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CAS No. : | 510-77-0 | MDL No. : | MFCD08063719 |
Formula : | C17H19NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QENVUHCAYXAROT-YOEHRIQHSA-N |
M.W : | 285.34 | Pubchem ID : | 10356588 |
Synonyms : |
Narwedin;(-)-Narwedine;3-Deoxy-3-oxo-galanthamine;Narwedine
|
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P261-P264-P270-P271-P280-P302+P352-P304+P340-P310-P330-P361-P403+P233-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301-H311-H331 | Packing Group: | Ⅲ |
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 |
---|---|---|
85.4% | Stage #1: With L-Selectride In tetrahydrofuran at -50 - -45℃; for 4 h; Stage #2: With hydrogen bromide In ethanol; water at 15 - 20℃; for 2 h; |
Lithium tri-sec-butyl borohydride (L-selectride), (1molar solution in THF, 360.8mL) was added dropwise to a suspension of (4aS,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one, [(−)-narwedine] 6 (50g, 0.175mol) in THF (1000mL) at −50 to −45°C for 1h after which the reaction mixture was stirred at −50 to −45°C for 3h. The completion of the reaction was monitored by qualitative HPLC analysis. Next, the reaction mixture was quenched by adding aqueous hydrogen peroxide (40percent w/w, 85g, 1mol) and the excess peroxide was destroyed by stirring the reaction with an aqueous sodium sulfite solution. The reaction mixture was concentrated under reduced pressure and the product was extracted into toluene (1250mL). The organic extract was concentrated under reduced pressure at 50–55°C to obtain (−)-galanthamine base as an oily mass, which was dissolved in a mixture of ethanol (200mL) and DM water (50mL). Aqueous hydrobromic acid (48percent w/w, 31.09g, 0.185mol) was then added to the (−)-galanthamine base solution and stirred at 15–20°C for 2h. The product was filtered and dried under vacuum at 50–55°C to obtain (−)-galanthamine 1 as a hydrobromide salt as white crystalline powder (55g, 85.4percent yield). Chromatographic purity: 99.85percent (by HPLC); enantiomeric purity: 100percent (by HPLC); mp: 253°C (dec); [α]25D=−96.5[α]D25=-96.5 (c 0.1, water); IR(KBr) (cm−1): 3561, 3043,3022, 2946, 2922, 2619, 2482, 1625, 1512, 1465, 1439, 1282, 1068; δH (300MHz, DMSO-d6): 1.90 (brs, 1H), 2.04 (dd, J = 15.6, 5.1 Hz, 2H), 2.23 (dd, J = 15.6 Hz, 1H), 2.49 (s, 3H), 2.97 (brs, 2H), 3.34 (m, 1H), 3.76 (s, 3H), 3.82 (brs, 1H), 4.09 (s, 1H), 4.48 (m, 2H), 4.59 (s, 1H), 4.78 (d, J = 14.1 Hz, 1H), 5.87 (dd, J = 6, 3 Hz, 1H), 6.12 (d, J = 9 Hz, 1H), 6.79 and 6.85 (2d, J = 8.4, 8.4 Hz, 2H), 9.82 (2brs, 1H); δC (100MHz, DMSO-d6): 30.9 (2×CH2), 35.1 (CH3), 46.4 (CH2), 55.6 (OCH3), 59.4 (CH2), 86.4 (CH), 111.9 (CH), 120.4, 122.8 (CH), 125.4 (CH), 129.8 (CH), 132.8, 144.8, 146.3; HRMS (ESI+): m/z 288.1608 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: With cerium(III) chloride heptahydrate In methanol; dichloromethane at -55 - -50℃; for 0.5 h; Stage #2: With sodium tetrahydroborate In methanol; dichloromethane at -55 - -50℃; for 2.5 h; |
A mixture of (4aS,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzezapin-6-one [(−)-narwedine] 6 (10g, 0.035mol), cerium chloride heptahydrate (13.07g, 0.035mol) in methylene chloride–methanol (1:1 v/v, 300mL) was stirred at −55 to −50°C for 30min after which sodium borohydride (3.33g, 0.088mol) was added in portions at −55 to −50°C over a period of 30min. The reaction mixture was stirred at −55 to −50°C for 2h and the completion of the reaction was monitored by qualitative HPLC analysis. Water (10mL) was then added to the reaction mixture and the temperature was raised to 25–30°C. The reaction mixture was concentrated under reduced pressure and the concentrated mass was stirred with chloroform (100mL). The inorganic residue was removed by filtration. The filtrate was washed with water (60mL) and the organic layer was concentrated under reduced pressure. The crude product was stirred with acetone (50mL) at reflux temperature. The slurry mass was cooled to 25–30°C, filtered and dried at 45–50°C under reduced pressure to yield (−)-epigalanthamine 3 as a white crystalline powder (6.85g, 68percent yield). Chromatographic purity: 96.49percent (by HPLC); enantiomeric purity: 97.71percent (by HPLC); mp: 181–182°C; [α]25D=−229.9[α]D25=-229.9 (c 1, CHCl3); IR (KBr, cm−1): 3151, 3031, 3011, 2945, 2916, 1623, 1508, 1459, 1445, 1436, 1272, 1053; δH (300MHz, CDCl3): 1.61–1.75 (m, 2H), 2.18 and 2.75 (dd, J = 12, 12 Hz, 2H), 2.36 (s, 3H), 3.07 and 3.22 (dd, J = 12.9, 12.1 Hz, 2H), 3.59 and 4.05 (dd, J = 15.3, 15 Hz, 2H), 3.83 (s, 3H), 4.60 (m, 2H), 5.79 (d, J = 10.2 Hz, 1H), 6.05 (d, J = 11.7 Hz, 2H), 6.55 and 6.62 (2d, J = 8.1, 8.1 Hz, 2H); δC (100MHz, CDCl3): 32.3 (2×CH2), 34.1 (CH3), 41.6 (CH2), 48.0, 53.8 (CH2), 55.8 (OCH3), 60.1 (CH2), 62.7 (CH), 88.4 (CH), 110.8 (CH), 121.5, 126.2 (CH), 128.9 (CH), 131.9 (CH), 132.9, 143.8, 146.6; HRMS (ESI+): m/z 288.1614 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen bromide at 100℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium aluminium tetrahydride In diethyl ether for 13h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With manganese(IV) oxide In chloroform for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -55 - -40℃; for 0.5h; | |
86% | With pyridinium chlorochromate In dichloromethane for 8h; Ambient temperature; | |
86% | With manganese(IV) oxide In dichloromethane at 20℃; for 14.5h; Cooling with ice; |
With manganese(IV) oxide In chloroform for 70h; Ambient temperature; | ||
With manganese(IV) oxide In chloroform for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium acetate In ethanol; water at 100℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.5% | With Lithium tri-sec-butylborohydride In tetrahydrofuran at -78℃; for 2h; | |
99.7% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 20℃; for 1h; | 2 30 g of galanthamine hydrochloride prepared in Example 1 and containing according to HPLC analysis 1.1 % of narwedine was dissolved in 120 ml of water and 1.2 g of sodium borohydride was added in six portions within about 30 minutes under stirring. The solution was stirred for another 30 minutes at laboratory temperature and then 12 ml of 25 % (w/w) aqueous ammonia and 200 ml of methyl isobutyl ketone were added to the solution. The organic phase was separated, concentrated to the volume about 100 ml and let to crystallize in refrigerator for 24 hours. The crystalline base of galanthamine was separated by filtration and dried, obtaining 19.3 g of galanthamine, which purity was determined by HPLC as 99.7 % and where the content of narwedine was 0.04 % (the HPLC record is presented on Figure 7). |
81.1% | With Lithium tri-sec-butylborohydride In tetrahydrofuran; hexane at -20 - 20℃; for 1h; |
75% | With Lithium tri-sec-butylborohydride In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; | |
Stage #1: Galanthaminone With Lithium tri-sec-butylborohydride Stage #2: With lithium hydroxide monohydrate; hydrogen bromide | 42 Examples 42-44; Examples 42-44 illustrate the effect of the pH during the quenching of the excess of L-selectride once the reduction of (-)-narwedine to (-)-galanthamine has been completed.; Examples 42 and 44 illustrate the effect of the deoxygenation by N2 bubbling of the solutions employed in the reduction of (-)-narwedine to (-)-galanthamine before their addition to the reactor. | |
Stage #1: Galanthaminone With Lithium tri-sec-butylborohydride Stage #2: With lithium hydroxide monohydrate | 43 Examples 42-44; Examples 42-44 illustrate the effect of the pH during the quenching of the excess of L-selectride once the reduction of (-)-narwedine to (-)-galanthamine has been completed.; Examples 42 and 44 illustrate the effect of the deoxygenation by N2 bubbling of the solutions employed in the reduction of (-)-narwedine to (-)-galanthamine before their addition to the reactor. | |
Stage #1: Galanthaminone With Lithium tri-sec-butylborohydride In tetrahydrofuran at -50 - -15℃; for 1.5 - 2h; Stage #2: With lithium hydroxide monohydrate; dihydrogen peroxide In tetrahydrofuran | I.V; 3 STEP V: Preparation of [4aS,6R,8aS]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol [(-)-Galantamine hydrobromide] Lithium tri-sec-butyl borohydride [L-selectride], (1 Molar solution in THF, 84.2 ml) was added drop wise to a uniform suspension of [4aS,8aS]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one [(-)-Narwedine] (20g, 0.070 mol) in THF (100 ml) at -20 to -15°C for 30 min and the reaction mass was stirred at -20 to -15°C for 1h. The completion of the reaction was monitored by qualitative HPLC. The reaction mixture was quenched by adding aqueous hydrogen peroxide (40% w/w, 21.32g. 0.25 mol) and the excess peroxide was destroyed by stirring the reaction mass with aqueous sodium sulfite solution. The reaction mixture was concentrated under reduced pressure and extracted the product into chloroform (200 ml). The organic extract was concentrated under reduced pressure at 40-45°C to obtain Galantamine base. Galantamine base residue was dissolved in methanol (40 ml) and stirred with aqueous hydrobromic acid (48% w/w, 14.21g, 0.084 mol) at 25-30°C for 3 h to obtain Galantamine hydrobromide. The product was filtered and dried under vacuum at 50-55°C. Yield: 22g (85.4%) Chromatographic Purity: >99% (by HPLC)EXAMPLE 3: Preparation of [4aS,6R,8aS]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H benzofuro[3a,3,2-ef][2]benzazepin-6-ol [(-)-Galantamine hydrobromide] Lithium tri-sec-butyl borohydride [L-selectride], (1 molar solution in THF, 433.4 ml) was added drop wise to a uniform suspension of [4aS,8aS]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one [(-)-Narwedine] (65 g, 0.228 mol) in THF (1300 ml) at -50 to -45°C for 1 h and stirred the reaction mass at -50 to -45°C for 1 h. The completion of the reaction was monitored by qualitative HPLC. The reaction mixture was quenched by adding hydrogen peroxide (40% w/w, 110.5 g, 1.3 mol) and the excess peroxide was destroyed by stirring the reaction mass with aqueous sodium sulfite solution. The reaction mixture was concentrated under reduced pressure and the product was extracted into toluene (1625 ml). The organic extract was concentrated under reduced pressure at 50-55°C to obtain Galantamine base. Galantamine base residue was dissolved in a mixture of ethanol (260 ml) and DM water (65 ml) and stirred with aqueous hydrobromic acid (48% w/w, 40.42 g, 0.24 mol) at 15-20°C for 2 h to obtain Galantamine hydrobromide. The product was filtered and dried under vacuum at 60-65°C. Yield: 71.5 g (85.4%) Chromatographic purity: >99.5% (by HPLC) Chiral purity: >99.9% (by HPLC) | |
Stage #1: Galanthaminone With Lithium tri-sec-butylborohydride In tetrahydrofuran for 1h; Stage #2: With ethanol In tetrahydrofuran | Step 3: The enantiomerically pure (-)narwedine with the general formula (V) that is obtained after recrystallization, as described in WO-A-96/12692, is mixed with a one-molar solution of 1-selectride in THF, allowed to stir for one hour, mixed with ethanol, and concentrated by evaporation. Enantiomerically pure galanthamine of general formula (I) for R1=CH3 is obtained by the enantiomerically selective reduction. Residual portions of palladium of less than 5 ppm are achieved by recrystallization that is repeated one or more times. Therefore, according to synthesis step 2.1, by being worked up with oxygen or peroxide, the palladium catalyst is converted into an insoluble, oxidized form that can be easily separated by recrystallization during the course of the purification. | |
With Lithium tri-sec-butylborohydride In tetrahydrofuran at -50 - -45℃; for 4h; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.7% | Stage #1: 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one With acetic acid In ethanol; water Heating / reflux; Stage #2: With triethylamine In ethanol; water at 0 - 80℃; for 22h; | 36 Example 36; Preparation of (-)-Narwedine from Racemic Narwedine; A suspension of 50.0 g of racemic narwedine in a mixture of 850 mL of ethanol, 50 mL of water and 12 mL of glacial acetic acid was heated to reflux temperature. After cooling to 75-80° C., 100 mL of triethylamine was added to the resulting solution. Next, the reaction mixture was cooled to 70° C., and 2.5 g of (-)-narwedine seeds were added to the solution. The resulting suspension was cooled to 40° C. over 100 minutes, and stirred at this temperature for 18 hours. Thereafter, the suspension was cooled to 0° C. over 4 hours, and stirred at this temperature for an additional hour. The suspension was then filtered using a Büchner funnel to yield 45.0 g of (-)-narwedine (Yield: 85.7%; HPLC (method 7) purity 99.7%. Enantiomeric excess by HPLC (method 8, chiral) higher than 97.8%). The XRD (29) for Example 36 is as follows and is illustrated in FIG. 6: |
80% | With triethylamine In ethanol | |
With oxygen; pyrographite; triethylamine In ethanol Reflux; Inert atmosphere; Resolution of racemate; | Step 2.1: The racemic narwedine (IV) that is obtained is taken up in a mixture of ethanol/triethylamine and mixed with activated carbon and a filter aid. The mixture is refluxed for one to four hours while being stirred intensively, whereby an air-nitrogen mixture is blown through the reactor with, for example, 5% by volume of oxygen. Surprisingly enough, it was found that by the treatment with activated carbon, on the one hand, and the oxygen contact, on the other hand, the reduction of the palladium portions of considerably above 95% in comparison to known, detectable amounts of palladium could be achieved. Step 2.2: The reaction mixture that is obtained according to step 2.1 is cooled and inoculated with (-)narwedine crystals, so that enantiomerically pure (-)narwedine with general formula (V) is obtained. |
With triethylamine In ethanol at 40 - 68℃; for 3h; | 1 Preparation of the compound of Example 1 levonavirdine a mixture of ethanol and triethylamine (9:1) added to the reaction flask,Navidin,Heated to reflux,Then the system is cooled to 65-68 ° C,Add 1g of levonavirdine,Cool down to 40 ° C,Stir for 3 hours.The suspension is concentrated to about one-third of the original volume at around 40 °C.The concentrate system is cooled to 5-10 ° C,Filter under reduced pressure,It was washed with ice-cold at 0-5 °C.Dry at 60 ° C under reduced pressure,Get the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.4% | Lithium tri-sec-butyl borohydride (L-selectride), (1molar solution in THF, 360.8mL) was added dropwise to a suspension of (4aS,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one, [(-)-narwedine] 6 (50g, 0.175mol) in THF (1000mL) at -50 to -45C for 1h after which the reaction mixture was stirred at -50 to -45C for 3h. The completion of the reaction was monitored by qualitative HPLC analysis. Next, the reaction mixture was quenched by adding aqueous hydrogen peroxide (40% w/w, 85g, 1mol) and the excess peroxide was destroyed by stirring the reaction with an aqueous sodium sulfite solution. The reaction mixture was concentrated under reduced pressure and the product was extracted into toluene (1250mL). The organic extract was concentrated under reduced pressure at 50-55C to obtain (-)-galanthamine base as an oily mass, which was dissolved in a mixture of ethanol (200mL) and DM water (50mL). Aqueous hydrobromic acid (48% w/w, 31.09g, 0.185mol) was then added to the (-)-galanthamine base solution and stirred at 15-20C for 2h. The product was filtered and dried under vacuum at 50-55C to obtain (-)-galanthamine 1 as a hydrobromide salt as white crystalline powder (55g, 85.4% yield). Chromatographic purity: 99.85% (by HPLC); enantiomeric purity: 100% (by HPLC); mp: 253C (dec); [alpha]25D=-96.5[alpha]D25=-96.5 (c 0.1, water); IR(KBr) (cm-1): 3561, 3043,3022, 2946, 2922, 2619, 2482, 1625, 1512, 1465, 1439, 1282, 1068; deltaH (300MHz, DMSO-d6): 1.90 (brs, 1H), 2.04 (dd, J = 15.6, 5.1 Hz, 2H), 2.23 (dd, J = 15.6 Hz, 1H), 2.49 (s, 3H), 2.97 (brs, 2H), 3.34 (m, 1H), 3.76 (s, 3H), 3.82 (brs, 1H), 4.09 (s, 1H), 4.48 (m, 2H), 4.59 (s, 1H), 4.78 (d, J = 14.1 Hz, 1H), 5.87 (dd, J = 6, 3 Hz, 1H), 6.12 (d, J = 9 Hz, 1H), 6.79 and 6.85 (2d, J = 8.4, 8.4 Hz, 2H), 9.82 (2brs, 1H); deltaC (100MHz, DMSO-d6): 30.9 (2×CH2), 35.1 (CH3), 46.4 (CH2), 55.6 (OCH3), 59.4 (CH2), 86.4 (CH), 111.9 (CH), 120.4, 122.8 (CH), 125.4 (CH), 129.8 (CH), 132.8, 144.8, 146.3; HRMS (ESI+): m/z 288.1608 [M+H]+. | |
Add 1M to the reaction flask under argon protectionLithium tri-sec-butyl borohydride-tetrahydrofuran,Anhydrous tetrahydrofuran,The mixture is cooled to -20 C.Keep around -15 C,Add levonavirdine (about 2h) in batches,The system was stirred at -15 C for 30 min.Then the system is warmed to 20 C,Stir for 1 hour to obtain an amber solution.Add ethanol,Temperature control 30 C,Keep it for 30 minutes.Filtering,The filter cake was washed with tetrahydrofuran.Combine all the resulting solutions,Add ethanol,Cool down to 0 C,Start dropping the hydrobromic acid solution,The temperature control is below 20 C,Adjust the pH to less than 1,Add loratamin crystals of L-hydrobromide,Crystallization at 0-5 C for 1 hour,Filtering,Ethanol washing,After draining,Get the filter cake,The filter cake was dried at 60 C to give galantamine hydrobromide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydrogen In ethyl acetate for 20h; | |
84% | With N,N,N,N,N,N-hexamethylphosphoric triamide; potassium hydride In toluene at 60℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With Li(sec-Bu)3BD In tetrahydrofuran; hexane at -20 - 20℃; for 1h; | |
37% | With sodium borodeuteride; deuteromethanol at 0 - 10℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
HJ(Kp:125grad),roter Phosphor in Eg. b. Siedetemperatur ---> Hydroxyapogalanthamin; | ||
LiAlH4 in Ae. ---> Epigalanthamin; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.8% | With Li(sec-Bu)3BT In tetrahydrofuran; hexane at -20 - 20℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 37 percent / NaBD4, CH3OD / 1 h / 0 - 10 °C 2: 52 percent / KH, HMPA / toluene / 8 h / 60 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 89.5 percent 2: 95 percent / 1.) LiAlH4, air; 2.) HCl 3: 80 percent / NEt3 / (-)-narwedine / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 95 percent / 1.) LiAlH4, air; 2.) HCl 2: 80 percent / NEt3 / (-)-narwedine / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In ethanol; at 20 - 40℃; for 19h;Heating / reflux; | Di-p-toluoyl-D-tartaric acid (5.79 g, 14.99 mmol) was dissolved in ethanol (100 ml) on warming to 400 C. and then synthetic racemic narwedine (8.52 g, 29.86 mmol) was added and the mixture was heated at reflux for 1 h then cooled to 400 C. and stirred for 16 hours at this temperature. The mixture was cooled to ambient temperature, stirred for 2 h and then the resultant white solid was isolated by filtration to give the 2:1 diastereomeric salt [(-)-narwedine]2[di-p-toluoyl-D-tartrate] (11.86 g, 83% yield, 94% e.e.). |
79% | In ethanol; at 40℃;Heating / reflux; | Racemic narwedine (100 mg, 0.35 mmol) was dissolved in ethanol (3 ml) upon heating to reflux. Di-p-toluoyl-D-tartaric acid (58 mg, 0.17 mmol) was added and the mixture was cooled slowly to 400 C., maintained at this temperature overnight, then cooled to ambient temperature. The white solid was isolated by filtration to afford the 2:1 diastereomeric salt [(-)-arwedine]2[di-p-toluoyl-D-tartrate] (79% yield, 98% e.e (-)-narwedine in salt). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In ethanol; at 40℃;Heating / reflux; | Racemic narwedine (100 mg, 0.35 mmol) was dissolved in ethanol (3 ml) on heating to reflux. Di-p-toluoyl-D-tartaric acid (58 mg, 0.17 mmol) was added then the reaction mixture was cooled to ambient temperature. The resulting white solid was isolated by filtration to afford the 1:1 diastereomeric salt [(-)-narwedine][di-p-toluoyl-D-tartrate] (90% yield, 98% e.e (-)-narwedine). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: (-)-narwedine With L-Selectride In tetrahydrofuran at -22 - 5℃; for 3.5h; Stage #2: With hydrogen bromide In tetrahydrofuran; ethanol; water at 0 - 5℃; for 2h; | 1 Example 1: Preparation of racemic galantamine hydrobromide; L-Selectride (lithium tri-sec-butylborohydride, l.OM solution in tetrahydrofuran)(396.5 g) was charged under nitrogen atmosphere, followed by tetrahydrofuran (100ml) at 0-5°C. This mixture was cooled to -20 to -22°C and narwedine (100 g) wascharged in lots over a period of about 3 hours at -18 to -20°C. Tetrahydrofuran (25 ml)was used to wash the addition vessel and the reaction mixture was stirred for 30minutes at -15 to -20°C. It was heated to 20°C and ethanol (400 ml) was added. Thereaction mixture was stirred for 30 minutes at 20 - 30°C, filtered and washed with amixture of tetrahydrofuran and ethanol (200 ml, 1:1). The filtrate was cooled to 0 to -5°C and aqueous hydrobromic acid (-48%, 82 ml) was added to adjust the pH to 3.0 to3.5 at 0 to -5°C. It was stirred for 2 hours at 0 - 5°C. The separated solids were filtered,washed with cold ethanol (300 ml) and air dried at 50 - 55°C till loss on drying was notmore than 2.5%.Yield: 116 g. |
Stage #1: (-)-narwedine With L-Selectride In tetrahydrofuran at -20 - 5℃; for 3.5h; Stage #2: With hydrogen bromide In tetrahydrofuran; ethanol; water at 0 - 5℃; for 2h; | 5 EXAMPLE 5; PREPARATION OF RACEMIC GALANT AMINE HYDROBROMIDE; L-Selectride (lithium tri-sec-butylborohydride, 1.0 M solution in tetrahydrofuran) (396.5 g) was charged under a nitrogen atmosphere, followed by THF (100 ml) at 00C- 50C. This mixture was cooled to -200C to -22°C and narwedine (100 g) was charged in lots over a period of about 3 hours at -180C to -200C. Tetrahydrofuran (25 ml) was used to wash the addition vessel and the reaction mixture was stirred for 30 minutes at -150C to -200C. It was heated to 2O0C and ethanol (400 ml) was added. The reaction mixture was stirred for 30 minutes at 200C - 3O0C, filtered and washed with a mixture of EPO tetrahydrofuran and ethanol (200 ml, 1 :1). The filtrate was cooled to 0°C to 50C and aqueous hydrobromic acid (-48%, 82 ml) was added to adjust the pH at 3.0 to 3.5 at 0°C to 50C. It was stirred for 2 hours at O0C - 50C. The separated solids were filtered, washed with cold ethanol (300 ml) and air dried at 5O0C - 55°C till loss on drying was NMT 2.5%.Yield: 116 grams |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With boron trifluoride-tetrahydrofuran complex In tetrahydrofuran at 0 - 20℃; for 0.5 - 1h; | 37; 38; 39; 40; 41 Example 37; Preparation of (-)-Narwedine-BF3 ; ComplexIn a 10 ml round-bottomed reaction flask, 0.50 g (1.75 mmol) of (-)-narwedine were suspended in 2.5 mL of THF at room temperature. Then, 0.19 mL (1.77 mmol, 1.01 equivalents) of BF3-THF complex was added, and the resulting suspension was stirred at room temperature for 1 hour. The solvent was then partially evaporated under reduced pressure, and diethyl ether was added to the suspension, which was then filtered at room temperature. The resulting white solid obtained was washed with diethyl ether twice to yield 039 g of (-)-narwedine-BF3 complex (Yield: 63% yield. The IR spectra of (-)-narwedine and (-)-narwedine-BF3 complex are illustrated in FIGS. 1 and 2 respectively. Elemental Analysis: C17H19NO3.BF3.1.25 H2O (375.67 g/mol); C: 54.35%; H, 5.77%; N: 3.73%; F: 15.17; Found: C, 54.35%; H, 5.92%; N, 3.40%; F, 15.10. The XRD (2θ) for Example 37 is as follows and is illustrated in FIG. 7:; Example 38; Preparation of (-)-Galanthamine.BF3 Complex; In a 25 ml round-bottomed reaction flask, 0.20 g (0.70 mmol) of (-)-narwedine was suspended in a solution of 0.075 mL (0.70 mmol, 1.0 equivalents) of BF3-THF in 1.4 mL of THF at 0° C. The suspension was stirred at 0° C. for 30 minutes. Next, 1.4 mL (1.40 mmol, 2.0 equivalents) of L-Selectride 1.0M solution in THF was added to the reaction flask. The solution was then stirred at 0° C. for 4 hours, heated to room temperature and stirred overnight to yield a white solid. The solid was filtered and washed with diethylether to yield 0.13 g of (-)-galanthamine-BF3 (Yield: 65%). The Ht spectra of (-)-galanthamine and (-)-galanthamine.BF3 complex are illustrated in FIGS. 3 and 4 respectively.; Example 39; Preparation of (-)-Galanthamine HydrobromideIn a three necked 250 ml round-bottomed reaction flask, 5.0 g (17.52 mmol) of (-)-narwedine was suspended in a solution of 1.93 mL (17.52 mmol, 1.0 equivalents) of BF3-THF in 25 mL of THF at 0° C. The suspension was stirred at 0° C. for 35 minutes after which 44 mL (44 mmol, 2.5 equivalents) of L-Selectride 1.0 M solution in THF was added to the reaction flask. The solution was then stirred at 0° C. for 6 hours. Next, 10 mL of THF were added to the reaction followed by 25 mL of methanol. The solvents were then distilled under vacuum, and the residue was dissolved in a mixture of 45 mL of ethyl acetate, 5 mL of THF and 20 mL of 0.1 M NaOH solution. The organic phase was then extracted and evaporated under vacuum. Next, the residue was dissolved in 45 mL of isopropanol, and the solution was filtered, cooled to 0° C. Thereafter, 42 mL (36.8 mmol, 2.1 equivalents) of 48% HBr solution in water was added to the solution to yield 5.26 g of (-)-galanthamine hydrobromide (Yield: 82% yield), which was isolated by filtration. The powder X-Ray diffraction pattern of (-)-galanthamine hydrobromide is illustrated in FIG. 5.; Example 40; Preparation of (-)-Galanthamine Hydrobromide; In this Example, all the solutions were bubbled with N2 and cooled to 0° C. prior to use. In a 2 L, round-bottomed cylindrical jacketed reactor, 78.6 g of (-)-narwedine was suspended in a solution of 38.5 g of BF3-THF in 409 mL of THF under nitrogen atmosphere. The suspension was then cooled to -20° C., and 689 mL of L-Selectride 1.0 M solution in THF was added to the suspension. The resulting solution was then heated to 0° C. over 3 hours, and 79 mL of deionized water was added to the solution, followed by the addition of 705 mL of ethanol and 79 mL of 48% HBr in water. The resulting suspension was then filtered using a Büchner funnel, under air atmosphere, and washed with 79 mL of ethanol to produce a quantitative yield of (-)-galanthamine hydrobromide (HPLC (method 7) result: 98.31% galanthamine, 0.56% dehydroxygalanthamine).; Example 41; Preparation of (-)-Galanthamine Hydrobromide, Substantially Free of Dehydroxygalanthamine Fall Steps Under Inert Atmosphere); In this Example, all the solutions were bubbled with N2 for 15 minutes and cooled to 0° C. prior to use. In a 500 mL, round-bottomed cylindrical jacketed reactor, 20.0 g of (-)-narwedine was suspended in a solution of 9.89 g of BF3-THF in 100 mL of THF under nitrogen atmosphere. The suspension was then cooled to -20° C., and 176 mL of L-Selectride 1.0 M solution in THF was added to the suspension. The resulting solution was then heated to 0° C. over 3 hours, and 20 mL of deionized water was added to the solution, followed by the addition of 180 mL of ethanol and 20 mL of 48% HBr in water. The resulting suspension was filtered under N2, and washed with 40 mL of ethanol to produce a quantitative yield of (-)-galanthamine hydrobromide (HPLC (method 7) result: 99.58% galanthamine, 0.02% dehydroxygalanthamine). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In ethanol at 40 - 80℃; for 72h; | 1.IV STEP IV:Preparation of [4aS,8aS]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro [3a,3,2-ef][2]benzazepin-6-one [(-)-Narwedine] 4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzaze-pin-6-one isomers [(+/-)-Narwedine] (30g, 0.105 mol) was dissolved in a mixture of ethanol (540 ml) and triethylamine (60 ml) at 75-80°C. The reaction mixture was cooled to 65-70°C and (-)-Narwedine (0.45g, 0.0016 mol) was added as a seed to the solution. The resulting mixture was slowly cooled to 40-42°C and stirred at 40-42°C for 3 days for complete dynamic resolution of (-)-Narwedine. The slurry reaction mass was cooled to 25-30°C. The obtained product was filtered and dried under vacuum at 50-55°C. Yield: 27g (90%) Chromatographic purity: > 99% (by HPLC) |
90% | With triethylamine In ethanol; water at 40 - 80℃; for 3h; | 2 EXAMPLE 2: Preparation of [4aS,8aS]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro [3a,3,2-ef][2]benzazepin-6-one [(-)-Narwedine] 4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one [(+/-)-Narwedine] (95 g, 0.333 mol) was dissolved in a mixture of DM water (72.2 ml), ethanol (1381 ml) and triethylamine (161.5 ml) at 75-80°C. The reaction mixture was cooled to 70-73°C and (-)-Narwedine (1.9 g, 0.0067 mol) was added as a seed to the solution. The resulting mixture was gradually cooled to 40-42°C and stirred at 40-42°C for 3 h for complete kinetic dynamic resolution of (-)-Narwedine. Then the slurry mass was cooled to 25-30°C and stirred for 1 h. The product was filtered and dried under vacuum at 55-65°C. Yield: 85.5 g (90%) Chromatographic purity: >99.5% (by HPLC) Chiral purity: >99.5% (by HPLC) |
90% | With triethylamine In ethanol; water at 40 - 80℃; for 3h; |
90% | With triethylamine In ethanol; water at 25 - 73℃; for 3h; Resolution of racemate; enantioselective reaction; | 2 (4aS,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one [(-)-narwedine] 6 4.2 (4aS,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one [(-)-narwedine] 6 (+-)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one [(+-)-narwedine] 5 (75 g, 0.263 mol) was dissolved in a mixture of demineralised water (57 mL), ethanol (1090 mL), and triethylamine (127.5 mL) at 75-80 °C. The reaction mixture was cooled to 70-73 °C and (-)-narwedine (1.5 g) was added as seed to the dissolved solution. The resulting mixture was gradually cooled to 40-42 °C and stirred at the same temperature for 3 h. The completion of the resolution was monitored by qualitative chiral HPLC analysis. Thereafter, the slurry was cooled to 25-30 °C, the product filtered and dried at 55-65 °C under reduced pressure to give (-)-narwedine 6 as a cream crystalline powder (67.5 g, 90%). Chromatographic purity: 99.92% (by HPLC); enantiomeric purity: 99.95% (by HPLC); mp: 190-192 °C; (c 1, CHCl3); IR(KBr) (cm-1): 1682 (C=O), 1620 (C=C), 1507, 1439; δH (300 MHz, DMSO-d6): 1.81 and 2.12 (dd, J = 14.1, 3.0 Hz, 2H), 2.28 (s, 3H), 2.76 and 2.96 (dd, J = 2.1, 2.1 Hz, 2H) 3.01 and 3.18 (dd, J = 3.3, 13.2 Hz, 2H), 3.60 and 4.13 (dd, J = 15.6, 15.3 Hz, 2H), 3.71 (s, 3H), 4.71(brs, 1H), 5.90 (d, J = 9 Hz, 1H), 6.63 and 6.76 (2d, J = 9, 6 Hz, 2H), 7.14 (d, J = 9 Hz, 1H); HRMS (ESI+): [M+H]+ m/z 286.1453. |
80% | With triethylamine In ethanol Reflux; Large scale; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1.5 h / 20 °C / Inert atmosphere 2.1: ferrous(II) sulfate heptahydrate / methanol / 20 °C / Cooling with ice 2.2: 1 h 3.1: calcium chloride / ethanol / 4 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 1.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1.5 h / 20 °C / Inert atmosphere 2.1: ferrous(II) sulfate heptahydrate / methanol / 20 °C / Cooling with ice 2.2: 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1.5 h / 20 °C / Inert atmosphere 2.1: ferrous(II) sulfate heptahydrate / methanol / 20 °C / Cooling with ice 2.2: 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; copper(l) iodide / dichloromethane; methanol / 0.5 h / 0 - 5 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 25 - 60 °C 2.2: 2 h / 25 - 30 °C / Inert atmosphere 3.1: manganese(IV) oxide / acetone / 20 h / 25 - 30 °C 4.1: triethylamine / water; ethanol / 3 h / 40 - 80 °C | ||
Multi-step reaction with 4 steps 1.1: cerium(III) chloride heptahydrate / dichloromethane; methanol / 0.5 h / 25 - 30 °C 1.2: 0.5 h / 0 - 5 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 25 - 60 °C 2.2: 2 h / 25 - 30 °C / Inert atmosphere 3.1: manganese(IV) oxide / acetone / 20 h / 25 - 30 °C 4.1: triethylamine / water; ethanol / 3 h / 40 - 80 °C | ||
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / toluene / Reflux; Large scale 2.1: lithium aluminium tetrahydride; hydrogen / tetrahydrofuran / 3 h / 60 - 65 °C / Inert atmosphere; Large scale 2.2: 0.25 h / Large scale 2.3: 0.33 h / 60 °C / pH < 1 / Large scale 3.1: triethylamine / ethanol / Reflux; Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 25 - 60 °C 1.2: 2 h / 25 - 30 °C / Inert atmosphere 2.1: manganese(IV) oxide / acetone / 20 h / 25 - 30 °C 3.1: triethylamine / water; ethanol / 3 h / 40 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: manganese(IV) oxide / acetone / 20 h / 25 - 30 °C 2: triethylamine / water; ethanol / 3 h / 40 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium hexacyanoferrate(III); potassium carbonate / toluene / 1 h / 50 - 60 °C / Large scale 2.1: toluene-4-sulfonic acid / toluene / Reflux; Large scale 3.1: lithium aluminium tetrahydride; hydrogen / tetrahydrofuran / 3 h / 60 - 65 °C / Inert atmosphere; Large scale 3.2: 0.25 h / Large scale 3.3: 0.33 h / 60 °C / pH < 1 / Large scale 4.1: triethylamine / ethanol / Reflux; Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride; hydrogen / tetrahydrofuran / 3 h / 60 - 65 °C / Inert atmosphere; Large scale 1.2: 0.25 h / Large scale 1.3: 0.33 h / 60 °C / pH < 1 / Large scale 2.1: triethylamine / ethanol / Reflux; Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: sulfuric acid / 6 h / 90 °C / Inert atmosphere; Large scale 2.1: ethanol / 4 h / Reflux; Large scale 3.1: sodium hydroxide; sodium tetrahydroborate / water / 1 h / 20 °C / Large scale 4.1: formic acid / 1,4-dioxane; N,N-dimethyl-formamide / 10 h / Reflux; Large scale 5.1: potassium hexacyanoferrate(III); potassium carbonate / toluene / 1 h / 50 - 60 °C / Large scale 6.1: toluene-4-sulfonic acid / toluene / Reflux; Large scale 7.1: lithium aluminium tetrahydride; hydrogen / tetrahydrofuran / 3 h / 60 - 65 °C / Inert atmosphere; Large scale 7.2: 0.25 h / Large scale 7.3: 0.33 h / 60 °C / pH < 1 / Large scale 8.1: triethylamine / ethanol / Reflux; Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1.1: bromine / methanol / 5 - 40 °C / Large scale 2.1: sulfuric acid / 6 h / 90 °C / Inert atmosphere; Large scale 3.1: ethanol / 4 h / Reflux; Large scale 4.1: sodium hydroxide; sodium tetrahydroborate / water / 1 h / 20 °C / Large scale 5.1: formic acid / 1,4-dioxane; N,N-dimethyl-formamide / 10 h / Reflux; Large scale 6.1: potassium hexacyanoferrate(III); potassium carbonate / toluene / 1 h / 50 - 60 °C / Large scale 7.1: toluene-4-sulfonic acid / toluene / Reflux; Large scale 8.1: lithium aluminium tetrahydride; hydrogen / tetrahydrofuran / 3 h / 60 - 65 °C / Inert atmosphere; Large scale 8.2: 0.25 h / Large scale 8.3: 0.33 h / 60 °C / pH < 1 / Large scale 9.1: triethylamine / ethanol / Reflux; Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: ethanol / 4 h / Reflux; Large scale 2.1: sodium hydroxide; sodium tetrahydroborate / water / 1 h / 20 °C / Large scale 3.1: formic acid / 1,4-dioxane; N,N-dimethyl-formamide / 10 h / Reflux; Large scale 4.1: potassium hexacyanoferrate(III); potassium carbonate / toluene / 1 h / 50 - 60 °C / Large scale 5.1: toluene-4-sulfonic acid / toluene / Reflux; Large scale 6.1: lithium aluminium tetrahydride; hydrogen / tetrahydrofuran / 3 h / 60 - 65 °C / Inert atmosphere; Large scale 6.2: 0.25 h / Large scale 6.3: 0.33 h / 60 °C / pH < 1 / Large scale 7.1: triethylamine / ethanol / Reflux; Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: sodium hydroxide; sodium tetrahydroborate / water / 1 h / 20 °C / Large scale 2.1: formic acid / 1,4-dioxane; N,N-dimethyl-formamide / 10 h / Reflux; Large scale 3.1: potassium hexacyanoferrate(III); potassium carbonate / toluene / 1 h / 50 - 60 °C / Large scale 4.1: toluene-4-sulfonic acid / toluene / Reflux; Large scale 5.1: lithium aluminium tetrahydride; hydrogen / tetrahydrofuran / 3 h / 60 - 65 °C / Inert atmosphere; Large scale 5.2: 0.25 h / Large scale 5.3: 0.33 h / 60 °C / pH < 1 / Large scale 6.1: triethylamine / ethanol / Reflux; Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: formic acid / 1,4-dioxane; N,N-dimethyl-formamide / 10 h / Reflux; Large scale 2.1: potassium hexacyanoferrate(III); potassium carbonate / toluene / 1 h / 50 - 60 °C / Large scale 3.1: toluene-4-sulfonic acid / toluene / Reflux; Large scale 4.1: lithium aluminium tetrahydride; hydrogen / tetrahydrofuran / 3 h / 60 - 65 °C / Inert atmosphere; Large scale 4.2: 0.25 h / Large scale 4.3: 0.33 h / 60 °C / pH < 1 / Large scale 5.1: triethylamine / ethanol / Reflux; Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: methanol / 1 h / 25 - 30 °C 2: triethylamine / water; ethanol / 3 h / 25 - 73 °C / Resolution of racemate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca.14%; 68% | A mixture of (4aS,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzezapin-6-one [(-)-narwedine] 6 (10g, 0.035mol), cerium chloride heptahydrate (13.07g, 0.035mol) in methylene chloride-methanol (1:1 v/v, 300mL) was stirred at -55 to -50C for 30min after which sodium borohydride (3.33g, 0.088mol) was added in portions at -55 to -50C over a period of 30min. The reaction mixture was stirred at -55 to -50C for 2h and the completion of the reaction was monitored by qualitative HPLC analysis. Water (10mL) was then added to the reaction mixture and the temperature was raised to 25-30C. The reaction mixture was concentrated under reduced pressure and the concentrated mass was stirred with chloroform (100mL). The inorganic residue was removed by filtration. The filtrate was washed with water (60mL) and the organic layer was concentrated under reduced pressure. The crude product was stirred with acetone (50mL) at reflux temperature. The slurry mass was cooled to 25-30C, filtered and dried at 45-50C under reduced pressure to yield (-)-epigalanthamine 3 as a white crystalline powder (6.85g, 68% yield). Chromatographic purity: 96.49% (by HPLC); enantiomeric purity: 97.71% (by HPLC); mp: 181-182C; [alpha]25D=-229.9[alpha]D25=-229.9 (c 1, CHCl3); IR (KBr, cm-1): 3151, 3031, 3011, 2945, 2916, 1623, 1508, 1459, 1445, 1436, 1272, 1053; deltaH (300MHz, CDCl3): 1.61-1.75 (m, 2H), 2.18 and 2.75 (dd, J = 12, 12 Hz, 2H), 2.36 (s, 3H), 3.07 and 3.22 (dd, J = 12.9, 12.1 Hz, 2H), 3.59 and 4.05 (dd, J = 15.3, 15 Hz, 2H), 3.83 (s, 3H), 4.60 (m, 2H), 5.79 (d, J = 10.2 Hz, 1H), 6.05 (d, J = 11.7 Hz, 2H), 6.55 and 6.62 (2d, J = 8.1, 8.1 Hz, 2H); deltaC (100MHz, CDCl3): 32.3 (2×CH2), 34.1 (CH3), 41.6 (CH2), 48.0, 53.8 (CH2), 55.8 (OCH3), 60.1 (CH2), 62.7 (CH), 88.4 (CH), 110.8 (CH), 121.5, 126.2 (CH), 128.9 (CH), 131.9 (CH), 132.9, 143.8, 146.6; HRMS (ESI+): m/z 288.1614 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 34.78% 2: 38.48% 3: 24.6% | With sodium tetrahydroborate In methanol; dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: methanol / 1 h / 25 - 30 °C 2.1: triethylamine / water; ethanol / 3 h / 25 - 73 °C / Resolution of racemate 3.1: cerium(III) chloride heptahydrate / methanol; dichloromethane / 0.5 h / -55 - 50 °C 3.2: 2.5 h / -55 - -50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: methanol / 1 h / 25 - 30 °C 2.1: triethylamine / water; ethanol / 3 h / 25 - 73 °C / Resolution of racemate 3.1: L-Selectride / tetrahydrofuran / 4 h / -50 - -45 °C 3.2: 2 h / 15 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol at 25 - 30℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate In methanol | ||
Multi-step reaction with 3 steps 1: methanol / 1 h / 25 - 30 °C 2: triethylamine / water; ethanol / 3 h / 25 - 73 °C / Resolution of racemate 3: sodium tetrahydroborate / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58 % ee | With manganese(IV) oxide Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With CYP96T1 In water at 30℃; Enzymatic reaction; | [0126] The concentration of CYP96T1 in Sf9 cell culture was determined to be 2.5 nM by CO-difference spectra. The temperature and pH optima for 4'-O-methylnorbelladine substrate were determined to be 30 °C (half height ±5-10 °C) and 6.5 (half height ±1), respectively. Testing of the CYP96T1 enzyme demonstrated that several structurally related alkaloids were C-C phenol coupled as detected by LC-MS/MS. These reactions were accompanied by a background reaction catalyzed by the Sf9 cells. 4'-O-methylnorbelladine was C-C phenol coupled into N-demethylnarwedine, (10ai?,4bi?)- and (10a 4bS)-noroxomaritidine in CYP96T1 assays. (10ai?,4bi?)- and (10a 4bS)-noroxomaritidine was identified by its identical liquid chromatographic retention time (Figure 15 A) and mass spectrometric fragmentation pattern with (10ai?,4bi?)- and (10a 4bS)-noroxomaritidine mixed standard (Figure 15 C and D) (Table 8). To determine the chirality of the noroxomaritidine product, 4'-O-methylnorbelladine assays with CYP96T1 were analyzed with a chiral-CBH column by LC-MS/MS. Chromatographic separation of (10ai?,4bi?)- and (10a 4bS)-noroxomaritidine standards was achieved preceding MS/MS analysis. All variants produced equivalent amounts of each epimer (Figure 16 A). A mass spectrometric comparison of standards (Figure 16 B and C) and enzymatically formed (10ai?,4bi?)- and (10a 4bS)-noroxomaritidine (Figure 16 D and E) yielded identical MS/MS fragmentation patterns. The enzyme is, therefore, producing both (10ai?,4bi?)- and (10a 4bS)-noroxomaritidine. A minor N- demethylnarwedine product was also detected in assays analyzed by HPLC on the Luna C8 column. The relative quantity of (10ai?,4bi?)- and (10a 4bS)-noroxomaritidine and N- demethylnarwedine formed in assays with CYP96T1 are quantified in Figure 18 A and B. HPLC was used to measure the relative contribution of these compounds to total product. (10ai?,4bi?)- and (10a 4bS)-noroxomaritidine account for -99% of the total product in CYP96T1 assays. (10aR,4bR)- and/or (10a5*,4b5)-noroxomaritidine and N- demethylnarwedine are also produced in assays containing only Sf9 cells and 4'-O- methylnorbelladine, but not in a no enzyme control, indicating Sf9 cells that have the ability to catalyze the C-C phenol couple with 4'-O-methylnorbelladine (Figure 15 A). Kinetic analysis of the CYP96T1 production of (10ai?,4bi?)- and (10a 4bS)-noroxomaritidine using nonlinear regression to the Michaelis-Menten kinetics equation for substrate inhibition show the Km to be in the low micro molar 1.13±0.5 μΜ with a kcat of 15.0±2.03 1/min (Table 8). In addition, the N-methylated form of 4'-O-methylnorbelladine ,4'-O-methyl-N- methylnorbelladine, was shown to produce several C-C phenol-coupled products when assayed with Sf9 cells alone as indicated by the detection of products with a mass reduction of 2 m/z, including narwedine and two unknown products (Figure 15 B). One product is enzymatically produced from 4'-O-methyl-N-methylnorbelladine by CYP96T1, as indicated by the increase of product in assays containing CYP96T1 as compared to the CPR-only control (Figure 15 B). These observations were confirmed by a MRM based relative quantification of selected transitions of these three products (Figure 18 C, D and E). The LC- MS/MS fragmentation pattern of the CYP96T1 product is a mixture of masses found in the para '-para products (10ai?,4bi?)- and (10a 4bS)-noroxomaritidine (165.1 m/z, 184.2 m/z, 195.0 m/z, 212.2 m/z, 229.0 m/z) and masses +14 m/z (120.1 m/z, 149.1 m/z, 243.2 m/z, 258.1 m/z, 271.0 m/z), representing the addition of a methyl moiety (Figure 15 E). For this reason, it appears the enzyme is capable of catalyzing formation of the para-para ' C-C phenol-couple regardless of N-methylation state. (Figure 18 D and E). To examine the ability of CYP96T1 to C-C phenol couple substrates with an altered carbon linker between the phenol groups, (S)- coclaurine and (i?)-coclaurine were also tested. Assays on ether (5)-coclaurine or (R)- coclaurine yield products with a mass -2 m/z which is consistent with a C-C phenol coupling. Product formation is not observed when norbelladine or N-methylnorbelladine is used as substrate. These results indicate the 4'-O-methylation state of norbelladine may be important for substrate-enzyme binding. The substrates 3'-O-methylnorbelladine and 3',4'-O- dimethylnorbelladine were tested to determine the relevance of 3'-O-methylation; products were not detected (Table 8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 2.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 3.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 6.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 7.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 7.2: 1 h / -10 °C 8.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 9.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 10.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 11.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 11.2: 3 h / -78 - 25 °C / Inert atmosphere 12.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 12.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 12 steps 1.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 2.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 6.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 7.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 7.2: 1 h / -10 °C 8.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 9.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 10.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 11.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 11.2: 3 h / -78 - 25 °C / Inert atmosphere 12.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 12.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 12 steps 1.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 2.1: 2-hydroxynitrobenzene / 36 h / 220 °C / Sealed tube; Inert atmosphere 3.1: bis-tri-n-butylstannane; azobisisobutyronitrile / tetrahydrofuran / 3 h / 80 °C / Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 6.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 7.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 7.2: 1 h / -10 °C 8.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 9.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 10.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 11.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 11.2: 3 h / -78 - 25 °C / Inert atmosphere 12.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 12.2: 16 h / 25 °C / 760.05 Torr |
Multi-step reaction with 13 steps 1.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 2.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 3.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 6.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 13 steps 1.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 2.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 6.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 13 steps 1.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 2.1: 2-hydroxynitrobenzene / 36 h / 220 °C / Sealed tube; Inert atmosphere 3.1: bis-tri-n-butylstannane; azobisisobutyronitrile / tetrahydrofuran / 3 h / 80 °C / Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 6.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 2.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 3.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 4.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 5.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 5.2: 1 h / -10 °C 6.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 7.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 8.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 9.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 9.2: 3 h / -78 - 25 °C / Inert atmosphere 10.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 10.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 10 steps 1.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 2.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 3.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 4.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 5.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 5.2: 1 h / -10 °C 6.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 7.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 8.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 9.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 9.2: 3 h / -78 - 25 °C / Inert atmosphere 10.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 10.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 11 steps 1.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 2.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 3.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 4.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 5.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 6.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 6.2: 1 h / -10 °C 7.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 8.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 9.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 10.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.2: 3 h / -78 - 25 °C / Inert atmosphere 11.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 11.2: 16 h / 25 °C / 760.05 Torr |
Multi-step reaction with 11 steps 1.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 2.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 3.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 4.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 5.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 6.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 6.2: 1 h / -10 °C 7.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 8.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 9.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 10.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.2: 3 h / -78 - 25 °C / Inert atmosphere 11.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 11.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 2.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 3.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 4.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 5.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 6.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 6.2: 1 h / -10 °C 7.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 8.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 9.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 10.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.2: 3 h / -78 - 25 °C / Inert atmosphere 11.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 11.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 11 steps 1.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 3.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 4.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 5.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 6.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 6.2: 1 h / -10 °C 7.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 8.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 9.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 10.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.2: 3 h / -78 - 25 °C / Inert atmosphere 11.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 11.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 11 steps 1.1: 2-hydroxynitrobenzene / 36 h / 220 °C / Sealed tube; Inert atmosphere 2.1: bis-tri-n-butylstannane; azobisisobutyronitrile / tetrahydrofuran / 3 h / 80 °C / Inert atmosphere 3.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 4.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 5.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 6.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 6.2: 1 h / -10 °C 7.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 8.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 9.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 10.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.2: 3 h / -78 - 25 °C / Inert atmosphere 11.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 11.2: 16 h / 25 °C / 760.05 Torr |
Multi-step reaction with 12 steps 1.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 2.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 3.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 4.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 5.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 6.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 7.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 7.2: 1 h / -10 °C 8.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 9.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 10.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 11.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 11.2: 3 h / -78 - 25 °C / Inert atmosphere 12.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 12.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 12 steps 1.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 3.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 4.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 5.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 6.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 7.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 7.2: 1 h / -10 °C 8.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 9.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 10.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 11.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 11.2: 3 h / -78 - 25 °C / Inert atmosphere 12.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 12.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 12 steps 1.1: 2-hydroxynitrobenzene / 36 h / 220 °C / Sealed tube; Inert atmosphere 2.1: bis-tri-n-butylstannane; azobisisobutyronitrile / tetrahydrofuran / 3 h / 80 °C / Inert atmosphere 3.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 4.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 5.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 6.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 7.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 7.2: 1 h / -10 °C 8.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 9.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 10.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 11.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 11.2: 3 h / -78 - 25 °C / Inert atmosphere 12.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 12.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 2.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 3.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 4.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 5.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 5.2: 1 h / -10 °C 6.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 7.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 8.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 9.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 9.2: 3 h / -78 - 25 °C / Inert atmosphere 10.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 10.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 9 steps 1.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 2.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 3.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 4.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 4.2: 1 h / -10 °C 5.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 6.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 7.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 8.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 8.2: 3 h / -78 - 25 °C / Inert atmosphere 9.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 9.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 6.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 7.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 7.2: 1 h / -10 °C 8.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 9.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 10.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 11.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 11.2: 3 h / -78 - 25 °C / Inert atmosphere 12.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 12.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 12 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 6.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 7.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 7.2: 1 h / -10 °C 8.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 9.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 10.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 11.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 11.2: 3 h / -78 - 25 °C / Inert atmosphere 12.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 12.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 13 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 6.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr |
Multi-step reaction with 13 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 6.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: bis-tri-n-butylstannane; azobisisobutyronitrile / tetrahydrofuran / 3 h / 80 °C / Inert atmosphere 2.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 3.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 4.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 5.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 5.2: 1 h / -10 °C 6.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 7.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 8.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 9.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 9.2: 3 h / -78 - 25 °C / Inert atmosphere 10.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 10.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 11 steps 1.1: bis-tri-n-butylstannane; azobisisobutyronitrile / tetrahydrofuran / 3 h / 80 °C / Inert atmosphere 2.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 3.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 4.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 5.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 6.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 6.2: 1 h / -10 °C 7.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 8.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 9.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 10.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.2: 3 h / -78 - 25 °C / Inert atmosphere 11.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 11.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 2.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 3.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 3.2: 1 h / -10 °C 4.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 5.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 6.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 7.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 7.2: 3 h / -78 - 25 °C / Inert atmosphere 8.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 8.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 9 steps 1.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 2.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 3.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 4.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 4.2: 1 h / -10 °C 5.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 6.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 7.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 8.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 8.2: 3 h / -78 - 25 °C / Inert atmosphere 9.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 9.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 2.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 3.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 3.2: 1 h / -10 °C 4.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 5.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 6.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 7.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 7.2: 3 h / -78 - 25 °C / Inert atmosphere 8.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 8.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 6.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 7.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 7.2: 1 h / -10 °C 8.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 9.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 10.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 11.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 11.2: 3 h / -78 - 25 °C / Inert atmosphere 12.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 12.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 12 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 6.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 7.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 7.2: 1 h / -10 °C 8.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 9.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 10.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 11.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 11.2: 3 h / -78 - 25 °C / Inert atmosphere 12.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 12.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 13 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 6.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr |
Multi-step reaction with 13 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 12.17 h / 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 4.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 5.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 6.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 13 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 4.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 5.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 6.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 13 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 12.17 h / 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 5.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 6.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 13 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 12.17 h / 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: 2-hydroxynitrobenzene / 36 h / 220 °C / Sealed tube; Inert atmosphere 4.1: bis-tri-n-butylstannane; azobisisobutyronitrile / tetrahydrofuran / 3 h / 80 °C / Inert atmosphere 5.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 6.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 14 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 12.17 h / 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 4.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 5.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 6.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 7.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 8.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 9.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 9.2: 1 h / -10 °C 10.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 11.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 12.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 13.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 13.2: 3 h / -78 - 25 °C / Inert atmosphere 14.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 14.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 14 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 12.17 h / 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 5.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 6.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 7.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 8.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 9.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 9.2: 1 h / -10 °C 10.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 11.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 12.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 13.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 13.2: 3 h / -78 - 25 °C / Inert atmosphere 14.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 14.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 14 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 12.17 h / 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: 2-hydroxynitrobenzene / 36 h / 220 °C / Sealed tube; Inert atmosphere 4.1: bis-tri-n-butylstannane; azobisisobutyronitrile / tetrahydrofuran / 3 h / 80 °C / Inert atmosphere 5.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 6.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 7.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 8.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 9.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 9.2: 1 h / -10 °C 10.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 11.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 12.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 13.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 13.2: 3 h / -78 - 25 °C / Inert atmosphere 14.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 14.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 2.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 2.2: 1 h / -10 °C 3.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 4.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 5.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 6.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 6.2: 3 h / -78 - 25 °C / Inert atmosphere 7.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 7.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 1.2: 1 h / -10 °C 2.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 3.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 4.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 5.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 5.2: 3 h / -78 - 25 °C / Inert atmosphere 6.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 6.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 2.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 3.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 4.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 4.2: 3 h / -78 - 25 °C / Inert atmosphere 5.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 5.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 2.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 3.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 3.2: 3 h / -78 - 25 °C / Inert atmosphere 4.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 4.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 2.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 2.2: 3 h / -78 - 25 °C / Inert atmosphere 3.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 3.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 1.2: 3 h / -78 - 25 °C / Inert atmosphere 2.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 2.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: lycoraminone With chloro-trimethyl-silane; lithium dipropan-2-ylazanide In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: With 2,6-di-tert-butyl-4-methylpyridine; oxygen; palladium diacetate In acetonitrile at 25℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 2.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 3.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 4.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 5.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 6.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 6.2: 1 h / -10 °C 7.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 8.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 9.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 10.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.2: 3 h / -78 - 25 °C / Inert atmosphere 11.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 11.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 11 steps 1.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 3.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 4.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 5.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 6.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 6.2: 1 h / -10 °C 7.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 8.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 9.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 10.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 10.2: 3 h / -78 - 25 °C / Inert atmosphere 11.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 11.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 12 steps 1.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 2.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 3.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 4.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 5.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 6.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 7.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 7.2: 1 h / -10 °C 8.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 9.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 10.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 11.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 11.2: 3 h / -78 - 25 °C / Inert atmosphere 12.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 12.2: 16 h / 25 °C / 760.05 Torr |
Multi-step reaction with 12 steps 1.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 3.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 4.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 5.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 6.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 7.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 7.2: 1 h / -10 °C 8.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 9.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 10.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 11.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 11.2: 3 h / -78 - 25 °C / Inert atmosphere 12.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 12.2: 16 h / 25 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 13 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 12.17 h / 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 4.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 5.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 6.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 13 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 12.17 h / 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 5.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 6.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 13 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 12.17 h / 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: 2-hydroxynitrobenzene / 36 h / 220 °C / Sealed tube; Inert atmosphere 4.1: bis-tri-n-butylstannane; azobisisobutyronitrile / tetrahydrofuran / 3 h / 80 °C / Inert atmosphere 5.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 6.1: BBr3 / dichloromethane / 1 h / -78 - 50 °C / Inert atmosphere 7.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 8.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 8.2: 1 h / -10 °C 9.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 10.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 11.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 12.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 12.2: 3 h / -78 - 25 °C / Inert atmosphere 13.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 13.2: 16 h / 25 °C / 760.05 Torr |
Multi-step reaction with 14 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 12.17 h / 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 4.1: 2-hydroxynitrobenzene / 5,5-dimethyl-1,3-cyclohexadiene / 36 h / 220 °C / Sealed tube; Inert atmosphere 5.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 6.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 7.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 8.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 9.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 9.2: 1 h / -10 °C 10.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 11.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 12.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 13.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 13.2: 3 h / -78 - 25 °C / Inert atmosphere 14.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 14.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 14 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 12.17 h / 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: n-butyllithium / toluene; hexane / 0.83 h / 0 - 25 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine / 48 h / 160 °C / Sealed tube; Molecular sieve; Inert atmosphere 5.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 6.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 7.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 8.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 9.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 9.2: 1 h / -10 °C 10.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 11.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 12.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 13.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 13.2: 3 h / -78 - 25 °C / Inert atmosphere 14.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 14.2: 16 h / 25 °C / 760.05 Torr | ||
Multi-step reaction with 14 steps 1.1: magnesium; iodine / tetrahydrofuran; ethylene dibromide / 25 °C / Inert atmosphere; Heating 1.2: 12.17 h / 0 - 25 °C / Inert atmosphere 2.1: (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol; dimethylsulfide borane complex / toluene; dichloromethane / 3 h / 25 °C / Inert atmosphere 3.1: 2-hydroxynitrobenzene / 36 h / 220 °C / Sealed tube; Inert atmosphere 4.1: bis-tri-n-butylstannane; azobisisobutyronitrile / tetrahydrofuran / 3 h / 80 °C / Inert atmosphere 5.1: 3,5-dimethyl-1H-pyrazole; chromium(VI) oxide / dichloromethane / -10 - 25 °C / Inert atmosphere 6.1: BBr3 / dichloromethane / 2 h / -78 - 0 °C / Inert atmosphere 7.1: potassium carbonate / propan-2-one / 10 h / 60 °C / Inert atmosphere 8.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 0.5 h 9.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 1 h / -10 °C 9.2: 1 h / -10 °C 10.1: trifluoroacetic acid / 1,2-dichloro-ethane / 9 h / 25 °C 11.1: potassium sec-butylborohydride / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 12.1: lithium aluminium hydride / tetrahydrofuran / 8.17 h / -78 - 80 °C 13.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 3 h / -78 °C / Inert atmosphere 13.2: 3 h / -78 - 25 °C / Inert atmosphere 14.1: lithium dipropan-2-ylazanide; chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 14.2: 16 h / 25 °C / 760.05 Torr |
Tags: 510-77-0 synthesis path| 510-77-0 SDS| 510-77-0 COA| 510-77-0 purity| 510-77-0 application| 510-77-0 NMR| 510-77-0 COA| 510-77-0 structure
Precautionary Statements-General | |
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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.
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