Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 2163-42-0 | MDL No. : | MFCD00082586 |
Formula : | C4H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QWGRWMMWNDWRQN-UHFFFAOYSA-N |
M.W : | 90.12 | Pubchem ID : | 75103 |
Synonyms : |
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 23.67 |
TPSA : | 40.46 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.68 cm/s |
Log Po/w (iLOGP) : | 1.2 |
Log Po/w (XLOGP3) : | 0.24 |
Log Po/w (WLOGP) : | -0.39 |
Log Po/w (MLOGP) : | -0.18 |
Log Po/w (SILICOS-IT) : | -0.19 |
Consensus Log Po/w : | 0.13 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.42 |
Solubility : | 34.4 mg/ml ; 0.382 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.65 |
Solubility : | 20.2 mg/ml ; 0.224 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.12 |
Solubility : | 119.0 mg/ml ; 1.32 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine | |
95% | With pyridine In tetrahydrofuran at 20℃; for 48h; | |
With pyridine |
With pyridine Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With lithium aluminium hydride In diethyl ether | |
87% | With borane In tetrahydrofuran at -78 - 20℃; | |
85% | With lithium aluminium hydride In diethyl ether for 3h; Heating; |
75% | Stage #1: Diethyl methylmalonate With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 1.5h; Stage #2: With sodium hydroxide; lithium hydroxide monohydrate for 0.333333h; | A According to Scheme A2, to a suspension of lithium aluminum hydride (152 mg, 4.00 mmol) in THF (3 mL) at 0°C was added diethyl methylmalonate A2a (348 mg, 2.00 mmol) dropwise. The reaction mixture was stirred at room temperature for 1.5 h, quenched with water (0.2 mL) and 5 N NaOH (0.2 mL), and further diluted with water (0.6 mL). After stirring for 20 min, the precipitated solid was filtered through Celite and washed with MeOH/CH2CI2. The filtrate was dried, concentrated, and purified by column chromatography to give 135 mg (75%) of A2b ; 1 H NMR (300 MHz, CDC13) 63. 68 (dd, J = 10. 7,4. 5Hz, 2H), 3.58 (dd, J = 10. 7,7. 6Hz, 2H), 3.50 (s, 2 H), 1.96-1. 89 (m, 1 H), 0.86 (d, J = 7.0 Hz, 3 H); MS (ES) m/z : 113 (M+Na+). |
60% | With lithium aluminium hydride In diethyl ether 1.) 2 h , room temperature , 2.) 1 h, reflux; | |
52.2% | With lithium aluminium hydride In tetrahydrofuran at 0 - 40℃; | 1.B.1 Step 1: 2-methylpropane-l ,3-diol (C463) To a solution of diethyl 2-methylmalonate (80.0 g, 458.0 mmol, 1.0 eq) in THF (1.0 L) was added L1AIH4 (52.4 g, 1.38 mol, 3.0 eq) in portions at 0 °C. Then the mixture was heated to 40 °C overnight. The mixture was cooled to 0 °C, quenched with H2O (52.4 mL), 15% aqueous NaOH (52.4 mL), and H2O (157.2 mL). Then Na2SC>4 (220 g) was added to the mixture. Then the mixture was filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography (Petroleum ether/EtOAc = 1 : 1) to give C464 (21.6 g, 52.2%) as a colorless oil. NMR (400 Hz, CDCb): d 3.70-3.63 (m, 2H), 3.59-3.54 (m, 2H), 3.24 (s, 2H), 1.95-1.88 (m, 1H), 0.84 (d, J = 6.8 Hz, 3H). |
52.2% | With lithium aluminium hydride In tetrahydrofuran at 0 - 40℃; | 1.B.1 Step 1: 2-methylpropane-l ,3-diol (C463) To a solution of diethyl 2-methylmalonate (80.0 g, 458.0 mmol, 1.0 eq) in THF (1.0 L) was added L1AIH4 (52.4 g, 1.38 mol, 3.0 eq) in portions at 0 °C. Then the mixture was heated to 40 °C overnight. The mixture was cooled to 0 °C, quenched with H2O (52.4 mL), 15% aqueous NaOH (52.4 mL), and H2O (157.2 mL). Then Na2SC>4 (220 g) was added to the mixture. Then the mixture was filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography (Petroleum ether/EtOAc = 1 : 1) to give C464 (21.6 g, 52.2%) as a colorless oil. NMR (400 Hz, CDCb): d 3.70-3.63 (m, 2H), 3.59-3.54 (m, 2H), 3.24 (s, 2H), 1.95-1.88 (m, 1H), 0.84 (d, J = 6.8 Hz, 3H). |
With copper chromite; ethanol at 150℃; Hydrogenation; | ||
With lithium aluminium hydride; diethyl ether | ||
With lithium aluminium hydride | ||
With lithium aluminium hydride In diethyl ether | ||
With lithium aluminium hydride | ||
With sodium hydroxide; lithium aluminium hydride 1.) THF, reflux, 2 h, 2.) H2=,; Yield given. Multistep reaction; | ||
With hydrogenchloride; lithium aluminium hydride 1.) ether; Multistep reaction; | ||
With lithium aluminium hydride In tetrahydrofuran for 48h; Heating; | ||
Stage #1: Diethyl methylmalonate With lithium aluminium hydride In diethyl ether at -78 - 20℃; for 16.5h; Inert atmosphere; Stage #2: With lithium hydroxide monohydrate In diethyl ether at -78℃; for 13h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 1 EXAMPLE 1 EXAMPLE 1 100 parts of 2-methyl-1,3-propanediol was mixed with 101 parts of acetyl chloride. The mixture was heated to 100° C. for 8 h to obtain 151 parts of 3-chloro-2-methylpropyl acetate (yield: 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 60% 2: 40% | In chloroform at 30℃; Pseudomonas fluorescens lipase (PFL); | |
> 99 % ee | With lipase-AK Amano In chloroform at 20℃; for 20h; | |
99 % ee | With lipase-AK "Amano" In chloroform at 20℃; for 20h; | 1E.1 (R)-3-tert-Butyldiphenylsiloxy-2-methylpropan-1-ol Vinyl acetate (286 mL, 3.11 mol) and lipase-AK“Amano” (17.1 g) were added to a solution of 2-methyl-1,3-propanediol (70 g, 777 mmol) in chloroform (1.5 L). The resulting mixture was stirred at rt for 20 h. The lipase was removed by filtration and washed with ethyl acetate. Then the filtrate was concentrated to provide a mixture of (S)-3-hydroxy-2- methylpropyl acetate (>99% ee) and 1,3-diacetoxy-2-methylpropane. The mixture was used in the next reaction step without separation. tert-Butyldiphenylsilylchloride (79 mL, 303 mmol) was added dropwise to a mixture of (S)-3-hydroxy-2-methylpropyl acetate and 1,3- diacetoxy-2-methylpropane (140 g, crude) and imidazole (41.3 g) in THF (620 mL). The resulting mixture was stirred at rt for 21 h. The reaction mixture was diluted with diethyl ether (1 L) and washed water (2 × 1 L) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. A 25% solution of sodium methoxide in methanol (61 mL) was added to a solution of a mixture of (R)-3-tert-butyldiphenylsiloxy-2- methylpropyl acetate and 1,3-diacetoxy-2-methylpropane (194 mg, crude) in methanol (1 L) at 0 C. The resulting mixture was stirred at rt for 24 h. The reaction mixture was diluted with diethyl ether (1 L) and n-pentane (1 L), washed with saturated ammonium chloride aqueous solution (1 L), water (2 × 1 L) and brine (1 L). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was passed through a column of silica (n-hexane/diethyl ether, 40:1 ~ 20:1 ~ 4:1) to provide (R)-3-tert-butyldiphenylsiloxy-2- methylpropan-1-ol (60.9 g) as a colorless oil.1H NMR (CDCl3, 400 MHz) δ = 7.69-7.67 (m, 4H, CH of Ph), 7.46-7.38 (m, 6H, CH of Ph), 3.75-3.57 (m, 4H, CH2OTBDPS, CH2OH), 2.03-1.96 (m, 1H, CH2CH(CH3)CH2), 1.06 (s, 9H, (CH3)3), 0.83 (d, 3H, J = 10.8 Hz, CH2CH(CH3)CH2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-Bromosuccinimide; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 0.5h; | General procedure: N-Bromosuccinimide (2.2 mmol) was added at 0 C to a mixture of diol (1.0 mmol) and triphenylphosphine (2.2 mmol) in dichloromethane (10.0 mL). The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated and the product was purified by column chromatography (Silicagel, 40-63 mum, pentane). |
With hydrogen bromide; In octane; water; at 130 - 133℃; for 14.0h;Dean-Stark; | General procedure: A one-neck rb flask was charged with diol (1equiv), 48% aq HBr (~3 equiv/OH), octane (~7:1 v/w ratio vs diol), fitted tothe fractionating column/Dean-Stark trap, and heated inan oil bath (145-150 C) w/rapid magnetic stirring. The aqueous (lower) layer of the initialazeotrope condensate (bp 89-92 C) was tapped offuntil about half of the theoretical amount of H2O had been collected;the azeotrope temp (still head) then began to rise. The condenser was set to total reflux forseveral h, reopened, and aq material collected for 1h more (head temp 96-100C). The final volume of aq distillatewas 90-100+% of theory (higher-boiling distillate contained up to 24% HBr). When the (pale tan) octane phase containedboth dibromide and bromoalkanol (6band 6c), washing with cold 85% v/v H2SO4 (10 mL,then 5 mL) removed all color and all bromoalkanol. For all three dibromides (3b, 4b, 6b) the neutralized octane solutionwas stripped of solvent (vigreux column, reduced pressure), and the essentiallypure residue (1H NMR) was kugelrohr distilled. A trace of 4-methyltetrahydropyran was foundin 4b before distillation. | |
With phosphorus tribromide; at 0 - 80℃; for 18.0h; | 2-Methylpropane-1,3-diol (10 g, 111 mmol) was added slowly to tribromophosphine (21.08 mL, 222 mmol) at 0C. After addition, the mixture was stirred at 80C for 18 h. The reaction mixture was cooled to rt and poured into a cooled aqueous solution of sodium carbonate (2.0 L) at 0C. The mixture was extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether) to give the title compound.1H NMR (CDCl3, 400MHz): delta 3.56 - 3.49 (m, 2H), 3.49 - 3.42 (m, 2H), 2.24 - 2.12 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N,N-dimethylaniline hydrochloride; <i>N</i>,<i>N</i>-dimethyl-aniline; phosphorus trichloride In 1,4-dioxane; diethyl ether at 0℃; | |
With phosphorus trichloride In diethyl ether; dichloromethane for 2h; Ambient temperature; | ||
With phosphorus trichloride In toluene at 30℃; for 3h; | 1.3; 2.3; 3.3 Step S3: Add 2-methyl-1,3-propanediol and toluene into the reaction kettle, stir and drop phosphorus trichloride under the conditions of a rotation speed of 150r/min and a temperature of 30°C, and carry out the reaction for 3h. Intermediate 6 is prepared. Intermediate 6 and deionized water are added to the reaction kettle. At a temperature of 100° C., reflux and potassium permanganate are added, and the reaction is carried out for 4 hours to obtain Intermediate 7. 4-Di-tert-butylphenol, toluene, and triethylamine were added to the reaction kettle, and at a speed of 120r/min and a temperature of 40°C, stirred and added Intermediate 7 and reacted for 3h to obtain Intermediate 8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 0 - 20℃; for 12h; | |
74.1% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran at 50℃; for 2h; Stage #2: benzyl bromide In tetrahydrofuran at 65℃; | 37.1 To a suspension of sodium hydride (16.04 g, 401.0 mmol, mass 60 %) in THF (600 mL)was added 2-methylpropane-1,3-diol (30.11 g, 334.1 mmol), the mixture was heated to 50 ocand stirred for 2 h, then bromomethylbenzene (57.08 g, 333.7 mmol) was added. The reactionsolution was heated to 65 oc and stirred overnight. The reaction mixture was diluted with water(500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were dried overNa2S04, filtered and concentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v) = 20/1-1 Oil) to give the title compound as light yellow liquid(44.6 g, yield 74.1 %).MS (ESI, pos.ion) m/z: 181.4 [M+Ht;1H NMR (600 MHz, CDCh) 8 (ppm): 7.37-7.27 (m, 3H), 4.52 (s, 2H), 3.65-3.57 (m, 2H), 3.54(dd, J = 9.1, 4.7 Hz, IH), 3.45-3.40 (m, IH), 2.42 (s, IH), 2.11-2.03 (m, IH), 0.89 (d, J = 7.0 Hz,3H). |
74.1% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran at 50℃; for 2h; Stage #2: benzyl bromide In tetrahydrofuran at 50 - 65℃; | 37.1 step 1) 3-(benzyloxy)-2-methylpropan-1-ol Sodium hydride (16.04 g, 401.0 mmol, mass fraction 60%) was suspended in THF (600 mL)To this was added 2-methylpropane-1,3-diol (30.11 g, 334.1 mmol)The reaction mixture was heated to 50 ° C and stirred for 2 hours. Then,To this was added benzyl bromide (57.08 g, 333.7 mmol).The reaction mixture was warmed to 65 ° C and stirred overnight.After the reaction,Diluted with water (500 mL)And extracted with EtOAc (500 mL x 3).The combined organic phases were dried over anhydrous sodium sulphate,Filtered and concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1 to 10/1)The title compound was a pale yellow liquid(44.6 g, yield 74.1%). |
61% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran; mineral oil at 50℃; for 1h; Stage #2: benzyl bromide In tetrahydrofuran; mineral oil at 65℃; | 11.a 3-Benzyloxy-2-methylpropan-l-ol[0184] A solution of 2-methyl-l,3-propanediol (2.0 g, 22 mmol) in THF (10 niL) was added drop-wise to a suspension of NaH (0.9 g, 60 % in mineral oil, 22 mmol) in THF (20 mL) . After complete addition, the mixture was stirred at 50 0C for 1 h. Benzyl bromide (2.6 mmol, 22 mmol) was added drop-wise and the resulting mixture was stirred at 65 0C overnight. The reaction was quenched by addition of saturated aqueous NH4Cl-solution. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl-solution, dried-79-SDI-10975vl Attorney Docket No. 12560-046-228(Na2SO4), concentrated, and purified by flash chromatography (SiO2, heptane:EtOAc, 10:1- 2:1) to give 2.4 g (61%) of 3-Benzyloxy-2-methylpropan-l-ol: 1U NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 4.53 (s, 2H), 3.58 (m, 4H), 3.43 (dd, J= 8.0, 9.0 Hz, IH), 2.45 (dd, J = 4.6, 7.0 Hz, IH), 2.06 (m, IH), 0.90 (d, J= 7.0 Hz, 3H). |
With sodium hydride 1.) THF, reflux, 1 h, 2.) reflux, 16 h; Yield given. Multistep reaction; | ||
With sodium hydride 1.) THF, r.t., 0.5 h, 2.) THF, r.t., 6 h; Yield given. Multistep reaction; | ||
Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran at 0 - 50℃; for 1.16667h; Stage #2: benzyl bromide at 65℃; for 12h; | 1-3 Preparation of a compound of formula 30-15 To a suspension of NaH (40 g, 1666.69 mmol) in dry THE’ (1000 mL) was added 2-methyipropane-i, 3-diol (31-15) (150 g, 1666.69 rnmol; 1 eq.) in dry THF (500 mL) at 0°C over a period of 10 mm. The reaction mixture was heated to 5000 for 1 h. At the same temperature Benzyl bromide (98.89 g,555.57 rnrnol) was added and reaction mixture was heated to65°C for 12 h. After completion, the reaction mixture was poured into saturated NH4C1 solution, extracted with EtOAc (2 times), EtOAc layer was washed with water, brine, dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure to get crude compound.The crude compound was purified by silica gel (60-120 mesh) column chromatography, eluted with 20% EtOAc/ pet ether to afford 3-(benzyloxy)-2-methylpropan-1-ol (30-15) as brown colour liquid (117 g, 78%); ‘H NMR (400 MHz, cdcl3) ö 7.38- 7.24 (m, 5H), 4.52 (s, 2H), 3.61 (dt, J = 6.7, 4.2 Hz,2H), 3.59 - 3.50 (m, 1H), 3.43 (dd, J = 9.1, 8.0 Hz, 1H),2.56 (dd, J = 6.5, 4.2 Hz, 1H), 2.14 - 2.01 (m, 1H), 0.89(d, J = 7.0 Hz, 3H); Mass (M+H) : 181, LCMS Purity: 66.04% | |
Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran at 70℃; for 1h; Stage #2: benzyl bromide In tetrahydrofuran at 70℃; for 2h; | 163 Example 163: (S)-N-(4-((2-((5-(tert-butyl)-1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo [4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropane- carboxamide and (R)-N-(4-((2-((5-(tert-butyl)-1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo [4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide [0890] Synthesis of compound (±)-163.1. To a suspension of sodium hydride (2.2 g, 55.48 mmol, 1.0 equiv) in THF (20 mL) was added solution of 2-methylpropane-l,3-diol (5.0 g, 55.48 mmol, 1.0 equiv) in THF (25 mL) and stirred at 70 °C for 1 h. To the mixture was added benzyl bromide (6.6 mL, 55.48 mmol, 1.0 equiv) and stirred at 70 °C for 2 h. It was cooled to rt and poured into ice, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash, 20-25% ethyl acetate in hexane) to afford (±)-163.1. MS (ES): m/z 181.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium hydride In tetrahydrofuran | |
95% | With 1H-imidazole at 20℃; | |
94% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.75h; Stage #2: tert-butyldimethylsilyl chloride In tetrahydrofuran; mineral oil at 20℃; for 1h; |
93% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: tert-butyldimethylsilyl chloride In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; | |
88% | With sodium hydride In tetrahydrofuran at 20℃; for 15h; | |
88% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran at 20℃; for 0.75h; Stage #2: tert-butyldimethylsilyl chloride In tetrahydrofuran at 20℃; for 15h; | |
84% | With 1H-imidazole In tetrahydrofuran at 40℃; for 4h; | |
79% | With triethylamine In hexane; acetonitrile at 20℃; for 24h; Inert atmosphere; | Typical procedure for the monosilylation of symmetric diols General procedure: In a flame-dried100 mL round-bottom flask equipped with a teflon magnetic stir bar,diol(5.0 mmol) was added to acetonitrile (12.5 mL) and hexanes (37.5 mL).Triethylamine (Et3N, 0.84 mL, 6.00 mmol, 1.2 equiv) and tertbutyldimethylsilylchloride (TBSCl, 0.53 g, 5.0 mmol, 1.0 equiv) were addedto the solution and the resulting biphasic mixture was stirred vigorously atroom temperature for 24 h under a N2 atmosphere. The reaction was quenchedwith saturated aqueous ammonium chloride (NH4Cl, 50 mL), and extractedwith ethyl acetate (EtOAc, 3 50 mL). The combined organic phase waswashed with brine (3 50 mL) and dried over anhydrous sodium sulfate(Na2SO4). The crude product was purified by silica gel column chromatography(10-15% EtOAc/hexanes). |
57% | With 1H-imidazole In N,N-dimethyl-formamide | |
56% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran for 1h; Inert atmosphere; Stage #2: tert-butyldimethylsilyl chloride In tetrahydrofuran at 20℃; for 72h; Inert atmosphere; | |
47% | With 1H-imidazole In N,N-dimethyl-formamide at 0℃; for 0.5h; | |
With 1H-imidazole In N,N-dimethyl-formamide | ||
With triethylamine In dichloromethane at 20℃; for 14h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.25% | With triethylamine In dichloromethane at 10 - 25℃; for 5h; | 64.1 Step 1: 93-2 To a mixture of 93-1 (10.0 g, 110.96 mmol) and TEA (33.68 g, 332.89 mmol) in DCM (250 mL) was added tosyl chloride (52.85 g, 277.41 mmol) in portions while the internal temperature was kept below 10 . After addition, the resulting mixture was warmed up to 25 and stirred for 5 hr. The reaction mixture was poured into water (300 mL) and the organic layer was separated. The aqueous phase was extracted with DCM (200 mL × 3) . The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column eluted with petroleum ether: ethyl acetate = 4: 1 to give 93-2 (43.0 g, 97.25%yield) .1H NMR (400 MHz, Chloroform-d) δ 7.67 (d, J = 8.3 Hz, 4H) , 7.28 (d, J = 8.1 Hz, 4H) , 3.90-3.74 (m, 4H) , 2.39 (s, 6H) , 2.15-2.01 (m, 1H) , 0.84 (d, J = 7.0 Hz, 3H) ppm. |
93.1% | With triethylamine In dichloromethane at 20℃; for 18h; | 7 4.1.7. 2-Methylpropane-1,3-diyl bis(4-methylbenzenesulfonate)(10) p-Toluenesulfonyl chloride (10.2 g, 53.2 mmol) was added to amixture of 2-methylpropane-1,3-diol 9 (1.2 g, 13.3 mmol) andtriethylamine (5.4 g, 54.3 mmol) in anhydrous dichloromethane(50 mL). The mixture was stirred at r.t. for 18 h. The mixture waswashed with brine (80 mL) and water (80 mL), dried over withNa2SO4 and evaporated. The residue was purified by flash columnchromatography (ethyl acetate/hexane, 1:3) on silica gel to yieldcompound 10 (4.94 g, 93.1%) as a white solid. m.p. 73-75 °C; 1HNMR and 13C NMR data are consistent with that previously reported[50]. |
93.1% | With triethylamine In dichloromethane at 20℃; for 18h; | 4.1.3. 2-Methylpropane-1,3-diyl bis(4-methylbenzenesulfonate) (7) p-Toluenesulfonyl chloride (10.2 g, 53.2 mmol) was added to amixture of 2-methylpropane-1,3-diol 6 (1.20 g, 13.3 mmol) and triethylamine(5.40 g, 54.3 mmol) in anhydrous dichloromethane (50 mL).The mixture was stirred at rt for 18 h. The mixture was washed withbrine (80 mL) and water (80 mL), dried over with Na2SO4, and evaporated.The residue was purified by flash column chromatography (ethylacetate/hexane, 1:3) on silica gel to yield compound 7 (4.94 g, 93.1%)as a white solid. m.p. 73-75 °C; 1H NMR (400 MHz, CDCl3) δ 7.75-7.73(m, 4H), 7.36-7.34 (d, J=8.4 Hz, 4H), 3.93-3.86 (m, 4H), 2.46 (s, 6H),2.20-2.12 (m, 1H), 0.92 (d, J=7.2 Hz, 3H); 13C NMR (100 MHz,CDCl3) δ 145.17, 132.62, 130.07, 127.99, 70.44, 33.13, 21.78, 13.08;HRMS (ESI) m/z (M+H)+ calcd for C18H23O6S2: 399.0936; found399.0939. |
83% | With pyridine at 20℃; for 14h; Inert atmosphere; | |
82% | With pyridine at 0 - 80℃; for 24.5h; Inert atmosphere; | 2-1 Synthesis Example 2-1. Preparation of 2-Methylpropane-1,3-diyl-bis(4-methylbenzenesulfonate) 150 mL of pyridine was added to a 250 mL reactor, and under a nitrogen atmosphere5.0 g (55.5 mmol) of 2-methylpropane-1,3-diol are added. After cooling the reaction flask to 0 ° C, p-toluenesulfonyl chloride (26.4 g, 138 mmol) is added slowly with stirring for 30 minutes. The reaction vessel is heated to 80 ° C and stirred for 24 hours. After completion of the reaction, the reaction mixture was extracted with distilled water and ethyl acetate, and the organic layer was separated. The ethyl acetate layer was washed twice with distilled water. The organic layer was dried over MgSO4, After concentration under reduced pressure, column purification was carried out with a mixed solvent of hexane and dichloromethane 5: 1 18.1 g (yield 82%) of 2-methylpropane-1,3-diyl-bis(4-methylbenzenesulfonate) was prepared. |
82% | With pyridine at 0 - 80℃; for 24.5h; Inert atmosphere; | 2.2-1 Synthesis Example 2-1.Preparation of 2-methylpropane-1,3-diyl-bis (4-methylbenzenesulfonate) 150 mL of pyridine was added to a 250 mL reactor, and under a nitrogen atmosphere2-methylpropane-1,3-diol5.0 g (55.5 mmol) is added. The reaction flask was cooled to 0 ° Cp-toluenesulfonyl chloride26.4 g (138 mmol) is slowly added over 30 minutes with stirring.The reaction vessel is heated to 80 ° C and stirred for 24 hours.After completion of the reaction, the reaction mixture was extracted with distilled water and ethyl acetate, and the organic layer was separated. The ethyl acetate layer was washed twice with distilled water.The organic layer was dried over MgSO4,After concentrating under reduced pressure, the residue was subjected to column purification using a mixed solvent of hexane and dichloromethane 5: 1 to obtain 2-methylpropane-1,3-diyl bis (4-methylbenzenesulfonate)18.1 g (82% yield) of |
81% | With pyridine at 20℃; for 12h; | |
77% | In pyridine 0 deg C, 2 h, r.t., overnight; | |
46.4% | With pyridine at 0 - 20℃; for 24h; | 31 Compound I2: To a solution of compound I1 (20 g, 222 mmol) in pyridine (200 mL) was added tosyl chloride (106 g, 555 mmol) at 0. The mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure to afford a crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether/EtOAc, 3/1, v/v) . Pure fractions were evaporated to dryness to afford compound I2 (41 g) as a yellow oil, yield: 46.4%. 1H NMR (400 MHz, CDCl 3) : δ ppm 0.93 (d, J = 6.7 Hz, 3H) , 1.98-2.20 (m, 1H) , 2.33 (s, 6H) , 3.92 (d, J = 4.0 Hz, 4H) , 7.37 (d, J = 4.8 Hz, 4H) , 7.77 (d, J = 4.6 Hz, 4H) . LCMS: Rt = 1.64 min, MS Calcd.: 398.1, MS Found: 398.7 [M+H] +. |
In pyridine at -15℃; | ||
With pyridine | ||
With pyridine at 0℃; | 505.1 2-Methylpropane-l,3-diol (50 g, 555 mmol) was dissolved in 555 ml pyridine and cooled to 00C. p-Toluenesulfonyl chloride (212 g, 1110 mmol) was added and stirring was continued over night. 200 ml H2O was added and the reaction was extracted with DCM (2 x IL). The combined organic extracts were dried over MgSO4 and evaporated. The product was recrystallized from EtOH/Hex and the product was obtained as a white solid. MS m/z: 399.0 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.1% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667h; Stage #2: tert-butylchlorodiphenylsilane In tetrahydrofuran; mineral oil at 20℃; | 1.B.2 Step 2: 3-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-l-ol (C464) To a solution of C463 (20.0 g, 221.9 mol, 1.0 eq) in THF (300 mL) was added NaH (60% in oil, 9.8g, 244.1 mmol, 1.1 eq) in portions at 0 °C, then the mixture was stirred at 0 °C for 10 minutes. TBDPSCI (67.1 g, 244.1 mmol, 1.1 eq) was added dropwise into the reaction, which was stirred at room temperature overnight. TLC showed that the reaction went to completion. The mixture was cooled to 0 °C, quenched with saturated aqueous MLCl (200 mL) and extracted with EtOAc (200 mL, x3). The organic phase was combined, washed with brine (100 mL), dried over Na2SC>4, and concentrated. The crude product was purified by silica gel column chromatography (Petroleum ether/EtOAc = 10:1) to give C464 (70.0 g, 96.1%) as a colorless oil. NMR (400 Hz, CDCb): d 7.75-7.68 (m, 4H), 7.46-7.38 (m, 6H), 3.74 (dd, J = 10.0, 4.8 Hz, 1H), 3.68 (d, J = 6.0 Hz, 2H), 3.61 (dd, J = 10.0, 8.0 Hz, 1H), 2.49 (s, 1H), 2.05- 1.96 (m, 1H), 1.09 (s, 9H), 0.84 (d, J = 6.8 Hz, 3H). |
96.1% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667h; Stage #2: tert-butylchlorodiphenylsilane In tetrahydrofuran; mineral oil at 20℃; | 1.B.2 Step 2: 3-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-l-ol (C464) To a solution of C463 (20.0 g, 221.9 mol, 1.0 eq) in THF (300 mL) was added NaH (60% in oil, 9.8g, 244.1 mmol, 1.1 eq) in portions at 0 °C, then the mixture was stirred at 0 °C for 10 minutes. TBDPSCI (67.1 g, 244.1 mmol, 1.1 eq) was added dropwise into the reaction, which was stirred at room temperature overnight. TLC showed that the reaction went to completion. The mixture was cooled to 0 °C, quenched with saturated aqueous MLCl (200 mL) and extracted with EtOAc (200 mL, x3). The organic phase was combined, washed with brine (100 mL), dried over Na2SC>4, and concentrated. The crude product was purified by silica gel column chromatography (Petroleum ether/EtOAc = 10:1) to give C464 (70.0 g, 96.1%) as a colorless oil. NMR (400 Hz, CDCb): d 7.75-7.68 (m, 4H), 7.46-7.38 (m, 6H), 3.74 (dd, J = 10.0, 4.8 Hz, 1H), 3.68 (d, J = 6.0 Hz, 2H), 3.61 (dd, J = 10.0, 8.0 Hz, 1H), 2.49 (s, 1H), 2.05- 1.96 (m, 1H), 1.09 (s, 9H), 0.84 (d, J = 6.8 Hz, 3H). |
79% | With 1H-imidazole In tetrahydrofuran at 40℃; for 4h; |
78% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: tert-butylchlorodiphenylsilane In tetrahydrofuran at 0 - 20℃; | |
74% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran at 20℃; for 0.75h; Stage #2: tert-butylchlorodiphenylsilane In tetrahydrofuran at 20℃; for 15h; | |
Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With toluene-4-sulfonic acid In toluene for 24h; Heating; | |
76% | With toluene-4-sulfonic acid In toluene at 120℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,6-di-(S)-((((4-Ph-Ph)2C(OH))C4H7N)CH2)-4-MeC6H2OH In toluene at -20℃; for 20h; Title compound not separated from byproducts.; | ||
With (S,S)-2,6-bis{2-[hydroxy(biphenyl-4-yl)methyl]pyrrolidin-1-ylmethyl}-4-methylphenol; diethylzinc In toluene at -20℃; for 20h; Inert atmosphere; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine In dichloromethane at 20℃; for 24h; | |
70% | Stage #1: 2-methyl-1.3-propanediol With 4-dimethylaminopyridine; triethylamine In dichloromethane at -78℃; for 0.5h; Inert atmosphere; Stage #2: pivaloyl chloride In dichloromethane at -78 - 25℃; for 4.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With titanium(IV) tetrabutoxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 4h; Inert atmosphere; chemoselective reaction; | General procedure for the phosphorylation of diols. General procedure: The diol (0.49 mmol) was dissolved in 1.0 mL of CH2Cl2. N,N-Diisopropylethylamine (0.130 mL, 0.746 mmol) was added to the solution, followed by tetrabenzylpyrophosphate (0.320 g, 0.594 mmol). Ti(OtBu)4 (19 μL, 0.049 mmol, 10 mol %) was added and the reaction was stirred for 4 h at room temperature. To quench the reaction, the crude solution was filtered through a 5 mL plastic syringe containing 2 mL of 20:1 Silica/MgSO4 and washed with 60 mL of 75% EtOAc/hexanes. The filtrate was concentrated under reduced pressure. The crude product was purified using silica gel chromatography. |
84% | With titanium(IV) tetrabutoxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 4h; Inert atmosphere; | General Procedure for the Phosphorylation of Diols General procedure: The diol (0.49 mmol) was dissolved in1.0 mL of CH2Cl2. N,N-Diisopropylethylamine (0.130 mL, 0.746 mmol) was added to thesolution, followed by tetrabenzylpyrophosphate (0.320 g, 0.594 mmol;). Ti(OtBu)4 (19 μL,0.049 mmol, 10 mol %) was added and the reaction was stirred for 4 h at room temperature. Toquench the reaction, the crude solution was filtered through a 5 mL plastic syringe containing 2mL of 20:1 Silica/MgSO4 and washed with 60 mL of 75% EtOAc/hexanes. The filtrate wasconcentrated under reduced pressure. The crude product was purified using silica gelchromatography. |
74% | With tetrahexylammonium iodide; silver(l) oxide In dichloromethane at 20℃; for 20h; |
54% | With titanium(IV) isopropylate; (R)-1,1'-Bi-2-naphthol; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 16h; Inert atmosphere; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: p-methoxybenzyl chloride With tetra-(n-butyl)ammonium iodide In tetrahydrofuran; mineral oil at 55℃; for 16h; | |
71% | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: p-methoxybenzyl chloride With sodium iodide In tetrahydrofuran at 50℃; for 20h; Further stages.; | |
Stage #1: 2-methyl-1.3-propanediol With sodium hydride Inert atmosphere; Stage #2: p-methoxybenzyl chloride Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<strong>[14814-09-6]3-Mercaptopropyltriethoxysilane</strong> (obtained from General Electric under the trade name Silquest A-1891, 438.8 grams, 1.84 mole), and 2-methyl-1,3-propanediol (purchased from Aldrich, 331.7 grams, 3.68 moles) were charged into a 1-liter round-bottomed flask equipped with a magnetic stirrer, short path condenser and receiver flask. Sulfuric acid (0.39 gram) was added to the reaction flask and the mixture was heated to 50 C. under a vacuum of initially 40 torr to about 1 torr (full vaccum) 3.5 hours. Ethanol (263 grams, 5.71 moles) was collected. The reaction product was then neutralized with 1.44 grams of 21% sodium ethoxy in ethanol and then stripped 1.5 hours. The weight of the product collected was 485.6 grams. GC analysis found a complex mixture that contained 3-({3-[2-mercapto-propyl)-5-methyl-[1,3,2]dioxasilinan-2-yloxy]-2-methyl-propyl}-diethoxy-silyanyl)-propane-1-thiol and higher molecular weight components. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; | A To a mixture of A2b (113 mg, 1.26 mmol), trifluoromethylphenol (156 mg, 0.963 mmol), and triphenylphosphine (252 mg, 0.962 mmol) in THF (3 mL) at 0°C was added diisopropyl azodicarboxylate (195 mg, 0.965 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was purified by column chromatography to provide 149 mg (51 %) of A2c ; 1 H NMR (400 MHz, CDCI3) 8 7.53 (d, J=8. 8Hz, 2H), 6.96 (d, J=8. 7Hz, 2H), 3.98 (m, 2H), 3.71 (m, 2H), 2.24-2. 16 (m, 1 H), 1.80 (s, 1 H), 1.05 (d, J = 7.0 Hz, 3 H); MS (ES) m/z : 235 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate In <i>tert</i>-butyl alcohol at 100℃; | 44 The title compound was prepared by adding 3, 5MM glass beads into a 40mL EPA vial. 2-METHYLPROPANE-1, 3-diol (560 mg, 3+eq. ), t-butyl alcohol (4 mL), 6-chloro pyrimidine-2,4-diamine (220 mg, 1 eq.), and sodium t-butoxide (264.9mg, 2 eq. ) were added to the vial and shook to break loose caked particles and places in a reaction block heated to 100°C and shaken overnight. Concentrate mixture and purify by flash column chromatography eluting with 100% EtOAc and ramping up to 15% methanol/EtOAc. The title compound was isolated as an oil. ESI 198.1 (M+L), C8HS4N402 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid In methanol at 25 - 60℃; for 2h; | 2 Example 2; Under a nitrogen atmosphere, 2-methyl-1,3-propanediol (26.86 g, 298 mmol) and sulfuric acid (8.2 g, 82 mmol) were added to a four-neck flask (interior content 100 ml) equipped with a stirrer, a thermometer and a funnel for dropwise addition, then a solution of sodium formyl cyclopropyl methyl ketone (10 g, 74.6 mmol) in methanol (20 g) was added dropwise with stirring at an internal temperature of 25°C over 1 hr. After the completion of the dropwise addition, the internal temperature was raised to 60°C and the mixture was further stirred for 1 hr. The obtained reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution (40 g) and the mixture was partitioned between the organic layer and the aqueous layer. The obtained organic layer was analyzed by gas chromatography. As a result, 2-(2-cyclopropyl-2-oxoethyl)-5-methyl-1,3-dioxane (9.92 g) was contained (yield 72%). This organic layer was concentrated and the residue was distilled at 50 Pa to give 2-(2-cyclopropyl-2-oxo-ethyl)-5-methyl-1,3-dioxane (9.11 g) from a fraction at 91-92°C. trans-2-(2-cyclopropyl-2-oxo-ethyl)-5-methyl-1,3-dioxane1H-NMR(300MHz, CDCl3, TMS, ppm) δ:0.70(d,J=6.6Hz,3H), 0.86-0.92(m,2H), 1.04-1.09(m,2H), 1.95-2.00(m,1H), 2.86(d,J=4.4Hz,2H), 3.26(t,J=11.6Hz,2H), 4.03(dd,J=11.8Hz,4.7Hz,2H), 4.92(t,J=5.2Hz,1H) cis-2-(2-cyclopropyl-2-oxo-ethyl)-5-methyl-1,3-dioxane1H-NMR(300MHz, CDCl3, TMS, ppm) δ:0.86-0.92(m,2H), 1.04-1.09(m,2H), 1.28,(d,J=6.6Hz,3H), 2.00-2.15(m,1H), 2.86(d,J=4.4Hz,2H), 3.79(d,J=11.4Hz,1H), 3.96(d,J=11.4Hz,2H), 4.99(t,J=5.2Hz,1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 120℃; for 1h; | 14 This example illustrates a continuous transesterification process for producing the composition of this invention. The wiped film reactor consisted of a vertically positioned glass tube, 5.1 cm inside diameter and 38 cm length, fitted with a water-cooled internal condenser, 15 cm length. Three rotating teflon wiper blades, 20 cm in length, were positioned 10 cm below the top of the reactor and coupled to a variable speed control with forward and reverse rotation option. The wiper blades were held against the inner walls of the reactor by centrifugal action. The reactor temperature was controlled by means of two electrical heating jackets, wrapped around the outside walls of the reactor. Thermocouples for temperature measurement were placed in the space between the outer wall of the reactor and the heating mantle. The top of the reactor was connected to a dry ice condenser fitted with a collection flask, a pressure gauge and a vacuum pump. The reactor feed system consisted of two liquid metering piston pumps which co-fed S-[3-(Triethoxysilyl)propyl]thiooctanoate and sulfuric acid having 2-methyl-1,3-propanol respectively to an in-line static mixer (22 cm length, 0.64 cm inner diameter). The reactant mixture was discharged into the reactor through a port situated 2.5 cm above the wiper blades. During the run, ethanol vapor produced was condensed in the dry ice condenser and collected. Non-evaporated product mixture (bottom product) and vapor mixture condensed on the internal condenser were removed continuously out of the system at a rate equal to the feed rate. To conduct the run, the heating jacket was heated to 120° C., the reactor pressure was reduced to 11 mm Hg, and S-[3-(Triethoxysilyl)propyl]thiooctanoate (10.0 g/min, 27.4 mmol) and sulfuric acid having 2-methyl-1,3-propanol (2.7 g diol/min, 30.0 mmol diol, 0.003 g/min H2SO4) were continuously fed to the system. At the end of one hour, product mixture (719.5 g), vapor mixture (20.0 gr), and ethanol lights (60.2 gr) were collected and analyzed. Gas chromatography analysis of the product mixture showed 9.7% ethanol, 1.9% unreacted 2-methyl-1,3-propanediol, 9.6% unreacted S-[3-(triethoxysilyl)propyl]thiooctanoate, 46.54% 3-(1-Methyl-1,3-propanedioxyethoxysilyl)-1-propyl thiooctanoate monomer, with the remaining to 100% consisting of related oligomers and siloxanes of 3-(1-Methyl-1,3-propanedioxyethoxysilyl)-1-propyl thiooctanoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With toluene-4-sulfonic acid In benzene | I Preparation Of 2-Vinyl-5-methyl-1,3-dioxane EXAMPLE I Preparation Of 2-Vinyl-5-methyl-1,3-dioxane Acrolein (59.5 grams) and 2-methyl-1,3-propanediol (83.8 grams) were added to benzene (100 grams) and p-toluenesulfonic acid (0.0596 gram) in a 500 ml flask equipped with a Dean-Stark trap, condenser, heating mantle and magnetic stirrer. The mixture was heated at reflux for four hours with continuous removal of the water of reaction. The reaction mixture was cooled, neutralized with calcium oxide, filtered, and distilled to yield 66 grams of 2-vinyl-5-methyl-1,3-dioxane (65 percent yield). When acrolein is condensed with 1,3-butanediol, the product obtained is 2-vinyl-4-methyl-1,3-dioxane (99 percent yield). |
65% | With toluene-4-sulfonic acid In benzene | I Preparation Of 2-Vinyl-5-methyl-1,3-dioxane In Accordance With Step (1) Of The Invention Process EXAMPLE I Preparation Of 2-Vinyl-5-methyl-1,3-dioxane In Accordance With Step (1) Of The Invention Process Acrolein (59.5 grams) and 2-methyl-1,3-propanediol (83.8 grams) were added to benzene (100 grams) and p-toluenesulfonic acid (0.0596 gram) in a 500 ml flask equipped with a Dean-Stark trap, condenser, heating mantle and magnetic stirrer. The mixture was heated at reflux for 4 hours with continuous removal of the water of reaction. The reaction mixture was cooled, neutralized with calcium oxide, filtered, and distilled to yield 66 grams of 2-vinyl-5-methyl-1,3-dioxane (65 percent yield). |
65% | With toluene-4-sulfonic acid In benzene | I Preparation Of 2-Vinyl-5-methyl-1,3-dioxane EXAMPLE I Preparation Of 2-Vinyl-5-methyl-1,3-dioxane Acrolein (59.5 grams) and 2-methyl-1,3-propanediol (83.8 grams) were added to benzene (100 grams) and p-toluenesulfonic acid (0.0596 gram) in a 500 ml flask equipped with a Dean-Stark trap, condenser, heating mantle and magnetic stirrer. The mixture was heated at reflux for four hours with continuous removal of the water of reaction. The reaction mixture was cooled, neutralized with calcium oxide, filtered, and distilled to yield 66 grams of 2-vinyl-5-methyl-1,3-dioxane (65 percent yield). When acrolein is condensed with 1,3-butanediol, the product obtained is 2-vinyl-4-methyl-1,3-dioxane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; acetic acid In methanol; acetic acid methyl ester; water | 1 EXAMPLE 1 EXAMPLE 1 A mixture of 2000 g of commercial 2-methylenepropane-1,3-diol diacetate of the following composition (analytical values): 94.9% by weight of 2-methylenepropane-1,3-diol diacetate, 1.5% by weight of acetic acid, 1.7% by weight of water, 0.2% by weight of methallylacetate, 0.5% by weight of acetoxyacetone, 0.4% by weight of 2-methylenepropane-1,3-diol acetate, and 0.8% by weight of unknown higher boiling substances, 4000 g of methanol and 80 g of sodium hydroxide are slowly heated under reflux in a 10 l three-necked flask equipped with stirrer, internal thermometer and fractionating attachment consisting of a 30 cm packed column and a dephlegmator at the head of the column. 2200 ml of an azeotropic mixture of methyl acetate and methanol boiling at 54° C. are continuously removed from the head of the column and the temperature at the head of the column is then allowed to rise to the boiling point of pure methanol. When a total of 3000 ml of distillate has been removed, the blackish brown distillation sump product is introduced into a hydrogenation autoclave, about 30 g of Raney nickel moistened with methanol are added and the substance is hydrogenated at 20° C. with cooling under a steady stream of hydrogen at 10 excess atmospheres until saturation is reached. After removal of the Raney nickel by filtration, the low boiling components are distilled off at normal pressure over a 30 cm packed column. The residue is then distilled off at 12 Torr. 905 g of colourless 2-methylpropane-1,3-diol are obtained, corresponding to 91% of the theoretical quantity; boiling point 110°-112° C./12 Torr; nD20 1.4445. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate In methanol | 3 EXAMPLE 3 EXAMPLE 3 1000 g of distilled 2-methylenepropane-1,3-diol diacetate (99.8%), 800 g of methanol and 7.5 g of sodium methylate are heated and the resulting methyl acetate is continuously distilled off at the head of a column as an azeotropic mixture with methanol. Finally, methanol is distilled off until the sump has been concentrated to 600 g. The sump product is then introduced into a hydrogenation autoclave, 100 g of Raney nickel moistened with methanol are added and hydrogen is forced in at a pressure of 15 excess atmospheres at 130° C. When the uptake of hydrogen is completed, the liquid hydrogenation product contains 70% by weight of 2-methylpropane-1,3-diol, which is isolated by distillation. 416 g (80% of the theoretical quantity) of 2-methylpropane-1,3-diol are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine at 20℃; for 3h; | ||
With triethylamine In dichloromethane at 0 - 20℃; for 16h; | 1 Preparation of 2-methylpropane-1,3-diyl dimethanesulfonate To a stirred solution of 2-methylpropane-l,3-diol (1 equiv.) in dichloromethane (0.45 M) was added methane sulfonyl chloride (2.8 equiv.), using triethylamine (2.8 equiv.) at 0 °C to room temperature for 16 h. Upon completion of reaction, the reaction mixture was washed with water and brine solution, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the crude intermediate. | |
With triethylamine In dichloromethane at 25℃; for 2h; | 180.1 Step 1 To a ice-cold solution of 2-methylpropane-l,3-diol (1 g, 11.10 mmol) and methanesulfonyl chloride (2.54 g, 22.19 mmol) in DCM (35 mL) was added triethylamine (1.460 g, 14.43 mmol) dropwise. The mixture was stirred for 2 h at 25 °C and concentrated. The residue was diluted with EtOAc (150 mL)/H20 (100 mL) and the organic phase was separated, dried over NaiSOr. and concetrated to afford the desired product 2-methylpropane- l,3-diyl dimethane sulfonate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 2-methyl-1.3-propanediol With pyridine In dichloromethane at 0℃; Inert atmosphere; Stage #2: p-toluenesulfonyl chloride In dichloromethane at 0℃; for 3h; Inert atmosphere; | |
67% | With triethylamine In dichloromethane at 20℃; for 4h; | a a) 3-hydroxy-2-methylpropyl 4-methylbenzenesulfonate a) 3-hydroxy-2-methylpropyl 4-methylbenzenesulfonate p-TsCI (1 .00 g, 5.25 mmol) was added to a solution of 2-methylpropane-1 ,3-diol (2.30 mL, 26.23 mmol) and TEA (1 .50 mL, 10.50 mmol) in DCM (20 mL) and stirred at room temperature. After 4 h, the reaction mixture was diluted with DCM (40 mL) and washed with water (30 mL). The organic layer was dried over anhydrousNa2S04 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (15>50% EtAcO/hexanes), affording 0.86 g of 3- hydroxy-2-methylpropyl 4-methylbenzenesulfonate [Rf= 0.40 (40% EtAcO/hexanes), colorless oil, 67% yield].LC-MS ESI+ m/z: 245 (M+1 , 99%) (method 5). |
65% | With triethylamine In dichloromethane at 5℃; | 10.1 Step 1 Synthesis of compound 19a 2-methyl-1,3-propanediol (2.0 g, 22.2 mmol) was dissolved in dichloromethane (30 ml), triethylamine (3.37 g, 33.3 mmol) was added under ice bath, and p-toluenesulfonyl chloride (TsCl, 4.23 g, 22.2 mmol) was added in batches while maintaining the temperature no higher than 5°C. After the addition, the reaction was stirred and reacted at the low temperature for 2-3 hours. TLC was used to monitor the completion of the reaction. After completion, 20 ml water was added, and the organic phase was separated, washed with saturated brine, concentrated and then purified by column chromatography to afford 3.52 g of compound 19a as colorless oily liquid. Yield: 65%. LC-MS(APCI): m/z=245.6(M+1)+. |
64% | Stage #1: 2-methyl-1.3-propanediol With pyridine In dichloromethane at 0℃; for 0.0833333h; Stage #2: p-toluenesulfonyl chloride at 20℃; Inert atmosphere; | |
31% | With pyridine In chloroform at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With Ir(CH2CHCH2)((C6H5)2PC10H6)2(OCOC6H2NO2CN); 2-nitro-4-carboxybenzonitrile; potassium carbonate In 1,4-dioxane at 90℃; for 144h; Inert atmosphere; Sealed tube; | |
51% | Stage #1: Allyl acetate With (S)-(-)-5,5'-dichloro-6,6'-dimethoxy-2,2'-bis(diphenylphosphino)-1,1'-biphenyl; bis(1,5-cyclooctadiene)diiridium(I) dichloride; caesium carbonate; 4-chloro-3-nitrobenzoate In 1,4-dioxane at 90℃; for 0.5h; Inert atmosphere; Stage #2: 2-methyl-1.3-propanediol In 1,4-dioxane at 90℃; for 72h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: 2-methyl-1.3-propanediol; 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine With sodium hydroxide In 1,2-dimethoxyethane; water; toluene at 70℃; for 17h; Stage #2: With hydrogenchloride In 1,2-dimethoxyethane; water; toluene at 20℃; | 82A 3-[5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-2-methylpropan-1-ol Add 4.8 ml of 12.5 N sodium hydroxide solution to a solution of 2.68 g (29.7 mmol) 2-methylpropane-1,3-diol in 45 ml toluene, 15 ml 1,2-dimethoxyethane and 15 ml water at 70° C. After adding 202 mg (0.59 mmol) tetra-n-butylammonium hydrogensulphate and 2.0 g (5.94 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, stir the reaction mixture for 17 h at 70° C. After cooling to room temperature, adjust to pH 7 with concentrated hydrochloric acid. Extract three times with 50 ml dichloromethane each time. Wash the combined organic extracts with satd. sodium chloride solution, dry over sodium sulphate, filter and concentrate by vacuum evaporation. Mix the raw product with methanol, filter, and purify the filtrate by preparative RP-HPLC (gradient: water/acetonitrile). 1.26 g (54% of theor.) of the desired product (racemate) is obtained. LC-MS (Method 8): Rt=2.73 min; m/z=391 (M+H)+ 1H-NMR (400 MHz, CDCl3): δ=8.58 (s, 1H), 7.55 (d, 2H), 7.48-7.35 (m, 5H), 7.00 (d, 2H), 4.48 (t, OH), 4.34 (dd, 1H), 4.24 (dd, 1H), 3.81 (s, 3H), 3.23-3.14 (m, 2H), 1.86-1.78 (m, 1H), 0.72 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Adipic acid; 1,1,1-tri(hydroxymethyl)propane; 2-methyl-1.3-propanediol; isophthalic acid at 150 - 225℃; for 7h; Stage #2: at 175 - 200℃; for 5h; | 1 A 2-liter, 4-neck, round-bottom flask was fitted with a mechanical stirrer, thermocouple, nitrogen inlet, steam-jacketed, Rashig ring packed Allyn condenser with take-off head and Fredrichs condenser and an addition funnel. The thermocouple was connected to a controller controlling a variable voltage transformer and heating mantle. Provision was also provided to apply vacuum to the system. The flask was charged with 465.8 g (3.188 mol) of adipic acid, 257.4 g (1.550 mol) isophthalic acid, 495.0 g (5.494 mol) of 2-methyl-1,3-propandiol and 87.6 g (0.653 mol) of trimethylol propane and stirred and heated to 150° C. under a slow flow of N2. Water began to form and steam was applied to the column jacket to facilitate removal. As water was collected, the temperature was increased in steps to 225° C. After about 7 hr the water distillation had slowed and 160 ml had collected. The reaction was cooled to 175° C. and 1.1 ml of Tyzor TBT catalyst (from DuPont Co.) was added. The pressure was reduced to 66.5 kPa (500 torr) and the temperature was maintained at 200° C. for an additional 5 hr until titration indicated an acid number less than 3.0. The reaction temperature was adjusted to 100° C. and an additional 1.1 ml Tyzor TBT catalyst was added and stirred about 30 minutes. Ethyl acetoacetate (476.0 g, 3.659) was added to the reaction mixture at about 8 ml/min under a slow flow of nitrogen and at 79.8 kPa (600 torr) pressure. When the addition was complete (60 min) the temperature was increased to 130° C. and the pressure reduced to 66.5 kPa (500 torr) with steam on the column jacket to facilitate removal of the ethanol byproduct. The temperature was increased to 135° C. and then 140° C. over the next 2 hours and then held at that temperature for 7 hours. On the basis of ethanol recovered, the transesterification conversion was 77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; | IX-1 Example (IX-1) At 0° C., 76.5 g (355 mmol) of diisopropyl azodicarboxylate (dissolved in 50 ml of tetrahydrofuran) were added dropwise to a solution of 14.5 g (161 mmol) of 2-methyl-1,3-propanediol (VIII-1), 52.6 g (323 mmol) of N-hydroxyphthalimide (VII) and 93.2 g (355 mmol) of triphenylphosphane in 500 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 16 h and then freed from the solvent under reduced pressure. The residue was taken up in 250 ml of MeOH/H2O (5:1) and the precipitated solid was filtered off. The solid was again taken up in 240 ml of MeOH/H2O (5:1), filtered again, washed with 60 ml of MeOH/H2O (5:1) and air-dried. This gave 2,2'-[(2-methylpropane-1,3-diyl)bis(oxy)]bis(1H-isoindole-1,3(2H)-dione) in a yield of 55.6 g (146 mmol, 90% of theory) of logP (HCO2H)=2.87. The stated logP values were determined in accordance with EEC Directive 79/831 Annex V.A8 by HPLC (high performance liquid chromatography) on a reversed-phase column (C 18). Temperature: 43° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With air; potassium iodide; palladium(II) iodide In ISOPROPYLAMIDE at 100℃; for 24h; Autoclave; | |
68% | With oxygen; potassium iodide; palladium(II) iodide In N,N-dimethyl acetamide at 100℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.2% | With thionyl chloride at 80 - 130℃; for 7h; Inert atmosphere; Schlenk technique; | |
76% | With pyridine; p-toluenesulfonyl chloride at 100 - 110℃; | |
With thionyl chloride; N,N-dimethyl-formamide at 80℃; for 24h; | 2.1 Example 2 1 Add 90.12 g of 2-methyl 1.3-propanediol (1.0 mol 1.0 eq) to the reaction flask.475.9 g of thionyl chloride (4 mol 4.0 eq), the amount of catalyst N, N-dimethylformamide, after the addition, the temperature was raised to 80 degrees for 24 hours;The thionyl chloride is concentrated and concentrated under reduced pressure; the residue is washed once with 100 ml of a 5% aqueous sodium carbonate solution and washed with 60 ml of saturated sodium chloride.A crude 2-methyl 1.3-dichloropropane was obtained in an amount of 120 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In ethanol at 120℃; Inert atmosphere; | 1C A solution of diphosphine (16 mmol) and triethylphosphine (16 mmol) in dry degassed solvent (4 mL) is added under a stream of argon or nitrogen to [Rh(CO)2(acac)] (8 mmol) under an argon atmosphere. The resulting solution is transferred in a gastight syringe to a 25-mL autoclave under an argon atmosphere. The autoclave is flushed twice with a 1:1 CO/H2 mixture and then pressurized to 30 bar with the CO/H2 mixture. The autoclave is then heated to 120° C. with stirring, the pressure is increased to 39.5 bars, allyl alcohol (1 mL) is then injected from a sidearm, and the autoclave pressurized to 40 bar with the CO/H2 mixture. The autoclave is kept at a constant pressure of 40 bar, and the gas uptake of the reaction is monitored in a ballast vessel from which the gas is delivered. When there is no further gas uptake, the autoclave is cooled and depressurized. The resulting solution is analyzed by gas chromatography to determine the products of the reaction. The reaction produces BDO, MPDiol, HBA, HMPA, and C3 products (n-propanol and propionaldehyde). The BDO-MPDiol selectivity (i.e., moles BDO+MPDiol produced/moles allyl alcohol converted*100%) and the ratio of BDO:MPDiol (l:b or linear:branched) is also measured.The results, shown in Table 1, demonstrate that the use of an alcohol solvent results in much higher BDO-MPDiol selectivity and the use of a diphosphine and trialkylphosphine unexpectedly results in significantly higher BDO:MPDiol (l:b) ratio than just using a trialkylphosphine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In isopropyl alcohol at 90℃; Inert atmosphere; Autoclave; | 3 Allyl alcohol is hydroformylated using phosphines 1A-1D and 2A-2D according to the following procedure:A solution of phosphine (0.12 mmol) in dry degassed isopropanol solvent (4 mL) is added under a stream of argon or nitrogen to [Rh(CO)2(acac)] (0.04 mmol) under an argon atmosphere. The resulting solution is transferred in a gastight syringe to a 25-mL autoclave under an argon atmosphere. The autoclave is flushed twice with a 1:1 CO/H2 mixture and then pressurized to 30 bar with the CO/H2 mixture. The autoclave is then heated to 90° C. with stirring, the pressure is increased to 39 bars, allyl alcohol (1 mL) is then injected from a sidearm, and the autoclave pressurized to 40 bar with the CO/H2 mixture. The autoclave is kept at a constant pressure of 40 bar, and the gas uptake of the reaction is monitored in a ballast vessel from which the gas is delivered. When there is no further gas uptake, the autoclave is cooled and depressurized. The resulting solution is analyzed by gas chromatography to determine the products of the reaction.The reaction produces HBA, HMPA, and C3 products (n-propanol and propionaldehyde). Some of the reactions produce BDO and MPD, as well, showing that some reactions undergo hydrogenation under the present conditions in addition to the hydroformylation. In some cases when BDO if formed 1-butanol is also formed via BDO dehydration. In these cases 1-butanol is also defined as a linear alcohol product.The aldehyde selectivity (i.e., moles HBA+HMPA produced/moles allyl alcohol converted*100%) and the aldehyde L:B ratio (linear:branched; HBA:HMPA) is measured. For those reactions that also produce BDO, 1-butanol and MPD, the alcohol selectivity (i.e., moles BDO+1-butanol+MPD produced/moles allyl alcohol converted*100%) and the ratio of alcohol L:B (linear:branched) is also measured. The total selectivity (HBA, HMPA, BDO, 1-butanol, MPD) demonstrates the is effectiveness of the catalyst systems at hydroformylation. The results are shown in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With pyridine In dichloromethane at 0 - 20℃; for 12h; | 4.5. (3E,5E)-2,5-Dimethylhepta-3,5-dien-1-ol (16) To a solution of 2-methyl-1,3-propanediol (1.350 g, 15.0 mmol) in dry CH2Cl2 (100 mL) cooled in an ice-water bath (ca. 0 °C) was added pyridine (2.42 mL, 20 mmol) and p-toluenesulfonyl chloride (3.15 g, 16.5 mmol) followed by stirring at room temperature for overnight (12 h). The reaction was quenched with saturated aqueous NH4Cl, and the resultant mixture was extracted with EtOAc (100 mL×3). The combined organic layer was washed with 10% aqueous HCl, saturated aqueous NaHCO3, and brine, and dried over anhydrous Na2SO4. The solid was filtered off and filtrate was condensed under reduced pressure. The residue was purified by flash column chromatography (silica gel, eluted with gradient from 20% EtOAc in PE to 100% EtOAc) to give, along with the bis-tosylate, the mono-tosylate (2.500 g, 68%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=7.6 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.02 (d, J=5.6 Hz, 2H), 3.60-3.49 (m, 2H), 2.45 (s, 3H), 2.04-1.96 (m, 1H), 0.92 (d, J=6.8 Hz, 3H) (OH signal is not identified). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; In dichloromethane; at 0 - 20℃; for 48.0h; | Methyl 3-[4-(3-hydroxy-2-methylpropoxy)phenyl]hex-4-ynoate 500 mg of <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong>, 1.01 ml of 2-methyl-1,3-propanediol and 1.20 g of resin-bound triphenylphosphine were initially charged in a 100 ml round-bottom flask in 30 ml of dichloromethane under argon and cooled to 0 C. At this temperature, 0.91 ml of diisopropyl azodicarboxylate, dissolved in 10 ml of dichloromethane, was slowly added dropwise. The ice cooling was removed and the mixture was stirred at room temperature for two days. The reaction mixture was filtered off from the resin and washed three times with 50 ml each time of dichloromethane. The filtrate was washed with 30 ml of 1N HCl, dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by means of RP-HPLC to obtain 486 mg of methyl 3-[4-(3-hydroxy-2-methylpropoxy)phenyl]hex-4-ynoate. C17H22O4 (290.36), LCMS (ESI-pos): 291.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 2-methyl-1.3-propanediol With n-butyllithium In tetrahydrofuran; hexane at 20℃; for 2h; Inert atmosphere; Stage #2: Chlorodiisopropylphosphane In tetrahydrofuran; hexane at 0℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; | General procedure: Appropriate diol (1 equiv), 1-bromomethyl pyrene (2.2 equiv), and 3 ml ([diol]=50 mM) anhydrous DMF were placed in a round-bottomed flask under N2. NaH (3.0 equiv) was added to the solution at room temperature. The reaction mixture was stirred for 1 h at this constant temperature. Following completion, the reaction was quenched with H2O. The solution was diluted with water, and extracted using DCM. The organic layer was filtered through Na2SO4 and evaporated to dryness. The resulting residue was purified over silica gel (1:5, EtOAc/Hexane) to yield the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With toluene-4-sulfonic acid In Petroleum ether at 0 - 20℃; for 3h; | 31 Synthesis of Compound 31.2. Synthesis of 2-(1-((R)-2-(S)-3-hydroxy-2-methylpropoxy)-2-phenylethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid (I-171) Synthesis of Compound 31.2. Into a 50-mL 3-necked round-bottom flask was placed 2-methylpropane-1,3-diol (20 g, 221.92 mmol, 1.00 equiv) and 4-methylbenzene-1-sulfonic acid (11 mg, 0.06 mmol). Then 3,4-dihydro-2H-pyran (5 g, 59.44 mmol, 0.27 equiv) was added at 0° C. The resulting solution was stirred for 3 h at room temperature. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). Purification afforded 6.9 g (18%) of 2-methyl-3-(oxan-2-yloxy)propan-1-ol as a light yellow liquid. Synthesis of Compound 31.3. Compound 31.3 was prepared from 31.2 in a manner analogous to the synthesis of compound 14.2. Isolated a colorless oil in 5% yield. Synthesis of Compound 31.7. Compound 31.7 was prepared in a manner analogous to compound 30.6. Isolated a colorless oil in 30% overall yield from 31.3 and 1.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With di-isopropyl azodicarboxylate; triphenylphosphine at 0 - 20℃; for 3h; | 156 Methyl 2-(4-methyl-1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetate To methyl 2-(N-(2,4,6-trichlorophenyl)sulfamoylamino)acetate (3.0 g, 8.3 mmol), 2-methylpropan-1,3-diol (1.18 mL, 8.3 mmol) and PPh3 (5.4 g, 20.7 mmol), was dropwisely added DIAD (4 mL, 20.7 mmol) with adjustment of external temperature to 0° C. The reaction mixture was agitated for 3 hr at room temperature, extracted with EtOAc, dried (Na2SO4), filtered and concentrated under reduced pressure, followed by column chromatography (MeOH/DCM 1%), finally giving the title compound (2.3 g, y=65%, solid). 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J=2.4 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 4.44 (d, J=17 Hz, 1H), 4.37-3.86 (m, 5H), 3.59-3.41 (m, 1H), 3.38-3.13 (m, 1H), 2.75-2.53 (m, 1H), 1.32 (t, J=7.1 Hz, 3H), 0.94 (t, J=7.1 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at -20 - 20℃; for 5h; Inert atmosphere; | 183 Ethyl 2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetate Ethyl 2-((N-(2,6-dichloro-4-(trifluoromethyl)phenyl)sulfamoyl)amino)acetate (300 mg, 0.76 mmol), 2-methylpropane-1,3-diol (75 mg, 0.76 mmol) and triphenylphosphine (498 mg, 1.90 mmol) were dissolved in anhydrous THF (30 mL), and then cooled down -20° C. after removal of air in the reactor by purging nitrogen gas. DIAD (384 mg, 1.90 mmol) was dropwisely added to the reaction mixture and agitated for 5 hr at room temperature. The resultant was concentrated under reduced pressure and purified by column chromatography (dichloromethane:hexane:ethyl acetate=5:4:1), finally yielding the title compound (225 mg, 66%, light yellow solid). 1H NMR (300 MHz, CDCl3): δ7.65 (s, 1H), 7.63 (s, 1H), 4.44-4.38 (m, 1H), 4.30-4.17 (m, 2H), 4.11-4.03 (m, 1H), 3.98-3.87 (m, 2H), 3.53-3.44 (m, 1H), 3.24-3.17 (m, 1H), 2.59 (m, 1H), 1.31 (t, 3H, J=7.1 Hz), 0.94 (d, 3H, J=6.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at -20 - 20℃; for 5h; Inert atmosphere; | 183 Methyl 6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,2,6-thia-diazinan-2-carboxylate 1,1-dioxide Methyl N-(2,6-dichloro-4-(trifluoromethyl)phenyl)sulfamoylcarbamate (6.00 g, 16.34 mmol), 2-methylpropane-1,3-diol (2.21 g, 24.51 mmol) and triphenylphosphine (10.71 g, 40.85 mmol) were dissolved in anhydrous THF (100 mL) in a reactor, and then cooled down -20° C. after removal of air in the reactor by purging nitrogen gas. DIAD (8.2 g, 40.8 mmol) was dropwisely added to the reaction mixture and agitated for 5 hr at room temperature. The resultant was concentrated under reduced pressure and purified by column chromatography (dichloromethane:hexane:ethyl acetate=5:4:1), finally yielding the title compound (3.9 g, 70%, white solid). 1H NMR (300 MHz, CDCl3): δ7.66 (s, 2H), 4.45-4.39 (m, 1H), 3.88 (s, 3H), 3.84-3.75 (m, 2H), 3.54-3.37 (m, 1H), 2.72-2.69 (m, 1H), 1.02 (d, 3H, J=6.7 Hz). |
70% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 5h; Inert atmosphere; | Methyl6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,2,6-thiadiazinane-2-carboxylate1,1-dioxide (3e) MethylN-(2,6-dichloro-4-(trifluoromethyl)phenyl)sulfamoylcarbamate 2e (6.00 g, 16.34 mmol), 2-methylpropane-1,3-diol (2.21 g, 24.51 mmol) andtriphenylphosphine (10.71 g, 40.85 mmol) were dissolved in anhydrous THF (100mL) in a reactor, and then cooled down to -20 °C. After removal of air bypurging nitrogen gas, DIAD (8.2 g, 40.8 mmol) was added dropwise to thereaction mixture and stirred for 5 h at room temperature. The reaction mixturewas concentrated under reduced pressure and purified by column chromatography(dichloromethane: hexane: ethyl acetate=5: 4:1) to give methyl6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,2,6-thiadiazinane-2-carboxylate1,1-dioxide 3e (3.9 g, 70%) as awhite solid. 1H-NMR (400 MHz, DMSO-d6): δ 8.12 (s, 2H), 4.31- 4.20 (m,1H) 3.77 (s, 3H), 3.76-3.62 (m, 3H), 2.60-2.45(m, 1H), 0.94 (d, J = 6.4 Hz, 3H). HPLC Purity 98.54%. LC/MS MH+ 421.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27 g | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 20℃; for 2h; Inert atmosphere; Cooling with ice; | 1.2 Under nitrogen atmosphere, a compound of formula (23-1) 20.0 g, a compound of formula (24-1) 30.3 g and triphenylphosphine 69.9 g were dissolved in a mixedsolution of toluene 450 ml and tetrahydrofuran 50 ml. Thereto was then added under ice-cooling diethyl azodicarboxylate 121 ml drop wise. The resulting reaction solution was raised to RT and stirred for about 2 hours. The resulting reaction mixed solution was concentratedunder reduced pressure and purified by column chromatography (Si02) by eluting with EtOAc: hexane (1:3-+1: 1) toafford a compound of formula (22-1) 27.0 g.‘H NMR (CDC13)ppm: 6.86-6.80 (4H, m), 3.90 (2H, ddd), 3.70 (3H, s),3.69 (2H, d), 2.18 (1H, tdd), 2.05 (1H, s), 1.02 (3H, t) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 2-Cyanopyridine; cerium(IV) oxide at 159.84℃; for 1h; Autoclave; | |
58% | With 2-Cyanopyridine; cerium(IV) oxide at 160℃; for 1h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.9 g | Stage #1: vinyl acetate; 2-methyl-1.3-propanediol In chloroform at 20℃; for 20h; Stage #2: tert-butylchlorodiphenylsilane With 1H-imidazole In tetrahydrofuran at 20℃; for 21h; Stage #3: With sodium methylate In methanol at 0 - 20℃; for 24h; | 1 Vinyl acetate (286 mL, 3.11 mol) and lipase- AK "Amano" (17.1 g) were added to a solution of 2-methyl-l,3-propanediol (70 g, 777 mmol) in chloroform (1.5 L). The resulting mixture was stirred at rt for 20 h. The lipase was removed by filtration and washed with ethyl acetate. Then the filtrate was concentrated to provide a mixture of (5,)-3-hydroxy- 2-methylpropyl acetate (>99 ee) and l,3-diacetoxy-2-methylpropane. The mixture was used in the next reaction step without separation. ie/t-Butyldiphenylsilylchloride (79 mL, 303 mmol) was added dropwise to a mixture of (lS')-3-hydroxy-2-methylpropyl acetate and 1,3- diacetoxy-2-methylpropane (140 g, crude) and imidazole (41.3 g) in THF (620 mL). The resulting mixture was stirred at rt for 21 h. The reaction mixture was diluted with diethyl ether (1 L) and washed water (2 x 1 L) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. A 25% solution of sodium methoxide in methanol (61 mL) was added to a solution of a mixture of (R)-3-iert-butyldiphenylsiloxy-2- methylpropyl acetate and l,3-diacetoxy-2-methylpropane (194 mg, crude) in methanol (1 L) at 0 °C. The resulting mixture was stirred at rt for 24 h. The reaction mixture was diluted with diethyl ether (1 L) and w-pentane (1 L), washed with saturated ammonium chloride aqueous solution (1 L), water (2 x 1 L) and brine (1 L). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was passed through a column of silica (w-hexane/diethyl ether, 40: 1 ~ 20: 1 ~ 4: 1) to provide (R)-3-/ert-butyldiphenylsiloxy-2- methylpropan- l-ol (60.9 g) as a colorless oil. 1H NMR (CDC13, 400 MHz) δ = 7.69-7.67 (m, 4H, CH of Ph), 7.46-7.38 (m, 6H, CH of Ph), 3.75-3.57 (m, 4H, CH2OTBDPS, CH2OH), 2.03-1.96 (m, 1H, CH2CH(CH3)CH2), 1.06 (s, 9H, (CH3)3), 0.83 (d, 3H, J = 10.8 Hz, CH2CH(CH3)CH2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.93 mg | With dipotassium peroxodisulfate; silver nitrate; trifluoroacetic acid In water at 80℃; for 0.5h; | 0785-1 Example 0785 0785-1 Potassium peroxodisulfate (6.72 g) was added to a mixture of 3,6-dichloropyridazine (2 g), trifluoroacetic acid (1.22 mL), 2-methylpropane-1,3-diol (2.65 g), silver nitrate (3.07 mg), and water (14 mL) at 80° C., followed by stirring at the same temperature for 30 minutes. After the reaction mixture was cooled on ice, sodium carbonate (10 g) and sodium chloride (1 g) were added thereto, followed by stirring at room temperature for 30 minutes. Insolubles were filtered off, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 2-(3,6-dichloropyridazin-4-yl)propan-1-ol (1.93 g). MS m/z (M+H): 207. |
With ammonium peroxydisulfate; silver nitrate; trifluoroacetic acid In water at 50℃; for 0.5h; | 34 2-(3,6-dichloropyridazin-4-yl)propan-1-ol (35a) To H2O (25 mL) was added TFA (4.97 g, 43.63 mmol, 3.23 mL) at 50° C., then 2-methylpropane-1,3-diol (6.65 g, 73.8 mmol, 6.59 mL) was added in the mixture, followed by addition of 3,6-dichloropyridazine (5 g, 33.6 mmol) and AgNO3 (7.70 g, 45.3 mmol). Then a solution of ammonia hydrogen thiosulfate (15.3 g, 67.1 mmol, 14.6 mL) in H2O (15 mL) was added in the mixture in portions at 50° C., and the resulting mixture was stirred at 50° C. for 0.5 hours. The reaction mixture was partitioned between H2O (45 mL) and EtOAc (50 mL). The organic phase was separated, washed with H2O (50 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate) to give 35a. MS mass calculated for [M+1]+ (C7H8Cl2N2O) requires m/z 207.0, LCMS found m/z 207.0; 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 3.93-3.84 (m, 2H), 3.45-3.30 (m, 1H), 1.35 (d, J=7.2 Hz, 3H). | |
With ammonium peroxydisulfate; silver nitrate; trifluoroacetic acid In water at 80℃; for 0.5h; | S29 2-(3,6-dichloropyridazin-4-yl)propan-1-ol (29b) To a mixture of 3,6-dichloropyridazine (2 g, 13.42 mmol) and 2-methylpropane-1,3-diol (2.65 g, 29.40 mmol, 2.62 mL) in H2O (10 mL) was added TFA (1.88 g, 16.48 mmol, 1.22 mL) and AgNO3 (3.07 g, 18.07 mmol) at 80° C. Then (NH4)2S2O8 (6.72 g, 10.93 mmol) was added in the mixture by one portion at 80° C. The mixture was stirred at 80° C. for 30 minutes. TLC showed the starting material was consumed completely. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (5 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate) to give 29b. 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 3.84-3.91 (m, 2H), 3.33-3.42 (m, 1H), 1.35 (d, J=7.0 Hz, 3H). |
3.4 g | With ammonium hydrogen thiosulfate; silver nitrate; trifluoroacetic acid at 50℃; for 0.5h; | 2-(3,6-dichloropyridazin-4-yl)propan-1-ol (18a) To a mixture of water (25 mL) and TFA (3.2 mL) at 50 °C was added 2-methylpropane-1,3 diol (6.65 g, 73.8 mmol), 3,6-dichloropyridazine (5 g, 33.6 mmol) and silvernitrate (7.7 g, 45.3 mmol). A solution of ammonium hydrogen thiosulfate (15.3 g, 67.1 mmol) in water (15 mL) was added in portions at 50 °C. After addition was complete, the reaction was stirred at 50 °C for 30 minutes, cooled to room temperature and partitioned between water (45 mL) and ethyl acetate (50 mL). The organic phase was washed with water (3 x 50 mL) and dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (petroleum ether / ethyl acetate) to yield the 2-(3,6-dichloropyridazin-4-yl)propan-1-ol (3.4 g, 16.4 mmol). MS mass calculated for [M+1] (C7H8Cl2N2O) requires m/z 207.0, LCMS found m/z 207.0. 1H NMR (400 MHz, CDCl3) d 7.52 (s, 1H), 3.93-3.84 (m, 2H), 3.45-3.30 (m, 1H) 1.35 (d, J = 7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.7 mg | Stage #1: 2-methyl-1.3-propanediol With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 20℃; for 0.5h; Stage #2: ethyl 2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate In tetrahydrofuran; toluene at 20℃; for 3h; | 29.3 (3) A solution was prepared by dissolving 13.5mg of 2-methypropan-1,3-diol in 1 mL of tetrahydrofuran and adding 39.3 mg of triphenylphosphine and 65 µL of a 40% toluene solution of diethyl azodicarboxylate to the mixture. After stirring the resultant solution at room temperature for 30 minutes, a reaction mixture solution prepared by adding 33.1 mg of ethyl 2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate to the solution was stirred at room temperature for 3 hours. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduced pressure, followed by purifying by a conventional method to obtain 67.7 mg of ethyl 2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate. ESI/MS m/e: 404.1 (M++H, C18H22N5O4S) |
67.7 mg | Stage #1: 2-methyl-1.3-propanediol With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 20℃; for 0.5h; Stage #2: ethyl 2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate In tetrahydrofuran; toluene at 20℃; for 3h; | 29.3 Example 29 Synthesis of 2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid (Compound No. 29) (Synthesis Method (C)) A solution was prepared by dissolving 13.5 mg of 2-methypropan-1,3-diol in 1 mL of tetrahydrofuran and adding 39.3 mg of triphenylphosphine and 65 μL of a 40% toluene solution of diethyl azodicarboxylate to the mixture. After stirring the resultant solution at room temperature for 30 minutes, a reaction mixture solution prepared by adding 33.1 mg of ethyl 2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate to the solution was stirred at room temperature for 3 hours. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduced pressure, followed by purifying by a conventional method to obtain 67.7 mg of ethyl 2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate. ESI/MS m/e: 404.1 (M++H, C18H22N5O4S) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.3% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 55℃; for 18h; | To a stirred solution of <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (2.270 g, 11.88 mmol), 2-methylpropane-1,3-diol (1.071 g, 11.88 mmol) and triphenylphosphane (3.428 g, 3.028 mL, 13.07 mmol) in tetrahydrofuran (71.82 mL) at 0 C. was added diisopropyl azodicarboxylate (2.643 g, 2.532 mL, 13.07 mmol). The ice bath was removed and the reaction was stirred at 55 C. for 18 h. The reaction was diluted with ethylacetate and washed twice with sodium bicarbonate and twice with brine. The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified on 220 g of silica gel utilizing a gradient of 0 to 15% ethyl acetate in dichloromethane to yield 3-(3-bromo-5-fluoro-phenoxy)-2-methyl-propan-1-ol (1.73 g, 6.57 mmol, 55.3%) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) delta 7.09-7.03 (m, 1H), 7.03-6.98 (m, 1H), 6.87 (dt, J=11.2, 2.3 Hz, 1H), 4.57 (t, J=5.3 Hz, 1H), 3.97 (dd, J=9.5, 5.9 Hz, 1H), 3.85 (dd, J=9.5, 6.3 Hz, 1H), 3.48-3.34 (m, 2H), 2.05-1.84 (m, 1H), 0.94 (d, J=6.8 Hz, 3H). ESI-MS m/z calc. 262.00046. found 265.0 (M+1)+; Retention time: 1.58 minutes (3 min run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: vinyl acetate; 2-methyl-1.3-propanediol With lipase-AK "Amano" In chloroform at 20℃; for 20h; Stage #2: (S)-3-hydroxy-2-methylpropyl acetate; tert-butylchlorodiphenylsilane With 1H-imidazole In tetrahydrofuran; chloroform at 20℃; for 21h; | 1E.1 (R)-3-tert-Butyldiphenylsiloxy-2-methylpropan-1-ol Vinyl acetate (286 mL, 3.11 mol) and lipase-AK“Amano” (17.1 g) were added to a solution of 2-methyl-1,3-propanediol (70 g, 777 mmol) in chloroform (1.5 L). The resulting mixture was stirred at rt for 20 h. The lipase was removed by filtration and washed with ethyl acetate. Then the filtrate was concentrated to provide a mixture of (S)-3-hydroxy-2- methylpropyl acetate (>99% ee) and 1,3-diacetoxy-2-methylpropane. The mixture was used in the next reaction step without separation. tert-Butyldiphenylsilylchloride (79 mL, 303 mmol) was added dropwise to a mixture of (S)-3-hydroxy-2-methylpropyl acetate and 1,3- diacetoxy-2-methylpropane (140 g, crude) and imidazole (41.3 g) in THF (620 mL). The resulting mixture was stirred at rt for 21 h. The reaction mixture was diluted with diethyl ether (1 L) and washed water (2 × 1 L) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. A 25% solution of sodium methoxide in methanol (61 mL) was added to a solution of a mixture of (R)-3-tert-butyldiphenylsiloxy-2- methylpropyl acetate and 1,3-diacetoxy-2-methylpropane (194 mg, crude) in methanol (1 L) at 0 C. The resulting mixture was stirred at rt for 24 h. The reaction mixture was diluted with diethyl ether (1 L) and n-pentane (1 L), washed with saturated ammonium chloride aqueous solution (1 L), water (2 × 1 L) and brine (1 L). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was passed through a column of silica (n-hexane/diethyl ether, 40:1 ~ 20:1 ~ 4:1) to provide (R)-3-tert-butyldiphenylsiloxy-2- methylpropan-1-ol (60.9 g) as a colorless oil.1H NMR (CDCl3, 400 MHz) δ = 7.69-7.67 (m, 4H, CH of Ph), 7.46-7.38 (m, 6H, CH of Ph), 3.75-3.57 (m, 4H, CH2OTBDPS, CH2OH), 2.03-1.96 (m, 1H, CH2CH(CH3)CH2), 1.06 (s, 9H, (CH3)3), 0.83 (d, 3H, J = 10.8 Hz, CH2CH(CH3)CH2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.7% | With camphor-10-sulfonic acid In water at 100℃; | 1 Example 1 Example 1 [0059] To a 2 liter 4-necked round bottom flask equipped with a dean-stark trap was added 250 g 2-methyl- 1,3 -propanediol (MPDO), 599.91 g Ethyl Levulinate (-1.5 eq.), and 0.5 mL of Camphorsulfonic Acid solution (40% in water). The flask was heated to 100 C and placed under vacuum, starting at 85 torr and gradually lowering to 20 torr over the course of the reaction in order to maintain a steady reflux. The lower aqueous phase in the dean- stark trap was periodically drained. After 4 hours water collection had ceased, and the reaction was quenched by addition of 10.00 g Na2HP04 and stirring for 18 hours while the reaction cooled. After filtration to remove the quenching agent, the reaction product was purified by fractional distillation to obtain 219.58 g of MPDO ketal of ethyl levulinate (product) (37.7% of theoretical), 99.44 purity (area % by GC-FID) and containing MPDO (0.49 area % by GC-FID). The product had the structure: [0060] To a 500 mL 3-necked round bottom flask equipped with a dean stark trap was added 30.09 g 2-methyl- 1,3 -propanediol and 215.65 g of the MPDO ketal of ethyl levulinate (~3 mole equivalents). The flask was heated to 110 C and a nitrogen sweep (0.4 scfh) was introduced into the flask to remove any residual water from the reagents. After 45 minutes the temperature was increased to 165 C and 0.05 mL of titanium tetra-isopropoxide transesterification catalyst was added, and the temperature further increased to 210 C. Distillate was periodically removed from the dean-stark trap over the course of the reaction. After 4 hours the flask was allowed to cool and stabilizers (0.28 g irganox 1010 and 0.28 g irgafos 168) were added. The product was purified by removal of low molecular weight impurities using a wiped film evaporator to obtain 139.36 g product having structure (la) (96.9% of theoretical) having purity of 96.46% (area % by GC-FID). |
37.7% | With camphor-10-sulfonic acid In water at 100℃; for 4h; Dean-Stark; | 11 To a 2 liter 4-necked round bottom flask equipped with a dean-stark trap was added 250 g 2-methyl-1,3-propanediol (MPDO), 599.91 g Ethyl Levulinate (1.5 eq.), and 0.5 mL of Camphorsulfonic Acid solution (40% in water). The flask was heated to 100 C and placed under vacuum, starting at 85 torr and gradually lowering to 20 torr over the course of the reaction in order to maintain a steady reflux. The lower aqueous phase in the dean-stark trap was periodically drained. After 4 hours water collection had ceased, and the reaction was quenched by addition of 10.00 g Na2HPO4 and stirring for 18 hours while the reaction cooled. After filtration to remove the quenching agent, the reaction product was purified by fractional distillation to obtain 219.58 g of MPDO ketal of ethyl levulinate (product) (37.7% of theoretical), 99.44 purity (area % by GC-FID) and containing MPDO (0.49 area % by GC-FID). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.9% | With titanium(IV) isopropylate at 110 - 210℃; Inert atmosphere; | 1 Example 1 Example 1 [0059] To a 2 liter 4-necked round bottom flask equipped with a dean-stark trap was added 250 g 2-methyl- 1,3 -propanediol (MPDO), 599.91 g Ethyl Levulinate (-1.5 eq.), and 0.5 mL of Camphorsulfonic Acid solution (40% in water). The flask was heated to 100 C and placed under vacuum, starting at 85 torr and gradually lowering to 20 torr over the course of the reaction in order to maintain a steady reflux. The lower aqueous phase in the dean- stark trap was periodically drained. After 4 hours water collection had ceased, and the reaction was quenched by addition of 10.00 g Na2HP04 and stirring for 18 hours while the reaction cooled. After filtration to remove the quenching agent, the reaction product was purified by fractional distillation to obtain 219.58 g of MPDO ketal of ethyl levulinate (product) (37.7% of theoretical), 99.44 purity (area % by GC-FID) and containing MPDO (0.49 area % by GC-FID). The product had the structure: [0060] To a 500 mL 3-necked round bottom flask equipped with a dean stark trap was added 30.09 g 2-methyl- 1,3 -propanediol and 215.65 g of the MPDO ketal of ethyl levulinate (~3 mole equivalents). The flask was heated to 110 C and a nitrogen sweep (0.4 scfh) was introduced into the flask to remove any residual water from the reagents. After 45 minutes the temperature was increased to 165 C and 0.05 mL of titanium tetra-isopropoxide transesterification catalyst was added, and the temperature further increased to 210 C. Distillate was periodically removed from the dean-stark trap over the course of the reaction. After 4 hours the flask was allowed to cool and stabilizers (0.28 g irganox 1010 and 0.28 g irgafos 168) were added. The product was purified by removal of low molecular weight impurities using a wiped film evaporator to obtain 139.36 g product having structure (la) (96.9% of theoretical) having purity of 96.46% (area % by GC-FID). |
96.9% | Stage #1: 2-methyl-1.3-propanediol; MPDO ketal of ethyl levulinate at 110℃; for 0.75h; Dean-Stark; Inert atmosphere; Stage #2: With titanium(IV) isopropylate at 165 - 210℃; for 4h; Dean-Stark; Inert atmosphere; | 11 To a 500 mL 3-necked round bottom flask equipped with a dean stark trap was added 30.09 g 2-methyl-1,3-propanediol and 215.65 g of the MPDO ketal of ethyl levulinate (3 mole equivalents). The flask was heated to 110 C and a nitrogen sweep (0.4 scfh) was introduced into the flask to remove any residual water from the reagents. After 45 minutes the temperature was increased to 165 C and 0.05 mL of titanium tetra-isopropoxide transesterification catalyst was added, and the temperature further increased to 210 C. Distillate was periodically removed from the dean-stark trap over the course of the reaction. After 4 hours the flask was allowed to cool and stabilizers (0.28 g irganox 1010 and 0.28 g irgafos 168) were added. The product was purified by removal of low molecular weight impurities using a wiped film evaporator to obtain 139.36 g product having structure (Ic) (also referred to as “PZ3”) (96.9% of theoretical) having purity of 96.46% (area % by GC-FID). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With graphene In neat (no solvent) at 100℃; for 10h; Sealed tube; | For a representative procedure: General procedure: A mixture of diol 1 (1mmol), benzaldehyde dimethyl acetal (1.25mol) and graphene (6mg) were stirred for 10h at 100°C. The resulting mixture was filtered on a nylon membrane, washed with a minimum amount of acetone and the crude was carefully concentrated under vacuum giving the corresponding cyclic acetal in excellent purity (>90%) without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With graphene In neat (no solvent) at 100℃; for 10h; Sealed tube; | For a representative procedure: General procedure: A mixture of diol 1 (1mmol), benzaldehyde dimethyl acetal (1.25mol) and graphene (6mg) were stirred for 10h at 100°C. The resulting mixture was filtered on a nylon membrane, washed with a minimum amount of acetone and the crude was carefully concentrated under vacuum giving the corresponding cyclic acetal in excellent purity (>90%) without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.3 g | With hydrogenchloride In 1,4-dioxane; 1,2-dimethoxyethane; water at -10℃; for 4h; | 20 preparation of 3,3-(3-methylpropylenedioxy)-estra-5(10),9(11)-dien-17-one (I-4) The estrogen-4,9-diene-3,17-dione (50.0 g, 0.18 mol) was added to the reaction flask,Ethylene glycol diethyl ether (500 ml),2-methyl-1,3-propanediol (20.0 ml, 0.19 mol)1N hydrogen chloride in dioxane (5.0 ml)The reaction at -10 4 hours.The reaction was quenched by the addition of triethylamine (100 ml) and the solvent was removed by concentration.The residue was dissolved in ethyl acetate and addedWater extraction to impurities, delamination, the organic phase concentrated to dry. The residue was crystallized from isopropyl ether, filtered, and the solid was collected and driedTo the title compound (42.3 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.6% | With zinc diacetate In acetonitrile at 80℃; for 5h; Autoclave; | 3 Example 3 Into a 10 ml capacity autoclave were sequentially added several masses of 2-methyl-1,3-propanediol, acetonitrile,The catalyst zinc acetate, the mass ratio of catalyst to diol is 2:100,The mass ratio of acetonitrile to diol is 2:1.Then the reactor is closed andCarbon oxysulfide gas to a specified pressure,The molar ratio of carbon oxysulfide to diol was 1:1, and the reactor was placed in an oil bath at 80°C for 5 hours under autogenous pressure.After the reaction was completed, it was cooled to room temperature, and the air was vented. Samples were sampled and calculated by nuclear magnetic resonance spectrometry. The test results are shown in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra(n-butyl)ammonium hydroxide; sodium hydroxide In water at 85℃; for 48h; | 27 Synthesis Example 27:H - (CH 2) 6 --O - (CH 2) 6 --O - CH 2 --CH (CH 3) - CH 2 --O - (CH 2) 6 --O - (CH 2) 6 --H(Abbreviation: PrMe (O 6 - 6) 2) The compound obtained in Synthesis Example 7H - (CH 2) 6 --O - (CH 2) 6 --Cl (49.5 g)H - O - CH 2 --CH (CH 3) - CH 2 - O - H (5.7 g) in 50% aqueous sodium hydroxide solution (11.9 g)In the presence of TBAH (1.9 g), at 85 ° C.,By reacting for 48 hours,H - (CH 2) 6 --O - (CH 2) 6 --O - CH 2 --CH (CH 3) -CH 2 --O - (CH 2) 6 --O - (CH 2) 6 - H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra(n-butyl)ammonium hydroxide; sodium hydroxide In water at 85℃; for 48h; | 26 Synthesis Example 26:H - (CH 2) 8 --O - (CH 2) 4 --O - CH 2 --CH (CH 3) - CH 2 --O - (CH 2) 4 --O - (CH 2) 8 - H(Abbreviation: PrMe (O 4 - 8) 2) The compound obtained in Synthesis Example 8H - (CH 2) 8 --O - (CH 2) 4 --Cl (48.9 g)H - O - CH 2 --CH (CH 3) - CH 2 - O - H (6.0 g) in 50% aqueous sodium hydroxide solution (12.4 g)In the presence of TBAH (1.6 g), at 85 ° C.,By reacting for 48 hours,H - (CH 2) 8 --O - (CH 2) 4 --O - CH 2 --CH (CH 3) - CH 2 --O - (CH 2) 4 --O - (CH 2) 8 --H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra(n-butyl)ammonium hydroxide; sodium hydroxide In water at 90℃; for 48h; | 28 Synthesis Example 28:H - (CH 2) 6 --O - (CH 2) 2 --O - (CH 2) 4 --O - CH 2--CH (CH 3) - CH 2 --O - (CH 2) 4 --O - (CH 2) 2 --O - (CH 2) 6 - H(Abbreviation: PrMe (O 4 - 2 - 6) 2) Synthesis Example 15H - (CH 2) 6 --O - (CH 2) 2 --O - (CH 2) 4 --Cl(50 g)H - O - CH 2 --CH (CH 3) - CH 2 - O - H (5.2 g) were dissolved in 50% aqueous sodium hydroxide solution (14.9 g)In the presence of TBAH (4.2 g), at 90 ° C.,By reacting for 48 hours,H - (CH 2) 6 --O - (CH 2) 2 --O - (CH 2)4 - O - CH2 --CH (CH3) - CH2 --O--(CH 2) 4 --O - (CH 2) 2 --O - (CH 2) 6 - H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra(n-butyl)ammonium hydroxide; sodium hydroxide In water at 85℃; for 47h; | 29 Synthesis Example 29:(CH 2) 6 --O - (CH 2) 2 --O - (CH 2) 2 --O - (CH 2) 6 --O - CH 2 --CH (CH 3) - CH 2 --O - ) 6 - H(Abbreviation: PrMe (O 6 - 2 - 6) 2 The compound obtained in Synthesis Example 16H - (CH 2) 6 --O - (CH 2) 2 --O - (CH 2) 6 --Cl (41.9 g)H - O - CH2 --CH (CH3) - CH2 --O - H (6.5 g)Were dissolved in 50% aqueous sodium hydroxide solution (10.2 g)In the presence of TBAH (1.4 g), at 85 ° C.,After reacting for 47 hours,H - (CH 2) 6 --O - (CH 2) 2 --O--(CH2) 6 --O - CH2 --CH (CH3)--CH2 --O - (CH2) 6 --O - (CH2) 2-O- (CH2) 6-H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra(n-butyl)ammonium hydroxide; sodium hydroxide In water at 85℃; for 51h; | 25 Synthesis Example 25:H - (CH 2) 12 --O - CH 2 --CH (CH 3) - CH 2 --O - (CH2) 12-H (abbreviation: PrMe (O12) 2) H - (CH 2) 12 --Cl (44.8 g)H - O - CH 2 --CH (CH 3) - CH 2 - O - H (6.3 g) in 50% aqueous sodium hydroxide solution (12.8 g)In the presence of TBAH (1.9 g), at 85 ° C.,By reacting for 51 hours,H - (CH 2) 12 --O - CH 2 --CH (CH 3) - CH 2 --O - (CH 2) 12 - H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | To a solution of 2-methyl-propane-1,3-diol (1 g, 11 1 mmol) and TEA (4.5 g, 44.4mmol) in THF (30 mL), was added MsCl (2.8 g, 24.4 mmol) slowly with ice-cooling under N2.The reaction was stirred at room temperature for 1 hr and filtered. The filtrate was concentratedto give a colorless oil. A mixture of this oil, <strong>[137-45-1]1,2-dihydro-pyrazol-3-one</strong> (993 mg, 11 1 mmol) andK2C03 (6.1 g, 44.4 mmol) m DMF (40 mL) was heated to 80 C for 12 hrs. The reaction wascooled and partitioned between EA (100 mL) and water (200 mL) and the layers were separated.The organic layer was washed with water (80 mL) and brme (50 mL), dned over Na2.S04 andconcentrated. The residue was purified by silica gel column (PE/EA '" 2/1) to give rac-6-methy 1-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (500 mg, yield: 33~~) as a white solid.[00700] 1B NNIR (300 MHz, CDCh): 5 '" 7.31 (s, 1B), 5.47 (s, IB), 4.27-4.23 (m, 2B), 3.87-3.68 (m, 2H), 2.47-2.45 (m, 1H), 1.23-1.09 (m, 3H). MS: m/z 139.0 (M+H'} |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38 % ee | With N,N,N,N,-tetramethylethylenediamine; C53H40N2O2 In tetrahydrofuran; toluene at -60℃; for 7h; enantioselective reaction; | General procedure for the desymmetrization of 1,3-diols with catalyst 1a under the optimal conditions General procedure: To a solution of catalyst 1a (0.1mol %), substrate 2a-n (1.0 equiv), and TMEDA (1.5 equiv) in dry toluene(0.2 M) was added (i-PrCO)2O (1.1 equiv) at -60 °C. The reaction mixture was added MeOH (2 mL) to quenchthe reaction and stirred for 30 min at room temperature. The resulting solution was added H2O (10 mL), thenextracted with Et2O (10 mL×3), dried over MgSO4, and concentrated in vacuo to give the crude mixture. Thepurification of the crude product by flash column chromatography on silica gel (eluent: hexane/Et2O = 2:1 toEt2O, v/v or hexane/EtOAc = 1:1, v/v) gave the monoacylate 3a-n, diacylate 4a-n and recovery of substrate2a-n. The enantiomeric ratios were determined by HPLC analysis |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With tributylphosphine; diamide In toluene at 100℃; for 1h; Inert atmosphere; | N-(6-(3-Hydroxy-2-methylpropoxy)isoquinolin-l-yl)-N-((4'-methoxy-3'-methyl-[l,l'- -4-yl)methyl)-3,3-dimethylbutanamide (E)-N1,N1,N2,N2-tetramethyldiazene- 1 ,2-dicarboxamide (276 mg, 1.60 mmol) was added to a mixture of Compound 7 (502 mg, 1.07 mmol), 2-methylpropane-l,3-diol (289 mg, 3.21 mmol), tributylphosphane (649 mg, 3.21 mmol), and toluene (10 mL). The mixture was stirred at 100 °C for 1 h under N2, poured into H20 (50 mL), and then extracted with EtOAc (3 x50 mL). The combined organic layers were washed with brine (2x50 mL), dried (Na2S04), filtered, and concentrated. The crude was purified by RP-HPLC (H20 (lOmMH4HC03)/ACN) to give Compound 10 (154 mg, 26%) as a white solid. 1H MR(400MHz, DMSO-i): δ 8.35 (d, IH), 7.75 (d, IH), 7.68 (d, IH), 7.38-7.50 (m, 5H), 7.24- 7.32 (m, 3H), 6.95-6.99 (m, IH), 5.12 (d, IH), 4.82 (d, IH), 4.62 (t, IH), 4.10 (dd, IH), 3.97 (dd, IH), 3.80 (s, 3H), 3.40-3.50 (m, 2H), 2.18 (s, 3H), 2.01-2.07 (m, IH), 1.83 (d, IH), 1.76 (d, IH), 0.99 (d, 3H), 0.85 (s, 9H); MS: 541.5 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 15h; | 5 Synthesis of (b'"): 2-Methyl-l,3-propanediol (4.72 g, 52.5 mmol) and diisopropylethylamine DIPEA (13.5 g, 105 mmol) in 200 ml of CH2C12 were added dropwise to a solution of (a' ") (6.98 g, 52.5 mmol) in 500 ml of CH2C12 at 0°C. The reaction mixture was stirred at room temperature for 15 hours. The mixture was then poured into 1500 ml of water and extracted twice with CH2C12. The combined organic phases were washed with water three times and concentrated to dryness under vacuum. The crude product was purified by chromatography on a column of silica gel, eluting with EtOAc to give 3.08 g of (b'") in the form of a white solid in a yield of 40%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (E)-bis(4-chlorobenzyl)-diazene-1,2-dicarboxylate; triphenylphosphine; trifluoroacetic acid In 1-methyl-pyrrolidin-2-one at 100℃; for 3h; | Intermediate 94: Methyl (2S)-4-(5-(3-hydroxy-2-methylpropoxy)-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate A mixture of 2-methylpropane-1,3-diol (146 mg, 1.62 mmol), (S)-methyl 4-(5-hydroxy-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate (50 mg, 0.16 mmol), (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (60 mg, 0.16 mmol), and triphenylphosphine (43 mg, 0.16 mmol) in NMP (0.30 mL) was degassed with Ar and then stirred and heated to 100° C. for 3 h. The reaction mixture was cooled to RT and purified directly by reverse phase HPLC (ACN/water with 0.1% TFA) to afford (2S)-methyl 4-(5-(3-hydroxy-2-methylpropoxy)-6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-oxobutanoate. LCMS (C19H25O6S) (ES, m/z): 381 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 5h; Inert atmosphere; | Methyl6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,2,6-thiadiazinane-2-carboxylate1,1-dioxide (3e) General procedure: MethylN-(2,6-dichloro-4-(trifluoromethyl)phenyl)sulfamoylcarbamate 2e (6.00 g, 16.34 mmol), 2-methylpropane-1,3-diol (2.21 g, 24.51 mmol) andtriphenylphosphine (10.71 g, 40.85 mmol) were dissolved in anhydrous THF (100mL) in a reactor, and then cooled down to -20 °C. After removal of air bypurging nitrogen gas, DIAD (8.2 g, 40.8 mmol) was added dropwise to thereaction mixture and stirred for 5 h at room temperature. The reaction mixturewas concentrated under reduced pressure and purified by column chromatography(dichloromethane: hexane: ethyl acetate=5: 4:1) to give methyl6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,2,6-thiadiazinane-2-carboxylate1,1-dioxide 3e (3.9 g, 70%) as awhite solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 5h; Inert atmosphere; | Methyl6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,2,6-thiadiazinane-2-carboxylate1,1-dioxide (3e) General procedure: MethylN-(2,6-dichloro-4-(trifluoromethyl)phenyl)sulfamoylcarbamate 2e (6.00 g, 16.34 mmol), 2-methylpropane-1,3-diol (2.21 g, 24.51 mmol) andtriphenylphosphine (10.71 g, 40.85 mmol) were dissolved in anhydrous THF (100mL) in a reactor, and then cooled down to -20 °C. After removal of air bypurging nitrogen gas, DIAD (8.2 g, 40.8 mmol) was added dropwise to thereaction mixture and stirred for 5 h at room temperature. The reaction mixturewas concentrated under reduced pressure and purified by column chromatography(dichloromethane: hexane: ethyl acetate=5: 4:1) to give methyl6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,2,6-thiadiazinane-2-carboxylate1,1-dioxide 3e (3.9 g, 70%) as awhite solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3 g | Stage #1: 2-methyl-1.3-propanediol With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1h; Cooling with ice; Stage #2: C29H24Br2O3 In tetrahydrofuran; mineral oil at 60℃; for 3h; | 3.3-3 (3-3) Synthesis of Intermediate 5 To a 200 mL three-neck flask, 40 mL of tetrahydrofuran (THF) and 0.56 g (oil-based, 60%) of sodium hydride (NaH) were added. After cooling in an ice bath, 3 mL of a tetrahydrofuran solution of 1.6 g of 2-methyl-1,3-propanediol was added and stirred at room temperature. After 1 hour, 2.5 g of the intermediate 4 was added and reacted at 60° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, and the organic layer was dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and hexane was added to the filtrate for recrystallization to obtain 2.3 g of an intermediate 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; calcium chloride In water at 30℃; for 24h; Inert atmosphere; | 19 Example-19 Under argon atmosphere, trans-4-(3,4,5-trifluorophenyl)cyclohexanecarbaldehyde (48.5 mg, 0.20 mmol) and 2-methyl-1,3-propanediol (19.8 mg, 0.22 mmol) A solution (0.2 mL) in which calcium chloride was saturated with 1N hydrochloric acid was added to the mixture of 1), and the mixture was stirred at 30° C. for 24 hours. 5-methyl-2-(trans-4-(3,4,5-trifluorophenyl)cyclohexyl)-1,3-dioxane obtained by extracting the reaction solution with toluene was analyzed by GC-MS. , Trans isomer: cis isomer=93.87:6.13 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 2-methyl-1.3-propanediol In dichloromethane at 20℃; for 0.5h; Stage #2: 2-Chloro-2-oxo-1,3,2-dioxaphospholane In dichloromethane at 0 - 20℃; for 12h; | 20 Example 20 The preparation method of compound 19 (bis(2-oxo-1,3,2-dioxaphosphorane) 2-methyl-1,3-propanediol ester) includes the following steps: To a 1000ml three-necked bottle, add 400g of dichloromethane and 90g of 2-methyl-1,3-propanediol (Reactant C) at room temperature, and stir at room temperature for 0.5h.The solution was colorless and transparent. The three-necked bottle was connected to an external gas absorption device, and then 300 g of Compound B prepared in Example 1 was slowly added to a 1000-ml three-necked bottle via a dropping funnel.Control the drop acceleration to 1 drop/second, the reaction temperature is 0 , with the addition of Compound B, a lot of heat is released and a lot of HCl gas is released,After all drops were completed, the solution was colorless and transparent, and then the reaction was slowly raised to room temperature and stirring was continued for 12h.Dichloromethane was removed by atmospheric distillation to obtain a pale yellow solid. The pale yellow solid was crystallized from ethanol and then vacuum dried for 3 hours to obtain 284 g of white solid with a yield of 94%. This product is compound 19 (bis(2-oxo-1,3,2-dioxaphosphorane) 2-methyl-1,3-propanediol ester), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In dichloromethane at 0 - 20℃; for 12h; | 20 Add 400g of dichloromethane and 90g of 2-methyl-1,3-propanediol (reactant C) to a 1000ml three-necked flask at room temperature, stir at room temperature for 0.5h, and the solution will be colorless and transparent. The three-necked flask is connected to an external gas absorption device. Subsequently, 300g of compound B prepared in Example 1 was slowly added to a 1000ml three-necked flask via a dropping funnel, the dropping rate was controlled to 1 drop/sec, and the reaction temperature was 0°C. With the dropping of compound B, a large amount of heat was released and A large amount of HCl gas is released. After all the drops are completed, the solution is colorless and transparent. Then the reaction is slowly raised to room temperature and stirring is continued for 12 hours. Distillation at atmospheric pressure to remove dichloromethane to obtain a light yellow solid. The light yellow solid is crystallized by ethanol and vacuum After drying for 3 hours, 254 g of a white solid was obtained with a yield of 94%.The product is compound 19 (bis(1,3,2-dioxaphospholane) 2-methyl-1,3-propanediol ester), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With boron trifluoride-butyl ether complex In tetrahydrofuran at 20℃; for 8h; Inert atmosphere; Cooling with ice; | 5; 5 (Example 1) Production of a compound represented by the formula (I-1) General procedure: Under a nitrogen atmosphere, 22.6 g of the compound represented by the formula (I-1-1), 13.9 g of the compound represented by the formula (I-1-2), and 226 mL of tetrahydrofuran were added to the reaction vessel.While cooling with ice, 26.4 g of boron trifluoride-ethyl ether complex was added dropwise, and the mixture was stirred at room temperature for 8 hours.The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with toluene. The organic layer was washed successively with water and saline.By performing column chromatography (silica gel, dichloromethane / hexane) and recrystallization (acetonitrile)Equation (I-25.9 g of the compound represented by 1) was obtained (yield 80%).No impurities were detected with the tert-butyl group eliminated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With toluene-4-sulfonic acid In benzene Reflux; | 5-Methyl-2,2-diphenyl-1,3-dioxane (1) A mixture of equimolar amounts of 2-methylpropane-1,3-diol (Sigma-Aldrich) (0.02 mol, 1.8 g) and benzophenone (3.64 g) in 50 mL of benzene contaning 0.1 g of p-toluenesulfonic acid was refluxed in a flask equipped with a Dean-Stark trap until water no longer separated. The mixture was cooled and washed with a 5 % solution of sodium hydrogen carbonate (10 mL) and water (2×10 mL), the solvent was distilled off, and the residue was recrystallized twice from 95 % ethanol. Yield 2.7 g (53 %), mp 114-115 °C. Found, %: C 80.36; H 7.11. C17H18O2. Calculated, %: C 80.31; H 7.09. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.6% | With toluene-4-sulfonic acid In toluene for 8h; Reflux; | 6 Preparation of compound III-6 Compound II-3 (100.1g, 0.45mol, 1.0eq.), 2-methyl-1,3-propanediol (81g, 0.90mol, 2.0eq.) was dissolved in toluene (1200mL), and p-toluenesulfonic acid was added (1.55g, 0.009mol, 0.02eq.); heated to reflux and stirred for 8h, TLC monitored the disappearance of raw materials. The solvent was removed by concentration under reduced pressure, EA was added to the residue, washed with saturated brine, dried, concentrated, and purified by column chromatography (PE/EA elution) to obtain compound III-6 as a pale yellow liquid 95.19g. The rate is 68.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With hydrogen at 60℃; | 1.3; 7.3; 8.3; 9.3 The hydrogenation reaction of 2-methylene-1,3-propanediol (compound (D)) adopts a fixed bed continuous reactor,The reaction temperature is 60°C, the hydrogen pressure is 2.0 MPa, the gas space velocity is 1000/h, and the liquid space velocity is 3/h.In this step, the conversion rate of 2-methylene-1,3-propanediol is 99%; the selectivity of 2-methyl-1,3-propanediol is 98%, and the yield is 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With scandium tris(trifluoromethanesulfonate) at 165℃; for 16h; Green chemistry; | General procedure for cyclization reaction of aromatic thiols with diols: General procedure: To a vial was added aromatic thiol (0.1 mmol), Sc(OTf)3 (5.0 mol%, based on aromatic thiol),)3and diol (0.1 mL). The reaction mixture was stirred at 165 °C for 16 h. The resulting mixturewas diluted with EtOAc (1.0 mL) and H2O (1.0 mL) was added. The mixture was well stirred,then the organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 1.0mL).The combined organic layer was dried on Na2SO4, and concentrated under reducedpressure. The residue was purified by PTLC (Wakogel B-5F, Hexane : EtOAc = 50 : 1) to givethe corresponding S-heterocycles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In toluene Reflux; | 7.1 1) Synthesis of 2-(bromomethyl)-5-methyl-2-(4-bromophenyl)-1,3-dioxane (II): When equipped with a condenser,Add 2-bromo-4'-bromoacetophenone (2.00g, 7.2mmol),2-methyl-1,3-propanediol (10mmol),P-toluenesulfonic acid (0.20g, 1.16mmol),Toluene (7.2mL) was used as solvent, heated to reflux, and TLC (VEA/VPE=1/10) followed the reaction. After the reaction was over, the reaction solution was transferred to a separatory funnel, washed with water, and the organic phase was dried with anhydrous sodium sulfate and filtered ,Spin dry toluene to obtain 2-(bromomethyl)-5-methyl-2-(4-bromophenyl)-1,3-dioxane; | |
With toluene-4-sulfonic acid In toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In toluene Reflux; | 12.1 1) Synthesis of 2-(bromomethyl)-5-methyl-2-(4-methoxyphenyl)-1,3-dioxane (II): When equipped with a condenser,Add 2-bromo-4'-methoxyacetophenone (10.0mmol),2-methyl-1,3-propanediol (12.0mmol),P-toluenesulfonic acid (0.20g, 1.16mmol),Toluene (13mL) was used as solvent, heated to reflux, and TLC (VEA/VPE=1/10) followed the reaction. After the reaction was over, the reaction solution was transferred to a separatory funnel, washed with water, and the organic phase was dried with anhydrous sodium sulfate and filtered. Spin dry toluene to obtain 2-(bromomethyl)-5-methyl-2-(4-methoxyphenyl)-1,3-dioxane; | |
With toluene-4-sulfonic acid In toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In toluene Reflux; | 2.1 1) Synthesis of 2-(bromomethyl)-5-methyl-2-phenyl-1,3-dioxane (II): When equipped with a condenser,Add α-bromoacetophenone (2.00g, 10.0mmol),2-methyl-1,3-propanediol (12.0mmol),P-toluenesulfonic acid (0.20g, 1.16mmol),Toluene (13mL) is used as solvent,Heat to reflux, TLC (VEA/VPE=1/10) to follow the reaction, after the reaction is over, transfer the reaction solution to a separatory funnel, wash with water, dry the organic phase with anhydrous sodium sulfate, and filter.Spin dry toluene to obtain 2-(bromomethyl)-5-methyl-2-phenyl-1,3-dioxane; | |
With toluene-4-sulfonic acid In toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With toluene-4-sulfonic acid In toluene at 90℃; for 24h; | 4-(Benzyloxy)-2-((5-methyl-l,3-dioxan-2-yl)methoxy)-6-((4-propylphenyl)ethynyl)- pyridine (17a) To a solution 16 (51.0 mg, 0.12 mmol) and catalytical amount of 4- toluenesulfonic acid in toluene (3.5 mL) was added 2-methylpropane-l,3-diol (0.02 mL, 0.13 mmol). The mixture was heated at 90 °C for 24 h in the uncapped vial, after which it was neutralized by the addition of aq. NaOH (1 M, 5 mL), water (5 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined extracts were washed with saturated CaCI2 (10 mL), dried over Na2S0, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (15% EtOAc in heptane) to afford 17a as a yellow oil (40.9 mg, 76%). Rf = 0.42 (EtOAc: heptane, 1 :3). JH NMR (600 MHz, CDCI3) d 7.51 - 7.47 (m, 2H), 7.39 (d, J = 3.8 Hz, 4H), 7.18 - 7.14 (m, 2H), 6.83 (d, J = 2.0 Hz, 1H), 6.34 (dd, J = 5.1, 2.0 Hz, 1H), 5.06 (s, 2H), 4.94 (t, J = 4.6 Hz, OH), 4.84 (t, J = 4.5 Hz, 1H), 4.43 (dd, J = 4.6, 1.6 Hz, 2H), 4.12 - 4.06 (m, 2H), 3.99 (dd, J = 11.8, 2.6 Hz, 1H), 3.90 - 3.85 (m, 1H), 3.39 - 3.31 (m, 2H), 2.63 - 2.57 (m, 2H), 2.16 (dtd, J = 11.2, 6.7, 4.6 Hz, 1H), 1.64 (dt, J = 14.7, 7.5 Hz, 2H), 1.31 (d, J = 7.0 Hz, 1H), 1.29 - 1.23 (m, 1H), 0.94 (t, J = 7.3 Hz, 3H), 0.72 (d, J = 6.7 Hz, 2H). 13C NMR (151 MHz, CDCI3) d 166.9, 164.8, 164.8, 143.9, 141.0, 135.8, 132.1, 128.8, 128.6, 128.5, 127.6, 119.7, 111.0, 111.0, 98.9, 95.6, 88.8, 88.8, 88.3, 73.3, 71.9, 70.1, 66.9, 38.1, 29.5, 24.4, 13.9, 12.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 0℃; for 7h; | Typical Procedure for TBS-Protected Methyl Halide Alcohols: General procedure: To a mixture of diol (1 equivalent) in dichloromethane (0.1 M), N-bromosuccinimide (1 equivalent) and triphenylphosphine (1 equivalent) was added at 0°C. The reaction stirred for 7 hours after which the reaction was concentrated. The crude mixture was purified by silica gel column chromatography (30% ethyl acetate/hexanes) to obtain colorless oil as the monobrominated alcohol. The alcohol was used in the next reaction. To a mixture of unprotected alcohol (1 equivalent) in THF (0.2 M), TBSCl (2 eqvuivalents) and imidazole were added (3 equivalents). The reaction stirred overnight and then quenched with water and extracted with ethyl acetate. The organic layers were dried over filtered and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (20% ethyl acetate/hexanes) to yield the desired product. | |
With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 0℃; for 7h; | Typical Procedure for TBS-Protected Methyl Halide Alcohols: General procedure: To a mixture of diol (1 equivalent) in dichloromethane (0.1 M), N-bromosuccinimide (1 equivalent) and triphenylphosphine (1 equivalent) was added at 0°C. The reaction stirred for 7 hours after which the reaction was concentrated. The crude mixture was purified by silica gel column chromatography (30% ethyl acetate/hexanes) to obtain colorless oil as the monobrominated alcohol. The alcohol was used in the next reaction. To a mixture of unprotected alcohol (1 equivalent) in THF (0.2 M), TBSCl (2 eqvuivalents) and imidazole were added (3 equivalents). The reaction stirred overnight and then quenched with water and extracted with ethyl acetate. The organic layers were dried over filtered and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (20% ethyl acetate/hexanes) to yield the desired product. |
Tags: 2163-42-0 synthesis path| 2163-42-0 SDS| 2163-42-0 COA| 2163-42-0 purity| 2163-42-0 application| 2163-42-0 NMR| 2163-42-0 COA| 2163-42-0 structure
[ 4704-94-3 ]
2-(Hydroxymethyl)propane-1,3-diol
Similarity: 1.00
[ 911855-78-2 ]
(R)-3-Methoxy-2-methylpropan-1-ol
Similarity: 0.75
[ 4704-94-3 ]
2-(Hydroxymethyl)propane-1,3-diol
Similarity: 1.00
[ 911855-78-2 ]
(R)-3-Methoxy-2-methylpropan-1-ol
Similarity: 0.75
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :