A preparation method of naltrexone

Abstract

The present invention belongs to the field of drug synthesis, and specifically relates to a method for preparing naltrexone, and the specific steps include: adding the noroxymorphone and an organic solvent into a reactor, adding cyclopropylcarbinol and a catalyst under stirring, reacting at room temperature under the protection of an inert gas; after the reaction is completed, the naltrexone product is obtained by separation and purification. The present invention achieves a significant improvement in reaction yield and purity under a larger production scale by innovatively adjusting the synthesis process conditions, and has good application value.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a method for preparing naltrexone. Background Art

[0002] Naltrexone is an opioid receptor antagonist that is primarily used to treat opioid-dependent people to help them prevent relapse after detoxification. It works by blocking opioid receptors, reducing cravings for opioids, thereby reducing the likelihood of relapse. In addition, naltrexone is also used as an adjunct to the treatment of ethanol dependence, helping alcohol-dependent people control their drinking behavior by reducing the desire to drink. It is sold in generic form as its hydrochloride salt (naltrexone hydrochloride) and under the trade names ReVia and Depade. In some countries, including the United States, a once-monthly extended-release injectable formulation is sold under the trade name ViVitrol.

[0003] Naltrexone can be prepared from noroxymorphone by various direct and indirect alkylation methods. One method is by direct alkylation of noroxymorphone or its salts with cyclopropylmethyl halide. This method has been disclosed in general form in WO91 / 05768 to Rice. WO2008 / 034973 to Sanofi-Avensisd (Chinese equivalent CN101516892A) describes a method for obtaining naltrexone with a yield of 88.6% by reacting noroxymorphone hydrochloride with cyclopropylmethyl bromide in dimethylacetamide in the presence of sodium bicarbonate. WO2008 / 138605 to Cilag describes the N-alkylation reaction of noroxymorphone with cyclopropylmethyl bromide in N-methyl-pyrrolidone in the presence of sodium bicarbonate. Mallinckrodt's WO2010 / 039209 describes the N-alkylation of noroxymorphone with cyclopropylmethyl bromide in the presence of a protic solvent. The implementation scheme in WO2010 / 039209 (Chinese equivalent CN102227433A) describes the addition of water / isopropanol or ethanol as a protic solvent to produce naltrexone as the main product, as well as byproducts such as 3-cyclopropylmethylnaltrexone and quaternary ammonium salts. CN103237804A discloses the reaction of 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%. In WO2013 / 164383 and US2011269964A1, naltrexone is synthesized by using noroxymorphone and cyclopropylmethyl chloride in the presence of NaHCO3, NaBr, and Bu3NMeBr.

[0004] Another method is to indirectly alkylate noroxymorphone or its salt with cyclopropanecarboxaldehyde or cyclopropylmethanol. CN101027307A records the preparation of naltrexone or its hydrochloride (yield 83%) by noroxymorphone and cyclopropanecarboxaldehyde under the catalysis of palladium or platinum. CN102227434A records the preparation of naltrexone base (yield 95%) by hydrogen transfer using noroxymorphone and cyclopropanecarboxaldehyde under the catalysis of triethylamine, formic acid and catalyst dichloro (p-methylisopropylbenzene) Ru (II) dimer. There are problems such as long reaction time, many by-products, incomplete reaction, and complicated separation and purification operations. US2015 / 126741A1 uses sodium triacetoxyborohydride as a catalyst to catalyze the synthesis of naltrexone from noroxymorphone and cyclopropanecarboxaldehyde. US2010 / 210843A1 and US2015 / 126741A1 also use noroxymorphone and cyclopropanecarboxaldehyde as raw materials for preparation. CN102046631A records the use of noroxymorphone and cyclopropanemethanol to prepare naltrexone (yield 74%) under the action of reagents such as methanesulfonyl chloride, triethylamine, and lithium bromide. Sipos, Attila et al., First Synthesis and Utilization of Oripavidine-A Concise and Efficient Route to Important Morphinans and Apomorphines [J], Helvetica Chimica Acta, 92 (7), 1359-1365; 2009, recorded that noroxymorphone and cyclopropanemethanol were used as raw materials, dichloro (pentamethylcyclopentadienyl) iridium (III) dimer ([Cp*IrCl2]2) was used as a catalyst, and naltrexone was obtained in a microwave reactor.

[0005] Through the analysis of the prior art, although the reaction of noroxymorphone and its hydrochloride with cyclopropylcarbinol to synthesize naltrexone can achieve good reaction results in the laboratory or on a small scale, the existing process has the defects of reduced efficiency and purity when scaled up for production. There is a need in the art to improve the method for preparing high-purity naltrexone and / or to find an alternative method for preparing naltrexone. In particular, a method that is easily applicable to industrial scale is needed. Summary of the invention

[0006] The object of the present invention is to provide an improved preparation method of naltrexone to solve the technical problems of fewer or lower efficiency chemical synthesis routes in the prior art, especially to solve the defects of decreased yield and product purity of the prior art under the scale-up of production.

[0007] In order to solve the above technical problems, the present invention provides an improved preparation method of naltrexone, comprising taking noroxymorphone and cyclopropylcarbinol as reaction raw materials, and preparing naltrexone by coupling reaction in an organic solvent under the action of a catalyst; the catalyst is PdCl2 (dppf), and the specific steps of the process are as follows:

[0008] The noroxymorphone and the organic solvent are added to a reactor, and cyclopropylcarbinol and a catalyst are added under stirring, and the reaction is carried out at room temperature under the protection of an inert gas; after the reaction is completed, the naltrexone product is obtained by separation and purification;

[0009] Wherein, the organic solvent is tert-butyl methyl ether.

[0010] In some embodiments, the reaction time of the coupling reaction is 8-20 h.

[0011] In some embodiments, the molar ratio of noroxymorphone to cyclopropylcarbinol is preferably 1:1-2.

[0012] In some embodiments, the molar ratio of noroxymorphone to the catalyst is preferably 1:0.01-0.1.

[0013] In some embodiments, the ratio of noroxymorphone to the organic solvent is 1 mol:(1-2) L.

[0014] The separation and purification operation is as follows: after the reaction is completed, evaporation and concentration are performed to recover the reaction solvent; water and cyclopentyl methyl ether are added to the residual liquid, the liquid is separated after sufficient stirring, the organic phase is heated to 50° C.-100° C. and then naturally cooled to room temperature, and then the suspension is further cooled to 5-10° C. within 1-10 hours, the crystals are filtered out, washed with cyclopentyl methyl ether, and vacuum dried to obtain the naltrexone product.

[0015] The present invention has the following beneficial effects:

[0016] The inventors surprisingly found that by using the existing raw materials noroxymorphone and cyclopropylcarbinol, under the action of preferred coupling reaction conditions (reaction solvent, catalyst, material ratio, post-treatment, etc.), naltrexone products can be obtained with high reaction yield and purity at a scaled-up production of tens of kilograms. DETAILED DESCRIPTION

[0017] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0018] The endpoints and any values ​​of the scope described in the present invention are not limited to the precise scope or value, and these scopes or values ​​should be understood to include values ​​close to these scopes or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered as specifically disclosed in this article.

[0019] Example 1

[0020] At room temperature, add tert-butyl methyl ether (80L) and noroxymorphone (60Kg, 208.83mol) to the reactor, start stirring, then add cyclopropylcarbinol (18Kg, 249.62mol) and PdCl2(dppf) (3.06Kg, 4.18mol), introduce nitrogen as a protective gas, and react at room temperature for 10h. After the reaction is completed, evaporate and concentrate to recover the reaction solvent. Add water (100L) to the residual liquid, and then slowly add 5wt% ammonium hydroxide until the pH is 9-10, filter out the precipitated crude product, and wash with water (100Kg*1). Cyclopentyl methyl ether (250 L) was added to the crude product, and the mixture was heated to 60°C with stirring to dissolve all the crude product. The mixture was naturally cooled to room temperature, at which time crystallization occurred. The suspension was then cooled to 5-10°C within 5 h, the crystals were filtered out, washed with cyclopentyl methyl ether (50 L*2), and vacuum dried to obtain 70.5 kg of naltrexone product with an HPLC purity of 99.5% and a yield of 98.9%.

[0021] HPLC normalization method: chromatographic column: Waters X-Bridge C18 column (4.6 mm×150 mm, 3.5 μm); mobile phase A was a mixture of 10 mmol / L sodium dihydrogen phosphate aqueous solution (adjusted to pH=8.0 with phosphoric acid) and acetonitrile (volume ratio 95:5), mobile phase B was acetonitrile, gradient elution (0~15 min, A 100%; 16~24 min, A 30%; 24.1~32 min, A100%); detection wavelength was 210 nm; flow rate was 1.0 mL / min; column temperature was 30 ℃; injection volume was 5 μL.

[0022] By comparison, the HPLC retention time of the product of this example is consistent with that of the naltrexone standard.

[0023] Example 2

[0024] Only the post-processing operation of Example 1 was changed, and other conditions were the same.

[0025] The post-treatment is as follows: after the reaction is completed, the reaction solvent is recovered by evaporation and concentration. Water (100 L) is added to the residual liquid, and then cyclopentyl methyl ether (250 L) is added, and the mixture is separated after sufficient stirring. The organic phase is heated to 60°C and then cooled naturally to room temperature, at which time crystallization occurs. The suspension is then cooled to 5-10°C within 5 hours, the crystals are filtered out, washed with cyclopentyl methyl ether (50 L*2), and vacuum dried to obtain 71 kg of naltrexone product with an HPLC purity of 99.3% and a yield of 99.4%.

[0026] Comparative Example 1

[0027] The catalyst PdCl2 (dppf) in Example 1 was replaced by an equimolar amount of PdCl2 (Xantphos), and the other conditions remained unchanged, to obtain 61.3 kg of naltrexone with a yield of only 86% and an HPLC purity of 99.1%.

[0028] Comparative Example 2

[0029] The reaction solvent tert-butyl methyl ether in Example 1 was replaced with an equal volume of isopropanol, and the other conditions remained unchanged, to obtain 64.2 kg of naltrexone with a yield of only 90% and an HPLC purity of 98.6%.

[0030] Comparative Example 3

[0031] Under the protection of inert gas nitrogen, PdCl2 (Xantphos) (6.4 Kg, 8.5 mol) and isopropanol (60 L) were added to the reactor at room temperature and stirred evenly, and then cyclopropylmethanol (15.9 Kg, 220.5 mol) was added and stirred evenly, and then noroxymorphone (50 Kg, 174 mol) was added. The reaction mixture was stirred at 25 ° C for 10 h. After the reaction was detected to be complete, 100 L of water and 100 L of dichloromethane were added to the reaction bottle, stirred, separated, the organic phase was dried, filtered, and the organic phase was concentrated under reduced pressure to obtain an oily substance. 60 L of n-hexane was added and slurried for 2 h to obtain 58.5 Kg of naltrexone with a yield of 82% and a HPLC purity of 98.1%.

[0032] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing naltrexone, It is characterized in that The method comprises taking noroxymorphone and cyclopropylcarbinol as reaction raw materials, and preparing naltrexone by coupling reaction in an organic solvent under the action of a catalyst; the catalyst is PdCl 2 (dppf), the specific steps of the process are as follows: The noroxymorphone and the organic solvent are added to a reactor, and cyclopropylcarbinol and a catalyst are added under stirring, and the reaction is carried out at room temperature under the protection of an inert gas; after the reaction is completed, the naltrexone product is obtained by separation and purification; Wherein, the organic solvent is tert-butyl methyl ether.

2. The preparation method according to claim 1, It is characterized in that The reaction time of the coupling reaction is 8-20h.

3. The preparation method according to claim 1, It is characterized in that The molar ratio of noroxymorphone to cyclopropylcarbinol is 1:1-2.

4. The preparation method according to claim 1, It is characterized in that The molar ratio of noroxymorphone to the catalyst is 1:0.01-0.

1.

5. The preparation method according to claim 1, It is characterized in that The dosage ratio of the noroxymorphone to the organic solvent is 1 mol:(1-2) L.

6. The preparation method according to claim 1, It is characterized in that The separation and purification operation is as follows: after the reaction is completed, evaporation and concentration are performed to recover the reaction solvent; water and cyclopentyl methyl ether are added to the residual liquid, the liquid is separated after sufficient stirring, the organic phase is heated to 50° C.-100° C. and then naturally cooled to room temperature, and then the suspension is further cooled to 5-10° C. within 1-10 hours, the crystals are filtered out, washed with cyclopentyl methyl ether, and vacuum dried to obtain the naltrexone product.