A preparation method of a naltrexone chiral compound

Abstract

The application relates to the technical field of drug synthesis, in particular to a preparation method of a chiral naltrexone compound. The chiral naltrexone compound is obtained through reduction and other reactions, and the chiral naltrexone compound has high chiral purity. The preparation method does not need separation and purification, and the product has high chiral purity.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing chiral naltrexone compounds. Background Technology

[0002] Morphine-based drugs, as opioid receptor agonists, are primarily used clinically for the treatment of moderate to severe pain and palliative care caused by severe trauma, burns, fractures, cancer, etc., as well as as opioid receptor antagonists to treat respiratory depression and for the treatment of opioid and alcohol addiction. Statistics show that in 2016, morphine-based drugs accounted for 7 of the top 200 most prescribed drugs globally, playing an irreplaceable role in the pharmaceutical market and possessing extremely important clinical value. Among these, alternative drugs include hydrocodone, oxycodone, buprenorphine, nalaxone, and naltrexone, all molecularly designed with the morphine core as the basic framework.

[0003]

[0004] The aforementioned morphine drugs all have carbonyl groups at the C6 position, which can be reduced to introduce amino groups, simultaneously constructing a chiral center at the C6 position. The literature J. Med. Chem. 1986, 29, 1551-1553 discloses the preparation of 6β-methylamino-17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxymorphinan by reducing naltrexone hydrochloride.

[0005]

[0006] 6β-methylamino-17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxymorphinan can be further used to prepare (2E)-N-[5R,6R-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphin-6-yl]-3-(furan-3-yl)-N-methylpropyl-2-enamide monohydrochloride, CAS No.: 152658-17-8.

[0007] The method yields a low yield of the 6β-methylamino-17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxymorphinan R configuration, and the diastereomeric S-configuration byproducts generated require separate purification and removal, increasing process costs.

[0008] Patent CN102803267A reports a direct reductive amination method. This method, catalyzed by transition metals Ru (ruthenium), Pd, or Pt, involves the reductive amination of naltrexone hydrochloride and methylamine to yield 6β-methylamino-17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxymorphinan, with the non-corresponding isomer S-configuration being the major product.

[0009]

[0010] Patent CN1111900A reports a reduction to obtain a benzyl-protected R-configuration product, followed by removal of the benzyl protecting group to obtain a methylamine naltrexone compound.

[0011]

[0012] This method involves a benzyl group introduction step, but this step uses high-temperature reflux, resulting in a long reaction time. The exposed phenolic hydroxyl groups of naltrexone are easily oxidized, forming quinone-type mutagenic impurities that may remain in the drug, increasing the risk of cancer for patients. Furthermore, the use of Pd / C and hydrogen for debenzylation makes the hydrogenation reaction a Class 18 hazardous reaction, posing fire and explosion hazards during production. The approval and construction of hydrogenation reaction workshops are subject to very strict management requirements by safety inspection departments. These limitations hinder the commercialization of this method. Summary of the Invention

[0013] The main objective of this invention is to address the problems of complex synthetic routes and diastereomer impurities associated with introducing low-alkylamine compounds at the C6 position of compounds of Formula 1, by providing a novel method for preparing naltrexone compounds.

[0014]

[0015] A first aspect of the present invention provides a method for preparing a compound of formula 4, the method comprising the following steps,

[0016] 1) Compound of Formula 1 reacts to give compound of Formula 2.

[0017]

[0018] 2) Compound 2 reacts to give compound 3.

[0019]

[0020] 3) The compound of formula 3 is reacted with an amine reagent to give the compound of formula 4.

[0021]

[0022] Among them, R1 is selected from C 1-6 Alkyl, C2-6 Alkenyl, wherein the alkyl or alkenyl group is optionally substituted with a 3-8 membered cycloalkyl group.

[0023] R2 is selected from H and C. 1-6 alkyl,

[0024] R3 is selected from C 1-6 alkyl.

[0025] In some implementations, R1 is selected from methyl, cyclopropylmethyl, and propenyl.

[0026] In some implementations, R2 is selected from H or methyl.

[0027] In some implementations, R3 is selected from C 1-4 Alkyl group, preferably -CH3.

[0028] In some implementations, R1 is cyclopropylmethyl.

[0029] In some implementations, R2 is H.

[0030] In some embodiments, step 1) further includes adding a reducing agent selected from one or more of sodium borohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride, preferably sodium borohydride.

[0031] In some embodiments, step 1) further includes the addition of a metal catalyst, the metal catalyst being selected from one or more of platinum catalysts, palladium catalysts, and ruthenium catalysts, preferably ruthenium catalysts, and more preferably ruthenium(II) dimers.

[0032] In some embodiments, in step 1), the reaction time for reacting the compound of formula 1 to obtain the compound of formula 2 is 1 to 6 hours, preferably 1 to 4 hours, more preferably 1 to 2 hours, and most preferably 2 hours.

[0033] In some embodiments, in step 1), the reaction temperature at which the compound of formula 1 is reacted to obtain the compound of formula 2 is -5°C to 25°C, preferably -5°C to 15°C, more preferably 0°C to 10°C, and most preferably 0±5°C.

[0034] In some embodiments, in step 1), the compound of formula 1 is reacted to obtain the compound of formula 2, wherein the compound of formula 2 has an S configuration at the C6 position.

[0035] In some embodiments, in step 2), the compound of formula 2 reacts with a sulfonic acid reagent to obtain the compound of formula 3, wherein the sulfonic acid reagent is trifluoromethanesulfonic anhydride.

[0036] In some embodiments, in step 2), the compound of formula 2 reacts with a sulfonic acid reagent to obtain the compound of formula 3, wherein the compound of formula 3 has an S configuration at the C6 position.

[0037] In some embodiments, in step 2), the reaction solvent for obtaining the compound of formula 3 from the compound of formula 2 is selected from chloroform solvent, preferably dichloromethane.

[0038] In some embodiments, step 2) further includes adding an alkaline reagent, which is selected from one or more of triethylamine, diisopropylethylamine, pyridine, and 2,6-dimethylpyridine, preferably one of triethylamine and diisopropylethylamine.

[0039] In some embodiments, in step 2), the reaction temperature for obtaining the compound of formula 3 from the compound of formula 2 is -5°C to 25°C, preferably -5°C to 15°C, more preferably 0°C to 10°C, and most preferably 0±5°C.

[0040] In some embodiments, in step 2), the reaction time for obtaining the compound of formula 3 from the compound of formula 2 is 1 to 6 hours, preferably 1 to 4 hours, and more preferably 2 to 3 hours.

[0041] In some embodiments, in step 3), the reaction of compound 3 to compound 4 further includes the addition of a basic reagent, wherein the basic reagent is selected from one or more of triethylamine, diisopropylethylamine, pyridine, and 2,6-dimethylpyridine, preferably triethylamine or diisopropylethylamine.

[0042] In some embodiments, step 3) further includes a post-processing step, wherein the post-processing step is as follows: after the reaction in step 3 is completed, 10% to 30% alkaline solution is added, and after stirring for a certain period of time, the mixture is slurried with an ether solvent to obtain compound of formula 4. The stirring time is 1 to 5 hours, preferably 1 to 3 hours. The alkaline solution is selected from one or more of sodium hydroxide solution and potassium hydroxide solution, and the ether solvent is selected from one or more of diethyl ether and methyl tert-butyl ether, preferably methyl tert-butyl ether.

[0043] In some embodiments, in step 3), the compound of formula 3 is given as a compound of formula 4, wherein the C6 position of the compound of formula 4 is in the R configuration.

[0044] In some embodiments, R1 is cyclopropylmethyl, R2 is H, and R3 is -CH3.

[0045] A second aspect of the invention provides the use of a compound of formula 4-1 in the preparation of compound (2E)-N-[5R,6R-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphone-6-yl]-3-(furan-3-yl)-N-methylpropyl-2-enamide or a pharmaceutically acceptable salt thereof, the structure of said compound of formula 4-1 being:

[0046]

[0047] In some embodiments, the pharmaceutically acceptable salt of compound (2E)-N-[5R,6R-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphine-6-yl]-3-(furan-3-yl)-N-methylpropyl-2-enamide is its hydrochloride salt.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] The method for preparing Formula 4 compounds provided by this invention has high chiral purity, high raw material conversion rate, and no need for separation and purification, which reduces the production cost of preparing high-purity chiral compounds. It is simple to operate and easy to scale up for production. Detailed Implementation

[0050] The following describes embodiments of the present invention, but the present invention is not limited thereto. The present invention is not limited to the various configurations described below, and various modifications can be made within the scope of the claims. Embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention.

[0051] Preparation of 6β-methylamino-17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxymorphinan (Formula 4-1)

[0052]

[0053] Example 1

[0054] 1 kg of methanol, 200 g of naltrexone hydrochloride (Formula 1-1), and 1.5 g of ruthenium(II) dimer (0.5%) were added sequentially to a reaction flask. The mixture was cooled to 0 ± 5 °C, and 20 g of sodium borohydride was slowly added. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 2.0 h until the reaction was complete. The reaction solution was concentrated to obtain a concentrated solution of compound 2-1. This concentrated solution was dissolved in 1.5 kg of dichloromethane, extracted, dried, and filtered to obtain compound 2-1, which was directly used in the next reaction step.

[0055] Compound of Formula 2-1 and 107 g of triethylamine were added sequentially to a reaction flask. The mixture was cooled to 0±5℃, and 224 g of trifluoromethanesulfonic anhydride was added dropwise. The reaction was maintained at this temperature for 2 h to obtain a solution of compound of Formula 3-1, which was directly used in the next reaction. 80 g of triethylamine was added to the solution of compound of Formula 3-1, followed by 53 g of methylamine hydrochloride. The reaction was maintained at this temperature for 3 h. After the reaction was completed, crude product of compound of Formula 4-1 was obtained. 20% sodium hydroxide solution was added to the crude product of compound of Formula 4-1, the temperature was raised to room temperature, and the mixture was stirred for 2 h. The mixture was separated into liquid and liquid phases. The organic phase was washed with 10% sodium chloride, and the organic phase was concentrated. The concentrate was pulped with 1 kg of methyl tert-butyl ether, filtered, and dried to obtain 153 g of compound of Formula 4-1, yield: 81%, chiral purity >99%.

[0056] Example 2

[0057] 200g of methanol, 40g of naltrexone hydrochloride (Formula 1-1), and 0.3g of ruthenium(II) dimer (0.5%) were added sequentially to a reaction flask. The mixture was cooled to 0±5℃, and 4g of sodium borohydride was slowly added. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 1.5h until the reaction was complete. The reaction solution was concentrated to obtain a concentrated solution of compound 2-1. This concentrated solution was dissolved in 0.3kg of dichloromethane, extracted, dried, and filtered to obtain compound 2-1, which was directly used in the next reaction step.

[0058] Compound of Formula 2-1 and 29 g of diisopropylethylamine were added sequentially to a reaction flask. The mixture was cooled to 0±5℃, and 45 g of trifluoromethanesulfonic anhydride was added dropwise. The reaction was maintained at this temperature for 2 h to obtain a solution of compound of Formula 3-1, which was directly used in the next reaction. 26 g of diisopropylethylamine was added to the solution of compound of Formula 3-1, followed by 11 g of methylamine hydrochloride. The reaction was maintained at this temperature for 2.5 h. After the reaction was complete, crude product of compound of Formula 4-1 was obtained. 20% sodium hydroxide solution was added to the crude product, the temperature was raised to room temperature, and the mixture was stirred for 2 h. The mixture was separated into liquid and liquid phases. The organic phase was washed with 10% sodium chloride, concentrated, and the concentrate was pulped using 0.2 kg of methyl tert-butyl ether. The concentrate was filtered, dried, and 28.3 g of compound of Formula 4-1 was obtained, with a yield of 75% and a chiral purity of >98% for the R configuration.

[0059] Comparative Example 1

[0060] Following the same procedure as in Example 1, but replacing sodium borohydride in Example 1 with 33g of sodium cyanoborohydride, we obtained 15g of compound 4-1, with a yield of 80% and a chiral purity of 72%.

[0061] The experimental results of Comparative Example 1 indicate that using sodium cyanoborohydride as a reducing agent cannot yield a product with high chiral purity.

[0062] Comparative Example 2

[0063] Following the same procedure as in Example 1, except that the trifluoromethanesulfonic anhydride in Example 1 was replaced with 16g of methanesulfonyl chloride, and the rest was the same as in Example 1, we obtained 12.8g of compound 4-1, with a yield of 72% and a chiral purity of 76%.

[0064] The experimental results of Comparative Example 2 indicate that choosing methanesulfonyl chloride as a sulfonic acid reagent cannot yield a product with high chiral purity.

[0065] Comparative Example 3

[0066] Following the same procedure as in Example 1, but replacing the trifluoromethanesulfonic anhydride in Example 1 with 26g of p-toluenesulfonyl chloride, we obtained 12.2g of compound 4-1, with a yield of 69% and a chiral purity of 61%.

[0067] The experimental results of Comparative Example 3 indicate that using p-toluenesulfonyl chloride as a sulfonic acid reagent cannot yield a product with high chiral purity.

[0068] Comparative Example 4

[0069] Following the same procedure as in Example 1, the sodium borohydride in Example 1 was replaced with sodium cyanoborohydride (33g) to obtain compound of formula 4-1 (15g), yield: 80%, R configuration chiral purity 72%.

[0070] Comparative Example 5

[0071] Following the same procedure as in Example 1, but replacing 7.5g of triethylamine with pyridine, we obtained 8.5g of compound 4-1, yield: 48%, chiral purity >98%.

[0072] The results of Comparative Example 5 show that the preparation of Compound 3-1 from Compound 2-1, using pyridine as a reaction reagent, yields a low product yield.

[0073] To more clearly illustrate the technical solution of this invention, further explanation is provided below with reference to specific embodiments and comparative examples. However, these are not intended to limit the invention and are merely some embodiments of the invention. Simple improvements to the invention based on its technical solution are all within the scope of protection of this invention. Unless otherwise stated, the instruments, reagents, materials, experimental animals, etc., used in this invention can all be obtained through conventional commercial means. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply.

Claims

1. A method for preparing a compound of formula 4, characterized in that, The preparation method includes the following steps: 1) Compound 1 reacts to give compound 2. 2) Compound 2 reacts to give compound 3. 3) Compound 3 reacts to yield compound 4. Among them, R1 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, wherein the alkyl or alkenyl group is optionally substituted with a 3-8 membered cycloalkyl group. R2 is selected from H and C. 1-6 alkyl, R3 is selected from C 1-6 alkyl.

2. The preparation method according to claim 1, characterized in that, Step 1) further includes adding a reducing agent, which is selected from one or more of sodium borohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride.

3. The preparation method according to claim 1, characterized in that, In step 2), the compound of formula 2 reacts with a sulfonic acid reagent to obtain the compound of formula 3, wherein the sulfonic acid reagent is trifluoromethanesulfonic anhydride.

4. The preparation method according to claim 1, characterized in that, In step 2), an alkaline reagent is added, wherein the alkaline reagent is selected from one or more of triethylamine, diisopropylethylamine, pyridine, and 2,6-dimethylpyridine.

5. The preparation method according to claim 1, characterized in that, In step 3), the compound of formula 3 reacts with the NH2-R3 reagent to give the compound of formula 4, wherein R3 is selected from C 1-4 alkyl.

6. The preparation method according to claim 1, characterized in that, Step 3) also includes a post-processing step, which is as follows: after the reaction is completed, 10% to 30% alkaline solution is added, and after stirring for a certain period of time, ether solvent is used to slurry to obtain compound of formula 4. The stirring time is 1 to 5 hours. The alkaline solution is selected from one or more of sodium hydroxide solution and potassium hydroxide solution, and the ether solvent is selected from one or more of diethyl ether and methyl tert-butyl ether.

7. The preparation method according to claim 2, characterized in that, Step 1 further includes adding a metal catalyst, which is selected from one or more of platinum catalysts, palladium catalysts, and ruthenium catalysts, preferably ruthenium catalysts.

8. The preparation method according to claim 7, characterized in that, In step 1, the reaction time for the compound of formula 1 to obtain the compound of formula 2 is 1 to 6 hours, preferably 1 to 4 hours, more preferably 1 to 2 hours; the reaction temperature is -5°C to 25°C, preferably -5°C to 15°C, more preferably 0 to 10°C.

9. The preparation method according to claim 1, characterized in that, In compound formula 4, R1 is cyclopropylmethyl, R2 is H, and R3 is -CH3.

10. Use of the compound of formula 4-1 in the preparation of compound (2E)-N-[5R,6R-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphone-6-yl]-3-(furan-3-yl)-N-methylpropyl-2-enamide or a pharmaceutically acceptable salt thereof, wherein the compound of formula 4-1 has the following structure:

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