46022-05-3

Basic information

• Product Name: (1R,2R)-(-)-1,2-CYCLOHEXANEDICARBOXYLIC ACID
• Synonyms: (1R,2R)-(-)-1,2-CYCLOHEXANEDICARBOXYLIC ACID;(1R,2R)-1,2-CYCLOHEXANEDICARBOXYLIC ACID;(R,R)-CYCLOHEXANE-1,2-DICARBOXYLIC ACID;(1R,2R)-(-)-trans-cyclohexane-1,2-dicar-boxylic acid;(1R,2R)-(?-trans-Cyclohexane-1,2-dicarboxylic acid;(1R 2R)-(-)-TRANS-CYCLOHEXANE-1 2-DICAR&;1,2-Cyclohexanedicarboxylic acid, (1R,2R)-;(1R,2R)-(-)-1,2-CYCLOHEXANEDICARBOXYLIC ACID 99+%
• CAS NO: 46022-05-3
• Molecular Formula: C₈H₁₂O₄
• Molecular Weight: 172.18
• EINECS: 1308068-626-2
• Product Categories: Carboxylic Acids (Chiral);Chiral Building Blocks;Synthetic Organic Chemistry;Chiral Reagents;Miscellaneous Reagents
• Mol File: 46022-05-3.mol
• Article Data: 13

Chemical Properties

• Melting Point: 184 °C
• Boiling Point: 384.075 °C at 760 mmHg
• Flash Point: 200.254 °C
• Appearance: /
• Density: 1.315 g/cm³
• Refractive Index: -18 ° (C=1, Acetone)
• Storage Temp.: Store below +30°C.
• Solubility: Soluble in acetone.
• PKA: 4.18±0.28(Predicted)
• CAS DataBase Reference: (1R,2R)-(-)-1,2-CYCLOHEXANEDICARBOXYLIC ACID(CAS DataBase Reference)
• NIST Chemistry Reference: (1R,2R)-(-)-1,2-CYCLOHEXANEDICARBOXYLIC ACID(46022-05-3)
• EPA Substance Registry System: (1R,2R)-(-)-1,2-CYCLOHEXANEDICARBOXYLIC ACID(46022-05-3)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36
• WGK Germany: WGK 3 highly water endangering
• Hazardous Substances Data: 46022-05-3(Hazardous Substances Data)

Usage

Uses

Chiral dicarboxylic acid guests with a two C spacer (1R,2R)-cyclohexane-1,2-dicarboxylic acid and Boc-L-aspartic acid] gave CD-active species.

Synthetic route

(R)-1-phenyl-ethyl-amine (3886-69-9) + racemic trans-cyclohexane-1,2-dicarboxylic acid → (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + C24H30N2O2

Conditions	Yield
Stage #1: (R)-1-phenyl-ethyl-amine; racemic trans-cyclohexane-1,2-dicarboxylic acid In methanol at 0 - 35℃; Inert atmosphere; Stage #2: With hydrogenchloride In water Inert atmosphere; enantioselective reaction;	A 25% B n/a

(R,R)-1,2-cyclohexane dicarboxylic acid (R)-1-phenylethyl amine salt → (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3)

Conditions	Yield
With hydrogenchloride In water	800 mg
With sodium hydroxide In chloroform; water for 0.5h; pH=10 - 11;

(x)C8H11N*C8H12O4 → (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3)

Conditions	Yield
With hydrogenchloride In water

trans-1,2-cyclohexanedicarboxylic acid (2305-32-0) → (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / 6.5 h / -70 - 20 °C / Resolution of racemate 2: hydrogenchloride / water View Scheme
With (R)-1-phenyl-ethyl-amine In methanol; isopropyl alcohol at 30 - 40℃;	29.4 g

2-(nitromethyl)cyclohexane-1-carbaldehyde → (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: dipyridinium dichromate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: acetic acid; sodium nitrite / dimethyl sulfoxide / 8 h / 40 °C / Inert atmosphere View Scheme

(1R,2R)-2-(nitromethyl)cyclohexane-1-carboxylic acid (1292320-69-4) → (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3)

Conditions	Yield
With acetic acid; sodium nitrite In dimethyl sulfoxide at 40℃; for 8h; Inert atmosphere;

trans-cyclohex-4-ene-1,2-dicarboxylic acid (88-98-2, 2305-26-2, 15573-40-7, 50987-15-0, 51096-07-2, 51096-08-3) → (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: palladium; hydrogen / methanol / 30 - 35 °C 2.1: ethanol / 30 h / 35 - 75 °C 2.2: 1 h View Scheme

(R)-1-phenyl-ethyl-amine (3886-69-9) + trans-1,2-cyclohexanedicarboxylic acid (2305-32-0) → (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3)

Conditions	Yield
Stage #1: (R)-1-phenyl-ethyl-amine; trans-1,2-cyclohexanedicarboxylic acid In ethanol at 35 - 75℃; for 30h; Stage #2: With hydrogenchloride In water; ethyl acetate for 1h;

trans-1,2-cyclohexanedicarboxylic acid (2305-32-0) → (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + (1S,2S)-cyclohexane-1,2-dicarboxylic acid (610-10-6, 1687-30-5, 2305-32-0, 21963-41-7, 46022-05-3, 610-09-3)

Conditions	Yield
With FS-Hydrodex β-6TBDM column Resolution of racemate;

cyclohex-4-ene-1,2-dicarboxylic acid (88-98-2) → (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogen / methanol / 20 °C / Autoclave 2: methanol / 2.5 h / 20 °C 3: sodium hydroxide / water; chloroform / 0.5 h / pH 10 - 11 View Scheme

dimethyl cis-1,2-cyclohexanedicarboxylate (1687-29-2) → (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + (1S,2S)-cyclohexane-1,2-dicarboxylic acid (610-10-6, 1687-30-5, 2305-32-0, 21963-41-7, 46022-05-3, 610-09-3)

Conditions	Yield
Stage #1: dimethyl cis-1,2-cyclohexanedicarboxylate With sodium methylate In methanol for 4h; Inert atmosphere; Reflux; Stage #2: With water; sodium hydroxide at 75℃; for 4h; Inert atmosphere; Stage #3: With hydrogenchloride In water at 0 - 5℃; pH=2; Inert atmosphere; Optical yield = 16.399 %ee; diastereoselective reaction;

racemic trans-cyclohexane-1,2-dicarboxylic acid → (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3)

Conditions	Yield
With (R)-1-phenyl-ethyl-amine at 5℃; Temperature;

(1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + β-naphthol (135-19-3) → trans-(1R,2R)-cyclohexane dicarboxylic acid di(2-naphthyl)ester

Conditions	Yield
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine	100%
With N,N-bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride; triethylamine In dichloromethane Esterification;

methanol (67-56-1) + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → (1R,2R)-1,2-cyclohexanedicarboxylic acid dimethyl ester (140459-96-7)

Conditions	Yield
With thionyl chloride at 20℃; for 2h; Reflux;	99%
With sulfuric acid at 40℃; for 18h;	97%
With sulfuric acid at 40℃; for 24h; Cooling with ice;	91%

(1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → trans-1,2-cyclohexanedicarboxylic anhydride (85-42-7, 13149-00-3, 14166-21-3, 31982-85-1, 71749-03-6, 97233-90-4)

Conditions	Yield
With acetyl chloride	98%
With acetic anhydride at 80℃; for 1h;
With acetic anhydride at 80℃; for 1h;

(1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → (+)-(1R,2R)-trans-1,2-bis(hydroxymethyl)cyclohexane (65376-05-8)

Conditions	Yield
With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; for 5h; Reflux;	88.4%
With Red-Al In tetrahydrofuran; toluene for 5h; Inert atmosphere; Reflux;	85.2%
Multi-step reaction with 2 steps 1: diethyl ether 2: LiAlH4 / diethyl ether View Scheme

uranyl nirate hexahydrate + cadmium(II) nitrate tetrhydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → O2U(2+)*2C8H10O4(2-)*Cd(2+)*3H2O

Conditions	Yield
In water; acetonitrile at 140℃; Autoclave; High pressure;	85%

cadmium(II) nitrate tetrhydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + trans-1,2-bis(4-pyridyl)ethylene (1135-32-6) → C8H10O4(2-)*2C12H10N2*3H2O*Cd(2+)

Conditions	Yield
In water at 140℃; for 72h; Sealed tube;	83%

diazomethane (186581-53-3, 908094-01-9) + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → (1R,2R)-1,2-cyclohexanedicarboxylic acid dimethyl ester (140459-96-7)

Conditions	Yield
In diethyl ether at 0℃; Inert atmosphere;	75%
In diethyl ether
In diethyl ether

uranyl nirate hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → O2U(2+)*C8H10O4(2-)

Conditions	Yield
With silver nitrate In water; acetonitrile at 140℃; Reagent/catalyst; Autoclave; High pressure;	75%

(1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → (R,R)-trans-2-aminocyclohexanecarboxylic acid hydrochloride

Conditions	Yield
Stage #1: (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid With acetyl chloride Heating; Stage #2: With ammonia In dichloromethane at 20℃; Stage #3: With bis-[(trifluoroacetoxy)iodo]benzene In water; acetonitrile at 20℃; Further stages.;	74%

nickel(II) chloride hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + trans-1,2-bis(4-pyridyl)ethylene (1135-32-6) → C8H10O4(2-)*2C12H10N2*3H2O*Ni(2+)

Conditions	Yield
In water at 140℃; for 72h; Sealed tube;	73.2%

di-tert-butyl dicarbonate (24424-99-5) + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → (1R,2R)-2-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (233661-54-6)

Conditions	Yield
Multistep reaction.;	67%

cobalt(II) chloride hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + trans-1,2-bis(4-pyridyl)ethylene (1135-32-6) → Co(2+)*C8H10O4(2-)*2C12H10N2*3H2O

Conditions	Yield
In water at 140℃; for 72h; Sealed tube;	65%

cadmium(II) nitrate tetrhydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + 9,10-di(1-H-imidazol-1-yl)-anthracene → [Cd(9,10-di(1H-imidazol-1-yl)anthracene)(1,2-chdc)]n

Conditions	Yield
In water; N,N-dimethyl-formamide at 120℃; for 72h; Sealed tube;	63%

uranyl nirate hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + Methyltriphenylphosphonium bromide (1779-49-3) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → [PPh3Me][H2NMe2]3[(UO2)4(R-t-1,2-chdc)6]·H2O

Conditions	Yield
In water at 140℃; for 168h; Autoclave; High pressure;	57%

1,2-bis(4'-pyridyl)ethane (4916-57-8) + nickel(II) chloride hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → C8H10O4(2-)*5H2O*Ni(2+)*C12H12N2

Conditions	Yield
With sodium hydroxide In water at 110℃; for 48h; Sealed tube;	52%

4,4'-bipyridine (553-26-4) + copper(II) perchlorate hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → 3C10H8N2*3Cu(2+)*2C8H11O4(1-)*2C8H10O4(2-)*4H2O

Conditions	Yield
In water at 110℃; for 72h; Sealed tube;	49%

cadmium(II) nitrate tetrhydrate + 1,4-bis(pyridin-4-ylmethyl)piperazine (357429-12-0) + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → [Cd2(trans-1,2-cyclohexanedicarboxylate)2(bis(4-pyridylmethyl)piperazine)]n

Conditions	Yield
With sodium hydroxide In water at 120℃; for 48h; High pressure;	43%

uranyl nirate hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + tetraphenylphosphonium bromide (2751-90-8) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → [PPh4][UO2(trans-(R)-1,2-cyclohexanedicarboxylate)(HCOO)]*(H2O)

Conditions	Yield
In water at 140℃; Autoclave; High pressure;	38%

(1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + Betulinic acid (472-15-1) → 3β-O-[(1'R,2'R)-2'-carboxycyclohexanecarbonyl]betulinic acid (1221184-26-4)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	35%

(1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + zinc(II) acetate dihydrate (5970-45-6) → 3Zn(2+)*2C8H10O4(2-)*2HO(1-)

Conditions	Yield
With sodium hydroxide In ethanol; water at 110℃; for 72h;	32.3%

[2,2]bipyridinyl (366-18-7) + uranyl nirate hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → O2U(2+)*C8H10O4(2-)*C10H8N2

Conditions	Yield
In water; acetonitrile at 140℃; Autoclave; High pressure;	27%

18-crown-6 ether (17455-13-9) + uranyl nirate hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + water (7732-18-5) + potassium nitrate → [(uranyl)10(potassium)5((1R,2R)-trans-1,2-cyclohexanedicarboxylate)4(oxalate)10(18-crown-6)5(OH)(H2O)3] tetrahydrate

Conditions	Yield
at 140℃; for 730.5h; High pressure;	27%

rubidium nitrate (13126-12-0) + uranyl nirate hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → [H2NMe2][(UO2)4Rb3(R-trans-1,2-cyclohexanedicarboxylate)6(H2O)1.75]*DMF

Conditions	Yield
In water at 150℃; High pressure;	24%

sodium nitrate (7631-99-4) + uranyl nirate hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → 2O2U(2+)*3C8H10O4(2-)*2Na(1+)*2H2O

Conditions	Yield
With 18-crown-6 ether In water; acetonitrile at 140℃; Autoclave; High pressure;	21%

hexadecylamine (143-27-1) + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → C40H78N2O2

Conditions	Yield
Stage #1: (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 0.25h; Inert atmosphere; Stage #2: hexadecylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere;	11%

lead(II) nitrate + uranyl nirate hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → 2O2U(2+)*3C8H10O4(2-)*4H2O*Pb(2+)

Conditions	Yield
In water; acetonitrile at 140℃; Autoclave; High pressure;	11%

caesium nitrate + uranyl nirate hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → [(UO2)4Cs4(R-trans-1,2-cyclohexanedicarboxylate)6(H2O)4]·3H2O

Conditions	Yield
In methanol; water at 150℃; High pressure;	10%

[2,2]bipyridinyl (366-18-7) + copper nitrate hemi(pentahydrate) + uranyl nirate hexahydrate + (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → O2U(2+)*2C8H10O4(2-)*C10H8N2*Cu(2+)*3H2O

Conditions	Yield
In water; acetonitrile at 140℃; Autoclave; High pressure;	9%

Upstream product

• 88-98-2 cyclohex-4-ene-1,2-dicarboxylic acid 
• 1687-29-2 dimethyl cis-1,2-cyclohexanedicarboxylate 
• 3886-69-9 (R)-1-phenyl-ethyl-amine 
• 2305-32-0 trans-1,2-cyclohexanedicarboxylic acid 
• 88-98-2 trans-cyclohex-4-ene-1,2-dicarboxylic acid 
• 1292320-69-4 (1R,2R)-2-(nitromethyl)cyclohexane-1-carboxylic acid 

Downstream Products

• 3205-34-3 (1S,2S)-(–)-1,2-di(hydroxymethyl)cyclohexane 
• 7436-01-3 (1S)-trans-1,2-bis-(toluene-4-sulfonyloxymethyl)-cyclohexane 
• 140459-96-7 (1R,2R)-1,2-cyclohexanedicarboxylic acid dimethyl ester 
• 1026905-91-8 2-(4-{(S)-2-[((1R,2R)-2-Carboxy-cyclohexanecarbonyl)-amino]-2-pentylcarbamoyl-ethyl}-phenoxy)-malonic acid dibenzyl ester 
• 31982-90-8 (1S,2S)-(+)-cyclohexane-1,2-dicarboxylic acid dimethyl ester 
• 233661-54-6 (1R,2R)-2-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid 
• 488703-60-2 (1S,2S)-2-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid 
• 85-42-7 trans-1,2-cyclohexanedicarboxylic anhydride 
• 158414-45-0 (R,R)-trans-2-aminocyclohexanecarboxylic acid hydrochloride 
• 31982-85-1 (1S,2S)-trans-1,2-cyclohexanedicarboxylic anhydride 
• 158414-45-0 (1S,2S)-(+)-2-aminocyclohexane-1-carboxylic acid hydrochloride 
• 568588-47-6 (1S,2S)-2-((S)-2-Hydroxy-1-phenyl-ethylcarbamoyl)-cyclohexanecarboxylic acid methyl ester 
• 568588-48-7 (1S,2S)-Cyclohexane-1,2-dicarboxylic acid bis-[((S)-2-hydroxy-1-phenyl-ethyl)-amide] 
• 46021-27-6 (1S,2S)-cyclohexane-1,2-dicarbonyl dichloride 

Relevant articles and documents

AN IMPROVED PROCESS FOR THE PREPARATION OF LURASIDONE HYDROCHLORIDE

Disclosed herein is an improved process for the preparation of Lurasidone and its pharmaceutically acceptable salts via novel intermediate and use thereof for the preparation of an antipsychotic agent useful for the treatment of schizophrenia and bipolar disorder. Further, present invention provides a cost effective and eco-friendly process for producing Lurasidone hydrochloride of formula (I) substantially free of residual solvent(s) at industrial scale.

A PROCESS FOR PREPARATION OF TRANS (LR,2R)-CYCLO HEXANE 1, 2-DICARBOXYLIC ACID

A commercially viable process for industrial preparation of trans-(l R,2R)-cyclohexane 1,2- dicarboxylic acid represented by compound of Formula-I, wherein the compound has more than 99% HPLC purity. The compound of Formula-I is a key intermediate in preparation of Lurasidone hydrochloride which is a well known antipsychotic agent used for treatment of schizophrenia.