CN102875427A - Synthetic method of 2-methoxy methylmesylate - Google Patents
Synthetic method of 2-methoxy methylmesylate Download PDFInfo
- Publication number
- CN102875427A CN102875427A CN2012103468160A CN201210346816A CN102875427A CN 102875427 A CN102875427 A CN 102875427A CN 2012103468160 A CN2012103468160 A CN 2012103468160A CN 201210346816 A CN201210346816 A CN 201210346816A CN 102875427 A CN102875427 A CN 102875427A
- Authority
- CN
- China
- Prior art keywords
- methylmesylate
- synthetic method
- organic phase
- methoxy methyl
- methoxy
- 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.)
- Granted
Links
- 238000010189 synthetic method Methods 0.000 title claims abstract description 14
- 239000012074 organic phase Substances 0.000 claims abstract description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 12
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 9
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- -1 glycol monomethyl methyl compound Chemical class 0.000 claims description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 239000012047 saturated solution Substances 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 abstract 2
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- IUQJDHJVPLLKFL-UHFFFAOYSA-N 2-(2,4-dichlorophenoxy)acetate;dimethylazanium Chemical compound CNC.OC(=O)COC1=CC=C(Cl)C=C1Cl IUQJDHJVPLLKFL-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000032696 parturition Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method of 2-methoxy methylmesylate. The synthetic method comprises the following steps of: taking methylsufonyl chloride and ethylene glycol monoethyl methyl ester compound as synthetic raw materials; taking N, N-dimethylaniline as a catalyst; and carrying out a coupling reaction in molecules at 0 to -5 DEG C under nitrogen protection so as to obtain the 2-methoxy methylmesylate. According to the synthetic method of the 2-methoxy methylmesylate, a simple recrystallizing method is adopted to separate an organic phase; operation is simple and convenient to carry out; cost is low, a chemical yield is high; and the synthetic method is suitable for industrial production, and has a good application prospect.
Description
Technical field:
The present invention relates to a kind of synthetic method of 2-methoxy methyl methylmesylate compound, belong to technical field of organic synthesis.
Background technology:
As a kind of important organic compound, 2-methoxy methyl methylmesylate structural unit is found in the key intermediate of many medicines and medicine.Therefore, their synthetic and application has obtained paying close attention to widely and studying.Its foreign literature report: o a cooled solution (0.deg. C.) of 2-methoxyethanol (0.8 mL) in CH
2Cl
2(50 mL) and TEA (2 mL) is added dropwise methanesulfonyl chloride (1.3 mL). After 5 min, the bath is removed and the reaction mixture allowed to warm to RT and stir for 1 hour at which point it is washed with 1.0 N NaOH, brine, dried (MgSO
4), and concentrated to give an oil. Yield quantitative.chromatographic column separation, the chromatographic column lock out operation that the literature adopts is complicated, and chemical yield is undesirable, cost is high, is difficult to be applicable to suitability for industrialized production.
Summary of the invention:
The object of the invention is for the deficiencies in the prior art, provide a kind of reaction conditions gentle, easy and simple to handle, purify simple, chemical yield is high, cost is low, is suitable for the synthetic method of the 2-methoxy methyl methylmesylate of suitability for industrialized production.
For realizing giving birth to above-mentioned purpose, the technical solution used in the present invention is as follows:
A kind of synthetic method of 2-methoxy methyl methylmesylate; it is characterized in that; the method is as synthesis material take Methanesulfonyl chloride and glycol monomethyl methyl compound; with N; accelerine is catalyzer; 0～-5 C carries out intermolecular linked reaction and makes 2-methoxy methyl methylmesylate under nitrogen protection, and its reaction formula is as follows:
In the formula, the structure formula I is Methanesulfonyl chloride, and the structure formula II is the ethylene glycol monomethyl ether compound, and the structure formula III is 2-methoxy methyl methylmesylate.
Described synthetic method mainly may further comprise the steps: the glycol monomethyl methyl compound is dissolved in the organic polar solvent under nitrogen protection, be cooled to 0～-5 C, stirred 15-20 minute, then add N, accelerine is catalyzer, the control temperature drips Methanesulfonyl chloride again at 0～-5 C, stirs 15～30 minutes at 0～-5 C after dropwising; Then temperature is adjusted to 10 ~ 15 C, under this temperature, stirred 50-60 minute, be cooled to again 0～-5 C, the sodium hydrogen carbonate solution that adds 1M, adopt recrystallization to isolate organic phase, wash isolated organic phase with sodium chloride saturated solution, add again anhydrous magnesium sulfate dry 1-2h to the organic phase and filter out organic phase, filter cake merges organic phase twice with washed with dichloromethane, be concentrated into absence of liquid and ooze, change as oil pump is concentrated into system and be concentrated into the dried weak yellow liquid that obtains till without bubble, the weak yellow liquid that obtains is put into rectifying column, temperature is controlled at 80 ~ 90 C, can be with the rectifying of 2-methoxy methyl methylmesylate out.
Described organic solvent is selected from methylene dichloride.
The present invention has following beneficial effect:
The present invention adopts simple recrystallization method to separate organic phase, and easy and simple to handle, cost is low, and chemical yield is higher, is applicable to suitability for industrialized production, has a good application prospect.
Embodiment
The present invention is further illustrated below in conjunction with specific embodiment.
Embodiment
Add 8000ml methylene dichloride (R1) to three mouthfuls of reaction flasks of 10000L, nitrogen protection.Add the glycol monomethyl methyl esters of 500g gram to R1, R1 is cooled to 0～-5 C and stirred 15 minutes.(temperature is not gone up) control temperature is at 0～-5 C to R1 for the DMA that adds the 640g gram, and the Methanesulfonyl chloride that drips 750g drips approximately the speed that 60min(drips in the R1 and controlled by temperature) R1 stirred 15～30 minutes at 0 C.The temperature of R1 is adjusted to 10 ~ 15 C.Then under this temperature, stirred 60 minutes.R1 is cooled to 0～-5 C.The sodium hydrogen carbonate solution that adds the 1M of 1500ml.(the reaction system endothermic temperature slightly descends) adopts recrystallization to isolate organic phase, the sodium chloride saturated solution that adds 1000ml washs isolated organic phase, the anhydrous magnesium sulfate that adds 256g dry 1h to the organic phase filters out organic phase, filter cake merges organic phase with methylene dichloride 150ml washed twice, be concentrated into absence of liquid and ooze, reconcentration is concentrated into the weak yellow liquid of the dried 1980g of obtaining till without bubble to system.The weak yellow liquid that obtains is put into rectifying column, and temperature is controlled at 80 ~ 90 C, can be with the rectifying of 2-methoxy methyl methylmesylate out.
After testing, chemical yield is 99%, the nuclear-magnetism product purity: 94% 2-methoxy methyl methylmesylate, 0.93% methylene dichloride, DMA 6%.
Claims (3)
1. the synthetic method of a 2-methoxy methyl methylmesylate; it is characterized in that; the method is as synthesis material take Methanesulfonyl chloride and glycol monomethyl methyl compound; with N; accelerine is catalyzer; 0～-5 C carries out intermolecular linked reaction and makes 2-methoxy methyl methylmesylate under nitrogen protection, and its reaction formula is as follows:
In the formula, the structure formula I is Methanesulfonyl chloride, and the structure formula II is the ethylene glycol monomethyl ether compound, and the structure formula III is 2-methoxy methyl methylmesylate.
2. the synthetic method of 2-methoxy methyl methylmesylate according to claim 1, it is characterized in that, described synthetic method mainly may further comprise the steps: the glycol monomethyl methyl compound is dissolved in the organic polar solvent under nitrogen protection, be cooled to 0～-5 C, stirred 15-20 minute, then add N, accelerine is catalyzer, the control temperature drips Methanesulfonyl chloride again at 0～-5 C, stirs 15～30 minutes at 0～-5 C after dropwising; Then temperature is adjusted to 10 ~ 15 C, under this temperature, stirred 50-60 minute, be cooled to again 0～-5 C, the sodium hydrogen carbonate solution that adds 1M, adopt recrystallization to isolate organic phase, wash isolated organic phase with sodium chloride saturated solution, add again anhydrous magnesium sulfate dry 1-2h to the organic phase and filter out organic phase, filter cake merges organic phase twice with washed with dichloromethane, be concentrated into absence of liquid and ooze, change as oil pump is concentrated into system and be concentrated into the dried weak yellow liquid that obtains till without bubble, the weak yellow liquid that obtains is put into rectifying column, temperature is controlled at 80 ~ 90 C, can be with the rectifying of 2-methoxy methyl methylmesylate out.
3. the synthetic method of 2-methoxy methyl methylmesylate according to claim 1 is characterized in that, described organic solvent is selected from methylene dichloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210346816.0A CN102875427B (en) | 2012-09-18 | 2012-09-18 | Synthetic method of 2-methoxy methylmesylate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210346816.0A CN102875427B (en) | 2012-09-18 | 2012-09-18 | Synthetic method of 2-methoxy methylmesylate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102875427A true CN102875427A (en) | 2013-01-16 |
| CN102875427B CN102875427B (en) | 2014-02-19 |
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|---|---|---|---|
| CN201210346816.0A Expired - Fee Related CN102875427B (en) | 2012-09-18 | 2012-09-18 | Synthetic method of 2-methoxy methylmesylate |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003093250A2 (en) * | 2002-05-03 | 2003-11-13 | Pharmacia & Upjohn Company | Positive allosteric modulators of the nicotinic acetylcholine receptor |
| EP1404360A1 (en) * | 2001-06-04 | 2004-04-07 | Nobex Corporation | Mixtures of calcitonin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| CN102321033A (en) * | 2011-08-22 | 2012-01-18 | 江苏辉丰农化股份有限公司 | Preparation method of tarceva |
| US20120083642A1 (en) * | 2010-10-04 | 2012-04-05 | Korea Institute Of Science And Technology | Ionic liquids, the method for preparing the same and method for removing acetylenes from olefin mixtures using the ionic liquids |
-
2012
- 2012-09-18 CN CN201210346816.0A patent/CN102875427B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1404360A1 (en) * | 2001-06-04 | 2004-04-07 | Nobex Corporation | Mixtures of calcitonin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| WO2003093250A2 (en) * | 2002-05-03 | 2003-11-13 | Pharmacia & Upjohn Company | Positive allosteric modulators of the nicotinic acetylcholine receptor |
| US20120083642A1 (en) * | 2010-10-04 | 2012-04-05 | Korea Institute Of Science And Technology | Ionic liquids, the method for preparing the same and method for removing acetylenes from olefin mixtures using the ionic liquids |
| CN102321033A (en) * | 2011-08-22 | 2012-01-18 | 江苏辉丰农化股份有限公司 | Preparation method of tarceva |
Non-Patent Citations (2)
| Title |
|---|
| SCATES, BRADLEY A. ET AL: "Polyethylene glycol-based homologated", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| SCHREKKER, HENRI S. ET AL: "Preparation, cation-anion interactions and", 《JOURNAL OF THE BRAZILIAN CHEMICAL SOCIETY》 * |
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| CN102875427B (en) | 2014-02-19 |
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Denomination of invention: Synthetic method of 2-methoxy methylmesylate Effective date of registration: 20170922 Granted publication date: 20140219 Pledgee: Huoqiu branch of China Postal Savings Bank Limited by Share Ltd. Pledgor: Anhui Shihua Chemical Co.,Ltd. Registration number: 2017340000248 |
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| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140219 |