179324-69-7

Basic information

• Product Name: Bortezomib
• Synonyms: Boronic acid, B-[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(2-pyrazinylcarbonyl)aMino]propyl]aMino]bu;MG-341 PS-341;BortezoMib Base;BortezoMib-D8;bortezoMib(other);MLM341;BortezoMib R;BortezoMib (PS-341, LDP-341, MLM341)
• CAS NO: 179324-69-7
• Molecular Formula: C₁₉H₂₅BN₄O₄
• Molecular Weight: 384.24
• EINECS: 1308068-626-2
• Product Categories: ProteasomeInhibitors;Apis;Inhibitor;Final material;API;peptides;Boron Derivatives;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Pepetides
• Mol File: 179324-69-7.mol
• Article Data: 22

Chemical Properties

• Melting Point: 122-124°C
• Appearance: yellow solid
• Density: 1.214
• Refractive Index: 1.564
• Storage Temp.: Hygroscopic, -20°C Freezer, Under Inert Atmosphere
• Solubility: Soluble in chloroform, dimethyl sulfoxide, ethanol and methanol.
• PKA: 9.66±0.43(Predicted)
• Stability: Hygroscopic and Moisture Sensitive
• CAS DataBase Reference: Bortezomib(CAS DataBase Reference)
• NIST Chemistry Reference: Bortezomib(179324-69-7)
• EPA Substance Registry System: Bortezomib(179324-69-7)

Safety Data

• Statements: 23/24/25-48/23/24/25
• Safety Statements: 9-27-36/37-45-60
• RTECS: ED7771666
• HazardClass: 6.1
• Hazardous Substances Data: 179324-69-7(Hazardous Substances Data)

Usage

Description

Bortezomib, a modified dipeptidyl boronic acid, is a therapeutic proteasome inhibitors used for the treatment of cancers. It is indicated for the treatment of relapsed multiple myeloma and mantle cell lymphoma. It is capable of inhibiting the mammalian 26S proteasome, which is important in regulating the intracellular concentration of specific proteins to maintain homeostasis within cells. The disruption of 26S proteasome function disrupts normal cellular homeostasis, leading to cytotoxic effect on various kinds of cancer cells.

Drug for Cancer treatment

Bortezomib is a drug for treatment of hematopoietic malignancies with the appearance being white or white-like crystalline powder. It is easily soluble in dimethyl sulfoxide, ethanol, but insoluble in aqueous solution. This product is the reversible inhibitor of the mammal cell 26S proteasome chymotrypsin-like activity. 26S proteasome is a large protein complex which can degrade ubiquitin. Ubiquitin proteasome pathway plays an important role in regulation of the intracellular concentration of specific proteins in order to maintain the stability of the intracellular environment. Proteolytic affects intracellular multi-level signalling cascade. The disruption of the normal intracellular environment can lead to cell death while the inhibition of the 26S proteasome can prevent the hydrolysis of specific proteins. In vitro tests have proved bortezomib exhibits cytotoxicity to multiple types of cancer cells. The in vivo models of preclinical tumor have proved that bortezomib is capable of delaying the tumor growth of multiple myeloma which is suitable for the treatment of multiple myeloma.

Description

Bortezomib, a potent ubiquitin proteasome (26S) inhibitor (Ki=0.6 nM), was launched in the US as a treatment for multiple myeloma. This proteasome is required for the proteolytic degradation of the majority of cellular proteins and is present in all cells. It is required for the control of inflammatory processes, cell cycle regulation and gene expression and is a novel target in cancer treatment. Bortezomib is a N-acyl-pseudodipeptidyl boronic acid and formulated as a mannitol ester. Aldehyde containing peptides are also proteasome inhibitors, but lack chiral stability (racemization) and selectivity against other proteases including cysteine proteases. Replacement of the aldehyde moiety by a boronic acid avoids these shortcomings and provides some measure of selective proteasome inhibition relative to many other serine proteases. It is prepared by coupling the pinanediol ester of leucine boronic acid with N-tert-Bocphenylalanine utilizing O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) as the coupling agent. The tert-Boc protecting group is then cleaved from the dipeptide and pyrazinecarboxylic acid is coupled to form the terminal amide. Hydrolysis of the boronate ester is accomplished via a two-phase transesterification procedure using isobutyl boronic acid and aqueous extraction. In a study of patients who had received at least two prior therapies and demonstrated disease progression on their most recent therapy, about twenty eight percent showed a response to bortezomib. The response lasted a median time of one year. Another trial in 54 patients with relapsed multiple myeloma showed similar responses. It is dosed intravenously at an exposure of 1.3 mg/m2/dose twice weekly for two weeks followed by a 10-day drug-holiday. At therapeutic doses, the plasma drug levels were reported to drop to near detection limits within minutes of intravenous dosing. Based upon an ex vivo proteasome activity assay using blood cells, the pharmacodynamic half-life ranged from 9 to 15 h in patients with advanced malignancies.

Chemical Properties

Yellow Solid

Originator

Millenium (LeukoSite, Proscript) (US)

Uses

Bortezomib is the first proteasome inhibitor to be approved b the US FDA for multiple myeloma, a blood cancer. A reversible inhibitor of the 26S proteasome-a barrel-shaped multiprotein particle found in the nucleus and cytosol of all eukaryotic cells. T

Uses

A potent, highly selective and reversible inhibitor of the 20S proteasome, Bortezomib is used as an antineoplastic agent, which controls the growth of cancer cells. It is also useful in the treatment of multiple myeloma.

Definition

ChEBI: L-Phenylalaninamide substituted at the amide nitrogen by a 1-(dihydroxyboranyl)-3-methylbutyl group and at Nalpha by a pyrazin-2-ylcarbonyl group. It is a dipeptidyl boronic acid tha reversibly inhibits the 26S proteasome.

Brand name

Velcade (Millennium).

General Description

Proteasomes normally function to degrade proteins that areno longer needed by the cell. Such proteins are normallymarked by the addition of ubiquitin, a 76 amino acid proteinthat is added to the -amino group of lysine residues onthe target proteins. The marked proteins are then hydrolyzedby the large barrel-shaped proteasomes to givepeptides of 7 to 8 residues that may be further hydrolyzedand reutilized by the cell. This process serves to regulateprotein levels within the cell, remove defective proteins,and becomes important in maintaining normal signal transduction.Inhibition of the proteasomes results in the buildup of ubiquitylated proteins, which disrupts cell-signalingprocesses and cell growth. The signaling bytranscription factor NF-B (nuclear factor B) appears tobe especially sensitive to bortezomib. NF-B is associatedwith the transcription of antiapoptotic and proliferativegenes but is under the control of IB (inhibitor of NF-B).IB can itself be phosphorylated by IKK (IB kinase),which marks IB for ubiquitylation and destruction allowingNF-B to mediate its antiapoptotic and proliferative effects effects.In the presence of the competitive inhibitor bortezomib(IC50＝0.6 nM), the 26S proteasome is inhibitedand the ubiquitylated IkB is still capable of inhibiting NF-kB, preventing its effects.

Pharmaceutical Applications

Bortezomib belong to the class of drugs called proteasome inhibitors and is licensed in the United States and the United Kingdom for the treatment of multiple myeloma. The drug has been licensed for patients in whom the myeloma has progressed despite prior treatment or where a bone marrow transplant is not possible or was not successful. It is marketed under the name Velcade? or Cytomib?. Velcade is administered via injection and is sold as powder for reconstitution. Bortezomib was the first drug approved in the new drug class of proteasome inhibitors and boron seems to be its active element. For the mode of action, it is believed that the boron atom binds with high affinity and specificity to the catalytic site of 26S proteasome and inhibits its action. Therapy with Bortezomib can lead to a variety of adverse reactions, including peripheral neuropathy, myelosuppression, renal impairment and gastrointestinal (GI) disturbances together with changes in taste. Nevertheless, the side effects are in most cases less severe than with alternative treatment options such as bone marrow transplantation.

Biochem/physiol Actions

Cell permeable: yes

Clinical Use

Proteasome inhibitor: Treatment of multiple myeloma for people who have already tried at least 1 prior therapy and have disease progression

Synthesis

Although the synthesis of dipeptidyl boronic acids have appeared on several reports, the synthetic details for bortezomib were not revealed. The synthetic route for the preparation of bortezomib is depicted in the scheme.The pinanediol ester of leucine boronic acid (56)was coupled with N-Boc phenylalanine (57) in the presence of TBTU followed by deprotection of the Boc group to provide 58. N-Acylation of 58 then furnished the dipeptide boronate ester 60. Deprotection of the boronic ester functionality was achieved by bi-phase transfer esterification with isobutyl boronic acid. Bortezomib (VI) was isolated by extractive workup.

Drug interactions

In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolised via cytochrome P450 enzymes, 3A4, 2C19, and 1A2. The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors.

Metabolism

In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolised via cytochrome P450 enzymes, 3A4, 2C19, and 1A2. The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors.

References

1) Adams et al. (1999), Proteasome inhibitors: a novel class of potent and effective antitumor agents; Cancer Res., 59 2615 2) Williams et al. (2003), Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts; Mol. Cancer Ther., 2 835 3) Richardson et al. (2003), Bortezomib (PS-341): a novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancers; Cancer Control, 10 361 4) Herve and Ibrahim (2017), Proteasome inhibitors to alleviate aberrant IKBKAP mRNA splicing and low IKAP/hELP1 synthesis in familial dysautonomia; Neurobiol. Dis., 103 113

InChI:InChI=1/C19H25BN4O4/c1-13(2)10-17(20(27)28)24-18(25)15(11-14-6-4-3-5-7-14)23-19(26)16-12-21-8-9-22-16/h3-9,12-13,15,17,27-28H,10-11H2,1-2H3,(H,23,26)(H,24,25)/t15-,17-/m0/s1

Synthetic route

dihydroxy-methyl-borane (13061-96-6) + bortezomib pinacol ester (1029701-48-1) → velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride In water; acetone at 20℃;	94%

N-[(1S)-1[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-benzyl]2-pyrazine carboxamide (205393-22-2) + dihydroxy-methyl-borane (13061-96-6) → velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride In water; acetone at 20℃; for 40h;	92%

C24H33BN4O4 → velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride; 2-methyl-propan-1-ol In methanol; pentane at 0 - 20℃; for 12h; Large scale;	86%

C26H37BN4O4 → velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride; 2-methyl-propan-1-ol In methanol; pentane at 0 - 20℃; for 12h; Large scale;	86%

(2S)-N-[(1R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl]-3-phenyl-2-(pyrazin-2-ylformamido)propanamide → velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride In methanol; water at 20℃;	82.3%

C25H35BN4O4 → velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride; 2-methyl-propan-1-ol In methanol; pentane at 0 - 20℃; for 12h; Large scale;	82%

N-[(1S)-1[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-benzyl]2-pyrazine carboxamide (205393-22-2) → velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride; Dihydroxy-isobutyl-boran In water at 20℃; Solvent; Temperature;	77%
With hydrogenchloride; Dihydroxy-isobutyl-boran In methanol; n-heptane; water at 25 - 30℃; for 1 - 2h; Product distribution / selectivity;	70%
With hydrogenchloride; Dihydroxy-isobutyl-boran; water In methanol; hexane at 20℃; for 18h;	56.4%

Dihydroxy-isobutyl-boran (84110-40-7) + C29H39BN4O4 → velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride In methanol; n-heptane; water at 0 - 25℃; for 2h;	71.5%

2-pyrazylcarboxylic acid (98-97-5) + N-benzyl-L-phenylalanine (19461-04-2) + (R)-1-amino-3-methylbutylboronic acid pinanediol ester hydrochloride → velcade (179324-69-7)

Conditions

Yield

Stage #1: N-benzyl-L-phenylalanine; (R)-1-amino-3-methylbutylboronic acid pinanediol ester hydrochloride With 4-methyl-morpholine; N-ethyl-N,N-diisopropylamine; isobutyryl chloride In tetrahydrofuran at 55℃; for 2h; pH=10; Inert atmosphere; Stage #2: With palladium on activated charcoal; hydrogen In tetrahydrofuran at 68℃; under 4560.31 Torr; for 2h; Stage #3: 2-pyrazylcarboxylic acid Concentration; Temperature; Solvent; pH-value; Pressure; Further stages;

67%

2-pyrazylcarboxylic acid (98-97-5) + C23H27BNO5Pol + N-Fmoc L-Phe (35661-40-6) → velcade (179324-69-7)

Conditions	Yield
Stage #1: C23H27BNO5Pol With piperidine In N,N-dimethyl-formamide for 0.333333h; 1-glycerol polystyrene resin; Stage #2: N-Fmoc L-Phe With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide for 2h; 1-glycerol polystyrene resin; Stage #3: 2-pyrazylcarboxylic acid Further stages;	54%

(S)-N-(1-(isopentylamino)-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide + phenylboronic acid (98-80-6) → velcade (179324-69-7)

Conditions

Yield

Stage #1: (S)-N-(1-(isopentylamino)-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide With [Rh(OH)(cod)]2; 4-((2'-((triisopropylsilyl)oxy)-[1,1'-binaphthalen]-2-yl)oxy)dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine; bis(pinacol)diborane In acetonitrile at 80℃; for 36h; Inert atmosphere; Sealed tube; Stage #2: phenylboronic acid With hydrogenchloride In methanol; water; pentane at 20℃; for 12h; Inert atmosphere; stereoselective reaction;

53%

bortezomib pinacol ester (1029701-48-1) → velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride; 2-methyl-propan-1-ol In methanol; pentane at 0 - 20℃; for 12h;	52%
With hydrogenchloride In methanol; pentane for 20h;	93.4 mg
Stage #1: bortezomib pinacol ester With hydrogenchloride; Dihydroxy-isobutyl-boran In methanol; n-heptane; water at 20℃; Stage #2: With sodium hydroxide In water
With hydrogenchloride; Dihydroxy-isobutyl-boran

2-pyrazylcarboxylic acid (98-97-5) + (CH3)2CHCH2CH(BO2C2(CH3)4)NHCOCH(CH2C6H5)NH3(1+)*Cl(1-)=(CH3)2CHCH2CH(BO2C2(CH3)4)NHCOCH(CH2C6H5)NH3Cl (1029701-41-4) → velcade (179324-69-7)

Conditions	Yield
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In not given 1. (2-pyrazine)CO2H, TBTU, i-Pr2EtN, 0°C - room temp.; 2. i-BuB(OH)2, pentane, MeOH, 1 N HCl;

(2S)-N-[1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl]-3-phenyl-2-(pyrazin-2-ylformamido)propanamide → [(1S)-1-[[(2S)-3-phenyl-2-[(pyrazine-2-carbonyl)amino]-1-oxopropyl]amino]-3-methylbutyl]boronic acid (1132709-14-8) + velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride In methanol; water at 20℃;

C32H43BN2O5 → velcade (179324-69-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogen; palladium 10% on activated carbon / N,N-dimethyl-formamide 2: N-ethyl-N,N-diisopropylamine / dichloromethane 3: methanol / Acidic conditions View Scheme

N-{(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide (789472-91-9) → velcade (179324-69-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane 2: methanol / Acidic conditions View Scheme

N-Cbz-L-Phe (1161-13-3) → velcade (179324-69-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane 2: hydrogen; palladium 10% on activated carbon / N,N-dimethyl-formamide 3: N-ethyl-N,N-diisopropylamine / dichloromethane 4: methanol / Acidic conditions View Scheme

2-pyrazylcarboxylic acid (98-97-5) → velcade (179324-69-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: thionyl chloride / toluene / 75 °C 2.1: sodium carbonate / toluene; water / 10 - 25 °C 3.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / -40 - -11 °C 4.1: hydrogenchloride; Dihydroxy-isobutyl-boran / water; methanol; n-heptane / 20 °C 4.2: 20 °C 5.1: hydrogenchloride / water; methanol / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran / 0.67 h / 0 °C 1.2: 3 h / 0 - 20 °C 2.1: sodium hydroxide / water; acetone / 2 h / 0 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / -10 - -5 °C 4.1: hydrogenchloride / water; acetone / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran / 0.67 h / 0 °C 1.2: 3 h / 0 - 20 °C 2.1: sodium hydroxide / water; acetone / 2 h / 0 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / -10 - -5 °C 4.1: hydrogenchloride / water; acetone / 40 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride 2: hydrogenchloride; Dihydroxy-isobutyl-boran View Scheme
Multi-step reaction with 4 steps 1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 20 °C 2: sodium hydroxide / methanol; water / 20 °C 3: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 20 °C 4: Dihydroxy-isobutyl-boran; hydrogenchloride / water; methanol; ethyl acetate View Scheme

(3aS,4S,6S,7aR)-2-(1-chloro-3-methylbutyl)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborole → velcade (179324-69-7)

Conditions

Yield

Multi-step reaction with 6 steps 1: hexane / -70 - 20 °C / Large scale 2: di-isopropyl ether / 2 h / -10 - 0 °C / Large scale 3: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 20 °C / Large scale 4: hydrogenchloride / toluene / 1 h / 0 °C / Large scale 5: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 20 °C / Large scale 6: hydrogenchloride; Dihydroxy-isobutyl-boran / hexane; 1,1,1-trideuteromethanol; water / 0 - 20 °C / Large scale View Scheme

1,1,1-trimethyl-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}-N-(trimethylsilyl)silanamine (514820-48-5) → velcade (179324-69-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: di-isopropyl ether / 2 h / -10 - 0 °C / Large scale 2: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 20 °C / Large scale 3: hydrogenchloride / toluene / 1 h / 0 °C / Large scale 4: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 20 °C / Large scale 5: hydrogenchloride; Dihydroxy-isobutyl-boran / hexane; 1,1,1-trideuteromethanol; water / 0 - 20 °C / Large scale View Scheme
Multi-step reaction with 4 steps 1.1: hydrogenchloride / tert-butyl methyl ether / -40 - 20 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / -40 - -11 °C 3.1: hydrogenchloride; Dihydroxy-isobutyl-boran / water; methanol; n-heptane / 20 °C 3.2: 20 °C 4.1: hydrogenchloride / water; methanol / 20 °C View Scheme

(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 → velcade (179324-69-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 20 °C / Large scale 2: hydrogenchloride / toluene / 1 h / 0 °C / Large scale 3: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 20 °C / Large scale 4: hydrogenchloride; Dihydroxy-isobutyl-boran / hexane; 1,1,1-trideuteromethanol; water / 0 - 20 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1.1: dichloromethane / 0.08 h / 0 °C / Inert atmosphere 1.2: 1 h / -3 - 2 °C 1.3: 0.25 h / 15 - 27 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / toluene / 0.17 h / Inert atmosphere 2.2: 3 h / 25 °C 3.1: hydrogenchloride; Dihydroxy-isobutyl-boran / methanol; n-heptane / 12 h / 20 °C View Scheme

tert-butyl [1-({3-methyl-1-[(3aS,4S,6S)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-1-oxo-3-phenylpropan-2-yl]carbamate → velcade (179324-69-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / toluene / 1 h / 0 °C / Large scale 2: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 20 °C / Large scale 3: hydrogenchloride; Dihydroxy-isobutyl-boran / hexane; 1,1,1-trideuteromethanol; water / 0 - 20 °C / Large scale View Scheme

N-{3-methyl-1-[(3aS,4S,6S)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide → velcade (179324-69-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 20 °C / Large scale 2: hydrogenchloride; Dihydroxy-isobutyl-boran / hexane; 1,1,1-trideuteromethanol; water / 0 - 20 °C / Large scale View Scheme

N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}-Nα-(pyrazin-2-ylcarbonyl)-L-phenylalaninamide → velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride; Dihydroxy-isobutyl-boran In hexane; 1,1,1-trideuteromethanol; water at 0 - 20℃; Concentration; Temperature; Large scale;

N-tert-butoxycarbonyl-L-phenylalanine (13734-34-4) → velcade (179324-69-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dichloromethane / 0.08 h / 0 °C / Inert atmosphere 1.2: 1 h / -3 - 2 °C 1.3: 0.25 h / 15 - 27 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / toluene / 0.17 h / Inert atmosphere 2.2: 3 h / 25 °C 3.1: hydrogenchloride; Dihydroxy-isobutyl-boran / methanol; n-heptane / 12 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: N-isopropylethylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / acetonitrile / 2 h / -10 - 5 °C 2: dichloromethane / 25 - 35 °C 3: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / acetonitrile / 0 - 10 °C 4: Dihydroxy-isobutyl-boran; hydrogenchloride / water / 20 °C View Scheme

(S)-3-phenyl-2-[(pyrazine-2-carbonyl)amino]propanoic acid (114457-94-2) → velcade (179324-69-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide / 0.33 h / 20 °C / Inert atmosphere 1.2: 4 h / 20 °C / Inert atmosphere 2.1: hydrogenchloride; Dihydroxy-isobutyl-boran / n-heptane; water; methanol / 1.5 h / 20 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / -40 - -11 °C 2.1: hydrogenchloride; Dihydroxy-isobutyl-boran / water; methanol; n-heptane / 20 °C 2.2: 20 °C 3.1: hydrogenchloride / water; methanol / 20 °C View Scheme
Multi-step reaction with 2 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / -10 - -5 °C 2: hydrogenchloride / water; acetone / 20 °C View Scheme

(R)-boroleu-(+)-pinanediol trifluoroacetic acid → velcade (179324-69-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide / 0.33 h / 20 °C / Inert atmosphere 1.2: 4 h / 20 °C / Inert atmosphere 2.1: hydrogenchloride; Dihydroxy-isobutyl-boran / n-heptane; water; methanol / 1.5 h / 20 - 30 °C View Scheme

N-((2S)-1-((3-methyl-1-((3aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)amino)-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide → velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride; Dihydroxy-isobutyl-boran In methanol; n-heptane; water at 20 - 30℃; for 1.5h;	4.2 g

acetone (67-64-1) + phenylboronic acid (98-80-6) → velcade (179324-69-7)

Conditions	Yield
With hydrogenchloride In hexane; acetonitrile

velcade (179324-69-7) → Pyrazine-2-carboxylic acid [(S)-1-((R)-1-hydroxy-3-methyl-butylcarbamoyl)-2-phenyl-ethyl]-amide (289472-78-2)

Conditions	Yield
With dihydrogen peroxide In ethanol; water at 20℃; for 1h; Oxidation; hydrolysis;	100%
With hydrogenchloride; oxygen In ethanol; water at 25℃; for 336h; pH=2.8; Kinetics; Product distribution; Further Variations:; with/without ascorbic acid; Oxidation; hydrolysis;
With oxygen In ethanol; water at 25℃; for 5844h; pH=6.9; Kinetics; Product distribution; Further Variations:; with/without EDTA; Oxidation; hydrolysis;

C16H29N3O4 + velcade (179324-69-7) → C35H50BN7O6

Conditions	Yield
In chloroform-d1 at 45℃;	95%

pinanediol + velcade (179324-69-7) → C29H39BN4O4

Conditions	Yield
In toluene for 3h; Inert atmosphere; Reflux;	91.2%

dopamine folic acid + velcade (179324-69-7) → C46H49BN12O9

Conditions	Yield
In dimethyl sulfoxide at 25℃;	80%

velcade (179324-69-7) → bortezomib (390800-88-1)

Conditions	Yield
In isopropyl alcohol; acetonitrile at 20℃; for 4h; Product distribution / selectivity;	76.9%

citric acid (77-92-9) + velcade (179324-69-7) → 5-(carboxymethyl)-2-((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid

Conditions	Yield
In ethyl acetate at 20 - 74℃; for 3h;	71.1%

C14H29N3O6 + velcade (179324-69-7) → C33H50BN7O8

Conditions	Yield
In chloroform-d1	70%

velcade (179324-69-7) → Pyrazine-2-carboxylic acid ((S)-1-carbamoyl-2-phenyl-ethyl)-amide + (S)-3-phenyl-2-[(pyrazine-2-carbonyl)amino]propanoic acid (114457-94-2)

Conditions	Yield
With sodium hydroxide; oxygen In dimethyl sulfoxide at 70℃; for 250h; pH=12.0; Kinetics; Product distribution; Oxidation; hydrolysis;
With sodium hydroxide; oxygen at 70℃; for 48h; pH=12; Oxidation; hydrolysis;

velcade (179324-69-7) → Pyrazine-2-carboxylic acid ((S)-1-carbamoyl-2-phenyl-ethyl)-amide + (S)-3-phenyl-2-[(pyrazine-2-carbonyl)amino]propanoic acid (114457-94-2) + Pyrazine-2-carboxylic acid [(S)-1-((R)-1-hydroxy-3-methyl-butylcarbamoyl)-2-phenyl-ethyl]-amide (289472-78-2) + Pyrazine-2-carboxylic acid [(S)-1-((S)-1-hydroxy-3-methyl-butylcarbamoyl)-2-phenyl-ethyl]-amide

Conditions	Yield
With dihydrogen peroxide In water at 20℃; for 1h; Kinetics; Product distribution; Further Variations:; Solvents; Oxidation; hydrolysis;

velcade (179324-69-7) → (S)-3-phenyl-2-[(pyrazine-2-carbonyl)amino]propanoic acid (114457-94-2)

Conditions	Yield
With hydrogenchloride; oxygen In dimethyl sulfoxide at 70℃; for 250h; pH=1.0; Kinetics; Product distribution; Oxidation; hydrolysis;
With hydrogenchloride; oxygen at 70℃; for 120h; pH=1.0; Oxidation; hydrolysis;

dopamine hydrochloride (62-31-7) + velcade (179324-69-7) → C27H33BN5O5(1-)*H(1+)

Conditions	Yield
With sodium dihydrogenphosphate; sodium hydroxide In dimethylsulfoxide-d6; water-d2 for 1h; pH=7.4;

Upstream product

• 179324-22-2 Z-Leu-Leu-Leu-B(OH)2 (MG262) 
• 179324-21-1 Z-Leu-Leu-BoroLeu-Pinanediol (MG261) 
• 17932-40-0 3-(2-BROMOACETAMIDO)-2,2,5,5-TETRAMETHYL-1-PYRROLIDINOXY 
• 179323-61-6 5-Pyrimidinemethanamine, alpha-methyl- (9CI) 
• 179323-60-5 1-PYRAZIN-2-YL-ETHYLAMINE 
• 179322-41-9 5-Pyrimidinemethanamine, alpha,alpha-dimethyl- (9CI) 
• 179322-40-8 Pyrimidine, 5-(1-isocyanatoethyl)- (9CI) 
• 179321-49-4 4-N-Boc-aminocyclohexanone 
• 179321-31-4 AKOS Z63P 
• 17931-67-8 hexahydro-2,5-methanopentalen-1(2H)-one 
• 17931-60-1 (2Z)-2-cyclopent-2-en-1-ylidenebutanedinitrile 
• 17931-56-5 dimethyl bicyclo[2.2.1]hept-2-ene-2,3-dicarboxylate 
• 17931-55-4 BICYCLO[3.3.1]NONAN-9-ONE 
• 179314-61-5 2-Chloro-6-fluorophenylacetyl chloride 

Downstream Products

• 179324-86-8 4,6-Methano-1,3,2-benzodioxaborole-2-methanamine 
• 179324-87-9 (aR,3aS,4S,6S,7aR)-Hexahydro-3a,8,8-trimethyl-alpha-(2-methylpropyl)-4,6-methano-1,3,2-benzodioxaborole-2-methanamine 2,2,2-trifluoroacetate 
• 179325-62-3 5-[1-[1,5-Bis(4-methoxyphenyl)pyrazol-3-yl]-1,1-dimethoxymethyl]-2-chlorobenzamide 
• 17932-56-8 Pyrimidine, 4-ethoxy-2-(trimethylsiloxy)- (7CI,8CI) 
• 17932-62-6 2-(triethoxysilyl)propiononitrile 
• 17932-70-6 diethyl {[dimethyl(phenyl)silyl]methyl}propanedioate 
• 179327-31-2 BENZENEPROPANENITRILE, 4-METHOXY-3-(1-METHYLETHOXY)-B-OXO- 
• 179328-22-4 N-METHYL-N-(4-MORPHOLIN-4-YLBENZYL)AMINE 
• 17933-03-8 3-Tolylboronic acid 
• 17933-09-4 iodo(dimethyl)borane 
• 179331-04-5 4-AMINOISATOIC ANHYDRIDE 
• 17933-10-7 Ethyldibromoborane 
• 179331-62-5 Acetamide, N-(3,5-difluoro-4-oxo-2,5-cyclohexadien-1-ylidene)- 
• 17933-16-3 CH3BBr2 

Recommend Products

• 289472-80-6  Pyrazine-2-carboxylic acid ((S)-1-carbamoyl-2-phenyl-ethyl)-amide 
• 114457-94-2  (S)-3-phenyl-2[(pyrazine-2-carbonyl)-amino]propionic acid 
• 179324-69-7  velcade 
• 289472-78-2  Pyrazine-2-carboxylic acid [(S)-1-((R)-1-hydroxy-3-methyl-butylcarbamoyl)-2-phenyl-ethyl]-amide 
• 289472-81-7  Pyrazine-2-carboxylic acid [(S)-1-((S)-1-hydroxy-3-methyl-butylcarbamoyl)-2-phenyl-ethyl]-amide 
• 1029701-48-1  bortezomib pinacol ester 
• 789472-91-9  N-{(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}phenylalanine amide 
• 1161-13-3  N-Cbz-L-Phe 
• 514820-48-5  1,1,1-trimethyl-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}-N-(trimethylsilyl)silanamine 
• 1310383-72-2  (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 
• 69-65-8  mannitol 
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