JP3097678B2 - Aphanorphin intermediate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an intermediate of aphanorphin, and using this intermediate as a starting material, (+)-
Aphanorphin can be produced.

[0002]

2. Description of the Related Art (+)-Aphanorphine has a benzomorphan skeleton which is an analog of morphine as an anesthetic, and its physiological activity is considered to be useful as a pharmaceutical (Chem. Rev.) 77, 1 page (1977
Year)). However, although the skeleton of aphanorphine as a natural product is known (Tetrahedrone Letters (Tetrahe
dron Lett.) Vol. 29, p. 4381 (1988)), the absolute configuration of which has not been determined, and the total synthesis has not yet been reported. Therefore, its pharmacological activity has not been fully elucidated.

[0003]

SUMMARY OF THE INVENTION
It has been desired to determine the absolute configuration of aphanorphine, which is useful as an anesthetic, to synthesize it, to elucidate its pharmacological activity, and to develop a production method thereof. The present inventors have determined the absolute configuration of aphanorphine useful as an anesthetic, and found a more efficient method for producing (+)-aphanorphin.
This is made clear in the specification of No. 51.

Accordingly, the compound of the present invention (+)-aphanorphine was first synthesized by the present inventors,
The compound of the present invention is a novel compound whose absolute configuration has been clarified. An object of the present invention is to provide an intermediate of aphanorphin.

[0005]

SUMMARY OF THE INVENTION The present invention is an aphanorphine intermediate represented by the following general formulas (I) and (II).

[0006]

Embedded image (R represents an alkyl group of C ₁ ~C _10). The general formula (I)
Starting with an aphanorphine intermediate represented by
After passing one or more compounds represented by the general formulas (II), (III) and (IV) into the general formula

[0007]

Embedded image (R in the formula represents a hydrogen atom or a C ₁ -C ₁₀ alkyl group) (+)-aphanorphine can be produced.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Next, a preferred example of the method for producing (+)-aphanorphine will be described. The intermediate (I) of aphanorphin, which is the compound of the present invention, is an easily available optically active tricyclo [5.2.1.0 ^2,6 ] deca-3.
(+)-Dienone compound (A) represented by the following formula, which can be easily obtained from -hydroxydiene:

[0009]

Embedded image (Journal of Chemical Society Chemical Communication (J. Chem. Soc. C
hem. Comunn.) 1989 p.271).

The compound (A) is reacted with a Grignard reagent to obtain a 1,4-adduct compound (B). When this is heated, a reverse Diels-Alder reaction occurs, and the enone compound (I) (wherein R in the general formula (I) is represented by C ₁ )
Is obtained. Next, the double bond of the enone compound (I) was oxidized with hydrogen peroxide to obtain an oxirane compound (C). After treatment with hydrazine, the hydroxyl group is oxidized with pyridine chromate hydrochloride to give a ketone, and the double bond is reduced with palladium-carbon to give 2- (m-methoxyphenyl)-
2-methylcyclopentanone (D) is obtained.

This compound (D) is α-formylated with sodium hydride and ethyl formate and reacted with 1,3-propanedithiol ditosylate to give an intermediate (II) (of the above formula (II)) R is represented by C ₁₎ is obtained. The obtained aphanorphine intermediate (II) is opened in a potassium hydroxide-t-butyl alcohol solution by stirring to form a carboxylic acid. This is treated with diazomethane to obtain an ester compound (E).

After oxidizing the ester compound (E) with an oxidizing agent such as metachloroperbenzoic acid to form a sulfoxide, further add trifluoroacetic acid, stir at room temperature, and heat and reflux to obtain the intermediate (III) (the above-mentioned general formula). Wherein R in (III) is represented by C ₁ ). Next, the ester of the intermediate (III) is converted to the alcohol compound (F) using a reducing agent such as lithium aluminum hydride.

The alcohol compound (F) and phthalimide are condensed by a Mitsunobu reaction, and further reacted with hydrazine.
An amine compound is obtained. The amine compound is heated under reflux in the presence of lead tetraacetate and anhydrous potassium carbonate to form an aziridine derivative (I
V) (wherein R in the general formula (IV) is represented by C ₁ ). This aziridine derivative (IV) is quickly reacted with methylfluorosulfonate, led to an ammonium salt, and treated with lithium aluminum hydride to give (+)-aphanorphine represented by the above general formula (V) (wherein R
Is a hydrogen atom).

The reaction temperature, reaction time, reaction solvent, etc. in each reaction of the above-mentioned synthesis methods naturally vary depending on the amount handled, etc., but the general formulas (I), (II), (III),
(+)-Aphanorphine can be produced via any or all of the intermediates represented by (IV). Thus, if via any of these intermediates, the method of manufacture is relevant to the present invention,
The effects of the reaction temperature, reaction time, reaction solvent, and the like can be changed within a range easily estimated by those skilled in the art.

When the enantiomer of dicyclopentadiene as a starting material is used as a starting material, (-)-aphanorphine can be obtained.

[0016]

According to the production method using the intermediate of the present invention,
Aphanorphin, which is a very promising compound as a drug (anesthetic), can be obtained efficiently.

[0017]

EXAMPLES The present invention will be described in more detail with reference to the following examples. However, the reaction temperature, reaction time, reaction solvent, etc. in each reaction naturally differ depending on the amount handled and the like.
The present invention is not limited only by the examples. Example 1 From a (+)-dienone compound (A) to 4- (m-methoxyphenyl) -4-methyl-cyclopent-2-enone
Preparation of (I) To a suspension of 2.37 g (97.5 mmol) of magnesium pieces in 80 ml of tetrahydrofuran was added 8.0 ml (63.7 mm) of m-bromoanisole.
ol) was slowly added dropwise, and the reaction solution was heated to reflux for 1 hour. The reaction solution was returned to room temperature, and CuBrSMe ₂ 385 mg (1.88 mmo
l) and 7.18 ml of hexamethylphosphoramide (41.3 mmo
After l) was added, the mixture was cooled to -70 ° C. After stirring for 10 minutes, 3.0 g (18.7 mmol) of compound (A) and 4.
8 ml (37.5 mmol) of a mixed tetrahydrofuran solution was added dropwise over 1 hour. After stirring at the same temperature for 2 hours, the temperature was raised to room temperature, 4.5 ml of triethylamine and 54 ml of n-hexane were added, and the mixture was filtered using Celite. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was removed under reduced pressure. Dissolve the residue in 100 ml of methanol and add potassium fluoride
1.09 g (8.8 mmol) was added at room temperature. After stirring for 5 minutes, water was added, extracted with dichloromethane, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography using 80 g of silica gel. -Adduct compound (B) (5- (m-methoxyphenyl) -5-methyl-tricyclo [5.4.
1.0. ^2,6 ] Deca-3-one-7-ene) 4.6
8 g were obtained. Since it could not be purified completely, it was used for the next reaction as it was.

A solution of 4.68 g of the mixture of compound (B) in 90 ml of o-dichlorobenzene was heated under reflux for 12 hours. The reaction solution was subjected to column chromatography using 100 g of silica gel, and a pale yellow oil (I) (4- (m-methoxyphenyl)) was obtained from a stream of ethyl ether-n-hexane (1:10 v / v). -3-methyl-cyclopent-2-enone) 3.29 g
(Total yield from compound (A) 87%) was obtained. IRν ^neat _max cm ⁻¹ : 1720; ¹ H-NMR (CDCl ₃ ) δ: 1.61 (S, 3H), 2.47 (d, 1H, J = 18.
6Hz), 2.70 (d, 1H, J = 18.6Hz), 3.80 (S, 3H), 5.19 (d,
1H, J = 5.6Hz), 6.7-7.4 (m, 4H), 7.67 (d, 1H, J = 5.6H)
z); MS (m / z): 204 (M ⁺⁺ 2), 203 (M ⁺⁺ 1), 202 (M ⁺ ), 202
(M ⁺ ), 187 (100%); Analytical value, calculated value C ₁₃ H ₁₄ O ₂ : C, 77.20; H, 6.98 Found value C, 77.20; H, 6.86 [α] ²⁹ _D −105.2 ° (c1. 38, CHCl ₃ )

Example 2 From enone compound (I) to 5- (m-methoxyphenyl)
-5-methyl-2,2- (propane-1,3-dithio)
Preparation of cyclopentanone (II) 3.29 g of compound (I) (1
To a solution of 6.3 mmol) in methanol (60 ml) were successively added a 30% aqueous hydrogen peroxide solution (5.5 ml, 48.9 mmol) and a 5% aqueous sodium hydroxide solution (6.5 ml, 8.14 mmol) under ice-cooling.
Stirred at room temperature for 2 hours. Water was added to the reaction solution, and the aqueous layer was extracted with ethyl ether. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using 60 g of silica gel, and the oxirane compound (C) as a yellow oily substance was obtained from a stream of ethyl ether-n-hexane (1: 7 v / v) (4- (m-
Methoxyphenyl) -4-methyl-2,3-epoxy-
2.64 g (yield 74%) of cyclopentanone) were obtained as a diastereomer mixture (5: 3).

IRν ^neat _max cm ^-1 : 1755; ¹ H-NMR (CDCl ₃ ) δ: 1.39 (S, 9 / 8H), 1.68 (S, 15 / 8H),
2.19 (d, 3 / 8H, J = 17.1Hz), 2.28 (d, 5 / 8H, J = 17.6H
z), 2.50 (d, 5 / 8H, J = 17.6Hz), 2.69 (d, 3 / 8H, J = 17.
1Hz), 3.48 (d, 3 / 8H, J = 2.7Hz), 3.51 (d, 5 / 8H, J =
2.2Hz), 3.80 (S, 15 / 8H), 3.83 (S, 9 / 8H), 3.84 (d, 5 / 8H,
J = 2.2Hz), 4.03 (d, 3 / 8H, J = 2.7Hz), 6.7-7.4 (m, 4H); MS (m / z): 220 (M ⁺⁺ 2), 219 (M ⁺⁺ 1), 218 (M ⁺ ) Anal., Calculated C ₁₃ H ₁₄ O ₃ : C, 77.20; H, 6.74 Found C, 71.55; H, 6.40

Oxirane compound (C) 100 mg (0.46 mmo
l) in 3 ml of methanol under ice-cooling
0.11 ml (2.3 mmol) and 26 μl (0.46 mmol) of acetic acid were added, and the mixture was stirred for 10 minutes and heated under reflux for 12 hours. Ethyl ether was added to the reaction solution, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using 10 g of silica gel, and ethyl ether-n-hexane (1: 8 v
/ v), 32 mg (34% yield) of a pale yellow oil (containing 5- (m-methoxyphenyl) -5-methylcyclopent-2-enol) was obtained from a diastereomer mixture (5:
Obtained as 3).

IRν ^neat _max cm ^-1 : 3400; ¹ H-NMR (CDCl ₃ ) δ: 1.32 (S, 3H), 1.95 (br.s, 1H), 2.2-
3.2 (m, 2H), 3.79 (S, 15 / 8H), 3.80 (S, 9 / 8H), 4.50 (m,
3 / 8H), 4.92 (m, 5 / 8H), 5.1-6.2 (m, 2H), 6.7-7.4 (m, 4
H); MS (m / z), 207 (M ⁺⁺ 3), 206 (M ⁺⁺ 2), 205 (M ⁺⁺ 1),
204 (M ⁺ , 100%) A solution of 141 mg (0.69 mmol) of the obtained 5- (m-methoxyphenyl) -5-methylcyclopent-2-enol in 5 ml of dichloromethane was added with pyridine chromate hydrochloride under ice-cooling.
223 ml (1.04 mmol) was added, and the mixture was stirred for 10 minutes and then stirred at room temperature for 4 hours. The reaction solution was filtered using florisil, and the filtrate was evaporated under reduced pressure to obtain 145 mg of a crude enone compound (5- (m-methoxyphenyl) -5-methyl-cyclopent-2-enone). This was used for the next reaction without purification.

To a solution of 145 mg of the crude enone compound in 5 ml of ethanol was added 20 mg of 10% palladium-carbon, and the mixture was stirred at room temperature for 8 hours under a stream of hydrogen. The reaction solution was filtered using celite, and the filtrate was evaporated under reduced pressure. Silica gel residue
10 g of the mixture was subjected to column chromatography, and a yellow oil (D) (2- (m-methoxyphenyl) -2-methyl-methyl) was obtained from a stream of ethyl ether-n-hexane (1:10 v / v). 103 mg of cyclopentanone (total yield from the hydrazine-treated compound: 71%) IRν ^neat _max cm ⁻¹ : 1750; ¹ H-NMR (CDCl ₃ ) δ: 1.37 (S, 3H), 1.7-2.2 ( m, 6H) 3.79
(S, 3H), 6.7-7.4 (m, 4H); MS (m / z): 205 (M ⁺ +1), 204 (M ⁺ ), 148 (100%); high-resolution mass spectrometry (exact mass) Calculated, C ₁₃ H ₁₆ O ₂ : 204.2682 (M ⁺ ) Found 204.1157 (M ⁺ )

Sodium hydride (60% w / w in oil) 39m
g (0.98 mmol) in 1 ml of benzene, 100 mg (0.49 mmol) of oil (D) and 80 μl of ethyl formate (0.98
(mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After adding water, the mixture was acidified with a 2N aqueous solution of sulfuric acid and extracted with ethyl ether. After drying the organic layer over magnesium sulfate, the solvent was removed under reduced pressure, and the crude α-formyl compound 120 mg
I got Next, 1,3-propanedithiol ditosylate 26 was added to an ethanol solution of 120 mg of the obtained crude α-formyl compound.
5 mg (0.64 mmol) and 351 mg (3.58 mmol) of potassium acetate
Was added and heated under reflux for 3 hours. After evaporating the solvent of the reaction solution under reduced pressure, water was added and the mixture was extracted with ethyl ether and washed with a saturated aqueous sodium chloride solution. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography using 10 g of silica gel, and a white oil (II) (5- (m-methoxyphenyl)) was obtained from a stream of ethyl ether-n-hexane (1:10 v / v). −
5-methyl-2,2- (propane-1,3-dithio)-
(Cyclopentanone) 80 mg (53% yield) was obtained. IRν ^neat _max cm ⁻¹ : 1725; ¹ H-NMR (CDCl ₃ ) δ: 1.55 (S, 3H), 1.9−2.7 (m, 10H),
3.78 (S, 3H), 6.7−7.41 (m, 4H); MS (m / z): 308 (M ⁺ ), 132 (100%);

Example 3 1-methoxycarbonyl-7-methoxy-1-methyl-
Preparation of 1,2-dihydronaphthalene (III) A solution of 3.60 g (11.7 mmol) of compound (II) in 90 ml of t-butyl alcohol was kept at 60 ° C., and 2.71 g of powdered potassium hydroxide was obtained.
(46.7 mmol) was added and the mixture was stirred as it was for 13 hours. Water was added, the mixture was acidified with cold concentrated hydrochloric acid, extracted with ethyl ether, the organic layer was dried over magnesium sulfate, and the solvent was distilled off. The obtained crude carboxylic acid was made into an ether solution, and diazomethane / ethyl ether was added. After evaporating the solvent, the residue was subjected to silica gel chromatography, and the ester compound (E) (2-
3.13 g (82%) of (m-methoxyphenyl) -2-methyl-5,5- (propane-1,3-dithio) -pentanoic acid methyl ester were obtained. IRν ^neat _max cm ^-1 : 1730; ¹ H-NMR (CDCl ₃ ) δ: 1.54 (S, 3H), 1.6-23 (m, 6H), 2.8
(m, 4H), 3.66 (S, 3H), 3.80 (S, 3H), 3.97 (t, 1H J = 6.
6Hz), 6.7-7.3 (m, 4H)

2.13 g (6.26 mmol) of ester compound (E)
Sodium bicarbonate 1.57 g (1
8 mmol), and meta-chloroperbenzoic acid 1.19 g under ice-cooling
(6.89 mmol) was added. After stirring for 5 minutes, water was added, extracted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and the solvent was distilled off to obtain a crude monosulfoxide compound. Then add 40 ml of toluene
Under cooling with the solution, trifluoroacetic acid was added dropwise. After stirring at room temperature for 20 minutes, the mixture was refluxed at 130 ° C. for 5 minutes, air-cooled, saturated aqueous sodium bicarbonate was added, the organic layer was separated, dried over magnesium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography to give compound (III) (1-methoxycarbonyl-7-methoxy-1-
Methyl-1,2-dihydronaphthalene) 804 mg (yield 55
%, 3.46 mmol). IRν ^neat _max cm ⁻¹ : 1730; ¹ H-NMR (CDCl ₃ ) δ: 1.51 (S, 3H), 2.22 (m, 1H), 2.95
(m, 1H), 3.66 (S, 3H), 3.78 (S, 3H), 5.83 (m, 1H), 6.4
0 (d, 1H, J = 9.5Hz, 6.7-7.1 (m, 3H)

Example 4 Preparation of aziridine derivative (IV) 804 mg (3.46 mmol) of the compound (III) obtained in Example 3 was added to a suspension of 132 mg (3.46 mmol) of lithium aluminum hydride in 10 ml of tetrahydrofuran under ice cooling. A 5 ml solution of tetrahydrofuran was added dropwise, the mixture was stirred at room temperature for 1 hour, concentrated aqueous ammonia was added under ice-cooling, the mixture was stirred for a while, filtered through celite, extracted with ethyl ether, dried over magnesium sulfate, and the solvent was distilled off. Remove the crude alcohol (F) 1
-Hydroxymethyl-7-methoxy-1-methyl-1,
2-Dihydronaphthalene was obtained. A part was purified by silica gel column chromatography to obtain the following data. IRν ^neat _max cm ^-1 : 3400; ¹ H-NMR (CDCl ₃ ) δ: 1.19 (S, 3H), 1.58 (exchangeable with S, 1H, D ₂ O), 1.9-2.5 (m, 2H), 3.43 (S, 2H), 3.70 (S, 3H),
5.68 (dt, 1H, J = 9.8, 4.1Hz, 6.28 (d, 1H, J = 9.8H
z), 6.55-6.95 (m, 3H) (α) ²⁷ _D -13.0 ° (c0.23, CHCl ₃ )

280 mg (1.37 mmol) of crude alcohol (F),
A mixture of 363 mg (2.47 mmol) of phthalimide and 647 mg (2.47 mmol) of triphenylphosphine was added to a solution of diisopropyl azodicarboxylate under ice-cooling.
0.49 ml (2.47 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 hours.
After the solvent was distilled off, the residue was subjected to silica gel column chromatography to obtain 7-methoxy-1-methyl-1-phthalimidylmethyl-1,2-dihydronaphthalene 300, a condensate.
mg (65.7% yield). IRν ^neat _max cm ⁻¹ : 1600, 1710; ¹ H-NMR (CDCl ₃ ) δ: 1.38 (S, 3H), 2.22-2.29 (m, 2H),
3.73 (S, 2H), 3.76 (S, 3H), 5.88 (dt, 1H, J = 9.5, 4.
4Hz, 6.46 (d, 1H, J = 9.5Hz, 6.7-7.1 (m, 3H), 7.6-7.
9 (m, 4H)

To a solution of 40 mg (0.12 mmol) of the obtained condensate in 3 ml of ethanol was added 17 μl (0.36 mmol) of hydrazine monohydrate.
Was added and heated under reflux for 40 minutes. After air cooling, the solvent was distilled off under reduced pressure, dichloromethane was added, and the mixture was filtered using Celite. The solvent was distilled off under reduced pressure to obtain 20 mg of a crude amine compound, 1-aminomethyl-1-methyl-7-methoxy-1,2-dihydronaphthalene. IRν ^neat _max cm ⁻¹ : 3300; ¹ H-NMR (CDCl ₃ ) δ: 1.16 (S, 3H), 1.42 (br.s, 2H, D ₂ O)
2.19 (m, 2H), 2.65 (S, 2H), 3.73 (S, 3
H), 5.70 (dt, 1H, J = 9.6, 4.6Hz) 6.29 (d, 1H, J = 9.
6-Hz) 6.5-7.0 (m, 3H) A solution of 194 mg (0.394 mmol) of lead tetraacetate (90%) and 211 mg (1.53 mmol) of anhydrous potassium carbonate in 3 ml of anhydrous benzene was kept at 60 ° C. Quickly add a solution of compound (20 mg) in benzene, reflux for 20 minutes, air-cool,
An aqueous solution of sodium hydroxide was added, extracted with ethyl ether, and dried over magnesium sulfate. The solvent was distilled off to obtain a crude aziridine derivative (IV).

Example 5 Preparation of (+)-Aphanorphine Methyl Ether (V) The crude aziridine derivative (IV) obtained in Example 4 was made into a 2 ml dichloromethane solution as quickly as possible, and 19.4 μl of methylfluorosulfonate was added under ice cooling. After stirring for 5 minutes, the solvent was distilled off to obtain a crude ammonium salt. Further, this was made into a 1 ml solution of tetrahydrofuran, and 1 ml of a tetrahydrofuran solution containing 9.4 mg of lithium aluminum hydride under ice cooling.
The suspension was added dropwise and stirred at room temperature for 30 minutes. Concentrated aqueous ammonia was added, and the mixture was stirred for a while, filtered through celite, and the solvent was distilled off. Add a 10% aqueous sodium hydroxide solution
Extracted with dichloromethane. After drying over potassium carbonate, the solvent was distilled off, and the obtained residue was subjected to preparative thin-layer chromatography to obtain 13 mg of (+)-aphanorphine methyl ether (R in the formula (V) is a methyl group) (yield: 13%). Rate 24.4
%). ¹ H-NMR (CDCl ₃ ) δ: 1.48 (S, 3H), 1.86 (d, 1H, J = 11.0
Hz, 2.01-2.05 (m, 1H), 2.49 (S, 3H), 2.77 (d, 1H, J =
9.15Hz), 2.83-2.89 (m, 2H), 3.03 (d, 1H, J = 17.1H
z), 3.43 (m, 1H), 3.78 (S, 3H), 6.69 (dd, 1H, J = 8.2
4, 3.05Hz), 6.78 (d, 1H, J = 2.45Hz), 7.02 (d, 1H, J =
8.55Hz MS (m / z): 218 (M ⁺ +1), 217 (M ⁺ ), 202 (100%); (α) ²⁷ _D −7.40 ° (c0.35, CHCl ₃ )

Example 6 Preparation of (+)-Aphanorphine (V) A dichloromethane solution of 13 mg (0.06 mmol) of (+)-Aphanorphine methyl ether obtained in Example 5 was added at -80 ° C.
Cooled to 1.0 M solution of boron tribromide in dichloromethane
After adding 0.2 ml (0.2 mmol), the temperature was raised to −10 ° C. in 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. After the combined dichloromethane layer was dried over potassium carbonate, the solvent was distilled off. The residue was subjected to preparative thin-layer chromatography, and (+)-aphanorphine (R in the formula (V) is a hydrogen atom) 18 mg
(Yield 71%); mp 204-205 ° C [α] ²⁷ _D + 40.1 ° (c0.12, hydrochloride, H ₂ O) Various spectral data are based on literature values (Tetrahedron Lett., 29 ,
4381 (1988)).

Claims (2)

(57) [Claims] 1. A compound of the general formula (R represents an alkyl group of C ₁ -C ₁₀₎ Afa nor fin intermediate represented by. 2. A compound of the general formula (R represents an alkyl group of C ₁ -C ₁₀₎ Afa nor fin intermediate represented by.