JPH0745513B2 - Method for producing bicyclic compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing a bicyclic peptide compound having a medicinal effect.

[Conventional technology]

The present inventors isolated a bicyclic hexapeptide (hereinafter referred to as RA compound) having a stronger carcinostatic effect than Akane grass, determined its structure, and filed a patent application (JP-A-58-21655).

[Problems to be solved by the invention] However, the extraction of RA compounds from madder grass has a drastic change in the content thereof from 0 mg to 500 mg / kg or more depending on the harvest time of madder grass, the region, etc. Cultivation is limited due to worldwide decline, and stable acquisition is difficult, and establishment of a chemical production method is essential for obtaining a large amount of RA compounds.

The object of the present invention is to provide the RA compound and its related compounds,
It is to provide a method of chemically manufacturing all steps.

[Means for solving problems]

The present invention can be summarized by the following general formula I: (In the formula, R ₁ and R ₅ are hydrogen or a methoxy group, R ₂ is a methoxy group, or a group bonded to R ₄ via oxygen, R ₃ is hydrogen, or a group bonded to R ₅ via oxygen, R ₄ is hydrogen or a group that bonds to R ₂ through oxygen, R ₅ is a methoxy group, or a group that bonds to R ₃ through oxygen, provided that R ₂ and R ₅ are methoxy groups at the same time. However, one of them is always a methoxy group) is an invention relating to a method for producing a bicyclic compound represented by the following general formula II: A compound represented by the formula (wherein R _{1 to} R ₆ are as defined above) or a reactive derivative of the free amino group and / or carboxy group thereof is condensed in the presence of a condensing agent. And

The RA compound has a 14-membered ring in which two molecules of N-methyltyrosine are amide-bonded and the phenol ring is also ether-bonded.
In addition to these 2 molecules of N-methyltyrosine, 2 molecules of L-alanine, 1 molecule of D-alanine, 1 molecule of N-methyltyrosine, 6 in total
Where the amino acid of the molecule has a structure in which a 18-membered ring forming a ring is bonded, of these, for 14-membered ring compounds, we have developed a method for producing compounds that can be precursors thereof,
We have already applied for a patent (Japanese Patent Application No. 61-79322).

Furthermore, as a result of continuing this research, the present invention was successfully achieved by successfully producing the RA compound.

The compounds according to the present invention are collectively referred to as RASY compounds and are represented by the general formula I above.

R ₁ , R ₃ and R ₆ are hydrogen, R ₂ is bonded to R ₄ via oxygen, and R ₅ is a methoxy group, and RSY-VII, R ₁ and R ₃ are hydrogen, and R ₂ is oxygen. via bonded to _{R 4, R 5, MeO R} 6 is a compound which is a methoxy group _{RASY-VII, R 1, R} 4, R 6 are hydrogen, R ₃ is through the oxygen bonded to R _5, A compound in which R ₂ is a methoxy group is iso RASY-VII, a compound in which R ₄ and R ₆ are hydrogen, a compound in which R ₃ is bonded to R ₅ via oxygen, and a compound in which R ₁ and R ₂ are methoxy groups are MeO iso RASY -Named it VII. Hereinafter, in the present specification, the compound name will be described by this abbreviation.

An example of the method for producing the compound according to the present invention will be described. The 14-membered ring dienone compound obtained by the method described in Japanese Patent Application No. 60-287976 is reduced with zinc / acetic acid to give a diphenyl ring compound, and the hydroxyl group is methyl. After removing the halogen element in the usual manner by catalytic reduction, the tetrapeptide having the protected amino group was combined with the 14-membered ring compound from which the amino protecting group was removed, and the compound from which both protecting groups were removed was removed. The ring is closed to produce an 18-membered ring.

Regarding the difference between the RASY compound according to the present invention and the RA compound disclosed in JP-A No. 58-21655 as a compound, RASY-V
II had the same molecular weight, NMR, and IR as TPC-B in the RA compound, and showed the same value in all in vitro cell killing tests using P388 cells, while Japanese Patent Application No. 60- 28797
The iso RASY-VII obtained by the same procedure using the product described in Example 1 of the specification No. 6 as a starting material is RA in terms of molecular weight.
Same as SY-VII but different in NMR and RASY-VI
The cell killing test carried out at the same time as I was also clearly different from RASY-VII (1/1000 activity of RASY-VII), so the RASY compound and the iso RASY compound are different compounds. The compound could be determined to be the same compound as the RASY compound. Also, in producing an 18-membered ring, there are stereoisomers that are thought to be due to the structure of the 14-membered ring, and before the formation of the 18-membered ring, there are always two compounds by NMR. The compound appeared to exhibit the same NMR with an 18-member ring closure. This was also in agreement with the characteristic that the RA compound from Akane was present in only one compound in terms of NMR.

As the carboxy protecting group used when producing the starting material of the method of the present invention, a commonly used protecting group can be generally used, but a carboxy protecting group which is not cleaved during the reaction depending on the subsequent reaction conditions of the protecting material is preferable. For example, benzyl alcohol, phenacyl alcohol, p-chlorobenzyl alcohol, p- can be removed by catalytic reduction.
Benzyl alcohols such as nitrobenzyl alcohol and o-cyanobenzyl alcohol, picolyl alcohol and their reactive esterified derivatives can be removed by acid treatment as t-butyl alcohol, diphenylmethyl alcohol and trityl alcohol. , Trimethylbenzyl alcohol, pentamethylbenzyl alcohol, etc. and their reactive esterified derivatives, and those which can be removed by alkali treatment include methyl alcohol, β-methylthioethyl alcohol, phthalimidomethyl alcohol, cyclopentyl alcohol, etc. Reactive esterified derivatives can mainly be used.

On the other hand, as the amino-protecting group, a suitable one for the subsequent reaction is selected in the same manner as the carboxy-protecting group.
Nitrobenzyloxycarboxylic acid, diisopropylmethyloxycarboxylic acid, benzhydryloxycarboxylic acid, benzylsulfonic acid and their reactive derivatives,
As those that can be removed by acid treatment, t-butoxycarboxylic acid, t-amyloxycarboxylic acid, benzyloxycarboxylic acid, p-methoxybenzyloxycarboxylic acid, p-biphenylisopropyloxycarboxylic acid and reactive derivatives thereof, In addition to formic acid, trifluoroacetic acid, β- (p-methylphenylthio) ethoxycarboxylic acid, o-nitrophenoxycarboxylic acid, 2-cyano-1,1-dimethylethoxycarboxylic acid can be removed by alkali treatment. Acid, β-
(P-Toluenesulfonyl) ethoxycarboxylic acids and their reactive derivatives are mainly available.

The condensing agent used in the method of the present invention is an organic or inorganic basic substance, bistrimethylsilylacetamide (BSA) and bistrimethylsilylurea (BS
A silyl compound such as U) and a coupling reagent mainly for activation of a carboxy group [eg, dicyclohexylcarbodiimide (DCC), carbonyldiimidazole,
Woodward reagent K, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), etc. are included. Condensation methods include azide method, mixed acid anhydride method, active ester method, symmetrical acid anhydride Method and the Mukaiyama method using a pyridinium salt are suitable, but even if these methods are adopted, it is desirable to avoid the conditions that induce optical isomerism and stereoisomerism of the target compound, and naturally use of a strong base ,
Reactions at high temperatures were unfavorable.

Cell growth inhibitory effect (IC ₅₀ ) The target compound was dissolved in dimethylsulfoxide (DMSO), diluted stepwise, and added to the suspension of P388 cells at a DMSO concentration of 0.1%. After the time culture, the number of cells was counted with a Coulter counter (ZBI model). The cell concentration when the target compound was added was 1.26 to 2.3 × 10 ⁴ cells / ml.

[Examples] Hereinafter, the present invention will be described in more detail with reference to Examples.
The present invention is not limited to these examples.

Example 1 After dissolving 400 mg of the compound (1) in 15 ml of 90% acetic acid, 800 mg of zinc dust was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The insoluble material was filtered off, and the filtrate was concentrated. To the residue was added saturated aqueous sodium hydrogen carbonate solution (40 ml), and the mixture was extracted with chloroform (30 ml). The aqueous layer was further extracted twice with 20 ml of chloroform, all the extracts were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column and ODS liquid chromatography, and the two components of the conformer (medium) were purified. There were obtained 150 mg of colorless and amorphous crystals of compound (2) which was a mixture (7: 3) of A and minor B).

Compound (2) IR (CHCl ₃ ): 3530, 1742, 1683, 1643 cm ⁻¹ NMR (CDCl ₃ ) δ: 2.55 (e, 3H, A), 270 (dd, J = 3Hz, 11H
z, 1H, A), 2.72 (s, 3H, B), 2.78 = 2.96 (m, 1H, A, B),
2.99 (s, 3H, B), 3.02 (s, 3H, A), 3.13 (dd, J = 5Hz, 11
Hz, 1H, B), 3.35 to 3.41 (m, 1H, A, B), 3.49 (s, 3H,
A), 3.54 (s, 3H, B), 3.57 to 3.67 (m, 1H, A, B), 4.61
(D, J = 2Hz, 1H, A), 4.72 (dd, J = 4Hz, 12Hz, 1H, A), 4.
92 (dd, J = 3Hz, 11Hz, 1H, A), 5.06 (d, J = 2Hz, 1H, B),
5.11 (d, J = 9Hz, 1H, A), 5.13 (d, J = 9Hz, 1H, A), 5.20
(S, 2H, B), 5.29 (dd, J = 5Hz, 12Hz, 1H, B), 5.54 (dd,
J = 5Hz, 12Hz, 1H, B), 6.07 (b, 1H, A, B), 6.95 (d, J = 2)
Hz, 1H, A), 6.98 (d, J = 2Hz, 1H, B), 7.13 to 7.48 (m, 7
H, A, B) After dissolving 150 mg of the compound (2) in 1 ml of methanol, an ether solution of diazomethane was added under ice-cooling until nitrogen gas was not generated and coloring occurred. Then, the mixture was allowed to stand at room temperature for 1 hour, concentrated under reduced pressure, purified by applying the residue to a silica gel column, and colorless amorphous crystals of compound (3), which was a mixture (7: 3) of two components of conformer (major A, minor B). 120
to obtain mg.

Compound (3) IR (CHCl ₃ ): 1740, 1680, 1643 cm ⁻¹ NMR (CDCl ₃ ) δ: 2.57 (s, 3H, A), 2.72 (dd, J = 3Hz, 10H
z, 1H, A), 2.82 (s, 3H, B), 2.86 to 2.95 (m, 1H, A, B),
3.00 (s, 3H, B), 3.03 (s, 3H, A), 3.18 (dd, J = 3Hz, 10
Hz, 1H, B), 3.36 to 3.46 (m, 1H, A, B), 3.48 (s, 3H,
A), 3.54 (s, 3H, B), 3.60 to 3.67 (m, 1H, A, B), 4.08
(S, 3H, A), 4.10 ((s, 3H, B), 4.50 (d, J = 2Hz, 1H,
A), 4.71 (dd, J = 4Hz, 12Hz, 1H, A), 4.93 (dd, J = 3Hz,
11Hz, 1H, A), 5.11 (d, J = 12Hz, 1H, A), 5.12 (d, J = 12)
Hz, 1H, A), 5.20 (s, 2H, B), 5.29 (bd, J = 12Hz, 1H,
B), 5.56 (dd, J = 5Hz, 11Hz, 1H, B), 6.98 (d, J = 2Hz, 1
H, A), 7.00 (b, 1H, B), 7.25 ~ 7.50 (m, 7H, A, B) After dissolving 110 mg of compound (3) in 3 ml of methanol, 150 mg of potassium acetate and 100 mg of 5% palladium-carbon were added under ice cooling,
Then, the mixture was vigorously stirred under a hydrogen atmosphere at room temperature for 6 hours. After completion of the reaction, the insoluble matter was filtered off, the filtrate was concentrated, 30 ml of saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with 20 ml of chloroform. The extracts were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by PTLC, and the compound (4), which was a mixture (5: 4) of two components of conformer (major A, minor B). 46 mg of colorless amorphous crystals of

Compound (4) Media AIR (KBr): 3460, 1760, 1636 cm ^-1 NMR (CDCl ₃ ) δ: 2.35 (s, 3H), 2.72 (s, 3H), 2.96 ~
3.24 (m, 4H), 3.40 (dd, J = 4Hz, 10Hz, 1H), 3.70 (s, 3
H), 3.94 (s, 3H), 4.29 (d, J = 2Hz, 1H), 4.35 (dd, J
= 4Hz, 11Hz, 1H), 6.61 (dd, J = 2Hz, 8Hz, 1H), 6.82
(D, J = 8Hz, 1H), 6.92 (dd, J = 2Hz, 9Hz, 1H), 7.14 (d
d, J = 2Hz, 8Hz, 1H), 7.25 (dd, J = 2Hz, 9Hz, 1H), 7.34
(Dd, J = 2Hz, 8Hz, 1H) Minor B IR (KBr): 3460, 1760, 1636cm ^-1 NMR (CDCl ₃ ) δ: 2.46 (s, 3H), 2.73 (s, 3H), 2.96 ~
3.12 (m, 4H), 3.53 (dd, J = 4Hz, 10Hz, 1H), 3.67 (s, 3
H), 3.86 (dd, J = 5Hz, 11Hz, 1H), 3.93 (s, 3H), 4.74
(D, J = 2Hz, 1H), 6.61 (dd, J = 2Hz, 8Hz, 1H), 6.75
(D, J = 8Hz, 1H), 7.05 (dd, J = 2Hz, 8Hz, 1H), 7.21〜
7.28 (m, 2H), 7.43 (dd, J = 2Hz, 8Hz, 1H) N-methyl-N-benzyloxycarbonyl-L-tyrosine 3
After dissolving 9.5 g, 30 g of alanine methyl ester hydrochloride and 23 g of N-hydroxybenzotriazole in 500 ml of methylene chloride, 30 ml of triethylamine was added under stirring at room temperature, and then a solution of 30 g of DCC in methylene chloride (dissolved in 150 ml of methylene chloride) was added over 30 minutes. The mixture was added dropwise and stirred for 12 hours.
The generated insoluble matter was filtered off, the filtrate was concentrated, 500 ml of ethyl acetate was added to the residue, and the insoluble matter was filtered off again. The filtrate was washed successively with 1N aqueous hydrochloric acid solution (500 ml), saturated saline solution (500 ml), saturated aqueous sodium hydrogen carbonate solution (500 ml) and saturated saline solution (500 ml), dried over magnesium sulfate and filtered, and the filtrate was concentrated. Then, it was purified by applying it to a silica gel column to obtain 48.1 g of a colorless oily compound (7).

Compound (7) IR (CHCl ₃ ): 3600, 3410, 1740, 1680 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.48 (d, J = 7 Hz, 3H), 2.86 (s, 3H),
2.93 (bd, J = 11Hz, 1H), 3.22 (bdd, J = 6Hz, 11Hz, 1
H), 3.71 (s, 3H), 4.49, 4.53 (each q, J = 7Hz, total 1H),
4.73,4.90 (each bm, total 1H), 5.11 (bs, 2H), 6.23 (b, 1
H), 6.67 (d, J = 8Hz, 2H), 6.92 (b, 1H) 6.96 (bd, J =
8Hz, 2H), 7.26 ~ 7.37 (m, 5H) After dissolving 40.6 g of compound (7) in 120 ml of methanol, add an ether solution of diazomethane under ice-cooling until the starting compound on TLC disappears, concentrate under reduced pressure, and purify the residue by applying it to a silica gel column for colorless and amorphous form of compound (8). 42 g of crystals were obtained.

Compound (8) IR (CHCl ₃ ): 3410, 1740, 1680 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.34 (d, J = 7 Hz, 3H), 2.84 (s, 3H),
2.93 (bm, 1H), 3.25 (bm, 1H), 3.72 (s, 3H), 3.77
(S, 3H), 4.50,4.53 (each q, J = 7Hz, total 1H), 4.90,5.03
(Each bm, total 1H), 5.11 (bs, 2H), 6.52, 7.02 (each b, total 1
H), 6.78 (bd, J = 8Hz, 2H), 7.11 (bd, J = 8Hz, 2H),
7.26 ~ 7.36 (m, 5H) After dissolving 42.5 g of the compound (8) in 300 ml of methanol, 5 g of 5% palladium carbon and 9.5 ml of concentrated hydrochloric acid were added, and then the mixture was vigorously stirred at room temperature under a hydrogen atmosphere for 4 hours. After completion of the reaction, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain 29.9 g of compound (9) as colorless crystals.

Compound (9) NMR (CDCl ₃ ) δ: 1.45 (d, J = 7Hz, 3H), 3.40 (m, 2H),
3.67 (s, 3H), 3.73 (s, 3H), 4.38 (bm, 2H), 6.80
(D, J = 9Hz, 2H), 7.25 (d, J = 9Hz, 2H), 8.95,9.91
(Each bs, total 2H) Compound (9) (29.64 g) and N-benzyloxycarbonialanine (25 g) were dissolved in methylene chloride (400 ml), triethylamine (14 ml) was added under ice-cooling, and DCC (23.1 g) dissolved in methylene chloride (dissolved in methylene chloride (150 ml)) was added under stirring. The mixture was added dropwise over a period of 1 minute, and the mixture was further stirred at room temperature for 15 hours. The generated insoluble matter was filtered off, the filtrate was concentrated, 500 ml of ethyl acetate was added to the residue, and the insoluble matter was filtered off again. The filtrate was washed successively with 500 ml of a saturated sodium hydrogen carbonate aqueous solution and 500 ml of a saturated saline solution, dried over magnesium sulfate and filtered, and then the filtrate was concentrated.
Then, it was purified by applying it to a silica gel column to obtain 42.4 g of colorless and amorphous crystals of compound (11).

Compound (11) IR (CHCl ₃ ): 3420, 3310, 1740, 1705, 1675, 1640 cm ⁻¹ NMR (CDCl ₃ ) δ: 0.41,1.27, 1.33, 1.37 (each d, J = 7 Hz, total 6)
H), 2.91, 2.96 (each s, 3H in total), 2.99 to 3.32 (m, 2H), 3.
70,3.74,3.75 (each s, total 6H), 4.23,4.50,4.84 (each m, total 3)
H), 4.90 to 5.16 (m, 2H), 6.79, 6.82 (each d, J = 9Hz, total 2)
H), 7.04, 7.10 (each d, J = 9Hz, total 2H), 7.25 to 7.37 (m, 5
H), 5.33, 5.60, 6.58, 8.10 (each bd, J = 7Hz, 8Hz, 7Hz, 7Hz,
2H in total) After dissolving 42.1 g of compound (11) in 500 ml of methanol, 5 g of 5% palladium carbon and 8.5 ml of concentrated hydrochloric acid were added, and then vigorously stirred at room temperature for 5 hours in a hydrogen atmosphere. After completion of the reaction, the insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, benzene was added to the residue, and the precipitated crystals were collected by filtration and dried to give 33.2 g of colorless crystals of compound (12).

Compound (12) NMR (CDCl ₃ ) δ: 0.69, 1.35, 1.46, 1.50 (each d, J = 7Hz, 7H
z, 7Hz, 9Hz, total 6H), 3.65, 3.69 (each s, total 3H), 3.73, 3.76
(Each s, total 3H), 4.35 to 4.83 (m, 3H), 6.78, 6.81 (each d, J
= 9Hz, total 2H), 7.08, 7.10 (each d, J = 9H, total 2H), 8.15, 8.
32 (each bs, 3H in total), 8.43 (d, J = 8Hz, 1H) Compound (12) 13.16g, N-benzyloxycarbonyl-D-
Alanine 11g and N-hydroxybenzotriazole 7.55g
Was dissolved in 500 ml of methylene chloride, 6 ml of triethylamine was added under ice-cooling, and then a solution of 10.17 g of DCC in methylene chloride (dissolved in 80 ml of methylene chloride) was added dropwise over 30 minutes, followed by stirring at room temperature for 37 hours. The generated impurities were filtered off, the filtrate was concentrated, 500 ml of benzene was added to the residue, and the insoluble matter was filtered off again. The filtrate was concentrated, and the residue was applied to a silica gel column for purification to obtain 18.28 g of colorless amorphous crystals of compound (14).

Compound (14) IR (CHCl ₃ ): 3420, 3300, 1720, 1660 cm ⁻¹ NMR (CDCl ₃ ) δ: 0.43, 1.22 to 1.37 (each m, 9H), 2.87, 2.9
5 (each s, total 3H), 3.04, 3.22 (each m, total 2H), 3.66, 3.70
(Each s, total 3H), 3.75, 3.76 (Each s, total 3H), 4.28, 4.50, 4.7
3,4.97 (each m, total 4H), 5.06 to 5.11 (m, 2H), 5.45, 5.75,
6.68, 8.21 (each d, J = 8Hz, 8Hz, 7Hz, 7Hz, total 3H), 6.77 to 6.
86 (m, 2H), 7.01 to 7.11 (m, 2H), 7.31 to 7.35 (m, 5H) Compound (14) (4.00 g) was dissolved in methanol (25 ml), 1N aqueous sodium hydroxide solution (8.5 ml) was added, and the mixture was stirred at room temperature for 1 hr. Next, the mixture was acidified with hydrochloric acid under ice cooling, extracted with chloroform, washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column purification to obtain 3.88 g of colorless amorphous crystals of compound (15). Obtained.

Compound (15) IR (CHCl ₃ ): 3420, 3300, 1720, 1660 cm ⁻¹ NMR (CDCl ₃ ) δ: 0.49, 1.23 to 1.45 (each m, total 9H), 2.83,
2.87,2.90,2.92 (each s, total 3H), 2.98,3.23 (each m, total 2)
H), 3.72, 3.74, 3.75, 3.79 (each s, 3H in total), 4.20, 4.37, 4.
49,4.71,4.89,5.00 (each m, 4H in total), 5.04 to 5.11 (m, 2
H), 5.53,5.93,8.00 (each bs, 3H in total), 6.82 (d, J = 8Hz, 2
H), 7.06 (d, J = 8Hz, 2H), 7.23 to 7.34 (m, 5H) Compound (4) 40 mg and compound (15) 120 mg were added to dioxane 3
After dissolution in ml, a DCC 50 mg dioxane solution (dissolved in dioxane 2 ml) was added dropwise at room temperature, and the mixture was further stirred for 4 hours.
The resulting insoluble matter was filtered off, the filtrate was concentrated, ethyl acetate was added to the residue, and the insoluble matter was filtered off again. After the filtrate was concentrated, the residue was purified by applying it to a silica gel column to obtain 60 mg of colorless amorphous crystals of compound (16).

Compound (16) IR (KBr): 3420, 3320, 1740, 1720, 1640cm ^-1 NMR (CDCl ₃ ) δ: 0.48 to 0.60, 1.22 to 1.37 (each m, total 9H),
2.54 (s, 3H), 2.72 to 3.28 (m, 6H), 2.87,2.89,2.95
(Each s, total 3H), 3.12, 3.17, 3.24 (each s, total 3H), 3.58, 3.6
2,3.63 (each s, 3H total), 3.77 (s, 3H), 3.94, 3.96 (each s, 3H)
3H), 4.16-4.37 (m, 2H), 4.37 (b, 1H), 4.58-4.
82 (m, 3H), 4.88-5.17 (m, 2H), 5.29 (m, 1H), 5.80
(M, 1H), 6.58 (b, 1H), 6.59 (m, 1H), 6.74 to 7.38
(M, 14H), 7.79 (b, 1H) Compound (16) 40 mg was added to methanol 1 ml and acetonitrile 1
After dissolving in a mixed solvent of ml, 0.5 ml of a 1N sodium hydroxide aqueous solution was added at room temperature, and the mixture was stirred for 2 hours. Next, 5 ml of saturated aqueous citric acid solution and 20 ml of saturated saline were added, and the mixture was extracted 3 times with 20 ml of chloroform. The extracts were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by PTLC to obtain 9.5 mg of colorless amorphous crystals of compound (17).

Compound (17) IR (KBr): 3420, 3320, 1725, 1640cm ^-1 NMR (CDCl ₃ ) δ: 0.44 to 0.56, 1.06 to 1.37 (each m, total 9H),
2.68 to 3.72 (m, 6H), 2.61, 2.78, 2.95, 3.11, 3.21 (each s,
Total 9H), 3.77, 3.78 (each s, total 3H), 3.94, 3.95 (each s, total 3)
H), 4.12 ~ 5.12 (m, 5H), 4.39 (bs, 1H), 5.05, 5.08
(Each s, total 2H), 5.50 (m, 2H), 6.32 (b, 1H), 6.60 (b
d, 1H), 6.76 to 7.43 (m, 15H), 8.27 (b, 1H) After dissolving 9.5 mg of compound (17) in 1 ml of methanol, 5 mg of 5% palladium carbon was added, and then 3% at room temperature under a hydrogen atmosphere.
I stirred it for a while. After completion of the reaction, the insoluble matter was filtered off and the filtrate was concentrated under reduced pressure to obtain 6.1 mg of compound (18).

The compound (18) obtained was dissolved in 2 ml of dioxane, and then DCC5m
A solution of g in dioxane (dissolved in 3 ml of dioxane) was added dropwise over 20 minutes, and the mixture was further stirred at room temperature for 15 hours. Then
The reaction solution was concentrated under reduced pressure, a small amount of ethyl acetate was added to the residue,
The insoluble matter was filtered off. The filtrate was concentrated, and the residue was purified by applying PTLC to obtain 3 mg of colorless and amorphous crystals of RASY-VII.

RASY-VII IR (KBr): 1660, 1640, 1630, 1510 cm ^-1 NMR (CDCl ₃ ) δ: 1.11 (d, J = 7Hz, 3H), 1.31 (d, J = 7H
z, 3H), 1.36 (d, J = 7Hz, 3H), 2.67 (bd, J = 10Hz, 1
H), 2.70 (s, 3H), 2.86 (s, 3H), 2.94 to 3.17 (m, 2
H), 3.13 (s, 3H), 3.47 (m, 1H), 3.55 to 3.80 (m, 2
H), 3.80 (s, 3H), 3.94 (s, 3H), 4.33 (bs, 1H), 4.
37 (t, J = 7Hz, 1H), 4.55 (dd, J = 5Hz, 12Hz, 1H), 4.72
~ 4.90 (m, 2H), 5.42 (bd, J = 10Hz, 1H), 6.36 (d, J =
8Hz, 1H), 6.44 (d, J = 7Hz, 1H), 6.59 (bd, J = 8Hz, 1)
H), 6.72 (d, J = 8Hz, 1H), 6.81 (d, J = 8Hz, 1H), 6.8
4 (d, J = 9Hz, 2H), 6.88 (dd, J = 2Hz, 8Hz, 1H), 7.05
(D, J = 9Hz, 2H), 7.18 to 7.30 (m, 2H), 7.43 (dd, J = 2
Hz, 8Hz, 1H) Example 2 Compound (19) (1.02 g) was treated in the same manner as compound (1) to produce MeO.
32 mg of colorless crystals of RASY-VII were obtained.

MeO RASY-VII IR (CHCl ₃ ): 1680, 1660, 1630 cm ^-1 NMR (CDCl ₃ ) δ: 1.10 (d, J = 7Hz, 3H), 1.31 (d, J = 7H
z, 3H), 1.36 (d, J = 7Hz, 3H), 2.67 (bd, J = 10Hz, 1
H), 2.72 (s, 3H), 2.87 (s, 3H), 2.90 to 3.15 (m, 2
H), 3.13 (s, 3H), 3.47 (m, 1H), 3.55 to 3.80 (m, 2
H), 3.79 (s, 3H), 3.80 (s, 3H), 3.97 (bs, 1H), 4.
00 (s, 3H), 4.42 (t, J = 7Hz, 1H), 4.55 (d, J = 10Hz, 1
H), 4.80 (t, J = 7Hz, 1H), 4.83 (t, J = 7Hz, 1H), 5.4
2 (bd, J = 10Hz, 1H), 6.20 (bs, 1H), 6.50 (d, J = 7Hz,
1H), 6.70 ~ 6.95 (m, 3H), 6.84 (d, J = 9Hz, 2H), 7.0
6 (d, J = 9Hz, 2H), 7.10 to 7.30 (m, 2H), 7.42 (dd, J =
2Hz, 9Hz, 1H) Example 3 2.18 g of compound (20) is treated in the same manner as compound (1) to produce iso
150 mg of white powder of RASY-VII was obtained.

iso RASY-VII NMR (CDCl ₃ ) δ: 0.98 (d, J = 7Hz, 3H), 1.41 (bd, J = 8H)
z, 3H), 1.45 (d, J = 7Hz, 3H), 2.22 (d, J = 16Hz, 1
H), 2.80 (s, 3H), 2.88 (s, 3H), 3.22 (s, 3H), 2.6
0 to 3.80 (complex, 6H), 3.62 (bd, J = 2Hz, 1
H), 3.80 (s, 6H), 3.96 (s, 3H), 4.36 (t, J = 7Hz, 1
H), 4.45 (bd, J = 11Hz, 1H), 4.65 (t, J = 7Hz, 1H),
4.81 (t, J = 7Hz, 1H), 5.26 (bd, J = 10Hz, 1H), 6.18
(D, J = 6Hz, 1H), 6.22 (bd, J = 2Hz, 1H), 6.67 (d, J =
9Hz, 1H), 6.84 (d, J = 9Hz, 2H), 7.02 (d, J = 9Hz, 2
H), 7.00 to 7.60 (complex, 5H) Example 4 Compound (21) (1.00 g) is treated in the same manner as compound (1) to produce MeO.
50 mg of colorless amorphous crystals of iso RASY-VII were obtained.

MeO iso RASY-VII NMR (CDCl ₃ ) δ: 0.97 (d, J = 7Hz, 3H), 1.39 (d, J = 7H
z, 3H), 1.44 (d, J = 7Hz, 3H), 2.24 (bd, J = 15Hz, 1
H), 2.79 (s, 3H), 2.87 (s, 3H), 3.11 (bd, J = 15Hz,
2H), 3.22 (s, 3H), 3.26 to 3.39 (m, 3H), 3.56 (dd, J
= 5Hz, 10Hz, 1H), 3.65 to 3.77 (m, 1H), 3.79 (s, 3
H), 3.91 (s, 3H), 3.93 (d, J = 2Hz, 1H), 4.35 ~ 4.48
(M, 2H), 4.61 (t, J = 7Hz, 1H), 4.83 (dd, J = 7Hz, 9H
z, 1H), 5.25 (bd, J = 10Hz, 1H), 6.55 (b, 1H), 6.59
(Bd, J = 2Hz, 8Hz, 1H), 6.67 (d, J = 9Hz, 1H), 6.76
(D, J = 8Hz, 1H), 6.83 (d, J = 9Hz, 2H), 7.0 to 7.2 (m,
6H), 7.54 (dd, J = 2Hz, 9Hz, 1H) [Effect of the invention] As described above, according to the present invention, the chemical total synthesis of the RA compound and its analogs became possible.

 ─────────────────────────────────────────────────── --- Continuation of front page (72) Inventor Takayuki Inaba 1-38-12 Takamatsu, Nerima-ku, Tokyo (56) References JP-A-60-109600 (JP, A) JP-A-58-21655 (JP, A) )

Claims (1)

[Claims] 1. The following general formula II: (In the formula, R ₁ and R ₆ are hydrogen or a methoxy group, R ₂ is a methoxy group, or a group bonded to R ₄ via oxygen, R ₃ is hydrogen, or a group bonded to R ₅ via oxygen, R ₄ is hydrogen or a group that bonds to R ₂ through oxygen, R ₅ is a methoxy group, or a group that bonds to R ₃ through oxygen, provided that R ₂ and R ₅ are methoxy groups at the same time. , But either one is always a methoxy group) or a reactive derivative of the free amino group and / or carboxy group thereof is condensed in the presence of a condensing agent. General formula I: A method for producing a bicyclic compound represented by the formula (wherein R _{1 to} R ₆ have the same meanings as those in formula II).