TWI292761B - C-14 oxidation of morphine derivatives - Google Patents

Description

1292761 V. INSTRUCTIONS (1) (Please read the note on the back and fill out this page.) The present invention relates to a process for the preparation of a 14-hydroxynormorphinone derivative, and also to the preparation of dihydromorphine A new synthetic pathway for the oxymor phone and a new intermediate in this pathway. Hydroxymorpholone is a key intermediate in the manufacture of important pharmaceutical opioids such as naltrexone and naloxone. The starting material commonly used in the manufacture of this type of opium is opiate, from which substances can be easily synthesized into opioids. Since the supply of opiates is limited, but their demand continues to increase, many alternative methods have been developed to prepare 14-hydroxymorphine derivatives. See, for example, EP 〇, 158, 476, US 5, 922, 876, and references cited therein. Also, in order to eliminate the need for (preparation) of opiates, Cooper, et al. (tetrahedron 5 5 (1 9 9 9 ), 11429-11436; W 0 00/6 6 5 88) recently described a Codeinone, Ministry of Economic Affairs, Intellectual Property Office, Staff Cooperatives, Codeinone Preparation 1 4 - The oxidation of ketoconin, which uses C 〇 ( 0 A c ) 3 as a metal at room temperature The oxidant, oxidized in acetic acid, yielded 51%. Other oxidation conditions and metal oxidants, such as Co (〇Ac) 3, FeCl3, C ο ( 0 A c ) 2 and several auxiliary oxidants under other conditions, R u〇4, Μ η (〇A c) 3, C u (〇A c ) 2, etc., proved to be not very effective in the method according to Cooper. And regardless of Cooper's findings, it is surprisingly found in the process for the production of 14-hydroxynormorphones of formula IV from the compounds of formula III 'when the reaction is in the presence of a mild base And use oxygen or this paper scale to apply Chinese National Standard (CNS) A4 specification (2l〇x297 public Chu) -4- 1292761 13⁄4 9t>- A7 B7 V. Description of invention (2 Air as co-oxidant cobalt (II) Salts can be used as effective oxidizing agents. Therefore, the present invention relates to a method for preparing a 14-hydroxynormorphone derivative represented by formula IV.

IV which comprises a compound of the formula I I I

(Please read the note on the back and then fill out this page.) Economic Zou Intellectual Property Bureau employee consumption cooperative printed III and cobalt (II) oxidant, reacted in the presence of mild alkali and air or oxygen as auxiliary oxidant; 1 is a (1-7C)alkyl group which is optionally substituted with one or more of the following groups: chlorine (eg, 1,1,1-trichloroethyl), butenyl, vinyl, benzyl, Phenyl or naphthyl; and R 2 is benzyl, or benzyl substituted by one or more (1 - 6 C ) alkoxy groups, or benzyl substituted by one or more halogens. The oxidizing method of the present invention is an effective method with excellent yield, and its yield is significantly improved when compared with the method described by Cooper et al. According to the present invention, the cobalt (;[]) oxidizing agent may be in the range of cobalt (II) salts (eg, CoF2, COCI2, CoBr2, c0(II) sulfate, Cο(II) nitrate, C ο (ii) ) Cool paper, (:o(II) propionate, etc. and its mixture) The paper size is selected according to Chinese National Standard (CNS) A4 specification (210X29*7 mm) -5-1292761 Δ7 ... ·_Β7_ DESCRIPTION OF THE INVENTION (3) (Please read the note on the back side and then fill out this page.) The preferred oxidizing agent in the process of the present invention is Co (〇Ac) 2, and preferably the auxiliary oxidizing agent is air. The reaction mixture of the present oxidation method Is a heterogeneous system; the oxidant is only dissolved in a small amount in the organic solvent used. As long as the system is heterogeneous, the amount of cobalt (II) used does not need to be very strict, and those skilled in the art will know how to select it. The auxiliary oxidant is introduced into the reaction mixture by aerating it into the solution and agitating the solution. Those skilled in the art will know which type of base is a mild base, however, the preferred base is acetic acid. Sodium, potassium acetate, phosphorus Sodium and potassium phosphate. The most preferred one is sodium acetate. Suitably, 1^ is a (1-7C) alkyl group, and ethyl is preferred. In terms of R2, benzyl is the best. The oxidation method of the invention is carried out in an organic solvent suitable for dissolving the compound of the type, and the (1 - 4 C) alcohol or a mixture thereof is preferred as the solvent, especially ethanol. The economic Zou Zhici Property Bureau 8 workers consumption cooperative The printing reaction temperature is usually higher than room temperature and can be selected depending on the boiling point of the solvent used. However, the temperature may not be higher than about 100 ° C to maintain sufficient oxygen in the solution. In the terms of 7C)alkyl, (1-6C)alkoxy, and (1-4C)alcohol, the alkyl group is a side chain of each having from 1 to 6 or 1 to 4 carbon atoms. Or a side chain-free alkyl group such as methyl, ethyl, isopropyl, tert-butyl, heptyl, etc. The compound of formula III can be prepared by methods well known in the art. Suitably, the method for preparing the compound of formula III comprises applying the paper size to the Chinese National Standard (CNS) A4 specification ( 21〇X29*7 mm) -6- 1292761 A7 13⁄4 Office P_B7 V. Invention Description (" 4 Formula I I morphine derivative

(Please read the precautions on the back and fill out this page.) By reacting with an oxidizing agent which can effectively oxidize the hydroxyl group of the allyl group to form a ketone group, here, the morphinone of the formula III can be prepared. Compound. More suitably, the oxidizing agent is sodium dichromate. R i is preferably an ethyl group. R2 is preferably the benzyl group. The novel process of the present invention can be conveniently used to prepare hydroxymorpholone. Accordingly, another aspect of the invention relates to a process for the preparation of hydroxymorpholone comprising a reaction step wherein the morphinone compound of formula III. is oxidized to a 1,4-hydroxynormorphone of formula IV. derivative. In particular, the method further comprises oxidizing the morphine derivative of formula II to a compound of formula I I I as described above. More particularly, a method of preparing hydroxyhydromorphone comprises the steps of: (a) morphine having formula I

The Ministry of Economic Affairs, the Intellectual Property Office, is printed by the X-C (= 〇) ORi (where Ri is as defined above and X is halogen (F, C1, Br or I, preferably C1)) The halogenated formate is reacted to convert it, and then reacted with R2 - X (where X (preferably c 1 ) and ruler 2 are as defined above). This paper scale applies to Chinese national standards. (CNS) A4 size (210X297 mm) 1292761 Λ 13⁄4 must 1. A7 B7 5. Inventive Note () 5 to form a morphine derivative of formula II; (b) oxidize morphine of formula II according to the aforementioned method to form a morphinone derivative of formula III; (c) oxidizing a morphinone derivative of the formula 根据I丨 according to the aforementioned method to form a 1,4-hydroxynormorphone derivative of the formula IV; (d) The monohydroxynormorphone derivative is deprotected at the 3-position and (simultaneously) reduces the double bond at the 7,8-position to form a 3,14-hydroxynormorphone derivative of formula V, which is Using methods well known in the art for such reactions, such as using hydrogen and palladium-carbon as catalysts, Read the notes on the back and fill out this page.)

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperative (e) Hydrolysis of the 3,1 4-hydroxynormorphone derivative of Formula V to the hydroxydihydromorphone of Formula VI, which is well known in the art. For such hydrolysis methods (eg, using sulfuric acid),

In the process for the preparation of hydroxyhydromorphone, the novel intermediates of the formulae I I , I I I and IV each form part of the invention. An intermediate of the formula I I, I I I and I V wherein R i is ethyl is particularly suitable. The intermediates of formulas II, III and I v in which R 2 is a benzyl group are also applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) -8 - 1292761 a7 B7 __. () 6 good. Most preferred are intermediates of formula 1 1 , I I I and I V wherein rule 2 is ethyl and R 2 is benzyl. (Please read the precautions on the back and then fill out this page.) The present invention is further illustrated by the following examples. Example 1 The number with the underlined line refers to the construction number (Β η = benzyl) in Scheme I. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Cooperatives (5α, 6α) - 3 - (Ye chloro) ~ 7 ' 8 - didehydro- 4, 5- - ring-based 6 - Zen morphine - 17 - Ethyl Carboxylate (2__) Morphine (1,8 g) was dissolved in 80 ml of toluene and the solution was dried by azeotropic distillation of water. Sodium carbonate (15 g) and sodium hydrogencarbonate (6 g) were added, and the solution was again dried by azeotropic distillation. Ethyl chloroformate (30 g) was slowly and partially added thereto at 7 8 ° C over a period of about 4 hours. Check if the reaction is complete with T L C. Excess reagents and salts are dissolved by the addition of water. The organic and aqueous layers were separated and the toluene layer was washed with water. The toluene solution was evaporated to dryness and the residue was dissolved in 70 mL of ethanol. The 3-carboxylic acid ethyl ester group was saponified by 6 g of potassium hydroxide (dissolved in 18 ml of ethanol) and 5 g of potassium carbonate at 5 5 °C. Check pH 値 (diluted 1: 1 in water) and its p Η system is greater than 11. 5 g of benzyl chloride was added to the alkaline solution, and the reaction was carried out at 75 ° C for 4 hours. Water (70 ml) was added to precipitate the product, which was filtered, washed with water and dried. The yield of the product (1) was 10 g. This paper scale applies to China National Standard Rate (CNS) A4 specification (210X297 mm) -9- 1292761 V. Invention description (7) 1 H NMR (600MHz, CDC13) δ 1·29 (ιώ, 3Η), 1.92 ( m,2H), 2 · 5 2 ( s,1 Η ),2 · 7 2 ( m,2 Η ), 2.85(m,lH),3.〇l(m,lH), 4- 01(m, lH), 4.17( m,3H), 4.87 (d,lH),4.89(d,lH), 5- 09(d,lH), 5.18(d,lH), 5.29(t,lH),5·72 (ΐ, 1Η), 6.53(d,lH), 6.75(d,lH), 7 · 3 7 ( m,5 H ). One (._5·.α) — 3 — (Benzyl) a 7 , 8 — 2 degassing 4 , · 5 — Ring — gas — 6 — mercaptomorphin-1 7 —carboxy — 7, ester (1) A Jones (] 〇nes ) reagent solution was prepared by dissolving 7.5 g of sodium dichromate·2 Η 20 in 2 2 ml of water and 6 ml of sulfuric acid. The compound (U (7.5 g) was dissolved in 60 ml of trichloroethylene and 28 ml of water was added. The p Η値 was adjusted to 5 with sulfuric acid. The mixture was heated under reflux for a period of 1 hour. The Jones reagent was slowly added thereto, and the oxidation reaction was continued for 1.5 hours under reflux. The excess oxidant was destroyed with 6 ml of 2-propanol. The phases were separated, and the organic phase was washed with 1% by weight of sodium hydrogencarbonate and water. The layers were dried over sodium sulphate. The solution was evaporated to dryness and the residue was dissolved in ethanol. Yield: </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> ( m, 2H), the paper scale applies to China National Standard Rate (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page). Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives - 10- 1292761 v ^ Δ7 Private l A7 _ _ B7_ V. Description of invention (Q) ο 2 · 8 ( m,2 Η ) , 2 · 9 ( m,1 Η ), 3.05( m,lH) ,4.02( m , lH), 4.19( m,2H) , 4.72(s,lH), 5.03( m,1H) , 5.18(s,2H), 6.12(dd,lH) ,6.57(d,lH), 6.64( m, lH) , 6.74(d,lH), 7 · 3 4 ( n,5 H ) (5α) — 3 —(benzyloxy)-7,8 —didehydro-4,5—epoxy—1 4 Hydroxy-6-ketomorphinan-1-7-carboxylic acid ethyl ester (1) The product in ethanol (solution D (9 g, dissolved in 135 ml) was heated to 60 ° C, added 2 6 g of cobalt (II) acetate, and 0.5 g of sodium acetate, and the air was ventilated under vigorous stirring. The reaction was followed by TLC. After the reaction was completed, the solution was treated with charcoal (3 g). Filtration. Distill the solution and transfer the concentrated solution (6.3 g (U, dissolved in 53 ml of ethanol) to the next step] H NMR of 4 (360 MHz, CH3〇H-d4)5 1.28(m,3H), 1.55(m,lH), 2.52(m,lH), 2.74(m,lH), 2.92( m,2H) ,4.05(m,lH), 4.15( m,2H) ,4.64 ( m,lH), 4.72(s,lH) ,4.85( m,lH), the paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (please read the notes on the back and fill in the form) page)

, 1T Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -11 - 1292761 V. Invention description (9) 5.1 (s, 2H), 6.05 (d, lH), 6.6 (d, lH), 6.76 (d, lH) , 6 · 9 1 ( m,1 Η ) , 7 · 3 ( m,5 Η ). (5α) - 4,5-Epoxy- 3,14-II zen 6-ketomorphinan- 1 7-carboxylic acid ethyl ester (5^) 6 ml of acetic acid was added to the solution of the previous step. The product (1) was reduced with hydrogen at 20 ° C under normal pressure, and palladium-carbon (5%) was used as a catalyst. After filtering and evaporating the ethanol, 5.4 g of the crude product (5) was obtained. The product was recrystallized from 2 parts (w / v) of ethyl acetate to obtain 4 · 7 g of product (and J. (5α) - 4,5 - a certain 3,14-dihydroxymorphinane a 6-keto (hypoxanthone) (6_) The product (U (4 · 7 g) was dissolved in 28 ml of water and 5 · 6 ml of sulfuric acid and refluxed for about 24 hours. The product was in ρ Η = 9 , precipitated by dilution with water, filtered and dried to obtain 4 · 6 g of crude product (D. The product is purified by dissolving in ethanol, under Ρ Η = 2, from this Precipitated in a solvent, dissolved in water, treated with charcoal, and precipitated at ρ Η = 9. 1 H NMR (400 MHz, DMS 〇-d6) 5 1.17 (m, lH), 1.41 (m) , lH), 1.72 (m, lH), 2.07 ( m, lH), 2.29 ( m, iH), 2.36 ( m, lH), this paper scale applies to Chinese national standards (CNS > A4 specifications (210X 297 public (please Read the precautions on the back and fill out this page. Τ 3⁄4 齐印和曰达时 苟 R Industrial Consumer Cooperative Print -12- 1292761 Δ7 A 7 Β7 5, invention description (&amp; 2.62 (m, lH), 3.9 (m, 4H), 4.68(s lH), 6.52 (d, lH), 6.56 (d, lH) Scheme 1 billion Ministry of Economic Affairs Chi Chi Property Office employees consumer cooperatives printed

(Please read the notes on the back and fill out this page.) The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210Χ 297 mm) -13-

Claims (1)

129276 A8 B8 C8 D8 l/\ tL· Acupoint, Patent Application Scope 2 6: No. 9 1 1 1 5230 Patent Application Chinese Patent Application Range ^Replacement of the Republic of China on September 15, 1995 1 4 monohydroxynormorphone derivatives please read the preparation method IV face note I page R2o ^ III Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative printed it containing the compound 'ncoa of formula III' and cobalt(II) oxidant in the presence of a mild base and air or oxygen as a co-oxidant; The cobalt (II) oxidant is a cobalt selected from the group consisting of CoF2, CoCl2, CoBr2, Co(II) sulfate, Co(II) nitrate, Co(II) acetate, C 〇 (II) propionate, and mixtures thereof (II) a salt, wherein Ri is a (1 C to 7 C) group; and R 2 is a benzyl group or a benzyl group substituted by one or more (1 C - 6 C) alkoxy groups, or The benzyl group is substituted by one or more halogens; and wherein the reaction temperature is usually higher than room temperature, and may be selected depending on the boiling point of the solvent used, but not higher than about 1 〇〇 °c. 2. The method of claim 1, wherein the oxidant is a Chinese standard (CNS) A4 specification (210X297 mm) for the paper scale. 1292761 A8 B8 C8 D8 VI. Patent application scope Co (〇A c ) 2 〇3. The method of claim 1 or 2, wherein the auxiliary oxidant is oxygen. 4. The method of claim 1 or 2, wherein the mild base is sodium acetate, potassium acetate, sodium phosphate or potassium phosphate. 5. The method of claim 4, wherein the mild base is sodium acetate. 6. The method of claim 1, wherein r 1 is an ethyl group. 7. The method of claim 1 or 2, wherein R 2 is a node. 8 - A morphinone derivative represented by the formula I I ί in the first item of the patent application. 9. A morphinone derivative according to item 8 of the patent application, wherein r i is an ethyl group. 1 吗 A morphinone derivative according to claim 8 or 9, wherein R 2 is a benzyl group. Printed by the Intellectual Property Office of the Ministry of Economic Affairs and the Consumer Cooperatives 1 1 · A method for preparing a compound represented by the formula I I I, which comprises The morphine derivative of the formula II is reactively contacted with an oxidizing agent capable of effectively oxidizing an allyl group to form a ketone group, and can be prepared as a Chinese standard (CNS) A4 specification (210X297) Thin ^ι ' -2- 1292761 8 88 8 ABCD Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, Printing VI, Applying for a Patent Scope, applying for a patent of the formula III, and R 1 and R 2 are for application. The scope of the patent scope is defined in Item 1. 1 2 · The method of claim 11, wherein the oxidizing agent is sodium dichromate. 1 3 · If the patent application scope is item 11 or item 12 The method, wherein Ri is ethyl and r2 is a benzyl 〇1 4 · a morphine derivative as shown in Formula II in claim 1 of the patent application. 1 5 · morphine derivative as claimed in claim 14 And R! is an ethyl group. 1 6 · A morphine derivative according to claim 14 or 15 of the patent application, wherein R 2 is a benzyl group. 1 7 · a method for preparing a hydroxydihydromorphone , which comprises a reaction step 'where morphine of formula III is shown The derivative is oxidized to a 1,4-hydroxynormorphone derivative as shown in Formula IV listed in the first paragraph of the patent application. 1 8 · The method of claim 17 is further included The compound of the formula II as defined in the scope of claim 1 is oxidized to form a morphinone I derivative of the formula III as defined in the first paragraph of the patent application. The method of claim 7, wherein the morphine is converted to hydroxyhydromorphone, which comprises the following steps: (a) the morphine of formula I is first to be smothered, and the paper size is applicable to China National Standard (CNS) A4. Specifications (210X297 mm) -3- 1292761 A8 B8 C8 D8 VI. Patent application scope 'NCH, HO ^ I is reacted with a haloformate as shown by the formula X - C ( = 〇) 〇 Ri (where Ri is as defined previously, and X is a halogen), followed by a ruler x x (where X and R 2 The reaction is converted to form a morphine derivative of formula II as defined in claim 11 of the patent application; (b) according to the method set forth in item 11 of the scope of the patent application Oxidation of morphine to form a morphinone derivative of formula III; (c) oxidizing the morphinone derivative of formula III according to the method set forth in claim 1 of the patent application to form 1,4-hydroxynormorphone of formula IV a derivative; (d) deprotecting the 3~ position of the 1,4-hydroxynormorphone derivative of formula IV, and reducing the double bond at the 7,8-position to form a formula V of 3,1 4 Hydroxynormorphone derivatives, please read the first note I page ordered by the Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperatives V; (e) hydrolyzing the 3,14-hydroxyl-morpholone derivative of formula V to the hydroxydihydromorphone of formula VI, 0 VI. This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -4 -