JPH07224068A - Production of 6-deaza-6-oxostaurosporine substance - Google Patents

Abstract

PURPOSE:To provide a process for the production of a 6-deaza-6- oxostaurosporine compound having pharmacological actions such as blood platelet coagulation inhibiting action and antibacterial action with simple procedure in high yield compared with conventional process. CONSTITUTION:This process for the production of a 6-deaza-6-oxostaurosporine compound comprises the reaction of a 7-unsubstituted staurosporine compound such as staurosporine, K-252, their derivatives, etc., with a quinone-based oxidizing agent in an inert solvent in the presence of a lower alcohol, the hydrolysis of the resultant 7-alkoxystaurosporine compound with an acid and the reductive deamination of the obtained 7-hydroxystaurosporine compound in an inert solvent. Another embodiment of the invention is a process for the production of a 6-deaza-6-oxostaurosporine compound comprising the reductive deamination of a 7-hydroxystaurosporine compound in an inert solvent.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a platelet aggregation inhibitory action,
Has pharmacological action such as antibacterial action, staurosporine, K-
252, a novel method for producing a 6-deaza-6-oxo form of a staurosporine compound such as a derivative thereof.

[0002]

2. Description of the Related Art Conventionally, various substances having an indolopyrrolocarbazole skeleton such as staurosporine and K-252 (hereinafter sometimes collectively referred to as "starrosporin-based substance") and derivatives thereof have been reported. There is. In particular, Japanese Unexamined Patent Publication No. 4-145085 discloses the following formula (1a) having a platelet aggregation inhibitory action.

[0003]

[Chemical 1] A 6-deaza-6-oxostaurosporine represented by the formula (1a) is disclosed, wherein the compound (1a) is prepared by reducing N-protected-7-oxostaurosporine with a reducing agent such as NaBH ₄ , and then using an amino protecting group. It is reported that the compound is produced by eliminating each isomer and then separating each isomer.

Japanese Unexamined Patent Publication (Kokai) No. 4-364186 also discloses a 6-deaza-6-oxostaurosporine derivative having an inhibitory effect on platelet aggregation, and reports that it is produced by the same method as described above. JP-A-5-24705
No. 6 discloses the following formula (1b) having an antibacterial action.

[0005]

[Chemical 2] A 6-deaza-6-oxo-K-252 derivative represented by the following formula is disclosed, and 7-oxo-K-252 obtained by the method described in JP-A-63-295589 is reduced with a reducing agent such as NaBH _4. It is reported that the compound is produced by reducing with. Japanese Examined Patent Publication (Kokoku) No. 5-74595 discloses the following formula having an antibacterial action and an antitumor action by a fermentation method.

[0006]

[Chemical 3] It is disclosed that UCN-01 represented by the following formula, so-called 7-hydroxystaurosporine can be obtained. JP-A-1-168689 discloses 7-hydroxy-K- having antitumor activity and protein kinase C inhibitory activity.
A 252 derivative is disclosed and is represented by the following formula (6):

[0007]

[Chemical 4] A synthetic method has been reported in which K-252 represented by is produced by an oxidation reaction with Pb (OAc) ₄ . WO89 /
No. 07105 discloses a 7-hydroxy or methoxystaurosporine derivative having a cell growth inhibitory action and a protein kinase C inhibitory action, and a synthetic method produced by the same oxidation reaction as above is reported. .

[0008]

However, according to the method disclosed in Japanese Patent Laid-Open No. 4-145085, the object (1a) is
The following formula (7), which is a precursor of

[0009]

[Chemical 5] In addition to the compound represented by the following formula (8) which is a positional isomer

[0010]

[Chemical 6] Since the formation of the compound represented by is inevitable, their separation is indispensable, but it is industrially very difficult. Further, also in the method for producing the compound (1b) by the method disclosed in JP-A-5-247056, the same problem as described above occurs.

Therefore, a known method for producing a 6-deaza-6-oxostaurosporine substance from a 7-oxostaurosporine substance is a by-product of a positional isomer.
It cannot be said to be an industrially preferable synthesis method.

[0012]

Therefore, the present inventors have
As a result of continuing various studies on a method for obtaining a 6-deaza-6-oxostaurosporine-based substance in a simple and high yield, 7-hydroxystauros was used as a starting material instead of the 7-oxostaurosporine-based substance. Focusing on the use of a porin substance, 6-deaza-6 was obtained by reductive deamination of this with a reducing agent such as NaBH _4.
-Oxostaurosporine-based material was found to be obtained in high yield.

However, since UCN-01 described in Japanese Patent Publication No. 5-74595, so-called 7-hydroxystaurosporine, is produced by a fermentation method, there is a problem that it cannot be easily produced. As a method for synthesizing a 7-hydroxystaurosporine substance, a method for producing a 7-unsubstituted staurosporine substance by an oxidation reaction with Pb (OAc) ₄ (JP-A-1-168689).
Japanese Patent Publication No. WO89 / 07105) is known, but according to this method, the yield is low, and there is a problem in processing lead waste after the reaction, which is not preferable in industry,
In addition, when the intended product is used as a medicine, there is a possibility that heavy metals may remain, which causes various problems.

Therefore, as a result of further studies on the method which can solve the above problems and can be applied industrially with high yield, the present inventors have found that the 7-unsubstituted staurosporine-based substance is obtained. By reacting a quinone-based oxidant in the presence of a lower alcohol in an inert solvent and hydrolyzing the obtained 7-alkoxystaurosporine-based substance, a 7-hydroxystaurosporine-based substance is easily and highly yielded. I found that can be obtained in. The present invention has been completed based on various findings as described above.

That is, the present invention relates to a 7-hydroxystaurosporine compound having a substituted tetrahydropyran ring or a substituted tetrahydrofuran ring (hereinafter, simply referred to as "7
-Hydroxystaurosporine compound ") is reductively deaminated in an inert solvent, and then, optionally, a protecting group for an amino group, a hydroxyl group and / or a carboxyl group is eliminated. 6-deaza-6-oxostaurosporine compound having a ring or a substituted tetrahydrofuran ring (hereinafter, simply,
"6-Deaza-6-oxostaurosporine compound"
Referred to as “)”.

In the present invention, a 7-alkoxystaurosporine compound having a substituted tetrahydropyran ring or a substituted tetrahydrofuran ring (hereinafter simply referred to as "7-alkoxystaurosporine compound") is acid-hydrolyzed. A 6-deaza-compound characterized in that the obtained 7-hydroxystaurosporine compound is reductively deaminated in an inert solvent, and then a protecting group for an amino group, a hydroxyl group and / or a carboxyl group is optionally eliminated. The present invention provides a method for producing a 6-oxostaurosporine compound.

Furthermore, the present invention also relates to 7-containing a substituted tetrahydropyran ring or a substituted tetrahydrofuran ring.
Unsubstituted staurosporine compound (hereinafter, simply referred to as “7-
The “unsubstituted staurosporine compound” is reacted with a quinone oxidant in the presence of a lower alcohol in an inert solvent, and the obtained 7-alkoxystaurosporine compound is acid-hydrolyzed to obtain 7 6-deaza-6-oxos, which comprises reductively deaminating a hydroxystaurosporine compound in an inert solvent, and then optionally removing a protecting group for an amino group, a hydroxyl group and / or a carboxyl group. A method for producing a taurosporine compound is provided.

The 7-unsubstituted staurosporine compound used as a starting material or starting material in the present invention is staurosporine, K-252, SF-237.
0, TAN-1030A, TAN999, RK-140
9B shows a substance having an indolopyrrolocarbazole skeleton such as 9B and constituting a substituted tetrahydropyran ring or a substituted tetrahydrofuran ring, a so-called staurosporine-based substance and a derivative thereof in which the 7-position is not substituted. .

If the examples of the 7-unsubstituted staurosporine compounds are represented by the general formula, for example, the following general formula (4)

[0020]

[Chemical 7] (In the formula, ring A and ring B are an aromatic ring which may have a substituent, R ¹ is a hydrogen atom or a lower alkyl group, and Z is —C.
^{H (OMe) -CH (NMeR 2} ) - or -CHR ⁴
(OR ³ )-, R ² is a hydrogen atom, lower alkyl, formyl, lower alkanoyl, optionally protected hydroxyl group,
Protecting group for amino acid acyl residue or amino group, R ³ is hydrogen atom, lower alkyl, lower alkanoyl or hydroxyl protecting group, R ⁴ is —COOR ⁵ or —CH ₂ COR
⁶ , R ⁵ represents a hydrogen atom or a lower alkyl group, and R ⁶ represents a hydrogen atom, a lower alkyl or a hydroxyl-protecting group).

Each group of the general formula (4) of the compound (4) can be defined as follows. The substituents which may be substituted on the aromatic ring represented by ring A and ring B are the same or different and include lower alkyl groups such as methyl, ethyl, propyl and isopropyl, nitro, amino, hydroxy and hydroxymethyl groups. .

-CH (OMe) -CH defined by the group Z
Of (NMeR ² )-and —CHR ⁴ (OR ³ ) —, the former group has the forward substitution position substituted with ═C (Me) — and the rear substitution position substituted with —CH ₂ —. And when the ring containing Z is a 6-membered ring, its bonding mode is Journal of Chemical Society Chemical Communication, 1978, 800-80.
The following formula (5) described on page 1

[0023]

[Chemical 8] It has a bond in the same direction as the 6-membered ribose of staurosporine represented by. Group Z is -CHR ⁴ (OR ³⁾ -
The bonding mode of the 5-membered ring in the case of
It has a bond in a direction that coincides with the structure of K-252 represented by the formula (6) described in JP-A-84.

The lower alkyl in the definition of the group R ¹ is a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl and isopropyl.

The lower alkyl in the definition of the group R ² is a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl and isopropyl. The lower alkanoyl refers to a linear or branched alkanoyl group having 2 to 5 carbon atoms, and examples thereof include acetyl, propionyl, butyryl, valeryl and the like. The protecting group for a hydroxyl group which may be protected represents a known protecting group for a hydroxyl group used in sugar chemistry, for example,
Benzyl, benzyloxymethyl, tetotahydropyranyl and the like can be mentioned.

The amino acid acyl residue refers to an acyl residue obtained by removing the hydroxyl group of the known amino acid carboxyl group, and examples of these amino acids include glycine, alanine, proline and the like. The amino-protecting group is a known amino-protecting group used in sugar chemistry or amino acid chemistry, and examples thereof include benzyloxycarbonyl, t-butoxycarbonyl, β, β, β-trichloroethoxycarbonyl and the like. .

The lower alkyl in the definition of the group R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. . The lower alkanoyl refers to a linear or branched alkanoyl group having 2 to 5 carbon atoms, and examples thereof include acetyl, propionyl, butyryl, valeryl and the like. The hydroxyl group-protecting group is a known hydroxyl group-protecting group used in sugar chemistry, and examples thereof include benzyl, benzyloxymethyl and tetrahydropyranyl.

The lower alkyl in the definition of the group R ⁵ is a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. .

The lower alkyl in the definition of the group R ⁶ is a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. . The hydroxyl protecting group refers to a known hydroxyl protecting group used in sugar chemistry,
For example, benzyl, benzyloxymethyl, tetrahydropyranyl and the like can be mentioned.

The above-mentioned 7-unsubstituted staurosporine compounds, for example, staurosporine, are disclosed in Japanese Patent Publication No. 57-5307.
The staurosporine derivative produced by the method described in JP-A No. 6-243846 / 1993 and the like is disclosed in JP-A-64-
34989, WO 89/07105, International Publication, JP-A-1-149791, JP-A-3-72.
485, JP-A-3-220194, JP-A-4-364186 and the like.
AN-1030A and its derivatives are disclosed in JP-A-1-246.
It is manufactured by the method described in Japanese Patent No. 288.

TAN999 is produced by the method described in JP-A-1-149791 and the like, and is K-252 (K-25
2a, same as SF-2370) is Japanese Patent Publication No. 3-67073.
The K-252 derivative is produced by the method described in JP-B-5-1794, JP-B-5-1795, JP-A-63-295588, etc. The-2370 derivative is disclosed in JP-A-61-268.
687, Japanese Patent Publication No. 2-15555, JP-A-6-6
Manufactured by the method described in JP-A-2-240689,
K-1409B is produced by the method described in JP-A-5-222054.

The examples of the 7-hydroxystaurosporine compound, which is the starting material or intermediate material of the present invention, can be represented by the general formula, for example, the following general formula (2)

[0033]

[Chemical 9] (Wherein ring A, ring B, R ¹ and Z have the same meaning as described above).

The above-mentioned 7-hydroxystaurosporine compound is preferably produced by the method of the present invention described later, but it can also be produced by the following method. That is, UCN-01 represented by formula (5), so-called 7
-Hydroxyoutaurosporine is Japanese Patent Publication 5-7459
No. 5, etc., and the 7-hydroxystaurosporine derivative is produced by the method described in WO 89/07105, International Publication No.
The K-252 derivative is produced by the method described in JP-A-1-168689.

In the production method shown below, when the defined group is changed under the conditions of the method for carrying out or is unsuitable for carrying out the method, a method commonly used in synthetic organic chemistry, for example, a functional group It is preferably attached to a means such as protection and deprotection (see, for example, Protective Groups in Organic Synthesis, Green, John Willy and Sons Incorporated (1991)).

In the present invention, the step of converting the 7-unsubstituted staurosporine compound to the 7-alkoxystaurosporine compound is to react the quinone derivative in the presence of a lower alcohol in an inert solvent. Done by. If an example of the 7-alkoxystaurosporine compound is represented by a general formula, for example, the following general formula (3)

[0037]

[Chemical 10] (In the formula, R represents a lower alkyl group, and ring A, ring B, R ¹
And Z has the same meaning as described above).

The lower alkyl group in the above definition of the group R is a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl and isopropyl. Examples of the inert solvent used in the above reaction include benzene, acetone, 1,4-dioxane, dichloromethane, chloroform and the like. Dichloromethane is an example of a preferred solvent.

Examples of the lower alcohol used in the above reaction include linear or branched alkanols having 1 to 4 carbon atoms, and preferably methanol, ethanol, propanol, isopropanol and the like. The lower alcohol is used in an amount of 1 to 50 times M, preferably 10 to 20 times M based on the 7-unsubstituted staurosporine compound.

Examples of the quinone-based oxidizing agent used in the above reaction include 2,3-dichloro-5,6-dicyano-p-benzoquinone, chloranil and o-chloranil. The ratio of the quinone-based oxidant used is 1.0 to 1.5 times M, preferably 1.0 to 1.2 times M, that of the 7-unsubstituted staurosporine compound.

The above reaction temperature is about 0 to 60 ° C., preferably 10 to 30 ° C. Since the progress of the reaction can be traced by thin layer chromatography (TLC), high performance liquid chromatography (HPLC), etc., the reaction may be appropriately terminated by eliminating the disappearance of the 7-unsubstituted staurosporine compound. Reaction time is 2-10
It's about time.

To collect the 7-alkoxystaurosporine compound from the reaction solution thus obtained, a non-hydrophilic organic solvent for extracting the 7-alkoxystaurosporine compound from the reaction solution, for example, After adding ethyl acetate and the like and washing with weakly alkaline water, the organic solvent is distilled off. When the 7-alkoxystaurosporine compound is further purified, it may be carried out by a known means for purifying an organic compound, for example, by appropriately combining extraction, crystallization, chromatography and the like.

Next, in the step of converting the 7-alkoxystaurosporine compound thus obtained into a 7-hydroxystaurosporine compound, the 7-alkoxystaurosporine compound is subjected to acid hydrolysis reaction. It is done by

The above acid hydrolysis reaction is preferably carried out in an inert solvent. Examples of the inert solvent include ether solvents such as tetrahydrofuran, 1,4-dioxane and diglyme, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidone and dimethyl sulfoxide. To be Preferably, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidone, etc. are used.

Examples of the acid used in the above-mentioned acid hydrolysis reaction include mineral acids such as sulfuric acid and hydrochloric acid, phosphoric acid anhydride, phosphoric acid such as pyrophosphoric acid, p-toluenesulfonic acid, methanesulfonic acid and camphorsulfonic acid. It is preferable to use sulfonic acid compounds such as Usually, the water required for the hydrolysis reaction is 5 with respect to the 7-alkoxystaurosporine compound.
It is about 100 to 100 times mol, preferably about 10 to 20 times mol. The reaction temperature is about 20 to 100 ° C, preferably 40 to
It is performed in the range of 70 ° C. Reaction progress is TLC, HPLC
Since it can be traced by a method such as the above, the reaction may be appropriately terminated after waiting for the maximum production of the 7-hydroxystaurosporine compound, but usually the reaction is completed in about 2 to 10 hours.

To collect the 7-hydroxystaurosporine compound from the reaction solution thus obtained, the reaction solution is neutralized with an aqueous alkaline solution, and the precipitated product is collected by filtration, washed and dried. It is done by When the 7-hydroxystaurosporine compound is further purified, it may be carried out by a known means for purifying an organic compound, for example, by appropriately combining extraction, crystallization, chromatography and the like.

The step of converting the 7-hydroxystaurosporine compound to the 6-deaza-6-oxostaurosporine compound is carried out by reductive deamination of the 7-hydroxystaurosporine compound in an inert solvent, and then If desired, the protective group for amino group, hydroxyl group and / or carboxyl group is eliminated. An example of the above-mentioned 6-deaza-6-oxostaurosporine compound is represented by the general formula, for example, the following general formula (1)

[0048]

[Chemical 11] (Wherein ring A, ring B, R ¹ and Z have the same meaning as described above).

Examples of the inert solvent used in the above reductive deamination reaction include alcohol solvents such as methanol, ethanol, propanol and butanol, ether solvents such as tetrahydrofuran, 1,4-dioxane and diglyme, and N. , N-dimethylformamide, N, N-
Examples thereof include organic solvents such as dimethylacetamide, 1,3-dimethyl-2-imidazolidone, dimethyl sulfoxide, and sulfolane, water, aqueous solvents such as buffer solutions, and mixed solvents thereof. It is preferable to use a mixed solvent of an ether solvent and a buffer solution, particularly a mixed solvent of 1,4-dioxane and a buffer solution.

As the reducing agent used in the above reductive deamination reaction, a reducing agent having the ability to reductively deaminate and lactone cyclize is used. For example, a metal-hydrogen complex compound may be mentioned, preferably sodium borohydride, sodium trimethoxyborohydride,
Examples include unsubstituted or substituted sodium borohydride such as sodium cyanoborohydride and sodium triacetoxyborohydride. The reducing agent is used in a proportion of about 2 to 20 times mol, preferably about 3 to 10 times mol, of the 7-hydroxystaurosporine compound.

In the above reductive deamination reaction,
Since the reaction proceeds advantageously under alkaline conditions, it is advantageous to proceed the reaction in the presence of a buffer solution having a pK of about 11 to 13, preferably about 11 to 12. The reaction temperature in the reductive deamination reaction is 10 to 9
It is performed at about 0 ° C, preferably about 50 to 90 ° C. Since the progress of the reaction can be traced by TLC, HPLC, etc., the reaction may be appropriately terminated after waiting for the maximum production of the product, but usually about 2 to 10 hours, preferably 4 to
The reaction is completed in about 7 hours. The reaction ends with.

To collect the 6-deaza-6-oxostaurosporine compound from the reaction solution thus obtained, the reaction solution is treated with an acid, for example, a mineral acid such as sulfuric acid or hydrochloric acid, phosphoric anhydride, or pyrroline. Phosphoric acids such as acids, organic acids such as acetic acid, p
-It is carried out by neutralizing with a sulfonic acid compound such as toluenesulfonic acid or methanesulfonic acid, and extracting with a non-hydrophilic solvent capable of extracting a 6-deaza-6-oxostaurosporine compound. .

When the 6-deaza-6-oxostaurosporine compound has a protecting group for an amino group, a hydroxyl group and / or a carboxyl group and it is necessary to remove the protecting group, sugar chemistry or It may be eliminated by a known method used for elimination of protecting groups for amino group, hydroxyl group and / or carboxyl group in amino acid chemistry. 6
When the -deaza-6-oxostaurosporine compound is further purified, it may be carried out by a known means for purifying an organic compound, for example, by appropriately combining extraction, crystallization, chromatography and the like.

[0054]

EXAMPLES The present invention will now be specifically described with reference to examples, but the present invention is not limited thereto. Example 1 Production of Compound A

[0055]

[Chemical 12] 4'-N- (β, β, β-trichloroethoxycarbonyl) staurosporine 944 mg (1.47 mmol)
Is dissolved in 10 ml of dichloromethane, to which 1 ml of methanol and 2,3-dichloro-5,6-dicyano-p are added.
-Benzoquinone (410 mg, 1.72 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, 60 ml of ethyl acetate was added to the reaction solution, washed twice with 60 ml of a saturated aqueous sodium hydrogen carbonate solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 970 mg of a 7-epi mixture of compound A. (1.41 mmol, yield 96%) was obtained.

¹ H-NMR (DMSO, 50 ° C.) δ;
9.23 (d, 1H, J = 8.9 Hz), 8.91 (b
rs, 1H), 8.34, 8.32 (each d, t
total, 1H, J = 7.8 Hz, 7.96 (d, 1)
H, J = 8.3 Hz), 7.64 (d, 1H, J = 8.
3 Hz), 7.5 (m, 2H), 7.4-7.3 (m,
2H), 7.01 (dd, 1H, J = 5.9, 8.9H
z), 6.51 (s, 1H), 4.7-4.5 (m, 3)
H), 4.33, 4.30 (each brs, tot)
al, 1H), 3.2 (s, 3H), 2.84 (br,
1H), 2.76 (s, 3H), 2.69, 2.64.
(Each, total, 3H), 2.40 (s,
3H), 2.4-2.2 (m, 1H) IR ν (KBr); 1710, 1340, 1140c.
m ^-1 MS (m / z); 670 (M ⁺ ) Elemental analysis (C ₃₂ H ₂₉ N ₄ O ₆ Cl ₃ ) Calculated value; C: 57.20, H: 4.35, N: 8.34 Measurement Value: C: 57.25, H: 4.17, N: 8.29

Example 2 Preparation of Compound B

[0058]

[Chemical 13] Compound A (14.7 g, 21.9 mmol) was added with N, N-dimethylformamide (495 ml) and 1N-hydrochloric acid (49.5 m).
1 was added, and the mixture was stirred at 60 to 65 ° C for 3.5 hours. After completion of the reaction, 300 ml of 3% aqueous ammonia was added under ice cooling, and the precipitated insoluble matter was collected by filtration. This is dried under reduced pressure (50
After that, the mixture was purified by silica gel column chromatography (chloroform-methanol-25% aqueous ammonia = 99: 1: 0.1), and 12.4 g (18.8 mmol, yield) of the 7-epi mixture of compound B was obtained. Rate of 85%).

¹ H-NMR (DMSO, 50 ° C.) δ;
9.23 (m, 1H), 8.7-8.3 (m, 2H),
8.0-7.2 (m, 6H), 7.01 (m, 1H),
6.5-6.3 (m, 2H), 4.8-4.5 (m, 2)
H), 4.34 (m, 1H), 3.21 (s, 3H),
2.8-2.7 (m, 4H), 2.4-2.2 (m, 4)
H) IR ν (KBr); 1710, 1350, 1140c
m ^-1 MS (m / z); 656 (M ⁺ ) Elemental analysis (C ₃₁ H ₂₇ N ₄ O ₆ Cl ₃ ) Calculated value; C: 56.59, H; 4.14, N: 8.52 measurement Value; C: 56.68, H: 4.02, N: 8.54

Example 3 Preparation of Compound C

[0061]

[Chemical 14] Compound B 1 g (1.38 mmol) was added to 1,4-dioxane 20 ml and 1M-sodium dihydrogen borate aqueous solution 2 m.
It was dissolved in 1 mixed solvent, 420 mg (8 times mol) of sodium borohydride was added thereto, and the reaction was carried out at 80 ° C. for 5 hours. After the reaction was completed, 2 ml of acetic acid was added to the reaction solution for neutralization, dichloromethane was added thereto, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was depressurized. Distilled off. The residue was purified by silica gel column chromatography (eluting solvent: toluene-ethyl acetate = 15: 1) to give compound C6.
40 mg (1.00 mmol, yield 72%) was obtained.

¹ H-NMR (DMSO, 50 ° C.) δ;
9.06 (d, 1H, J = 9.0 Hz), 8.1-7.
3 (m, 7H), 7.03 (m, 1H), 6.01
(D, 1H, J = 16.0 Hz), 5.95 (d, 1
H, J = 16.0 Hz), 4.98 (m, 2H), 4.
71 (m, 1H), 4.37 (m, 1H), 3.48
(M, 1H), 2.80 (s, 3H), 2.68 (s,
3H), 2.39 (s, 3H), 2.30 (m, 1H) IR ν (KBr); 1745, 1710, 1340,
1140 cm ^-1 MS (m / z); 642 (MH ⁺ ) Elemental analysis (C ₃₁ H ₂₆ N ₃ O ₆ Cl ₃ ) Calculated value; C: 57.91, H: 4.08, N: 6.54 measurement Value; C: 58.03, H: 3.97, N: 6.70

Example 4 Preparation of Compound D

[0064]

[Chemical 15] Compound C (600 mg, 0.93 mmol) was dissolved in tetrahydrofuran (20 ml), and 1M-ammonium acetate aqueous solution (40 ml) was added thereto, followed by zinc powder (4 g).
The reaction was carried out at room temperature for 2 hours. After the reaction was completed, zinc was removed from the reaction solution by filtration, the filtrate was concentrated under reduced pressure, and the precipitated insoluble matter was collected by filtration. This insoluble material was purified by recrystallizing from dichloromethane-ethanol to give compound D313 mg.
(0.67 mmol, yield 72%) was obtained. The compound D obtained above was in agreement with the analysis result of the compound described in Example 2 of JP-A-4-145085 or Reference Example 2 of WO93 / 18771.

[0065]

According to the present invention, a platelet aggregation inhibitory action,
A 6-deaza-6-oxostaurosporine substance having a pharmacological action such as an antibacterial action can be obtained more simply and in a higher yield than conventionally known methods.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Satoshi Omura 5-12-7 Seta, Setagaya-ku, Tokyo

Claims (3)

[Claims] 1. A 7-hydroxystaurosporine compound having a substituted tetrahydropyran ring or a substituted tetrahydrofuran ring is reductively deaminated in an inert solvent, and then optionally a protecting group for an amino group, a hydroxyl group and / or a carboxyl group. And a substituted tetrahydropyran ring or a substituted tetrahydrofuran ring. 6-deaza-6-oxostaurosporine-based compound 2. A 7-hydroxystaurosporine compound having a substituted tetrahydropyran ring or a substituted tetrahydrofuran ring obtained by acid hydrolysis of a 7-alkoxystaurosporine compound having a substituted tetrahydropyran ring or a substituted tetrahydrofuran ring. 6-deaza-6 having a substituted tetrahydropyran ring or a substituted tetrahydrofuran ring, characterized in that reductive deamination of is carried out in an inert solvent, and then optionally a protecting group of amino group, hydroxyl group and / or carboxyl group is eliminated. -Method for producing oxostaurosporine compound. 3. A substituted tetrahydropyran ring or a 7-unsubstituted staurosporine compound having a substituted tetrahydropyran ring or a substituted tetrahydrofuran ring is reacted with a quinone oxidant in the presence of a lower alcohol in an inert solvent. The 7-alkoxystaurosporine compound having a substituted tetrahydrofuran ring is acid-hydrolyzed, and the obtained 7-hydroxystaurosporine compound having a substituted tetrahydropyran ring or a substituted tetrahydrofuran ring is reductively deaminated in an inert solvent. Then, if desired, a protecting group for an amino group, a hydroxyl group and / or a carboxyl group is eliminated to produce a 6-deaza-6-oxostaurosporine compound having a substituted tetrahydropyran ring or a substituted tetrahydrofuran ring. Law.