flask were dissolved. Into the flask, p-toluenesulfonic acid (0.001 mol) was added. The flask was set in a Dean-Stark apparatus. The content of the flask was heated at 90 C. for 5 hours, It was refluxed while dehydrating. The content of the obtained flask was depressurized, Toluene was distilled off. Ion exchanged water was added to the mixture after distillation under reduced pressure, and the mixture was extracted with chloroform. After drying the obtained organic layer, The organic layer was depressurized and chloroform was distilled off. As a result, the compound (C-1) was obtained as a crude product. The yield of the compound (C-1) was 2.84 g, and the yield of the compound (C-1) from the compound (A-1) was 90 mol%.
With toluene-4-sulfonic acid; In di-isopropyl ether; cyclohexene; for 12h;Dean-Stark; Reflux;
In a reaction vessel equipped with a Dean-Stark apparatus, 20.0 g of a compound represented by the formula (D-6-4)28.4 g of 2-trifluoromethylacrylic acid,1.8 g of p-toluenesulfonic acid monohydrate,300 mL of cyclohexane,150 mL of diisopropyl ether was added.And heated under reflux for 12 hours while removing water.It was diluted with dichloromethane and washed sequentially with a 5% aqueous sodium hydrogen carbonate solution and brine.Purification was carried out by column chromatography (silica gel, dichloromethane)34.0 g of a compound represented by the formula (D-6-5) was obtained.
34 g
With toluene-4-sulfonic acid; In di-isopropyl ether; cyclohexane; for 12h;Dean-Stark; Reflux;
20.0 g of the compound represented by the formula (I-6-10), 28.4 g of acrylic acid, 1.8 g of p-toluenesulfonic acid monohydrate, 300 mL of cyclohexane and 150 mL of diisopropyl ether were put into a reactor equipped with a Dean-Stark apparatus, and heated under reflux for 12 hours while removing water. This was diluted with dichloromethane, and washed sequentially with an aqueous solution of 5% sodium hydrogencarbonate, and salt water. Purification through column chromatography (silica gel, dichloromethane) gave 34.0 g of the compound of the formula (I-6-12).
1-(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)-4-chlorobutane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With 1H-imidazole; dmap; In dichloromethane; at 20℃; for 16h;Inert atmosphere;
To a 100 mL roundbottom flask equipped with a magnetic stir bar was added CH2Cl2 (50.0ml), <strong>[928-51-8]4-chloro-1-butanol</strong> (1.0 mL, 10.0 mmol, 1.0 equiv.), imidazole(817.0 mg, 12.0 mmol (1.2 equiv.), and 4-dimethylaminopyridine (122.2 mg, 1.0 mmol, 0.1 equiv.)and the mixture was stirred. tert-Butyldiphenylchlorosilane (2.85 mL, 11.0 mmol, 1.1 equiv.) wasthen added. The mixture was left to stir for 16 hours at room temperature open to the atmosphere,then concentrated under reduced pressure. The crude residue was purified with the Biotage IsoleraOne purification system with 2-10% EtOAc in hexanes to afford the title compound as a clearcolorless oil (2.58 g, 74% yield)
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20.0℃; for 12.0h;
5,6-dimethylpyrazine acid (248 mg, about 2 mmol, prepared as Example 2), 4-chloro-1-butanol (2.4mmol), EDCI (2.4mmol) and DMAP (0.2mmol) were added to dry methylene chloride (20mL), stir at room temperature for 12 hours, then dilute with dichloromethane (20mL), The saturated aqueous NaCl solution was washed, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain an oily liquid. The hederagenin(236mg, 0.5mmol), K2CO3 (207mg, 1.5mmol) and oily liquid were added to DMF (20mL), The mixture was stirred at 85 C for 4 hours. It was then diluted with ethyl acetate (20 mL), washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain a white powder, H-17. Yield: 27% (after chromatograph with DCM / MeOH, 1% -2%) as a white powder, m.p .: 134.7 C.
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 24h; Inert atmosphere;
2 Example 2The synthesis method of azobenzonitrile monomer 2 is as follows:
Weigh 2g of 4-(phenyldiazo)phenol, 1.59g of 1-chlorobutanol,1.95g of potassium iodide and 2.03g of potassium carbonate in a reaction flask, vacuumed, and filled with nitrogen;In a nitrogen atmosphere, inject 80 mL of DMF and place the reaction flask in an oil bath.After stirring at 80 ° C for 24 h, a large amount of water was added to precipitate a yellow solid, which was filtered and dried.The product 2 is obtained, wherein the structural formula of the product 2 is:
3-(4-hydroxybutyl)-1-phenethyl-1H-imidazol-3-ium chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
In toluene at 80℃; for 0.333333h; Microwave irradiation; Green chemistry;
3.2.1. General procedures for the synthesis of imidazolium halides (1-17)using the microwave method
General procedure: The alkyl halides (1.1 eq) were added to a solution of 1-pentyl-1Himidazole(1 eq) in toluene. The solution was then treated with irradiationfor 20 min in a closed vessel at 80 °C using a CEM Microwave. Thecompletion of the reaction was indicated by the formation of an oil orsolid phase from the initially clear homogenous mixture composed ofN,N-pentylimidazole and the alkyl halide in toluene. The product waseither filtered or extracted, and then washed with ethyl acetate. TheIL/salt was then dried at reduced pressure.
With dmap; dicyclohexyl-carbodiimide In dichloromethane for 16h; Reflux; Inert atmosphere;
2; 3 Step (A-2),
In a dry one-neck flask (100 mL), the third compound (3.62 mmol, 1 equiv) and dichloromethane (30 mL) having the structure represented by formula (15) were added, and the mixture was stirred and dissolved. Into the reaction solution,Add dicyclohexylcarbodiimide (3.62 mmol, 1 equiv), the fourth compound (3.62 mmol, 1 equiv) with the structure represented by formula (16), and 4-dimethylaminopyridine (catalyst equivalent).Stir to dissolve under the protection of argon, heat to reflux for 16h,Complete the second reaction. After the reaction, the reaction solution was diluted with dichloromethane and filtered, and the filtrate was dried with anhydrous magnesium sulfate.The solvent was removed in vacuo, and the crude product was collected. The crude product was purified by column chromatography (silica gel, n-hexane/ethyl acetate=20/1, V/V) to obtain the fifth compound having the structure represented by formula (17) with a yield of 81%.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
3.3.2. Synthesis of Intermediate b
First, 3.32 g (20.00 mmol) of intermediate a, 4.60 g (24.00 mmol) of EDCI, and 1.95 g(16.00 mmol) of DMAP were added into a 100 mL two-necked flask. Subsequently, 50.0 mLof DCM and 2.9 mL (30.00 mmol) of C4H9ClO were added to the flask. The mixture wasstirred until the starting material was completely consumed as judged by TLC. The organicphase was washed with deionized water (50.0 mL 2) and saturated aqueous NaHCO3(50.0 mL 2), then dried with magnesium sulfate and the solvent was removed using arotary evaporator. Finally, the mixture was further purified by column chromatography(silica gel, petroleum ether: ethyl acetate = 4:1 v/v) to give the intermediate b (4.14 g, yield81.2%, m.p. 157.4 C) as a white solid. Spectroscopic data of intermediate b: 1H NMR (CDCl3, 25 C, 500 MHz): 8.44-8.87(d, J = 1.5 Hz, 1H, CHO), 8.05 (s, 1H, NH), 7.64-7.66 (d, J = 3.5 Hz, 2H, Ph-H), 7.15-7.16 (d, J= 7.1 Hz, 2H, Ar-H), 4.34-4.36 (t, 2H, OCH2), 3.62-3.64 (t, 2H, CH2CH2Cl), 1.94-1.96 (m,4H, CH2CH2CH2CH2Cl); LC-MS (ESI) m/z: [M H] Calcd for C12H14ClNO3 255.70; Found255.07. IR (KBr, cm1): 3307 (nN-H), 1527 (amide I), 1287 (amide II), 1708 (nC=O ester), 1606(nC=C benzene ring), 1302 (nC-H methylene), 1179 (nC-O ester).
ethanedioic acid 1,2-bis(4-chlorobutyl) ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 52%
2: 5 %Chromat.
With N,N,N,N,-tetramethylethylenediamine; 1,5-dimethyl-9-azanoradamantane N-oxyl; oxygen; copper chloride (I) at 23℃; for 24h; Molecular sieve; Green chemistry;
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
