JPWO2022144911A5

JPWO2022144911A5 -

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Publication number: JPWO2022144911A5
Application number: JP2023533312A
Authority: JP
Publication date: 2024-03-04

Description

３－Ｏ，Ｎ－ビス－エトキシカルボニル－ノルモルフィン（２．００ｇ、４．８ｍｍｏｌ）の無水酢酸（１１．３４ｍＬ、１２０．０ｍｍｏｌ）中撹拌溶液に、ジメチルスルホキシド（３．４１ｍＬ、４８．０ｍｍｏｌ）を窒素の不活性雰囲気下で一度に添加し、得られた混合物を８０℃で１．５時間撹拌し、その時点でＨＰＬＣ分析により反応混合物中で＜２％の式（ＩＩＩ）の化合物が検出された。次いで、トリエチルアミン（６．６９ｍＬ、４８．０ｍｍｏｌ）を反応混合物に一度に添加し、８０℃で２．５時間撹拌し、その時点でＨＰＬＣ分析により反応混合物中で＜２％の式（ＩＶ）の化合物が検出された。反応混合物を室温に冷却し、水（５０ｍＬ）で希釈し、シクロペンチルメチルエーテル（３×５０ｍＬ）で抽出した。合わせた有機抽出物を飽和重炭酸ナトリウム水溶液（３×２５ｍＬ）、水（２５ｍＬ）で洗浄し、硫酸マグネシウムで乾燥させて真空中で濃縮すると、得られた表題化合物のＨＰＬＣ分析により決定して９６．２７％の純度を有する表題化合物２．０４ｇ（理論値の９３％）が残った。
実施例１３ａ：ステップ３ａ：過酢酸を用いた式（ＶＩ）の化合物の調製：
３－Ｏ，Ｎ－ビス－エトキシカルボニル－１４－ノルモルフィノン（Ｒ ^１及びＲ ^２＝エトキシカルボニルを有する化合物ＶＩ）
無水酢酸（１５ｍＬ、１２０．０ｍｍｏｌ）中の３－Ｏ，Ｎ－ビス－エトキシカルボニル－ノルモルフィンジエノールアセテート（５．０ｇ、１１．０ｍｍｏｌ）の撹拌溶液に、５０％Ｈ _２Ｏ _２水溶液（８．１０ｍＬ、１１４ｍｍｏｌ）を、不活性窒素雰囲気下で一度に添加し、得られた混合物を４０℃で４時間撹拌し、その時点でＨＰＬＣ分析により反応混合物中で＜２％の式（Ｖ）の化合物が検出された。反応混合物を室温に冷却し、水（５０ｍＬ）で希釈し、２Ｍアンモニア水溶液（７２ｍＬ）の添加により、ｐＨをゆっくりと８まで調整した。混合物をクロロホルム（３×６０ｍＬ）で抽出した。合わせた有機抽出物をブライン（７５ｍＬ）で洗浄し、硫酸マグネシウムで乾燥させて真空中で濃縮すると、得られた表題化合物のＨＰＬＣ分析により決定して９２．３１％の純度を有する表題化合物４．６０ｇ（理論値の９８％）が残った。 To a stirred solution of 3-O,N-bis-ethoxycarbonyl-normorphine (2.00 g, 4.8 mmol) in acetic anhydride (11.34 mL, 120.0 mmol) was added dimethyl sulfoxide (3.41 mL, 48.0 mmol). was added in one portion under an inert atmosphere of nitrogen and the resulting mixture was stirred at 80° C. for 1.5 h, at which point <2% of the compound of formula (III) was detected in the reaction mixture by HPLC analysis. It was done. Triethylamine (6.69 mL, 48.0 mmol) was then added to the reaction mixture in one portion and stirred at 80° C. for 2.5 h, at which point there was <2% of formula (IV) in the reaction mixture by HPLC analysis. Compound detected. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with cyclopentyl methyl ether (3 x 50 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3 x 25 mL), water (25 mL), dried over magnesium sulfate and concentrated in vacuo to yield a 96% title compound as determined by HPLC analysis. 2.04 g (93% of theory) of the title compound remained with a purity of .27%.
Example 13a: Step 3a: Preparation of compound of formula (VI) using peracetic acid:
3-O,N-bis-ethoxycarbonyl-14-normorphinone (compound VI with R ¹ and R ² =ethoxycarbonyl)
To a stirred solution of 3-O,N-bis-ethoxycarbonyl-normorphine dienol acetate (5.0 g, 11.0 mmol) in acetic anhydride (15 mL, 120.0 mmol) was added 50% aqueous H ₂ _O ( 8 .10 mL, 114 mmol) was added in one portion under an inert nitrogen atmosphere and the resulting mixture was stirred at 40 °C for 4 h, at which point <2% of formula (V) was found in the reaction mixture by HPLC analysis. Compound detected. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and the pH was slowly adjusted to 8 by addition of 2M aqueous ammonia (72 mL). The mixture was extracted with chloroform (3 x 60 mL). The combined organic extracts were washed with brine (75 mL), dried over magnesium sulfate and concentrated in vacuo to yield the title compound 4. with a purity of 92.31% as determined by HPLC analysis of the title compound. 60 g (98% of theory) remained.

Claims

A method for preparing noroxymorphone from morphine, comprising:

1) reacting morphine of formula (II) to obtain a compound of formula (III);
2a) oxidizing the compound of formula (III) with an oxidizing agent to obtain a compound of formula (IV);
2b) acylating the compound of formula (IV) with an acylating agent to obtain a compound of formula (V);
3a) subjecting the compound of formula (V) to peroxyoxidation to obtain a compound of formula (VI);
3b) reducing the compound of formula (VI) to obtain a compound of formula (VII); and 4) hydrolyzing the compound of formula (VII) to obtain noroxymorphone of formula (I). including,
In the formula, R ¹ and R ² are independently a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 1 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 1 to 20 carbon atoms. Substituted alkylaryl groups, or substituted or unsubstituted alkenyl groups having 2 to 20 carbon atoms, or substituted or unsubstituted alkoxycarbonyl groups having 1 to 20 carbon atoms in the alkyl residue, or substituted or unsubstituted An aryloxycarbonyl group, or a substituted or unsubstituted alkylaryloxycarbonyl group having 1 to 20 carbon atoms in the alkyl residue, or a cyanide group, or a cyanide group, or a group of the formula Si(R ⁴ ) ₃ (wherein the group R ⁴ is R 3 is selected from substituted or unsubstituted alkyl groups and substituted or unsubstituted aryl groups each having 1 to 6 carbon atoms, which may be the same or different, and each R ³ is selected from 1 to 20 carbon atoms in the alkyl residue. a substituted or unsubstituted alkylcarbonyl group having from 1 to 20 carbon atoms in the alkyl residue, or a substituted or unsubstituted arylcarbonyl group having from 1 to 20 carbon atoms in the alkyl residue; a substituted or unsubstituted alkenylcarbonyl group having 5 carbon atoms;
step 2a is performed using Albright-Goldman oxidation conditions;
Step 2a and step 2b can be combined into a one-pot single-step conversion,
A method in which step 3a and step 3b can be combined into a one-pot single-step conversion.

2. The method of claim 1, wherein the compound of formula (III) is oxidized to form the compound of formula (IV) using an oxidizing agent typically utilized in Albright-Goldman oxidation conditions.

3. The method of claim 2, wherein the oxidizing agent is dimethyl sulfoxide (DMSO) and an acyclic or cyclic organic acid anhydride.

The acid anhydride is acetic anhydride, benzoic anhydride, propionic anhydride, butanoic anhydride, pentanoic anhydride, hexanoic anhydride, isobutyric anhydride, isovaleric anhydride, acrylic anhydride, Methacrylic anhydride, angelic anhydride, crotonic anhydride, pivalic anhydride, trifluoroacetic anhydride, difluoroacetic anhydride, monofluoroacetic anhydride, pentafluoropropionic anhydride, chloroacetic anhydride, anhydride The group consisting of succinic acid, maleic anhydride, glutaric anhydride, adipic anhydride, 3-methylglutaric anhydride, 3,3-dimethylglutaric anhydride, hexafluoroglutaric anhydride, phthalic anhydride, homophthalic anhydride 4. A method according to any one of claims 2 and 3, selected from:

A method according to claim 1, wherein the oxidation reaction in step 2a may suitably be carried out at atmospheric pressure and at a temperature of about 0°C to 120°C.

A method according to claim 5, wherein the oxidation reaction is carried out at 55°C to 65°C.

4. The method of claim 3, wherein the acylating agent is acetic anhydride.

2. The method of claim 1, wherein the acylation in step 2b is carried out in the presence of sodium acetate or triethylamine.

The method of claim 1, wherein step 3a is carried out using preformed performic acid under substantially anhydrous conditions in glacial acetic acid at a temperature of -10°C to 100°C.

10. The method of claim 9, wherein the performic acid is prepared by treating formic acid with 30% or more hydrogen peroxide.

Step 3a is carried out with peracetic acid under substantially anhydrous conditions in glacial acetic acid at a temperature of -10°C to 100°C, said peracetic acid may be preformed or generated in situ. 2. The method of claim 1, wherein:

2. The method of claim 1, wherein the reducing agent used in step 3b) is 10% palladium on carbon.

A method according to claim 12 , wherein the reduction is carried out in glacial acetic acid at a temperature range of 25°C to 80°C.

2. The method of claim 1, wherein the hydrolysis in step 4 is carried out in the presence of an acidic hydrolysis catalyst such as sulfuric acid or a basic hydrolysis catalyst such as potassium hydroxide.

15. A method according to any one of claims 1 to 14 , wherein the process steps 2a, 2b, 3a and 3b are carried out in different pots.

16. Any one of claims 1 to 15 , wherein process steps 1, 2a, 2b, 3a, 3b and 4 are carried out in a batch reactor, or a continuous flow reactor, or a microwave reactor, or a combination thereof. The method described in.

The method according to any one of claims 1 to 16 , wherein R ¹ and R ² are ethoxycarbonyl groups and R ³ is an acetyl group.