Dezocine (Dalgan) synthesis

G.Patton

Expert
Joined
Jul 5, 2021
Messages
2,580
Solutions
3
Reaction score
2,604
Points
113
Deals
1

Introduction

Dezocine, sold under the brand name Dalgan, is an atypical opioid analgesic which is used in the treatment of pain. It is used by intravenous infusion and intramuscular injection. Dezocine is an opioid receptor modulator, acting as a partial agonist of the μ- and κ-opioid receptors. It has a similar profile of effects to related opioids acting at the μ-opioid receptor, including analgesia and euphoria. Unlike other opioids acting at the κ-opioid receptor, however, Dezocine does not produce side effects such as dysphoria or hallucinations at any therapeutically used dose.

Dezocine is a member of the benzomorphan group of opioids. It is related to other benzomorphan opioids, such as Pentazocine. Dezocine is unusual among opioids as it is one of the few primary amines known to be active as an opioid (along with bisnortilidine, an active metabolite of tilidine).

Dezocine [(−)-13β-amino-5,6,7,8,9,10,11,12-octahydro-5α-methyl-5,11-methanobenzocyclodecen-31-ol, hydrobromide] is a pale white crystal powder. It has no apparent odor. The salt is soluble at 20 mg/mL, and a 2% solution has a pH of 4.6.

The synthesis of Dezocine begins with the condensation of 1-methyl-7-methoxy-2-tetralone with 1,5-dibromopentane through use of NaH or potassium tert-butoxide. This yields 1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone, which is then cyclized with NaH to produce 5-methyl-3-methoxy-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzocyclodecen-13-one. The product is then treated with hydroxylamine hydrochloride, to yield an oxime. A reduction reaction in hydrogen gas produces an isomeric mixture, from which the final product is crystallized and cleaved with HBr.

Equipment and glassware:

  • 10 L Round bottom flask (RBF) or batch reactor;
  • 2 L and 200 mL RBF;
  • Magnetic or top stirrer;
  • Laboratory grade thermometer (0 °C to 100 °C);
  • 2 L Separatory funnel;
  • ~50 L Nitrogen gas baloon (1 bar);
  • Vacuum distillation apparatus;
  • Rotovap machine (large);
  • Vacuum source;
  • Glass rod and spatula;
  • Retort stand and clamp for securing apparatus;
  • Laboratory scale (0.1 — 1000 g is suitable);
  • 2 L x2; 1 L x2; 500 mL x2; 100 mL x3 Beakers;
  • Buchner flask and funnel, 2 L;
  • Reflux condenser;
  • 200 mL Parr apparatus or 500 mL RBF;
  • Hydrogen gas (H2) source;
  • TLC kit (optional);
  • Water bath.

Reagents:

  • 238 g (2.14 mol) tert-BuOK;
  • 366 g (1.91 mol) of 7-methoxy-1-methyl-2-tetralone (1);
  • 2.8 L tert-Butyl alcohol (tert-BuOH);
  • 1.330 kg (5.76 mol) 1,5-Dibromopentane;
  • 1.0 g Sodium iodide (NaI);
  • ~ 1.5 L Distilled water (H2O);
  • ~300 mL Benzene;
  • 750 mL Dimethylformamide (DMF);
  • 12.6 g, 0.299 mol Sodium hydride (NaH) 57% dispersion in mineral oil;
  • ~500 mL Diethyl ether (Et2O);
  • 14 g, 0.2 mol Hydroxylamine hydrochloride (NH2OH*HCl);
  • 16.5 g, 0.2 mol Sodium acetate (AcONa);
  • 450 mL Methanol (MeOH);
  • ~ 500 g Magnesium sulphate (MgSO4);
  • 3 tsp (14.8 mL) of Ni/Raney;
  • 100 ml Ethanole (EtOH);
  • 50 mL Ammonium hydroxide (NH4OH) aq. concentrated solution;
  • 60 mL Hydrobromic acid 48% (HBr);
  • ~ 200 mL Hydrochloric acid (HCl) conc.;
  • ~ 50 g Activated Carbon;
  • ~200 mL Hexane.
QbHR8BhS2v
(5R,11S,13S)-13-Amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methanobenzocyclodecen-3-ol:
Boiling Point: 392.6 °C at 760 mm Hg;
Melting Point: 269-270 °C;
Molecular Weight: 245.36 g/mole;
Density: 1.082 g/mL;
CAS Number: 53648-55-8.


Procedure

1-(5-bromopentyl)-7-methoxy-1-methyl-2-tetralone (2)
A solution of 238 g (2.14 mol) of tert-BuOK and 366 g (1.91 mol) of 7-methoxy-1-methyl-2-tetralone (1) in 1.3 L of tert-BuOH under N2 was stirred for 45 min. This solution was added over 30 min to a stirred solution of 1.330 kg (5.76 mol) of 1,5-dibromopentane and 1.0 g of NaI in 1.5 L of tert-BuOH under N2 in 10 L round bottom flask or batch reactor. The mixture was stirred 2 h, concentrated to 1.5 L, and diluted with H2O, and the organic layer was separated. The aqueous layer was extracted with C6H6 and the combined organic portions were washed with dilute acid followed by H2O, dried (MgSO4), concentrated, and distilled to give 443 g of 1-(5-bromopentyl)-7-methoxy-1-methyl-2-tetralone, b.p. 160-195 °C (0.7 mm Hg).
CqMmZDXSfJ

5,6,7,8,9,10,11,12-octahydro-3-methoxy-5-methyl-5,11-methanobenzocyclodecen-13-one (3)
In a typical procedure, a solution of 92 g (0.271 mol) of 1-(5-bromopentyl)-7-methoxy-1-methyl-2-tetralone (2) in 250 ml of DMF was added slowly to a stirred mixture of NaH (12.6 g, 0.299 mol of a 57% dispersion in mineral oil) washed free of mineral oil and 500 mL of DMF in 2L RBF with reflux condencer. The reaction mixture was warmed at 85 °C for 3 h. Dilution of the mixture with H2O followed by Et2O extraction, drying with MgSO4, and distillation gave 45.6 g (65%) of 5,6,7,8,9,10,11,12-octahydro-3-methoxy-5-methyl-5,11-methanobenzocyclodecen-13-one, b.p. 150-175 °С (0.5 mm Hg). The distillate solidified. A portion was recrystallized from n-hexane and had m.p. 68-76 °C.
PTdD8y4szR

5,6,7,8,9,10,11,12-octahydro-3-methoxy-5-methyl-5,11-methanobenzocyclodecen-13-one oxime (4)
A solution of NH2OH was prepared by mixing NH2OH*HCl (14 g, 0.2 mol) and AcONa (16.5 g, 0.2 mol) in 450 mL of MeOH. After 1 h, the mixture was filtered and the filtrate was treated with 10 g (0.04 mol) of 5,6,7,8,9,10,11,12-octahydro-3-methoxy-5-methyl-5,11-methanobenzocyclodecen-13-one (3). After 5 h of reflux in 2 L RBF with reflux condenser the solution was concentrated to 200 mL, and upon cooling and filtering, 8.0 g of oxime (4), m.p. 174-176 °C, was obtained.
XuPC7AMB2o

5,6,7,8,9,10,11,12-octahydro-3-methoxy-5a-methyl-5,1-methanobenzocyclodecen-13b-amine HCI (5)
Reduction Procedure. In a typical reduction, a mixture of 18.5 g of 5,6,7,8,9,10,11,12-octahydro-3-methoxy-5-methyl-5,11-methanobenzocyclodecen-13-one oxime, 3 tsp (14.8 mL) of Ni/Raney, 100 ml of EtOH, and 50 mL of concentrated NH4OH was hydrogenated in a Parr apparatus at 45 psi (3.1 bar) and 50 °С. The catalyst was removed and the fitrate was concentrated and distilled to give 13.1 g of oil, b.p. 140-143 °С (0.2 mm Hg). GC-MS analysis showed two isomers (95:5). Conversion to the HCl salt gave, after recrystallization from H2O, 9.5 g of 5,6,7,8,9,10,11,12-octahydro-3-methoxy-5a-methyl-5,1-methanobenzocyclodecen-13b-amine HCl (5), m.p. 311-312 °С.
3ewMlKbsBE
[Patton note: you can use hydrogenation without pressure by bubbling hydrogen gas (H2) via solution. Also, you have to add twice or more amount of Ni/Re catalyst in this case. Consider that reaction time will be increased 4x fold or more. Check reaction by TLC.]
RXu8pmUZS3
Dezocine (6)
Cleavage of CH3O- Group. In a typical procedure, 3.0 g of 5,6,7,8,9,10,11,12-octahydro-3-methoxy-5a-methyl-5,11-methanobenzo-cyclodecen-13p-amine (5) was refluxed 30 min in 60 mL of 48% HBr under N2. The solution was concentrated at the residue recrystallized from H2O (treated with activated C) to give the phenol Dezocine (6), m.p. 269-270°С.
NzicNSqI7d
 
Last edited by a moderator:
  • Free product samples

    Testing products from new vendors and manufacturers.

    Get free samples for testing now!

  • Always stay in touch with BB forum. Element/Matrix.

    Connect notifications to always stay in touch with the forum!

    Connect

Top