CN102746295B - Preparation method for 4-substituted-7-azaindole - Google Patents

Preparation method for 4-substituted-7-azaindole Download PDF

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CN102746295B
CN102746295B CN201210205860.XA CN201210205860A CN102746295B CN 102746295 B CN102746295 B CN 102746295B CN 201210205860 A CN201210205860 A CN 201210205860A CN 102746295 B CN102746295 B CN 102746295B
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azaindole
organic solvent
oxidation
azaindoles
replacement
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CN102746295A (en
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谢应波
姚为建
张庆
张华�
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SHANGHAI DAMAS REAGENT CO Ltd
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SHANGHAI DAMAS REAGENT CO Ltd
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Abstract

The invention relates to the field of organic synthesis and medicine, and discloses a preparation method for 4-substituted-7-azaindole. Firstly, N-oxide-7-azaindole is prepared by employing 7-azaindole as a raw material and hydrogen peroxide as an oxidizing agent; then 4-halogenated-7-azaindole is synthesized by adding acetonitrile and phosphorus oxyhalides (POX3) and by using diisopropyl ethyl amine as a catalyst; and 4-methoxy-7-azaindole is synthesized by reacting the synthesized 4-halogenated-7-azaindole and alkoxide. The 4-substituted-7-azaindole synthesized by the method has high yield and low cost, and the method is easy for industrialization.

Description

The preparation method of 4 replacement-7-azaindoles
Technical field
The present invention relates to organic synthesis and field of medicaments, be specially a kind of synthetic method of 4 replacement-7-azaindoles.
Background technology
7-azaindole, as the important a member of azaindole family, is the isoelectronic species of indoles and purine, and the 7-azaindole of therefore usining can form and much have bioactive molecule as parent nucleus.
Although 7-azaindole and derivative thereof are so general not as indoles at the natural occuring article of occurring in nature, because it has special physico-chemical property and pharmaceutical activity, have caused the great interest of people.Especially the 7-azaindole of 4 replacements, as 4-bromo-7-azaindole, the chloro-7-azaindole of 4-and 4-methoxyl group-7-azaindole etc., can be used as intermediate, for the synthesis of the medicine with antitumour activity or treatment disease of immune system.
Current 4 synthetic methods that replace 7-azaindole mainly contain two kinds: in the time of (1) synthetic azepine indole ring, bring substituting group into; (2) synthetic by be oxidized-7-of N-azaindole.
Wherein second method is because its easy operation and higher yield become 4 main synthesis methods that replace 7-azaindole.Tetrahedron 65 (2009) 4814-4819, the synthetic route of having introduced the chloro-7-azaindole of a kind of synthetic 4-is as follows:
First use oxygenant 2-methyl-4-chlorophenoxyacetic acid (MCPA) to synthesize N-oxidation-7-azaindole, this oxygenant price comparison is expensive, and because have strong uv-absorbing, is mingled in product, is difficult for removing.Second step reacts (not adding other solvents) by phosphorus oxychloride with N-oxidation-7-azaindole, and yield is on the low side, below 80%.Whole route cost is higher, is difficult for industrialization.
Therefore, be necessary to improve prior art, improve the purity of N-oxidation-7-azaindole, reduce the cost of preparation, improve the yield of product, adapt to the requirement of suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of 4 replacement-7-azaindoles, the method cost is lower, be easy to industrialization.
The present invention be take 7-azaindole as raw material, take tetrahydrofuran (THF) or ethylene glycol monomethyl ether or propylene glycol monomethyl ether as solvent, and hydrogen peroxide is first synthetic N-oxidation-7-azaindole of oxygenant.Synthetic N-oxidation-7-azaindole, with acetonitrile and three oxyhalogen phosphorus POX 3(as POCl 3or POBr 3deng) as solvent (POCl 3or POBr 3simultaneously as reactant), with DIPEA (diisopropyl ethyl amine, equivalent is 0.1～0.15), be catalyzer, temperature of reaction is 80 ℃～100 ℃, synthetic 4-halo-7-azaindole.Synthetic 4-halo-7-azaindole, usings DMF etc. as solvent, and alkoxide (as sodium methylate etc.) reaction, temperature is 110 ℃～130 ℃, the synthetic 4-methoxyl group-7-azaindole of reaction.
The preparation method of 4 replacement-7-azaindoles, described 4 replacement 7-azaindoles are 4-halo-7-azaindole or 4-alkoxyl group-7-azaindole; As shown in the formula (I), R is haloid element or alkoxyl group to its structure; Preferably, R is Cl, Br or C1～C4 alkoxyl group;
Comprise the following steps:
(1) synthetic N-oxidation-7-azaindole: 7-azaindole mixes with organic solvent I, adds hydrogen peroxide, 5～15 ℃ are reacted 2～5 hours, obtain N-oxidation-7-azaindole;
The mol ratio of 7-azaindole and hydrogen peroxide is that 1:1.1～2(is preferably 1.1～1.3); Organic solvent I is tetrahydrofuran (THF), ethylene glycol monomethyl ether or propylene glycol monomethyl ether;
(2) the N-oxidation-7-azaindole of step (1) further replaces 4 replacement-7-azaindoles of acquisition.
When R is haloid element, step (2) comprising:
(A) N-oxidation-7-azaindole mixes with organic solvent II, then adds POX 3mix, 80～100 ℃ of reactions dripped catalyzer diisopropyl ethyl amine after 20～60 minutes, continued 80～100 ℃ of reactions 2～8 hours; X is haloid element; Organic solvent II is acetonitrile or tetrahydrofuran (THF).
N-oxidation-7-azaindole and POX 3and the mol ratio of diisopropyl ethyl amine is 1:2～10:0.05～0.2, be preferably 1:5～10:0.1～0.15; The amount ratio of N-oxidation-7-azaindole and acetonitrile is 0.5～2mmol/ml;
(B) remove acetonitrile and POX 3after, adding water at-5～0 ℃, the amount ratio of water and step (A) N-oxidation-7-azaindole is 1ml:0.5～2mmol;
(C) regulating pH is 8.5～9.5, gets precipitation, obtains 4-halo-7-azaindole;
When R is alkoxyl group, comprise the following steps:
I.N-oxidation-7-azaindole mixes with organic solvent II, then adds POX 3mix, 80～100 ℃ of reactions dripped catalyzer diisopropyl ethyl amine after 20～60 minutes, continued 80～100 ℃ of reactions 2～8 hours; X is haloid element; Organic solvent II is acetonitrile or tetrahydrofuran (THF).
N-oxidation-7-azaindole and POX 3and the mol ratio of diisopropyl ethyl amine is 1:2～10:0.05～0.2, be preferably 1:5～10:0.1～0.15; The amount ratio of N-oxidation-7-azaindole and acetonitrile is 0.5～2mmol/ml;
II. remove acetonitrile and POX 3after, adding water at-5～0 ℃, in water and step I, the amount ratio of N-oxidation-7-azaindole is 1ml: 0.5～2mmol;
III. regulating pH is 8.5～9.5, gets precipitation, obtains 4 halogen replacement-7-azaindoles;
IV.4 position halogen replacement-7-azaindole and alkali metal alcoholates mix with organic solvent II I, and 100～150 ℃ are reacted 4～10 hours; The mol ratio of 4-halo-7-azaindole and alkali metal alcoholates is 1～1.5; 4 halogen replacement-7-azaindoles and organic solvent II I amount ratio are 0.2～1mmol/ml; Organic solvent II I is dimethyl formamide DMF or methyl-sulphoxide DMSO.
V. after removing organic solvent II I, add water, with organic solvent I V extraction, merge organic phase, the dry solid of getting.Preferred, by the alcohol for solid obtaining (methyl alcohol or ethanol) recrystallization.
Preparation method's of the present invention advantage is: (1) the first step oxygenant is elected hydrogen peroxide as, and price comparison is cheap, and easily removes, and is beneficial to subsequent reactions; (2) second step adopts acetonitrile as solvent, and DIPEA, as catalyzer, has improved more than 5% yield (prior art is directly to make solvent with three oxyhalogen phosphorus); (3) by the method for the synthetic 4-methoxyl group-7-azaindole of 4-halo-7-azaindole, yet there are no report; (4) whole piece synthetic route, yield is high, and cost is lower, is easy to industrialization.
Accompanying drawing explanation
Fig. 1 is the chloro-7-azaindole of embodiment 2 gained 4-nuclear magnetic spectrogram
Fig. 2 is embodiment 3 gained 4-bromo-7-azaindole nuclear magnetic spectrograms
Fig. 3 is the nuclear magnetic spectrogram of embodiment 4 gained 4-methoxyl group-7-azaindoles
Embodiment
Synthesizing of embodiment 1N-oxidation-7-azaindole
By 7-azaindole (12.6 grams, 0.102mol) join in tetrahydrofuran (THF) (120ml), with ice bath, reaction is cooled to 5 ℃ simultaneously, by (6.1 grams, hydrogen peroxide, 0.122mol) under agitation condition, drop in reaction system, temperature is slowly risen to room temperature, and react 3 hours.Reaction solvent is threaded to 30 milliliters revolving in steaming, then adds wherein 60 ml n-hexanes, separate out pale solid.Filter and use normal hexane washing leaching cake, filter cake is dried to obtain to 12.8 grams of target products (0.0954mol), yield is 93.6%.
Synthesizing of the chloro-7-azaindole of embodiment 24-
By N-oxidation-7-azaindole (5.8 grams, 0.043mol) join in acetonitrile (60ml), under normal temperature and agitation condition, add POCl 3(32.7 grams, 0.215mol).By reactant be warming up to 80 ℃～100 ℃ and react drip after 30 minutes diisopropyl ethyl amine (0.55 gram, 0.0043mol), drip and finish, continue 80 ℃～100 ℃ reactions 5 hours.By acetonitrile and POCl 3by underpressure distillation, remove.Under condition of ice bath, in remaining mixture, add water (60ml), then this mixed solution is alkalized to pH=9 ± 0.2 with 50% the NaOH aqueous solution, produce precipitation in a large number.Filter and filter cake is washed with water to dry and obtain 5.6 grams of the chloro-7-azaindoles of 4-(CAS55052-28-3) (0.0367mol), as shown in Figure 1, yield is 85.6% to nuclear magnetic spectrogram.Total recovery 80.12%.
Synthesizing of embodiment 34-bromo-7-azaindole
By N-oxidation-7-azaindole (6.2 grams, 0.046mol) join in acetonitrile (80ml), under normal temperature and agitation condition, add POBr3 (65.7 grams, 0.231mol).By reactant be warming up to 80 ℃～100 ℃ and react drip after 30 minutes diisopropyl ethyl amine (0.59 gram, 0.0046mol), drip and finish, continue 80 ℃～100 ℃ reactions 5 hours.By acetonitrile and and part POBr 3by underpressure distillation, remove.Under condition of ice bath, remaining oily mixture is added dropwise to (80ml) in water, then this mixed solution is alkalized to pH=9 ± 0.2 with 50% the NaOH aqueous solution, produce precipitation in a large number.Filter and filter cake washed with water to dry and obtain 4-bromo-7-azaindole (CAS 348640-06-2) 7.1 grams (0.0364mol),, nuclear magnetic spectrogram as shown in Figure 2 yield is 79.2%.Total recovery is 74.1%
Synthesizing of embodiment 44-methoxyl group 7-azaindole
By 4-bromo-7-azaindole (3.8 grams, 0.019mol) and sodium methylate (1.3 grams, 0.024mol) join DMF(50ml at normal temperatures) in.Reaction is warming up to 110 ℃～130 ℃ and react 8 hours, is down to room temperature.DMF is removed by underpressure distillation, then add 30ml water in residuum.With 20ml ethyl acetate extraction 3 times, organic phase is merged, dry, be spin-dried for and obtain faint yellow solid, with methyl alcohol or ethyl alcohol recrystallization, obtain 1.6 grams of 4-methoxyl group 7-azaindoles (CAS 122379-63-9), as shown in Figure 3, yield is 57.2% to nuclear magnetic spectrogram.Total recovery is 42.4%.
Embodiment 4
Take embodiment 2～4 products as synthetic other compounds of raw material.
(1) the embodiment chloro-7-azaindole of 2 product 4-(CAS 55052-28-3):
According to the record of WO2006/46023A1, the good antitumour activity of compd A 1 obtaining by above reaction formula.
(2) embodiment 3 product 4-bromo-7-azaindoles (CAS 348640-06-2):
According to the record of US2007/149561A1, the compd A 2 obtaining by above reaction formula has the pharmaceutical activity for the treatment of hyperplasia and disease of immune system.
(3) embodiment 4 product 4-methoxyl group 7-azaindoles (CAS 122379-63-9):
According to the record of US2012/53178A1, the compound A-13 obtaining by above reaction formula, has good antitumour activity.

Claims (4)

  1. The preparation method of 1.4 replacement-7-azaindoles, is characterized in that, described 4 replacement 7-azaindoles are 4-halo-7-azaindole or 4-alkoxyl group-7-azaindole; As shown in the formula (I), R is Cl, Br or C1～C4 alkoxyl group to its structure;
    Comprise the following steps:
    (1) synthetic N-oxidation-7-azaindole: 7-azaindole mixes with organic solvent I, adds hydrogen peroxide, 5～15 ℃ are reacted 2～5 hours, obtain N-oxidation-7-azaindole; Organic solvent I is tetrahydrofuran (THF), ethylene glycol monomethyl ether or propylene glycol monomethyl ether;
    The mol ratio of 7-azaindole and hydrogen peroxide is 1:1.1～2;
    (2) the N-oxidation-7-azaindole of step (1) further replaces 4 replacement-7-azaindoles of acquisition; Be specially:
    When R is haloid element, step comprises:
    (A) N-oxidation-7-azaindole mixes with organic solvent II, then adds POX 3mix, 80～100 ℃ of reactions dripped catalyzer diisopropyl ethyl amine after 20～60 minutes, continued 80～100 ℃ of reactions 2～8 hours; X is haloid element; Described organic solvent II is acetonitrile or tetrahydrofuran (THF);
    N-oxidation-7-azaindole and POX 3and the mol ratio of diisopropyl ethyl amine is 1:2～10:0.05～0.2; The amount ratio of N-oxidation-7-azaindole and organic solvent II is 0.5～2mmol/ml;
    (B) remove organic solvent II and POX 3after, adding water at-5～0 ℃, in water and step (A), the amount ratio of N-oxidation-7-azaindole is 1ml:0.5～2mmol;
    (C) regulating pH is 8.5～9.5, gets precipitation, obtains 4-halo-7-azaindole;
    When R is alkoxyl group, comprise the following steps:
    I.N-oxidation-7-azaindole mixes with organic solvent II, then adds POX 3mix, 80～100 ℃ of reactions dripped catalyzer diisopropyl ethyl amine after 20～60 minutes, continued 80～100 ℃ of reactions 2～8 hours; X is haloid element; Described organic solvent II is acetonitrile or tetrahydrofuran (THF);
    N-oxidation-7-azaindole and POX 3and the mol ratio of diisopropyl ethyl amine is 1:2～10:0.05～0.2; The amount ratio of N-oxidation-7-azaindole and organic solvent II is 0.5～2mmol/ml;
    II. except organic solvent II and POX 3after, adding water at-5～0 ℃, in water and step I, the amount ratio of N-oxidation-7-azaindole is 1ml:0.5～2mmol;
    III. regulating pH is 8.5～9.5, gets precipitation, obtains 4 halogen replacement-7-azaindoles;
    IV.4 position halogen replacement-7-azaindole and alkali metal alcoholates mix with organic solvent II I, and 100～150 ℃ are reacted 4～10 hours; The mol ratio of 4-halo-7-azaindole and alkali metal alcoholates is 1～1.5; 4 halogen replacement-7-azaindoles and organic solvent II I amount ratio are 0.2～1mmol/ml; Organic solvent II I is dimethyl formamide or dimethyl sulfoxide (DMSO);
    V. after removing organic solvent II I, add water, with organic solvent I V extraction, merge organic phase, the dry solid of getting.
  2. 2. the preparation method of 4 replacement-7-azaindoles described in claim 1, is characterized in that, the 7-azaindole in step (1) and the mol ratio of hydrogen peroxide are 1:1.1～1.3.
  3. 3. the preparation method of 4 replacement-7-azaindoles described in claim 1, is characterized in that, the solid that step V is obtained alcohol recrystallization.
  4. 4. the preparation method of 4 replacement-7-azaindoles described in claim 1, is characterized in that, N-oxidation-7-azaindole and POX in step (A) or step I 3and the mol ratio of diisopropyl ethyl amine is 1:5～10:0.1～0.15.
CN201210205860.XA 2012-06-20 2012-06-20 Preparation method for 4-substituted-7-azaindole Expired - Fee Related CN102746295B (en)

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CN108794472A (en) * 2018-09-04 2018-11-13 南通雅本化学有限公司 A kind of preparation method of the chloro- 7- azaindoles of 4-

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CN1404392A (en) * 2000-02-22 2003-03-19 布里斯托尔-迈尔斯斯奎布公司 Antiviral azaindole derivatives

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US6884889B2 (en) * 2002-03-25 2005-04-26 Bristol-Myers Squibb Co. Processes for the preparation of antiviral 7-azaindole derivatives

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CN1404392A (en) * 2000-02-22 2003-03-19 布里斯托尔-迈尔斯斯奎布公司 Antiviral azaindole derivatives

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