CN1986544A - Preparing process of 4,4-diazaindole - Google Patents
Preparing process of 4,4-diazaindole Download PDFInfo
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- CN1986544A CN1986544A CNA2005101118548A CN200510111854A CN1986544A CN 1986544 A CN1986544 A CN 1986544A CN A2005101118548 A CNA2005101118548 A CN A2005101118548A CN 200510111854 A CN200510111854 A CN 200510111854A CN 1986544 A CN1986544 A CN 1986544A
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- methylpyrazine
- diaza indoles
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Abstract
The process of preparing 4, 7-diazaindole includes the following steps: 1. reaction of amino-3-methyl pyrazine and pivaloyl chloride or Boc anhydride to obtain 2-pivaloyl amino-3-methyl pyrazine or 2-tert-butyloxyformamido-3-methyl pyrazine; 2. reaction of the obtained 2-pivaloyl amino-3-methyl pyrazine or 2-tert-butyloxyformamido-3-methyl pyrazine with R2Li and HCOR3 to produce aldehyde intermediate; and 3. eliminating the protecting ring of the intermediate to obtain 4, 7-diazaindole. The present invention is one effective process of synthesizing 4, 7-diazaindole as one medicine intermediate.
Description
Technical field:
The invention belongs to the organic synthesis field, relate to specifically a kind of 4, the preparation method of 7-diaza indoles.
Background technology:
4,7-diaza indoles (having another name called " pyrroles [2,3-b] pyrazine ") is the pharmaceutical intermediate of outbalance, but not having effective synthetic method so far prepares this product.Once two kinds of preparation methods had been reported in the document, a kind of method is that the 2-amino-3-methyl pyrazine generates 2-formamido group-3-methylpyrazine earlier under the effect of formic acid/diacetyl oxide, high temperature closes ring and obtains 4,7-diaza indoles (KhimiyaGeterorsiklicheskikh Soedinenii under the effect of sodium ethylate then; 1973; 6; 858).Another kind method is at first to react with triethyl orthoformate under the acidic alcohol effect with the 2-amino-3-methyl pyrazine, generates the formamidine intermediate with the methylphenylamine reaction thereafter, at high temperature closes ring again and obtains 4,7-diaza indoles (J.Chem.Soc.PT1; 1976; 13; 1361-1363; Chemistry ﹠amp; Industry, 1975; 5; 215-216);
Document synthetic route 1:
Document synthetic route 2:
In the document synthetic route, all use the pyritous condition.Use superelevation in the route 1 especially 325 ℃, be unfavorable for laboratory operation.And method two is also used highly acid acidic alcohol condition simultaneously at pyritous, operates abnormally dangerous.
Summary of the invention:
The technical issues that need to address of the present invention are: 4, avoid high temperature in the 7-diaza indoles preparation process, strong acid is unfavorable for the method for experimental implementation, and a kind of preparation 4 is provided, the method for 7-diaza indoles easy handling.
Technical scheme of the present invention:
Of the present invention 4,7-diaza indoles synthesis technique is as follows:
The present invention is by 2-amino-3-methyl pyrazine and pivaloyl chloride or Boc anhydride reaction; protect the amino in the 2-amino-3-methyl pyrazine earlier; under the effect of lithium alkylide, generate the aldehyde intermediate then with the reaction of benzamide type (or manthanoate) compound; this intermediate need not separate directly under acidic conditions deprotection close encircle 4,7-diaza indoles.
In the above-mentioned technology, R
1Be the tertiary butyl or tert.-butoxy, R
2Be wherein a kind of of methyl, normal-butyl, sec-butyl and the tertiary butyl.R
3Be wherein a kind of of dimethylamino, piperidyl, N-methyl-N phenyl and oxyethyl group.We have adopted easy-operating protecting group (use reagent pivaloyl chloride or Boc acid anhydrides) that raw material 2-amino-3-methyl pyrazine is protected, and avoid the not easy-operating condition of high temperature strong acid used in the document, and can obtain higher productive rate.This service temperature is 0～40 ℃.In addition, we adopt the condition of lithium alkylide at first to generate aldehyde, and this service temperature is-25～25 ℃.This intermediate directly closes ring, the not easy-operating hot conditions of avoiding document to use with a kind of or its mixture process in hydrochloric acid, sulfuric acid, the phosphoric acid then.This service temperature is 50～100 ℃.
Beneficial effect of the present invention:
Reaction process of the present invention is selected rationally; with maneuverable protective material the amino in the raw material 2-amino-3-methyl pyrazine is protected; close ring in easy-operating condition then; the hot conditions of having avoided prior art to use; make 4, the preparation of 7-diaza indoles can be carried out under safety and maneuverable condition.
Embodiment:
The following example helps to understand the present invention, but is not limited to content of the present invention.
Embodiment 1
1,4,7-diaza indoles synthetic
The first step: 2-amino-3-methyl pyrazine synthetic
With reference to the technology of US5861401, get productive rate 71% with 2-chloro-3-methylpyrazine and ammoniacal liquor reaction.
1H?NMR(400MHz，DMSO-d
6)：δ7.72(d，J＝2.4Hz，1H)，7.56(d，J＝2.4，1H)，6.10(s，br，2H)，2.22(s，3H)。
Second step: 2-pivaloyl amido-3-methylpyrazine synthetic
With the 2-amino-3-methyl pyrazine (24g, 0.22mol) be dissolved in methylene dichloride (500mL) and triethylamine (63mL, 0.44mol) in.Be chilled to 0 ℃ under the nitrogen protection, drip (40g, 0.33mol) pivaloyl chloride.Finish, be warming up to stirring at room naturally 40 minutes, again 40 ℃ of heated and stirred 4 hours.TLC follows the tracks of reaction, and after reaction finished, reaction solution was poured in the frozen water, and organic phase is washed with saturated sodium bicarbonate solution, and drying concentrates.Crude product gets 2-pivaloyl amido-3-methylpyrazine (34g, 0.18mol, productive rate 80%) with ethyl acetate/normal hexane recrystallization.
1H?NMR(400MHz，CDCl
3)：δ8.36(d，J＝2.4Hz，1H)，8.20(d，J＝2.4，1H)，7.78(s，br，1H)，2.48(s，3H)，1.35(s，9H)。
The 3rd step: 4,7-diaza indoles synthetic
Anhydrous THF (500mL) is joined in 2 liters of there-necked flasks, be chilled to-10 ℃ under the nitrogen protection, and the dropping n-Butyl Lithium (hexane solution of 2.5M, 150mL).Controlled temperature-10-5 ℃, stir after 10 minutes and to drip 2-pivaloyl amido-3-methylpyrazine (29g, anhydrous THF solution 0.15mol) (300ml) is in the process-5-0 ℃.After this temperature stirs 4 hours, and dropping DMF (37mL, 0.48mol).Finish, stirred 40 minutes at 0 ℃, add 3M HCl (500mL), stir layering after 0.5 hour, (2 * 200mL) extractions merge water with ethyl acetate (500mL) washing, then 100 ℃ of heating 6 hours to organic phase with 3M HCl.TLC follows the tracks of reaction, and reaction finishes the back and transfers pH to 8～9 with 6M NaOH, with ethyl acetate (3 * 200ml) extractions.Organic phase merges uses anhydrous Na
2SO
4Drying concentrates, and the crude product chromatography column gets 4,7-diaza indoles (8g, yield 43%).
1H?NMR(400MHz，CDCl
3)：δ10.13(s，br，1H)，8.50(d，J＝3.6，1H)，8.28(d，J＝3.6，1H)，7.66(dd，J＝4.8?&?2.8，1H)，6.77(dd，J＝4.8?&?2.8，1H)。
Embodiment 2
2,4,7-diaza indoles synthetic
Anhydrous THF (40mL) is joined in the 250mL there-necked flask, be chilled to-10 ℃ under the nitrogen protection, and the dropping n-Butyl Lithium (hexane solution of 2.5M, 10mL).Controlled temperature-10-5 ℃, stir after 10 minutes and to drip 2-pivaloyl amido-3-methylpyrazine (1.93g, anhydrous THF solution 10mmol) (20ml), in the process controlled temperature-5-0 ℃.After this temperature stirs 4 hours, and dropping N-formyl piperidine (0.36g, 3.2mmol).After 40 minutes, reaction solution rises to room temperature 0 ℃ of stirring, adds 3M HCl (40mL), stirs layering after 0.5 hour, and (2 * 15mL) extractions merge water ethyl acetate (50mL) washing to organic phase, then 100 ℃ of heating 6 hours with 3M HCl.TLC follows the tracks of reaction, and reaction finishes the back and transfers pH to 8～9 with 6MNaOH, (3 * 20mL) extractions of water ethyl acetate.Organic phase merges uses anhydrous Na
2SO
4Drying concentrates, and the crude product chromatography column gets 4,7-diaza indoles (0.6g, 5mmol, yield 50%).
1H?NMR(400MHz，CDCl
3)：δ10.13(s，br，1H)，8.50(d，J＝3.6，1H)，8.28(d，J＝3.6，1H)，7.66(dd，J＝4.8?&?2.8，1H)，6.77(dd，J＝4.8?&?2.8，1H)。
Embodiment 3
3,4,7-diaza indoles synthetic
The first step: uncle's 2-butyloxy formylamido-3-methylpyrazine synthetic
With the 2-amino-3-methyl pyrazine (1.09g, 10mmol) be dissolved in acetonitrile (40mL) and triethylamine (2.02g, 20mol) in.Under the normal temperature, (0.12g 1mmol), drips Boc acid anhydrides (3.27g, acetonitrile 20mmol) (5mL) solution, stirred overnight at room temperature then to add 4-(N, N-dimethylamino) pyridine.TLC followed the tracks of reaction, finds that the raw material unreacted is complete, with reaction solution reflux 4 hours.After reaction finished, concentration of reaction solution, chromatography column got uncle's 2-butyloxy formylamido-3-methylpyrazine (1.17g, 5.6mmol, productive rate 56%).
1H?NMR(400MHz，CDCl
3)：δ8.39(d，J＝2.4Hz，1H)，8.25(d，J＝2.4，1H)，7.98(s，br，1H)，2.51(s，3H)，1.45(s，9H)。
Second step: 4,7-diaza indoles synthetic
Anhydrous THF (20mL) is joined in the 100mL there-necked flask, be chilled to-10 ℃ under the nitrogen protection, and the dropping n-Butyl Lithium (hexane solution of 2.5M, 5mL).Controlled temperature-10～-5 ℃ are stirred and are dripped uncle 2-after 10 minutes butyloxy formylamido-(controlled temperature is lower than 0 ℃ to the 3-methylpyrazine in the process for 1.05g, anhydrous THF solution 5mmol) (10mL).After this temperature stirs 4 hours, and adding DMF (1.17g, 16mmol).Finish, stirred 1 hour, add 5.5M HCl (30mL), then 45～50 ℃ of heating 2 hours at 5～20 ℃.TLC follows the tracks of reaction, is chilled to 20 ℃ after reaction finishes, and adds isopropyl acetate (50mL), is chilled to 5 ℃, transfers pH to 8～9 with 5M NaOH, during controlled temperature be no more than 15 ℃.Organic phase is separated, and (2 * 20mL) extract water with ethyl acetate.Organic phase merges uses anhydrous Na
2SO
4Drying concentrates, and the crude product chromatography column gets 4,7-diaza indoles (0.39g, 3.3mmol, yield 65%).
1H?NMR(400?MHz，CDCl
3)：δ10.13(s，br，1H)，8.50(d，J＝3.6，1H)，8.28(d，J＝3.6，1H)，7.66(dd，J＝4.8?&?2.8，1H)，6.77(dd，J＝4.8?&?2.8，1H)。
Embodiment 4
4,4,7-diaza indoles synthetic
Anhydrous THF (40mL) is joined in the 250mL there-necked flask, be chilled to-20 ℃ under the nitrogen protection, and the dropping n-Butyl Lithium (hexane solution of 2.5M, 10mL).Controlled temperature-20～-15 ℃ are stirred and are dripped 2-pivaloyl amido-3-methylpyrazine (1.93g, anhydrous THF solution 10mmol) (20ml), controlled temperature in the process-20 ℃ after 10 minutes.After this temperature stirs 18 hours, and dropping DMF (0.23g, 3.2mmol).After 40 minutes, reaction solution rises to room temperature 0 ℃ of stirring, adds 3M HCl (40mL), stirs layering after 0.5 hour, and (2 * 15mL) extractions merge water ethyl acetate (50mL) washing to organic phase, then 100 ℃ of heating 6 hours with 3M HCl.TLC follows the tracks of reaction, and reaction finishes the back and transfers pH to 8～9 with 6MNaOH, (3 * 20mL) extractions of water ethyl acetate.Organic phase merges uses anhydrous Na
2SO
4Drying concentrates, and the crude product chromatography column gets 4,7-diaza indoles (0.38g, 3.2mmol, yield 32%).
1H?NMR(400MHz，CDCl
3)：δ10.13(s，br，1H)，8.50(d，J＝3.6，1H)，8.28(d，J＝3.6，1H)，7.66(dd，J＝4.8?&?2.8，1H)，6.77(dd，J＝4.8?&?2.8，1H)。
Embodiment 5
5,4,7-diaza indoles synthetic
Anhydrous THF (40mL) is joined in the 250mL there-necked flask, be chilled to-10 ℃ under the nitrogen protection, and the dropping n-Butyl Lithium (hexane solution of 2.5M, 10mL).Controlled temperature-5～0 ℃ stirs and drips 2-pivaloyl amido-3-methylpyrazine (1.93g, anhydrous THF solution 10mmol) (20ml), controlled temperature in the process-5～0 ℃ after 10 minutes.Finish, rise to 20 ℃ and stirred 1 hour, and dropping DMF (0.23g, 3.2mmol).After stirring 40 minutes under this temperature, add 3M HCl (40mL), stir layering after 0.5 hour, (2 * 15mL) extractions merge water with ethyl acetate (50mL) washing, then 100 ℃ of heating 6 hours to organic phase with 3M HCl.TLC follows the tracks of reaction, and pH to 8～9 are transferred with 6M NaOH in reaction end back, and (3 * 20mL) extract water with ethyl acetate.Organic phase merges uses anhydrous Na
2SO
4Drying concentrates, and the crude product chromatography column gets 4,7-diaza indoles (0.43g, 3.6mmol, yield 36%).
1H?NMR(400MHz，CDCl
3)：δ10.13(s，br，1H)，8.50(d，J＝3.6，1H)，8.28(d，J＝3.6，1H)，7.66(dd，J＝4.8?&?2.8，1H)，6.77(dd，J＝4.8?&?2.8，1H)。
Embodiment 6
6,4,7-diaza indoles synthetic
Anhydrous THF (40mL) is joined in the 250mL there-necked flask, be chilled to-20 ℃ under the nitrogen protection, and the dropping s-butyl lithium (hexane solution of 1.6M, 15.6mL).Controlled temperature-20～-15 ℃ are stirred and are dripped 2-pivaloyl amido-3-methylpyrazine (1.93g, anhydrous THF solution 10mmol) (20ml), controlled temperature in the process-20 ℃ after 10 minutes.After this temperature stirs 5 hours, and dropping DMF (0.23g, 3.2mmol).After 40 minutes, reaction solution rises to room temperature 0 ℃ of stirring, adds 1.5M H
2SO
4(40mL), stir layering after 0.5 hour, organic phase 1.5M H
2SO
4(2 * 15mL) extractions merge water with ethyl acetate (50mL) washing, then 100 ℃ of heating 6 hours.TLC follows the tracks of reaction, and pH to 8～9 are transferred with 6M NaOH in reaction end back, and (3 * 20mL) extract water with ethyl acetate.Organic phase merges uses anhydrous Na
2SO
4Drying concentrates, and the crude product chromatography column gets 4,7-diaza indoles (0.49g, 4.1mmol, yield 41%).
1H?NMR(400MHz，CDCl
3)：δ10.13(s，br，1H)，8.50(d，J＝3.6，1H)，8.28(d，J＝3.6，1H)，7.66(dd，J＝4.8?&?2.8，1H)，6.77(dd，J＝4.8?&?2.8，1H)。
Claims (5)
1. one kind 4, the preparation method of 7-diaza indoles, this method may further comprise the steps:
A.2-amino-3-methyl pyrazine and pivaloyl chloride or Boc anhydride reaction obtain 2-pivaloyl amido-3-methylpyrazine or uncle's 2-butyloxy formylamido-3-methylpyrazine;
B. with the 2-pivaloyl amido-3-methylpyrazine or uncle's 2-butyloxy formylamido-3-methylpyrazine and the R that obtain
2Li, HCOR
3Reaction generates the aldehyde intermediate;
C. with the aldehyde intermediate reaction solution of b step, need not separation and purification, directly under acidic conditions deprotection close encircle 4,7-diaza indoles;
The reaction formula of step a, b, c synthesis technique is:
R wherein
1Be the tertiary butyl or tert.-butoxy, R
2A kind of in methyl, normal-butyl, sec-butyl and the tertiary butyl; R
3A kind of in dimethylamino, piperidyl, N-methyl-N phenyl and the oxyethyl group.
2. according to claim 14, the preparation method of 7-diaza indoles is characterized in that, the temperature of reaction of step a is 0～40 ℃.
3. according to claim 14, the preparation method of 7-diaza indoles is characterized in that, the temperature of reaction of step b is-25～25 ℃.
4. according to claim 14, the preparation method of 7-diaza indoles is characterized in that, step c temperature of reaction is 50～100 ℃.
5. according to claim 14, the preparation method of 7-diaza indoles is characterized in that, described acidic conditions is a kind of or its mixture in hydrochloric acid, sulfuric acid, the phosphoric acid.
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