41708-76-3

Basic information

• Product Name: indicine-N-oxide
• Synonyms: indicine-N-oxide;Indicin-N-oxid;DNAWGBOKUFFVMB-PZIGJSDBSA-N
• CAS NO: 41708-76-3
• Molecular Formula: C₁₅H₂₅NO₆
• Molecular Weight: 315.363
• Mol File: 41708-76-3.mol
• Article Data: 4

Chemical Properties

• Melting Point: 130.5°C (rough estimate)
• Boiling Point: 454.91°C (rough estimate)
• Flash Point: °C
• Appearance: /
• Density: 1.1359 (rough estimate)
• Refractive Index: 1.5000 (estimate)
• PKA: 12.54±0.29(Predicted)
• CAS DataBase Reference: indicine-N-oxide(CAS DataBase Reference)
• NIST Chemistry Reference: indicine-N-oxide(41708-76-3)
• EPA Substance Registry System: indicine-N-oxide(41708-76-3)

Safety Data

• RIDADR: 1544
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 41708-76-3(Hazardous Substances Data)

Usage

Description

Heliotropiurn indicurn also contains this base which has the structure given above based upon comparison with the preceding alkaloid. The base has proved to be highly active against transplanted neoplasts, Walker-256 carcinosarcoma, melanoma B-16, leukaemia L-12l 0, leukaemia P-388 and leukaemia P-1534 in mice and rats, giving up to 91 per cent inhibition of transplanted growth at a daily dosage of 200 mgm. per kilo.

Uses

Indicine N-oxide is a pyrrolizidine alkaloid that is isolated from Heliotropium indicum, one of the most widely used herbs in India. Indicine N-oxide exhibits antitumour and antimitotic activity in humans, and has subsequently undergone Phase I & II trials in adults and children with leukemia and solid tumours.

References

Rao, McBride., U.S. Patent, 3,717,710 February 20,1973

InChI:InChI=1/C15H25NO6/c1-9(2)15(20,10(3)17)14(19)22-8-11-4-6-16(21)7-5-12(18)13(11)16/h4,9-10,12-13,17-18,20H,5-8H2,1-3H3

Synthetic route

(+)-indicine (480-82-0) → (+)-indicine N-oxide (41708-76-3)

Conditions	Yield
With 3-chloro-benzenecarboperoxoic acid In acetone for 2h; Ambient temperature;	81%
With 3-chloro-benzenecarboperoxoic acid In acetone for 2h; Ambient temperature;	81%
With 3-chloro-benzenecarboperoxoic acid In chloroform for 0.333333h; Ambient temperature;
With 3-chloro-benzenecarboperoxoic acid In acetone for 1h; Ambient temperature;

(2R,3S)-2,3-dihydroxy-2-(1-methylethyl)butyric acid (23944-50-5) → (+)-indicine N-oxide (41708-76-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: concd hydrochloric acid / Ambient temperature 2: 1.) DCC, DMAP; 2.) 0.6 M HCl / 1.) toluene, r.t., 3 d; 2.) r.t., 8 h 3: MCPBA / acetone / 1 h / Ambient temperature View Scheme
Multi-step reaction with 4 steps 1: conc. aq. HCl / 1.5 h / 25 °C 2: 1.) N,N'-carbonyldiimidazole (CDI), 2.) imidazoylsodium / 1.) DMF, 15 min, 2.) DMF, 25 deg C, 24 h 3: 0.6 N aq. HCl / 24 h / 25 °C 4: m-chloroperbenzoic acid / CHCl3 / 0.33 h / Ambient temperature View Scheme

4(R)-(1-methylethyl)-2,2,5(S)-trimethyl-1,3-dioxolane-4-carboxylic acid (95462-07-0) → (+)-indicine N-oxide (41708-76-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) DCC, DMAP; 2.) 0.6 M HCl / 1.) toluene, r.t., 3 d; 2.) r.t., 8 h 2: MCPBA / acetone / 1 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 1: 1.) N,N'-carbonyldiimidazole (CDI), 2.) imidazoylsodium / 1.) DMF, 15 min, 2.) DMF, 25 deg C, 24 h 2: 0.6 N aq. HCl / 24 h / 25 °C 3: m-chloroperbenzoic acid / CHCl3 / 0.33 h / Ambient temperature View Scheme

(2S,3R,4S)-3-Benzyloxy-3-isopropyl-pentane-1,2,4-triol → (+)-indicine N-oxide (41708-76-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: NaIO4, KMnO4 / 2-methyl-propan-2-ol; H2O / 1 h / Ambient temperature 2: hydrogen / 10 percent Pd/C / methanol / 3 h / Ambient temperature 3: concd hydrochloric acid / Ambient temperature 4: 1.) DCC, DMAP; 2.) 0.6 M HCl / 1.) toluene, r.t., 3 d; 2.) r.t., 8 h 5: MCPBA / acetone / 1 h / Ambient temperature View Scheme

(2R,3S)-2-Benzyloxy-3-hydroxy-2-isopropyl-butyric acid → (+)-indicine N-oxide (41708-76-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen / 10 percent Pd/C / methanol / 3 h / Ambient temperature 2: concd hydrochloric acid / Ambient temperature 3: 1.) DCC, DMAP; 2.) 0.6 M HCl / 1.) toluene, r.t., 3 d; 2.) r.t., 8 h 4: MCPBA / acetone / 1 h / Ambient temperature View Scheme

Acetic acid (3R,4S,5S)-2-acetoxy-4-benzyloxy-4-isopropyl-5-methyl-tetrahydro-furan-3-yl ester → (+)-indicine N-oxide (41708-76-3)

Conditions

Yield

Multi-step reaction with 6 steps 1: NaBH4 / ethanol / 1.) r.t., overnight; 2.) reflux, 20 h 2: NaIO4, KMnO4 / 2-methyl-propan-2-ol; H2O / 1 h / Ambient temperature 3: hydrogen / 10 percent Pd/C / methanol / 3 h / Ambient temperature 4: concd hydrochloric acid / Ambient temperature 5: 1.) DCC, DMAP; 2.) 0.6 M HCl / 1.) toluene, r.t., 3 d; 2.) r.t., 8 h 6: MCPBA / acetone / 1 h / Ambient temperature View Scheme

(1'S,2S,5R)-2-(t-butyl)-5-(1'hydroxyethyl)-5-isopropyl-1,3-dioxolan-4-one (132585-75-2) → (+)-indicine N-oxide (41708-76-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 9.3 percent / camphorsulfonic acid / benzene / 72 h / Heating 2: 1) DCC, DMAP, 2) 1 M HCl / 1) toluene, r.t., 6 d, 2) r.t., 28 h 3: 81 percent / m-chloroperoxybenzoic acid / acetone / 2 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 1: 62 percent / camphorsulfonic acid / benzene / 72 h / Heating 2: 1) DCC, DMAP, 2) 1 M HCl / 1) toluene, r.t., 6 d, 2) r.t., 22 h 3: 81 percent / m-chloroperoxybenzoic acid / acetone / 2 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 1: 12 percent / camphorsulphonic acid / benzene / 72 h / Heating 2: 1.) 2.3 eq. DCC, 0.3 eq. DMAP; 2.) 1M HCl / 1.) toluene, rt, 6 days; 2.) rt, 22 h 3: 81 percent / m-CPBA / acetone / 2 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 1: 77 percent / camphorsulphonic acid / benzene / 72 h / Heating 2: 1.) 2.3 eq. DCC, 0.3 eq. DMAP; 2.) 1M HCl / 1.) toluene, rt, 6 days; 2.) rt, 22 h 3: 81 percent / m-CPBA / acetone / 2 h / Ambient temperature View Scheme

(2R,4R,5S)-2-(t-butyl)-4-isopropyl-5-methyl-1,3-dioxolane-4-carboxylic acid (126453-22-3) → (+)-indicine N-oxide (41708-76-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) DCC, DMAP, 2) 1 M HCl / 1) toluene, r.t., 6 d, 2) r.t., 28 h 2: 81 percent / m-chloroperoxybenzoic acid / acetone / 2 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: 1.) 2.3 eq. DCC, 0.3 eq. DMAP; 2.) 1M HCl / 1.) toluene, rt, 6 days; 2.) rt, 22 h 2: 81 percent / m-CPBA / acetone / 2 h / Ambient temperature View Scheme

(2S,4R,5S)-2-(t-butyl)-4-isopropyl-5-methyl-1,3-dioxolane-4-carboxylic acid (126331-49-5) → (+)-indicine N-oxide (41708-76-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) DCC, DMAP, 2) 1 M HCl / 1) toluene, r.t., 6 d, 2) r.t., 22 h 2: 81 percent / m-chloroperoxybenzoic acid / acetone / 2 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: 1.) 2.3 eq. DCC, 0.3 eq. DMAP; 2.) 1M HCl / 1.) toluene, rt, 6 days; 2.) rt, 22 h 2: 81 percent / m-CPBA / acetone / 2 h / Ambient temperature View Scheme

retronecine (480-85-3) → (+)-indicine N-oxide (41708-76-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) DCC, DMAP, 2) 1 M HCl / 1) toluene, r.t., 6 d, 2) r.t., 28 h 2: 81 percent / m-chloroperoxybenzoic acid / acetone / 2 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: 1) DCC, DMAP, 2) 1 M HCl / 1) toluene, r.t., 6 d, 2) r.t., 22 h 2: 81 percent / m-chloroperoxybenzoic acid / acetone / 2 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: 1.) 2.3 eq. DCC, 0.3 eq. DMAP; 2.) 1M HCl / 1.) toluene, rt, 6 days; 2.) rt, 22 h 2: 81 percent / m-CPBA / acetone / 2 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: 1.) 2.3 eq. DCC, 0.3 eq. DMAP; 2.) 1M HCl / 1.) toluene, rt, 6 days; 2.) rt, 22 h 2: 81 percent / m-CPBA / acetone / 2 h / Ambient temperature View Scheme

(+/-)-trachelanthic acid (23944-47-0) → (+)-indicine N-oxide (41708-76-3)

Conditions	Yield
Multi-step reaction with 5 steps 2: conc. aq. HCl / 1.5 h / 25 °C 3: 1.) N,N'-carbonyldiimidazole (CDI), 2.) imidazoylsodium / 1.) DMF, 15 min, 2.) DMF, 25 deg C, 24 h 4: 0.6 N aq. HCl / 24 h / 25 °C 5: m-chloroperbenzoic acid / CHCl3 / 0.33 h / Ambient temperature View Scheme

trans-α-isopropylcrotonic acid (94773-28-1) → (+)-indicine N-oxide (41708-76-3)

Conditions	Yield
Multi-step reaction with 6 steps 1: 85 percent / OsO4, HClO3 3: conc. aq. HCl / 1.5 h / 25 °C 4: 1.) N,N'-carbonyldiimidazole (CDI), 2.) imidazoylsodium / 1.) DMF, 15 min, 2.) DMF, 25 deg C, 24 h 5: 0.6 N aq. HCl / 24 h / 25 °C 6: m-chloroperbenzoic acid / CHCl3 / 0.33 h / Ambient temperature View Scheme

(4R,5S)-4-Isopropyl-2,2,5-trimethyl-[1,3]dioxolane-4-carboxylic acid (7R,7aR)-7-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-1-ylmethyl ester (95363-32-9) → (+)-indicine N-oxide (41708-76-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 0.6 N aq. HCl / 24 h / 25 °C 2: m-chloroperbenzoic acid / CHCl3 / 0.33 h / Ambient temperature View Scheme

Upstream product

• 95363-32-9 (4R,5S)-4-Isopropyl-2,2,5-trimethyl-[1,3]dioxolane-4-carboxylic acid (7R,7aR)-7-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-1-ylmethyl ester 
• 94773-28-1 trans-α-isopropylcrotonic acid 
• 23944-47-0 (+/-)-trachelanthic acid 
• 480-85-3 retronecine 
• 126331-49-5 (2S,4R,5S)-2-(t-butyl)-4-isopropyl-5-methyl-1,3-dioxolane-4-carboxylic acid 
• 126453-22-3 (2R,4R,5S)-2-(t-butyl)-4-isopropyl-5-methyl-1,3-dioxolane-4-carboxylic acid 
• 132585-75-2 (1'S,2S,5R)-2-(t-butyl)-5-(1'hydroxyethyl)-5-isopropyl-1,3-dioxolan-4-one 
• 95462-07-0 4(R)-(1-methylethyl)-2,2,5(S)-trimethyl-1,3-dioxolane-4-carboxylic acid 
• 23944-50-5 (2R,3S)-2,3-dihydroxy-2-(1-methylethyl)butyric acid 
• 480-82-0 (+)-indicine 

Downstream Products

• 480-82-0 lycopsamine A 

Relevant articles and documents

An Efficient Enantioselective Synthesis of Indicine N-Oxide, an Antitumor Pyrrolizidine Alkaloid

Indicine N-oxide (1), a pyrrolizidine alkaloid potentially useful for an anticancer drug was synthesized in the natural form through regioselective coupling of (+)-retronecine (2) and the protected necic acids 16a and 16b, the latter being efficiently prepared from the optically pure lactone 5.

Total syntheses of indicine N-oxide, intermedine N-oxide, and their enantiomers using carbohydrate as a chiral educt

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