75143-89-4

Usage

Uses

Used in Pharmaceutical Industry:
3-Isobutylglutaric acid is used as an intermediate in the synthesis of pregabalin for its anticonvulsant properties. Pregabalin is approved by the United States Food and Drug Administration (FDA) to treat neuropathic pain associated with conditions such as diabetic peripheral neuropathy, spinal cord injury, and postherpetic neuralgia. Additionally, pregabalin is FDA-approved for the management of fibromyalgia and as adjunctive therapy for partial-onset seizures in adults with epilepsy. The use of 3-isobutylglutaric acid in the synthesis process contributes to the development of these therapeutic applications.

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

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

Downstream Products

• 185815-59-2 3-isobutylglutaric anhydride 
• 181289-15-6 (±)?3?(carbamoylmethyl)?5?methylhexanoic acid 
• 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 
• 930280-42-5 (3S)-5-methyl-3-(2-oxo-2-{[(1S)-1-phenylethyl]amino}ethyl)hexanoic acid 
• 930280-44-7 {(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)methyl]pentyl}carbamic acid methyl ester 
• 930585-94-7 (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid 

Relevant academic research and scientific papers

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.

Method for preparing 3-isobutylglutaric acid

The invention discloses a method for preparing 3-isobutylglutaric acid. The method includes the following steps: carrying out a Knoevenagel condensation reaction on isovaleraldehyde and diethyl malonate with hexahydropyridine acetate as a catalyst in a cyclohexane solvent; carrying out a heating decarboxylation reaction on a product obtained by the first step in a solution composed of sodium chloride, DMSO and water; carrying out a Michael addition and decarboxylation reaction on a product obtained by the second step and diethyl malonate in an alcohol solvent of an alkali; and carrying out a hydrolysis reaction on a product obtained by the third step under an acidic condition to obtain the 3-isobutylglutaric acid product. The method of the invention uses the cheap and easily available isovaleraldehyde and diethyl malonate as raw materials, overcomes the defect of large steric hindrance of carbon-carbon a double bond in 5-methyl-2-cyano-2-hexenoate in the prior art, shortens the reaction time, and increases the reaction conversion rate of the isovaleraldehyde, thereby ensuring the overall yield of the 3-isobutylglutaric acid product.

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.

Pregabalin intermittent synthesis method

The invention discloses a pregabalin intermittent synthesis method. The method comprises the following step of (1) preparation of 2-cyano-5-methyl-2-hexenyl ethyl ester (A), wherein 94.6 g (1.1mol) ofisovaleraldehyde, 113 g (1.0 mol) of ethyl cyanoacetate, 127 ml of n-hexane and 1.00 g (0.01mol) of di-n-propylamine are put into a 1000 ml reaction bottle in sequence, heating is conducted, reflux reaction is carried out, a water separator is used for water separation, the reaction is carried out until no moisture is separated out, and cooling is conducted. Compared with the prior art, the pregabalin intermittent synthesis method has the following advantages that when methyl tertiary butyl ether is used as a solvent, layering is hard, impurities cannot be removed, the solvent cannot be recycled, the raw material cost is improved, and the amide is low, so that the methyl tertiary butyl ether is not suitable for being used as the solvent; ethyl acetate can be used, however, the intersolubility of the ethyl acetate and water is large, thus a small amount of amide crude product is dissolved in the water, the amide yield is low, meanwhile, the ethyl acetate recovery is low, and by using methylbenzene, the defects of the ethyl acetate are avoided, so that the methylbenzene is selected as an ammoniation solvent. There are no corresponding HPLC standards of the quality situation of amide, however, the quality of the amide obtained by adopting a technology is qualified in later detection.

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.

Preparation method and application of high-purity dimethyl 3-isobutylglutarate

The invention provides a preparation method and application of high-purity dimethyl 3-isobutylglutarate. Specifically, the invention provides the method for preparing dimethyl 3-isobutylglutarate shown as a formula 2, and the method comprises the step of enabling 3-isobutylglutaric acid to react in methanol in the presence of potassium permanganate and concentrated sulfuric acid, so as to obtain the high-purity dimethyl 3-isobutylglutarate. The method is simple, easy to control, high in product conversion rate, mild in reaction condition, convenient for industrial production and low in cost, the product is easy to purify, and the purity is up to 99% or above.

Method for synthesizing optically pure (R)-3-carbamoymethyl-5-methylhexanoic acid

The invention relates to the technical field of fine chemical engineering production and in particular discloses a method for synthesizing optically pure (R)-3-carbamoymethyl-5-methylhexanoic acid. The method comprises the following steps: 1, synthesizing 2-cyano-5-methyl-2-ene ethyl hexanoate; 2, synthesizing 3-isobutyl-2-cyano-4-ethoxycarbonyl-ethyl glutarate; 3, synthesizing 3-isobutylglutaricanhydride; 4, synthesizing (+/-)-3-carbamoymethyl-5-methylhexanoic acid; and 5, synthesizing the (R)-3-carbamoymethyl-5-methylhexanoic acid. According to the method disclosed by the invention, the defects in the prior art are overcome, and the provided synthetic method is low in raw material cost, high in reaction speed, simple and feasible, is suitable for large-scale industrial production and has very high economic benefits.

Method for preparing Pregabalin intermediate

The invention provides a method for preparing a Pregabalin intermediate. The method comprises the steps: subjecting cyanoacetamide and isovaleraldehyde to an acylation reaction in the presence of a catalyst, i.e., n-propylamine so as to obtain 3-isobutylglutaric acid, wherein a temperature for the acylation reaction is controlled to 35 DEG C to 40 DEG C; and adding a dehydrant, i.e., acetic anhydride into the obtained 3-isobutylglutaric acid, so as to carry out dehydrated cyclization, thereby obtaining the Pregabalin intermediate, i.e., 3-isobutyl glutaric anhydride, wherein the mole ratio ofthe cyanoacetamide to the isovaleraldehyde to the n-propylamine to the acetic anhydride is 1: (0.4 to 0.6): (0.02 to 0.03): (0.4 to 0.6). According to the method, through controlling the reaction temperature and a material proportioning ratio, side reactions participating in the reaction are less, and then, the obtained product is less in impurity. The Pregabalin intermediate, i.e., 3-isobutyl glutaric anhydride with higher yield and purity is obtained, the yield is greatly increased, and the one-time yield of the product is 80.6%.

Preparation method for 3-carbamoymethyl-5-methylhexanoic acid

The invention relates to a preparation method for 3-carbamoymethyl-5-methylhexanoic acid, and the product can be used as a pregabalin intermediate. The preparation method comprises the steps that a condensation compound is generated by catalytic condensation using isovaleraldehyde and cyanoacetamide as raw materials under mild conditions; the condensation compound is hydrolyzed to generate 3-Isobutylglutaric acid under acidic conditions; 3-isobutylglutaric anhydride is generated through an anhydride reaction; the final product 3-carbamoymethyl-5-methylhexanoic acid is generated through an amidation reaction. The preparation method for 3-carbamoymethyl-5-methylhexanoic acid effectively improves the condensation reaction efficiency through catalytic condensation of a base catalyst, and is high in production yield, less in by-products, mild in reaction conditions, and is beneficial to treatment of three wastes, and provides an environment-friendly technological route for industrialized mass production. The preparation method is an operation-safety, high-yield, low-cost and environment-friendly route.

Method for synthesizing Pregabalin by taking gamma-isobutylglutaric anhydride as intermediate

The invention discloses a method for synthesizing Pregabalin by taking gamma-isobutylglutaric anhydride as an intermediate. The method comprises the steps: carrying out Knoevenagel condensation on isovaleraldehyde and methyl cyanoacetate in an ethanol solvent by taking piperidine as a catalyst; carrying out Michael addition on the condensation product and diethyl malonate in a n-hexane solvent by taking di-n-propylamine as a catalyst; carrying out hydrolyzing decarboxylation on the addition product under the catalysis of strong acid and under the condition of heating; dehydrating the hydrolyzing decarboxylation product in a THF solvent under the catalysis of phosphorus pentoxide and under the condition of heating; enabling the dehydrated hydrolyzing decarboxylation product to subject to ammonolysis reaction with urea; carrying out Hoffman degradation on the ammonolysis reaction product; and finally, carrying out chiral resolution on the Hoffman degradation product by taking (S)-(+)-mandelic acid as a resolving agent. According to the method, isovaleraldehyde and methyl cyanoacetate, which are cheap and are readily available, serve as raw materials and are subjected to Knoevenagel condensation, Michael addition, acid hydrolyzing decarboxylation and dehydrating, so as to obtain the intermediate gamma-isobutylglutaric anhydride; and the gamma-isobutylglutaric anhydride is subjected to ammonolysis, Hoffman degradation and chiral resolution, thereby obtaining Pregabalin. The reaction route is simple, and the yield of reaction of each step is relatively high, so that the total yield and purity of final Pregabalin are guaranteed.