Process for producing novel 4-benzoazonine derivatives

Abstract

An object of the present invention is to provide a novel tetrahydroazepine compound and a process for producing the same. The present invention relates to a tetrahydroazepine compound represented by the formula (10) or a salt thereof, and a process for producing the said compound or a salt thereof. ##STR00001## (In the formula, R.sup.1 is an optionally substituted alkyl group, R.sup.2 is an optionally substituted alkyl group and one of the XY bond and the YZ bond is a carbon-carbon double bond and the other is a carbon-carbon single bond).

Claims

1. A tetrahydroazepine compound represented by the formula (10) or a salt thereof, ##STR00019## wherein in the formulae, R.sup.1 is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group, R.sup.2 is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group and one of the XY bond and the YZ bond is a carbon-carbon double bond and the other is a carbon-carbon single bond.

2. The compound or the salt thereof according to claim 1, wherein R.sup.1 is methyl group and R.sup.2 is methyl group in the formula (10).

3. A process for producing the tetrahydroazepine compound or the salt thereof according to claim 1, comprising (f): a step where a compound represented by the formula (9) or a salt thereof is made to react with at least one dehydrating agent selected from the group consisting of boron trifluoride ether complex, trifluoroacetic acid, trifluoroacetic acid anhydride, trimethylsilyl trifluoromethanesulfonate, aluminum chloride, titanium (IV) chloride, tin (IV) chloride, triphenylmethyl perchlorate, bismuth triflate, ytterbium triflate, scandium triflate, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid and phosphorus pentaoxide, ##STR00020## wherein in the formulae, R.sup.1 is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group, R.sup.2 is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group and one of the XY bond and the YZ bond is a carbon-carbon double bond and the other is a carbon-carbon single bond.

4. The process according to claim 3, further comprising (e): a step where a compound represented by the formula (8) or a salt thereof is made to react with a methylating agent to give a compound represented by the formula (9) or a salt thereof, ##STR00021## wherein in the formulae, R.sup.1 and R.sup.2 have the same meanings as mentioned in claim 3.

5. The process according to claim 4, further comprising (d): a step where a compound represented by the formula (7) or a salt thereof is made to react with an acid to give a compound represented by the formula (8) or a salt thereof, ##STR00022## wherein in the formulae, R.sup.1 is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group, R.sup.2 is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group and the two R.sup.3's are the same or different, and each is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group, or the two R.sup.3's may be bonded to each other to form a ring together with oxygen atoms to which the two R.sup.3's are bonded.

6. The process according to claim 5, further comprising (c): a step where a compound represented by the formula (6) or a salt thereof is made to react with a reducing agent to give a compound represented by the formula (7) or a salt thereof, ##STR00023## wherein in the formulae, R.sup.1, R.sup.2 and R.sup.3 have the same meanings as mentioned in claim 5.

7. The process according to claim 6, further comprising (b): a step where a compound represented by the formula (5) or a salt thereof is made to react with a compound represented by the formula (15) to give a compound represented by the formula (6) or a salt thereof, ##STR00024## wherein in the formulae, R.sup.1 is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group, R.sup.2 is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group, the two R.sup.3's are the same or different, and each is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group, or the two R.sup.3's may be bonded to each other to form a ring together with oxygen atoms to which the two R.sup.3's are bonded and A is an eliminating group.

8. The process according to claim 7, further comprising (a): a step where a compound represented by the formula (4) or a salt thereof is made to react with an alkylating agent to give a compound represented by the formula (5) or a salt thereof, ##STR00025## wherein in the formulae, R.sup.2 and R.sup.3 have the same meanings as mentioned in claim 7.

9. A process for producing the 4-benzoazonine compound represented by the formula (11) or a salt thereof, comprising (g): a step where a tetrahydroazepine compound represented by the formula (10) or a salt thereof is made to react with an acid, ##STR00026## wherein in the formulae, R.sup.1 is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group, R.sup.2 is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group and one of the XY bond and the YZ bond is a carbon-carbon double bond and the other is a carbon-carbon single bond.

10. The process according to claim 9, comprising at least one step(s) selected from the group consisting of (a) to (f): (a): a step where a compound represented by the formula (4) or a salt thereof is made to react with an alkylating agent to give a compound represented by the formula (5) or a salt thereof, ##STR00027## wherein in the formulae, R.sup.2 has the same meaning as mentioned in claim 9, and the two R.sup.3's are the same or different, and each is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group, or the two R.sup.3's may be bonded to each other to form a ring together with oxygen atoms to which the two R.sup.3's are bonded; (b): a step where a compound represented by the formula (5) or a salt thereof is made to react with a compound represented by the formula (15) to give a compound represented by the formula (6) or a salt thereof, ##STR00028## wherein in the formulae, R.sup.1 and R.sup.2 have the same meanings as mentioned in claim 9, R.sup.3 has the same meaning as mentioned in the step (a) and A is an eliminating group; (c): a step where a compound represented by the formula (6) or a salt thereof is made to react with a reducing agent to give a compound represented by the formula (7) or a salt thereof, ##STR00029## wherein in the formulae, R.sup.1 and R.sup.2 have the same meanings as mentioned in claim 9, R.sup.3 has the same meaning as mentioned in the step (a); (d): a step where a compound represented by the formula (7) or a salt thereof is made to react with an acid to give a compound represented by the formula (8) or a salt thereof, ##STR00030## wherein in the formulae, R.sup.1 and R.sup.2 have the same meanings as mentioned in claim 9, R.sup.3 has the same meaning as mentioned in the step (a); (e): a step where a compound represented by the formula (8) or a salt thereof is made to react with a methylating agent to give a compound represented by the formula (9) or a salt thereof, ##STR00031## wherein in the formulae, R.sup.1 and R.sup.2 have the same meanings as mentioned in claim 9; and (f): a step where a compound represented by the formula (9) or a salt thereof is made to react with at least one dehydrating agent selected from the group consisting of boron trifluoride ether complex, trifluoroacetic acid, trifluoroacetic acid anhydride, trimethylsilyl trifluoromethanesulfonate, aluminum chloride, titanium (IV) chloride, tin (IV) chloride, triphenylmethyl perchlorate, bismuth triflate, ytterbium triflate, scandium triflate, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid and phosphorus pentaoxide, ##STR00032## wherein in the formulae, R.sup.1, R.sup.2, the XY bond and the YZ bond have the same meanings as mentioned in claim 9.

11. A process for producing a compound represented by the formula (13) or a salt thereof, comprising: (a): a step where a compound represented by the formula (4) or a salt thereof is made to react with an alkylating agent to give a compound represented by the formula (5) or a salt thereof, ##STR00033## wherein in the formulae, R.sup.2 is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group and the two R.sup.3's are the same or different, and each is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group, or the two R.sup.3's may be bonded to each other to form a ring together with oxygen atoms to which the two R.sup.3's are bonded; (b): a step where a compound represented by the formula (5) or a salt thereof is made to react with a compound represented by the formula (15) to give a compound represented by the formula (6) or a salt thereof, ##STR00034## wherein in the formulae, R.sup.1 is an alkyl group optionally substituted with halogen atom, aryl group, alkoxy group, allyl group or vinyl group, R.sup.2 and R.sup.3 have the same meanings as mentioned in the step (a) and A is an eliminating group; (c): a step where a compound represented by the formula (6) or a salt thereof is made to react with a reducing agent to give a compound represented by the formula (7) or a salt thereof, ##STR00035## wherein in the formulae, R.sup.1 has the same meaning as mentioned in the step (b), R.sup.2 and R.sup.3 have the same meanings as mentioned in the step (a); (d): a step where a compound represented by the formula (7) or a salt thereof is made to react with an acid to give a compound represented by the formula (8) or a salt thereof, ##STR00036## wherein in the formulae, R.sup.1 has the same meaning as mentioned in the step (b), and R.sup.2 and R.sup.3 have the same meanings as mentioned in the step (a); (e): a step where a compound represented by the formula (8) or a salt thereof is made to react with a methylating agent to give a compound represented by the formula (9) or a salt thereof, ##STR00037## wherein in the formulae, R.sup.1 has the same meaning as mentioned in the step (b), and R.sup.2 has the same meaning as mentioned in the step (a); (f): a step where a compound represented by the formula (9) or a salt thereof is made to react with at least one dehydrating agent selected from the group consisting of boron trifluoride ether complex, trifluoroacetic acid, trifluoroacetic acid anhydride, trimethylsilyl trifluoromethanesulfonate, aluminum chloride, titanium (IV) chloride, tin (IV) chloride, triphenylmethyl perchlorate, bismuth triflate, ytterbium triflate, scandium triflate, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid and phosphorus pentaoxide, ##STR00038## wherein in the formulae, R.sup.1 has the same meaning as mentioned in the step (b), and R.sup.2 has the same meaning as mentioned in the step (a) and one of the XY bond and the YZ bond is a carbon-carbon double bond and the other is a carbon-carbon single bond (g): a step where a tetrahydroazepine compound represented by the formula (10) or a salt thereof is made to react with an acid, ##STR00039## wherein in the formulae, R.sup.1 has the same meaning as mentioned in the step (b), and R.sup.2 has the same meaning as mentioned in the step (a) and the XY bond and the YZ bond have the same meanings as mentioned in step (f), (h): a step where a 4-benzoazonine compound represented by the formula (11) or a salt thereof is made to react with an organic acid to give a compound represented by the formula (12) or salt thereof and (i) a step where an OR.sup.1 group in the compound represented by the formula (12) or a salt thereof is deprotected to give the compound represented by the formula (13) or a salt thereof, ##STR00040## wherein in the formulae, R.sup.1 has the same meaning as mentioned in the step (b), and R.sup.2 has the same meaning as mentioned in the step (a).

Description

EXAMPLES

(1) The present invention will now be specifically illustrated by way of Referential Examples and Examples although the present invention shall not be limited thereto.

(2) Melting point was measured using a melting point measuring device (type MP-21, Yamato) and the thermometer was not corrected.

(3) Nuclear magnetic resonance spectra (.sup.1H-NMR) were measured using a nuclear magnetic resonance device (type AVANCE III 500, Bruker BioSpin) where tetramethylsilane (TMS) (=0) was used as an internal standard substance.

(4) Mass spectrum (MS) was measured using POLARIS Q (Thermo Fisher Scientific).

(5) Silica gel column chromatography was carried out using silica gel PSQ-1008 (Fuji Silysia Chemical LtD.) or Wakogel C-300HG (Wako Pure Chemical Industries, LtD.).

(6) In conducting thin-layer chromatography, Silica gel F254 (Merck, No. 5715) or TLC plate NH (Fuji Silysia Chemical LtD.) was used and the detection was done using an UV lamp and a 5 w/v % ethanolic solution of phosphomolybdic acid as a coloring reagent. As to the reagent and the solvent, commercially available ones were used just as they were.

Referential Example 1

(7) The compound (4a) was produced according to the following reaction formula 3.

(8) ##STR00016##

Synthesis of 1,4-dioxa-9-azaspiro[4.6]undecan-8-one (4a)

(9) Under a nitrogen atmosphere, water (5.0 kg) and sodium hydrogen carbonate (592 g, 7.0 ml) were successively added at room temperature to a solution of 1,4-cyclohexandione monoethylene acetal (la) (1.0 kg, 6.4 mol) in DCM (6.7 kg). After that, hydroxylamine hydrochloride (490 g, 7.1 mol) was added thereto by dividing into several times followed by stirring at room temperature for 12 hours. The DCM layer was separated and then water (3.74 kg) and sodium hydrogen carbonate (1.62 kg, 19.3 mol) were successively added thereto at room temperature. After MsCl (998 g, 7.0 mol) was gradually dropped into the reaction mixture at 0 C. to 5 C., temperature of the mixture was raised to room temperature followed by stirring for 2 days. The DCM layer was separated and an aqueous layer was extracted with DCM (44.98 kg). The DCM layers were combined, the solvent was distilled off therefrom at 35 C. to 42 C., toluene (2.6 kg) was added to the residue followed by stirring for 1 hour at 55 C. to 60 C. Heptane (4.2 kg) was further added thereto followed by stirring for 1 hour at 55 C. to 60 C. The solid deposited therefrom was collected by filtration and dried in vacuo at 35 C. to 45 C. to give 795 g (73%) of the title compound (4a).

(10) Compound (4a):

(11) Melting point: 93 C. to 95 C.

(12) .sup.1H-NMR (CDCl.sub.3) : 1.78-1.88 (m, 4H), 2.48-2.55 (m, 2H), 3.24-3.32 (m, 2H), 3.94-4.02 (m, 4H), 6.06 (s, 1H).

Example 1

(13) The compound (13a) was produced according to the following reaction formula 4.

(14) ##STR00017## ##STR00018##

(1-1) Synthesis of 9-methyl-1,4-dioxa-9-azaspiro-[4.6]undecan-8-one (5a): Step (a)

(15) Under nitrogen atmosphere, a mixture of the compound (4a) (774 g, 4.5 mol) and toluene (6.7 kg) was stirred at room temperature for 30 minutes and potassium t-butoxide (760 g, 6.8 mol) was gradually added thereto. After the mixture was stirred at room temperature for 1 hour, methyl iodide (950 g, 6.7 mol) was gradually dropped thereinto followed by stirring for 1 hour more. The reaction was stopped by addition of water (800 g) thereto and, after that, a toluene layer was separated out therefrom and then an aqueous layer was extracted with dichloromethane (22.8 kg). An organic layer was concentrated in vacuo at 35 C. to 45 C. to give 814.5 g (97%) of the title compound 5a as an amorphous solid.

(16) Compound (5a):

(17) .sup.1H-NMR (CDCl.sub.3) : 1.75-1.86 (m, 4H), 2.52-2.60 (m, 2H), 3.00 (s, 3H), 3.36-3.46 (m, 2H), 3.92-4.01 (m, 4H)

(1-2) Synthesis of 10-[(4-methoxyphenyl)methyl]-8-methyl-1,4-dioxa-8-azaspiro[4.6]undecan-9-one (6a): Step (b)

(18) Under nitrogen atmosphere, a 2.5 mL/L solution of n-butyl lithium in hexane (2.1 L, 5.3 mol) was gradually dropped into a solution of diisopropylamine (540 g, 5.3 mol) in toluene (3.5 kg) at 20 C. to 10 C. followed by stirring for 3 hours. After that, a solution of the compound 5a (800 g, 4.3 mol) in toluene (3.5 kg) was gradually dropped thereinto at 5 C. to 0 C., the mixture was stirred for 1 hour and then 4-methoxybenzyl chloride (680 g, 4.3 mol) was gradually dropped thereinto at 5 C. to 0 C. After the mixture was stirred at 5 C. to 5 C. for 1 hour, 0.5 mol/1 hydrochloric acid (14.0 kg, corresponding to 7 mol as hydrogen chloride) was gradually dropped thereinto at 0 C. to 10 C. followed by stirring for 30 minutes. The organic layer was separated therefrom, washed with 10 wt % aqueous solution of sodium hydrogen carbonate (2.0 g) and concentrated in vacuo at 30 C. to 40 C. to give 945 g (72%) of the title compound as an oily substance.

(19) Compound (6):

(20) .sup.1H-NMR (CDCl.sub.3) : 1.52 (dd, J=11.1, 14.1 Hz, 1H), 1.72-1.77 (m, 3H), 2.53 (dd, J=9.4, 14.4 Hz, 1H), 2.93-3.00 (m, 1H), 3.02 (s, 3H), 3.03-3.10 (m, 1H), 3.18 (dd, J=5.5, 14.4 Hz, 1H), 3.45-3.49 (m, 1H), 3.76-3.88 (m, 7H), 6.81-6.86 (m, 2H), 7.16 (d, J=8.7 Hz, 2H).

(1-3) Synthesis of 10-[(4-methoxyphenyl)methyl]-8-methyl-1,4-dioxa-8-azaspiro[4.6]undecane 4-nitrobenzoate (7a): Step (c)

(21) Under nitrogen atmosphere, a solution of the compound 6a (900 g, 2.9 mol) in toluene (4.5 kg) was gradually dropped into a 70 wt % solution of Red-Al in toluene (3.4 kg, 11.8 mol as Red-Al) at 15 C. to 25 C. followed by stirring at 15 C. to 25 C. for 2 hours. Under cooling with ice, a 30 wt % aqueous solution of potassium sodium tartrate (6.7 kg) was carefully added thereto, the mixture was stirred for 30 minutes and a toluene layer was separated therefrom. 4-Nitrobenzoic acid (0.46 kg, 2.8 mol) was added to the toluene layer at 15 C. to 25 C. followed by stirring for 2 hours. The solid deposited therefrom was collected by filtration to give 1.16 kg (86%) of the title compound 7a.

(22) Compound (7a):

(23) Melting point: 97-100 C.

(24) .sup.1H-NMR (DMSO-d.sub.6) : 1.66 (dd, J=10.5, 14.3 Hz, 1H), 1.72-1.76 (m, 1H), 1.88-1.94 (m, 2H), 2.08-2.25 (m, 1H), 2.36-2.53 (m, 6H), 2.66-2.78 (m, 1H), 2.81-2.92 (m, 2H), 3.58-3.63 (m, 1H), 3.70-3.83 (m, 6H), 6.84 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 8.11 (d, J=8.7 Hz, 2H), 8.25 (d, J=8.7 Hz, 2H).

(25) (1-4) Synthesis of 6-[(4-methoxyphenyl)methyl]-1-methylazepan-4-one (8a): Step (d)

(26) Under nitrogen atmosphere, a mixture of the compound 7a (1.16 kg, 2.5 mol) and 6 mol/L hydrochloric acid (4.4 kg, 28.8 mol as hydrogen chloride) was stirred at 25 C. for 2 hours and, after that, the solid was filtered off. The filtrate was adjusted to pH 10 to 12 using a 50 wt % aqueous solution of sodium hydroxide and extracted with toluene (5.5 kg). The organic layer was concentrated in vacuo at 45 C. to 55 C. to give 575 g (92%) of the title compound 8a as an oily product.

(27) Compound (8):

(28) .sup.1H-NMR (CDCl.sub.3) : 2.18-2.31 (m, 2H), 2.34 (s, 3H), 2.36-2.42 (m, 1H), 2.45-2.53 (m, 3H), 2.54-2.63 (m, 2H), 2.73-2.84 (m, 3H), 3.78 (s, 3H), 6.83 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.5 Hz, 2H).

(1-5) Synthesis of 6-[(4-methoxyphenyl)methyl]-1,4-dimethylazepan-4-ol (9a): Step (e)

(29) Under nitrogen atmosphere, a solution of the compound 8a (378 g, 1.5 mol) in toluene (1.1 kg) was gradually dropped into a 3.0 mol/L solution of methyl magnesium chloride in THF (2 L, 6.0 mol as methyl magnesium chloride) at 0 C. to 5 C. followed by stirring for 30 minutes. After the reaction mixture was carefully added to ice water (3 kg) at 0 C. to 20 C., a toluene layer was separated and an aqueous layer was extracted with toluene (3.8 kg). The organic layers were combined and concentrated in vacuo at 45 C. to 55 C. to give 378 g (88%) of the title compound 9a as an oily product.

(30) Compound (9a):

(31) .sup.1H-NMR (CDCl.sub.3) : 1.13-1.22 (m, 3H), 1.60-2.02 (m, 4H), 2.13-2.88 (m, 10H), 3.79 (s, 3H), 6.79-6.84 (m, 2H), 7.02-7.08 (m, 2H).

(1-6) Synthesis of 3-[(4-methoxyphenyl)methyl]-1,5-dimethyl-2,3,6,7-tetrahydroazepine (10a) and 3-[(4-methoxy-phenyl)methyl]-1,5-dimethyl-2,3,4,7-tetrahydroazepine (10b): Step (f)

(32) p-TsOH (1.0 g, 5.7 mmol) was added to a solution of the compound 9a (0.5 g, 1.9 mmol) in toluene (5 mL) and the mixture was heated to reflux for 20 hours. After the reaction mixture was allowed to cool, it was adjusted to pH 1213 using a 10 wt % aqueous solution of sodium hydroxide and extracted with ethyl acetate (10 mL). After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was evaporated to dryness in vacuo and the resulting residue was isolated/purified by silica gel column chromatography (Wakogel C-300HG, chloroform:methanol=99:1) to give the title compounds 10a (0.02 g, 4%) and 10b (0.01 g, 2%) as an oil product each.

(33) Compound (10a):

(34) .sup.1H-NMR (CDCl.sub.3) : 1.70 (s, 3H), 2.10 (dd, J=7.5, 15.8 Hz, 1H), 2.15 (dd, J=1.9, 11.9 Hz, 1H), 2.22-2.28 (m, 1H), 2.33 (s, 3H), 2.44 (dd, J=10.1, 15.7 Hz, 1H), 2.52-2.63 (m, 2H), 2.70-2.77 (m, 1H), 2.68 (d, J=12.1, 1H), 2.80 (dd, J=7.5, 11.7 Hz, 1H), 3.78 (s, 3H), 5.31-5.35 (m, 1H), 6.82 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H).

(35) MS (EI): m/z 245 [M].sup.+.

(36) Compound (10b):

(37) .sup.1H-NMR (CDCl.sub.3) : 1.67 (s, 3H), 1.99 (d, J=15.1 Hz, 1H), 2.00-2.09 (m, 1H), 2.18 (dd, J=10.0, 15.0 Hz, 1H), 2.29 (s, 3H), 2.40 (d, J=12.1 Hz, 1H), 2.43 (dd, J=7.1, 13.8 Hz, 1H), 2.51 (dd, J=7.1, 13.8 Hz, 1H), 2.71 (dd, J=3.8, 12.1 Hz, 1H), 2.92-3.04 (m, 2H), 3.79 (s, 3H), 5.45-5.50 (m, 1H), 6.82 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.6 Hz, 2H).

(38) MS (EI): m/z 245 [M.sup.+].

(1-7) Synthesis of the Compound (10a) and the Compound (10b): Step (f)

(39) The same process as in the above (1-6) was carried out except that p-TsOH was changed to P.sub.2O.sub.3 to produce the compound 10 (84.1%).

(1-8) Synthesis of the Compound (10a) and the Compound (10b): Step (f)

(40) The same process as in the above (1-6) was carried out except that p-TsOH was changed to BF.sub.3.Et.sub.2O complex to produce the compound 10 (93.8%).

(1-9) Synthesis of the Compound (10a) and the Compound (10b): Step (f)

(41) The same process as in the above (1-6) was carried out except that p-TsOH was changed to TFA/TFAA to produce the compound 10 (80.4%).

(42) (1-10) Synthesis of the Compound (10a) and the Compound (10b): Step (f)

(43) The same process as in the above (1-6) was carried out except that p-TsOH was changed to MsOH to produce the compound 10 (71%).

(44) (1-11) Synthesis of the Compound (10a) and the Compound (10b): Step (f)

(45) The same process as in the above (1-6) was carried out except that p-TsOH was changed to TfOH to produce the compound 10 (87%).

(46) The yields shown in the above (1-7) to (1-11) are the reaction yields by taking out the crude reaction solution followed by determining by means of high-performance liquid chromatography.

(1-12) Synthesis of 2,3,4,5,6,7-hexahydro-1,4-dimethyl-10-methoxy-1,6-methano-1H-4-benzoazonine (11a): Step (g)

(47) A mixture (1.18 g, 4.8 mmol) of the compound l0a and the compound 10b dissolved in anhydrous DCM (5 mL) was dropped into a mixture of aluminum chloride (1.9 g, 14.2 mmol) and anhydrous DCM (5 mL) during 3 minutes under cooling with ice. After stirring at room temperature for 5 hours, the reaction mixture was added to water (5 mL) at the temperature of not higher than 10 C. After adjusting the pH to 1011 using a 15 wt % aqueous solution of sodium hydroxide, ethyl acetate (100 mL) was added thereto and the solid was removed using Celite. An organic layer was separated therefrom and an aqueous solution was extracted with ethyl acetate (50 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After that, the solvent was evaporated in vacuo and the resulting residue was purified by means of silica gel column chromatography (PSQ-100B, chloroform:methanol=49:1) to give the title compound 11a (1.15 g, 97%) as an oily product.

(48) Compound (11a):

(49) .sup.1H-NMR (CDCl.sub.3) : 1.26 (s, 3H), 1.65-1.78 (m, 4H), 1.81 (dd, J=7.1, 13.4 Hz, 1H), 2.18-2.26 (m, 4H), 2.34-2.41 (m, 1H), 2.42-2.49 (m, 1H), 2.56-2.62 (m, 1H), 2.80 (dd, J=4.5, 15.5 Hz, 1H), 2.98-3.06 (m, 1H), 3.79 (s, 3H), 6.69 (dd, J=2.7, 8.4 Hz, 1H), 6.79 (d, J=2.7 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H).

(50) MS (E/I): m/z 245 [M].sup.+.

Example 2

(2-1) Synthesis of 2,3,4,5,6,7-hexahydro-1,4-dimethyl-10-methoxy-1,6-methano-1H-4-benzoazonine (11a): One-Pot Synthesis: Steps (f) and (g)

(51) Under nitrogen atmosphere, p-TsOH (196 g, 1.1 mol) was added to a solution of the compound 9a (100 g, 0.38 mol) in toluene (600 g) at 25 C. followed by heating to reflux for 20 hours. After being allowed to cool, water (800 g) was gradually dropped thereinto at 15 C. to 25 C. followed by stirring for 30 minutes. An aqueous layer was separated, adjusted to pH 1213 at 15 C. to 25 C. using a 30 wt % aqueous solution of sodium hydroxide and extracted with MTBE (21 L). After an organic layer was concentrated in vacuo at 25 C. to 35 C., the residue was diluted with dichloromethane (500 mL). This diluted solution was gradually dropped, at 0 C. to 5 C., into a mixture of aluminum chloride (151 g, 1.13 mol) and DCM (500 mL) followed by stirring for 30 minutes. After that, temperature of the above was raised to 15 C.25 C. followed by stirring for 20 hours. The reaction mixture was dropped into water (1 L) at 0 C. to 10 C. followed by adjusting the pH to 1213 at 15 C. to 25 C. using a 30 wt % aqueous solution of sodium hydroxide. This was extracted with MTBE (21 L) and organic layers were combined followed by concentrating in vacuo at 15 C. to 25 C. to give 68 g (73%) of the title compound 11a as an oily product.

Example 3

(3-1) Synthesis of ()-(1S,6S)-2,3,4,5,6,7-hexahydro-1,4-dimethyl-10-methoxy-1,6-methano-1H-4-benzoazonine (12a): Step (h)

(52) D-Mandelic acid (9.5 g, 0.06 mol) was added to a solution of the compound 11a (31.6 g, 0.13 mol) in MTBE (310 mL) at 15 C. to 25 C. followed by stirring for 1 hour. The deposited solid was collected by filtration and washed with MTBE (31 mL). A 1 mol/L aqueous solution of sodium hydroxide (49 mL, 49 mmol as sodium hydroxide) was added to the resulting solid at 15 C. to 25 C. followed by stirring for 1 hour. This was extracted with toluene (2150 mL) and concentrated in vacuo at 45 C. to 55 C. to give 12.0 g (38%) of the title compound 12a as an oily product.

(53) Compound (12a):

(54) .sup.1H-NMR (CDCl.sub.3) : 1.26 (s, 3H), 1.65-1.78 (m, 4H), 1.81 (dd, J=7.1, 13.4 Hz, 1H), 2.18-2.26 (m, 4H), 2.34-2.41 (m, 1H), 2.42-2.49 (m, 1H), 2.56-2.62 (m, 1H), 2.80 (dd, J=4.5, 15.5 Hz, 1H), 2.98-3.06 (m, 1H), 3.79 (s, 3H), 6.69 (dd, J=2.7, 8.4 Hz, 1H), 6.79 (d, J=2.7 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H).

(55) MS (EI): m/z 245 [M].sup.+

(3-2) Synthesis of ()-(1S,6S)-2,3,4,5,6,7-hexahydro-1,4-dimethyl-1,6-methano-1H-4-benzoazonin-10-ol (Eptazocine): Step (i)

(56) Under nitrogen atmosphere, the compound 12a (10 g, 0.04 mol) was added to a 48 wt % solution of hydrogen bromide in acetic acid (50 mL) at 10 C. to 20 C. followed by stirring for 15 minutes. This was warmed at 35 C. to 40 C. and stirred for 12 hours. After the reaction mixture was allowed to stand, it was concentrated in vacuo. Further, toluene (100 mL) was added to the residue and acetic acid was azeotropically distilled whereupon a solid 13b was prepared. The resulting solid was dissolved in water (200 mL) and its pH was adjusted to 11-12 using a 2.5 mol/L aqueous solution of sodium hydroxide. After it was stirred at 20 C. to 30 C. for 8 hours under nitrogen atmosphere, its pH was adjusted to 7-8 by 6 mol/L hydrochloric acid and the suspension was stirred for 1 hour. The solid was collected by filtration and washed with water (50 mL). After that, the solid was added to ethanol (300 mL) and the resulting slurry was stirred for 1 hour at 70 C. to 75 C. and allowed to cool down to 20 C.30. The solid was collected by filtration, washed with ethanol (50 mL) and dried at 70 C. to 80 C. in vacuo to give 8.2 g (87%) of the title compound 13a.

(57) Compound (13a):

(58) .sup.1H-NMR (DMSO-d.sub.6) : 1.16 (s, 3H), 1.50-1.65 (m, 4H), 1.66-1.71 (m, 1H), 2.08-2.16 (m, 4H), 2.23-2.35 (m, 2H), 2.48-2.53 (m, 1H), 2.68 (dd, J=4.5, 15.3 Hz, 1H), 2.87-2.93 (m, 1H), 6.50 (dd, J=2.5, 8.1 Hz, 1H), 6.63 (d, J=2.5 Hz, 1H).