Manufacturing Process
Codeine is a component of gum opium and can also be produced by
methylation of morphine using known prior art techniques.
A solution of codeine (30 g, 100.2 mmol), acetic anhydride (18.4 g, 180.2
mmol), triethylamine (18.25 g, 180.2 mmol) and 4-dimethylaminopyridine
(0.5 g) in dry ethyl acetate (620 ml) was stirred at rt. under nitrogen for 12
hr, added saturated aqueous sodium bicarbonate solution until no acetic
anhydride detected. The organic portion was separated, washed with water (3times 120 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo
to dryness to give 6-acetylcodeine as white solids (34.0 g, 99% yield).
Preparation of 6-acetylnorcodeine hydrochloride.
A solution of 6-acetylcodeine (10.0 g, 29.3 mmol), 1-chloroethyl
chloroformate (5.51 g, 37.8 mmol), and proton sponge (1.0 g) in methylene
chloride (80 ml) was heated at reflux for 80 min. The reaction mixture was
evaporated in vacuo to dryness. The residue was chromatographed on silica
gel with ethyl acetate to give 6-acetyl-17-(1-chloroethoxycarbonyl)norcodeine
as an oil (12.13 g), which was dissolved in methanol with a few drops of conc.
HCl. The solution was heated at reflux for 1 hr and evaporated in vacuo to
almost dryness. The residue was added hexane and filtered to give 6-
acetylnorcodeine hydrochloride (10.7 g, 100% yield).
Preparation of norcodeine hydrochloride.
A solution of 6-acetylcodeine (10.0 g, 29.3 mmol), 1-chloroethyl
chloroformate (5.56 g, 38.1 mmol), and proton sponge (1.0 g) in methylene
chloride (50 ml) was heated at reflux for 50 min. The reaction mixture was
evaporated in vacuo to about 30 ml. Methanol (25 ml) and concentrated HCl
(2 ml) were added. The solution was heated at reflux for 40 min. and
evaporated in vacuo to almost dryness. The residue was added hexane and
filtered to give norcodeine hydrochloride (8.8 g, 93% yield).
Preparation of 17-cyclopropylmethylnorcodeine.
A mixture of norcodeine hydrochloride (11.48 g, 27.8 mmol),
(chloromethyl)cyclopropane (5.14 g, 55.6 mmol), sodium carbonate (14.73 g,
139.0 mmol), and potassium iodide (4.61 g, 27.8 mmol) in ethanol (250 ml)
was heated at reflux for 20 hr, cooled, and evaporated in vacuo to dryness.
The residue was basified with NH4OH, and extracted with methylene chloride.
The extract was washed with water and evaporated in vacuo to dryness. The
residue (11.7 g) was chromatographed on silica gel with a eluting solvent
system of methanol/ethyl acetate (10/90) to give 17-
cyclopropylmethylnorcodeine (10.68 g, 91% yield).
Preparation of 17-cyclopropylmethylnorcodeinone.
To a solution of DMSO (14.50 g, 185.6 mmol) in methylene chloride (80 ml)
at -78°C, was added a solution of oxalyl chloride (11.78 g, 92.8 mmol) in
methylene chloride (20 ml) in 20 min. After stirring at -78°C for 20 min., a
solution of 17-cyclopropylmethylnorcodeine (9.0 g, 26.5 mmol) in methylene
chloride (40 ml) was added dropwise in 50 min. The reaction mixture was
stirred at -74° to -76°C for 3 hr, added triethylamine (9.39 g, 92.8 mmol),
allowed to warm up to rt., added methylene chloride (200 ml), washed with
water (10 times 50 ml), and evaporated in vacuo to dryness. The residue was
mixed with hexane and filtered to give 17-cyclopropylmethylnorcodeinone
(8.85 g, 99% yield).
Preparation of 17-cyclopropylmethylnorcodeinone dienol acetate.
A mixture of 17-cyclopropylmethylnorcodeinone (3.55 g, 10.5 mmol), acetic anhydride (20 ml, 210.4 mmol), sodium acetate (1.3 g, 15.8 mmol), and
toluene (6 ml) was heated at 71°-73°C for 14 hr. The reaction mixture was
cooled, added methylene chloride (250 ml), water (50 ml), and sodium
bicarbonate (73.5 g), stirred for 4 hr, and filtered. The organic portion of the
filtrate was separated, washed with water (30 ml), dried over anhydrous
sodium sulfate, and evaporated in vacuo to dryness. The residue (3.94 g) was
chromatographed on silica gel with 100% ethyl acetate to give 17-
cyclopropylmethylnorcodeinone dienol acetate (2.87 g, 72% yield).
Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone. A solution of
17-cyclopropylmethylnorcodeinone (0.20 g, 0.59 mmol), formic acid (90%,
0.304 g), water (0.504 g), EtOAc (0.27 g), and hydrogen peroxide (30%, 0.17
g) was heated at 42°-43°C for 15 hr, added water (20 ml), basified with
Na2CO3 (1.02g), and extracted with EtOAc (80 ml and 2 times 20 ml). The
combined extract was washed with water, dried over anhydrous sodium
sulfate, and evaporated in vacuo to dryness to give 17-cyclopropylmethyl-14-
hydroxynorcodeinone (0.10 g, 56% yield). The Rf value in TLC and the IR
spectrum of the product were comparable to those obtained from an authentic
sample.
Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone.
A solution of 17-cyclopropylmethylnorcodeinone dienol acetate (1.00 g, 2.63
mmol), formic acid (8 ml, 90%), and hydrogen peroxide (0.37 g, 30%, 3.26
mmol) was heated at 44°-45°C for 6 hr, added water (20 ml) and ethyl
acetate (80 ml), basified with sodium bicarbonate. The organic portion was
separated, washed with water (15 ml), dried over anhydrous sodium sulfate
and evaporated in vacuo to dryness, the residue (0.9 g) was chromatographed
on silica gel with methanol/methylene chloride (2.5/97.5) to give 17-
cyclopropylmethyl-14-hydroxynorcodeinone (0.72 g, 78% yield).
Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone.
A solution of 17-cyclopropylmethylnorcodeinone dienol acetate (0.5 g, 1.31
mmol), 3-chloroperbenzoic acid (0.36 g, 2.10 mmol) and oxalic acid (0.27 g,
2.90 mmol) in acetic acid (7 ml) was stirred at rt. overnight, added cold water
(35 ml), basified with sodium carbonate, and extracted with methylene
chloride (100 ml). The extract was washed with water (2 times 30 ml), dried
over anhydrous sodium sulfate, and evaporated in vacuo to dryness. The
residue (0.41 g) was chromatographed on silica gel to give 17-
cyclopropylmethyl-14-hydroxynorcodeinone (0.34 g, 74% yield). The Rf value
in TLC and the IR spectrum of the product were comparable to those obtained
from an authentic sample.
Preparation of 3-methylnaltrexone.
A mixture of 17-cyclopropylmethyl-14-hydroxynorcodeinone (0.30 g, 0.85
mmol) and Pd/C (5%, 0.45 g) in ethanol (35 ml) was hydrogenated in a Parr
hydrogenator at rt. under 28 psi of hydrogen gas. The mixture was filtered.
The filtrate was evaporated in vacuo to dryness to give 3-methylnaltrexone
(0.30 g, 99% yield).
Preparation of naltrexone from 3-methylnaltrexone.
A solution of 3-methylnaltrexone (0.48 g, 1.35 mmol) in methylene chloride
(30 ml) was cooled with an ice-water bath, and then added a solution of
boron tribromide (5.4 ml, 1 M solution in methylene chloride, 5.4 mmol). The
reaction mixture was stirred at rt. for 15 hr, basified with NH4OH, and
extracted with methylene chloride (60 ml). The extract was washed with water
(2 times 15 ml), dried over anhydrous sodium sulfate, and evaporated in
vacuo to dryness to give naltrexone (0.45 g, 98% yield).
Biological Functions
Naltrexone (Trexan) is three to five times as potent as
naloxone and has a duration of action of 24 to 72 hours,
depending on the dose. It is used orally in the treatment
of opioid abstinence. Naltrexone exhibits a large firstpass
effect in the liver. However, the major metabolite,
6-β-naltrexol, is also a pure opioid antagonist and contributes
to the potency and duration of action of naltrexone.
Administration of naltrexone orally blocks the
subjective effects of abused opioids and is used to decrease
the craving for opioids in highly motivated recovering
addicts. However, high doses of the opioids
can overcome the naltrexone blockade and lead to
seizures or respiratory depression and death. In addition,
it has been reported recently that naltrexone can
reduce the craving for alcohol in alcoholic patients.
Naltrexone also has been used with success in treating
apneic episodes in children, an effect hypothesized to
be due to blockade of β-endorphin–induced respiratory
depression.
Naltrexone can induce hepatotoxicity at doses only
five times the therapeutic dose and should be used with
care in patients with poor hepatic function or liver damage.
Side effects of the use of naltrexone are more frequently
observed than following naloxone administration.
Such side effects include headache, difficulty
sleeping, lethargy, increased blood pressure, nausea,
sneezing, delayed ejaculation, blurred vision, and increased
appetite.
