* 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.
With hydrogenchloride; Dihydroxy-isobutyl-boran In water at 20℃;
The compound of formula III ((iS ,2S , 3R,5S)-Pinanediol N-(2-pyrazinecarbonyl)-L- phenylalanine-L-leucine boronate ) was extracted from the aqueous layer by using 2x500m1 of di-isopropyl ether. To this di-isopropyl ether solution, 26.2 g of isobutylboronic acid and lOOmi of conc. HC1 were added and the reaction mixture wasstirred for 2-4 hours at room temperature. NaOH solution was added and the pH was adjusted to 10 to 12. The reaction mixture was stirred for 20-30 minutes and the layers were separated. 500m1 of ethyl acetate was added to the aqueous layer and the pH of the solution was adjusted to 5 to 5.5 by using a solution of HC1. Organic layer was separated and di-isopropyl ether (1500m1) was added and the reaction mixture wasstirred at 0 to 5 degree Celsius for 12 to 15 hours. The solid obtained was filtered and washed with di-isopropyl ether (2xlOOml) and dried to obtain the title compound.Yield: 77.0percent (50g)HPLC Purity: -99.9percent
70%
With hydrogenchloride; Dihydroxy-isobutyl-boran In methanol; n-heptane; water at 25 - 30℃; for 1 - 2 h;
EXAMPLE-2: PROCESS FOR PREPARING BORTEZOMIB (FORMULA I); To a stirred mixture of compound of Formula IX (13.6 g) in methanol (272 ml) at 25- 300C, was charged n-heptane (272 ml), and isobutylboronic acid (3.2 g). Charged 2N HCI (272 ml) to the reaction mass under vigorous stirring and maintained the reaction mass at 25-300C for 1 -2 hours. After the completion of the reaction, separated the n-heptane layer and discarded. Charged n-heptane (272 ml * 2) to the aqueous layer and stirred vigorously for 10-15 minutes. Separated the n-heptane layer and the aqueous layer obtained was concentrated under vacuum at 35 to 480C. The aqueous layer was extracted with dichloromethane (272 ml) under vigorous stirring. The extraction process is repeated (272 ml *2) and the obtained dichloromethane layers were pooled and washed with saturated sodium bicarbonate solution, followed brine solution. The organic layer is separated, concentrated under vacuum to give 6 ml of the reaction mass and allowed to cool to 25-300C. Purity: 95.13percent by HPLC.Charged Toluene (102 ml) to the above reaction mass and stirred at 25-300C for 2-3 hours. Filtered the solid obtained under vacuum washed with 5percent dichloromethane in toluene and dried at 45-500C under vacuum for 5 hours to give crude Bortezomib.Yield: 7.O g (70percent)Purity by HPLC: 99.22percentImpurity-B by HPLC: 0.43percentPolymorphic Form: Form-BXRD Pattern: As Illustrated in Fig -5 EXAMPLE-4: PROCESS FOR PREPARING BORTEZOMIB FOLLOWED BY PURIFICATION; To a stirred mixture of compound of formula IX (68.3 g) in methanol (1.22 L) at 25- 300C, was charged n-heptane (1.36 L), and isobutyl boron ic acid (16.13 g). Charged 1 N HCI (13.6 L) to the reaction mass under stirring and maintained the reaction mass at 25-300C for 1 -2 hours. After the completion of the reaction, separated the n- heptane layer and discarded. Charged n-heptane (1.36 L * 2) to the aqueous layer and stirred vigorously for 10-15 minutes. Separated the n-heptane layer and the aqueous layer obtained was concentrated under vacuum. The aqueous layer was extracted with dichloromethane (13.6 L) under vigorous stirring. The extraction process is repeated (13.6 L *2) and the obtained dichloromethane layers were pooled and washed with saturated sodium bicarbonate solution, followed by brine solution. The organic layer was separated, concentrated under vacuum to give crude Bortezomib (47.0 g)Purity by HPLC: 95.62percent Impurity-B by HPLC: 0.59percent <n="44"/>Purification 1 : Bortezomib (25 g, Purity: 95.62percent) and 5percent ethylacetate in Toluene (250 ml) were taken into a round bottom flask and stirred at 25 to 350C for 2-3 hours. Filtered the solid obtained under vacuum washed with 5percent ethylacetate in toluene and dried at 500C under vacuum for 5 hours to give Bortezomib.Yield: 18.O g (72percent) Purity by HPLC: 99.68percent Impurity-B by HPLC: 0.27percentPurification 2: Bortezomib (18.0 g, purity 99.68percent) and methanol (54 ml) were taken into a round bottom flask and stirred. Filtered the reaction mass through scinted funnel and washed the bed with 18 ml methanol. Demineralized water (72 ml) was added to the obtained filtrate and stirred for 2 hours at a temperature of about 27°C. The reaction suspension was filtered and washed the solid with aqueous methanol (108 ml; Water : methanol 1 :1 ). The obtained solid was dried at a temperature of about 500C for about 5 hours to afford 14 g of title compound.Yield: 14.O g (77percent) Purity by HPLC: 99.83percentImpurity B: 0.15percent (by HPLC) Chiral Purity by HPLC: 99.85percentEXAMPLE-5: PROCESS FOR PREPARING BORTEZOMIB FOLLOWED BY PURIFICATION:;To a stirred mixture of compound of formula IX (10.25 g) in methanol (174.5 ml) at 25-300C, was charged n-heptane (205 ml), and isobutylboronic acid (2.42 g). Charged 0.5N HCI (205 ml) to the reaction mass under stirring and maintained the reaction mass at 25-300C for 1 -2 hours. After the completion of the reaction, separated the n-heptane layer and discarded. Charged n-heptane (205 ml * 2) to the aqueous layer and stirred vigorously for 10-15 minutes. Separated the n-heptane layer and the aqueous layer obtained was concentrated under vacuum. The aqueous layer was extracted dichloromethane (205 ml) under vigorous stirring. The <n="45"/>extraction process is repeated (205 ml) and the obtained dichloromethane layers were pooled and washed with saturated sodium bicarbonate solution, followed brine solution. The organic layer is separated, concentrated under vacuum to give crude Bortezomib (5.8 g).Purity by HPLC: 95.81 percent Impurity-B by HPLC: 0.34percentPurification 1 : Bortezomib (5 g, Purity: 95.81 percent) and 5percent dichloromethane in Toluene (40 ml) were taken into a round bottom flask and stirred at 25 to 350C for 2-3 hours. Filtered the solid obtained under vacuum, washed with 5percent dichloromethane in toluene and dried at 500C under vacuum for 5 hours to give Bortezomib.Yield: 4.2 g (84percent) Purity by HPLC: 99.12percent Impurity-B by HPLC: 0.31 percentPurification 2: Bortezomib (4.2 g, purity 99.12percent) and methanol (12.6 ml) were taken into a round bottom flask and stirred. Demineralized water (12.6 ml) was added to the reaction mass and stirred for 2 hours at a temperature of about 27°C. The reaction suspension was filtered and washed the solid with aqueous methanol (25.2 ml; water : methanol 1 :1 ). The obtained solid was dried at a temperature of about 500C for about 5 hours to afford 2.95 g of title compound.Yield: 2.95 g (70percent)Purity by HPLC: 99.70percent Impurity-B by HPLC: 0.2percent Chiral Purity: 99.83percent (by HPLC) EXAMPLE-12: PROCESS FOR PREPARING BORTEZOMIB FOLLOWED BY PURIFICATION:; To a stirred mixture of compound of formula IX (27.3 g) in methanol (491.4 ml) at 25-300C, was charged n-heptane (546 ml), and isobutylboronic acid (6.4 g). Charged 1.0 N HCI (546 ml) to the reaction mass under stirring and maintained the <n="49"/>reaction mass at 25-300C for 1 -2 hours. After the completion of the reaction, separated the n-heptane layer and discarded. Charged n-heptane (546 ml * 2) to the aqueous layer and stirred vigorously for 10-15 minutes. Separated the n-heptane layer and the aqueous layer obtained was concentrated under vacuum to remove methanol. The aqueous layer was extracted with dichloromethane (546 ml) under vigorous stirring. The extraction process is repeated with dichloromethane (546 ml x 2) and the obtained dichloromethane layers were pooled and washed with saturated sodium bicarbonate solution, followed brine solution. The organic layer is separated, concentrated under vacuum to give crude Bortezomib (19.0 g).Purity by HPLC: 96.66percent Isomeric impurity by HPLC: 0.46percentPurification 1 : Bortezomib (17 g, Purity: 96.66percent) and 5percent ethylacetate in Toluene (136 ml) were taken into a round bottom flask and stirred at 25 to 350C for 2-3 hours. Filtered the solid obtained under vacuum, washed with 5percent ethylacetate in toluene and dried at 500C under vacuum for 5 hours to give Bortezomib.Yield: 14.O g (82.3percent) Purity by HPLC: 98.61 percentIsomeric impurity by HPLC: 0.34 percentPurification 2: Bortezomib (14 g, purity 98.61 percent) and methanol (42 ml) were taken into a round bottom flask and stirred. Filtered the reaction mass through sintered funnel and washed with methanol (14 ml). Charged filtrate into a round bottom flask and add demineralized water (56 ml) to the reaction mass and stirred for about 2 hours at a temperature of about 27°C. The reaction suspension was filtered and washed the solid with aqueous methanol (84 ml, water: methanol 1 :1 ). The obtained solid was dried at a temperature of about 500C for about 5 hours to afford 8.5 g of title compound.Yield: 8.5 g (60percent) Purity by HPLC: 99.84percent Isomeric impurity by HPLC: 0.12percent
22 mg
With hydrogenchloride; Dihydroxy-isobutyl-boran In methanol; n-heptane at 20℃; for 12 h;
46 g of the compound obtained from example 5 was dissolved in 368.0 ml of methanol ina reaction flask. 368.0 ml of heptane was added to the solution at room temperaturefollowed by addition of 14.72 g of 2-methyl-1-propyl boronic acid. 230.0 ml of iNhydrochloric acid solution was added drop wise and the reaction mass was stirred for12 hours.After completion of the reaction, the heptane layer was separated and discarded. The aqueous methanol layer was washed with more heptane and then concentrated at 35 °C under vacuum to remove the methanol completely. The residue obtained was dissolved in 368.0 ml of dichloromethane and cooled to 3±2 °C. The pH of the solution was adjusted to 12±0.1 with 2N NaOH solution. The dichioromethane layer was separated and the aqueous layer was washed with more dichloromethane. The aqueous layer was transferred to a clean flask and cooled to 3±2 °C. 460.0 ml of 2N HC1 was then added and the reaction mass was extracted with dichioromethane. The dichloromethane was washed with saturated brine solution till the pH of the washings was neutral. The dichloromethane layer was dried over sodium sulphate and dichioromethane was evaporated below 35 °C under vacuum. To the oil obtained, 184.0 ml of acetone was added and distilled at below 50 °C followed by further addition of 368.0 ml of fresh acetone and the reaction mass was stirredat 25 °C, cooled to 5 ± 2 °C and stirred. The solid obtained was filtered, washed with chilled acetone and then dried in vacuum at 43 ± 2 °C for 10 hours.Yield: 22.0 gPurity : 99.7percentChiral purity - 99.87percent
Stage #1: With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 0℃; for 0.5 h; Stage #2: at 0 - 25℃; for 24 h;
N-(Pyrazine-2-ylcarbonyl)-L-phenylalanine sodium salt (1.8 g) and TBTU (2.2 g) were suspended in dichloromethane (115 ml ) in a beaker. The suspension was charged to a jacketed flask and the beaker was washed with dichloromethane (115 ml). The suspension was cooled to 0°C and stirred for 30 minutes. (1R)-(S)-Pinanediol 1-ammonium trifluoroacetate-3- methylbutane-1 -boronate (2.3 g) in dichloromethane (115 ml) was charged to the jacketed flask, the beaker was washed with dichloromethane (115 ml), and the washing added to the jacketed flask. The resulting mixture was stirred for 30 minutes at 00C. The mixture was then warmed from O0C to 25°C over a period of 150 minutes and stirred over night (21 hours). The mixture was extracted with 2 x 230 ml H2O, 2 x 230 ml 1percent H3PO4, 1 x 230 ml and 1 x 195 ml 2percent K2CO3, 2 x 230 ml 10percent NaCl , 2 x 230 ml H2O. The organic layer was transferred to a 500 ml flask and dried over Na2SO4 (26.5 g) which was subsequently filtered off and washed with 100 <n="15"/>ml dichloromethane. The title product was isolated by evaporation to provide an oil (2.77 g, purity 84.0 percent, yield 87.1 percent); MS (m/z): 1053 βM+NEUf, 1036 [2M+H]+, 519 [M+H]+.
Reference：
[1] Patent: WO2009/4350, 2009, A1, . Location in patent: Page/Page column 13; 14; title page; sheet 1
3
[ 114457-94-2 ]
[ 205393-22-2 ]
Yield
Reaction Conditions
Operation in experiment
86%
With 4-methyl-morpholine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In dichloromethane; acetonitrile at -15 - 25℃; for 1.5 h;
Example 3: Compound of formula (4)Mix the (S)-3-phenyl-2-(pyrazine-2-carboxamido)propanoic acid (10.85 g,40.0 mmol) with the trifluoroacetate salt of the compound of formula (2) (16.27g, 40.0 mmol) in 215 ml of anhydrous dichloromethane at 20-25°C. Cool the formed white suspension under stirring to -15°C and add N-methylmorpholine (17.7 ml, 160 mmol) while keeping the internal temperature at -10°C. Add the T3P reagent (2,4,6-triprop-l-yl-l,3,5-trioxa-2,4,6- triphosphinane-2,4,6-trioxide, 38.2 g of 50percent solution in acetonitrile, 60 mmol)at the same temperature. Stir the reaction mixture at -10 to -15°C for 1.5 hours.Warm the reaction mixture to 20-25°C and add 215 ml of water. Separate the layers and was the organic layer with 210 ml of brine. Dry the organic extract with anhydrous sodium sulphate and evaporate the volatiles (5 mbar, 40°C) to an oily residue. Transfer the residue to silic gel pad (54.3 g, Silica gel 60 Merck, 40-63 μιη, 230-400 Mesh) and elute crude product with a mixture of n-heptane/MTBE (460 ml). Evaporate volatiles (5mbar, 40°C) and yield 18.12 g of a yellow residue (86percent).HPLC: Chemical purity 98.69percent (IN), Chiral purity 99.7percent.
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 14, p. 4192 - 4199
5
[ 98-97-5 ]
[ 205393-22-2 ]
Yield
Reaction Conditions
Operation in experiment
46 g
Stage #1: With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In toluene for 0.166667 h; Inert atmosphere Stage #2: With N-ethyl-N,N-diisopropylamine In toluene at 25℃; for 3 h;
5) Preparation of N- {( 1 R)-3-methyl- 1 -[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6- methano- 1,3 ,2-benzodioxaborol-2-yl jbutyl} -Na-(pyrazin-2-ylcarbonyl)-L-pbenylalaninamide of formula (VII)400 ml toluene and 40.0 g of the compound obtained from example 4 were charged into a reaction flask under nitrogen atmosphere followed by addition of 12.2 g of pyrazine-2- carboxylic acid of formula (VI) and 32.0 g of TBTU. The reaction mixture was stirred for 10 minutes and cooled to 0 ± 5 °C. 64.0 ml N,N’-diisopropyl ethyl amine diluted with 80.0 ml of toluene was added drop wise to the reaction mass and the reaction mass was warmed to 25 °C and stirred for 3 hours.After completion of the reaction, the reaction mass was washed with 2 x 400 ml purified water. The layers were separated and the toluene layer was washed with 400 ml of 1percent phosphoric acid solution, 400 ml of 2percent potassium carbonate solution and fmally with 400 ml of 10percent sodium chloride solution. The toluene layer was dried with sodium sulphate and distilled completely under vacuum at below 37 °C.Yield:46.Og
(1S,2S,3R,5S)-pinanediol L-phenylalanine-L-leucine boronate hydrochloride[ No CAS ]
[ 205393-22-2 ]
(1S,2S,3R,5S)-pinanediol N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucine boronate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at -1.2 - 24.9℃; for 2.1833299999999998h;Industry scale;
1. In a fume hood a three-necked glass reaction flask equipped with a Claisen head, temperature recorder and a mechanical stirrer was flushed with nitrogen. 2. (1S, 2S,3R,5S)-Pinanediol L-phenylalanine-L-leucine boronate, HCl salt (1.85 kg) was charged to the flask. 3.2-Pyrazinecarboxylic acid (0.564 kg) was charged to the flask. 4. 2-(H-Benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, TBTU (1.460 kg) was charged to the flask. 5. Dichloromethane (18.13 L) was charged to the flask. 6. The stirring motor was adjusted to provide stirring at 272 RPM. 7. Using a cooling bath, the reaction mixture was cooled to-1.2 C. 8. N,N-Diisopropylethylamine (1.865 kg) was charged to a glass flask and transferred to the reaction over a period of 50 minutes using a peristaltic pump maintaining a reaction temperature range of -1.2 C to 2.8 C. 9. A dichloromethane rinse (0.37 L) of the flask into the reaction mixture was used to complete the addition. 10. The reaction mixture was allowed to warm and stirred for an additional 81 minutes. 11. The temperature at the start of the stir time was 15 C, and 24.9 C at the end. 12. A sample was then removed for in-process testing by RP-HPLC. The percent conversion was determined to be 99.9%. 13. The reaction mixture was transferred in approximately two equal halves to two rotary evaporator flasks. The reaction mixture was concentrated under reduced pressure using two rotary evaporators, maintaining an external bath temperature of 33-34 C. 14. Ethyl acetate (12.95 L) was divided into two approximately equal portions and charged to the two rotary evaporator flasks. 15. The mixtures in each flask were then concentrated under reduced pressure using a rotary evaporator, maintaining an external bath temperature of 33-34 C. 16: - - The-residues in each rotary evaporator flask were then transferred back to the reaction flask using ethyl acetate (12.95 L). 17. In a glass flask equipped with a stirrer, a 1% aqueous phosphoric acid solution (12.34 L) was prepared by mixing D.I. water (12.19 L) and phosphoric acid (0.148 kg). 18. In a glass flask equipped with a stirrer, a 2% aqueous potassium carbonate solution (12.34 L) was prepared by mixing D. I. water (12.09 L) and potassium carbonate (0.247 kg). 19. In a glass flask equipped with a stirrer, a 10% aqueous sodium chloride solution (12.34 L) was prepared by mixing D. I. water (12.34 L) and sodium chloride (1.234 kg). 20. D. I. water (12.34 L) was charged to the reaction flask containing the ethyl acetate solution and the mixture stirred at 382 RPM for 7 minutes. The layers were allowed to separate and the aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 21. Again, D. I. water (12.34 L) was charged to the reaction flask containing the ethyl acetate solution and the mixture stirred at 398 RPM for 7 minutes. The layers were allowed to separate and the aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 22. The 1% phosphoric acid solution prepared in Step 17 was charged to the reaction flask containing the ethyl acetate solution and the mixture stirred at 364 RPM for 8 minutes. The layers were allowed to separate and the acidic aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 23. The 2% potassium carbonate solution prepared in Step 18 was charged to the reaction flask containing the ethyl acetate solution and the mixture stirred at 367 RPM for 8 minutes. The layers were allowed to separate and the basic aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 24. The 10% sodium chloride solution prepared in Step 19 was charged to the reaction flask containing the ethyl acetate solution and the mixture stirred at 374 RPM for 8 minutes. The layers were allowed to separate and the aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 25. The ethyl acetate solution was transferred under vacuum in approximately two equal halves to two rotary evaporator flasks and concentrated under reduced pressure using a rotary evaporator, maintaining an external bath temperature of 34 C. 26. n-Heptane (14.8 L)-was divided into two approximately equal portions and charged to the two rotary evaporator flasks. The mixtures in each flask were then concentrated under reduced pressure using a rotary evaporator, maintaining an external bath temperature of 34 C.
(aR,3aS,4S,6S,7aR)-hexahydro-3a,8,8-trimethyl-α-(2-methylpropyl)-4,6-methano-1,3,2-benzodioxaborole-2-methanamine 2,2,2-trifluoroacetate[ No CAS ]
[ 114457-94-2 ]
[ 205393-22-2 ]
Yield
Reaction Conditions
Operation in experiment
86%
With 4-methyl-morpholine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In dichloromethane; acetonitrile; at -15 - 25℃; for 1.5h;
Example 3: Compound of formula (4)Mix the <strong>[114457-94-2](S)-3-phenyl-2-(pyrazine-2-carboxamido)propanoic acid</strong> (10.85 g,40.0 mmol) with the trifluoroacetate salt of the compound of formula (2) (16.27g, 40.0 mmol) in 215 ml of anhydrous dichloromethane at 20-25C. Cool the formed white suspension under stirring to -15C and add N-methylmorpholine (17.7 ml, 160 mmol) while keeping the internal temperature at -10C. Add the T3P reagent (2,4,6-triprop-l-yl-l,3,5-trioxa-2,4,6- triphosphinane-2,4,6-trioxide, 38.2 g of 50% solution in acetonitrile, 60 mmol)at the same temperature. Stir the reaction mixture at -10 to -15C for 1.5 hours.Warm the reaction mixture to 20-25C and add 215 ml of water. Separate the layers and was the organic layer with 210 ml of brine. Dry the organic extract with anhydrous sodium sulphate and evaporate the volatiles (5 mbar, 40C) to an oily residue. Transfer the residue to silic gel pad (54.3 g, Silica gel 60 Merck, 40-63 muiotaeta, 230-400 Mesh) and elute crude product with a mixture of n-heptane/MTBE (460 ml). Evaporate volatiles (5mbar, 40C) and yield 18.12 g of a yellow residue (86%).HPLC: Chemical purity 98.69% (IN), Chiral purity 99.7%.
Step-h) Preparation of Formula IX:; <n="41"/>To a stirred mixture of compound of Formula VIII (28.6 g) in dichloromethane (400 ml) at 25-300C under nitrogen atmosphere, were charged N-hydroxysuccinimide (13.3 g) and DCC (23.9 g) and stirred for 10-20 minutes. Charged compound of Formula-V (40 g) to the reaction mass was and stirred for 15-20 minutes.Charged diisopropylethylamine (DIPEA) (27 ml) and maintained the reaction mass at 25-300C for 2-3 hours. The reaction mass was filtered and the solid was washed with dichloromethane (80 ml). The filtrate obtained was washed with 1 N HCI, followed by washing with sodium bicarbonate solution. Concentrated the organic layer up to 2 volumes with respect to Formula-V. Charged methanol (200 ml) and concentrated up to 2 volumes with respect to Formula-V. The concentrated mass obtained is the title compound (Formula IX).
Alternately, compound of Formula IX may also be prepared by using EDCHCI, and Hydroxybenzotriazole by a process as described below: N-(2-pyrazinecarbonyl)-L-phenylalanine (500 mg) was suspended in dichloromethane (10 ml) and cooled to about -5C to about 00C. Hydroxybenzotriazole (HOBt:310 mg) was charged in to the reaction mass followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCI, 385 mg) and stirred for 15 minutes. (1 R)-(S)-pinanediol 1 -ammonium trifluoroacetate-3-methylbutane-i -boronate (695 mg) was added to the reaction mixture and stirred for about 10 minutes at a temperature of about 5C Diisopropyl ethyl amine (0.6 ml) was charged to the reaction mixture and stirred for about 30 minutes at a temperature of about 5C The reaction mixture was allowed to warm to a temperature of about 25C to about 300C and stirred for about 1 hour followed by the addition of 1 N hydrochloric acid (30 ml). The layers were separated and the organic layer was washed with 1 N hydrochloric acid (15 ml) and saturated sodium bicarbonate solution (2x30 ml). The organic layer was concentrated completely to afford title compound. <n="42"/>Purity by HPLC: 84.98% Note that it is believed that 9.01 % measured by HPLC is Bortezomib that is formed prior to the final Bortezomib step. Thus, overall purity should be 84.98% + 9.0% or 93.99% as measured by HPLC.
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine hydrochloride[ No CAS ]
[ 114457-94-2 ]
[ 205393-22-2 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at -40 - -11℃;
A 500 ml three neck round bottomed flask equipped with a stir bar, addition funnel, ther60 mocouple, nitrogen inlet/outlet and cooling bath is chargedwith 11 g (99.9 mmol) of(S)-3-phenyl-2-[(pyrazine-2-carbo- nyl)-amino]-propionic acid, 15.5.0 g (40.6 mmol) of o-(7- azabenzotriazol- 1 -yl)-N,N,N?N?-tetramethyluroniumhexafluorophosphate (HATU), 12.2 g (40.6 mmol) of (1R)-1 -[(3a5,45,65,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1 ,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt (87:13 mixture of isobutyl diastereomers (R:S)) and 165 mE of N,N-dimethylformamide (DMF). The pale yellow reaction solution is cooled to -35 C. where 12.6 g (17 mE, 97.3 mmol) of N,N-di-isopropyl ethyl amine is added dropwise over six minutes at -34 C. to -35 C. The resulting solution is then stirred overnight at -40 to -11 C. The reaction mixture is quenched onto 600 ml of a 1:1 cold water/ethyl acetate mixture. Afier transferring into a reparatory funnel the layers are separated. The organic phase is then washed successively with 10% aqueous sodium hydrogen phosphate (1 x200 mE), 8% aqueous sodium bicarbonate(2x200 mE) and saturated sodium chloride (1 x200 mE). The product solution is dried over magnesium sulfate then filtered. The filtrate is evaporated to dryness in vacuo to give 19.57 g (37.7 mmol, 93%) of the title compound as a light brown foam with an HPEC purity of 92 A %. ?H NMR (d6-DMSO, 400 MHz) oe 9.15 (d, 1H, J=1 .44 Hz), 8.87 (d, 1H, J=2.48 Hz), 8.7 (m, 3H), 7.25 (m, 4H), 7.18 (m, 1H), 4.89 (q, 1H, J=6.88, 15.4 Hz), 4.13 (dd, 1H, J=1.8, 8.56 Hz), 3.15 (d, 2H, J=6.88 Hz), 2.7 (m, b, 1H), 2.22 (m, b, 1H), 2.05 (m, b, 1H), 1.87 (t, 1H, J=5.40 Hz), 1.81 (s, b, 1H), 1.67 (d, b, 1H),1.52 (m, b, 1H), 1.13-1.33 (m, 9H), 0.83 (dd, 6H, J=2.48, 6.56 Hz), 0.80 (s, 3H).
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