JPS595188A - Production of 10-hydroxycamptothecin - Google Patents

Abstract

PURPOSE:The treatment of 1,2,6,7-tetrahydrocamptothecin with an oxidizing agent such as lead tetra-acetate simplifies the process to give the titled compound used as an antitumor agent causing no cross resistance with existing carcinostatic agents. CONSTITUTION:1,2,6,7-Tetrahydrocamptothecin is dissolved in a solvent such as methanol and oxidized by adding an oxidizing agent thereto, such as lead tetra- acetate, celium (IV) ammonium nitrate, Fremy's salt, chromic acid, perchromate salt, potassium permanganate or ferric chloride. The reaction mixture is evaporated to dryness under reduced pressure and the residue is purified by subjecting to column chromatography to give the objective compound. 1,2,6,7-Tetrahydrocamptothecin, as a starting compound, is obtained by catalytic hydrogenation of camptothecin.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 10-hydroxycamptothecin.

More specifically, the present invention uses 1,2,6,7-tetrahydrocamptothecin as lead tetraacetate, CAN.

Treatment with a substance selected from the group consisting of fert-salts, chromium salts, cytochromates, potassium permanganate and ferric chloride as oxidizing agents, characterized by the formula ζ The present invention provides a method for producing 10-hydroxycamptothecin.

Camptothecin is a deciduous tree (Oamptothec).
It is an alkaloid extracted and isolated from Nys8aceae) and has a strong nucleic acid synthesis inhibitory effect.The effect is rapid and reversible, and it has the unique property of not exhibiting cross-resistance with existing anticancer drugs. It is an antitumor substance with a mechanism of action, and is effective against murine leukemia L1210. Rat Walker 256 sarcoma etc. experiment $4
Although it has been recognized to have a strong anticancer effect against 11 cancers, its usefulness as a pharmaceutical is naturally limited due to its toxic effects.

It has been reported that 1o-hydroxycamptothecin, which is the target substance of the method of the present invention, is less toxic than camptothecin and has excellent pharmacological activity. The synthesis of 1o-hydroxycamptothecin by chemical conversion of the resulting camptothecin poses a very important challenge.

The present inventors previously provided a method for synthesizing 10-hydroxycamptothecin from tetrahydrocamptothene (Japanese Patent Application No. 138411/1982), but this method starts from tetrahydrocamptothene and The problem was that it had to go through a process.

The present inventors have developed 10-
When we searched for a method to obtain hydroxycamptothecin, we surprisingly found that when 1,2,6,7-titrahydrocamptothecin was treated with the following substances as oxidizing agents, hydroxylation at the 10-position and formation of aromatic nuclei occurred. It has been found that 10-hydroxycamptothecin can be obtained in good yield in one step by proceeding all at once.

That is, the substances used as oxidizing agents here include lead tetraacetate, CAN (cerium nitrate (M ammonium),
Fremy salt [potassium nitron disulfonate: (KS
O5)2NO) is selected from the group consisting of chromic acid, dichromate, potassium permanganate and ferric chloride.

The present invention has been made based on the above findings.

The present invention will be explained in detail below. First, the raw material 1
, 2,6.7-titrahydrocambutothecin can be efficiently obtained by hydrogenating camptothecin in acetic acid or dioxane-acetic acid in the presence of a platinum catalyst at normal pressure and room temperature. By treating futetrahydrocamptothecin with the substances listed above as oxidizing agents, 1°-hydroxycamptothecin is obtained in one step. Examples of the solvent used in this treatment include acetic acid, methanol, ethanol, chloroform, pyridine, ben7ane, methylene chloride, dioxane, THF, water, etc., and it is preferable to use a mixed solvent thereof.

The amount of the substance used as the above-mentioned oxidizing agent is usually about 1 to 5 equivalents. This reaction usually proceeds at a temperature range of 0°C to room temperature with stirring for 10 minutes to several hours.

In some cases, only aromatized forms of camptothecin are produced as by-products, which can be separated using silica gel chromatography. Furthermore, when the reaction is carried out using lead tetraacetate in acetic acid, 10-acetoxycamptothecin is produced as a by-product, but this can be easily quantitatively converted to 10-hydroxycamptothecin by treatment with an acid or base. I can do it. The present invention will be described in more detail with reference to Examples below, but the present invention is not limited to these Examples.

Example 1 a) 1,2,6.7-titrahydrocambutotecin Cambutotecin (5007#f, 1.46 mmot) was suspended in acetic acid (100 mA), platinum oxide (100 mA) was added, and the mixture was stirred at room temperature. Approximate pressure contact (15 hours, approximately 14Dfn)
1 of hydrogen). After removing the catalyst, the reaction mixture was dried under reduced pressure, and the residue was dissolved in chloroform (200ml) and dissolved in aqueous sodium bicarbonate solution (100ml).
A), then washed with saturated brine (100 m/liter), dried the chloroform layer over magnesium sulfate, filtered, dried under reduced pressure, and purified by silica gel (20,1 column chromatography (chloroform)) to obtain the title compound. 285mf (conversion rate 566%, yield 76,7
%)can get. 113 mg (crude) of unreacted starting material was recovered.

m, p, (decomposition) 240-242°C [from MeOH] K
Br +・IRmaxνff1− , 3470, 1745, 164
5,1565゜1495.1165.1030゜b) 1,2.6.7-titrahydrocamptothene (500 mW, 1.42 mmo7) obtained in a) was dissolved in acetic acid (50d), lead tetraacetate (1,9L4
Add mmoA) and stir at room temperature for 10 minutes. The obtained reaction mixture was dried under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to obtain 1
0-acetoxycamptothecin (145m7.252%
) together with 10-hydroxycamptothecin (580 m
g, Section 765) is obtained. The obtained 10-acetoxycamptothecin can be quantitatively converted to 10-hydroquincamptothecin by treatment with sodium ethoxydide in ethanol.

10-Hydroquine camptothecin m, p, (min M) 270-272'C [from pyridine-methanol] NMR (in DMSO-a6) δ: 0.8
8 (3H, t, J=7Hz, -aH2an3), 1.8
6 (2H, q, J=7H2, -CH20H3), 5
．． 22 (2H, s.

C-5-H), 5.40 (2H,s, c-17-H),
6.47 (IH, s.

0-2O-OH), 7.2 (2H, m, c-9-H and C-14-H), 7.41(1)1. a, a,
J=9Hz, 2Hz, 0-1l-H), 8D
1 (1, H.

a, J=9Hz, c-12-H), 8,4ro(IH,s, C-7-H)I4i1;, vCm-"
:345D, 172o, 1655, 1590, 150
5゜265 Example 2 1.2,6.7-CitrahyF rocamptothecin (50゜
, 0.142 mmot) in methanol (20rn1.)
CAN (cerium (IV) ammonium nitrate) (396 mg, 0.71 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. This reaction mixture was dried under reduced pressure, and the residue was purified by silica gel column chromatography to give a concentration of 1"' and camptothecin (40 mg, 809) and 10-hydroxycamptothecin (6 my, 11.6
%) is obtained.

Example 6 1.2,6.7-titrahydrocamptothecin (50 m
2.0.142mmo? ) was dissolved in methanol (20-), and potassium trosodisulfonate (95q, 0.654 mmo)) was added to Flemy's salt and the mixture was heated for 60 min at room temperature.
Stir for a minute. This reaction mixture was dried under reduced pressure and the residue was purified by silica gel column chromatography.
Camptothecin (9 mq, 18.21 mq) and 10-hydroxycamptothecin (31 mq, 60.0%) were obtained.

Example 4 1.2,6.7-titrahi F rocamptothecin (50 m
g, 0.142 mmoA) in pyridine (20 m/) 1. .

Chromic anhydride (28 ml, 0.28 mmol) was added to this and stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10
0 mA) and count the precipitate. The P solution was extracted with chloroform, the chloroform layer was dried under reduced pressure, and the residue was treated with silica gel column chromatography together with the precipitate obtained earlier to obtain camptothecin (25 mg, 50,6
h) together with 1[1-hydroxycamptothecin (12
+〃y, 23.2%) is obtained.

Example 5 The same procedure as in Example 4 is repeated except that sodium dichromate (83.4 W, 0.28 mmol) is used instead of chromic anhydride. Camptothecin (2
1rng, 425%) as well as 10-hydroxycamptothecin (9 mW, 18.2%).

Example 6 The same procedure as in Example 4 is repeated except that potassium permanganate (112 mV, 0.71 mm07) is used instead of chromic anhydride. Power〉Ptothecin (18
1, 364%) as well as 10-hydroxycamptothecin (6rng, 12.IL).

Example 7 The same procedure as in Example 4 is repeated except that anhydrous ferric chloride (115 to 0.71 mmo) is used instead of chromic anhydride. Duinptothecin (40mg, 81
．． 0%) as well as 10-human quinecambutothecin (
7m2.14.2%) is obtained.

Patent Applicant: Yakult Co., Ltd. Head Office Procedures Amendment (Method) 1930, 1939
Mr. Kazuo Wakasugi, Commissioner of the Japan Patent Office, 1966 Patent Application No. 1//390 2 Title of the Invention 10 - Process for Producing Hydroquine Camptothecin 3 Person Who Makes Amendment Relationship to the Case Address of Patent Applicant Higashi-Shinbashi, Minato-ku, Tokyo / chome / number / number q name (
Otsugg) Yakult Honsha Co., Ltd. Deputy Director Address: Kojimachi 3-chome, Chiyoda-ku, Tokyo Sogo Daiichi Building Peep Story (,2 Otsu5) 96g (Delivery date: September 2nd, 1920) 7. After the engraving of the statement of contents of the amendment (pages 1 and 2) (no changes to the contents)
Continued Amendment Written by Kazuo Wakasugi, Director General of the Japan Patent Office, July 8, 1939.Indication of Case 1, 1939, Patent Application No. 1//Left q0 No. 2, Title of Invention 1. Process for producing 10-hydroxycamptothecin. 3. Relationship with the case of the person making the amendment Patent applicant address No. 77, Higashi-Shinbashi, Minato-ku, Tokyo Name (
6gg) Yakult Honsha Co., Ltd. 4, Agent Address: Sogo Daiichi Building 6, 3-chome, λ, Kojimachi, Chiyoda-ku, Tokyo Subject of amendment Section 7 of the detailed description of the invention in the specification
, Contents of the amendment (1) "Water" in line 3 on the left page of the specification is corrected to "water, trifluoroacetic acid."

(2) After line 73 on page 10, add the following sentence on a new line.

“Example g/, 2,1..7-titrahydrocamphutotisin (
Ushio OTn? ,0. /lI2mmot)
Luo o acetic acid board top

Claims (1)

[Claims] 1.2,6.7-Titrahydrocambutotecin with a substance selected from the group consisting of lead tetraacetate, CAN, Flemy's salt, chromic acid, dichromate, potassium permanganate and ferric chloride. A method for producing 10-hydroxycamptothecin represented by the formula, characterized in that it is treated using an oxidizing agent.