CN102746295A - Preparation method for 4-substituted-7-azaindole - Google Patents
Preparation method for 4-substituted-7-azaindole Download PDFInfo
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- CN102746295A CN102746295A CN201210205860XA CN201210205860A CN102746295A CN 102746295 A CN102746295 A CN 102746295A CN 201210205860X A CN201210205860X A CN 201210205860XA CN 201210205860 A CN201210205860 A CN 201210205860A CN 102746295 A CN102746295 A CN 102746295A
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- azaindole
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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
Technical field
The present invention relates to organic synthesis and field of medicaments, be specially a kind of compound method of 4 replacement-7-azaindoles.
Background technology
The 7-azaindole is the isoelectronic species of indoles and purine as the important a member of azaindole family, therefore can constitute the molecule of a lot of biologically actives as parent nucleus with the 7-azaindole.
Though 7-azaindole and verivate 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 4 substituted 7-azaindoles like 4-bromo-7-azaindole, 4-chloro-7-azaindole and 4-methoxyl group-7-azaindole etc., can be used as midbody, are used for the synthetic medicine that has antitumour activity or treat disease of immune system.
Present 4 compound methods that replace the 7-azaindole mainly contain two kinds: bring substituting group when the azepine indole ring is synthesized in (1) into; (2) synthetic through N-oxidation-7-azaindole.
Wherein second method is because its easy operation and higher yield become 4 main synthesis methods that replace the 7-azaindole.Tetrahedron 65 (2009) 4814-4819, the synthetic route of having introduced a kind of synthetic 4-chloro-7-azaindole is following:
With the synthetic N-oxidation of oxygenant 2-methyl-4-chlorophenoxyacetic acid (MCPA)-7-azaindole, this oxygenant price comparison is expensive, and because have the intensive uv-absorbing, is mingled in the product, is difficult for removing earlier.Second step, yield was on the low side, below 80% with POCl3 and N-oxidation-7-azaindole reaction (not adding other solvents).Whole route cost is higher, is difficult for industriallization.
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 industrial production requirement.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of 4 replacement-7-azaindoles, this method cost is lower, be easy to industriallization.
The present invention is a raw material with the 7-azaindole, is solvent with THF or EGME or propylene glycol monomethyl ether, and ydrogen peroxide 50 is the earlier synthetic N-oxidation of oxygenant-7-azaindole.Synthetic N-oxidation-7-azaindole is with acetonitrile and three oxyhalogen phosphorus POX
3(like POCl
3Or POBr
3Deng) as solvent (POCl
3Or POBr
3Simultaneously as reactant), be catalyzer with DIPEA (diisopropyl ethyl amine, equivalent are 0.1～0.15), temperature of reaction is 80 ℃～100 ℃, synthetic 4-halo-7-azaindole.Synthetic 4-halo-7-azaindole, with DMF etc. as solvent, and alkoxide (like sodium methylate etc.) reaction, temperature is 110 ℃～130 ℃, the synthetic 4-methoxyl group of reaction-7-azaindole.
The preparation method of 4 replacement-7-azaindoles, said 4 replacement 7-azaindoles are 4-halo-7-azaindole or 4-alkoxyl group-7-azaindole; Its structure is suc as formula shown in (I), and R is haloid element or alkoxyl group; Preferably, R is Cl, Br or C1～C4 alkoxyl group;
May further comprise the steps:
(1) synthetic N-oxidation-7-azaindole: the 7-azaindole mixes with organic solvent I, adds hydrogen peroxide, and 5～15 ℃ were reacted 2～5 hours, and obtained N-oxidation-7-azaindole;
The mol ratio of 7-azaindole and hydrogen peroxide is 1:1.1～2 (being preferably 1.1～1.3); Organic solvent I is THF, EGME or propylene glycol monomethyl ether;
(2) the N-oxidation-7-azaindole of step (1) further replaces 4 replacement-7-azaindoles of acquisition.
When R was haloid element, step (2) comprising:
(A) N-oxidation-7-azaindole mixes with organic solvent II, adds POX again
3Mix, 80～100 ℃ of reactions drip the catalyzer diisopropyl ethyl amine after 20～60 minutes, continue 80～100 ℃ of reactions 2～8 hours; X is a haloid element; Organic solvent II is acetonitrile or THF.
N-oxidation-7-azaindole and POX
3The mol ratio that reaches diisopropyl ethyl amine is 1:2～10:0.05～0.2, is 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 entry under-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 deposition, obtains 4-halo-7-azaindole;
When R is alkoxyl group, may further comprise the steps:
I.N-oxidation-7-azaindole mixes with organic solvent II, adds POX again
3Mix, 80～100 ℃ of reactions drip the catalyzer diisopropyl ethyl amine after 20～60 minutes, continue 80～100 ℃ of reactions 2～8 hours; X is a haloid element; Organic solvent II is acetonitrile or THF.
N-oxidation-7-azaindole and POX
3The mol ratio that reaches diisopropyl ethyl amine is 1:2～10:0.05～0.2, is 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 entry under-5～0 ℃, the amount ratio of N-oxidation-7-azaindole is 1ml: 0.5～2mmol among water and the step I;
III. regulating pH is 8.5～9.5, gets deposition, 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 ℃ were 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 N DMF or methyl-sulphoxide DMSO.
V. add water after removing organic solvent II I, with organic solvent I V extraction, merge organic phase, drying is got solid.Preferred, the solid that obtains is used alcohol (methyl alcohol or ethanol) recrystallization.
Preparing method's of the present invention advantage is: (1) the first step oxygenant is elected ydrogen peroxide 50 as, and price comparison is cheap, and removes easily, is beneficial to subsequent reactions; (2) second steps adopted acetonitrile as solvent, and DIPEA has improved the yield more than 5% (prior art is directly to make solvent with three oxyhalogen phosphorus) as catalyzer; (3) by the method for the synthetic 4-methoxyl group of 4-halo-7-azaindole-7-azaindole, also be not reported; (4) whole piece synthetic route, yield is high, and cost is lower, is easy to industriallization.
Description of drawings
Fig. 1 is embodiment 2 gained 4-chloro-7-azaindole nuclear magnetic spectrograms
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
With the 7-azaindole (12.6 grams 0.102mol) join in the THF (120ml), simultaneously with ice bath with reaction cooled to 5 ℃; With ydrogen peroxide 50 (6.1 grams; 0.122mol) under agitation condition, drop in the reaction system, temperature is slowly risen to room temperature, and reacted 3 hours.Reaction solvent is threaded to 30 milliliters revolving in the steaming, to wherein adding 60 ml n-hexanes, separates out pale solid again.Filter and use the normal hexane washing leaching cake, dry filter cake to such an extent that title product 12.8 restrains (0.0954mol), yield is 93.6%.
Synthesizing of embodiment 24-chloro-7-azaindole
(5.8 grams 0.043mol) join in the acetonitrile (60ml), under normal temperature and agitation condition, add POCl with N-oxidation-7-azaindole
3(32.7 grams, 0.215mol).Reactant is warming up to 80 ℃～100 ℃ and react and drip diisopropyl ethyl amine after 30 minutes (0.55 gram 0.0043mol), drips and finishes, and continues 80 ℃～100 ℃ reactions 5 hours.With acetonitrile and POCl
3Remove through underpressure distillation.Under condition of ice bath, in remaining mixture, add entry (60ml), then this mixed solution is alkalized to pH=9 ± 0.2 with 50% the NaOH aqueous solution, produce in a large number and precipitate.Filter and filter cake water washing and drying is obtained 4-chloro-7-azaindole (CAS55052-28-3) 5.6 grams (0.0367mol), nuclear magnetic spectrogram is as shown in Figure 1, and yield is 85.6%.Total recovery 80.12%.
Synthesizing of embodiment 34-bromo-7-azaindole
(6.2 grams 0.046mol) join in the acetonitrile (80ml), and (65.7 restrain, 0.231mol) under normal temperature and agitation condition, to add POBr3 with N-oxidation-7-azaindole.Reactant is warming up to 80 ℃～100 ℃ and react and drip diisopropyl ethyl amine after 30 minutes (0.59 gram 0.0046mol), drips and finishes, and continues 80 ℃～100 ℃ reactions 5 hours.With acetonitrile and and part POBr
3Remove through underpressure distillation.Under condition of ice bath, remaining oily mixture is dripped in the entry (80ml), then this mixed solution is alkalized to pH=9 ± 0.2 with 50% the NaOH aqueous solution, produce in a large number and precipitate.Filter and filter cake water washing and drying obtained 4-bromo-7-azaindole (CAS 348640-06-2) 7.1 grams (0.0364mol),, nuclear magnetic spectrogram yield as shown in Figure 2 is 79.2%.Total recovery is 74.1%
Synthesizing of embodiment 44-methoxyl group 7-azaindole
(3.8 grams, 0.019mol) (1.3 restrain, and 0.024mol) join at normal temperatures among the DMF (50ml) with sodium methylate with 4-bromo-7-azaindole.Reaction is warming up to 110 ℃～130 ℃ and reacted 8 hours, reduces to room temperature.DMF is removed through underpressure distillation, in residuum, add 30ml water again.With 20ml ethyl acetate extraction 3 times, organic phase is merged, drying is revolved the dried faint yellow solid that obtains, and obtains 4-methoxyl group 7-azaindole (CAS 122379-63-9) 1.6 grams with methyl alcohol or ethyl alcohol recrystallization, and nuclear magnetic spectrogram is as shown in Figure 3, and yield is 57.2%.Total recovery is 42.4%.
With embodiment 2～4 products is synthetic other compounds of raw material.
(1) embodiment 2 product 4-chloro-7-azaindoles (CAS 55052-28-3):
According to the record of WO2006/46023A1, by compd A 1 good anti-cancer activity that above reaction formula obtained.
(2) embodiment 3 product 4-bromo-7-azaindoles (CAS 348640-06-2):
According to the record of US2007/149561A1, has the pharmaceutical activity of treatment hyperplasia and disease of immune system by the compd A 2 that above reaction formula obtained.
(3) embodiment 4 product 4-methoxyl group 7-azaindoles (CAS 122379-63-9):
According to the record of US2012/53178A1,, has good anti-cancer activity by the compound A-13 that above reaction formula obtained.
Claims (9)
1.4 the preparation method of position replacement-7-azaindole is characterized in that, said 4 replacement 7-azaindoles are 4-halo-7-azaindole or 4-alkoxyl group-7-azaindole; Its structure is suc as formula shown in (I), and R is haloid element or alkoxyl group;
May further comprise the steps:
(1) synthetic N-oxidation-7-azaindole: the 7-azaindole mixes with organic solvent I, adds hydrogen peroxide, and 5～15 ℃ were reacted 2～5 hours, and obtained N-oxidation-7-azaindole;
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.
2. the preparation method of said 4 the replacement-7-azaindoles of claim 1 is characterized in that, R is Cl, Br or C1～C4 alkoxyl group.
3. the preparation method of claim 1 or 2 said 4 replacement-7-azaindoles is characterized in that, the 7-azaindole in the step (1) and the mol ratio of hydrogen peroxide are 1:1.1～1.3.
4. the preparation method of claim 1 or 2 said 4 replacement-7-azaindoles is characterized in that, organic solvent I is THF, EGME or propylene glycol monomethyl ether in the step (1).
5. the preparation method of claim 1 or 2 said 4 replacement-7-azaindoles is characterized in that, when R was haloid element, step (2) comprising:
(A) N-oxidation-7-azaindole mixes with organic solvent II, adds POX again
3Mix, 80～100 ℃ of reactions drip the catalyzer diisopropyl ethyl amine after 20～60 minutes, continue 80～100 ℃ of reactions 2～8 hours; X is a haloid element;
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 acetonitrile is 0.5～2mmol/ml;
(B) remove acetonitrile and POX
3After, adding entry under-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 deposition, obtains 4-halo-7-azaindole;
When R is alkoxyl group, may further comprise the steps:
I.N-oxidation-7-azaindole mixes with organic solvent II, adds POX again
3Mix, 80～100 ℃ of reactions drip the catalyzer diisopropyl ethyl amine after 20～60 minutes, continue 80～100 ℃ of reactions 2～8 hours; X is a haloid element;
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. remove acetonitrile and POX
3After, adding entry under-5～0 ℃, the amount ratio of N-oxidation-7-azaindole is 1ml:0.5～2mmol among water and the step I;
III. regulating pH is 8.5～9.5, gets deposition, 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 ℃ were 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;
V. add water after removing organic solvent II I, with organic solvent I V extraction, merge organic phase, drying is got solid.
6. the preparation method of said 4 the replacement-7-azaindoles of claim 5 is characterized in that, the solid that step V obtains is used pure recrystallization.
7. the preparation method of said 4 the replacement-7-azaindoles of claim 5 is characterized in that, step (A) or the said organic solvent II of step I are acetonitrile or THF.
8. the preparation method of said 4 the replacement-7-azaindoles of claim 5 is characterized in that, N-oxidation-7-azaindole and POX among step (A) or the step I
3And the mol ratio of diisopropyl ethyl amine is 1:5～10:0.1～0.15.
9. the preparation method of said 4 the replacement-7-azaindoles of claim 5 is characterized in that, organic solvent II I is N or DMSO 99.8MIN..
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777747A (en) * | 2016-04-05 | 2016-07-20 | 叶芳 | 4-chloro-7-azaindole and preparation method thereof |
| 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- |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999012918A1 (en) * | 1997-09-05 | 1999-03-18 | Yoshitomi Pharmaceutical Industries, Ltd. | Tryptase inhibitor |
| CN1404392A (en) * | 2000-02-22 | 2003-03-19 | 布里斯托尔-迈尔斯斯奎布公司 | Antiviral azaindole derivatives |
| WO2003082289A1 (en) * | 2002-03-25 | 2003-10-09 | Bristol-Myers Squibb Company | Process for the preparation of antiviral 7-azaindole derivatives |
-
2012
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999012918A1 (en) * | 1997-09-05 | 1999-03-18 | Yoshitomi Pharmaceutical Industries, Ltd. | Tryptase inhibitor |
| CN1404392A (en) * | 2000-02-22 | 2003-03-19 | 布里斯托尔-迈尔斯斯奎布公司 | Antiviral azaindole derivatives |
| WO2003082289A1 (en) * | 2002-03-25 | 2003-10-09 | Bristol-Myers Squibb Company | Process for the preparation of antiviral 7-azaindole derivatives |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777747A (en) * | 2016-04-05 | 2016-07-20 | 叶芳 | 4-chloro-7-azaindole and preparation method thereof |
| 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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