13149-00-3

Basic information

• Product Name: CIS-1,2-CYCLOHEXANEDICARBOXYLIC ANHYDRIDE
• Synonyms: CIS-1,2-CYCLOHEXANEDICARBOXYLIC ANHYDRIDE (HHPA);1,3-Isobenzofurandione, hexahydro-, (3aR,7aS)-rel-;CIS-1,2-CYCLOHEXANEDECARBOXYLICANHYDRIDE;CIS-1,2-CYCLOHEXANEDICARBOXYLIC ANHYDRIDE;CIS-HEXAHYDROPHTHALIC ANHYDRIDE;CIS-HHPA;CIS-CYCLOHEXANE-1,2-DICARBOXYLIC ANHYDRIDE;HEXAHYDROPHTHALIC ACID ANHYDRIDE
• CAS NO: 13149-00-3
• Molecular Formula: C₈H₁₀O₃
• Molecular Weight: 154.16
• EINECS: 236-086-3
• Product Categories: Pharmaceutical Intermediates
• Mol File: 13149-00-3.mol
• Article Data: 14

Chemical Properties

• Melting Point: 32-34 °C(lit.)
• Boiling Point: 158 °C17 mm Hg(lit.)
• Flash Point: >230 °F
• Appearance: White to almost white/Crystalline Low Melting Solid
• Density: 1.23
• Vapor Pressure: 0.003mmHg at 25°C
• Refractive Index: 1.4750 (estimate)
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Sensitive: Moisture Sensitive
• BRN: 83214
• CAS DataBase Reference: CIS-1,2-CYCLOHEXANEDICARBOXYLIC ANHYDRIDE(CAS DataBase Reference)
• NIST Chemistry Reference: CIS-1,2-CYCLOHEXANEDICARBOXYLIC ANHYDRIDE(13149-00-3)
• EPA Substance Registry System: CIS-1,2-CYCLOHEXANEDICARBOXYLIC ANHYDRIDE(13149-00-3)

Safety Data

• Hazard Codes: Xn
• Statements: 41-42/43
• Safety Statements: 23-24-26-37/39
• WGK Germany: 1
• F: 10-21
• Hazardous Substances Data: 13149-00-3(Hazardous Substances Data)

Usage

Chemical Properties

white to almost white cryst. low melting solid

Uses

(3aR,7aS)-rel-Hexahydro-1,3-isobenzofurandione is a reagent used in the synthesis of Pregabalin (P704800), a GABA analogue used as an anticonvulsant. Also used to prepare P2X7 receptor antagonists.

Purification Methods

It has been obtained by heating the trans-acid or anhydride at 200o. Crystallise it from *C6H6/Et2O or distil it. [Kohler & Jansen J Am Chem Soc 60 2145 1938, Abell J Org Chem 22 769 1957, Beilstein 17 II 452, 17 III/IV 5931.]

InChI:InChI=1/C8H10O3/c9-7-5-3-1-2-4-6(5)8(10)11-7/h5-6H,1-4H2/t5-,6+

Synthetic route

cis-1,2,3,6-tetrahydrophthalic anhydride (935-79-5) → 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3)

Conditions	Yield
With hydrogen; palladium on activated charcoal In 1,4-dioxane for 24h;	96%
With acetic acid; platinum Hydrogenation;
With ethyl acetate; platinum Hydrogenation;
With silica gel; nickel at 130℃; Hydrogenation;
With nickel; ethyl acetate Hydrogenation;

(1R,2S)-cyclohexane-1,2-dicarboxylic acid (610-09-3) → 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3)

Conditions	Yield
With Isopropenyl acetate; Montmorillonite KSF for 0.0666667h; Irradiation;	94%
With Isopropenyl acetate; Montmorillonite KSF for 0.0666667h; Product distribution; Irradiation; var. microwave lenghts, var. reaction time, other carboxylic diacids;	94%
With 4-methyl-morpholine; methyl chloroformate In tetrahydrofuran at 20℃; for 0.25h;
With 2,6-bis[(2,2,6,6-tetramethylpiperidin-1-yl)methyl]phenylboronic acid In propiononitrile	99 %Spectr.

(1R,2S)-cyclohexane-1,2-dicarboxylic acid (610-09-3) + trans-1,2-cyclohexanedicarboxylic acid (2305-32-0) → 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3)

Conditions	Yield
With acetyl chloride

(+/-)-trans-1,2-cyclohexanedicarboxylic anhydride (14166-21-3) → 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3)

Conditions	Yield
at 200℃;

trans-1,2-cyclohexanedicarboxylic acid (2305-32-0) → 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3)

Conditions	Yield
With trifluoroacetic anhydride

(1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3)

Conditions	Yield
With 2,6-bis[(2,2,6,6-tetramethylpiperidin-1-yl)methyl]phenylboronic acid In propiononitrile stereoselective reaction;	89 %Spectr.

1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → hexahydro-isobenzo[c]furan-1-one (6939-71-5)

Conditions	Yield
With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 2h; Inert atmosphere;	100%
With sodium tetrahydroborate In tetrahydrofuran at 0 - 20℃; for 5h;	91%
With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 2h;	85%

methanol (67-56-1) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → dimethyl cis-1,2-cyclohexanedicarboxylate (1687-29-2)

Conditions	Yield
With sulfuric acid at 20 - 60℃;	100%
With sulfuric acid
With thionyl chloride for 4h; Inert atmosphere; Reflux;

methanol (67-56-1) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → (1S,2R)-2-(methoxycarbonyl)cyclohexanecarboxylic acid (88335-92-6)

Conditions	Yield
at 100℃; for 1h;	100%
With polymer-supported Cinchona-based sulfonamide In mBTE at 20℃; for 3h; optical yield given as %ee; enantioselective reaction;	99%
Stage #1: methanol; 1,2-cis-cyclohexanedicarboxylic anhydride; C28H31N3O3S In di-isopropyl ether at -20℃; for 4h; Stage #2: With hydrogenchloride In di-isopropyl ether; water Product distribution / selectivity;	99%

1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → cis-1-carboxy-2-(aminocarboxyl)-2-cyclohexane (6294-84-4, 92116-89-7, 92116-90-0)

Conditions	Yield
With ammonium hydroxide at 25℃;	100%
With ammonium hydroxide	88%
With ammonia In water
With ammonium hydroxide

cyclohexylamine (108-91-8) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → 2-cyclohexylcarbamoyl-cyclohexanecarboxylic acid

Conditions	Yield
Stage #1: cyclohexylamine; 1,2-cis-cyclohexanedicarboxylic anhydride In N,N-dimethyl acetamide at 20℃; for 24h; Stage #2: In N,N-dimethyl acetamide; xylene at 140℃; for 48h;	100%

tert-butylamine (75-64-9) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → 2-tert-butylcarbamoyl-cyclohexanecarboxylic acid

Conditions	Yield
Stage #1: tert-butylamine; 1,2-cis-cyclohexanedicarboxylic anhydride In N,N-dimethyl acetamide at 20℃; for 24h; Stage #2: In N,N-dimethyl acetamide; xylene at 140℃; for 48h;	100%

methanol (67-56-1) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → cis-2-methoxycarbonylcyclohexane-1-carboxylic acid (2484-60-8, 2778-62-3, 7719-08-6, 52782-07-7, 88335-91-5, 88335-92-6, 96894-64-3, 111955-05-6)

Conditions	Yield
at 100℃; for 1h;	100%
With 1,4-diaza-bicyclo[2.2.2]octane
With magnetite nanoparticles In tert-butyl methyl ether at 20℃; for 18h; Inert atmosphere;
Reflux;
Heating;

methanol (67-56-1) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → cyclohexane-1,2-dicarboxylic acid monomethyl ester (88335-91-5)

Conditions	Yield
With 1-((1R,2R)-2-(dimethylamino)cyclohexyl)-3-phenylthiourea In diethyl ether at 20℃; for 24h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;	99%
With tert-butyl methyl ether; C28H29N3O3S at 20℃; for 24h; enantioselective reaction;	99%
With 1,4-bis(dihydroquinidinyl)anthraquinone In diethyl ether at -20℃; for 48h;	97%

aniline (62-53-3) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → N-phenyltetrahydrophthalimide (26491-47-4) + 2-Phenylcarbamoyl-cyclohexanecarboxylic acid

Conditions	Yield
Stage #1: aniline; 1,2-cis-cyclohexanedicarboxylic anhydride In N,N-dimethyl acetamide at 20℃; for 24h; Stage #2: In N,N-dimethyl acetamide; xylene at 140℃; for 48h;	A 97% B n/a

diethylzinc (557-20-0) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → (1RS,2SR)-2-propionylcyclohexanecarboxylic acid

Conditions	Yield
With [2,2]bipyridinyl; bis(acetylacetonate)nickel(II); trifluorotoluene In tetrahydrofuran; hexane at 0 - 20℃; for 48h;	96%
With [2,2]bipyridinyl; bis(1,5-cyclooctadiene)nickel (0); 1-trifluoromethyl-4-vinyl-benzene In tetrahydrofuran at 0 - 23℃; for 12h; Product distribution; Further Variations:; Reagents;	92%

(R)-2-amino-3-methylbutanol (4276-09-9) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → cis-(2'S)-(+)-N-<1-(1-methylethyl)-2-hydroxyethyl>-3a,4,5,6,7,7a-hexahydro-1H-isoindolimide (122383-33-9)

Conditions	Yield
at 220℃; for 2.5h;	95%

1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) + benzyl alcohol (100-51-6) → (1R,2S)-cis-2-benzyloxycarbonyl-cyclohexane-1-carboxylic acid (151434-99-0)

Conditions	Yield
With quinindine In toluene at -55℃; for 96h; Inert atmosphere; enantioselective reaction;	95%
tributylphosphine In [D3]acetonitrile for 24h;	70%
With quinindine In toluene at -50℃; for 120h; Inert atmosphere;	60%

2-cyanoethylamine (151-18-8) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → 3-(1,3-dioxo-octahydroisoindol-2-yl)propionitrile (192824-58-1, 260435-04-9)

Conditions	Yield
at 200℃; for 0.5h;	95%

3-methylantranilic acid (4389-45-1) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → C16H17NO4 (1185155-84-3)

Conditions	Yield
at 110℃; for 10h; Inert atmosphere; neat (no solvent);	95%

1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → (3aR,7aS)-2-hydroxyhexahydro-1H-isoindol-1,3(2H)-dione (18886-85-6)

Conditions	Yield
With hydroxyammonium sulfate; sodium hydroxide In water at 90℃; for 1.25h;	94%
With hydroxylamine sulfate; sodium hydroxide In water at 90℃; for 2.25h;	94%
With hydroxyammonium sulfate; sodium hydroxide In water at 90℃; for 2.25h;	94%
With methanol; hydroxylamine
With water; hydroxylamine

1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → cis-1,2-cyclohexanedimethanol (15753-50-1)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; Reflux;	94%
With lithium aluminium tetrahydride In tetrahydrofuran for 24h; Heating;	89.4%
With lithium aluminium tetrahydride In tetrahydrofuran for 3h; Reduction; Heating;	88%

methylamine hydrochloride (593-51-1) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → 2-methylhexahydro-1H-isoindole-1,3(2H)-dione (83248-53-7)

Conditions	Yield
With sodium acetate In acetic acid for 24h; Heating;	94%

(S)-1-phenyl-3,3-bis(trifluoromethyl)propan-1,3-diol (141329-76-2) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → (1R,2S)-Cyclohexane-1,2-dicarboxylic acid mono-((S)-4,4,4-trifluoro-3-hydroxy-1-phenyl-3-trifluoromethyl-butyl) ester (141329-77-3)

Conditions	Yield
With sodium hydride In toluene at -78℃; for 1h; Product distribution; other ς-symmetric cyclic dicarboxylic acid anhydride and glutaric anhydrides, other reagents; var. reaction conditions;	94%

1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → (1S,6R)-8-oxabicyclo[4.3.0]nonan-7-one (65376-02-5)

Conditions	Yield
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; C77H108O6P2 In ethyl acetate at 80℃; for 20h; Inert atmosphere; Glovebox; enantioselective reaction;	94%
Multi-step reaction with 3 steps 1.1: toluene / 1 h / 20 °C 2.1: ZnCl2; HMDS / toluene / 2 h / Heating 3.1: chiral 2-methyl-1-oxa-3-aza-2-boracyclopenta[a]indene; BH3*THF / tetrahydrofuran / 18 h / 25 °C 3.2: NaBH4 / ethanol / 4 h / 50 °C 3.3: aq. H2SO4 / 2 h / 80 °C View Scheme

4-chlorophenyl trifluoromethanesulfonate (29540-84-9) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → cis-2-(4-chlorobenzoyl)cyclohexane-1-carboxylic acid (52240-18-3, 52240-19-4)

Conditions	Yield
With [2,2]bipyridinyl; bis(1,5-cyclooctadiene)nickel (0); chloro-trimethyl-silane; zinc(II) iodide; zinc In N,N-dimethyl acetamide at 80℃; for 12h; Inert atmosphere; Sealed tube;	94%

methylamine (74-89-5) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → (S)-trans-N-methylcyclohexane-1,2-dicarboximide (117307-10-5)

Conditions	Yield
With acetyl chloride In ethanol for 0.166667h; Inert atmosphere; Reflux;	93%

benzylamine (100-46-9) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → 2-benzylhexahydro-1H-isoindole-1,3(2H)-dione (66050-00-8)

Conditions	Yield
at 200℃; for 0.5h;	92%
Stage #1: benzylamine; 1,2-cis-cyclohexanedicarboxylic anhydride In toluene at 20℃; for 1h; Inert atmosphere; Stage #2: With 1,1,1,3,3,3-hexamethyl-disilazane; zinc(II) chloride In toluene for 2h; Inert atmosphere; Reflux;	74%

2-amino-2-hydroxymethyl-1,3-propanediol (77-86-1) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → polymer; monomer(s): cis-1,2-cyclohexanedicarboxylic anhydride; tris(hydroxymethyl)aminomethane

Conditions	Yield
at 110℃; for 5h;	92%

toluene (108-88-3) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → cis-2-(4-methylbenzoyl)cyclohexane-1-carboxylic acid

Conditions	Yield
With aluminium trichloride	91.8%
With aluminium trichloride

1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) + benzene (71-43-2) → (1S*,2R*)-2-benzoylcyclohexane-1-carboxylic acid (86528-42-9)

Conditions	Yield
With aluminium trichloride	91%
With aluminium trichloride In dichloromethane Friedel-Crafts acylation; Heating;	20%

4,4'-diamino-4''-cyanotriphenylamine + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → 4,4'-di(1,2-cyclohexanedicarboxyimido)-4''-cyanotriphenylamine (1416570-70-1)

Conditions	Yield
With acetic acid at 140℃; for 3h;	91%

diphenyl boric ester of (R)-2-methoxy-1-phenylethanol (109459-38-3) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → Cyclohexane-1,2-dicarboxylic acid mono-((R)-2-methoxy-1-phenyl-ethyl) ester

Conditions	Yield
With diphenylboryl triflate In toluene at 0℃; for 61h;	90%

aniline (62-53-3) + 1,2-cis-cyclohexanedicarboxylic anhydride (13149-00-3) → cis-2-phenyl-octahydroisoindole-1,3-dione (92670-99-0)

Conditions	Yield
Stage #1: aniline; 1,2-cis-cyclohexanedicarboxylic anhydride In tetrahydrofuran at 40℃; for 0.5h; Inert atmosphere; Stage #2: at 190℃; for 4h; Inert atmosphere;	90%
Stage #1: aniline; 1,2-cis-cyclohexanedicarboxylic anhydride In tetrahydrofuran at 40℃; for 0.5h; Inert atmosphere; Stage #2: at 190℃; for 4h; Inert atmosphere;	86%
at 200℃; for 2h;	36%

Upstream product

• 610-10-6 (1S,2S)-cyclohexane-1,2-dicarboxylic acid 
• 46022-05-3 (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid 
• 2305-32-0 trans-1,2-cyclohexanedicarboxylic acid 
• 610-09-3 (1R,2S)-cyclohexane-1,2-dicarboxylic acid 
• 14166-21-3 (+/-)-trans-1,2-cyclohexanedicarboxylic anhydride 
• 935-79-5 cis-1,2,3,6-tetrahydrophthalic anhydride 

Downstream Products

• 73771-07-0 2-(3-morpholino-propyl)-(3ar,7ac)-hexahydro-isoindole-1,3-dione 
• 76756-35-9 cis-2-(ethoxycarbonyl)cyclohexanecarboxylic acid 
• 6966-15-0 (+/-)-2t-(4-methoxy-benzoyl)-cyclohexane-r-carboxylic acid 
• 6966-15-0 cis-2-(4'-methoxybenzoyl)cyclohexane-1-carboxylic acid 
• 7506-66-3 cis-hexahydrophthalimide 
• 18886-85-6 (3aR,7aS)-2-hydroxyhexahydro-1H-isoindol-1,3(2H)-dione 
• 167390-12-7 C₃₁H₃₁NO₆S 
• 167390-15-0 C₃₃H₃₅NO₆S 
• 167390-13-8 C₃₉H₄₇NO₆S 
• 167390-16-1 C₄₁H₅₁NO₆S 
• 101776-03-8 cis-2-cyclohexyl-octahydroisoindole-1,3-dione 
• 92670-99-0 cis-2-phenyl-octahydroisoindole-1,3-dione 
• 66050-00-8 2-benzylhexahydro-1H-isoindole-1,3(2H)-dione 

Relevant articles and documents

Enzymatische Synthesen chiraler Bausteine aus prochiralen meso-Substraten: Herstellung von Methyl(hydrogen)-1,2-cycloalkandicarboxylaten

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RECYCLABLE POLYMERS BASED ON RING-FUSED GAMMA-BUTYROLACTONES

The invention discloses a class of new polymers, trans-ring-fused poly(4-hydroxybutyrate)s (RF-P4HB) that exhibit a unique set of properties, including robust thermal stability and mechanical strength, quantitative recyclability to the building block monomers via thermolysis and/or chemical catalysis, and convenient production from the chemical ring-opening polymerization under ambient temperature and pressure. Another unique property is the formation of crystalline stereocomplexed polymers with high melting temperature upon mixing the two enantiomeric RF-P4HB chains via stereocomplexing co-crystallization. This invention also provides the corresponding ring-fused lactone monomer structures that enable the synthesis of the RF-P4HB polymers, through trans-fusing of rings to the parent γ-butyrolactone ring. Furthermore, a polymerization or copolymerization process for the synthesis of RF-P4HB polymers and copolymers is disclosed.

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