1072833-77-2

Usage

Uses

Used in Oncology:
(R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutylboronic acid is used as an anticancer agent for the treatment of patients with multiple myeloma. It functions as a proteasome inhibitor, preventing cell growth in solid tumors and thus targeting cancer cells effectively.
Used in Combination Therapy:
In the field of oncology, (R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutylboronic acid is utilized in combination therapy to enhance the treatment outcomes for multiple myeloma patients. The synergistic effects of (R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutylboronic acid with other anticancer agents contribute to improved efficacy and potentially better patient outcomes.

Synthetic route

dihydroxy-methyl-borane (13061-96-6) + (R)-2,5-dichloro-N-(2-((3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)amino)2-oxoethyl)benzamide → Ixazomib (1072833-77-2)

Conditions	Yield
With hydrogenchloride In water; acetone at 20℃;	93%

dihydroxy-methyl-borane (13061-96-6) + 2,5-dichloro-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexa-hydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide (1201903-02-7) → Ixazomib (1072833-77-2)

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

2,5-dichloro-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexa-hydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide (1201903-02-7) + boric acid (11113-50-1) → Ixazomib (1072833-77-2)

Conditions	Yield
With hydrogenchloride In di-isopropyl ether at 20℃; for 5h;	86.5%

2,5-dichloro-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexa-hydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide (1201903-02-7) → Ixazomib (1072833-77-2)

Conditions	Yield
With hydrogenchloride; Dihydroxy-isobutyl-boran In methanol; hexane; water	76.5%
With hydrogenchloride; Dihydroxy-isobutyl-boran In methanol; hexane at 20℃;	63%

N-(fluoren-9-ylmethoxycarbonyl)glycine (29022-11-5) + C23H27BNO5Pol + 2,5-dichlorobenzoic acid (50-79-3) → Ixazomib (1072833-77-2)

Conditions	Yield
Stage #1: C23H27BNO5Pol With piperidine In N,N-dimethyl-formamide for 0.333333h; 1-glycerol polystyrene resin; Stage #2: N-(fluoren-9-ylmethoxycarbonyl)glycine 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: 2,5-dichlorobenzoic acid Further stages;	49%

(R)-2,5-dichloro-N-(2-((3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)amino)2-oxoethyl)benzamide → Ixazomib (1072833-77-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethyl acetate / 12 h / 120 °C 2: hydrogenchloride; water / ethyl acetate / 0.5 h / 20 °C View Scheme
Stage #1: (R)-2,5-dichloro-N-(2-((3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)amino)2-oxoethyl)benzamide With boron trichloride In dichloromethane at -78℃; Inert atmosphere; Stage #2: With methanol for 0.166667h;	23.0 mg

(R)-[N-(2,5-dichlorobenzoyl)glycyl]leucine borate diethanolamine ester → Ixazomib (1072833-77-2)

Conditions	Yield
With hydrogenchloride; water In ethyl acetate at 20℃; for 0.5h;

2,5-dichlorobenzoic acid (50-79-3) → Ixazomib (1072833-77-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: benzotriazol-1-ol; dicyclohexyl-carbodiimide / dichloromethane / 0.5 h 1.2: 12 h / 20 °C 2.1: lithium hydroxide; water / tetrahydrofuran / 0.5 h / 20 °C 3.1: benzotriazol-1-ol; dicyclohexyl-carbodiimide; N-ethyl-N,N-diisopropylamine / 20 °C 4.1: ethyl acetate / 12 h / 120 °C 5.1: hydrogenchloride; water / ethyl acetate / 0.5 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: benzotriazol-1-ol / dichloromethane / 0.17 h / -10 °C 1.2: 0.5 h 1.3: 20 °C 2.1: lithium hydroxide monohydrate / methanol; water / 2 h 3.1: benzotriazol-1-ol / dichloromethane / 0.17 h / -10 °C 3.2: 0.5 h 4.1: Dihydroxy-isobutyl-boran; hydrogenchloride / methanol; water; hexane View Scheme
Multi-step reaction with 5 steps 1: acetonitrile / 1 h / 20 °C / Inert atmosphere 2: sodium hydroxide; water / 1 h / 0 - 10 °C 3: acetonitrile / 20 - 30 °C 4: 1 h / 0 - 10 °C 5: hydrogenchloride / di-isopropyl ether / 5 h / 20 °C View Scheme

(S)-N-(2,5-dichlorobenzoyl)glycine methyl ester → Ixazomib (1072833-77-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: lithium hydroxide; water / tetrahydrofuran / 0.5 h / 20 °C 2: benzotriazol-1-ol; dicyclohexyl-carbodiimide; N-ethyl-N,N-diisopropylamine / 20 °C 3: ethyl acetate / 12 h / 120 °C 4: hydrogenchloride; water / ethyl acetate / 0.5 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: lithium hydroxide monohydrate / methanol; water / 2 h 2.1: benzotriazol-1-ol / dichloromethane / 0.17 h / -10 °C 2.2: 0.5 h 3.1: Dihydroxy-isobutyl-boran; hydrogenchloride / methanol; water; hexane View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide / water; acetone / 2 h / 0 °C 2: 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 3: hydrogenchloride / water; acetone / 20 °C View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide / water; acetone / 2 h / 0 °C 2: 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 3: hydrogenchloride / water; acetone / 40 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: lithium hydroxide monohydrate / methanol; water / 3 h / 20 °C / Cooling with ice 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.67 h / -5 °C 2.2: 6.67 h / 20 °C 3.1: hydrogenchloride; Dihydroxy-isobutyl-boran / methanol; hexane / 20 °C View Scheme

2-[(2,5-dichlorobenzoyl)amino]acetic acid (667403-46-5) → Ixazomib (1072833-77-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: benzotriazol-1-ol; dicyclohexyl-carbodiimide; N-ethyl-N,N-diisopropylamine / 20 °C 2: ethyl acetate / 12 h / 120 °C 3: hydrogenchloride; water / ethyl acetate / 0.5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol / dichloromethane / 0.17 h / -10 °C 1.2: 0.5 h 2.1: Dihydroxy-isobutyl-boran; hydrogenchloride / methanol; water; hexane View Scheme
Multi-step reaction with 3 steps 1: acetonitrile / 20 - 30 °C 2: 1 h / 0 - 10 °C 3: hydrogenchloride / di-isopropyl ether / 5 h / 20 °C View Scheme

C12H9Cl2N3O2 → Ixazomib (1072833-77-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1 h / 0 - 10 °C 2: hydrogenchloride / di-isopropyl ether / 5 h / 20 °C View Scheme

C10H6Cl2N2O → Ixazomib (1072833-77-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide; water / 1 h / 0 - 10 °C 2: acetonitrile / 20 - 30 °C 3: 1 h / 0 - 10 °C 4: hydrogenchloride / di-isopropyl ether / 5 h / 20 °C View Scheme

Ixazomib (1072833-77-2) + 2,2'-iminobis[ethanol] (111-42-2) → 2,5-dichloro-N-[(2-((1R)-3-methyl-1-[1,3,6,2]-dioxaborolan-2-yl)-butylamino)-2-oxyethyl]benzamide

Conditions	Yield
In ethyl acetate at 20℃; for 2h; Product distribution / selectivity;	100%

Ixazomib (1072833-77-2) + citric acid (77-92-9) → 2,2’-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid

Conditions	Yield
In acetone at 20℃; for 0.5h;	95%
In ethyl acetate at 60℃; for 0.5h;

Ixazomib (1072833-77-2) + citric acid (77-92-9) → 4-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid (1201902-80-8)

Conditions	Yield
In ethyl acetate at 60 - 74℃; for 3h;	94%

Ixazomib (1072833-77-2) + 2,2'-iminobis[ethanol] (111-42-2) → N-(R)-(2-((1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl)amino)-2-oxoethyl)-2,5-dichlorobenzamide

Conditions	Yield
In ethyl acetate at 20 - 74℃; for 3h;	85.4%
In ethyl acetate at 60 - 74℃; for 3h;	557 mg

Ixazomib (1072833-77-2) + N-methylimino diacetic acid → 2,5-dichloro-N-{[(R)-3-methyl-1-(6-methyl-4,8-dioxo-[1,3,6,2]dioxazaborolan-2-yl)-butylcarbamoyl]methyl}-benzamide

Conditions	Yield
In dimethyl sulfoxide; toluene for 18h; Reflux;	83.4%

Ixazomib (1072833-77-2) + C14H29N3O6 → C28H44BCl2N5O8

Conditions	Yield
In chloroform-d1	67%

N-Methyldiethanolamine (105-59-9) + Ixazomib (1072833-77-2) → 2,5-dichloro-N-{[(R)-3-methyl-1-(6-methyl-[1,3,6,2]dioxazaborolan-2-yl)-butylcarbamoyl]methyl}-benzamide

Conditions	Yield
In ethyl acetate at 20℃;	66%

Ixazomib (1072833-77-2) + diisopropanolamine (110-97-4) → 2,5-dichloro-N-[(R)-1-(4,8-dimethyl-[1,3,6,2]dioxazaborolan-2-yl)-3-methyl-(butylcarbamoyl)methyl]-benzamide

Conditions	Yield
In ethyl acetate at 20℃;	64%

Ixazomib (1072833-77-2) + (R)-Mandelic Acid (611-71-2) → 2-chloro-5-chloro-N-[2-({(1R)-3-methyl-1-[(5R)-4-oxo-5-phenyl-1,3,2-dioxaborolan-2-yl]butyl}amino)-2-oxoethyl]benzamide (1201902-85-3)

Conditions	Yield
In ethyl acetate for 0.666667h;	57%

Ixazomib (1072833-77-2) → (R)-(1-(2-(2,5-dichlorobenzamido)-d2-acetamido)-3-methylbutyl)boronic acid

Conditions	Yield
With dimethylsulfoxide-d6; water-d2; potassium carbonate In tetrahydrofuran at 65℃; for 5h;	55.6%
With water-d2; sodium methylate at 0℃; for 72h;	630 mg

triethanolamine (102-71-6) + Ixazomib (1072833-77-2) → N-(R)-(2-((1-(6-(2-hydroxyethyl)-1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl)amino)-2-oxoethyl)-2,5-dichlorobenzamide

Conditions	Yield
In ethyl acetate at 20 - 74℃; for 3h;	53.3%

Ixazomib (1072833-77-2) → C20H21(2)H2BCl2N2O9

Conditions	Yield
Multi-step reaction with 2 steps 1: water-d2; sodium methylate / 72 h / 0 °C 2: ethyl acetate / 48 h / 40 °C View Scheme

D2-citric acid (78468-60-7) + Ixazomib (1072833-77-2) → C20H21(2)H2BCl2N2O9

Conditions	Yield
In acetic acid butyl ester at 90℃; for 14h;	51 mg

Ixazomib (1072833-77-2) + D4-citric acid → C20H19(2)H4BCl2N2O9

Conditions	Yield
In acetic acid butyl ester at 90℃; for 14h;	53 mg

Ixazomib (1072833-77-2) + C19H19N3O9 → C33H34BCl2N5O11

Conditions	Yield
In ethyl acetate at 20℃;

Ixazomib (1072833-77-2) + Reaxys ID: 36479190 → Reaxys ID: 36479266

Ixazomib (1072833-77-2) + Reaxys ID: 36479191 → Reaxys ID: 36479267

Upstream product

• 50-79-3 2,5-dichlorobenzoic acid 
• 667403-46-5 2-[(2,5-dichlorobenzoyl)amino]acetic acid 
• 1201903-02-7 2,5-dichloro-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexa-hydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide 
• 11113-50-1 boric acid 
• 13061-96-6 dihydroxy-methyl-borane 
• 29022-11-5 N-(fluoren-9-ylmethoxycarbonyl)glycine 

Downstream Products

• 1239908-20-3 2,2’-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid 
• 1201902-80-8 4-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid 
• 1201902-85-3 2-chloro-5-chloro-N-[2-({(1R)-3-methyl-1-[(5R)-4-oxo-5-phenyl-1,3,2-dioxaborolan-2-yl]butyl}amino)-2-oxoethyl]benzamide 

Relevant academic research and scientific papers

A solid-phase approach for the synthesis of α-Aminoboronic acid peptides

A solid-phase synthesis of α-Aminoboronic acid peptides using a 1-glycerol polystyrene resin is described. Standard Fmoc solid-phase peptide chemistry is carried out to construct bortezomib and ixazomib. This approach eliminates the need for liquid-liquid extractions, silica gel column chromatography, and HPLC purifications, as products are isolated in high purity after direct cleavage from the resin.

Borate compound and pharmaceutically acceptable salt thereof, and preparation method and application of boric acid ester compound and pharmaceutically acceptable salt thereof

The invention relates to a borate compound as shown in a formula (1), a pharmaceutically acceptable salt thereof, a preparation method and application thereof. The borate compound is novel in structure and has a proteasome inhibition function. The stability of the borate compound disclosed by the invention in a solution is far higher than that of Ixazomib. Especially when the pH is 1.2 and the pH is 6.8, the stability of the compound provided by the invention is more advantageous. Besides, microsome stability results show that the compound has good stability in five different liver microsomes, the half-life period of the microsomes of Ixazomib in cynomolgus monkeys is too long, the medicine is basically not metabolized, and serious toxicity can be caused. The compound can be used for preparing medicines for treating inflammation, immune-related diseases, cancers or hyperproliferative diseases and changing antigen peptides generated by proteasomes in organisms.

Virtues of Volatility: A Facile Transesterification Approach to Boronic Acids

Boronic acids are an increasingly important compound class for many applications, including C-C bond formation reactions, medicinal chemistry, and diagnostics. The deprotection of boronic ester intermediates is frequently a problematic and inefficient step in boronic acid syntheses. We describe an approach that highly facilitates this transformation by leveraging the volatility of methylboronic acid and its diol esters. The method is performed under mild conditions, provides high yields, and eliminates cumbersome and problematic purification steps.

Synthesis and application of peptide borate compounds

The invention belongs to the field of drug synthesis, and specifically relates to a series of novel peptide borate compounds or pharmaceutical salts thereof, and a preparation method and pharmaceutical application thereof. The structure of the peptide borate compounds or the pharmaceutical salts thereof is as shown in a formula I which is described in the specification. The compounds of the invention can be used for preparing proteasome inhibitors, and thus can be further used for treating solid tumors and blood tumors.

Novel boric acid salicylate derivatives and pharmaceutical composition thereof

The invention discloses novel boric acid salicylate derivatives and pharmaceutical composition thereof and also provides pharmaceutically acceptable salt, a preparation method, an application of the pharmaceutical composition of the derivatives. The provided compounds have a remarkable inhibition function on tumor cells, can be used for preventing and/or treating tumor-related diseases, especiallymultiple myeloma and have broad application prospects.

Synthetic process research of ixazomib

The invention discloses a synthesis method of ixazomib. The yield and the purity of a target product can be greatly increased with the method.

A PROCESS FOR THE PREPARATION OF IXAZOMIB CITRATE

The present invention relates to a process for the preparation of compound of formula (I), wherein, R1 and R2 are each independently hydroxy, alkoxy, aryloxy, or aralkoxy; or R1 and R2 together form a moiety derived from an alpha-hydroxy carboxylic acid compound or a beta-hydroxy carboxylic acid compound, wherein the atom attached to boron in each case is an oxygen atom; or R1 and R2 together form the boronate esters of boronic acid.

CU-AND NI-CATALYZED DECARBOXYLATIVE BORYLATION REACTIONS

The invention is directed to methods of converting a carboxylic acid group in a compound, via a redox active ester, to a corresponding boronic ester by treatment with bis(pinacolato)diboron-alkyllithium complex in the presence of a ligand, a Ni(ll) salt or a copper salt, and an Mg(ll) salt, in the presence of an alkyllithium or a lithium hydroxide or alkoxide salt. The product pinacolato boronate ester can be cleaved to provide a boronic acid. The invention is also directed to methods of preparing various compounds of medical value comprising boronic acid groups, and to novel boronic-acid containing compounds of medicinal value, including an atorvastatin boronic acid analog, a vancomycin aglycone boronic acid analog, and boronic acid containing elastase inhibitors mCBK319, mCBK320, mCBK323, and RPX-7009.

Deuterated dipeptide boric acids or esters thereof, and synthetic methods and uses of the compounds

Deuterated dipeptide boric acids or esters thereof, or crystal forms thereof, or pharmaceutically acceptable hydrates or solvates thereof are disclosed. The general structure of the compounds is shown as a formula (a) in the specification, wherein R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen, deuterium or halogens, or C1-C4 alkyl one or a plurality of or all hydrogen atoms of which are deuterated; and at least one of the R1, the R2, the R3, the R4, the R5 and the R6 is deuterated or deuterium. The compounds can effectively inhibit proteasomes and effectively treat or prevent cancer, cardiovascular disease, inflammation, immune disease, nephropathy, vasculogenesis or prostate disease.

Synthetic method of proteasome inhibitor MLN9708

The invention provides a synthetic method of a proteasome inhibitor MLN9708. The method comprises: taking 2,5-dichloro benzoic acid as an initial raw material, and performing condensation and saponification to prepare N-(2,5-dichlorobenzoyl) glycine; joining N-(2,5-dichlorobenzoyl) glycine to L-leucine boronic acid pinacol ester hydrochloride; purifying the obtained product through forming a complex with diethanolamine and performing hydrolysis for deprotection to obtain corresponding free boric acid; and reacting the obtained product with citric acid to obtain MLN9708. The method is cheap and available in raw materials, simple and convenient to operate, mild in reaction conditions and easy for industrial production.