75143-89-4

Basic information

• Product Name: 3-isobutylglutaric acid
• Synonyms: 3-isobutylglutaric acid;3-Isobutylglutaric acid 99%;3-(2-Methylpropyl)pentanedioic Acid;Pentanedioic acid,3-(2-Methylpropyl)-;Pregabalin IMpurity I;3-Isobutylpentanedioic acid;Pregabalin Impurity B(3-IsoButylglutaricAcid);3-Isobutylglutaric acid(99%)
• CAS NO: 75143-89-4
• Molecular Formula: C₉H₁₆O₄
• Molecular Weight: 188.22
• EINECS: 1592732-453-0
• Product Categories: intermidiate of Pregablin;Aliphatics;Impurities;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 75143-89-4.mol
• Article Data: 22

Chemical Properties

• Melting Point: 47 °C
• Boiling Point: 326.197 °C at 760 mmHg
• Flash Point: 165.289 °C
• Appearance: /
• Density: 1.126 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.472
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• Solubility: Methanol (Slightly), Water (Slightly)
• PKA: 4.19±0.10(Predicted)
• CAS DataBase Reference: 3-isobutylglutaric acid(CAS DataBase Reference)
• NIST Chemistry Reference: 3-isobutylglutaric acid(75143-89-4)
• EPA Substance Registry System: 3-isobutylglutaric acid(75143-89-4)

Safety Data

• Hazardous Substances Data: 75143-89-4(Hazardous Substances Data)

Usage

Chemical Properties

Pale Brown Solid

Uses

An impurity of Pregabalin (P704800) with anticonvulsant properties.

Application

3-Butylglutaric acid is an intermediate in the synthesis of pregabalin.Pregabalin is approved by the United States Food and Drug Administration (FDA) to treat neuropathic pain associated with diabetic peripheral neuropathy, spinal cord injury, and postherpetic neuralgia. Pregabalin is FDA-approved for the treatment of fibromyalgia. Pregabalin also has FDA approval as adjunctive therapy for partial-onset seizures in adults with epilepsy.

InChI:InChI=1/C9H16O4/c1-6(2)3-7(4-8(10)11)5-9(12)13/h6-7H,3-5H2,1-2H3,(H,10,11)(H,12,13)

Synthetic route

2,4-dicyano-3-isobutylglutaramide → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With sulfuric acid for 12h; Reflux;	99.4%
With hydrogenchloride; water at 140℃; for 30h; pH=1 - 2; Temperature; Reagent/catalyst;	85%

1,5-diethy 3-isobutylpentanedioate → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride In water for 4h; Time; Reflux;	91%

(3R)‐3‐(carbamoylmethyl)‐5‐methylhexanoic acid (181289-33-8) → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
Stage #1: (3R)‐3‐(carbamoylmethyl)‐5‐methylhexanoic acid With water; sodium hydroxide for 5h; Reflux; Stage #2: With hydrogenchloride In water pH=7; Reflux;	85%

2‑cyano‑5‑methylhex‑2‑enoic acid methyl ester (868-52-0) + diethyl malonate (105-53-3) → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
Stage #1: 2‑cyano‑5‑methylhex‑2‑enoic acid methyl ester; diethyl malonate With piperidine at 55℃; for 2h; Stage #2: With hydrogenchloride In water at 100 - 120℃; for 72h;	85%

2,4-dicyano-3-isobutylglutaramide → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With sulfuric acid Heating;	42%

malonic acid (141-82-2) + isovaleraldehyde (590-86-3) → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With piperidine auf dem Wasserbade unter Rueckfluss und Erhitzen dann im Vakuum zur Abspaltung von Kohlendioxyd;

2-isobutyl-propane-1,1,3,3-tetracarboxylic acid tetraethyl ester (102710-09-8) → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride for 24h; Heating; Yield given;
With hydrogenchloride; water at 100 - 125℃; for 20 - 24h; Product distribution / selectivity;
Stage #1: 2-isobutyl-propane-1,1,3,3-tetracarboxylic acid tetraethyl ester With hydrogenchloride; sodium hydroxide; ethanol; water at -10 - -5℃; for 2 - 3h; Stage #2: With hydrogenchloride; water; acetic acid In ethanol pH=5 - 6; Stage #3: With hydrogenchloride; water at 100 - 125℃; for 20 - 24h; Product distribution / selectivity;
With hydrogenchloride; water at 100 - 105℃; for 72h; Heating / reflux;
With hydrogen bromide In water at 100℃; for 72h; Product distribution / selectivity;

2-oxo-6-imino-4-isobutyl-3-cyano-piperidine-carboxylic acid-(5)-amide → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride

isopentylidene-bis-malonic acid ester → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride

1,1,3-triethyl 3-cyano-2-(2-methylpropyl)propane-1,1,3-tricarboxylate → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With water; hydrogen bromide at 100 - 125℃; for 6 - 10h; Product distribution / selectivity;
With hydrogenchloride; water at 100 - 125℃; for 50 - 125h; Product distribution / selectivity;
With hydrogenchloride; water for 72h; Reflux;
With hydrogenchloride Reflux;

C16H23NO6 → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride; water at 100 - 125℃; for 15 - 20h; Product distribution / selectivity;

C17H24O8 (392669-46-4) → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride; water at 100 - 125℃; for 12 - 15h; Product distribution / selectivity;

C18H28O8 → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride; water at 100 - 125℃; for 12 - 15h; Product distribution / selectivity;

C15H23NO6 → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride; water at 110 - 115℃; for 10 - 12h; Product distribution / selectivity;

isovaleraldehyde (590-86-3) + 3-methyl-ξ-pentenedioic acid dimethyl ester → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: KF 2: HCl conc. / 24 h / Heating View Scheme

(3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid (930585-94-7) → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
Stage #1: (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid With hydrogenchloride; water at 100 - 105℃; for 20 - 24h; Stage #2: With sodium hydroxide In water pH=10 - 11; Stage #3: With hydrogenchloride In water pH=1.5 - 2; Product distribution / selectivity;
Stage #1: (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid With sulfuric acid; water at 120 - 125℃; for 1 - 2h; Stage #2: With sodium hydroxide In water at 20 - 25℃; pH=10 - 11; Stage #3: With hydrogenchloride In water pH=1.5 - 2; Product distribution / selectivity;

(S)‑3‑carbamoylmethyl‑5‑methylhexanoic acid (181289-34-9) → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride; water for 24h; Reflux;

isovaleraldehyde (590-86-3) + diethyl malonate (105-53-3) → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
Stage #1: isovaleraldehyde With di-n-propylamine; ethyl 2-cyanoacetate In cyclohexane at 25 - 30℃; for 2h; Reflux; Stage #2: diethyl malonate With di-n-propylamine at 25 - 50℃; for 5.17h; Stage #3: With hydrogenchloride; water for 48h; Product distribution / selectivity; Reflux;

diethyl 2-(3-methylbutylidene)malonate (51615-30-6) → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: di-n-propylamine / 16 h / 15 - 55 °C 2: hydrogen bromide / water / 72 h / 100 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium chloride / dimethyl sulfoxide; water / 3 h / 185 °C / Inert atmosphere 2.1: sodium methylate / 0.5 h / Reflux 2.2: 4 h / Reflux 3.1: hydrogenchloride / water / 4 h / Reflux View Scheme

isovaleraldehyde (590-86-3) → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: piperidine; pyridine; acetic acid / hexane / 48 h / Reflux; Inert atmosphere 2: di-n-propylamine / 16 h / 15 - 55 °C 3: hydrogen bromide / water / 72 h / 100 °C View Scheme
Multi-step reaction with 2 steps 1: tetramethyl ammoniumhydroxide; trimethyldodecylammonium chloride / ethanol / 6 h / 25 °C 2: water; hydrogenchloride / 30 h / 140 °C / pH 1 - 2 View Scheme
Multi-step reaction with 2 steps 1.1: piperidine / hexane / 100 °C / Dean-Stark 2.1: piperidine / 2 h / 55 °C 2.2: 72 h / 100 - 120 °C View Scheme
Multi-step reaction with 4 steps 1.1: acetic acid; piperidine / cyclohexane / 3 h / Reflux 2.1: sodium chloride / dimethyl sulfoxide; water / 3 h / 185 °C / Inert atmosphere 3.1: sodium methylate / 0.5 h / Reflux 3.2: 4 h / Reflux 4.1: hydrogenchloride / water / 4 h / Reflux View Scheme

C17H27NO6 → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride In water; glycerol at 100℃; for 6h; Temperature;

C16H25NO6 → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride In water; glycerol at 100℃; for 6h; Concentration; Temperature;

isovaleraldehyde (590-86-3) + cyanoacetic acid amide (107-91-5) → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
Stage #1: isovaleraldehyde; cyanoacetic acid amide With propylamine at 15 - 40℃; for 5h; Stage #2: With sulfuric acid at 10 - 132℃; for 10h; pH=1;
Stage #1: isovaleraldehyde; cyanoacetic acid amide With morpholine In water at 6 - 12℃; for 20h; Stage #2: With hydrogenchloride In water at 105 - 110℃; for 18h;	480 g
Stage #1: isovaleraldehyde; cyanoacetic acid amide With water; triethylamine at 20 - 30℃; Stage #2: With hydrogenchloride at 70 - 100℃;

2-cyano-3-isobutyl-4-ethylformylglutaric acid diethyl ester → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride for 72h; Reflux;	160.6 g

2,4-dicyano-3-isobutyl-glutaric acid → 5-methyl-3-carboxymethylhexanoic acid (75143-89-4)

Conditions	Yield
With hydrogenchloride In water at 10 - 15℃; for 10h; Reflux;	200 g

methanol (67-56-1) + 5-methyl-3-carboxymethylhexanoic acid (75143-89-4) → 1,5-dimethy 3-isobutylpentanedioate (145328-03-6)

Conditions	Yield
With ammonium cerium (IV) nitrate at 20℃; for 12h;	95%
With chloro-trimethyl-silane for 12h;	90%
With potassium permanganate; sulfuric acid for 10h; Reagent/catalyst; Temperature; Reflux;	83.1%
With sulfuric acid at 40 - 45℃; for 14h; Temperature; Reflux;	100 g

5-methyl-3-carboxymethylhexanoic acid (75143-89-4) + Isobutyl bromide (78-77-3) → 1,5-diisobutyl 3-isobutylpentanedioate

Conditions	Yield
Stage #1: 5-methyl-3-carboxymethylhexanoic acid With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0 - 20℃; for 0.166667h; Stage #2: Isobutyl bromide In acetonitrile at 0℃; for 12h;	95%

5-methyl-3-carboxymethylhexanoic acid (75143-89-4) → (±)‑3‑(carbamoylmethyl)‑5‑methylhexanoic acid (181289-15-6)

Conditions	Yield
With urea In 5,5-dimethyl-1,3-cyclohexadiene at 130℃; for 3h; Temperature; Solvent;	93.5%
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate In acetonitrile at 5 - 20℃; for 0.5h; Solvent;	72.4%
With hydrogenchloride; ammonium hydroxide; acetic anhydride In tert-butyl methyl ether; water; ethyl acetate

5-methyl-3-carboxymethylhexanoic acid (75143-89-4) + ethanol (64-17-5) → 1,5-diethy 3-isobutylpentanedioate

Conditions	Yield
With ammonium cerium (IV) nitrate at 20℃; for 24h;	93%
With hydrogenchloride
With thionyl chloride In 1,2-dichloro-ethane at 55 - 65℃;

allyl iodid (556-56-9) + 5-methyl-3-carboxymethylhexanoic acid (75143-89-4) → 1,5-diallyl 3-isobutylpentanedioate (1403953-90-1)

Conditions	Yield
Stage #1: 5-methyl-3-carboxymethylhexanoic acid With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0 - 20℃; for 0.166667h; Stage #2: allyl iodid In acetonitrile at 0℃; for 12h;	93%

5-methyl-3-carboxymethylhexanoic acid (75143-89-4) → 3-isobutylglutarimide

Conditions	Yield
Stage #1: 5-methyl-3-carboxymethylhexanoic acid With urea at 180℃; for 2h; Stage #2: With pyrographite In ethanol; water at 80℃; for 0.5h; Reagent/catalyst; Temperature;	92%
Stage #1: 5-methyl-3-carboxymethylhexanoic acid With ammonium hydroxide at 100℃; for 2h; Stage #2: With pyrographite In ethanol for 0.5h; Reagent/catalyst; Reflux;	88.5%
Multi-step reaction with 2 steps 1: phosphorus pentoxide / 3 h / 95 °C 2: urea / 1 h / 30 °C View Scheme
With urea at 30℃; for 1h; Concentration; Temperature;

5-methyl-3-carboxymethylhexanoic acid (75143-89-4) → 3-isobutylglutaric anhydride (185815-59-2)

Conditions	Yield
With propionic acid anhydride at 140 - 145℃; for 6h;	91%
With acetyl chloride at 20 - 55℃; for 3.08333h; Inert atmosphere;	85%
at 150℃; unter vermindertem Druck;

5-methyl-3-carboxymethylhexanoic acid (75143-89-4) + formamide (77287-34-4, 77287-35-5, 60100-09-6) → C10H15NO4

Conditions	Yield
at 160℃; for 5h;	87%

5-methyl-3-carboxymethylhexanoic acid (75143-89-4) → 3-isobutylpentane-1,5-diol

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux; Inert atmosphere; Schlenk technique;	82%

propan-1-ol (71-23-8) + 5-methyl-3-carboxymethylhexanoic acid (75143-89-4) → 1,5-dipropyl 3-isobutylpentanedioate

Conditions	Yield
With ammonium cerium (IV) nitrate at 20℃; for 24h;	80%

5-methyl-3-carboxymethylhexanoic acid (75143-89-4) → 3-isobutylpentane-1,1,5,5-d4-1,5-diol

Conditions	Yield
With sodium borodeuteride; iodine In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Schlenk technique;	60%

5-methyl-3-carboxymethylhexanoic acid (75143-89-4) + 1-([1,1'-biphenyl]-4-yl)pentan-1-ol (50673-89-7) → 3-Isobutyl-pentanedioic acid mono-(1-biphenyl-4-yl-pentyl) ester

Conditions	Yield
	32%

5-methyl-3-carboxymethylhexanoic acid (75143-89-4) + acetyl chloride (75-36-5) → β-isobutyl-glutaric acid-anhydride

5-methyl-3-carboxymethylhexanoic acid (75143-89-4) → 2,6-dimethyl-4-isobutylheptane-2,6-diol

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / TMSCl / 12 h 2: 56 percent / tetrahydrofuran; diethyl ether / 10 h / Ambient temperature View Scheme

5-methyl-3-carboxymethylhexanoic acid (75143-89-4) → 3-isobutyl-N-phenyl-glutaramic acid

Conditions	Yield
Multi-step reaction with 2 steps 1: 150 °C / unter vermindertem Druck View Scheme

Upstream product

• 181289-34-9 (S)?3?carbamoylmethyl?5?methylhexanoic acid 
• 868-52-0 2?cyano?5?methylhex?2?enoic acid methyl ester 
• 105-53-3 diethyl malonate 
• 590-86-3 isovaleraldehyde 
• 107-91-5 cyanoacetic acid amide 
• 185815-56-9 2,4-dicyano-3-isobutylglutaramide 
• 51615-30-6 diethyl 2-(3-methylbutylidene)malonate 
• 181289-33-8 (3R)‐3‐(carbamoylmethyl)‐5‐methylhexanoic acid 
• 930585-94-7 (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid 
• 392669-46-4 C₁₇H₂₄O₈ 
• 102710-09-8 2-isobutyl-propane-1,1,3,3-tetracarboxylic acid tetraethyl ester 
• 141-82-2 malonic acid 

Downstream Products

• 185815-59-2 3-isobutylglutaric anhydride 
• 148553-50-8 pregabilin 
• 181289-33-8 (3R)‐3‐(carbamoylmethyl)‐5‐methylhexanoic acid 
• 185815-61-6 (R)-3-(carbamoylmethyl)-5-methylhexanoic acid (R)-(+)-α-phenylethylamine 
• 128013-69-4 (R,S)-3-iso-butyl-4-aminobutyric acid 
• 1385049-51-3 R-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid 1-phenylpropylamine salt 
• 181289-25-8 (3S)-3-(2-methoxy-2-oxoethyl)-5-methylhexanoic acid 
• 156048-92-9 (3R)-3-(2-methoxy-2-oxoethyl)-5-methylhexanoic acid 
• 1434278-53-1 (R)-methyl 3-((benzyloxycarbonylamino)methyl)-5-methylhexanoate 
• 1434278-54-2 (R)-3-((benzyloxycarbonylamino)methyl)-5-methylhexanoic acid 
• 930585-94-7 (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid 
• 930280-43-6 (R)-3-isobutylpentanedioic acid amide-((S)-1-phenylethyl)amide 
• 1310495-04-5 (S)-3-(aminomethyl)-5-methyl-N-((S)-1-phenylethyl)hexanamide 
• 930280-44-7 {(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)methyl]pentyl}carbamic acid methyl ester 

Relevant articles and documents

Development of a new synthesis approach for S-pregabalin by optimizing the preparation stages

In the present study, we aimed to optimize the synthesis stages of S-pregabalin ((S)-3-(aminomethyl)-5-methylhexanoic acid), a well-known anticonvulsant drug. We used appropriate solvents and compounds to reach a straightforward and applicable method. The advantages of this research were avoiding use of expensive and environment pollutant reagents and solvents, and also using a recoverable reagent. Discarding prevention of the intermediates and reagents besides attaining a higher yield of the obtained product were the additional achievements. All structures were characterized by FT-IR, 1H NMR, and the purity of S-pregabalin was evaluated using the HPLC assay.

AN IMPROVED PROCESS FOR THE PREPARATION OF PREGABALIN

The present invention relates to an improved process for the preparation of 3-isobutyl glutaric acid compound of formula-1 which is used as the key intermediate in the preparation of Pregabalin compound of formula-A. The present invention also relates to an improved process for the preparation of (S)-3-(aminomethyl)-5-methylhexanoic acid compound of formula-A.

Preparation method of pregabalin intermediate (R)-3-carbamoyl methyl-5-methylhexanoic acid

The invention relates to a preparation method of key intermediate (R)-3-carbamoyl methyl-5-methylhexanoic acid of pregabalin treating epilepsy, neuropathic pain and anxiety. The method uses cyanoacetamide and isovaleraldehyde as starting materials to prepare 3-isobutylglutaric acid, 3-isobutylglutaric acid is esterified, enzymatically reacted and aminolyzed to produce the pregabalin intermediate (R)-3-carbamoyl methyl-5-methylhexanoic acid. The invention has the advantages of low cost, simple reaction, environmental friendliness and high yield, and is suitable for industrial production.