CN102249921B - 2-(2,3-3,5-dimethylphenyl) diester malonate, Preparation Method And The Use - Google Patents
2-(2,3-3,5-dimethylphenyl) diester malonate, Preparation Method And The Use Download PDFInfo
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- CN102249921B CN102249921B CN201010174407.8A CN201010174407A CN102249921B CN 102249921 B CN102249921 B CN 102249921B CN 201010174407 A CN201010174407 A CN 201010174407A CN 102249921 B CN102249921 B CN 102249921B
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- dimethylphenyl
- diester malonate
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Abstract
The invention discloses a kind of 2-(2, 3-3,5-dimethylphenyl) diester malonate, its preparation method and the intermediate 1-(2 for the synthesis of hydrochloric acid Dexmedetomidine thereof, 3-3,5-dimethylphenyl) purposes of ethanol, the present invention is with 2, 3-mesitylenic acid is starting raw material, 2 are made through chloride, after 3-dimethyl benzoyl chloride, obtained 2-(2 is reacted with diester malonate under triethylamine and Magnesium Chloride Anhydrous exist, 3-3,5-dimethylphenyl) diester malonate, described 2-(2, 3-3,5-dimethylphenyl) diester malonate sulphuric acid hydrolysis obtains 1-(2, 3-3,5-dimethylphenyl) ethyl ketone, again through the obtained 1-(2 of reductive agent reduction, 3-3,5-dimethylphenyl) ethanol.The inventive method is easy and simple to handle, starting material are cheap and easy to get, reaction conditions is gentle, gained finished product purity is high, without the need to special separation and purification, is suitable for large-scale production.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, especially a kind of synthesis is applicable to the preparation method that Intensive Care treatments period starts hydrochloric acid Dexmedetomidine intermediate 1-(2, the 3-3,5-dimethylphenyl) ethanol of intubate and use respirator patient calmness.
Background technology
Hydrochloric acid Dexmedetomidine (English name: dexmedetomidine hydrochloride; Chemical name: (R)-4-[1-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazoles mono-hydrochloric salts) be alpha 2-adrenoceptor agonist that is efficient, highly selective, there is the effects such as the calmness of dose-dependently, analgesia, anxiety, sympathetic nerve suppression, few side effects and light, in 1999 the U.S. approval be used for intensive care unit(ICU) (ICU) be grown up calmness, analgesia, and in neurosurgery, for premedicate, general anesthesia adjuvant, Postoperative Analgesia After, succeed in many clinical practices such as treatment withdrawal reaction application.
1-(2,3-3,5-dimethylphenyl) ethanol (I) is the intermediate of synthetic hydrochloric acid Dexmedetomidine, document (Chinese Journal of Pharmaceuticals, 2008,39 (6): 467-469) report is with 2,3-mesitylenic acid (II) is starting raw material, through LiAlH
4be reduced into (2,3-3,5-dimethylphenyl) methyl alcohol (VII), 2 are oxidized to activated manganese dioxide, 3-dimethylbenzaldehyde (VIII), 1-(2,3-3,5-dimethylphenyl) ethanol (I) is obtained again with Grignard reagent methylpyridinium iodide magnesium generation grignard reaction.
The first step LiAlH in this method
4reduction and final step Grignard reagent methylpyridinium iodide magnesium generation grignard reaction all need strict anhydrous condition, and reagent is expensive, inflammable and explosive, operate unfriendly, make to synthesize 1-(2,3-3,5-dimethylphenyl) ethanol (I) cost increase, and activated manganese dioxide needs now-making-now-using, unfriendly to environment.
Therefore, in above-mentioned synthesis 1-(2,3-3,5-dimethylphenyl) ethanol (I) technique, the main technical problem existed is described above, severe reaction conditions, and additive reagent cost intensive, operation inconvenience etc., be unsuitable for industrial production.
Summary of the invention
The technical issues that need to address of the present invention are preparation methods of open a kind of 1-(2,3-3,5-dimethylphenyl) ethanol (I), to overcome the defect that above-mentioned prior art exists, provide the synthetic method being more conducive to suitability for industrialized production.
Thinking of the present invention is realized by following technical proposals.
By 2,3-mesitylenic acid (II) acyl chlorides turns to 2, after 3-dimethyl benzoyl chloride (III), obtained 2-(2 is reacted with diester malonate (IV) under triethylamine and Magnesium Chloride Anhydrous exist, 3-3,5-dimethylphenyl) diester malonate (V), V sulphuric acid hydrolysis obtains 1-(2,3-3,5-dimethylphenyl) ethyl ketone (VI), again through obtained 1-(2, the 3-3,5-dimethylphenyl) ethanol (I) of reductive agent reduction.Its reaction formula is as follows:
Wherein 2-(2,3-3,5-dimethylphenyl) diester malonate (V) is for having no the compound of bibliographical information, can find out to there are keto-acid (V-keto-acid) and enol form (V-enol form) two kinds of tautomers from HNMR collection of illustrative plates simultaneously, but based on enol form, R is Me (methyl) or Et (ethyl).
The chloride reagent wherein preparing III used is thionyl chloride or oxalyl chloride, preferred thionyl chloride, and its consumption is equivalent to 1 ~ 5 equivalent of II, is preferably 1.3 ~ 2.5 equivalents; Solvent for use is the aprotic solvent such as methylene dichloride, toluene, is preferably methylene dichloride.
When preparing V, diester malonate (IV) consumption is 1 ~ 2 equivalent of III, preferably 1.2 ~ 1.5 equivalents, and Magnesium Chloride Anhydrous consumption is 0.6 ~ 0.75 equivalent of III, and triethylamine consumption is 2.4 ~ 3 equivalents of III; Organic solvent used is selected from acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ether, isopropyl ether, the tertiary ether of first, methylene dichloride, chloroform, ethyl acetate or its mixed solvent, ethyl acetate.
It is metal borohydride, metal hydride that VI is reduced to I reductive agent used, or the combination of hydrogenation catalyst and hydrogen, but comprehensive material cost and the factor such as easy and simple to handle, preferred sodium borohydride or POTASSIUM BOROHYDRIDE in alcoholic solvent as methyl alcohol, ethanol reduction obtain I.
Method of the present invention comprises following concrete steps:
II is dissolved in methylene dichloride, adds a certain amount of thionyl chloride, drip several DMF initiation reactions, treat stirred overnight at room temperature, steam and desolventize to obtain acyl chlorides III; Diester malonate (IV), triethylamine and Magnesium Chloride Anhydrous to be put in ethyl acetate stirring at room temperature 45 minutes, slightly being chilled at 10 DEG C is slowly added dropwise in this system by the crude product of above-mentioned obtained III, drip off rear continuation and at room temperature stir end reaction in 50 minutes, use the dilute hydrochloric acid of 10%, saturated sodium bicarbonate, saturated common salt water washing successively, organic layer through anhydrous magnesium sulfate drying, except the crude product of V obtained after desolventizing; The crude product of this V is directly dissolved in acetic acid/aqueous systems, after adding sulfuric acid heating hydrolysis, through water dilution, extraction into ethyl acetate, washing, drying, obtain the crude product of VI except desolventizing, VI is dissolved in ethanol, under room temperature, 4h is reduced with sodium borohydride, steaming desolventizes, and be dissolved in water resistates, is extracted with ethyl acetate, organic layer desolventizes to obtain the product of I through saturated common salt water washing, anhydrous magnesium sulfate drying, steaming.Reach more than 75%, HNMR display purity with the common four-step reaction total recovery of II calculating synthesis I higher, follow-up synthesis can be directly used in.
The present invention is compared with the prior art, the inventive method mild condition, easy and simple to handle, the operate continuously that responds, and gained intermediate is directly used in the next step without the need to purifying; And this law agents useful for same is all cheap and easy to get, calculates synthesis I totally four step total recoverys more than 70% with II, avoid LiAlH
4, activated manganese dioxide, the expensive reagent such as Grignard reagent methylpyridinium iodide magnesium use, overcome the defect in prior art, can provide again and more be conducive to industrial processing condition, be easy to large-scale production.
Embodiment
Further illustrate the present invention below by embodiment, but these embodiments do not form any restriction to the present invention.
Embodiment one
II (8.25g) is dissolved in 80mL methylene dichloride, adds 8.90g thionyl chloride, drip several DMF initiation reactions, treat stirred overnight at room temperature, steam and desolventize to obtain acyl chlorides III; 11.71g diethyl malonate, 14.73g triethylamine and 3.50g Magnesium Chloride Anhydrous to be put in 70mL ethyl acetate stirring at room temperature 45 minutes, slightly being chilled at 10 DEG C is slowly added dropwise in this system by above-mentioned obtained acyl chlorides III, drip off rear continuation and at room temperature stir end reaction in 50 minutes, use the dilute hydrochloric acid of 10%, saturated sodium bicarbonate, saturated common salt water washing successively, organic layer through anhydrous magnesium sulfate drying, except the crude product 18.60g of V obtained after desolventizing; In order to obtain the sample for analysis of V, get wherein 3.40g through silica gel column chromatography (eluent: sherwood oil: ethyl acetate=20: 1) purifying obtains the sterling of 2.81g V is colourless transparent liquid, with II calculated yield 96%,
1the ratio of H-NMR collection of illustrative plates display V-keto-acid and V-enol form is approximately 2: 5 [ESI-MS m/z:[M+1]
+293.1;
1h-NMR (CDCl
3): (1) V-keto-acid: δ 1.23-1.31 (m, 6H, CH (CO
2cH
2c
h 3)
2), 2.33 (s, 3H, ArC
h 3), 2.40 (s, 3H, ArC
h 3), 4.19-4.28 (m, 4H, CH (CO
2c
h 2cH
3)
2), 5.23 (s, 1H, C
h(CO
2cH
2cH
3)
2), 7.14-7.18 (t, 1H, Ar-H), 7.29-7.31 (d, 1H, Ar-H), 7.37-7.39 (d, 1H, Ar-H); (2) V-enol form: δ 0.80-0.84 (t, 3H, CH
2c
h 3), 1.35-1.39 (t, 3H, CH
2c
h 3), 2.27 (s, 3H, ArC
h 3), 2.30 (s, 3H, ArC
h 3), 3.85-3.92 (q, 2H, C
h 2cH
3), 4.33-4.39 (q, 2H, C
h 2cH
3), 7.04-7.11 (m, 2H, Ar-H), 7.19-7.21 (d, 1H, Ar-H), 13.43 (s, 1H, ArC (O
h)=C (CO
2cH
2cH
3)
2) .]; Be dissolved in 10mL acetic acid, 3mL water by the crude product 15.1g of above-mentioned obtained V, add the 3mL vitriol oil, reflux was chilled to room temperature after 4 hours, and add the dilution of 50mL water, extract with ethyl acetate 100mL × 3, organic layer uses saturated NaHCO after merging successively
3the aqueous solution, saturated aqueous common salt respectively wash once, through anhydrous MgSO
4drying, pressure reducing and steaming solvent obtains 5.30g weak yellow liquid VI [ESI-MS m/z:[M+1]
+149.0;
1h-NMR (CDCl
3): δ 2.31 (s, 3H, ArC
h 3), 2.34 (s, 3H, ArC
h 3), 2.56 (s, 3H, COC
h 3), 7.14 (t, 1H, Ar-H), 7.25 (d, 1H, Ar-H), 7.39 (d, 1H, Ar-H)]; Be dissolved in 20mL ethanol by above-mentioned obtained VI 4.0g, add 0.80g sodium borohydride, in stirred at ambient temperature reaction 4h, steaming desolventizes, and adds 12mL water dissolution resistates, extracts with ethyl acetate 50mL × 3, with saturated common salt water washing, anhydrous MgSO after organic layer merges
4drying, pressure reducing and steaming solvent obtain the light colorless oil I of 3.37g [
1h-NMR (CDCl
3): δ 1.41 (d, 3H, CH (OH) C
h 3), 1.78 (s, 11H, O
h), 2.23 (s, 3H, ArC
h 3), 2.29 (s, 3H, COC
h 3), 5.17 (q, 1H, C
h(OH) CH
3), 7.08 (d, 1H, Ar-H), 7.14 (t, 1H, Ar-H), 7.37 (d, 1H, Ar-H)], calculate synthesis I four-step reaction total recovery 82%, HNMR display purity about more than 95% altogether with II, follow-up synthesis can be directly used in.
Embodiment two
II (8.25g) is dissolved in 80mL methylene dichloride, adds 10.20g thionyl chloride, drip several DMF initiation reactions, treat stirred overnight at room temperature, steam and desolventize to obtain acyl chlorides III; 9.64g dimethyl malonate, 14.73g triethylamine and 3.50g Magnesium Chloride Anhydrous to be put in 70mL ethyl acetate stirring at room temperature 45 minutes, slightly being chilled at 10 DEG C is slowly added dropwise in this system by above-mentioned obtained acyl chlorides III, drip off rear continuation and at room temperature stir end reaction in 50 minutes, use the dilute hydrochloric acid of 10%, saturated sodium bicarbonate, saturated common salt water washing successively, organic layer through anhydrous magnesium sulfate drying, except the crude product 15.46g of V obtained after desolventizing; In order to obtain the sample for analysis of V, get wherein 3.0g through silica gel column chromatography (eluent: sherwood oil: ethyl acetate=20: 1) purifying obtains the sterling of 2.63g V is colourless transparent liquid, with II calculated yield 93%,
1the ratio of H-NMR collection of illustrative plates display V-keto-acid and V-enol form is approximately 1: 4 [ESI-MS m/z:[M+1]
+265.1;
1h-NMR (CDCl
3): (1) V-keto-acid: δ 2.34 (s, 3H, ArC
h 3), 2.41 (s, 3H, ArC
h 3), 3.77 (s, 3H, CO
2c
h 3), 3.81 (s, 3H, CO
2c
h 3), 5.29 (s, 1H, C
h(CO
2me)
2), 7.17-7.19 (m, 1H, Ar-H), 7.30-7.33 (d, 1H, Ar-H), 7.36-7.38 (d, 1H, Ar-H); (2) V-enol form: δ 2.28 (s, 3H, ArC
h 3), 2.32 (s, 3H, ArC
h 3), 3.42 (s, 3H, CO
2c
h 3), 3.91 (s, 3H, CO
2c
h 3), 7.04-7.12 (m, 2H, Ar-H), 7.20-7.22 (d, 1H, Ar-H), 13.37 (s, 1H, ArC (O
h)=C (CO
2me)
2) .]; Be dissolved in 7mL acetic acid, 2mL water by the crude product 10.50g of above-mentioned obtained V, add the 2mL vitriol oil, reflux was chilled to room temperature after 4 hours, and add the dilution of 40mL water, extract with ethyl acetate 100mL × 3, organic layer uses saturated NaHCO after merging successively
3the aqueous solution, saturated aqueous common salt respectively wash once, through anhydrous MgSO
4drying, pressure reducing and steaming solvent obtains 5.30g weak yellow liquid VI; Be dissolved in 20mL ethanol by above-mentioned obtained VI 4.0g, add 2.0g POTASSIUM BOROHYDRIDE, in stirred at ambient temperature reaction 6h, steaming desolventizes, and adds 12mL water dissolution resistates, extracts with ethyl acetate 50mL × 3, with saturated common salt water washing, anhydrous MgSO after organic layer merges
4drying, pressure reducing and steaming solvent obtains 3.29g colorless oil I, calculates synthesis I four-step reaction total recovery 80% altogether, can be directly used in follow-up synthesis with II.
Claims (2)
1.2-(2,3-dimethylbenzoyl) diester malonate, as shown in formula V,
Wherein R represents methyl or ethyl.
2. the preparation method of 2-described in claim 1 (2,3-dimethylbenzoyl) diester malonate, its reaction formula is as follows:
Wherein: R represents Me (methyl) or Et (ethyl),
It is characterized in that; with formula (II) Suo Shi 2; 3-mesitylenic acid is starting raw material; formula (III) shown 2 is made through chloride; after 3-dimethyl benzoyl chloride; 2-(2,3-dimethylbenzoyl) diester malonate shown in obtained formula (V) is reacted with diester malonate formula (IV) Suo Shi under triethylamine and Magnesium Chloride Anhydrous exist.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102976899A (en) * | 2012-12-21 | 2013-03-20 | 桂林理工大学 | Method for preparing medetomidine intermediate 1-(2, 3-xylyl) ethanol |
| CN103819339A (en) * | 2014-03-25 | 2014-05-28 | 杜承贤 | Preparation method of organic intermediate diethyl butyryl-propanedioate |
| CN105503565B (en) * | 2016-01-04 | 2017-10-13 | 浙江理工大学 | The one-pot synthesis method of one inter-species acetylbenzoic acid |
| CN109503469B (en) * | 2018-11-16 | 2020-08-04 | 浙江理工大学 | Preparation method of 2-acetylpyridine |
| CN111348996B (en) * | 2018-12-24 | 2023-09-08 | 江苏联化科技有限公司 | 2-benzoyl malonate compound, and preparation method and application thereof |
| WO2020132792A1 (en) * | 2018-12-24 | 2020-07-02 | 江苏联化科技有限公司 | 2-benzoyl malonate compound, preparation method therefor and application thereof |
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