99189-60-3

Basic information

• Product Name: 1,1-Cyclohexanediacetic acid mono amide
• Synonyms: 1,1-Cychexanediaceticacidmonoamide;1,1-CYCLOHESANEDIACETIS ACID MONOAMIDE;2-(1-CARBAMOYLMETHYL-CYCLOHEXYL)-ACETAMIDE;1-(2-Amino-2-oxoethyl)cylohexaneacetic Acid;1-(Carbamoylmethyl)cyclohexaneacetic Acid;CAM (1,1-Cyclohexane diacetic acid monoamide);1-(2-Amino-2-oxoethyl)cyclohexaneacetic acid, 1-[(Aminocarbonyl)methyl]cyclohexaneacetic acid, 3,3-Pentamethyleneglutaramic acid;1,1-Cyclohexanediacetic acid monoamide,97%
• CAS NO: 99189-60-3
• Molecular Formula: C₁₀H₁₇NO₃
• Molecular Weight: 198.26
• EINECS: 449-430-4
• Product Categories: INTERMEDIATESOFGABAPENTIN;Organic acids;Pharmaceutical intermediates
• Mol File: 99189-60-3.mol
• Article Data: 10

Chemical Properties

• Melting Point: 141-146 °C(lit.)
• Boiling Point: 443.6 °C at760mmHg
• Flash Point: 222.1 °C
• Appearance: White powder
• Density: 1.135 g/cm³
• Vapor Pressure: 4.14E-09mmHg at 25°C
• Storage Temp.: -20°C
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 4.72±0.10(Predicted)
• CAS DataBase Reference: 1,1-Cyclohexanediacetic acid mono amide(CAS DataBase Reference)
• NIST Chemistry Reference: 1,1-Cyclohexanediacetic acid mono amide(99189-60-3)
• EPA Substance Registry System: 1,1-Cyclohexanediacetic acid mono amide(99189-60-3)

Safety Data

• Hazard Codes: T
• Statements: 61
• Safety Statements: 22-24/25-45-53
• WGK Germany: 3
• Hazardous Substances Data: 99189-60-3(Hazardous Substances Data)

Usage

Chemical Properties

White powder

Uses

1,1-Cyclohexanediacetic acid monoamide is an impurity of Gabapentin (G117250), an amino acid structurally related to γ-Aminobutyric Acid (GABA), designed to cross the blood brain barrier.?Gabapentin is used as an anticonvulsant.

General Description

1,1-Cyclohexanediacetic acid monoamide, also known as gabapentin amide, has neurological properties. It is an important intermediate formed during the synthesis of a potential antiepileptic drug, gabapentin.

InChI:InChI=1/C10H17NO3/c11-8(12)6-10(7-9(13)14)4-2-1-3-5-10/h1-7H2,(H2,11,12)(H,13,14)/p-1

Synthetic route

3-azaspiro[5,5]undecane-2,4-dione (1130-32-1) → [1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3)

Conditions	Yield
With water; sodium hydroxide at 50℃; for 6h; Reagent/catalyst;	93%
With sodium hydroxide
Stage #1: 3-azaspiro[5.5]undecane-2,4-dione With sodium hydroxide; water at 95 - 105℃; for 6h; Heating / reflux; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 20 - 40℃; for 1h; pH=6.5; Industry scale; Stage #3: With hydrogenchloride In water; isopropyl alcohol at 35 - 40℃; for 1h; pH=4.0 - 4.5; Industry scale;
Stage #1: 3-azaspiro[5.5]undecane-2,4-dione With sodium hydroxide; water for 1h; Heating / reflux; Stage #2: With hydrogenchloride In water at 25℃; pH=5;

spiro[cyclohexane-1,9’-(3,7-diazabicycle-[3.3.1]nonane)]-2’,4’,6’,8’-tetraone (90961-78-7) → [1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3)

Conditions	Yield
With water; sodium hydroxide at 100 - 105℃; for 18h;	80.8%

1,1-cyclohexanediacetic acid anhydride (1010-26-0) → [1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3)

Conditions	Yield
Stage #1: 1,1-cyclohexanediacetic acid anhydride With ammonia In water; acetic acid; toluene at 10 - 30℃; for 1.33333h; pH=> 8; Stage #2: With hydrogenchloride In water at 40 - 45℃; for 0.333333h; pH=3.8 - 4.2;
Stage #1: 1,1-cyclohexanediacetic acid anhydride With sodium hydroxide; water; ammonium chloride at 0 - 30℃; for 4h; Stage #2: With hydrogenchloride; water pH=2 - 3; Product distribution / selectivity;
Stage #1: 1,1-cyclohexanediacetic acid anhydride With ammonia; water In isopropyl alcohol at 5℃; for 1h; Stage #2: With hydrogenchloride; water In isopropyl alcohol at 15 - 20℃; for 15h; pH=2 - 3; Product distribution / selectivity;

1,1-cyclohexanediacetic acid (4355-11-7) → [1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: acetic anhydride / 2 h / 130 °C 2.1: ammonia / benzene / 5 h / 25 - 105 °C 2.2: 1.5 h / 55 °C / pH 4 View Scheme
Multi-step reaction with 2 steps 1: acetic anhydride / 0.5 h / 110 °C 2: ammonium hydroxide / 1 h View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → gabapentin-lactam (64744-50-9)

Conditions	Yield
Stage #1: [1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid With sodium hydroxide; sodium hypochlorite In water at 0 - 40℃; for 3.5h; Stage #2: With hydrogenchloride In water at 100 - 105℃; for 3h; pH=8.2 - 8.8; Product distribution / selectivity; Heating / reflux;	100%
Stage #1: [1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid With sodium hydroxide; sodium hypochlorite In water at 0 - 50℃; for 3h; Stage #2: With hydrogenchloride In water at 100 - 105℃; for 3h; pH=11 - 12; Product distribution / selectivity;	93.8%
Stage #1: [1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid With sodium hydroxide In water at 20 - 30℃; for 0.5h; Stage #2: With sode de l'acide trichloroisocyanurique In water at 0 - 20℃; for 5h; Stage #3: In water; toluene at 80℃; for 8h; Reagent/catalyst;	85%
Multi-step reaction with 2 steps 1.1: trichloroisocyanuric acid / methanol / 1.75 h / 20 - 25 °C 2.1: sodium hydroxide / water / 4 h / 0 - 20 °C 2.2: 8 h / 80 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → C10H16ClNO3

Conditions	Yield
With trichloroisocyanuric acid In methanol at 20 - 25℃; for 1.75h;	100%

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 1-(aminomethyl)-1-cyclohexaneacetic acid sodium salt (63562-00-5)

Conditions	Yield
With sodium hypobromide; sodium hydroxide In water at 40 - 55℃; Reagent/catalyst; Temperature; Hofmann Rearrangement; Flow reactor;	91.98%
With sodium hydroxide; sodium hypobromide In water at 0 - 10℃; for 2 - 3h; Product distribution / selectivity; Hofmann Rearrangement;	67%
With sodium hydroxide; sodium hypochlorite In water at 0 - 10℃; for 2 - 3h; Product distribution / selectivity; Hofmann Rearrangement;	65%

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 1-(aminomethyl)cyclohexaneacetic acid hydrochloride

Conditions	Yield
Stage #1: [1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid With sodium hydroxide; sodium hypochlorite In water at -5 - 25℃; for 9h; Stage #2: With hydrogenchloride In water; butan-1-ol pH=1.5;	75%
Stage #1: [1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid With sodium hydroxide; bromine In water at -8 - 40℃; for 2h; Stage #2: With hydrogenchloride; water for 4h; pH=2;
Multi-step reaction with 2 steps 1.1: sodium hydroxide / water / 0.5 h / 20 - 30 °C 1.2: 5 h / 0 - 20 °C 1.3: 8 h / 80 °C 2.1: hydrogenchloride; water / 10 h / 100 °C View Scheme
Multi-step reaction with 3 steps 1.1: trichloroisocyanuric acid / methanol / 1.75 h / 20 - 25 °C 2.1: sodium hydroxide / water / 4 h / 0 - 20 °C 2.2: 8 h / 80 °C 3.1: hydrogenchloride; water / 10 h / 100 °C View Scheme
Stage #1: [1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid With sodium hypochlorite; sodium hydroxide In water; benzene at 100℃; Stage #2: at 95℃; for 3h; Temperature;

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → gabapentin hemisulphate

Conditions	Yield
Stage #1: [1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid With sodium hydroxide; sodium hypochlorite In water at -5 - 25℃; for 9h; Stage #2: With sulfuric acid In water; butan-1-ol pH=1.5;	73.8%

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → H-Gpn-OH (60142-96-3)

Conditions	Yield
With sodium carbonate In benzyl alcohol pH=7 - 7.5; Product distribution / selectivity;	68.6%
With sodium hydroxide; sodium hypochlorite In water at -10 - 20℃; for 8h; Hofmann Rearrangement;
Stage #1: [1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid With sodium hypochlorite; sodium hydroxide In water at 40℃; Hofmann Rearrangement; Stage #2: With sodium metabisulfite In water Product distribution / selectivity;

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((methyleneamino)methyl)cyclohexyl)acetic acid (1262837-02-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((ethylideneamino)methyl)cyclohexyl)acetic acid (1262837-03-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((benzylideneamino)methyl)cyclohexyl)acetic acid (1262837-04-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((4-methoxybenzylideneamino)methyl)cyclohexyl)acetic acid (1262837-05-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((2-hydroxybenzylideneamino)methyl)cyclohexyl)acetic acid (1262837-06-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((2-chloro-6-fluorobenzylideneamino)methyl)cyclohexyl)acetic acid (1262837-08-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((2-chlorobenzylideneamino)methyl)cyclohexyl)acetic acid (1262837-09-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((4-fluorobenzylideneamino)methyl)cyclohexyl)acetic acid (1262837-10-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((4-ethoxybenzylideneamino)methyl)cyclohexyl)acetic acid (1262837-11-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-(((pyridin-2-yl)methyleneamino)methyl)cyclohexyl)acetic acid (1262837-12-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((1-(4-ethoxyphenyl)ethylideneamino)methyl)cyclohexyl)acetic acid (1262837-13-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((1-(pyridin-2-yl)ethylideneamino)methyl)cyclohexyl)acetic acid (1262837-14-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → C18H22N2O2 (1262837-15-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((1-(1H-indol-3-yl)ethylideneamino)methyl)cyclohexyl)acetic acid

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((1-(pyridin-3-yl)ethylideneamino)methyl)cyclohexyl)acetic acid (1262837-17-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → 2-(1-((1-(naphthalen-2-yl)ethylideneamino)methyl)cyclohexyl)acetic acid (1262837-18-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hypobromide; sodium hydroxide / 15 h / 55 °C 2: sulfuric acid / ethanol / 20 °C View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → gabapentin oxalate

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hypochlorite; sodium hydroxide / benzene; water / 100 °C 1.2: 3 h / 95 °C 2.1: 2 h / pH 5 View Scheme

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → Reaxys ID: 34429109

Conditions	Yield
With alkali metal hypohalogenate Hofmann Rearrangement;

[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid (99189-60-3) → piperidine-2,6-dione (1121-89-7)

Conditions	Yield
With acetic acid In toluene at 70℃; for 6h; Temperature;

Upstream product

• 90961-78-7 spiro[cyclohexane-1,9’-(3,7-diazabicycle-[3.3.1]nonane)]-2’,4’,6’,8’-tetraone 
• 4355-11-7 1,1-cyclohexanediacetic acid 
• 1010-26-0 1,1-cyclohexanediacetic acid anhydride 
• 1130-32-1 3-azaspiro[5.5]undecane-2,4-dione 

Downstream Products

• 1121-89-7 piperidine-2,6-dione 
• 1262837-18-2 2-(1-((1-(naphthalen-2-yl)ethylideneamino)methyl)cyclohexyl)acetic acid 
• 1262837-17-1 2-(1-((1-(pyridin-3-yl)ethylideneamino)methyl)cyclohexyl)acetic acid 
• 1262837-15-9 C₁₈H₂₂N₂O₂ 
• 1262837-14-8 2-(1-((1-(pyridin-2-yl)ethylideneamino)methyl)cyclohexyl)acetic acid 
• 1262837-13-7 2-(1-((1-(4-ethoxyphenyl)ethylideneamino)methyl)cyclohexyl)acetic acid 
• 1262837-12-6 2-(1-(((pyridin-2-yl)methyleneamino)methyl)cyclohexyl)acetic acid 
• 1262837-11-5 2-(1-((4-ethoxybenzylideneamino)methyl)cyclohexyl)acetic acid 
• 1262837-10-4 2-(1-((4-fluorobenzylideneamino)methyl)cyclohexyl)acetic acid 
• 1262837-09-1 2-(1-((2-chlorobenzylideneamino)methyl)cyclohexyl)acetic acid 
• 1262837-08-0 2-(1-((2-chloro-6-fluorobenzylideneamino)methyl)cyclohexyl)acetic acid 
• 1262837-06-8 2-(1-((2-hydroxybenzylideneamino)methyl)cyclohexyl)acetic acid 
• 1262837-05-7 2-(1-((4-methoxybenzylideneamino)methyl)cyclohexyl)acetic acid 
• 1262837-04-6 2-(1-((benzylideneamino)methyl)cyclohexyl)acetic acid 

Relevant articles and documents

Preparation method of glutaryl imide derivative

The invention discloses a preparation method of a glutaryl imide derivative, which comprises the following steps: in a negative pressure state, dropwise adding acetic anhydride into molten 1, 1-cyclohexyl diacetic acid, and reacting to obtain 1, 1-cyclohexyl diacetic anhydride; adding ammonia water into an ammoniation kettle, dropwise adding 1, 1-cyclohexanediacetic anhydride to carry out ammoniation reaction, and adding hydrochloric acid to adjust the pH value, so as to obtain precipitated crystals, namely pentane valeric acid; adding pentane valeric acid, a toluene solvent and glacial aceticacid into the reaction kettle, heating, stirring, reacting, cooling, and carrying out suction filtration to obtain a filter cake; and adding the filter cake into ammonia water for soaking and stirring, carrying out suction filtration again, leaching with deionized water, and drying to obtain glutaryl imide. According to the preparation method of a glutaryl imide derivative, acetic anhydride and 1, 1-cyclohexyldiacetic acid are used as raw materials, so that the reaction efficiency is effectively improved, the product yield is increased, the production cost of the product is reduced, and producing benefits are improved.

Preparation method of gabapentin intermediate

The invention provides a preparation method of a gabapentin intermediate, and relates to the field of chemical organic synthesis. The preparation method comprises the following steps: taking cyanoacetic acid and cyclohexanone as raw materials, carrying out condensation, hydrolysis and decarboxylation reactions to obtain imide in an intermediate body, and further carrying out alkaline hydrolysis toobtain the intermediate cyclohexyl diacetate monoamide. The preparation method of the gabapentin intermediate provided by the invention has the advantages of readily available raw materials, mild reaction conditions, high safety factor, strong operability, simple process, easiness in industrialization, high product purity and stable quality.

A process for synthesis of gabapentin

The invention discloses a gabapentin synthesis technology. The gabapentin synthesis technology comprises the following steps of 1, preparing 1,1-cyclohexane diacetic anhydride, 2, preparing 3,3-cyclopentaneglutaramic acid, 3, preparing gabapentin hydrochloride, 4, adding the gabapentin hydrochloride into an oxalic acid solution, adjusting a pH value to 2-5, carrying out stirring, carrying out pressure reduction condensation to obtain filter cake, dissolving the filter cake in ethanol, carrying out stirring for dissolution, and carrying out pressure reduction drying to obtain fined gabapentin oxalate, and 5, adding the fined gabapentin oxalate into absolute ethanol, adjusting a PH value to 7-8, carrying out stirring, adding active carbon into the mixture, carrying out heating reflux, carrying out filtration, carrying out pressure reduction drying to obtain a gabapentin hydrate, adding the gabapentin hydrate into absolute ethanol, carrying out heating dissolution, carrying out cooling, carrying out filtration, concentrating the filtrate, carrying out cooling for crystal precipitation, carrying out filtration, carrying out washing by absolute ethanol and carrying out drying to obtain gabapentin. Gabapentin obtained by the gabapentin synthesis technology has high content and a high yield.