Method of preparing 14-hydroxymorphinane derivatives
专利摘要:
N-substituted-14-hydroxy-3-substituted-morphinan derivatives have been found to possess potent narcotic agonist or antagonist activity. In particular, the compound N-Cyclobutylmethyl-3,14-dihydroxymorpinan has been found to posess potent agonist/antagonist activity as a non-narcotic analgesic. An improved total snythesis of these compounds is described herein from the starting material 2-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline. A preferred feature of the process involves borane reduction of 2-cyclobutylcarbonyl-9,10-dihydroxy-1-(p-methoxybenzyl)perhydroisoquin oline (Va) to provide the corresponding cyclobutylmethyl derivative complexed with borane which is converted directly to N-cyclobutylmethyl-14 beta -hydroxy-3-methoxymorphinan (LVa) by treating with acid. 公开号:SU727140A3 申请号:SU772462807 申请日:1977-03-23 公开日:1980-04-05 发明作者:Монкович Иво;Бачанд Кэрол;Вонг Хенри;Лим Гари 申请人:Бристоль-Мейерз Компани (Фирма); IPC主号:
专利说明:
The invention relates to a new method for producing 14-hydroxymorphinan derivatives of the general formula (I) where r R '* is cyclobutyl or cyclopropyl; - hydrogen Or lower alkyl having valuable pharmacological properties. A known 12-stage method for producing 11-cyclopropylmethyl-14 rg-hydroxy-15 -3-methoxymorphinan, N-cyclobutylmethyl-14 | L-hydroxy-3-methoxymorphinan, N-cyclopropylmethyl-3.14 p> -dihydroxymorphinan and 1H -cyclobutylmethyl-3,14p-dihydroxymorphinan, including treatment with 7-methoxy-3,4-dihydro-1 (2H) -naphthalenone 1,4-dibromobutane and tert-amyl alcohol in the presence of a strong base to form spiroketone, which is treated with a solution of acetonitrile in the presence of n-butyllithium to give 1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2,2-tetramethylene-1-naphthal enacetonitrile, then the 1-nitrile group is converted into a 1- (2-aminoethyl) group, after which the amino derivative of 9-hexahydro-6-methoxyphenanthrene is obtained by acid hydrolysis, which is converted to 14-hydroxymorphinan derivatives through the stages of epoxidation and acylation [1]. The purpose of the invention is the expansion of the raw material base for the synthesis of morphinan derivatives and simplification of the process. The goal is achieved by the method consisting in the fact that the compound of General formula (II) where R is cyclobutyl or cyclopropyl, R 1 is lower alkyl., is reduced with boron in an inert organic solvent at .50-115 ° C and the resulting boron complex with the compound of the general formula (III) where R is cyclobutyl or cyclopropyl, and R 1 is lower alkyl, treated with phosphoric, orthophosphoric or pyrophosphoric, preferably aqueous, acid, preferably anhydrous phosphoric acid and phosphorus pentoxide, to obtain a compound of general formula (IY) where R, R have the above meanings, and, if desired, the compound is converted by cleaving the R'O - ether group in the compound of general formula (V) About where R is cyclobutyl or cyclopropyl, treatment with N3802115 To restore the compound of the general formula (II), boron is preferably used in the form of boron or boron dimethyl sulfide generated as a result of the reaction of sodium borohydride and boron trifluoride or sodium borohydride and tetrahydrofuran boron trifluoride, or sodium borohydride and boron trifluoride alkyl etherate. Boron is preferably used in a ratio of 1 mol of the compound of formula (II) to 1.33-2.0 mol of boron. Example 1. 2-Cyclobutylcarbonyl-1- (p-methoxybenzyl) -1,2,3,4,5,6,7, 8-octahydroisoquinoline. Triethylamine (22.2 g, 0.22 mol) is slowly added to 1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydro-Isoquinoline hydrochloride (29.4 g, 0.1 mol) dissolved in 200 ml of methylene chloride, with stirring and cooling in an ice bath. Then, cyclobutyl carbonyl chloride (13 g, 0.0107 mol) in 30 ml of methylene chloride was added dropwise to the mixture with stirring, while maintaining the temperature at 0 - (+ 5) ° C. After stirring the reaction mixture for 1 h at room temperature, add 100 ml of water, the mixture is oxidized by the addition of 50 ml of 100% sulfuric acid and the methylene chloride layer is separated. If desired, a methylene chloride solution containing the desired compound can be used directly for the next step, or it can be concentrated to give an oil that solidifies upon standing. After recrystallization of a sample of such a solid material from acetone, a crystalline product is obtained, mp. 89-91 ° C. Various organic tertiary amines, commonly used as proton acceptors in acylation reactions, can be replaced with triethylamine in the above reaction. Such amines are three (lower) alkylamines, for example trimethylamine, triethylamine and the like, pyridine, dimethylaylin, N-methylpiperidine, etc. Example 2. 2-Cyclobutylcarbonyl-9, 10-Epoxy-1- (p-methoxybenzyl) -perhydroisoquinoline. Method A. Oxidation of peracetic acid. To a solution of 2-cyclobutylcarbonyl-1- (p-methoxybenzyl) -1,2,3,4,5,6,7, 8-octahydroisoquinoline (0.1 mol) in 230 ml of methylene chloride add peracetic acid (40% ., 23.8 g, 0.12 mol) at such a rate that the temperature is maintained at 30–35 ° C. After stirring the resulting solution at room temperature for 1 h, 200 ml of water are added, and the excess of peracetic acid is destroyed by 100 ml of a 10% sodium bisulfite solution. The methylene chloride phase is separated and concentrated under reduced pressure to give an oily precipitate consisting, according to gas chromatography, of isomeric target epoxides in a ratio of 23:78. The two epoxides can be separated, if desired, on a chromatographic column using alumina or silica (manifestation with diethyl ether). The melting point of the trans epoxide is 82-84 ° C, and the cis epoxide is 82-84 ° C, the configuration is determined relative to the p-methoxybenzyl group and the oxirane group. Method B. Oxidation of pertrifluoroacetic acid. To a solution of 2-cyclobutylcarbonyl-1 - (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (0.05 mol) in 125 ml of methylene chloride was added sodium carbonate (20. g, 0.19 mol) and the mixture is cooled to 0 ° C. A solution of perftrifluoroacetic acid is prepared by mixing trifluoroacetic anhydride (16.6 g, 0.077 mol) and 90% hydrogen peroxide (2.94 g, 0.077 mol) in 35 mol of methylene chloride at 0 ° C. The peracid solution is added dropwise to the reaction mixture at such a rate that the reaction temperature is maintained at 0 to 5’C. Upon completion of the dropping, the reaction mass is stirred for 0.5 h at a temperature of 0 to 5 ° C, and the excess peracid is destroyed with a 10% sodium bisulfite solution with stirring until the evolution of carbon dioxide ceases. The methylene chloride phase is washed with water, dried with anhydrous sodium sulfate and concentrated under reduced pressure to an oily precipitate consisting, according to gas chromatography, of isomeric epoxides with a trans: cis ratio of about 35:65. Example 3. 2-Cyclobutylcarbonyl-9,10-dihydroxy-1 - (p-methoxybenzyl) -perhydroisoquinoline. The mixture of isomeric epoxides of Example 2 by peracetic acid oxidation was dissolved in 300 ml of acetone and cooled to 0 ° C. To this solution, first 30 ml of water are poured, and then 30 mp concentrated sulfuric acid at such a rate that the temperature is maintained below 25 ° C. After stirring the reaction mixture for 1.5 hours at 25 ° C., 150 ml of water and 300 ml of toluene are added. The resulting two-phase mixture was made alkaline with a sodium hydroxide solution and the toluene layer was separated and concentrated to an oily residue. This oil, mixed with 300 ml of cyclohexane, gives a suspension of a white solid, which is collected on a filter. This substance mainly includes the target trans-diol, which, as shown by gas chromatography, contains the isomeric trans-diol. The yield of the trans-diol is determined by the starting amine and is 75%. The cyclohexane filtrate is treated with sulfuric acid to obtain trans-40 diol in 10% yield. Further purification of the white solid is carried out by crystallization from acetonitrile to obtain a compound with so pl. 145-147 ^ 0. Instead of the concentrated sulfuric acid used above, other acids such as nitric, hydrochloric, hydrobromic or strong organic acids can be used, for example, alkyl sulfonic acid, trifluoroacetic acid. Example 4. 2-Cyclobutylmethyl-9,10-dihydroxy-1- (p-methoxybenzyl) perhydroisoquinoline. To a solution of 2-cyclobutylcarbonyl-9,1O-dihydroxy-1- (p-methoxybenzyl) perhydroisoquinoline (3 g, 0.08 mol) in 300 ml of tetrahydrofuran is added boron dimethyl sulfide in a pure solution (14 ml, 0.14 mol) with using a needle syringe in a nitrogen atmosphere. The resulting mixture was heated for 2 hours, and 60 butyl methyl amine can be used directly for the next reaction, or it can be hydrolyzed with aqueous acid, for example, hydrochloric acid, to obtain the target diol of example .3, so pl. 120-122 ^ 0. The restoration of the amido function of the trans-diol of Example 3 with the corresponding boron compounds also gives the target product, Pr and measure 5. Cyclobutylmethyl-14-hydroxy-3-methoxymorphinan. Method A. Cyclization by a boron complex. To the residue of the boron complex from the boron reduction reaction (0.08 mol) of Example 4, 320 g of anhydrous phosphoric acid (obtained from 85% phosphoric acid and phosphorus pentoxide) and 50 g of phosphorus pentoxide are added. The mixture was stirred at room temperature for 0.5 h, and then at 70–75 ° C for 4 h. The reaction mass was diluted with 200 mp water and then poured into a mixture of 600 ml of concentrated ammonium hydroxide and 1 l of ice fragments. The mixture was extracted with 400 ml of heptane and the heptane extract was dried with sodium sulfate. The concentration of the dried heptane extract gives 23.1 g (85% yield) of the expected product in the form of an oil. This oil is dissolved in acetone and treated with anhydrous hydrogen chloride to obtain a crystalline hydrochloride salt of the target product, so pl. 248-250 b SS method B. Cyclization of the intake complex of any type. 1.5 g of 2-cyclobutylmethyl-9,10-dihydroxy-1- (p-methoxybenzyl) -ergy other ochinol and 16.0 g of anhydrous phosphoric acid are stirred at 80-85 ° C for 23 hours. The reaction mixture diluted with 20 ml of water and poured into a mixture of ice and 35 ml of concentrated ammonium hydroxide. The mixture was extracted with 40 ml of methylene chloride and the methylene chloride extract was concentrated to obtain 1.15 g of an oil. According to gas chromatograph This oil contains 57% N-cyclobutylmethyl-14 [ό-hydroxy-3-methoxymorphine —, 27% dehydrogenated by-product and 15% non-cyclized starting material. Example 6. Levorotatory N-cyclobutylmethyl-G4 β-hydroxy-3-methoxymorphinan. The replacement in example 1 of the dextrorotatory 1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline hydrochloride with racemic and sequential use of the methods of examples 2-5 gives the target levorotatory product. The operations described in examples and 5 are as follows. thereby concentrated under reduced pressure to remove the solvent. , The resulting boron complex cyclo7 To a solution of levorotatory 2-cyclobutylcarbonyl-9,10-dihydroxy-2- (p-methoxybenzyl) - perga drois oxy nolin (10 g, 0-, 0267 mol) in 100 ml of toluene add a pure solution of boron dimethyl sulfide (6 ml, 0.057 mol ) using a needle syringe under nitrogen pressure. The resulting solution was heated and cooled for 3 hours, concentrated under reduced pressure until approximately 40 ml of solvent was removed, and the levorotatory cyclobutylmethylamine boron complex was used directly in the cyclization reaction. The levorotatory cyclobutylmethylamine is cyclized by adding the above toluene complex in parts to 200 g of anhydrous phosphoric acid and 35 g of phosphorus pentoxide with stirring, while maintaining the temperature at 0-25 ° C. After the addition is complete, the mixture is heated and stirred for 5 hours at 70 ° C, and then 400 ml of concentrated ammonium hydroxide with a large amount of ice are poured into the mixture to maintain the temperature at 25 ° C. The mixture is then extracted with toluene, the extract is washed with water, and then concentrated under reduced pressure to obtain levorotatory M-cyclobutylmethyl-14 [5-hydroxy-3-methoxymorphinan. The oily base is converted to sulfate by treatment with sulfuric acid to obtain 7.2 g (61% yield) of levorotatory N-cyclobutylmethyl-! 4β-hydroxy-3-methoxyforminan, mp 232-237 ° C, [<ί · 1 L Ό -55,4 C ( 0.56, CH ^ OH). Example 7. 2-Cyclopropyl carbonyl-1- (p-methoxybeneyl) -1,2,3, 4,5,6,7,8-octahydroisoquinoline. This compound is prepared according to Example 1, replacing cyclobutylcarbonyl chloride with an equimolar amount of cyclopropylcarbonyl chloride. Example 8. 2-Cyclopropylcarbonyl-9, 10-Epoxy-1- (p-methoxybenzyl) -perhydroisoquinoline. This compound is obtained as in example 2, but the starting racemic compound used in this example is replaced with an equimolar amount of the target product of example 7. Example 9. 2-Cyclopropylcarbonyl-9,10-dihydroxy-1- (p-methoxybenzyl) perhydroisoquinoline. Replacing in example 3 the racemic starting compounds used therein with an equimolar amount of the target product of example 8 gives the compound indicated in the title of example. 60 Example 10. 2-Cyclopropylmethyl-9,10-dihydroxy- (p-methoxybenzyl) perhydroisoquinoline. This compound was prepared as in Example 4, but the racemic starting material 65 used in Example 4 was replaced with an equimolar amount of the target compound of Example 9. Example 11. N-Cyclopropylmethyl l-1 4 | 3-hydroxy-3-methoxy morphine an. By replacing the racemic starting compound in method B of Example 5 with an equimolar amount of the expected product of Example 10, the title compound <q Example 12 is obtained. N-Cyclobutylmethyl -3.14β-hydroxymorphinan. A mixture of N-cyclobutylmethyl-! 4β-hydroxy-3-methoxymorphinan (1.0 g, 2.58 mol) and 10 ml of 48% hydrobromic acid is heated and cooled15 is given in a nitrogen atmosphere for min. After cooling, the reaction mixture was diluted with water and made basic with aqueous ammonium hydroxide. . The aqueous basic mixture is extracted with • 20 several portions of chloroform, and the combined chloroform extracts are dried with anhydrous sodium sulfate. After evaporation of the solvent, the residue - oil (730 mg) was extracted with dry ether and the resulting solution was filtered through diatomic charcoal. The filtrate is treated with a saturated solution of hydrogen chloride in dry ether. The hydrochloride salt thus obtained was collected and crystallized from methanol-acetone to give 565 mg (56.5%) of N-cyclobutylmethyl-Z, 14-hydroxymorphinan hydrochloride, so pl. 272-274 ° C. NMR and IR spectra 5 are consistent with the structure. Found,%: C 68.10; H, 8.14; .N 3.80. C 21 H 29 N0 2. HCe-i / 2 CH-, OH. Calculated,%: C 67.97, H 8.49; N, 3.49. Oxidation of the -filtered dry ether solution of the aforementioned with certain acids gives various pharmaceutically available salts 45 with an acid supplement. The 3-methoxy ester function of N-cyclobutylmethyl-14-β-hydroxy-3-methoxymorphinan can also be cleaved by treatment with 50 ether ester cleaving agents such as NaSCjH ^, boron tribromide or pyridine hydrochloride to obtain the desired dimethylated product.
权利要求:
Claims (6) [1] This invention relates to a new process for the preparation of 14-hydroxymorphinan derivatives of the general formula (I) N-CHQ-B where R is cyclobutyl or cyclopropyl R is hydrogen or lower alkyl with valuable pharmacological properties. A 12-step process is known for the preparation of H-cyclogropylmethyl-14 pr-hydrox-3-methoxymorphinan, N-cyclobutylmethyl-14 | b-hydroxy-3-methoxymorphinan N 14p-dihydroximorphinan, in. Accurate treatment of 7-methoxy-3,4-dihydro-1 (2H) naphthalenone with 1,4-dibromobutane and tert-amyl alcohol in the presence of a STRONG base to form a spiroketone, which is treated with an acetonitrile solution in the presence of n- butyl lithium to obtain 1-hydroxy-7-methoxy-1, 2,3,4-tetrahydro-2,2-tetramethylene-1-naphthal then the 1-nitrile group is converted into a 1- (2-aminoethyl) group, after which the amino derivative of 9-hexahydro-6-methoxyphenanthrene is obtained by acid hydrolysis, which through stages, epoxidation and acylation is converted into 14-hydroxymorphinan derivatives. expansion of the resource base for the synthesis of morphinan derivatives and simplification of the process. The objective is achieved by the method in which the compound of the general formula (II) where R is cyclobutyl or cyclopropyl. lower alkyl, is reduced with boron in an inert organic solvent at .50-115 ° C and the resulting boron complex with a compound of the general formula (III),, LlN-CHj-B OT / LoH where R is cyclobutyl or cyclopropyl and R is lower alkyl, treated with phosphoric, rtofesphasic or pyrophosphoric, preferably aqueous, acid, preferably anhydrous phosphoric acid and phosphorus pentoxide to obtain the compound of general formula (IV) where R, R have the above values, and if desired, convert the resulting compound by splitting the RO-ester group in conjunction where R is cyclobutyl or cyclopropyl, by treatment with NaSC2Hg-, hydrobromic acid, boron tribromide or hydrochloric pyridine, followed by isolation of the target compound by known methods. Boron is preferably used in the form of dimethyl sulfate boron or boron generated by the reaction of sodium borohydride and trofluoride boron or sodium borohydride and bortrefluoride tetrahydrofuran comalum: eca, or boron hydride sodium alkyl ether of trifluoride hydrogen sulfide. Boron is preferably used in a ratio of 1 mol of the compound of formula (II) to 1.33-2.0 mol of boron. Example 1. 2-Cyclobutylcarbonyl-1- (p-methoxybenzyl) -1,2,3,4,5,6 8-octahydroisoquinoline. Triethylamine (22.2 g, 0.22 mol) is slowly added to 1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline hydrochloride (29.4 0.1 mol ), dissolved in 200 ml of methylene chloride, with stirring and cooling in an ice bath. Then, cyclobutylcarboni chloride (13 g, 0.0107 mol) in 30 ml of methylene chloride is added dropwise to the mixture in 13 ml of methylene chloride, while maintaining the temperature at 0 - (+ 5) С. After stirring the reaction mixture for 1 h at room temperature, 100 ml of water are added, the mixture is oxidized by the addition of 50 ml of 100% sulfuric acid and the methylene chloride layer is separated. If desired, the methylene chloride solution containing the desired compound can be used directly for the next step or it can be concentrated and an oil is obtained which cures upon settling. After recrystallization of a sample of such solid material from acetone, a crystalline product is obtained, mp. 89-91 ° C. Various organic tertiary amines, commonly used as proton acceptors in acylation reactions, can be replaced by triethylamine in the above reaction. Such amines are three (lower) -alkylamines, for example, trimethylamine, triethylamine and the like, pyridine, dimethylaniline, N-methylpiperidine, etc. Example 2. 2-Cyclobutylcarbonyl-9, 10 epoxy-1- (p-methoxybenzyl) -perhydroisochiVOLINA. Method A. Oxidation with peracetic acid. To a solution of 2-cyclobutylcarbonyl-1- (p-methoxybenzyl) -1,2,3,4,5,6,7, 8-octahydroisoquinoline (0.1 mol) in 230 ml of methylene chloride is added peracetic acid (40% - , 23.8 g, 0.12 mol) at such a rate that the temperature was maintained at 30-35 ° C. After stirring the resulting solution at room temperature for 1 h, 200 ml of water are added, and an excess of peracetic acid is destroyed by 100 ml of a 10% sodium bisulfite solution. The methylene chloride phase is separated and concentrated under reduced pressure, which gives an oily residue composed according to gas chromatography from isomeric target epoxides in a ratio of 23:78. Two epoxides can be separated, if desired, on a chromatographic column using alumina or silica (development with diethyl ether). The melting point of the epoxide is trans configuration 82-84 ° C, and the epoxide cis configuration 82-84 ° C, the configuration is determined relative to the p-methoxybenzyl group and the oxirane group. Method B. Oxidation with pertrifluoroacetic acid. a solution of 2-cyclobutylcarbonyl-1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (0.05 mol) in 125 ml of methylene chloride is added with sodium carbonate (, 0, 19 mol) and the mixture is cooled to 0 ° C. A solution of pertrifluoroacetic acid is made by mixing trifluoroacetic anhydride (16.6 g, 0.077 mol) and 90% hydrogen peroxide (2.94 g, 0.077 mol) in 35 mol of methylene chloride at 0 ° C. The peracid solution is added dropwise to the reaction mixture at such a rate that the reaction temperature is maintained from 0 to. After the completion of the dropping, the reaction mass is stirred for 0.5 hours at a temperature from 0 to, and the excess peracid is destroyed with a 10% solution of sodium bisulfite with stirring until carbon dioxide evolution ceases. The methylene chloride phase is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to an oily residue consisting of isomeric epoxides according to gas chromatography with a trans ratio of cis of about 35:65. Example 3. 2-Cyclobutylcarbonyl-9, 10-dihydroxy-1 (p-methoxyb zyl) -perhydroisoquinoline. The mixture of isomeric epoxides, Example 2 of oxidation with peracetic acid, is dissolved in 300 ml of acetone and cooled to. 30 ml of water are poured into this solution first, and then 30 MP of concentrated sulfuric acid at such a rate that the temperature is kept lower. After stirring the reaction mixture for 1.5 hours at 25 ° C, 150 ml of water and 300 ml of toluene are added. The resulting biphasic mixture is alkalinized with sodium hydroxide solution and the toluene layer is separated and concentrated to an oily residue. This oil, mixed with 300 ml of cyclohexane, gives a suspension of white solid, which is collected on a filter. This substance mainly includes the target trans-diol, which, as gas chromatography shows, isomeric trans-diol. The trans diol run is determined on the starting amine and is 75%. The cyclohexane filtrate is treated with sulfuric acid to produce a trans diol in 10% yield. Further purification of the white solid is carried out by crystallization from acetonitrile to obtain the compound with m.p. 145-147 ° C. Instead of the concentrated sulfuric acid used above, other acids can be used, such as nitrous, hydrochloric, hydrobromic or strong organic acids, for example alkylsulfonic acid, trifrtic acetic acid. Example 4. 2-Cyclobutylmethyl-9,10-dihydroxy-1- (p-methoxybenzyl) -perhydroisoquinoline. To a solution of 2-cyclobutylcarbonyl-9, 10-DIHYDROXI-1- (p-methoxybenzyl) -perhydroisoquinoline (30 g, 0.08 mol in 300 ml of tetrahydrofuran, add boron dimethyl sulfide in a neat solution (14 ml, 0.14 mol) with using a needle syringe under nitrogen atmosphere. The resulting mixture is heated for 2 hours and then concentrated under reduced pressure to remove the solvent. The boron complex of cyclobutylmethyl amine formed can be used directly for the next reaction or can be hydrolyzed with an aqueous acid, for example hydrochloric, to obtain The target diol of Example 3, mp 120-122 0. The reduction of the amido function of the trans diol of Example 3 with the corresponding boric compounds also gives the desired product. Example 5. Cyclobutylmethyl-14-hydroxy-3-methoxymorphinan. Method A. Cyclization boron complex. To the remainder of the boron complex from the boron reduction reaction (0.08 mol) from example 4, 320 g of anhydrous phosphoric acid (obtained from 85% phosphoric acid and phosphorus pentoxide) and 50 g of phosphorus pentoxide are added. The mixture is stirred at room temperature for 0.5 h and then at 70-75 s for 4 h. The reaction mass is diluted with 200 ml of water and then poured into a mixture of 600 ml of concentrated ammonium hydroxide and 1 l of ice fragments. The mixture is extracted with 400 ml of heptane and the heptane extract is dried with sodium sulfate. The concentration of the dried heptane extract gives 23.1 g (yield 85%) of the desired product as an oil. This oil is dissolved in acetone and treated with anhydrous hydrogen chloride to obtain the crystalline hydrochloride salt of the target product, m.p. 248-250 Method B. Cycles of a boron complex of any type. 1.5 g of 2-cyclobutylmethyl-9,10-dihydroxy-l- (p-methoxybenzyl) -perhydroisoquinoline and 16.0 g of anhydrous phosphoric acid are stirred at 80-85 ° C for 23 hours. The reaction mixture is diluted with 20 ml of water and poured into a mixture of ice and 35 ml of concentrated ammonium hydroxide. The mixture is extracted with 40 ml of methylene chloride and the methylene chloride extract is concentrated to obtain 1.15 g of oil. According to gas chromatography data, the oil contains 57% N-cyclobutylmethyl-14 4-hydroxy-3-methoxymorphine, 27% dehydrogenated by-product, and 15% uncyclized starting material. Example 6. Left-handed N-cyclobutylmethyl-14p-hydroxy-3-methoxymorphinan. Substitution in Example 1 of the 1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline hydrochloride dextrorotatory for racemic and sequential use of the methods of Examples 2-5 gives the target levorotatory product. The operations described in examples 4 and 5 are carried out as follows. To a solution of the levovrashte 2-cyclobutylcarbonyl-9, 1O-dihydroxy-2- (p-methoxybenzyl) -perhydroeoquinoline (10 g, mol) in 100 ml of toluene add a pure solution of dimethyl boron sulfide (b ml / 0,057 mol using a needle syringe under The solution is heated and cooled for 3 hours, concentrated under reduced pressure to remove about 40 m of solvent and the boron complex of the left rotating cyclobutylmethylamine is used directly in the cyclization reaction. The cyclization of the levorotatory cyclobutylmethylamine by adding the above toluene complex in parts to 200 g of anhydrous phosphoric acid and 35 g of phosphorus pentoxide with stirring, maintaining the temperature at about 25 ° C. After the addition is complete, the mixture is heated and stirred for 5 hours at 10 ° C, and then poured into a mixture of 400 ml of concentrated ammonium hydroxide with a large amount of ice to maintain the temperature at. Next, the mixture is extracted with toluene, the extract is washed with water, and then concentrated under reduced pressure to obtain a levorotatory N-cyclobuty lmethyl-14 (b-hydroxy-3-methoxymorphinan. The oily base is converted to sulphate by treatment with sulfuric acid to obtain 7.2 g (yield 61%) of the levorotatory N-cyclobutylmethyl-14 p | -hydfOxy-3-methoxyforminan, m.p. 232-237С, -55.4С (with О, 56 СНо, ОН) Example 7, 2-Cyclopropylcarbonyl-1- (p-methoxybenzyl) -1,2,3, 4,5,6, 7,8-octahydroisoquinoline. This compound was prepared as in Example 1, replacing cyclobutylcarbonyl chloride with an equimolar amount of cyclopropylcarbonyl chloride. Example 8. 2-and klopropylcarbonyl-9, 10-ZPOXI-1- (p-methoxybenzyl) -perhydroisoquinoline. This compound is obtained as in Example 2, but the starting racemic compound used in this example is replaced by an equimolar amount of the target product of Example 7. Example 9. 2-Cyclopropyl-Nyl-9,10-dihydroxy-1- (p-methoxybenzyl) -perhydroisoquinoline. Replacing in example 3 the racemic starting compounds used there with an equimolar amount of the target product of example 8 gives the nentle coagent indicated in the title of Example 10. 2-Cyclopropylmethyl-9,10-dihydroxy- (p-methoxybenzi-perhydroisoquinoline. This compound is prepared as in step 4, but the different raw starting material used in example 4 is replaced with an equimolar amount of the target compound of example 9. Example 11. N-Cyclopropylmethyl-14 (3-hydroxy-3-methoxy morphine As a result of the substitution in Method B of Example 5 of the racemic starting material. unit by equimolar amount of the desired product of Example 10 semi-EUOT compound indicated in the title. Example 12. N-Diclobutylmethyl-3,14 -hydroxymorphinan. A mixture of N-cyclobutylmethyl-14p-hydroxy-3-methoxymorphinan (1.0 g, 2.58 mol) and 10 MP of 48% hydrobromic acid are heated and cooled in a nitrogen atmosphere for 5 minutes After cooling, the reaction mixture is diluted with water and alkalinized with aqueous ammonium hydroxide. The aqueous basic mixture is extracted with several portions of chloroform, and the combined chloroform extracts are dried with anhydrous sodium sulfate. After evaporation of the solvent, the residue - oil (730 mg) is extracted with dry ether and the resulting solution is filtered through dihydric charcoal. The filtrate is treated with a saturated solution of hydrogen chloride in dry ether. The hydrochloride salt thus obtained is collected and crystallized from methanol-acetone to obtain 565 mg (56.5%) of N-cyclobutylmethyl-3, 14-hydroxymorphinan hydrochloride, m.p. 272-274 C. The NMR and IR spectra are consistent with the structure. Found,%: C 68.10; H 8.14; N 3.80. her-1/2 sleep. 21 2. i: c 67.97, H 8.49; Calculated N 3.49. Oxidation of a -filtered solution of the dry ester, indicated above, with certain acids gives various pharmaceutically available salts with acid addition. 3-methoxyether function of N-cyclobutylmethyl-14 | α-hydroxy-3-methoxymorphinan can also be cleaved by treating with ether cleaving agents, such as NaSCj Hy, boron tribromide or hydrochloric pyridine, to obtain the desired dimethylated product. Claims 1. A method of producing 14-hydroxymorphinan derivatives of the general formula I, where R is cyclobutyl or cyclopropyl, and R is H or NI 3111 HI alkyl, which is reduced by reducing the compound of formula II : N-C (he r where R is cyclobutyl or cyclopropyl, and R is lower alkyl, by reacting with boron in an inert organic solvent at a temperature of from 50 to and the resulting complex of boron with a compound of general formula (III) where R is cyclobutyl or cyclopropyl, and R is lower alkyl, treated with phosphoric, orthophosphoric or pyrophosphoric acid to obtain a compound of the general formula (IV) N-CHj-R OH where R, R are as defined above, and if desired, convert the resulting compound to a compound of the general formula (V) ... N-CH 2-R ABOUT where R is cyclobutyl or cyclopropyl, by splitting the Ro-ester group by treatment with NaSCj Hj-, hydrobromic acid, boron tribromide or hydrochloric pyridine, followed by isolation of the target product. [2] 2 ,. The method according to claim 1, about tl and h. Yusch and with the fact that the compound of formula (II) is reduced from dimethyl boron sulfide. [3] 3. A method according to claim 1, characterized in that a compound of formula (II) is reduced by boron generated by the reaction of sodium borohydride and boron trifluoride or sodium borohydride and bortrax of a tetrahydrofuran complex or sodium borohydride and boron trifluoride alkyl ether. [4] 4. The method according to PP.1-3, about tl and h ayusch and the fact that boron is used 0 in the ratio of 1 mol of the compound of formula (11) to 1.33-2.0 mol of boron. [5] 5. The method according to claims 1-4, about t. L and h and the fact that the boron complex of compound (III) is treated with anhydrous phosphoric acid and phosphorus pentoxide. [6] 6. The method according to claims 1-5, which is borne in that boric the complex of compound (III) is hydrolyzed with aqueous acid. Sources of information taken into account in the examination 1. US Patent No. 3819635, cl. 260-286, publ. 06.25.74. Note. The priority of 23.03.76 according to the application (669795 deviates since the combination of the two stages of the preparation of the borane complex and the cyclization into one did not find reflection in the claims of this application.
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公开号 | 公开日 US4139534A|1979-02-13|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题 US3634429A|1969-09-30|1972-01-11|Hoffmann La Roche|Morphinan derivatives and preparation thereof| BE788478A|1971-09-08|1973-03-06|Bristol Myers Co|PROCESS FOR PREPARING ANALGESIC COMPOUNDS| US3775414A|1972-05-10|1973-11-27|Bristol Myers Co|Process for the preparation of 14-hydroxymorphinan derivatives| US3919237A|1972-07-07|1975-11-11|Hoffmann La Roche|Preparation of isomorphinan derivative| US3980641A|1975-07-31|1976-09-14|Bristol-Myers Company|Process for the preparation of 14-hydroxymorphinans| US4058531A|1976-03-23|1977-11-15|Bristol-Myers Company|Process for the preparation of 14-hydroxymorphinan derivatives|US4202982A|1976-03-23|1980-05-13|Bristol-Myers Company|Process for the preparation of 14-hydroxymorphinan derivatives| DE2964643D1|1978-11-15|1983-03-03|Goedecke Ag|1,2,3,4-tetrahydro-6-oxo-2,8a-methano-6h-dibenz-azocines, medicaments containing them, and process for their preparation| US4514569A|1982-01-28|1985-04-30|Hendrickson James B|Synthesis of 1-substituted isoquinolines| US4613668A|1983-12-22|1986-09-23|The United States Of America As Represented By The Department Of Health And Human Services|Short total synthesis or morphinan compounds which uses cyclization of a cycloalkylcarbonyl compound selected from cyclopropylcarbonyl and cyclobutylcarbonyl| JP6980687B2|2016-03-29|2021-12-15|ヒカル リミテッド|Improved method for the production of butorphanol tartrate| CN112142668A|2019-06-28|2020-12-29|苏州盛迪亚生物医药有限公司|Preparation method of butorphanol tartrate and intermediate thereof|
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申请号 | 申请日 | 专利标题 US05/769,808|US4139534A|1977-02-17|1977-02-17|Process for the preparation of 14-hydroxymorphinan derivatives| 相关专利
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