Derivative of 14-hydroxynjrmorphinone, derivative of morphinone, derivative of morphine, methods for preparing derivative of 14-hydroxynormorphinone, derivative of morphinone, noroxymorphone

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to compounds, namely, to derivative of 14-hydrxoynormorphinone of the formula (IV) , derivative of morphinone of the formula (III) , derivative of morphine of the formula (II) wherein R1 represents (C1-C7)-alkyl; R2 represents benzyl or benzyl substituted with one or some (C1-C6)-alkoxy-groups, or benzyl substituted with one or some halogen atom. Also, invention relates to a method for synthesis of derivative of 14-hydroxynormorphinone of the formula (IV) involving interaction of compound of the formula (III) with cobalt (II) as oxidant in the presence of a weak base and air or oxygen as co-oxidant. Also, invention relates to a method for synthesis of derivative of morphinone of the formula (III) involving interaction of derivative of morphine of the formula (II) with oxidizing agent that is effective in oxidation of allyl hydroxy-groups. Mainly, invention relates to a method for synthesis of noroxymorphone. The process involves oxidation of derivative of morphinone of the formula (III) to derivative of 14-hydroxynormorphinone of the formula (IV), removal of protection from 3-position and reduction of double bond at 7,8-position in derivative of 14-hydroxynormorphinone of the formula (IV) to yield derivative of 3,14-hydroxynormorphinone of the formula (V) and hydrolysis of derivative of 3,14-hydroxynormorphinone of the formula (V) to yield noroxymorphone of the formula (VI) wherein formulae (V) and (VI) are given in the invention description. Invention provides synthesis of noroxymorphone using novel intermediate compounds.

EFFECT: improved method of synthesis.

25 cl, 1 sch, 1 ex

 

This invention relates to a method for producing derivatives of 14-hydroxymorphinone to the new synthetic direction of obtaining noroxymorphone, as well as to new intermediate compounds in the indicated direction.

Noroxymorphone is a key intermediate compound for important medicinal opioids, such as naltrexone and naloxone. The common starting material for obtaining these opioids is thebaine, from which they can be easily synthesized. However, thebaine naturally in small quantities only in the heads of poppy and opium. Because delivery of thebaine is limited, and the demand for it increases, developed many alternative approaches for obtaining derivatives of 14-hydroxymorphinan. See, for example, EP 0158476, US 5922876 and described in this description of the link.

In addition, in an attempt to satisfy the need to thebaine (receipt) Coop et al. (Tetrahedron 55 (1999), 11429-11436; WO 00/66588) recently described the oxidation method of obtaining 14-hydroxycotinine of codeinone in 51% yield and use(SLA)3as the metal oxidant in acetic acid at room temperature. According to Coop, other oxidizing conditions for metal oxidants such as Co(SLA)3under other conditions, FeCl3With(SLA)2in the combined multiple deoxidants, RUO Li4, Mn(OAc)3, Cu(OAc)2and so, was not very appropriate.

Unexpectedly, and despite the development of a Coop, it was found that upon receipt derivatives of 14-hydroxymorphinone formula IV from compounds of formula III as an effective oxidant can be used salts of cobalt (II) in the case where the interaction is carried out in the presence of a weak base, and as deoxidant use oxygen or air. Therefore, the present invention relates to a method for producing derivatives of 14-hydroxymorphinone formula IV

including the interaction of the compounds of formula III

with oxidant cobalt (II) in the presence of weak bases and air or oxygen as cookiedata;

where R1represents (1-7C)alkyl, optionally substituted by one or more chlorine atoms (such as 1,1,1-trichloroethyl), butenyl, vinyl, benzyl, phenyl or naphthyl;

R2represents benzyl or benzyl substituted by one or more (1-6C)alkoxycarbonyl, or benzyl substituted by one or more Halogens.

The method of oxidation in accordance with the present invention is an efficient method with high yield, significantly improved compared with the method described Cop et al.

Oxidant cobalt (II) in accordance with the present invention can be selected from a number of salts of cobalt (II), such as CoF2, CoCl2, CoBr2, Co(II)sulfate, With(II)nitrate, Co(II)acetate, Co(II)propionate, and the like, and mixtures thereof. The preferred oxidant in the method in accordance with this invention is From(SLA)2and the preferred deoxidant is air. The reaction mixture in accordance with this method of oxidation is a heterogeneous system; the oxidant is dissolved only in small quantities in the used organic solvent. Used a number of salts of cobalt (II) has no critical values while the system is heterogeneous, and the person skilled in the art knows how to choose them enough. Deoxidant injected into the reaction mixture, barbotine it through the solution with stirring.

Specialist in the art know, what kind of bases implies the term "weak base", however, the preferred bases are sodium acetate, potassium acetate, sodium phosphate and potassium phosphate. Most preferred is sodium acetate.

Preferably R1represents (1-7C)alkyl, most preferred is ethyl. For R2most preferred is benzyl.

The oxidation process in the accordance with the present invention is carried out in an organic solvent, well suitable for dissolving compounds of this type, preferably, (1-4C)alcohols or mixtures thereof. Preferred is ethanol.

The reaction temperature is usually above room temperature and may be selected depending on the boiling point of the employed solvent. However, the temperature does not exceed about 100°in order to maintain a sufficient amount of oxygen in solution.

In terms of (1-7C)alkyl, (1-6C)alkoxy and (1-4C)alcohols, the alkyl group is a branched or unbranched alkyl group having 1-7, 1-6 or 1-4 carbon atoms, respectively, such as methyl, ethyl, isopropyl, tert-butyl, heptyl, etc.

The compound of formula III can be appropriately obtained by methods well known in the art. Preferably, the method of obtaining the compounds of formula III includes the interaction morphine derivative of the formula II

with any oxidizing agent effective to oxidize the allylic hydroxy groups with the formation of Citigroup, resulting in connection of morphinone formula III. Preferably the oxidizing agent is sodium dichromate. Preferably R1represents ethyl, R2most preferably represents benzyl.

A new way according to what Subramaniam can be appropriately used to obtain noroxymorphone. Therefore, another aspect of this invention relates to a method of obtaining noroxymorphone, including the stage of interaction in which the connection of morphinone formula III to oxidize derived 14-hydroxymorphinone formula IV. In particular, preferred is a method, further comprising the oxidation of morphine derivative of formula II to obtain the compounds of formula III, as described above.

Especially preferred is a method of obtaining noroxymorphone, comprising the following stages:

(a) the conversion of morphine, having the formula I

by interacting with complex air californiaca formula X-C(=O)OR1where R1has the previously indicated meaning, and X represents a halogen (F, Cl, Br or I, preferably Cl),

subsequent interaction with R2-X, where X (preferably Cl) and R2have these values, obtaining morphine derivative of formula II;

(b) oxidation of morphine formula II with derivatization of morphinone formula III in accordance with the previously described manner;

(C) oxidation derived morphinone formula III with derivatization 14-hydroxymorphinone formula IV in accordance with the previously described manner;

(d) removing protection from position 3 and (simultaneously) the restoration of the double bond in position 7,proizvodnjo 14-hydroxymorphinone formula IV with derivatization 3,14-hydroxymorphinone formula V with the use of methods, well known in the art for interaction of this type, for example, using hydrogen and palladium on carbon as catalyst

(e) hydrolysis derived 3,14-hydroxymorphinone formula V with getting noroxymorphone formula VI using methods well known in the art for hydrolysis of this type, for example, with the use of sulfuric acid

In accordance with the method of obtaining noroxymorphone each new intermediate compounds of formulas II, III and IV refers to various aspects of the present invention. In particular, the intermediate compounds of formulas II, III and IV are preferred in the case when R1represents ethyl. Also preferred are the intermediate compounds of formulas II, III and IV, in which R2represents benzyl. Most preferred are the intermediate compounds of formulas II, III and IV, in which R1represents ethyl, and R2represents benzyl.

Further, the invention is illustrated by the following example.

EXAMPLE 1

The underlined numbers refer to the number of structures in scheme I (Bn = benzyl).

Complex ethyl ester (5α,6α)-3-(benzyloxy)-7,8-didehydro-4,5-epoxy-6-hydroxymorphinan-17-karbonvansty (2)

Morphine (1, 8 g) dissolved in 80 ml of toluene and the solution is dried by azeotropic distillation of water. Add sodium carbonate (15 g) and sodium bicarbonate (6 g) and the solution is again dried by azeotropic distillation. Slowly and in portions for approximately 4 hours at 78°With add ethylchloride (30 g). Completion of reaction is checked by means of TLC. The excess reagent and salts are dissolved by adding water. The layers separated, and the toluene layer washed with water. The toluene solution is evaporated to dryness, and the residue is dissolved in 70 ml of ethanol. The group of complex ethyl ester 3-carboxylic acid omelet 6 g of potassium hydroxide (dissolved in 18 ml of ethanol and 5 g of potassium carbonate in 55°C. Determine the pH (1:1 dilution with water), which is >11. To the resulting basic solution was added 5 g of benzylchloride and interaction is carried out for 4 hours at 75°C. the Product is precipitated by adding water (70 ml), filtered, washed with water and dried. The yield of product (2) is 10,1H NMR (600 MHz, CDCl3) δ of 1.29 (m, 3H), of 1.92 (m, 2H), 2,52 (s, 1H), 2,72 (m, 2H), 2,85 (m, 1H), 3,01 (m, 1H), 4,01 (m, 1H), 4,17 (m, 3H), 4,87 (d, 1H), 4,89 (d, 1H), 5,09 (d, 1H), 5,18 (d, 1H), from 5.29 (t, 1H), 5,72 (t, 1H), 6,53 (d, 1H), 6.75 in (d, 1H), 7,37 (m, 5H).

Complex ethyl ester (5α)-3-(benzyloxy)-7,8-didehydro-4,5-epoxy-6-oxopropanal-17-carboxylic acid (3)

Get solution of Jones reagent by dissolving 7.5 g of sodium dichromate&#hwn 2About 22 ml of water and 6 ml of sulfuric acid. Connection (2) (7.5 g) was dissolved in 60 ml of trichloroethylene and add 28 ml of water. the pH is brought to 5 with sulfuric acid. The mixture is refluxed slowly for one hour add the Jones reagent. The oxidation is continued for another 1.5 hours while boiling under reflux. The excess oxidant destroy using 6 ml of 2-propanol. The layers separated, the organic layer washed with 10% sodium bicarbonate solution and water and dried with sodium sulfate. The solution is evaporated to dryness and the residue is dissolved in ethanol. Output: ˜9 g of the product (3).1H NMR (200 MHz, CDCl3) δ of 1.28 (m, 3H), of 1.92 (m, 2H), 2,8 (m, 2H), 2,9 (m, 1H), 3,05 (m, 1H), was 4.02 (m, 1H), 4,19 (m, 2H), 4.72 in (s, 1H), to 5.03 (m, 1H), 5,18 (s, 2H), 6,12 (DD, 1H), to 6.57 (d, 1H), only 6.64 (m, 1H), 6,74 (d, 1H), 7,34 (m, 5H).

Complex ethyl ester (5α)-3-(benzyloxy)-7,8-didehydro-4,5-epoxy-14-hydroxy-6-oxopropanal-17-carboxylic acid (4)

A solution of the product (3) in ethanol (9 g in 135 ml) heated to 60°add 2.6 g of cobalt acetate (II), 0.5 g of sodium acetate and with vigorous stirring through a solution bubbled air. The resulting reaction mixture is subjected to TLC. Upon completion of the interaction, the solution is treated with charcoal (0.3 g) and filtered. The solution distil to the desired volume and the concentrated solution (6.3 g (4) in 53 ml of ethanol) is transferred to the next stud is Yu. 1H NMR 4 (360 MHz, CH3HE-d4) δ of 1.28 (m, 3H), of 1.55 (m, 1H), 2,52 (m, 1H), 2,74 (m, 1H), 2,92 (m, 2H), of 4.05 (m, 1H), 4,15 (m, 2H), with 4.64 (m, 1H), 4.72 in (s, 1H), around 4.85 (m, 1H), 5,1 (s, 2H), equal to 6.05 (d, 1H), and 6.6 (d, 1H), 6,76 (d, 1H), 6,91 (m, 1H), and 7.3 (m, 5H).

Complex ethyl ester (5α)-4,5-epoxy-3,14-dihydroxy-6-oxopropanal-17-carboxylic acid (5)

To the solution from the previous stage, add 6 ml of acetic acid. The product (4) restore, using hydrogen and palladium on carbon (5%) as catalyst (0.9 g)at 20°C and normal pressure. After filtration and evaporation of the ethanol of 5.4 g of crude product (5). The product is recrystallized from 2 parts (wt./about.) ethyl acetate, receiving of 4.7 g of the product (5).

(5α)-4,5-epoxy-3,14-digidroksimorfinan-6-he (noroxymorphone) (6)

The product (5) (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 is precipitated at pH 9 by dilution with water and after filtration and drying obtain 4.6 g of the crude product (6). The product is purified by dissolving it in ethanol, deposition from the specified solvent at pH 2, dilution with water, treatment with charcoal and precipitation at pH 9.1H NMR (400 MHz, DMSO-d6) δ 1,17 (m, 1H), 1,41 (m, 1H), 1,72 (m, 1H), 2,07 (m, 1H), to 2.29 (m, 1H), a 2.36 (m, 1H), 2,62 (m, 1H), 3,9 (m, 4H), and 4.68 (s, 1H), of 6.52 (d, 1H), 6,56 (d, 1H).

SCHEME 1

1. The way the floor is ing derived 14-hydroxymorphinone formula IV

including the interaction of the compounds of formula III

with oxidant cobalt (II) in the presence of weak bases and air or oxygen as deoxidant in an organic solvent at a temperature not exceeding 100°C;

where R1is a (C1-C7)alkyl; and

R2represents benzyl or benzyl substituted by one or more (C1-C6)alkoxygroup, or benzyl substituted by one or more Halogens.

2. The method according to claim 1, wherein the oxidant is(SLA)2.

3. The method according to claim 1 or 2, in which deoxidant represents oxygen.

4. The method according to claim 1 or 2, in which deoxidant represents the air.

5. The method according to claim 1 or 2, in which the weak base is a sodium acetate, potassium acetate, sodium phosphate or potassium phosphate.

6. The method according to claim 5, in which the weak base is a sodium acetate.

7. The method according to claim 1 or 2, in which R1is a (C1-C7)alkyl.

8. The method according to claim 7, in which R1represents ethyl.

9. The method according to claim 1 or 2, in which R2represents benzyl.

10. Derived 14-hydroxymorphinone formula IV,

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where R1is a (C1-C7)alkyl; and

R2represents benzyl or benzyl substituted by one or more (C1-C6)alkoxygroup, or benzyl substituted by one or more Halogens.

11. Derived 14-hydroxymorphinone of claim 10, in which R1represents ethyl.

12. Derived 14-hydroxymorphinone of claim 10 or 11, in which R2represents benzyl.

13. Derived morphinone formula III,

where R1is a (C1-C7)alkyl; and

R2represents benzyl or benzyl substituted by one or more (C1-C6)alkoxygroup, or benzyl substituted by one or more Halogens.

14. Derived morphinone indicated in paragraph 13, in which R1represents ethyl.

15. Derived morphinan according to item 13 or 14, in which R2represents benzyl.

16. The method of obtaining the compounds of formula III, including interaction morphine derivative of the formula II

with an oxidizing agent effective to oxidize the allylic hydroxyl groups with obtaining ketogroup, the result is a compound of formula III, as defined in claim 1, with R1and R2matter, ukasannyi claim 1.

17. The method according to clause 16, in which the oxidizing agent is a sodium dichromate.

18. The method according to item 16 or 17, in which R1represents ethyl.

19. The method according to item 16 or 17, in which R2represents benzyl.

20. Morphine derivative of the formula II

where R1is a (C1-C7)alkyl; and

R2represents benzyl or benzyl substituted by one or more (C1-C6)alkoxygroup, or benzyl substituted by one or more Halogens.

21. Morphine derivative according to claim 20, in which R1represents ethyl.

22. Morphine derivative according to claim 20 or 21, in which R2represents benzyl.

23. The method of producing noroxymorphone, including the stage of interaction, which derived morphinone formula III to oxidize derived 14-hydroxymorphinone formula IV, as defined in claim 1; removing protection from position 3 and the restoration of the double bond in position 7, 8 derived 14-hydroxymorphinone formula IV with derivatization 3,14-hydroxymorphinone formula V

and hydrolysis derived 3,14-hydroxymorphinone formula V with getting noroxymorphone formula VI

24. The method according to item 23, further what about including the oxidation of compounds of formula II, as specified in article 16, to obtain the derivative of morphinone having the formula III as defined in claim 1.

25. The method according to item 23, in which the conversion of morphine into noroxymorphone includes the following stages:

(a) the conversion of morphine, having the formula I

by interacting with complex air californiaca formula X-C(=O)OR1where R1has these values, X represents a halogen, with subsequent interaction with R2-X, where X and R2have these values, obtaining morphine derivative of the formula II, as defined in article 16;

(b) oxidation of morphine formula II with derivatization of morphinone formula III in accordance with the method described in article 16;

(c) oxidation derived morphinone formula III with derivatization 14-hydroxymorphinone formula IV in accordance with the method described in claim 1;

(d) removing protection from position 3 and the restoration of the double bond in position 7, 8 derived 14-hydroxymorphinone formula IV with derivatization 3,14-hydroxymorphinone formula V

(e) hydrolysis derived 3,14-hydroxymorphinone formula V with getting noroxymorphone formula VI



 

Same patents:

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to compounds, namely, to derivative of 14-hydrxoynormorphinone of the formula (IV) , derivative of morphinone of the formula (III) , derivative of morphine of the formula (II) wherein R1 represents (C1-C7)-alkyl; R2 represents benzyl or benzyl substituted with one or some (C1-C6)-alkoxy-groups, or benzyl substituted with one or some halogen atom. Also, invention relates to a method for synthesis of derivative of 14-hydroxynormorphinone of the formula (IV) involving interaction of compound of the formula (III) with cobalt (II) as oxidant in the presence of a weak base and air or oxygen as co-oxidant. Also, invention relates to a method for synthesis of derivative of morphinone of the formula (III) involving interaction of derivative of morphine of the formula (II) with oxidizing agent that is effective in oxidation of allyl hydroxy-groups. Mainly, invention relates to a method for synthesis of noroxymorphone. The process involves oxidation of derivative of morphinone of the formula (III) to derivative of 14-hydroxynormorphinone of the formula (IV), removal of protection from 3-position and reduction of double bond at 7,8-position in derivative of 14-hydroxynormorphinone of the formula (IV) to yield derivative of 3,14-hydroxynormorphinone of the formula (V) and hydrolysis of derivative of 3,14-hydroxynormorphinone of the formula (V) to yield noroxymorphone of the formula (VI) wherein formulae (V) and (VI) are given in the invention description. Invention provides synthesis of noroxymorphone using novel intermediate compounds.

EFFECT: improved method of synthesis.

25 cl, 1 sch, 1 ex

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Nalmefene prodrugs // 2495042

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14 cl, 5 ex, 1 tbl, 1 dwg

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