CN103319396A - Method for preparing 1-methylindole-3-carboxylic acid - Google Patents
Method for preparing 1-methylindole-3-carboxylic acid Download PDFInfo
- Publication number
- CN103319396A CN103319396A CN2012100753223A CN201210075322A CN103319396A CN 103319396 A CN103319396 A CN 103319396A CN 2012100753223 A CN2012100753223 A CN 2012100753223A CN 201210075322 A CN201210075322 A CN 201210075322A CN 103319396 A CN103319396 A CN 103319396A
- Authority
- CN
- China
- Prior art keywords
- carboxylic acid
- preparing
- skatole
- methylindole
- indole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 10
- HVRCLXXJIQTXHC-UHFFFAOYSA-N 1-methylindole-3-carboxylic acid Chemical compound C1=CC=C2N(C)C=C(C(O)=O)C2=C1 HVRCLXXJIQTXHC-UHFFFAOYSA-N 0.000 title abstract 4
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 230000001035 methylating effect Effects 0.000 claims abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 125000005911 methyl carbonate group Chemical group 0.000 claims 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 1
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 235000010755 mineral Nutrition 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 abstract description 3
- 229960003727 granisetron Drugs 0.000 abstract description 3
- 238000007069 methylation reaction Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 229940127239 5 Hydroxytryptamine receptor antagonist Drugs 0.000 abstract 1
- 239000003420 antiserotonin agent Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 230000011987 methylation Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000011935 selective methylation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- -1 sodium alkoxide Chemical class 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
Landscapes
- Indole Compounds (AREA)
Abstract
The invention relates to a method for preparing 1-methylindole-3-carboxylic acid. The method prepares 1-methylindole-3-carboxylic acid in an easy, safe and highly effective manner by methylating indole-3-carboxylic acid with methylation reagents under base-catalytic conditions. 1-methylindole-3-carboxylic acid is an important intermediate for synthesis of a 5-HT receptor antagonist, granisetron.
Description
Technical field
The invention belongs to technical field of organic synthesis, particularly a kind of method for preparing 1-skatole-3-carboxylic acid.
Background technology
1-skatole-3-carboxylic acid is the important intermediate of synthetic drugs granisetron.US4946966 reported the Indole-3-Carboxylic Acid carried out methylated synthetic schemes, but has two nitrogen-atoms on the indole ring, all might be methylated, thereby affects the yield of target product.The selective methylation method of reporting among the US4946966 is to adopt anhydrous polar solvent, does alkali with sodium alkoxide and reacts.But this severe reaction conditions is unfavorable for large-scale industrialization production.The present invention program can carry out in water-containing solvent, and raw material reaction is complete, and avoids using high malicious methylating reagent, and convenient operation is fit to and large-scale industrialization production.
Summary of the invention
The technical problem that the present invention solves is to overcome the deficiencies in the prior art, and the preparation method of a kind of 1-skatole-3-carboxylic acid is provided, and the simultaneous reactions time is short, mild condition, and target product yield is high.
The objective of the invention is to be achieved through the following technical solutions, may further comprise the steps:
1) in reaction vessel, adds acetonitrile and Indole-3-Carboxylic Acid, fully stirring and dissolving;
2) under the room temperature condition, in above-mentioned Indole-3-Carboxylic Acid's acetonitrile solution, add methylcarbonate, wet chemical, return stirring reaction 2-3 hour;
3) be 1 with reaction solution with the hydrochloric acid adjust pH, cooled and filtered had both got 1-skatole-3-crude carboxylic acid.
4) crude product obtains 1-skatole-3-carboxylic acid (mp:215 ℃) with ethyl alcohol recrystallization.
The present invention uses salt of wormwood as catalyzer methylation reaction to be carried out catalysis on the prior art basis, compared with prior art, has greatly improved the speed of response of methylation reaction, only needs reaction in 2-3 hour namely fully.Use methylcarbonate to replace methyl-sulfate and the methyl iodide of high poison, be conducive to the protection of personnel and environment.Simultaneous reactions carries out in water-containing solvent, convenient operation.Preparation method's production cost of the present invention is low, is suitable for suitability for industrialized production, also helps simultaneously the reduction of derived product granisetron cost.
Embodiment
Embodiment 1:
In the 50L reactor, add the 30L acetonitrile, stir the lower Indole-3-Carboxylic Acid 3.0kg (18.5mol) of adding, stir adding methylcarbonate 4L after ten minutes, continued stirring at room 20 minutes, add the wet chemical 6L (110mol) for preparing, slowly temperature rising reflux is 2 hours.React complete after, be cooled to room temperature, add the dilution of 5L water, be 1 with the hydrochloric acid adjust pH, obtain 1-skatole-3-crude carboxylic acid 4.3kg after the suction filtration drying, with ethanol crude product is carried out recrystallization, obtain 1-skatole-3-carboxylic acid 2.9kg, yield 85.6%, m.p.215 ℃.
The above embodiment only is that preferred implementation of the present invention is described; be not that scope of the present invention is limited; design under the prerequisite of spirit not breaking away from the present invention; various distortion and improvement that those of ordinary skills make technical scheme of the present invention all should fall in the definite protection domain of claims of the present invention.
Claims (5)
1. a method for preparing 1-skatole-3-carboxylic acid is characterized in that, in the mixed solvent of acetonitrile and water, mineral alkali exists lower, with methylating reagent the Indole-3-Carboxylic Acid is methylated.
2. a kind of method for preparing 1-skatole-3-carboxylic acid as claimed in claim 1 is characterized in that, the ratio of acetonitrile and water is 5: 1.
3. a kind of method for preparing 1-skatole-3-carboxylic acid as claimed in claim 1 is characterized in that, mineral alkali is salt of wormwood or cesium carbonate.
4. a kind of method for preparing 1-skatole-3-carboxylic acid as claimed in claim 1 is characterized in that, methylating reagent is methylcarbonate.
5. a kind of method for preparing 1-skatole-3-carboxylic acid as claimed in claim 1 is characterized in that, the volume ratio of acetonitrile and water is 5: 1, and alkali is salt of wormwood, and methylating reagent is methylcarbonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100753223A CN103319396A (en) | 2012-03-21 | 2012-03-21 | Method for preparing 1-methylindole-3-carboxylic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100753223A CN103319396A (en) | 2012-03-21 | 2012-03-21 | Method for preparing 1-methylindole-3-carboxylic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103319396A true CN103319396A (en) | 2013-09-25 |
Family
ID=49188489
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012100753223A Pending CN103319396A (en) | 2012-03-21 | 2012-03-21 | Method for preparing 1-methylindole-3-carboxylic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103319396A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0323105A1 (en) * | 1987-12-22 | 1989-07-05 | Beecham Group Plc | Novel process |
| CN1429816A (en) * | 2003-01-23 | 2003-07-16 | 宁波市天衡制药厂 | New method of preparing Granisetron intermediate |
| CN1451660A (en) * | 2002-04-19 | 2003-10-29 | 浙江海正药业股份有限公司 | Process for preparing granisetron and its salt |
| EP1484321A1 (en) * | 2003-06-03 | 2004-12-08 | Chemagis Ltd. | Process for preparing 1-methylindazole-3-carboxylic acid |
| WO2007088557A1 (en) * | 2006-02-01 | 2007-08-09 | Natco Pharma Limited | Process for highly pure crystalline granisetron base |
-
2012
- 2012-03-21 CN CN2012100753223A patent/CN103319396A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0323105A1 (en) * | 1987-12-22 | 1989-07-05 | Beecham Group Plc | Novel process |
| CN1451660A (en) * | 2002-04-19 | 2003-10-29 | 浙江海正药业股份有限公司 | Process for preparing granisetron and its salt |
| CN1429816A (en) * | 2003-01-23 | 2003-07-16 | 宁波市天衡制药厂 | New method of preparing Granisetron intermediate |
| EP1484321A1 (en) * | 2003-06-03 | 2004-12-08 | Chemagis Ltd. | Process for preparing 1-methylindazole-3-carboxylic acid |
| WO2007088557A1 (en) * | 2006-02-01 | 2007-08-09 | Natco Pharma Limited | Process for highly pure crystalline granisetron base |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130925 |