JPH0421669A - 3-carbomethoxyindole derivative and its production - Google Patents

Abstract

NEW MATERIAL:A 3-carbomethoxyindole derivative expressed by formula I (R<1> is hydroxy or lower alkoxy; R<2> is H or amino-protecting group) and salts thereof. EXAMPLE:1-Carbobenzoxy-3-carbomethoxyindole. USE:Useful as an intermediate for medicines, agricultural chemicals and fine chemicals, especially as an intermediate for CC-1065, etc., having a structure effectively used as, e.g. a carcinostatic agent. PREPARATION:A phenylhydroxylamine derivative expressed by formula II (R<3> is H, hydroxy or lower alkoxy; R<4> is amino-protecting group) is allowed to react with methyl propiolate in the presence of a base in an organic solvent such as benzene, preferably at 15-30 deg.C to afford the objective compound expressed by formula III in formula I. The mixing ratio of the compound expressed by formula II to the methyl propiolate is preferably within the range of (1:1) to (1:5).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel 3-carbomethoxyindole derivative and a method for producing the same.

[Prior Art] A large number of compounds having an indole skeleton are known in pharmaceuticals, agrochemicals, and various fine chemicals, and constitute a useful and important product group.

In the future, its importance will further increase, and research is currently being conducted on the synthesis of new indole derivatives and their production methods all over the world.

Among these studies, there are surprisingly few efficient synthetic methods for 3-carbomethoxyindoles (in particular, there are almost no known examples of introducing oxygen functional groups into the 4-7 positions of the indole ring (P, E., Peterson, J., P., Wol.
fm and C, Niemann, J, Org, Che
+w,.

23303 (19581: S, Nakatsuk
a, O, Asano, ni Ueda, T, Goto
, Heterocycles, 26.1471゜(
19871) - especially 3 with an oxygen function in the 6-position
Although carboalkoxyindole derivatives are considered to be important intermediates for many pharmaceutical products, their synthesis method is completely unknown, and almost no such derivatives are known.

[Problems to be Solved by the Invention] The object of the present invention is to provide a novel 3-
An object of the present invention is to provide a carbalkoxiindole derivative and a method for producing the same.

[Means for Solving the Problems] The inventors of the present application first conducted extensive research into a general efficient method for synthesizing 3-carbomethoxyindole, and as a result, they synthesized phenylhydroxylamine and methyl propiolate in the presence of a base. It has been found that the desired compound can be easily obtained in good yield when the reaction is carried out. Furthermore, the present inventors have found that this production method can be easily applied to the production of novel 3-carbalkoxyindole derivatives having an oxygen functional group at the 6-position, and have completed the present invention.

That is, the present invention provides 3-carbomethoxyindole derivatives represented by -maximum [N (wherein R' is a hydroxy group or a lower alkoxy group, and R2 is a hydrogen atom or a protecting group for an amino group) and their Provide salt.

Furthermore, the present invention provides a phenylhydroxylamine derivative represented by -max [H coHR' (wherein 1 represents a hydrogen atom, a hydroxy group or a lower alkoxy group, and R4 represents a protecting group for an amino group). -6 formula [+11] (wherein R3 and R
4 has the same meaning as general formula [11]) A method for producing a 3-carbomethoxyindole derivative represented by the following and a salt thereof is provided.

[Effect of the invention] The present invention provides a novel 3-carbalkoxiindole derivative having an oxygen functional group at the 6-position.The indole derivative of the present invention is important as an intermediate for pharmaceuticals, agricultural chemicals, and fine chemicals. It is.

Furthermore, the present invention provides a method for easily and efficiently producing a novel 3-carbalkoxyindole derivative having an oxygen functional group at the 6-position.

[Detailed Description of the Invention] As mentioned above, the indole derivative of the present invention is represented by the above formula [II]. - In formula [II, R' is a hydroxy group or a lower alkoxy group. R2 is a hydrogen atom or a protecting group for an amino group. Here, the protecting group for the amino group refers to a protecting group that is commonly used in peptide chemistry, and specifically includes a carbobenzoxy group (Z group), a tert-butyloxycarbonyl group (Boc group), and a p-methoxy group. Benzyloxycarbonyl group (Z (Oklel group), inbornyloxycarbonyl group (Iboc group), 9-fluorenylmethyloxycarbonyl group (Fsoc group),
formyl group (HCO group), phthaloyl group (pht group),
Other protecting groups for amino groups, such as p-h luenesulfonyl group (Tos group), triphenylmethyl group (fTrt group), etc., are described in "Fundamentals and Experiments of Peptide Synthesis" by Izumiya et al., published by Maruzen Co., Ltd., 1985. published on January 20th, and they can also be adopted in the present invention.

Among the indole derivatives of the present invention, the most preferred are those in which R' is a methoxy group and R2 is a hydrogen atom.

The indole derivative of the present invention represented by the above-mentioned formula [III] or an indole derivative serving as an intermediate thereof is a combination of a phenylhydroxylamine derivative represented by the above-mentioned formula [II], methyl propiolate (CHEC-Co,
In the formula [II], R3 represents a hydrogen atom, a hydroxy group or a lower alkoxy group, and R4 represents a protecting group for an amino group. Preferred bases include organic bases such as triethylamine and diisopropylethylamine. Further, the reaction can be carried out in an organic solvent, and examples of preferred organic solvents include benzene, acetonitrile, tetrahydrofuran, nitromethane, chloroform, and methylone chloride.

The mixing ratio of the phenylhydroxylamine derivative and methyl propiolate is not particularly limited, but is usually about 1:1 to 1:5 in terms of molar ratio. Further, the amount of the base added is not particularly limited, but is usually equivalent to 1:
It is about 5.

The reaction temperature is not particularly limited, but is from room temperature to the boiling point of the solvent used, preferably about 15°C to 30°C.8 The reaction time is also not particularly limited, but is usually about 1 to 2 hours. In some cases, the yield can be improved by adding a radical scavenger or reducing agent such as sodium borohydride. The amount of these used is usually equivalent or less in molar ratio.

Although the phenylhydroxylamine derivative represented by the general formula [11], which is the starting material for the above reaction, is an unstable compound, the following can be obtained by reducing an easily available nitrobenzene derivative with zinc based on a known method. It can be synthesized according to the chemical reaction formula (T, 5her
adsky, E., Nov, S., Segal and A.
, Frank, J., Chew, Sac.
Perkxnrans l.

+1977).

CH A compound in which R2 is a hydrogen atom in the general formula [II,
- Can be obtained by removing the corresponding protecting group of R4 of the compound represented by the formula [+11] by a known method. For example, when R2 is a carbobenzoxy group, 0% The desired compound in which R2 is a hydrogen atom can be easily obtained by hydrogenation using palladium-carbon as a catalyst.

The compounds of the present invention have use as intermediates in pharmaceuticals, agrochemicals and fine chemicals. More specifically, it can be used, for example, as an intermediate such as CC-1065, which has an interesting structure as an anticancer agent.

[Examples] Hereinafter, the present invention will be explained in more detail based on Examples, but the present invention is not limited to the following Examples.

Synthesis of 1-lupobenzoxy-3-carbomethoxyindole on Higashi Jll N-phenylhydroxylamine (100B, 0.41
ms+all and methyl propiolate (0,075m
l, 0.84 m■ol) and nitromethane (3■1)
To this was added diisopropylethylamine (0,085 ml, 0.94 mmall) under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was distilled off and the resulting residue was subjected to silica gel column chromatography. Separation and purification using benzene-acetone (100:2
v/v) White needle-shaped crystals were obtained from the eluate and recrystallized from methanol to obtain 1-carbobenzoxy-3-carbomethoxyindole (113B, 89%) with a melting point of 89.0.
Obtained as white needle-like crystals at a temperature of 91.0°C to 91.0°C.

IR "clN cm-': 1745 and 17
10 fc=ol sail N M R (CD(:1.1 :δ3.92 f3H,
s, OMel, 5.48 (2H.

s, -0CHJrl, 7.33-7.51 (7H,
ra, Ar old, 8.16 (LH, dd, J=2.0
and 8.0 Hz, 4-old, 11.20 fLH.

bd, J: 8.0 Hz, 7-H), 8.30 (I
H, s, 2-H1 heavy analysis ale: 309 (M”
1.265.91 (100%) Elemental analysis: C+sH
+JO4 Calculated value: C, 69,89; H, 4,89; N,
4.53 Actual measurement value: C, 69,68, H, 4,80
; N, 4.5315 liters In the synthesis shown in Example 1, methyl propiolate,
Table 1 shows the results of the study by changing the base, solvent, and additives as shown in Table 1.

Ellconitriethylamine MM: N-Methylmorpholine Pr1NEt Nidiisopropylethylamine and 3-carbomethoxyindole Compound obtained according to Example 1 (160 wag, 0.00 wt.
52 wool) was dissolved in methanol (25 ml),
10% Pd-C (10B) was added to this and stirred at room temperature under a hydrogen stream for 6 hours. After the reaction was completed, the catalyst was filtered off, the solvent of the filtrate was distilled off, and the residue was purified by silica gel column chromatography. Separate and purify and add benzene-acetone (10.1.
White powder crystals were obtained from the v/vl eluate and recrystallized from methanol to give 3-carboxindole (90 w
ag, 100%) with a melting point of 1495-1505"C (C
, Zahi and A., Ferratini, Ber.
23.2297 (1470~ in 18901 data)
148.0° C.) as prismatic crystals.

I RL ""z cm-': 3450 (NH
I, 1690 (C=OIN M R(CDC1al
, δ3.90 f3H,s, OMel, 7.26-7
．． 31 t2H, ■, 5- and 6-old, 7.40-7.
44 (Il,■.

7-H), 7.93 f2H, d, J=3.0
Hz, 1-Hl, 8.18-8.22 flH
, ■, 4H), 8.60 (IH, bs, 1-
H mass spectrometry: ale: 175 (M”), 144
(100%1 calculated value: C,,H,NO2: 175
．． 0633 (M"1 actual value: 175.0635 Synthesis of 1-carboxy-3-carbomethoxy-6-methoxyindole a) N-carbobenzoxy-N-(3-methoxyphenyl)-hydroxyl Synthesis of amine m-nitroanisole (5.80 g, 37.9 mmol) and 85% zinc (5.80 g, 37.9 mmol)
, 83g, 75.8 m01) and 50% ethanol (
After the reaction, the reaction solution was filtered through celite, the filtrate was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed. Oil obtained by distillation (
5.99gl was used in the next reaction without isolation and purification.

Carbobenzoxy chloride (6,5011) was added to the above hydroxylamine (5,99 g ether droplets), and then potassium carbonate (3,0 g and water (15 ff) were added at 0°C.
l) and stirred at the same temperature for 1 hour. After the reaction was completed, saturated brine was added to the warm reaction solution, extracted with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue obtained by distillation was separated and purified by silica gel column chromatography, and N-carbobenzoxy-N-(3-methoxyphenyl)-hydroxylamine (8 , 48 g, 82%) as a pale pink oil.

I RL ``IIt-crs-'' 330ro (O
H), 1700 fc=01NMR(CDC1
,1:δ3.75f3H,s, OMel, 5.2
5f2H,s, -CH,Arl, 6.73 flH,b
dd, J=2.0 and 8.0 Hz, 4-H), 7.
06 (II, t, J=8.0Hz, 5-H), 7
．． 39 flH, bs, OHI mass spectrometry ■/e (M”l CtsHISNO,: 2
73.1001 Calculated value: 273.1001 Actual value: 273.0973 bll-carbobenzoxy-3-carbomethoxy-6-
Synthesis of methoxyindole Hydroxylamine obtained in a) (7531 g, 2.
76 mIIal) and methyl propiolate (0,25
ml, 2.81 mmoil, the reaction was carried out in the same manner as in Example 1, and when recrystallized from methanol, I-carbobenzoxy-3-carbomethoxy-6-
Methoxyindole (melting point 117.0℃) 28711
Ig/IReCHe+]cw-1, 1745 and 1705
fc=o)NMR(CDCI, δ3.83
f3H,s, -CO,Mel, 3.93(
3H,s, ArOMel, 5.50[2H,s
, -OCH, Arl, 696 (IH, dd, J=2.
2 and 8.8 Hz, 5-old, 717-7.51 [5H
, rn, Arl, 7.74 (LH, bs, 7-old, 8.00 (IHd, J=8.8 Hz,
4-Old, 8.19 (IH, s, 2-Old Mass Spectrometry m/e: 339 fM”) 294.204.91
f100% 1 elemental analysis C,,H,,NO.

Calculated value: C67.25, H5.05, N 4.13
Actual value: C67, 36, H5, 13, N 4.10
Support 5±1 In the synthesis of the compound shown in Example 4, methyl propiolate, base, solvent, and additives were changed as shown in Table 2, and the results of the study are shown in the same table.

Table 2 Synthesis of EtJ:) ethylamine-3-carbomethoxy-6-methoxyindole Compound f270 mg, 0.
Five oils of 80 layers were treated in the same manner as in Example 3, and 3-carbomethoxy-6-methoxyindole was recrystallized from methanol to obtain white prismatic crystals (150a+g, 92%).

Melting point: 147.0-148.0℃ IR "Cl5c+s-': 1695 (C=O
) N M R (CD(:1.1 :δ 3.82 (3H,s, ArOMel, 3.92f3
H,s, -COaMe), 6.86(IH,d, J
:2.2 Hz, 7-H), 6.93(IH, dd
.

J=8.8 and 2.2 Hz, 5-Hl, 7.79
flH, d, J=3.0゜2-H), 8.04[IH
, d, J=8.8 Hz, 4-Hl, 8.71f
lH.

bs, 1-Hl Mass spectrometry m/e: 205 (M”, 100%), 1
90.174 Elemental analysis C,,H,,N O.

Claims (3)

[Claims] (1) General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] (However, in the formula, R^1 is a hydroxy group or lower alkoxy group, and R^2 is a hydrogen atom or a protecting group for an amino group. ) A 3-carbomethoxyindole derivative and a salt thereof. (2) The 3-carbomethoxyindole derivative and its salt according to claim 1, wherein R^1 is a methoxy group and R^2 is hydrogen. (3) General formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (However, in the formula, R^3 represents a hydrogen atom, hydroxy group, or lower alkoxy group, and R^4 represents the protection of an amino group. The general formula [III] is characterized by reacting a phenylhydroxylamine derivative (indicating a group) with methyl propiolate in the presence of a base. A method for producing a 3-carbomethoxyindole derivative represented by the following formula (wherein R^3 and R^4 have the same meanings as in general formula [II]) and a salt thereof.