CN114621239A - Preparation method of naltrexone - Google Patents

Preparation method of naltrexone Download PDF

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CN114621239A
CN114621239A CN202011452095.2A CN202011452095A CN114621239A CN 114621239 A CN114621239 A CN 114621239A CN 202011452095 A CN202011452095 A CN 202011452095A CN 114621239 A CN114621239 A CN 114621239A
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naltrexone
noroxymorphone
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preparation
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张贵民
丁军
崔国梅
刘忠
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom

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Abstract

The invention belongs to the technical field of drug synthesis, and provides a preparation method of naltrexone, which takes noroxymorphone and cyclopropanemethanol as raw materials and PdCl2(Xantphos) as a catalyst, and carrying out the reaction. The method has the characteristics of simple and convenient operation, mild reaction conditions and the like, and the product obtained by the method has high yield and purity and is more suitable for industrial production.

Description

Preparation method of naltrexone
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of naltrexone.
Background
Naltrexone is an opioid receptor antagonist used primarily to control alcohol dependence and opioid dependence. The primary use of naltrexone is in the treatment of alcohol dependence. It is sold in its normal form as its hydrochloride salt (naltrexone hydrochloride) and under the trade names ReVia and Depad. In some countries, including the united states, monthly slow release injectable formulations are sold under the trade name ViVitrol.
Naltrexone can be prepared from noroxymorphone by a variety of direct and indirect alkylation processes. One method is by direct alkylation of noroxymorphone with cyclopropylmethyl bromide. This method has been disclosed in general form in WO91/05768 to Rice. WO2008/034973 to Sanofi-Avensisd (chinese equivalent CN101516892A) describes a method to obtain naltrexone in 88.6% yield by reacting noroxymorphone hydrochloride with cyclopropylmethyl bromide in dimethylacetamide in the presence of sodium bicarbonate. WO2008/138605 to Cilag describes the N-alkylation of noroxymorphone with cyclopropylmethyl bromide in N-methyl-pyrrolidone in the presence of sodium bicarbonate. Mallinckrodt WO2010/039209 describes noroxymorphone with cyclopropylmethyl bromide as a protonN-alkylation in the presence of a solvent. The embodiment of WO2010/039209 (chinese family CN102227433A) describes that by-products such as 3-cyclopropyl methyl naltrexone and quaternary ammonium salt are produced in addition to naltrexone, which is a main product, by adding water/isopropanol or ethanol as a protic solvent. CN103237804A discloses reacting noroxymorphone with cyclopropylmethyl halide in the presence of N-ethyl 2-pyrrolidone. In example 1, the composition of the reaction mixture (in% area) was checked by HPLC: naltrexone 97.3%, noroxymorphone 1.4%, 3-cyclopropylmethylnaltrexone 0.4%. Noroxymorphone and cyclopropyl methyl chloride in NaHCO in WO2013/164383, US2011269964A13,NaBr,Bu3And synthesizing naltrexone under the action of NMeBr. The reaction route is as follows:
Figure BDA0002827493230000011
CN101027307A describes the preparation of naltrexone or its hydrochloride salt using noroxymorphone and cyclopropanecarboxaldehyde under the catalysis of palladium or platinum (yield 83%). CN102227434A describes the preparation of naltrexone base (yield 95%) by hydrogen transfer of noroxymorphone with cyclopropanecarboxaldehyde under the catalysis of triethylamine, formic acid and the catalyst dichloro (p-cymene) ru (ii) dimer. Long reaction time, more byproducts, incomplete reaction, complex separation and purification operation and the like. US2015/126741a1 uses sodium triacetoxyborohydride as a catalyst to catalyze noroxymorphone and cyclopropanecarboxaldehyde to synthesize naltrexone. US2010/210843a1, US2015/126741a1 were also prepared from noroxymorphone and cyclopropanecarboxaldehyde as starting materials. The reaction route is as follows:
Figure BDA0002827493230000021
CN102046631A describes the preparation of naltrexone (yield 74%) from noroxymorphone and cyclopropanemethanol under the action of reagents such as methanesulfonyl chloride, triethylamine, lithium bromide, etc. Sipos, Attila et al, First Synthesis and inactivation of Oripavidine-A convention and Efficient Route to Important Morphinans and Apomorphines[J]Helvetica Chimica Acta,92(7), 1359-; 2009, discloses the use of (pentamethylcyclopentadienyl) dichloro iridium (III) dimer ([ Cp ] IrCl) as a starting material for noroxymorphone and cyclopropanemethanol2]2) Is used as a catalyst and is carried out in a microwave reactor to obtain the naltrexone. The reaction route is as follows:
Figure BDA0002827493230000022
by analyzing the prior art, noroxymorphone and hydrochloride thereof are main raw materials for synthesizing naltrexone, and the naltrexone is obtained by reacting with cyclopropyl halide, cyclopropyl formaldehyde and cyclopropyl methanol, and the problems of more byproducts, complex catalyst, difficult operation, difficult industrialization and the like exist respectively.
Disclosure of Invention
Aiming at the problems of the existing naltrexone preparation technology, the invention provides a novel naltrexone preparation method. The target product prepared by the method has higher purity and yield and lower production cost.
The technical scheme of the invention is as follows:
a process for preparing naltrexone from noroxymorphone and cyclopropylmethanol as raw materials and 4, 5-bis (diphenylphosphine) -9, 9-dimethyl xanthene palladium dichloride (PdCl) under protection of inert gas2(Xantphos)) as a catalyst, reacting, and carrying out aftertreatment to obtain the naltrexone. The route is as follows:
Figure BDA0002827493230000031
preferably, the preparation method comprises the following steps:
adding PdCl into a three-mouth bottle at room temperature under the protection of inert gas2(Xantphos) and a reaction solvent are stirred uniformly, then the cyclopropanemethanol is added and stirred uniformly, then the noroxymorphone is added, the reaction mixture is stirred and reacted at a controlled temperature, and then the mixture is added into a reaction bottleExtracting with water and extraction solvent, concentrating the organic phase to dryness to obtain oily substance, and pulping with solvent to obtain naltrexone.
Preferably, the reaction solvent is one of isopropanol, 1, 4-dioxane and methyl tert-butyl ether, and is further preferably isopropanol.
Preferably, the molar use ratio of noroxymorphone to ciprofloxacin is 1: 1-1: 1.5, and more preferably 1: 1.3.
Preferably, the noroxymorphone and PdCl2The molar ratio of (Xantphos) is 1:0.03 to 1:0.1, more preferably 1: 0.05.
Preferably, the temperature-controlled reaction is carried out at 20-35 ℃.
Preferably, the reaction time is 5-10 h.
Preferably, the extraction solvent is one of dichloromethane, ethyl acetate and toluene, and more preferably dichloromethane.
Preferably, the pulping solvent is one of n-hexane, isopropyl ether and petroleum ether, and more preferably n-hexane.
The inert gas is one of nitrogen and argon.
The invention has the technical effects that:
the invention provides a new method for preparing naltrexone, which is simple and easy to implement and operate; using PdCl2(Xantphos) is used as a catalyst, the problems that in the prior art, dichloro (p-cymene) Ru (II) dimer has long reaction time, and many byproducts are difficult to separate and purify are solved, and the obtained product has high yield and purity and is easy for industrial production.
Drawings
FIG. 1 is an HPLC chromatogram of naltrexone obtained in example 1;
FIG. 2 is the HPLC chromatogram for naltrexone obtained in example 2.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
HPLC detection, the chromatographic conditions are as follows:
column: octadecyl silica gel bonded silica gel as filler (SB-C)18,l＝0.15m,Φ＝4.6mm,5μm)
Mobile phase A: with the aqueous phase (1.1g/L sodium octane sulfonate, phosphoric acid to adjust pH to 2.3)
Mobile phase B: acetonitrile
Column temperature: 40 deg.C
A detector: UV at 230nm
Injection volume: 10 μ l
Analysis time: 60min
HPLC gradient
Time (minutes) Mobile phase A (%) Mobile phase B (%)
0 90 10
45 55 45
47 90 10
60 90 10
Identification data for naltrexone:
1H NMR(600MHz,CDCl3)δ6.73(d,J＝8.1Hz,1H),6.60(d,J＝8.1Hz,1H),5.72(bs,1H,OH),4.76(s,1H),3.21(d,J＝5.9Hz,1H),3.11-3.03(m,2H),2.73(dd,J＝12.0,4.8Hz,1H),2.56(dd,J＝18.4,6.0Hz,1H),2.50-2.34(m,3H),2.36(ddd,J＝14.5,3.0,3.0Hz,1H),2.18(ddd,J＝12.2,3.8,3.8Hz,1H),1.92(m,1H),1.66(ddd,J＝14.2,14.2,3.3Hz,1H),1.57(ddd,J＝12.8,2.7Hz,1H),0.88(m,1H),0.56(m,2H),0.16(m,2H)；
13C NMR(150MHz,CDCl3):d＝209.90,142.51,138.90,129.05,124.04,119.77,117.91,90.46,70.32,61.94,59.21,51.04,43.60,36.41,31.36,30.65,22.62,9.37,4.02,3.78.
in the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1
Adding PdCl into a three-mouth bottle at room temperature under the protection of inert gas nitrogen2(Xantphos) (6.43g, 8.50mmol) and isopropanol (60mL) are stirred uniformly, then cyclopropanemethanol (15.86g, 0.22mol) is added, after stirring uniformly, noroxymorphone (50.00g, 0.17mol) is added, the reaction mixture is stirred for 8 hours at 25 ℃, the completion of the reaction is detected, 100mL of water and 100mL of dichloromethane are added into a reaction bottle, stirring and liquid separation are carried out, an organic phase is dried by anhydrous sodium sulfate, suction filtration is carried out, an organic phase is subjected to reduced pressure concentration to obtain an oily substance, 60mL of n-hexane is added and pulping is carried out for 1 hour to obtain the product naltrexone, the yield is 96.5%, and the HPLC purity is 99.834%.
Example 2
Adding PdCl into a three-mouth bottle at room temperature under the protection of inert gas nitrogen2(Xantphos) (14.14g, 18.70mmol) and isopropanol (60mL) were stirred well, then cyclopropylmethanol (15.86g, 0.22mol) was added, after stirring well, noroxymorphone (50.00g, 0.17mol) was added, the reaction mixture was stirred at 25 ℃ for 5h, detection of reaction completion was added 100mL water, 100mL dichloro-oxymorphone to the reaction flaskMethane, stirring, separating, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure to obtain an oily substance, adding 60ml of n-hexane, and pulping for 1h to obtain the product naltrexone, wherein the yield is 95.5%, and the HPLC purity is 99.801%.
Example 3
Adding PdCl into a three-mouth bottle at room temperature under the protection of inert gas nitrogen2(Xantphos) (2.57g, 3.40mmol) and isopropanol (60mL) are stirred uniformly, then cyclopropanemethanol (15.86g, 0.22mol) is added, after stirring uniformly, noroxymorphone (50.00g, 0.17mol) is added, the reaction mixture is stirred for 10 hours at 25 ℃, the completion of the reaction is detected, 100mL of water and 100mL of dichloromethane are added into a reaction bottle, stirring and liquid separation are carried out, the organic phase is dried by anhydrous sodium sulfate, suction filtration is carried out, the organic phase is concentrated under pressure to obtain oily matter, 60mL of n-hexane is added and pulped for 1 hour to obtain the product naltrexone, the yield is 93.4%, and the HPLC purity is 99.753%.
Example 4
Adding PdCl into a three-mouth bottle at room temperature under the protection of inert gas nitrogen2(Xantphos) (12.85g, 17.00mmol) and isopropanol (60mL) are stirred uniformly, then cyclopropanemethanol (15.86g, 0.22mol) is added, after stirring uniformly, noroxymorphone (50.00g, 0.17mol) is added, the reaction mixture is stirred for 6 hours at 25 ℃, the completion of the reaction is detected, 100mL of water and 100mL of dichloromethane are added into a reaction bottle, stirring, liquid separation, drying of an organic phase with anhydrous sodium sulfate, suction filtration and reduced pressure concentration of the organic phase are carried out, an oily substance is obtained, 60mL of n-hexane is added and pulping is carried out for 1.5 hours, the product naltrexone is obtained, the yield is 94.8%, and the HPLC purity is 99.813%.
Example 5
Adding PdCl into a three-mouth bottle at room temperature under the protection of inert gas nitrogen2(Xantphos) (12.85g, 17.00mmol) and 1, 4-dioxane (60mL) are stirred uniformly, then cyclopropanemethanol (15.86g, 0.22mol) is added, after stirring uniformly, noroxymorphone (50.00g, 0.17mol) is added, the reaction mixture is stirred for 8 hours at 25 ℃, the completion of the reaction is detected, 100mL of water and 100mL of ethyl acetate are added into a reaction bottle, stirring and liquid separation are carried out, the organic phase is dried by anhydrous sodium sulfate, suction filtration is carried out, and the organic phase is concentrated under reduced pressure to obtain oilAdding 60ml of n-hexane into the mixture, and pulping for 1h to obtain the product naltrexone, wherein the yield is 94.6%, and the HPLC purity is 99.802%.
Example 6
Adding PdCl into a three-mouth bottle at room temperature under the protection of inert gas nitrogen2(Xantphos) (3.86g, 5.10mmol) and isopropanol (60mL) are stirred uniformly, then cyclopropanemethanol (15.86g, 0.22mol) is added, after stirring uniformly, noroxymorphone (50g, 0.17mol) is added, the reaction mixture is stirred for 10 hours at 25 ℃, the completion of the reaction is detected, 100mL of water and 100mL of dichloromethane are added into a reaction bottle, stirring and liquid separation are carried out, an organic phase is dried by anhydrous sodium sulfate, suction filtration is carried out, an organic phase is subjected to reduced pressure concentration to obtain an oily substance, 60mL of n-hexane is added for pulping for 1 hour to obtain a product naltrexone, the yield is 93.9%, and the HPLC purity is 99.764%.
Example 7
Adding PdCl into a three-mouth bottle at room temperature under the protection of inert gas nitrogen2(Xantphos) (6.43g, 8.50mmol) and 1, 4-dioxane (60mL) are stirred uniformly, then cyclopropanemethanol (12.26g, 0.17mol) is added, after stirring uniformly, noroxymorphone (50.00g, 0.17mol) is added, the reaction mixture is stirred for 8 hours at 25 ℃, the completion of the reaction is detected, 100mL of water and 100mL of dichloromethane are added into a reaction bottle, stirring is carried out, liquid separation is carried out, the organic phase is dried by anhydrous sodium sulfate, suction filtration is carried out, the organic phase is subjected to reduced pressure concentration to obtain oily matter, 60mL of n-hexane is added for pulping for 1 hour to obtain the product naltrexone, the yield is 94.4%, and the HPLC purity is 99.803%.
Example 8
Adding PdCl into a three-mouth bottle at room temperature under the protection of inert gas nitrogen2(Xantphos) (6.43g, 8.50mmol) and isopropanol (60mL) are stirred uniformly, then cyclopropanemethanol (18.75g, 0.26mol) is added, after stirring uniformly, noroxymorphone (50.00g, 0.17mol) is added, the reaction mixture is stirred for 8h at 25 ℃, the completion of the reaction is detected, 100mL of water and 100mL of dichloromethane are added into a reaction bottle, stirring, liquid separation, drying of an organic phase anhydrous sodium sulfate, suction filtration and reduced pressure concentration of the organic phase are carried out, an oily substance is obtained, 60mL of n-hexane is added for 1h, the product naltrexone is obtained, the yield is 96.1%, and the HPLC purity is 99.798%.
Example 9
Adding PdCl into a three-mouth bottle at room temperature under the protection of inert gas nitrogen2(Xantphos) (6.43g, 8.50mmol) and methyl tert-butyl ether (60mL) are stirred uniformly, then methyl cyclopropane (15.86g, 0.22mol) is added, after stirring uniformly, noroxymorphone (50.00g, 0.17mol) is added, the reaction mixture is stirred for 10h at 20 ℃, the completion of the reaction is detected, 100mL of water and 100mL of dichloromethane are added into a reaction bottle, stirring, liquid separation, drying of an organic phase with anhydrous sodium sulfate, suction filtration and reduced pressure concentration of the organic phase are carried out, an oily substance is obtained, 60mL of isopropyl ether is added and pulping is carried out for 1h, the product naltrexone is obtained, the yield is 95.4%, and the HPLC purity is 99.724%.
Example 10
Adding PdCl into a three-mouth bottle at room temperature under the protection of inert gas nitrogen2(Xantphos) (6.43g, 8.50mmol) and isopropanol (60mL) are stirred uniformly, then cyclopropanemethanol (15.86g, 0.22mol) is added, after stirring uniformly, noroxymorphone (50.00g, 0.17mol) is added, the reaction mixture is stirred for 6h at 35 ℃, the completion of the reaction is detected, 100mL of water and 100mL of toluene are added into a reaction bottle, stirring and liquid separation are carried out, an organic phase is dried by anhydrous sodium sulfate, suction filtration is carried out, an organic phase is subjected to reduced pressure concentration to obtain an oily substance, 60mL of petroleum ether is added and pulping is carried out for 1h to obtain the product naltrexone, the yield is 95.9%, and the HPLC purity is 99.730%.

Claims (9)

1. A preparation method of naltrexone is characterized in that noroxymorphone and cyclopropanemethanol are taken as raw materials, PdCl is taken as PdCl under the protection of inert gas2(Xantphos) is used as a catalyst to carry out reaction to obtain naltrexone; the route is as follows:
Figure FDA0002827493220000011
2. the preparation method according to claim 1, comprising the following steps: adding PdCl into a three-mouth bottle at room temperature under the protection of inert gas2(Xantphos) and a reaction solvent are uniformly stirred, then cyclopropanemethanol is added, the mixture is uniformly stirred, then noroxymorphone is added, the reaction mixture is stirred and reacted at a controlled temperature, water and an extraction solvent are added into a reaction bottle for extraction after the detection reaction is finished, an organic phase is concentrated to be dry to obtain an oily substance, and then the solvent is used for pulping to obtain the product naltrexone.
3. The method of claim 2, wherein the reaction solvent is one of isopropanol, 1, 4-dioxane, and methyl tert-butyl ether.
4. The method of claim 2, wherein the molar ratio of noroxymorphone to ciprofloxacin is from 1:1 to 1: 1.5.
5. The method of claim 2, wherein the noroxymorphone and PdCl are present2The molar ratio of (Xantphos) is 1: 0.03-1: 0.1.
6. The preparation method according to claim 2, wherein the temperature-controlled reaction is carried out at 20-35 ℃.
7. The method of claim 2, wherein the extraction solvent is one of dichloromethane, ethyl acetate, and toluene.
8. The method according to claim 2, wherein the solvent is one of n-hexane, isopropyl ether and petroleum ether.
9. The preparation method of claim 8, wherein the temperature-controlled reaction time is 5-10 h.
CN202011452095.2A 2020-12-10 2020-12-10 Preparation method of naltrexone Pending CN114621239A (en)

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