CN102372674A - Synthesis method for pharmaceutical intermediate 3-formyl-4-halogeno pyrazole - Google Patents
Synthesis method for pharmaceutical intermediate 3-formyl-4-halogeno pyrazole Download PDFInfo
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- CN102372674A CN102372674A CN2010102550050A CN201010255005A CN102372674A CN 102372674 A CN102372674 A CN 102372674A CN 2010102550050 A CN2010102550050 A CN 2010102550050A CN 201010255005 A CN201010255005 A CN 201010255005A CN 102372674 A CN102372674 A CN 102372674A
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- pyrazoles
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Abstract
The present invention relates to an important pharmaceutical intermediate 3-formyl-4-halogeno (bromine or iodine) pyrazole. The technical scheme of the present invention comprises that: the synthesis method for the pharmaceutical intermediate 3-formyl-4-halogeno (bromine or iodine) pyrazole comprises the following steps that: 2,2-dimethoxy acetaldehyde and N,N-dimethylformamide dimethyl acetal are adopted as raw materials to generate 4-dimethylamino-1,1-dimethoxy-3-butanone; the 4-dimethylamino-1,1-dimethoxy-3-butanone directly reacts with hydrazine hydrate without purification to obtain a key intermediate 3-dimethoxymethyl-1-hydropyrazole; after bromination or iodo, the 3-dimethoxymethyl-1-hydropyrazole is subjected to deprotection to obtain the 3-formyl-4-bromopyrazole or 3-formyl-4-iodopyrazole.
Description
Technical field: the compound method that the present invention relates to important medicine intermediate 3-aldehyde radical-4-halo (bromine or iodine) pyrazoles.
Background technology:
3-aldehyde radical-4-bromine pyrazoles or 3-aldehyde radical-4-iodine pyrazoles is important medicine intermediate; It can be used for synthesizing a lot of small-molecule drugs; Like J.Med.Chem.2008,51, this piece of 282-297 document should be that the synthetic fragment of raw material is studied thromboembolic disorders with it; This piece of US2003/45581 patent report is the synthetic cancer therapy drug segment of starting raw material with it.But these two pieces of documents are all less than the source of indicating this raw material, and (Eur JMed Chem (1993) 28 129-140) reports the compound method of its analogue 3-aldehyde radical pyrazoles, and its compound method of bibliographical information is not arranged at present as yet though document is arranged.
Summary of the invention:
The object of the present invention is to provide the compound method of medicine intermediate 3-aldehyde radical-4-halo (bromine or iodine) pyrazoles, the synthetic cost of this method is low, and operation and aftertreatment are simple, are easy to industriallization.
Technical scheme of the present invention: the compound method of medicine intermediate 3-aldehyde radical-4-halo (bromine or iodine) pyrazoles may further comprise the steps:
With 2,2-dimethoxy acetaldehyde 1 and N, dinethylformamide dimethylacetal (DMF-DMA) 2 generates 4-dimethylamino-1,1-dimethoxy-3-butanone 3 for raw material; Compound 3 need not purifying and directly reacts with Hydrazine Hydrate 80 and obtain key intermediate 3-dimethoxy-methyl-1-hydrogen pyrazoles 4; Pass through bromo or iodo then, deprotection obtains 3-aldehyde radical-4-bromine pyrazoles 7 or 3-aldehyde radical-4-iodine pyrazoles 9 again.
Reaction formula is following:
Reaction formula 1
Reaction formula 2
With reference to reaction formula 1: the first step reaction is for 2, and 2-dimethoxy acetaldehyde normal temperature (15 to 20 ℃) joins among the DMF-DMA, reaction spend the night (12-16 hour) of refluxing.Reaction solution is revolved the dried 4-of obtaining dimethylamino-1,1-dimethoxy-3-butanone 3.
The reaction of second step adds Hydrazine Hydrate 80 (85%wt), 15 to 20 ℃ of stirred overnight of reaction solution again for compound 3 is soluble in water; Reaction solution extracts with MTBE, and organic phase is revolved the dried key intermediate 3-dimethoxy-methyl-1-hydrogen pyrazoles 4 that obtains.
Three-step reaction is for to be dissolved in 3-dimethoxy-methyl-1-hydrogen pyrazoles 4 in the methylene dichloride; At 0 ℃ of methanol solution that drips tribromo father-in-law pyridine down; After dripping, reaction solution rises to room temperature (20-30 ℃), and room temperature reaction spends the night and obtains 4-bromo-3-dimethoxy-methyl pyrazoles 6.
Four-step reaction is that 4-bromo-3-dimethoxy-methyl pyrazoles 6 is soluble in water, and 0 ℃ drips acetic acid, stirs and obtained 3-aldehyde radical-4-bromine pyrazoles 7 in 2 hours.
For 3-dimethoxy-methyl-1-hydrogen pyrazoles 4 is dissolved in the methylene dichloride, normal temperature adds salt of wormwood and iodine then with reference to reaction formula 2, the five step reaction, and stirring at normal temperature is spent the night and obtained 4-iodo-3-dimethoxy-methyl pyrazoles 8.
Six-step process is that 4-iodo-3-dimethoxy-methyl pyrazoles 8 is soluble in water, and 0 ℃ drips acetic acid, stirs and obtained 3-aldehyde radical-4-iodine pyrazoles 9 in 2 hours.
Beneficial effect of the present invention: the invention provides a kind of synthetic route of novelty, can prepare important medicine intermediate quickly and easily from raw material cheap, that be easy to get.This process yield is high, and aftertreatment and convenient purification are fit to extensive the generation.
Embodiment: following instance helps to understand content of the present invention, the present invention includes but is not limited to following related content:
Embodiment 1
Reaction formula 1
1.4-dimethylamino-1,1-dimethoxy-3-butanone 3 synthetic
With 2,2-dimethoxy acetaldehyde 1 (118g, 1mol) room temperature joins N, dinethylformamide dimethylacetal 2 (119g, 1mol) in, reaction solution refluxes and to spend the night then.With the reaction solution cool to room temperature, reconcentration obtains the product 4-dimethylamino-1 of 150g, 1-dimethoxy-3-butanone 3 (yield: 87%).
2.3-dimethoxy-methyl-1-hydrogen pyrazoles 4 is synthetic
With 4-dimethylamino-1,1-dimethoxy-3-butanone 3 (150g 0.87mol) is dissolved in the 300mL water, add then Hydrazine Hydrate 80 (500mL, 85%wt).Reaction solution stirring at normal temperature again spends the night.Reaction solution is poured in the 300mL water, and the MTBE with 1L extracts 5 times again.The organic phase that merges is used anhydrous sodium sulfate drying.After the siccative filtration, filtrating concentrating obtains product 3-dimethoxy-methyl-1-hydrogen pyrazoles 4 (productive rates: 81%) of 100g
1H-NMR(CDCl
3，400MHz)：δ7.602-7.597(d，J＝2Hz，1H)，6.348-6.342(d，J＝2Hz，1H)，5.619(s，1H)，3.369(s，6H).
3.4-bromo-3-dimethoxy-methyl-1-hydrogen pyrazoles 6 is synthetic
(7.5g 0.053mol) is dissolved in the methylene dichloride (50mL), drips tribromo father-in-law pyridine (16.7g down at 0 ℃ with 3-dimethoxy-methyl-1-hydrogen pyrazoles 4; 0.053mol) methyl alcohol (20mL) solution, after dripping, reaction solution rises to room temperature; Room temperature reaction spends the night. at room temperature add S-WAT, stir half a hour after, filter; Filtrating is revolved dried at low temperatures, obtains 4-bromo-3-dimethoxy-methyl pyrazoles 6 (8g, yields: 80%).
1H-NMR(CDCl
3，400MHz)：δ7.99(s，1H)，7.57(s，1H)，5.55(s，1H)，2.93(s，3H)，2.86(s，3H).
4.3-aldehyde radical-4-bromine pyrazoles 7
With 4-bromo-3-dimethoxy-methyl pyrazoles 6 (8g, 0.036mol) in water-soluble (40mL), 0 ℃ drips down acetic acid (10mL), reaction solution stirred after 2 hours has faint yellow solid to separate out, and filters, and promptly gets 3-aldehyde radical-4-bromine pyrazoles 7 (5g; Yield: 80%)
Embodiment 2
1.4-iodo-3-dimethoxy-methyl-1-hydrogen pyrazoles 8 is synthetic
(60g 0.42mol) is dissolved in the methylene dichloride (500mL), under 15 ℃, adds K respectively with 3-dimethoxy-methyl pyrazoles 4
2CO
3(116.62g, 0.84mol), I
2(106.60g, 0.42mol), under this temperature, the reaction stirred overnight.With reacting liquid filtering, filtrating concentrate 100g 4-iodo-3-dimethoxy-methyl-1-hydrogen pyrazoles 8 (yields: 89%).
1H-NMR(CD
3COCD
3，400MHz)：δ7.96(s，1H)，7.63(s，1H)，5.42(s，1H)，2.93(s，3H)，2.77(s，3H).
2.3-aldehyde radical-4-iodine pyrazoles 9 is synthetic
(0 ℃ drips acetic acid (200mL) down for 100g, 0.37mol) water-soluble (500mL), and reaction solution stirred after 2 hours has yellow solid to separate out, and filters, and solid drying gets 3-aldehyde radical-4-iodine pyrazoles 9 (78g with 4-iodo-3-dimethoxy-methyl pyrazoles 8; Yield: 94%).
Claims (7)
1. the compound method of medicine intermediate 3-aldehyde radical-4-halo pyrazoles may further comprise the steps:
With 2,2-dimethoxy acetaldehyde and N, dinethylformamide dimethylacetal are that raw material generates 4-dimethylamino-1,1-dimethoxy-3-butanone; 4-dimethylamino-1,1-dimethoxy-3-butanone need not purifying and directly react with Hydrazine Hydrate 80 and obtain key intermediate 3-dimethoxy-methyl-1-hydrogen pyrazoles; Pass through bromo-reaction or iodide reaction then, deprotection obtains 3-aldehyde radical-4-bromine pyrazoles or 3-aldehyde radical-4-iodine pyrazoles again.
2. the compound method of medicine intermediate 3-aldehyde radical according to claim 1-4-halo pyrazoles is characterized in that 2,2-dimethoxy acetaldehyde and N, and the reaction of dinethylformamide dimethylacetal refluxes and spends the night.
3. the compound method of medicine intermediate 3-aldehyde radical according to claim 1-4-halo pyrazoles is characterized in that 4-dimethylamino-1, and 1-dimethoxy-3-butanone needs earlier soluble in water, adds the 85%wt Hydrazine Hydrate 80 again, 15 to 20 ℃ of stirred overnight; Reaction solution extracts with MTBE, and organic phase is revolved the dried key intermediate 3-dimethoxy-methyl-1-hydrogen pyrazoles that obtains.
4. the compound method of medicine intermediate 3-aldehyde radical according to claim 1-4-halo pyrazoles; It is characterized in that described bromo-reaction is for to be dissolved in 3-dimethoxy-methyl-1-hydrogen pyrazoles in the methylene dichloride; At 0 ℃ of methanol solution that drips tribromo father-in-law pyridine down; After dripping, reaction solution rises to room temperature, and room temperature reaction spends the night and obtains 4-bromo-3-dimethoxy-methyl pyrazoles.
5. the compound method of medicine intermediate 3-aldehyde radical according to claim 1-4-halo pyrazoles; It is characterized in that described iodide reaction is for to be dissolved in 3-dimethoxy-methyl-1-hydrogen pyrazoles in the methylene dichloride; Normal temperature adds salt of wormwood and iodine then, and stirring at normal temperature is spent the night and obtained 4-iodo-3-dimethoxy-methyl pyrazoles.
6. the compound method of medicine intermediate 3-aldehyde radical according to claim 1-4-halo pyrazoles; Deprotection is after it is characterized in that described bromo-reaction: 4-bromo-3-dimethoxy-methyl pyrazoles is soluble in water; 0 ℃ drips acetic acid, stirs and obtained 3-aldehyde radical-4-bromine pyrazoles in 2 hours.
7. the compound method of medicine intermediate 3-aldehyde radical according to claim 1-4-halo pyrazoles; Deprotection is after it is characterized in that described iodide reaction: 4-iodo-3-dimethoxy-methyl pyrazoles is soluble in water; 0 ℃ drips acetic acid, stirs and obtained 3-aldehyde radical-4-iodine pyrazoles in 2 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299302A (en) * | 2017-01-11 | 2018-07-20 | 西南科技大学 | A kind of new method preparing 3- acetyl pyrazoles |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003035065A1 (en) * | 2001-10-26 | 2003-05-01 | Aventis Pharmaceuticals Inc | Benzimidazoles and analogues and their use as protein kinases inhibitors |
| WO2007043677A1 (en) * | 2005-10-14 | 2007-04-19 | Sumitomo Chemical Company, Limited | Hydrazide compound and pesticidal use of the same |
| CN101693690A (en) * | 2009-10-13 | 2010-04-14 | 东南大学 | N,N-substituent-1-(1H-pyrazole-3-yl) methylamine and preparation method thereof |
-
2010
- 2010-08-17 CN CN2010102550050A patent/CN102372674A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003035065A1 (en) * | 2001-10-26 | 2003-05-01 | Aventis Pharmaceuticals Inc | Benzimidazoles and analogues and their use as protein kinases inhibitors |
| WO2007043677A1 (en) * | 2005-10-14 | 2007-04-19 | Sumitomo Chemical Company, Limited | Hydrazide compound and pesticidal use of the same |
| CN101693690A (en) * | 2009-10-13 | 2010-04-14 | 东南大学 | N,N-substituent-1-(1H-pyrazole-3-yl) methylamine and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| HELIO A. STEFANI等: "A mild and efficient method for halogenation of 3,5-dimethyl pyrazoles by ultrasound irradiation using N-halosuccinimides", 《TETRAHEDRON LETTERS》 * |
| MARIA ISABEL RODRIGUEZ-FRANCO等: "A mild and efficient method for the regioselective iodination of pyrazoles", 《TETRAHEDRON LETTERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299302A (en) * | 2017-01-11 | 2018-07-20 | 西南科技大学 | A kind of new method preparing 3- acetyl pyrazoles |
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Application publication date: 20120314 |