JPH029032B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 11-nitro-1,2,6,7-
This invention relates to tetrahydrocamptothecin and its production method. More specifically, the present invention relates to a novel 11-nitro-1,2,6,7-tetrahydrocamptothecin and a method for producing the same, namely, the catalytic reduction of camptothecin to obtain 1,2,6,
A formula characterized by treatment with 7-tetrahydrocamptothecin, sulfuric acid and nitric acid, The present invention provides a method for producing 11-nitro-1,2,6,7-tetrahydrocamptothecin represented by:

Camptothecin is an alkaloid extracted and isolated from plants such as Camptothecaacuminata Nyssaceae, and has a strong effect of inhibiting nucleic acid synthesis.Its action is rapid and reversible, and has cross-resistance with existing anticancer drugs. It is an antitumor substance with a unique mechanism of action that does not show
Although it has been recognized to have a strong anticancer effect on experimentally transplanted cancers such as 256 sarcoma, its usefulness as a drug is naturally limited due to its toxic effects.

Therefore, attempts have been made to chemically convert camptothecin into other substances, that is, to convert it into camptothecin derivatives, thereby reducing toxicity while retaining anticancer activity.

However, camptothecin itself is poorly soluble in various organic solvents, and camptothecin has resistance to electrophilic substitution reactions due to the heterocycle it has in its chemical structure. However, there are various obstacles, and the reality is that it is not as easy to obtain new derivatives as it is to plan on paper.

The present inventors first catalytically reduced camptothecin in acetic acid or a solvent such as dioxane-acetic acid using a platinum catalyst, and after acylating the 1-position of the resulting 1,2,6,7-tetrahydrocamptothecin, 1-acyl-10 by treatment with
-Nitro-1,2,6,7-tetrahydrocamptothecin was obtained, and various 10-
We succeeded in obtaining substituted camptothecin derivatives.

After that, further experiments were carried out, and the results of the research were 1.
We found that when 2,6,7-tetrahydrocamptothecin is directly treated with sulfuric nitric acid, the 11-position is selectively nitrated to yield 11-nitro-1,2,6,7-tetrahydrocamptothecin. .

The present invention has been made based on this knowledge. The present invention will be explained in detail below.

In the method for producing 11-nitro-1,2,6,7-tetrahydrocamptothecin of the present invention, the reduction of camptothecin B ring, which is the first reaction, uses acetic acid, dioxane-acetic acid, dioxane-hydrochloric acid, etc. as a solvent. However, hydrogenation can be carried out efficiently by hydrogenation at normal pressure and room temperature in the presence of a catalyst for catalytic reduction such as a platinum catalyst. The obtained 1,2,6,7-tetrahydrocamptothecin is selectively nitrated at the 11-position by treatment with sulfuric acid and nitric acid, resulting in 11-nitro-
1,2,6,7-tetrahydrocamptothecin can be obtained. This 11-nitro-1,2,
6,7-tetrahydrocamptothecin can be converted into other 11-tetrahydrocamptothecin by converting its nitro group into various substituents or by oxidizing (forming an aromatic nucleus) if desired.
substituted camptothecin or 11-substituted-1,2,6,
Since it can be derived into 7-tetrahydrocamptothecin derivatives, it is an important intermediate for the synthesis of various 11-substituted camptothecin derivatives.

For example, oxidation (aromatic nucleation) of 11-nitro-1,2,6,7-tetrahydrocamptothecin can lead to 11-nitrocamptothecin, which cannot be obtained by nitration of camptothecin itself with sulfuric acid. Also, 11−
Nitro-1,2,6,7-tetrahydrocamptothecin or 11-nitrocamptothecin is converted into an amino group by converting its nitro group into an amino group by reduction or catalytic reduction with metals such as iron or tin in hydrochloric acid. The 11-amino group corresponding to can be obtained. These 11-amino bodies can be converted to 11-amino by acylating or alkylating the amino group.
It can be derived as an acylamino form or an 11-alkylamino form. The amino group of this 11-amino compound can also be converted into various other functional groups by converting it into a diazonium salt. For example, this
By diazotizing the 11-amino compound in an aqueous sulfuric acid solution and then heating, the 11-hydroxy substituted compound is
Furthermore, an 11-methoxy substituted product can be obtained by treating the above diazonium salt with methanol. Furthermore, 11-chlorocamptothecin or 11-bromocamptothecin can be obtained by diazotizing the above 11-amino compound in hydrochloric acid or hydrobromic acid and then treating with cuprous chloride or cuprous bromide. can.

Examples of the present invention are listed below, but the present invention is not limited to these Examples.

Example 1 (a) Production of 1,2,6,7-tetrahydrocamptothecin Camptothecin (500 mg, 1.43 mmo) was suspended in acetic acid (100 ml), platinum oxide (100 mg) was added, and catalytic reduction was carried out at room temperature under normal pressure ( 1.5 hours, approx. 140
ml of hydrogen). After removing the catalyst, the reaction mixture was dried under reduced pressure, the residue was dissolved in chloroform (200 ml), 5% aqueous sodium bicarbonate solution (100 ml), and then saturated brine (100 ml).
ml), the chloroform layer was dried over magnesium sulfate, filtered, dried under reduced pressure, and purified by column chromatography (chloroform) on silica gel (20 g) to give the title compound as yellow-white crystals (285 mg (conversion rate)). 56.3%, yield 76.7%)
can get. 113 mg (crude) of unreacted starting material was recovered. mp (decomposition) 240-242℃ [from MeOH] IRν ^KBr _nax cm ^-1 : 3470, 1745, 1645, 1565, 1495,
1165, 1030 (b) Production of 11-nitro-1,2,6,7-tetrahydrocamptothecin 1,2,6,7-tetrahydrocamptothecin (100 mg, 0.254 mmol) obtained in (a) above was dissolved in concentrated sulfuric acid ( 5 ml), add to this under an ice-salt bath,
61% nitric acid (d=1.38) (25.5μ, 0.305mmol)
Add slowly while stirring. After the addition is complete, stirring is continued for 1 hour. Pour the reaction solution into ice water (100
dilute with chloroform (100 ml) and extract with chloroform (100 ml).
ml x 3 times). This chloroform layer was dried with magnesium sulfate, dried under reduced pressure, and the residue was subjected to silica gel chromatography (CHCl ₃ ).
Camptothecin (16mg, 16.2%) when purified with
Along with this, the title compound (58 mg, 51.4%) was obtained.

m.p178℃ (decomposition) (from CHCl ₃ -hexane) MS: m/e397 [M ⁺ ] (as C ₂₀ H ₁₉ N ₃ O ₆ = 397) IRνKBrmaxcm ^-1 : 3450, 3120, 1740, 1650,
1570, 1525, 1342, 1324, 1295, 1250, 1150 NMR (in DMSO- _d6 ) δ: 0.75 (3H, t, J=
7Hz, -CH ₂ C H ₃ ), 1.72 (2H, q, J = 7
Hz, -CH ₂ CH ₃ ), 2.36 (1H, br.m, C-6
-H), 2.70-2.87 (2H, m, C-7-H),
3.99-4.11 (2H, m, C-5-H), 4.99
(1H, br.m, C-2-H), 5.22 (2H, s,
C-17-H), 6.29 (1H, br.s, NH), 6.52
(1H, s, C-20-OH), 7.13-7.46 (4H,
m, C-9-H, C-10-H, C-12-H and C-14-H) Example 2 Preparation of 11-nitrocamptothecin 1,2,6 obtained in Example 1(a) , 7-tetrahydrocamptothecin (352 mg, 1.00 mmol) was dissolved in concentrated sulfuric acid (15 ml) and added to this solution under an ice-salt bath.
Add 61% nitric acid (90 μ, 1.2 mmol) with stirring.
Drips slowly. Thereafter, stirring was continued for 1 hour, the reaction solution was diluted with ice water (200 ml), and extracted with chloroform (200 ml x 3 times). This chloroform layer is dried over magnesium sulfate and then dried under reduced pressure. Dissolve the residue in dioxane (30 ml) and add DDQ (416 mg, 0.83 mmol) to 160
Boil at reflux for minutes. After that, it was dried under reduced pressure, the residue was dissolved in chloroform (300 ml), and water (100 ml×
3 times). After drying this chloroform layer with magnesium sulfate, the solvent is distilled off and the residue is purified by silica gel column chromatography (CHCl ₃ ) to obtain the title compound (121 mg, 30.8%) along with camptothecin (23 mg).

mp246℃ (decomposition) [from CHCl ₃ ] Elemental analysis value (as C ₂₀ H ₁₅ N ₃ O ₆ ) Calculated value: C, 61.10; H, 3.75; N, 10.43 Measured value: C, 61.07; H, 3.84; N , 10.68 MS: m/e393 [M ⁺ ] IRν ^KBr _nax cm ^-1 : 1745, 1660, 1600, 1535, 1345,
1230, 1155 NMR (in DMSO- _d6 ) δ: 0.89 (3H, t, J=7
Hz, -CH ₂ C H ₃ ), 1.88 (2H, q, J = 7Hz, -
CH2CH3 ), 5.34 (2H, s, C-5 _- H), _5.44
(2H, s, C-17-H), 6.55 (1H, s, C-
20-OH), 7.42 (1H, s, C-14-H), 8.40
~8.42 (2H, m, C-9-H and C-10-
H), 8.87 (1H, s, C-7-H), 8.95 (1H,
s, C-12-H) Reference Example 1 Production of 11-aminocamptothecin 11-nitrocamptothecin (100 mg, 0.254 mmol) obtained in Example 2 was dissolved in a mixed solvent of ethanol (30 ml) and dioxane (20 ml). , add platinum oxide (15 mg), and perform catalytic reduction at room temperature and pressure for 1 hour. When the catalyst is removed and the solvent is dried under reduced pressure, the title compound is obtained quantitatively.

MS: m/e363 [M ⁺ ] (as C ₂₀ H ₁₇ N ₃ O ₄ = 363) IRν ^KBr _nax cm ^-1 : 3390, 3330, 3220, 1735, 1645,
1590, 1505, 1250, 1155, 1045 NMR (in DMSO- _d6 ) δppm: 0.92 (3H, t, J
= 7.5Hz), 1.86 (2H, q, J = 7.5Hz), 5.11
(2H, s), 5.36 (2H, d, J=3Hz), 5.00~
5.40 (2H, br.), 7.04 (1H, s), 7.35 (1H,
s), 6.90-7.80 (2H, m), 8.32 (1H, s) Reference Example 2 Production of 11-dimethylaminocamptothecin 11-Aminocamptothecin (5 mg, 0.014 mmol) obtained in Reference Example 1 was dissolved in acetone (10 ml). To this were added anhydrous potassium carbonate (15 mg) and methyl iodide (1 ml), and the mixture was stirred at room temperature for 30 minutes. Thereafter, insoluble matters were removed by filtration, and the liquid was dried to give the title compound (5 mg, 91.3%).

MS: m/e391 [M ⁺ ] (as C ₂₂ H ₂₁ N ₃ O ₄ = 391) Reference Example 3 Production of 11-acetaminocamptothecin 11-Aminocamptothecin (5 mg, 0.014 mmol) obtained in Reference Example 1 was Suspend in chloroform (5 ml), add pyridine (0.5 ml) and acetic anhydride (0.1 ml), and stir at room temperature for 1 hour. After that, the solvent was removed to dryness under reduced pressure to obtain the title compound (5 mg, 88.2%).
is obtained.

MS: m/e405 [M ⁺ ] (as C ₂₂ H ₁₉ N ₃ O ₅ = 405) NMR (in DMSO-d ₆ ) δppm: 0.90 (3H, t, J
= 7.5Hz), 1.86 (2H, q, J = 7.5Hz), 2.15
(3H, s), 5.23 (2H, s), 5.39 (2H, s),
6.41 (1H, s), 7.35 (1H, s) 7.66 (1H, s),
7.81~8.05 (2H, m), 8.54 (1H, s), 10.39
(1H, s) Reference Example 4 Production of 11-chlorocamptothecin 11-nitrocamptothecin (200 mg,
Dissolve 0.509 mmol) in a mixture of ethanol (60 ml) and dioxane (40 ml), add platinum oxide (30 mg), and perform catalytic reduction at room temperature and pressure for 1 hour.
After removing the catalyst and distilling off the solvent under reduced pressure, 11-aminocamptothecin is obtained. Dissolve this in 18% hydrochloric acid (20 ml), and gradually add an aqueous solution of sodium nitrite (35 mg, 0.560 mmol) while stirring in an ice-salt bath. After stirring for 10 minutes, the resulting aqueous solution of diazonium salt was
Cuprous chloride (252 mg,
2.545 mmol) of 18% hydrochloric acid solution (10 ml). After the addition is complete, continue stirring for 100 minutes. The reaction solution was diluted with ice water (200 ml) and extracted with chloroform (200 ml x 3). After drying this chloroform layer with magnesium sulfate, it was distilled off under reduced pressure to obtain 11-chlorocamptothecin (107 mg,
56.0% yield) is obtained. Add this to chloroform
Recrystallization from hexane gives pale yellow needles.

mp257℃ (decomposition) [from CHCl ₃ -hexane] Elemental analysis value (as C ₂₀ H ₁₅ N ₂ O ₄ Cl) Calculated value: C, 62.52; H, 3.89; N, 7.02; Cl, 8.98 Actual value: C, 62.75; H, 3.95; N, 7.32; Cl, 9.26 MS: m/e382 [M ⁺ ], 384 [M + 2] IRν ^KBr _nax cm ^-1 : 1745, 1655, 1605, 1590, 1225,
1155 NMR (in DMSO- _d6 ) δ: 0.89 (3H, t, J=7
Hz, -CH ₂ C H ₃ ), 1.87 (2H, q, J = 7Hz, -
CH2CH3 ₎ , 5.27 (2H, s, C-5 _- H), 5.42
(2H, s, C-17-H), 6.50 (1H, s, C-
20-OH), 7.35 (1H, s, C-14-H), 7.71
(1H, dd, J=9Hz, 2Hz, C-10-H),
8.12-8.29 (2H, m, C-9-H and C-12
-H), 8.71 (1H, s, C-7-H) Reference Example 5 Production of 11-bromocamptothecin 11-nitrocamptothecin (300 mg,
0.763 mmol) was catalytically reduced as in Reference Example 4 to obtain 11-aminocamptothecin. this
Dissolve in 18% hydrogen bromide water (24 ml), and gradually add an aqueous solution of sodium nitrite (58 mg, 0.843 mmol) dropwise in an ice-salt bath. After stirring for 10 minutes after the dropwise addition, the aqueous solution of the diazonium salt produced was heated at 60 to 70°.
of cuprous bromide (1094 mg, 7.63 mmol) heated to
Drop it dropwise into a 24% hydrogen bromide solution (10 ml). After the addition is complete, stirring is continued for 1 hour. The reaction solution was diluted with ice water (200 ml) and extracted with chloroform (200 ml x 3). After drying this chloroform layer with magnesium sulfate, it was distilled off under reduced pressure.
11-bromocamptothecin (133 mg, 40.8% yield)
is obtained. When this is recrystallized from chloroform, pale yellow needle crystals are obtained.

mp260-261℃ (decomposition) [from CHCl ₃ ] MS: m/e426 [M ⁺ ], 428 [M+2]
(as C ₂₀ H ₁₅ N ₂ O ₄ Br = 426) IRν ^KBr _nax cm ^-1 : 1745, 1655, 1600, 1225, 1155 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7
Hz, -CH ₂ C H ₃ ), 1.87 (2H, q, J = 7Hz, -
CH2CH3 ₎ , 5.25 (2H, s, C-5 _- H), 5.41
(2H, s, C-17-H), 6.48 (1H, s, C-
20-OH), 7.34 (1H, s, C-14-H), 7.79
(1H, dd, J=9Hz, 2Hz, C-10-H),
8.08 (1H, d, J=9Hz, C-9-H), 8.35
(1H, d, J=2Hz, C-12-H), 8.69 (1H,
s, C-7-H) Reference Example 6 Production of 11-hydroxycamptothecin 11-nitrocamptothecin (100 mg,
0.254 mmol) was catalytically reduced as in Reference Example 4 to obtain 11-aminocamptothecin. This is 17
% sulfuric acid (6 ml), and an aqueous solution of sodium nitrite (19 mg, 0.275 mmol) was slowly added dropwise under an ice-salt bath. Thereafter, stir for 10 minutes, then add concentrated sulfuric acid (1 ml) and boil under reflux for 1.5 hours. The reaction solution was diluted with ice water (100 ml), chloroform (100 ml) was added, and after shaking, the precipitated insoluble matter was removed.
Purification by silica gel column chromatography gives the title compound (25 mg, 27.0%).

mp＞300℃ [from Py-MeOH] MS: m/e364 [M ⁺ ] (as C ₂₀ H ₁₆ N ₂ O ₅ = 364) IRν ^KBr _nax cm ^-1 : 3470, 1740, 1645, 1610, 1590,
1565, 1480, 1460, 1375, 1235, 1155 NMR (in DMSO- _d6 ) δ: 0.89 (3H, t, J = 7
Hz, -CH ₂ C H ₃ ), 1.87 (2H, q, J = 7Hz, -
CH2CH3 ₎ , 5.20 (2H, s, C-5 _- H), 5.41
(2H, s, C-17-H), 6.47 (1H, s, C-
20-OH), 7.22-7.35 (3H, m, C-14-H,
C-10-H and C-12-H) 7.94 (1H, d,
J=9Hz, C-9-H), 8.52 (1H, s, C-
7-H) Reference Example 7 Production of 11-methoxycamptothecin 11-hydroxycamptothecin (20 mg,
0.055mmol) was suspended in methanol and added to it.
Add 0.6% diazomethane in ether (10 ml) and stir at room temperature for 3 hours. Thereafter, the solvent was removed to dryness under reduced pressure to obtain the title compound (18 mg, 86.8%).

mp277-279℃ (decomposition) [from CHCl ₃ ] MS: m/e378 [M ⁺ ] (as C ₂₁ H ₁₈ N ₂ O ₅ = 378) IRν ^KBr _nax cm ^-1 : 3450, 2920, 1740, 1655, 1615 ,
1505, 1450, 1375, 1235, 1150 NMR (in DMSO- _d6 ) δ: 0.89 (3H, t, J=8
Hz, -CH ₂ C H ₃ ), 1.87 (2H, q, J = 8Hz, -
CH2CH3 ₎ , 3.97 (3H, s, _C -11- OCH3 ₎ ,
5.24 (2H, s, C-5-H), 5.42 (2H, s, C
-17-H), 6.48 (1H, s, C-20-OH),
7.29-7.40 (2H, m, C-10-H and C-14
-H), 7.55 (1H, d, J=2Hz, C-12-
H), 8.02 (1H, d, J=9Hz, C-9-H),
8.59 (1H, s, C-7-H)

Claims (1)

[Claims] 1 formula 11-nitro-1,2,6,7-tetrahydrocamptothecin represented by 2. 1, obtained by catalytic reduction of camptothecin
Formula characterized by treating 2,6,7-tetrahydrocamptothecin with sulfuric acid and nitric acid A method for producing 11-nitro-1,2,6,7-tetrahydrocamptothecin represented by