CN103467296B - The preparation method of the bromo-4-HBA methyl esters of a kind of 3- - Google Patents
The preparation method of the bromo-4-HBA methyl esters of a kind of 3- Download PDFInfo
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- CN103467296B CN103467296B CN201210188821.3A CN201210188821A CN103467296B CN 103467296 B CN103467296 B CN 103467296B CN 201210188821 A CN201210188821 A CN 201210188821A CN 103467296 B CN103467296 B CN 103467296B
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Abstract
The invention discloses the preparation method of the bromo-4-HBA methyl esters of a kind of 3-as shown in Equation 2, it comprises the following step: in halogenated alkanes solvents and/or ether solvent, take Glacial acetic acid as catalyzer, by compound 1 and Br
2carry out bromo-reaction as follows; The temperature of described reaction is-10 DEG C ~ 50 DEG C.Preparation method's solvent load of the present invention is few, simple to operate, and aftertreatment is easy, and yield is high, is suitable for suitability for industrialized production.
Description
Technical field
The present invention is specifically related to the preparation method of the bromo-4-HBA methyl esters of a kind of 3-.
Background technology
3-bromo-4-HBA methyl esters is the important intermediate preparing many medicines.The synthesis of the bromo-4-HBA methyl esters of 3-is normally raw material by methyl p-hydroxybenzoate, obtain with bromine reaction, because two ortho positions of hydroxyl are more active, the two bromo by product of easy generation, therefore in reaction except containing 3-bromo-4-HBA methyl esters list bromo-derivative, also containing the bromo-4-HBA methyl esters of 3,5-bis-.
How to improve the productive rate of the bromo-4-HBA methyl esters of 3-, have many documents and patent report, as Kikushima, Kotaro; Moriuchi, Toshiyuki; Hirao, Toshikazu.Tetrahedron, 2010,66 (34): 6906-6911, adopt AlBr
3for bromizating agent, NH
4vO
3for catalyzer, dioxane is solvent, passes into oxygen reaction, and the main drawback of the method uses reagent more malicious, NH
4vO
3indissoluble solution, needs comparatively high temps, complicated operation, and aftertreatment bothers.
US20110098271 and Basabe, Pilar; Diego, Alberto; Delgado, Sergio; Etal; Etal.Tetrahedron.2003, the method of 59 (46): 9173-9177 reports is that bromine reacts 24h as reactant in methylene dichloride, the main drawback of the method is that raw material P-hydroxybenzoic acid first is not dissolved in methylene dichloride, reaction is carried out in two-phase, mix uneven, reaction is not easy to carry out.
Also document is had to adopt HBr and H
2o
2acetic acid is the method that raw material and methyl p-hydroxybenzoate react in water, as Koini, EftychiaN.; Alvonitis, Nicolaos; Calogeropoulou, TheodoraSynlett.2011, (11): 1537-1542, we repeat the method, but reaction yield is lower.
Uwabe, Shin-itsu; Torraca, KarenE.; Buchwald, StephenLJournaloftheAmericanChemicalSociety.2001,123 (49): 12202-12206 use poisonous reagent chloroform as solvent.
WO2005030192, Esumi, Tomoyuki; Makado, Gouki; Zhai, Haifeng; Shimizu, Yasuhiro; Mitsumoto, Yasuhide; Fukuyama, Yoshiyasu.Bioorganic & MedicinalChemistryLetters.2004,14 (10): 2621-2625 and Oberhauser, Thomas, JournalofOrganicChemistry.1997, the method for 62 (13): 4504-4506 reports is with HBF
4, NBS does raw material, and acetonitrile prepares the bromo-4-HBA methyl esters of 3-as solvent, and main drawback is toxic solvent, and production cost is high.
Summary of the invention
Technical problem to be solved by this invention is in the preparation method in order to overcome the bromo-4-HBA methyl esters of existing 3-, reaction yield is low, complicated operation, solvent toxicity large, high in cost of production defect, and provides the preparation method of the bromo-4-HBA methyl esters of a kind of 3-.Preparation method's solvent load of the present invention is few, simple to operate, and aftertreatment is easy, and yield is high, is suitable for suitability for industrialized production.
The invention provides the preparation method of the bromo-4-HBA methyl esters of a kind of 3-as shown in Equation 2, it comprises the following step: in halogenated alkanes solvents and/or ether solvent, take Glacial acetic acid as catalyzer, by compound 1 and Br
2carry out bromo-reaction as follows; The temperature of described reaction is-10 DEG C ~ 50 DEG C;
In the present invention, described halogenated alkanes solvents is preferably methylene dichloride and/or chloroform.Described ether solvent is preferably ether and/or Isosorbide-5-Nitrae-dioxane.The volume mass of halogenated alkanes solvents and/or ether solvent and compound 1 is 25 ~ 40ml/g than preferably.
Described Br
2can bromine form participate in reaction.
Described compound 1, Br
2be preferably 1.0 with the mol ratio of Glacial acetic acid: (1.0 ~ 1.2): (1.0 ~ 1.2), better is 1.0: 1.1: 1.1.
The temperature of described reaction is preferably 10 DEG C ~ 40 DEG C, and better is 15 DEG C ~ 35 DEG C, and best is 20 ~ 30 DEG C.
Till time of described reaction no longer can be carried out by detection reaction.
In the present invention, each step of described preparation method can be determined by the Conventional wisdom of those skilled in the art, described preparation method preferably comprises the following step: in the mixed solution of halogenated alkanes solvents and/or ether solvent, compound 1 and Glacial acetic acid, drip bromine, in dropping process, the temperature of mixed solution controls at-10 DEG C ~ 5 DEG C (preferably-5 DEG C ~ 5 DEG C), after dropwising, react at 10 DEG C ~ 40 DEG C.
Wherein, described halogenated alkanes solvents is preferably methylene dichloride and/or chloroform.Described ether solvent is preferably ether and/or Isosorbide-5-Nitrae-dioxane.The volume mass of halogenated alkanes solvents and/or ether solvent and compound 1 is 25 ~ 40ml/g than preferably.
In above-mentioned preferred steps, the mol ratio of described compound 1, bromine and Glacial acetic acid is preferably 1.0: (1.0 ~ 1.2): (1.0 ~ 1.2), better is 1.0: 1.1: 1.1.
In above-mentioned preferred steps, described is preferably 15 DEG C ~ 35 DEG C 10 DEG C ~ 40 DEG C temperature of carrying out reacting, and better is 20 ~ 30 DEG C.
In above-mentioned preferred steps, time of described reaction is generally 24 hours ~ 35 hours, preferably 32 hours till no longer can being carried out by detection reaction.
In preparation method of the present invention, after reaction terminates, the further refined product of simple aftertreatment can be adopted, as extraction go out, extract, wash, drying, concentrate, recrystallization, the product that purity is very high can be obtained.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is: preparation method's solvent load of the present invention is few, simple to operate, and aftertreatment is easy, and yield is high, is suitable for suitability for industrialized production.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Room temperature in following each embodiment refers to 20 ~ 30 DEG C.
Embodiment 1:
Glacial acetic acid (90ml is added in the methylene dichloride (300ml) of methyl p-hydroxybenzoate (21.42g, 0.148mol, 1eq), 0.155mol, 1.1eq), be stirred to and dissolve completely, ice bath cools to less than 5 DEG C, bromine (8.0ml, 0.155mol, 1.1eq) is slowly dripped in reaction mixture, drip process control temp at 0 ~ 5 DEG C, dropwise, room temperature reaction 32h, in reaction process, receive HBr tail gas.After reaction terminates, in reaction solution, add Na
2s
2o
3the aqueous solution (35.2g, 264ml), stir 1h, then add methyl alcohol (200ml), extraction, which floor has wash 2 times with water, and saturated sodium-chloride washes 1 time, anhydrous sodium sulfate drying, vacuum concentration obtains white solid, with toluene (4: 1) recrystallization, obtain white solid 20.4g, productive rate 78.2%.Fusing point: 105.8 ~ 106.7, MS (ESI
-): [M-H]
-: 228.95, HPLC:98.7%.
Embodiment 2
Glacial acetic acid (5ml is added in the methylene dichloride (45ml) of methyl p-hydroxybenzoate (1.19g, 7.8mmol, 1eq), 7.88mmol, 1.1eq), be stirred to and dissolve completely, ice bath cools to less than 5 DEG C, bromine (0.4ml, 7.88mmol, 1.1eq) is slowly dripped in reaction mixture, drip process control temp at 0 ~ 5 DEG C, dropwise, room temperature reaction 35h, in reaction process, receive HBr tail gas.After reaction terminates, in reaction solution, add Na
2s
2o
3the aqueous solution (2.32g, 40ml), stir 1h, then add methyl alcohol (20ml), extraction, which floor has wash 2 times with water, and saturated sodium-chloride washes 1 time, anhydrous sodium sulfate drying, vacuum concentration obtains white or light yellow solid, with toluene (4: 1) recrystallization, obtain white solid 1.24g, productive rate 77.5%.Fusing point: 105.8 ~ 106.7, HPLC:98.2%.
Embodiment 3
Glacial acetic acid (30ml is added in the methylene dichloride (180ml) of methyl p-hydroxybenzoate (7.14g, 0.0468mol, 1eq), 0.0515mol, 1.1eq), be stirred to and dissolve completely, ice bath cools to less than 5 DEG C, bromine (2.6ml, 0.0515mol, 1.1eq) is slowly dripped in reaction mixture, drip process control temp at 0 ~ 5 DEG C, dropwise, room temperature reaction 24h, in reaction process, receive HBr tail gas.After reaction terminates, in reaction solution, add Na
2s
2o
3the aqueous solution (27.8g, 264ml), stir 1h, then add methyl alcohol (120ml), extraction, which floor has wash 2 times with water, and saturated sodium-chloride washes 1 time, anhydrous sodium sulfate drying, vacuum concentration obtains white, with toluene (4: 1) recrystallization, obtain white solid 7.36g, productive rate 73.4%.Fusing point: 105.8 ~ 106.7, HPLC:98.7%
Embodiment 4
Glacial acetic acid (90ml is added in the chloroform (300ml) of methyl p-hydroxybenzoate (21.42g, 0.148mol, 1eq), 0.155mol, 1.1eq), be stirred to and dissolve completely, cool to-10 DEG C, bromine (8.0ml, 0.155mol, 1.1eq) is slowly dripped in reaction mixture, drip process control temp at-10 DEG C, dropwise ,-10 DEG C of reaction 32h, receive HBr tail gas in reaction process.After reaction terminates, in reaction solution, add Na
2s
2o
3the aqueous solution (35.2g, 264ml), stir 1h, then add methyl alcohol (200ml), extraction, which floor has wash 2 times with water, and saturated sodium-chloride washes 1 time, anhydrous sodium sulfate drying, vacuum concentration obtains white solid, with toluene (4: 1) recrystallization, obtain white solid 20.4g, productive rate 78.2%.Fusing point: 105.8 ~ 106.7, MS (ESI
-): [M-H]
-: 228.95, HPLC:98.7%
Embodiment 5
To 1 of methyl p-hydroxybenzoate (15.215g, 0.1mol, 1eq), Glacial acetic acid (63ml, 0.11mol, 1.1eq) is added in 4 dioxane (150ml), be stirred to and dissolve completely, ice bath cools to less than 5 DEG C, in reaction mixture, slowly drip bromine (5.12ml, 0.11mol, 1.1eq), drip process control temp at 0 ~ 5 DEG C, dropwise, 50 DEG C of reaction 32h, receive HBr tail gas in reaction process.After reaction terminates, in reaction solution, add Na
2s
2o
3the aqueous solution (27.3g, 264ml), stir 1h, then add methyl alcohol (150ml), extraction, which floor has wash 2 times with water, and saturated sodium-chloride washes 1 time, anhydrous sodium sulfate drying, vacuum concentration obtains white solid, with toluene (4: 1) recrystallization, obtain white solid 16.7g, productive rate 72.2%.Fusing point: 105.8 ~ 106.7, MS (ESI
-): [M-H]
-: 228.95, HPLC:98.7%
Comparative example
To methyl p-hydroxybenzoate (7.14g, 0.0468mol, methylene dichloride (180ml) 1eq), ice bath cools to less than 5 DEG C, in reaction mixture, slowly drip bromine (2.6ml, 0.0515mol, 1.1eq), drip process control temp at 0 ~ 5 DEG C, dropwise, room temperature reaction 32h, receives HBr tail gas in reaction process.After reaction terminates, in reaction solution, add Na
2s
2o
3the aqueous solution (27.8g, 264ml), stir 1h, then add methyl alcohol (120ml), extraction, organic layers with water washes 2 times, and saturated sodium-chloride washes 1 time, anhydrous sodium sulfate drying, and it is raw material, almost unreacted that vacuum concentration obtains white solid.
Claims (3)
1. a preparation method for the bromo-4-HBA methyl esters of 3-as shown in Equation 2, is characterized in that comprising the following step:
Glacial acetic acid 0.155mol is added in the methylene dichloride 300ml of methyl p-hydroxybenzoate 0.148mol, be stirred to and dissolve completely, ice bath cools to less than 5 DEG C, slowly bromine 0.155mol is dripped in reaction mixture, drip process control temp at 0 ~ 5 DEG C, dropwise, room temperature reaction 32h, in reaction process, receive HBr tail gas; After reaction terminates, in reaction solution, add Na
2s
2o
3aqueous solution 35.2g, stir 1h, then add methyl alcohol 200ml, extraction, organic layers with water washes 2 times, and saturated sodium-chloride washes 1 time, anhydrous sodium sulfate drying, and vacuum concentration obtains white solid, with toluene 4:1 recrystallization, obtains white solid 20.4g, productive rate 78.2%.
2. the preparation method of the bromo-4-HBA methyl esters of 3-, it is characterized in that comprising the following step: in the methylene dichloride 45ml of methyl p-hydroxybenzoate 7.8mmol, add Glacial acetic acid 7.88mmol, be stirred to and dissolve completely, ice bath cools to less than 5 DEG C, in reaction mixture, slowly drip bromine 7.88mmol, drip process control temp at 0 ~ 5 DEG C, dropwise, room temperature reaction 35h, receives HBr tail gas in reaction process; After reaction terminates, in reaction solution, add Na
2s
2o
3aqueous solution 2.32g, stir 1h, then add methyl alcohol 20ml, extraction, organic layers with water washes 2 times, and saturated sodium-chloride washes 1 time, anhydrous sodium sulfate drying, and vacuum concentration obtains white or light yellow solid, with toluene 4:1 recrystallization, obtain white solid 1.24g, productive rate 77.5%.
3. the preparation method of the bromo-4-HBA methyl esters of 3-, it is characterized in that comprising the following step: in the chloroform 300ml of methyl p-hydroxybenzoate 0.148mol, add Glacial acetic acid 0.155mol, be stirred to and dissolve completely, cool to-10 DEG C, in reaction mixture, slowly drip bromine 0.155mol, drip process control temp at-10 DEG C, dropwise,-10 DEG C of reaction 32h, receive HBr tail gas in reaction process; After reaction terminates, in reaction solution, add Na
2s
2o
3aqueous solution 35.2g, stir 1h, then add methyl alcohol 200ml, extraction, organic layers with water washes 2 times, and saturated sodium-chloride washes 1 time, anhydrous sodium sulfate drying, and vacuum concentration obtains white solid, with toluene 4:1 recrystallization, obtains white solid 20.4g, productive rate 78.2%.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0208447A1 (en) * | 1985-06-21 | 1987-01-14 | Richter Gedeon Vegyeszeti Gyar R.T. | Use of compositions for the manufacture of a medicament for the treatment of psychiatric disorders |
CN101225045A (en) * | 2008-01-31 | 2008-07-23 | 浙江科技学院 | Micro-wave synthetic method for preparing methyl salicylate |
CN101786954A (en) * | 2009-10-09 | 2010-07-28 | 李松伦 | Preparation method of butyl p-hydroxybenzoate |
-
2012
- 2012-06-08 CN CN201210188821.3A patent/CN103467296B/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0208447A1 (en) * | 1985-06-21 | 1987-01-14 | Richter Gedeon Vegyeszeti Gyar R.T. | Use of compositions for the manufacture of a medicament for the treatment of psychiatric disorders |
CN101225045A (en) * | 2008-01-31 | 2008-07-23 | 浙江科技学院 | Micro-wave synthetic method for preparing methyl salicylate |
CN101786954A (en) * | 2009-10-09 | 2010-07-28 | 李松伦 | Preparation method of butyl p-hydroxybenzoate |
Non-Patent Citations (3)
Title |
---|
3-溴-4-羟基-5-甲氧基苯甲酸甲酯的合成;闫慧丽等;《科学技术与工程》;20110228;第11卷(第5期);第1671-1815页 * |
Short and efficient synthesis of (1)-subersic acids;Pilar Basabe 等;《Tetrahedron 》;20031231;第59卷;第9173–9177页 * |
苯酚一元溴化的定位效应;黄青山等;《河北化工》;20031231(第6期);第25页 * |
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