625-08-1

Basic information

• Product Name: BETA-HYDROXYISOVALERIC ACID
• Synonyms: RARECHEM AL BO 2324;3-B-HYDROXYBUTYRIC ACID;3-HYDROXY-3-METHYLBUTANOIC ACID;3-HYDROXY-3-METHYL BUTYRIC ACID;BETA-HYDROXYISOVALERIC ACID;BETA-HYDROXY-3-METHYL BUTYRIC ACID;BETA-HYDROXY BETA-METHYLBUTYRATE;HYDROXYISOVALERIC ACID, BETA-
• CAS NO: 625-08-1
• Molecular Formula: C₅H₁₀O₃
• Molecular Weight: 118.13
• EINECS: 1592732-453-0
• Product Categories: Pharmaceutical Raw Materials;Diagnostic;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals;Diagnostic, Metabolites & Impurities, Pharmaceuticals, Intermediates & Fine Chemicals
• Mol File: 625-08-1.mol
• Article Data: 18

Chemical Properties

• Melting Point: −80 °C(lit.)
• Boiling Point: 88 °C1 mm Hg(lit.)
• Flash Point: 113 °C
• Appearance: Pale yellow/Liquid
• Density: 0.938 g/mL at 25 °C(lit.)
• Vapor Pressure: 0.00567mmHg at 25°C
• Refractive Index: n20/D 1.4415(lit.)
• Storage Temp.: Refrigerator
• PKA: 4.38±0.10(Predicted)
• Water Solubility: Soluble in water and ethanol.
• BRN: 1743952
• CAS DataBase Reference: BETA-HYDROXYISOVALERIC ACID(CAS DataBase Reference)
• NIST Chemistry Reference: BETA-HYDROXYISOVALERIC ACID(625-08-1)
• EPA Substance Registry System: BETA-HYDROXYISOVALERIC ACID(625-08-1)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36
• RIDADR: UN 3334
• WGK Germany: 3
• F: 10-13-21
• Hazardous Substances Data: 625-08-1(Hazardous Substances Data)

Usage

Description

β-Hydroxy β-methylbutyric acid (HMB), or β-hydroxy β- methylbutyrate, is a metabolite of the essential amino acid leucine and is synthesized in the human body. It plays a part in protein synthesis and was discovered by Dr. Steven L. Nissen at Iowa State University. It has been used in scientific studies to purportedly increase muscle mass and decrease muscle breakdown. Nissen held the original patent on the metabolite as a nutritional supplement. It was discovered in pigs, and small quantities can also be found in grapefruit, alfalfa, and catfish. As a supplement it is usually sold as a calcium salt. Research published in the Journal of Applied Physiology has shown that HMB may have an effect on increasing muscle weight and strength. A review in Nutrition & Metabolism provides an in depth and objective analysis of HMB research. The same study lists as HMB' s proposed mechanisms of action the following: Increased sarcolemmal integrity via conversion to HMG-CoA Enhanced protein synthesis via the mTOR pathway Depression of protein degradation through inhibition of the ubiquitin pathway Three grams of Calcium beta-hydroxy-beta-methylbutyrate per day may help muscles combat protein breakdown, assist in muscle repair and support increased endurance. Studies suggest its benefits may be greater for the untrained. Also, well-controlled scientific studies have found increases in muscle mass and decreases in body fat in 70 year old men. It has helped patients with chronic obstructive pulmonary disease in hospital intensive care units, muscle wasting associated with HIV or AIDS and with cancer, and trauma victims with severe injuries. The human body produces about 0.2 - 0.4 grams per day. Standard doses in research studies have been 1.5 to 3.0 grams per day, usually divided into two doses.

Chemical Properties

colorless to light yellow liquid

Uses

Different sources of media describe the Uses of 625-08-1 differently. You can refer to the following data:
1. β-Hydroxyisovaleric Acid is a metabolite of the essential amino acid Leucine and is synthesized in the human body. Studies suggest that β-Hydroxyisovaleric Acid may have an effect on increasing muscle weight and strength. The presence of elevated β-Hydroxyisovaleric Acid is a sensitive marker of biotin deficiency and may indicate the presence of a genetic disorder such as biotinidase deficiency or holocarboxylase synthetase deficiency.
2. 3-Hydroxy-3-methylbutyric acid is a useful biochemical for synthesis and proteomics research. It is used as an indicator of biotin deficiency. Further, it is used to increase muscle mass and decrease muscle breakdown. In addition to this, it is involved in the protein synthesis.

Definition

ChEBI: A 3-hydroxy monocarboxylic acid that is isovaleric acid substituted at position 3 by a hydroxy group. Used as indicator of biotin deficiency.

InChI:InChI=1/C5H10O3/c1-5(2,8)3-4(6)7/h8H,3H2,1-2H3,(H,6,7)

Synthetic route

ethyl 3-hydroxy-3-methylbutanoate (18267-36-2) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With water; sodium hydroxide at 20℃;	93%
With sodium hydroxide In water at 20℃;	93%

6,6-dimethyl-4-oxo-2-phenyl-[1,3]oxazinane-3-carboxylic acid tert-butyl ester → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With lithium hydroxide; water In ethanol at 20℃; for 3h; Hydrolysis;	91%

C11H16NO2(1+)*I(1-) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
Stage #1: C11H16NO2(1+)*I(1-) With sodium hydroxide In water at 90℃; for 1h; Stage #2: With hydrogenchloride In water	54%

C11H16NO2(1+)*Cl(1-) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
Stage #1: C11H16NO2(1+)*Cl(1-) With sodium hydroxide In water at 90℃; for 1h; Stage #2: With hydrogenchloride In water	41%

3-hydroxy-3-methylbutyronitrile (13635-04-6) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With water In aq. phosphate buffer at 37℃; for 24h; Reagent/catalyst; Enzymatic reaction;	26%

4,4-dimethyloxetan-2-one (1823-52-5) → 3-Hydroxy-3-methylbutyric acid (625-08-1) + isobutene (115-11-7)

Conditions	Yield
With water

3-methylbutyric acid (503-74-2) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With alkaline permanganate

2-methylpent-4-en-2-ol (624-97-5) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With permanganate(VII) ion
With chromic acid

chloroform (67-66-3) + 5-acetoxy-5-methyl-hex-1-en-3-one (873380-25-7) → formic acid (64-18-6) + 3-Hydroxy-3-methylbutyric acid (625-08-1) + acetic acid (64-19-7)

Conditions	Yield
beim Ozonisieren und Zersetzen des Ozonids mit H2O2;

(±)-4-methyl-1,2,4-pentanetriol (871888-50-5) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With permanganate(VII) ion

4-Hydroxy-4-methyl-2-pentanone (123-42-2) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With sodium hypobromide
With 1,4-dioxane; alkaline aqueous sodium hypochlorite
With sodium hypochlorite

4-hydroxy-6-methyl-heptanoic acid → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With permanganate(VII) ion in alkalischer Loesung;

tert-butyl 3-hydroxy-3-methylbutyrate (5292-12-6) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With 1,4-dioxane; hydrogenchloride

ethyl acetate (141-78-6) + acetone (67-64-1) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With potassium hydroxide; diethyl ether

chloroacetic acid ethyl ester (105-39-5) + acetone (67-64-1) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With zinc Zersetzen des Reaktionsprodukts mit verduennter Schwefelsaeure und Verseifen des entstehenden Aethylesters mit waessr.Kalilauge;

acetone (67-64-1) + ethyl iodoacetae (623-48-3) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With zinc Zersetzen des Reaktionsprodukts mit verduennter Schwefelsaeure und Verseifen des entstehenden Aethylesters mit waessr.Kalilauge;

4-hydroxy-4-methyl-2-oxo-pentanal (10435-98-0) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With dihydrogen peroxide

bromoacetic acid tert-butyl ester (5292-43-3) + acetone (67-64-1) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
(i) Zn, I2, (ii) (hydrolysis); Multistep reaction;

lithium α-lithioacetate (94953-76-1) + acetone (67-64-1) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

2-methyl-1-buten-4-ol (763-32-6) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With nitric acid; sodium nitrite 1) 20 deg C, 4 h, 2) 50-60 deg C, 4 h; Yield given. Multistep reaction;

4-methyl-2-oxopentanoic acid (816-66-0) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
With oxygen; iron(III); ascorbic acid; diothiothreitol

4-isobutyl-γ-butyrolactone (18432-37-6) + KOH-solution + potassium permanganate → 3-Hydroxy-3-methylbutyric acid (625-08-1)

4,4-dimethyloxetan-2-one (1823-52-5) + water (7732-18-5) → 3-Hydroxy-3-methylbutyric acid (625-08-1) + isobutene (115-11-7)

diethyl ether (60-29-7) + ethyl acetate (141-78-6) + acetone (67-64-1) + KOH → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
anfangs unter Eiskuehlung und Verseifen mit alkoh. KOH;

3-methyl-butane-1,3-diol (2568-33-4) + KMnO4 → 3-Hydroxy-3-methylbutyric acid (625-08-1)

2-methylpent-4-en-2-ol (624-97-5) + chamaeleon solution → formic acid (64-18-6) + 3-Hydroxy-3-methylbutyric acid (625-08-1) + oxalic acid (144-62-7)

2-methylpent-4-en-2-ol (624-97-5) + chromic acid solution → formic acid (64-18-6) + 3-Hydroxy-3-methylbutyric acid (625-08-1) + acetone (67-64-1)

perchloric acid (7601-90-3) + 3-Methylbutenoic acid (541-47-9) → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
at 82.4℃; Kinetics;
at 99.8℃; Kinetics;
at 111.8℃; Kinetics;

3-Methylbutenoic acid (541-47-9) + aqueous NaClO4 → 3-Hydroxy-3-methylbutyric acid (625-08-1)

Conditions	Yield
at 82.4℃; Kinetics;
at 99.8℃; Kinetics;
at 111.8℃; Kinetics;

ethyl 4-amino-3-O-benzyl-4,6-dideoxy-2-O-methyl-1-thio-β-D-glucopyranoside (861819-35-4) + 3-Hydroxy-3-methylbutyric acid (625-08-1) → ethyl 3-O-benzyl-4,6-dideoxy-4-(3-hydroxy-3-methylbutanamido)-2-O-methyl-1-thio-β-D-glucopyranoside (861819-36-5)

Conditions	Yield
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 dichloromethane at 20℃; for 1h;	100%

3-Hydroxy-3-methylbutyric acid (625-08-1) + 3,5-dimethylaminoaniline (108-69-0) → C13H19NO2

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 14h;	100%

3-Hydroxy-3-methylbutyric acid (625-08-1) + 4-bromodeacetyl colchicine → 4-bromo-N-(3-hydroxy-3-methylbutyryl)deacetyl colchicine

Conditions	Yield
Stage #1: 3-Hydroxy-3-methylbutyric acid With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 4-bromodeacetyl colchicine In N,N-dimethyl-formamide at 20℃;	98.4%

3-Hydroxy-3-methylbutyric acid (625-08-1) + (R)-benzyl 2-aminopropanoate hydrochloride (5557-81-3, 5557-83-5, 34404-37-0) → (R)-benzyl 2-(3-hydroxy-3-methylbutanamido)propanoate

Conditions	Yield
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 dichloromethane at 0 - 20℃; for 1h;	98%

3-Hydroxy-3-methylbutyric acid (625-08-1) + 4-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride → 4-(6-(4-(3-hydroxy-3-methylbutanoyl)-4,7-diazaspiro[2.5]octan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Conditions	Yield
With 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 48h;	98%

3-Hydroxy-3-methylbutyric acid (625-08-1) + 2-methoxy-phenylamine (90-04-0) → C12H17NO3

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 14h;	98%

5-methoxycarbonylpentyl 4-amino-3-O-benzyl-4,6-dideoxy-2-O-methyl-β-D-glucopyranosyl-(1->3)-2,4-di-O-benzyl-α-L-rhamnopyranosyl-(1->3)-2,4-di-O-benzyl-α-L-rhamnopyranosyl-(1->2)-3,4-di-O-benzyl-α-L-rhamnopyranoside + 3-Hydroxy-3-methylbutyric acid (625-08-1) → 5-methoxycarbonylpentyl 3-O-benzyl-4,6-dideoxy-4-(3-hydroxy-3-methylbutyramido)-2-O-methyl-β-D-glucopyranosyl-(1->3)-2,4-di-O-benzyl-α-L-rhamnopyranosyl-(1->3)-2,4-di-O-benzyl-α-L-rhamnopyranosyl-(1->2)-3,4-di-O-benzyl-α-L-rhamnopyranoside

Conditions	Yield
With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 1h;	97%
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 dichloromethane at 20℃; for 1h;	97%

3-Hydroxy-3-methylbutyric acid (625-08-1) + C89H71F102N9O8 → C94H79F102N9O10

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	96%

3-Hydroxy-3-methylbutyric acid (625-08-1) + Ν,Ν',Ν''-[boroxin-2,4,6-triyltris[[(1R)-3-methylbutane-1,1-diyl]imino(2-oxoethane-2,1-diyl)]]tris(2,5-dichlorobenzamide) (1201903-03-8) → 2,5-dichloro-N-(2-{[(1R)-1-(4,4-dimethyl-6-oxo-1,3,2-dioxaborinan-2-yl)-3-methylbutyl]amino}-2-oxoethyl)benzamide (1201902-88-6)

Conditions	Yield
In ethyl acetate at 25 - 60℃;	95%

3-Hydroxy-3-methylbutyric acid (625-08-1) + C45H69NO17 (1040140-55-3) → C50H77NO19 (1040140-56-4)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In tetrahydrofuran for 10h;	92%

5-methoxycarbonylpentyl 4-amino-3-O-benzyl-4,6-dideoxy-2-O-methyl-β-D-glucopyranosyl-(1->3)-2,4-di-O-benzyl-α-L-rhamnopyranoside + 3-Hydroxy-3-methylbutyric acid (625-08-1) → 5-methoxycarbonylpentyl 3-O-benzyl-4,6-dideoxy-4-(3-hydroxy-3-methylbutyramido)-2-O-methyl-β-D-glucopyranosyl-(1->3)-2,4-di-O-benzyl-α-L-rhamnopyranoside

Conditions	Yield
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 dichloromethane at 20℃; for 2h;	90%

5-(4-(4-(5-amino-4-(benzyloxy)tetrahydro-3-methoxy-6-methyl-2H-pyran-2-yloxy)tetrahydro-3,5-dihydroxy-6-methyl-2H-pyran-2-yloxy)-3,5-dihydroxytetrahydro-6-methyl-2H-pyran-2-yloxy)-6-(benzyloxy)tetrahydro-2-methyl-2H-pyran-3,4-diol + 3-Hydroxy-3-methylbutyric acid (625-08-1) → C44H65O18N

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In tetrahydrofuran for 10h;	90%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In tetrahydrofuran for 10h;	90%

3-Hydroxy-3-methylbutyric acid (625-08-1) + (3aR,6aR)-5-[1-(2-fluorophenyl)-1H-indazol-4-yl]hexahydropyrrolo[3,4-b]pyrrol-6(1H)-one → (3aR,6aR)-5-[1-(2-fluorophenyl)-1H-indazol-4-yl]-1-(3-hydroxy-3-methylbutanoyl)hexahydropyrrolo[3,4-b]pyrrol-6-(1H)-one

Conditions	Yield
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In acetonitrile for 2h;	90%

3-Hydroxy-3-methylbutyric acid (625-08-1) + m-Anisidine (536-90-3) → C12H17NO3

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 14h;	90%

C81H99NO18 + 3-Hydroxy-3-methylbutyric acid (625-08-1) → C86H107NO20

Conditions	Yield
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 dichloromethane at 20℃; for 1h;	89%
With diazoacetic acid ethyl ester; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane	73%

5-methoxycarbonylpentyl 4-amino-3-O-benzyl-4,6-dideoxy-2-O-methyl-β-D-glucopyranosyl-(1->3)-2,4-di-O-benzyl-α-L-rhamnopyranosyl-(1->3)-2,4-di-O-benzyl-α-L-rhamnopyranoside + 3-Hydroxy-3-methylbutyric acid (625-08-1) → 5-methoxycarbonylpentyl 3-O-benzyl-4,6-dideoxy-4-(3-hydroxy-3-methylbutyramido)-2-O-methyl-β-D-glucopyranosyl-(1->3)-2,4-di-O-benzyl-α-L-rhamnopyranosyl-(1->3)-2,4-di-O-benzyl-α-L-rhamnopyranoside

Conditions	Yield
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 dichloromethane at 20℃; for 2h;	86%

3-Hydroxy-3-methylbutyric acid (625-08-1) + methyl 4-amino-4,6-dideoxy-2-O-methyl-β-D-glucopyranoside → methyl 4,6-dideoxy-4-(3-hydroxy-3-methylbutanamido)-2-O-methyl-β-D-glucopyranoside

Conditions	Yield
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 dichloromethane at 20℃; for 0.333333h;	85%

3-Hydroxy-3-methylbutyric acid (625-08-1) + methyl 3-O-(4-amino-3-O-benzyl-4,6-dideoxy-2-O-methyl-β-D-glucopyranosyl)-2,4-di-O-benzyl-1-thio-α-L-rhamnopyranoside (1149356-84-2) → methyl 2,4-di-O-benzyl-3-O-[3-O-benzyl-4,6-dideoxy-4-(3-hydroxy-3-methylbutanamido)-2-O-methyl-β-D-glucopyranosyl]-1-thio-α-L-rhamnopyranoside (1149356-85-3)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 1.5h;	85%

3-Hydroxy-3-methylbutyric acid (625-08-1) → 1-Amino-2-methyl-propan-2-ol (2854-16-2)

Conditions	Yield
Stage #1: 3-Hydroxy-3-methylbutyric acid With 4-methyl-morpholine; diphenyl phosphoryl azide In tetrahydrofuran at 25℃; for 2.25h; Curtius Rearrangement; Stage #2: With water In tetrahydrofuran for 2h; Reagent/catalyst; Reflux;	85%

3-Hydroxy-3-methylbutyric acid (625-08-1) + aniline (62-53-3) → β-hydroxy-isovaleric acid anilide (99985-75-8)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 14h;	85%

3-Hydroxy-3-methylbutyric acid (625-08-1) + C65H70N2O18 → N-benzyloxycarbonylaminoethyl 4-(3-hydroxy-3-methylbutamido)-2-O-acetyl-3-O-benzoyl-4,6-dideoxy-β-D-glucopyranosyl-(1->3)-2-O-benzoyl-4-O-benzyl-α-D-rhamnopyranosyl-(1->3)-2-O-benzoyl-4-O-benzyl-α-D-rhamnopyranoside (1206451-89-9)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 18h; Inert atmosphere;	82%

ethanol (64-17-5) + 3-Hydroxy-3-methylbutyric acid (625-08-1) → ethyl 3-hydroxy-3-methylbutanoate (18267-36-2)

Conditions	Yield
With toluene-4-sulfonic acid In cyclohexane at 85℃; for 5h; Reagent/catalyst; Solvent; Molecular sieve;	80%

3-Hydroxy-3-methylbutyric acid (625-08-1) + 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile → 4-(6-(4-(3-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	80%

3-Hydroxy-3-methylbutyric acid (625-08-1) + methyl 4-amino-4,6-dideoxy-2-O-methyl-α-D-glucopyranoside (861819-29-6) → methyl 4,6-dideoxy-4-(3-hydroxy-3-methylbutanamido)-2-O-methyl-α-D-glucopyranoside

Conditions	Yield
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 dichloromethane at 20℃; for 0.5h;	79%

C64H72N2O16 + 3-Hydroxy-3-methylbutyric acid (625-08-1) → 3-[(N-benzyloxycarbonyl)amino]propyl-O-(4-(3-hydroxy-3-methylbutanamido)-3-O-benzyl-4,6-dideoxy-β-D-glucopyranosyl)-(1->3)-O-(2-O-benzoyl-4-O-benzyl-α-L-rhamnopyranosyl)-(1->3)-2-O-benzoyl-4-O-benzyl-α-L-rhamnopyranoside (927680-52-2)

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 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 20℃; for 4h;	78%

5-methoxycarbonylpentyl 4-amino-2-O-benzoyl-3-O-benzyl-4,6-dideoxy-β-D-glucopyranosyl-(1->2)-(2,4-di-O-benzoyl-α-L-rhamnopyranosyl)-(1->3)-(2,4-di-O-benzyl-α-L-rhamnopyranosyl)-(1->2)-3,4-di-O-benzyl-α-L-rhamnopyranoside + 3-Hydroxy-3-methylbutyric acid (625-08-1) → 5-methoxycarbonylpentyl 2-O-benzoyl-3-O-benzyl-4,6-dideoxy-4-(3-hydroxy-3-methylbutyramino)-β-D-glucopyranosyl-(1->2)-(2,4-di-O-benzoyl-α-L-rhamnopyranosyl)-(1->3)-(2,4-di-O-benzyl-α-L-rhamnopyranosyl)-(1->2)-3,4-di-O-benzyl-α-L-rhamnopyranoside

Conditions	Yield
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 dichloromethane at 20℃; for 2h;	78%

5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride + 3-Hydroxy-3-methylbutyric acid (625-08-1) → TAK-285

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 72h;	77%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 120h;

1-hydroxy-pyrrolidine-2,5-dione (6066-82-6) + 3-Hydroxy-3-methylbutyric acid (625-08-1) → β-hydroxyisovaleric acid succinimidyl ester (1314864-92-0)

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h;	77%

Upstream product

• 624-97-5 2-methylpent-4-en-2-ol 
• 67-66-3 chloroform 
• 873380-25-7 5-acetoxy-5-methyl-hex-1-en-3-one 
• 123-42-2 4-Hydroxy-4-methyl-2-pentanone 
• 105-39-5 chloroacetic acid ethyl ester 
• 67-64-1 acetone 
• 623-48-3 ethyl iodoacetae 
• 816-66-0 4-methyl-2-oxopentanoic acid 
• 2568-33-4 3-methyl-butane-1,3-diol 
• 7601-90-3 perchloric acid 
• 541-47-9 3-Methylbutenoic acid 
• 75-65-0 tert-butyl alcohol 
• 871888-50-5 (±)-4-methyl-1,2,4-pentanetriol 
• 86558-50-1 2-chloro-3-hydroxy-3-methylbutanoic acid 

Downstream Products

• 940304-44-9 N-(tert-butyl)-3-{2-chloro-4-[(5-{2-[(3-hydroxy-3-methylbutanoyl)amino]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]phenoxy}-5-(trifluoromethyl)benzamide 
• 940349-70-2 C₃₁H₃₀ClN₅O₄ 
• 940349-74-6 C₃₀H₃₄ClF₂N₅O₃ 
• 940308-40-7 N-[2-(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-3-hydroxy-3-methylbutanamide 
• 940308-42-9 N-[2-(4-{[1-(3-fluorobenzyl)-1H-indol-5-yl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-3-hydroxy-3-methylbutanamide 
• 1042430-63-6 N-benzyloxycarbonylaminoethyl 3-O-benzoyl-4,6-dideoxy-4-(3-hydroxy-3-methylbutanamido)-2-O-methyl-β-D-glucopyranoside 
• 1149356-85-3 methyl 2,4-di-O-benzyl-3-O-[3-O-benzyl-4,6-dideoxy-4-(3-hydroxy-3-methylbutanamido)-2-O-methyl-β-D-glucopyranosyl]-1-thio-α-L-rhamnopyranoside 
• 1033806-78-8 N-(tert-butyl)-5-{2-chloro-4-[(5-{2-[(3-hydroxy-3-methylbutanoyl)amino]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]phenoxy}nicotinamide 
• 1201902-88-6 2,5-dichloro-N-(2-{[(1R)-1-(4,4-dimethyl-6-oxo-1,3,2-dioxaborinan-2-yl)-3-methylbutyl]amino}-2-oxoethyl)benzamide 
• 1246759-75-0 methyl 4-(4-fluorophenyl)-2-(2-hydroxy-2-methylpropyl)-1H-benzimidazole-6-carboxylate 
• 940307-59-5 N-[2-(4-{[4-(3-acetylphenoxy)-3-chlorophenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-3-hydroxy-3-methylbutanamide 
• 1403682-94-9 2-[N-(benzyloxycarbonyl)amino]ethyl [2,3-di-O-acetyl-4-(3-hydroxy-3-methylbutanamido)-4,6-dideoxy-β-D-glucopyranosyl]-(1→3)-2-O-benzoyl-4-O-benzyl-α-L-rhamnopyranoside 
• 889453-40-1 benzyl 3-(tert-butyldimethylsilyloxy)-3-methylbutyrate 

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