485-49-4

Basic information

• Product Name: (+)-Bicuculline
• Synonyms: 5-g)isoquinolin-5-yl)-,(r-(r*,s*))-lo(;bicucullin;furo(3,4-e)-1,3-benzodioxol-8(6h)-one,6-(5,6,7,8-tetrahydro-6-methyl-1,3-dioxo;PLUS-BICUCULLINE;(+)-BICUCULLINE 1(S),9(R);(6R)-6-[(5S)-5,6,7,8-Tetrahydro-6-methyl-1,3-dioxolo[4,5-g]lisoquinolin-5-yl]furo[3,4-e]-1,3-benzodioxol-8(6H)-one;NSC 3219;NSC 32192)
• CAS NO: 485-49-4
• Molecular Formula: C₂₀H₁₇NO₆
• Molecular Weight: 367.35
• EINECS: 207-619-7
• Product Categories: Alkaloids;Intermediates & Fine Chemicals;Pharmaceuticals;GABA/Glycine receptor;GABA;chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;Inhibitors
• Mol File: 485-49-4.mol
• Article Data: 2

Chemical Properties

• Melting Point: 193-197 °C
• Boiling Point: 497.92°C (rough estimate)
• Flash Point: 281.8 °C
• Appearance: pale yellow solid
• Density: 1.3694 (rough estimate)
• Vapor Pressure: 7.98E-12mmHg at 25°C
• Refractive Index: 1.5600 (estimate)
• Storage Temp.: 0-6°C
• Solubility: Benzene, Chloroform, DMSO, Ethyl Acetate
• PKA: 4.84(at 25℃)
• Merck: 14,1203
• BRN: 98786
• CAS DataBase Reference: (+)-Bicuculline(CAS DataBase Reference)
• NIST Chemistry Reference: (+)-Bicuculline(485-49-4)
• EPA Substance Registry System: (+)-Bicuculline(485-49-4)

Safety Data

• Hazard Codes: T,N,Xn
• Statements: 23/24/25-50-36/37/38-20/21/22
• Safety Statements: 36/37-45-61-36-26
• RIDADR: UN 1544 6.1/PG 2
• WGK Germany: 3
• RTECS: LV0909840
• F: 10-23
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 485-49-4(Hazardous Substances Data)

Usage

Chemical Properties

Pale Yellow Solid

Uses

Different sources of media describe the Uses of 485-49-4 differently. You can refer to the following data:
1. GABAA receptor antagonist.
2. GABAa antagonist
3. Alkaloid naturally occurring in the d-form. Shows GABA antagonist activity.

General Description

Bicuculline is a convulsant alkaloid. It was originally isolated from the plant Dicentra cucullaria.

Biological Activity

Classical GABA A antagonist.

Biochem/physiol Actions

(+)-Bicuculline acts as a competitive inhibitor of GABA liganding binding to the receptor.

Safety Profile

A poison by intraperitoneal route.When heated to decomposition it emits toxic vapors ofNOx.

Purification Methods

It crystallises from CHCl3/MeOH as plates. The crystals melt at 177o, then solidify and re-melt at 193-195o [Manske Canad J Research 21B 13 1943]. It is soluble in CHCl3, *C6H6, EtOAc but sparingly soluble in EtOH, MeOH and Et2O. [Stereochem: Blaha et al. Collect Czech Chem Commun 29 2328 1964, Snatzke et al. Tetrahedron 25 5059 1969, Pharmcol: Curtis et al. Nature 266 1222 1970, Beilstein 27 III/IV 1900].

InChI:InChI=1/C20H17NO6/c1-21-5-4-10-6-14-15(25-8-24-14)7-12(10)17(21)18-11-2-3-13-19(26-9-23-13)16(11)20(22)27-18/h2-3,6-7,17-18H,4-5,8-9H2,1H3/p+1/t17-,18+/m0/s1

Synthetic route

formaldehyd (50-00-0) + (+)-Norbicuculline (185022-39-3) → bicuculline (485-49-4)

Conditions	Yield
With formic acid at 100℃; for 0.25h;	81%

(+/-)-bicuculline (56083-00-2) → bicuculline (485-49-4)

Conditions	Yield
With L-(-)-tartaric acid

(-)-bicucine → bicuculline (485-49-4)

Conditions	Yield
With hydrogenchloride

8-oxo-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-6-carboxylic acid (64395-07-9) → bicuculline (485-49-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: thionyl chloride / benzene / 2 h / Heating 2: aq. NaOH / benzene / 1 h 3: 76 percent / POCl3 / 1 h / 100 °C 4: NaBH4, AcOH / CH2Cl2 / 4 h / 0 - 5 °C 5: 81 percent / HCOOH / 0.25 h / 100 °C View Scheme

5-formyl-benzo[1,3]dioxole-4-carboxylic acid (58343-48-9) → bicuculline (485-49-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: 1) HCl, 2) H2SO4 / 1) H2O, 0-5 deg C, 5 h, 2) H2O, reflux, 2 h 2: thionyl chloride / benzene / 2 h / Heating 3: aq. NaOH / benzene / 1 h 4: 76 percent / POCl3 / 1 h / 100 °C 5: NaBH4, AcOH / CH2Cl2 / 4 h / 0 - 5 °C 6: 81 percent / HCOOH / 0.25 h / 100 °C View Scheme

8-Oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxole-6-carbonyl chloride (1026278-40-9) → bicuculline (485-49-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: aq. NaOH / benzene / 1 h 2: 76 percent / POCl3 / 1 h / 100 °C 3: NaBH4, AcOH / CH2Cl2 / 4 h / 0 - 5 °C 4: 81 percent / HCOOH / 0.25 h / 100 °C View Scheme

8-Oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxole-6-carboxylic acid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide (185022-35-9) → bicuculline (485-49-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 76 percent / POCl3 / 1 h / 100 °C 2: NaBH4, AcOH / CH2Cl2 / 4 h / 0 - 5 °C 3: 81 percent / HCOOH / 0.25 h / 100 °C View Scheme

6-[7,8-Dihydro-6H-[1,3]dioxolo[4,5-g]isoquinolin-(5E)-ylidene]-6H-furo[3',4':3,4]benzo[1,2-d][1,3]dioxol-8-one; hydrochloride → bicuculline (485-49-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaBH4, AcOH / CH2Cl2 / 4 h / 0 - 5 °C 2: 81 percent / HCOOH / 0.25 h / 100 °C View Scheme

methyl iodide (74-88-4) + bicuculline (485-49-4) → bicuculline methiodide (40709-69-1, 55950-07-7, 59614-39-0)

Conditions	Yield
In chloroform for 45h; Ambient temperature;	100%

phenylcarbonochloridothioate (1005-56-7) + bicuculline (485-49-4) → (2-{6-[Chloro-(8-oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxol-6-yl)-methyl]-benzo[1,3]dioxol-5-yl}-ethyl)-methyl-thiocarbamic acid O-phenyl ester

Conditions	Yield
In dichloromethane at 20℃; for 1h;	87%

formaldehyd (50-00-0) + bicuculline (485-49-4) → 6-(9'-chloromethyl-6'-methyl-5',6',7',8'-tetrahydro-1',3'-dioxolo<4,5-g>isoquinolin-5'-yl)furo<3,4-e>-1,3-benzodioxol-8(6H)-one (130480-93-2)

Conditions	Yield
With hydrogenchloride at 48 - 50℃; for 3h;	80%

bicuculline (485-49-4) → 6-(6',7'-dihydroxy-2'-methyl-1',2',3',4'-tetrahydroisoquinolin-1'-yl)furo<3,4-e>-1,3-benzodioxol-8(6H)-one hydrobromide (130480-92-1)

Conditions	Yield
With boron tribromide In dichloromethane at -70℃;	72%

bicuculline (485-49-4) → C20H18N2O6 + C20H18N2O6

Conditions	Yield
With chloro(meso-tetrakis(2,6-dichlorophenyl)porphyrinato)manganese(III); O-(2,4-dinitrophenyl)hydroxylamine In methanol; dichloromethane for 2h;	A 65% B 29%

bicuculline (485-49-4) → C20H17NO7

Conditions	Yield
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; for 0.5h;	45%

methyl iodide (74-88-4) + bicuculline (485-49-4) → adlumidiceine (51059-65-5)

Conditions	Yield
Reaktion ueber mehrere Stufen;

formaldehyd (50-00-0) + acetic acid (64-19-7) + bicuculline (485-49-4) → 6-(9'-acetoxymethyl-6'-methyl-5',6',7',8'-tetrahydro-1',3'-dioxolo<4,5-g>isoquinolin-5'-yl)furo<3,4-e>-1,3-benzodioxol-8(6H)-one (130480-94-3)

Conditions	Yield
With sulfuric acid for 2h; Ambient temperature;

phenylcarbonochloridothioate (1005-56-7) + bicuculline (485-49-4) → (2-{6-[chloro-(8-oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxol-6-yl)-methyl]-benzo[1,3]dioxol-5-yl}-ethyl)-methyl-thiocarbamic acid O-phenyl ester + (2-{6-[chloro-(8-oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxol-6-yl)-methyl]-benzo[1,3]dioxol-5-yl}-ethyl)-methyl-thiocarbamic acid O-phenyl ester

Conditions	Yield
In dichloromethane at 20℃; for 1h; Addition; ring cleavage; Title compound not separated from byproducts;

methyl iodide (74-88-4) + bicuculline (485-49-4) + AgCl + KOH → adlumidiceine (51059-65-5)

Conditions	Yield
anschliessend Erhitzen des Methohydroxids in H2O;

bicuculline (485-49-4) → aobamidine (59614-38-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / CHCl3 / 45 h / Ambient temperature 2: 28 percent / sodium carbonate / H2O View Scheme

bicuculline (485-49-4) → 6-(9'-aminomethyl-6'-methyl-5',6',7',8'-tetrahydro-1',3'-dioxolo<4,5-g>isoquinolin-5'-yl)furo<3,4-e>-1,3-benzodioxol-8(6H)-one (130480-96-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 80 percent / concd HCl / 3 h / 48 - 50 °C 2: NH3gas / methanol / 0 - 4 °C View Scheme

bicuculline (485-49-4) → 6-(9'-hydroxymethyl-6'-methyl-5',6',7',8'-tetrahydro-1',3'-dioxolo<4,5-g>isoquinolin-5'-yl)furo<3,4-e>-1,3-benzodioxol-8(6H)-one (79076-81-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: concd H2SO4 / 2 h / Ambient temperature 2: 80 percent / NH3gas / methanol / 0 - 4 °C View Scheme

bicuculline (485-49-4) → 6-(6'-methyl-5',6',7',8'-tetrahydro-1',3'-dioxolo<4,5-g>-9'-(piperazin-1-ylmethyl)-isoquinolin-5'-yl)furo<3,4-e>-1,3-benzodioxol-8(6H)-one (130480-95-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 80 percent / concd HCl / 3 h / 48 - 50 °C 2: 86 percent / methanol / 48 h / Ambient temperature View Scheme

bicuculline (485-49-4) → [(S)-6-Methyl-5-((R)-8-oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxol-6-yl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-9-ylmethyl]-carbamic acid tert-butyl ester (130481-01-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / concd HCl / 3 h / 48 - 50 °C 2: NH3gas / methanol / 0 - 4 °C 3: 90 percent / Et3N / tetrahydrofuran; H2O / 18 h View Scheme

bicuculline (485-49-4) → N-[(S)-6-Methyl-5-((R)-8-oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxol-6-yl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-9-ylmethyl]-succinamic acid (130480-97-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / concd HCl / 3 h / 48 - 50 °C 2: NH3gas / methanol / 0 - 4 °C 3: 38 percent / ethanol / 1.5 h / 78 °C View Scheme

bicuculline (485-49-4) → 4-[(S)-6-Methyl-5-((R)-8-oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxol-6-yl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-9-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (130503-31-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / concd HCl / 3 h / 48 - 50 °C 2: 86 percent / methanol / 48 h / Ambient temperature 3: 10 percent / Et3N / tetrahydrofuran; H2O / 48 h View Scheme

bicuculline (485-49-4) → (4-{[(S)-6-Methyl-5-((R)-8-oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxol-6-yl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-9-ylmethyl]-carbamoyl}-phenyl)-carbamic acid tert-butyl ester (130480-98-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / concd HCl / 3 h / 48 - 50 °C 2: NH3gas / methanol / 0 - 4 °C 3: 27 percent / Et3N / tetrahydrofuran / 18 h / Ambient temperature View Scheme

bicuculline (485-49-4) → 6-(6',7'-diacetoxy-2'-methyl-1',2',3',4'-tetrahydroisoquinolin-1'-yl)furo<3,4-e>-1,3-benzodioxol-8(6H)-one hydrobromide (130481-00-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 72 percent / boron tribromide / CH2Cl2 / -70 °C 2: 77 percent / pyridine / 2 h / Ambient temperature View Scheme

bicuculline (485-49-4) → 6-(9'-(p-aminobenzamidomethyl)-6'-methyl-5',6',7',8'-tetrahydro-1',3'-dioxolo<4,5-g>isoquinolin-5'-yl)furo<3,4-e>-1,3-benzodioxol-8(6H)-one hydrochloride

Conditions	Yield
Multi-step reaction with 4 steps 1: 80 percent / concd HCl / 3 h / 48 - 50 °C 2: NH3gas / methanol / 0 - 4 °C 3: 27 percent / Et3N / tetrahydrofuran / 18 h / Ambient temperature 4: 52 percent / concd HCl, acetic acid / 1 h / Ambient temperature View Scheme

bicuculline (485-49-4) → N-[(S)-6-Methyl-5-((R)-8-oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxol-6-yl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-9-ylmethyl]-succinamic acid methyl ester; hydrochloride

Conditions	Yield
Multi-step reaction with 4 steps 1: 80 percent / concd HCl / 3 h / 48 - 50 °C 2: NH3gas / methanol / 0 - 4 °C 3: 38 percent / ethanol / 1.5 h / 78 °C 4: 100 percent / HCl / 24 h / 0 - 4 °C View Scheme

Upstream product

• 56083-00-2 (+/-)-bicuculline 
• 185022-35-9 8-Oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxole-6-carboxylic acid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide 
• 1026278-40-9 8-Oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxole-6-carbonyl chloride 
• 58343-48-9 5-formyl-benzo[1,3]dioxole-4-carboxylic acid 
• 64395-07-9 8-oxo-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-6-carboxylic acid 
• 50-00-0 formaldehyd 
• 185022-39-3 (+)-Norbicuculline 
• 5936-28-7 (+)-β-hydrastine hydrochloride 
• 118-08-1 hydrastine 
• 34408-04-3 (S)-6,7-dihydroxy-3-((R)-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-3H-isobenzofuran-1-one 
• 72785-35-4 (S)-3-((R)-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-6,7-dihydroxy-3H-isobenzofuran-1-one 
• 75-09-2 dichloromethane 
• 118-08-1 (-)-β-hydrastine 
• 19730-80-4 (-)-Bicuculline 

Downstream Products

• 59614-38-9 aobamidine 
• 130480-98-7 (4-{[(S)-6-Methyl-5-((R)-8-oxo-6,8-dihydro-furo[3',4':3,4]benzo[1,2-d][1,3]dioxol-6-yl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-9-ylmethyl]-carbamoyl}-phenyl)-carbamic acid tert-butyl ester 
• 40709-69-1 bicuculline methiodide 

Relevant articles and documents

Synthesis, anti-GABA activity and preferred conformation of bicuculline and norbicuculline enantiomers

Synthesis of erythro-(±)-[1SR,9RS]-norbicuculline and threo-(±)-[1SR,9SR]-noradlumidine from piperonal was performed using Bischler-Napieralski cyclization as a key step. Resolution gave rise to (+)-[1S,9R]-norbicuculline ([1S,9R] norBIC) and (-)-[1R,9S]-norbicuculline ([1R,9S] norBIC) in >99.5% enantiomeric purity. Bicuculline enantiomers were readily obtained by methylation of the latter products. [1S,9R]BIC was about 70 times more potent than [1R,9S]BIC as an inhibitor of GABA(A) receptor binding and was about 100 and 900 times more potent than [1S,9R] norBIC at pH 7.1 and 5.0 respectively. Similarly, [1S,9R] norBIC was much less potent than [1S,9R]BIC as an inhibitor of GABA-specific 36Cl- ion flux. The observed increase of about two orders of magnitude in the in vitro biological activity caused by N2-CH3 substitution in [1S,9R] norBIC was attributed to different conformations for erythro- and nor-erythro-bicucullines indicated by 1H nuclear Overhauser enhancements of [1S,9R]BIC and [1S,9R] norBIC.

Alkaloids of Corydalis incisa Pers. V. The structures of corydalispirone and corydalisol

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