CN104829444A - Post-treatment method of [alpha]-bromotricycle[3.3.1.13,7]decane-1-acetic acid - Google Patents
Post-treatment method of [alpha]-bromotricycle[3.3.1.13,7]decane-1-acetic acid Download PDFInfo
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- CN104829444A CN104829444A CN201410048194.2A CN201410048194A CN104829444A CN 104829444 A CN104829444 A CN 104829444A CN 201410048194 A CN201410048194 A CN 201410048194A CN 104829444 A CN104829444 A CN 104829444A
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- decane
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- acetic acid
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Abstract
The invention provides a post-treatment method of [alpha]-bromo-tricycle[3.3.1.13,7]decane-1-acetic acid. The method includes following steps: (1) concentrating a [alpha]-bromo-tricycle[3.3.1.13,7]decane-1-acetic acid reaction liquid prepared through a method in the prior art to form a white solid; (2) heating the white solid in a solvent to dissolve the white solid, performing cooling crystallization when the solution is clarified, and filtering and drying the solution to obtain pure [alpha]-bromo-tricycle[3.3.1.13,7]decane-1-acetic acid solid; and finally (3) concentrating the mother solution obtained through the filtration in the step (2) to obtain a solid, heating the solid to dissolve the solid, and performing cooling crystallization when the solution is clarified to obtain the pure [alpha]-bromo-tricycle[3.3.1.13,7]decane-1-acetic acid. The method is increased in yield, is reduced in waste gas, waste water and solid waste, is simplified in processes and is beneficial to industrialized production.
Description
Technical field
The present invention relates to alpha-brominated three ring [3.3.1.1
3,7] preparation method's technical field of decane-1-acetic acid.
Background technology
In patent (CN1791401) with 1-adamantane acetic acid for raw material is through thionyl chloride, N-bromo-succinimide (NBS), finally hydrolysis obtains object product alpha-brominated three ring [3.3.1.1
3,7] decane-1-acetic acid.Hydrolysis reaction occurs in tetrahydrofuran (THF) (THF), is guaranteeing that hydrolysis reaction occurs completely, for the alpha-brominated three ring [3.3.1.1 of compound
3,7] aftertreatment of decane-1-acetic acid, the method that patent (CN1791401) is taked is distilled by THF, obtains (water and oil) two-phase mixture, then add crystal seed, and make temperature of reaction reach room temperature, there is coarse grain.Add water and acetonitrile, the above-mentioned suspension of stirred at ambient temperature 2 hours, by solid filtering, and uses acetonitrile wash.This filtrate contains first object product, dry under room temperature, productive rate 66%.Then grind mother liquor (1-2 hour) with water and acetonitrile under room temperature, then filter, make the second batch product (16%) of solid drying.
The shortcoming that the method exists: 1) productive rate is lower, is 82%, can reach 92% after aftertreatment improves; 2) need a large amount of price that uses higher, the larger acetonitrile of toxicity is as solvent (often produce 1kg product and need 3.82L acetonitrile), and used in combination with water, and be unfavorable for direct recycling, solvent utilization ratio is low; 3) complex operation, need distill and obtain water, oily two-phase, add crystal seed, when obtaining second batch object product, need grind mother liquor.
Summary of the invention
Object of the present invention solves prior art problem exactly, provides one to improve productive rate, reduces the three wastes, simplifies operation, is beneficial to the alpha-brominated three ring [3.3.1.1 of suitability for industrialized production
3,7] post-treating method of decane-1-acetic acid.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
A kind of alpha-brominated three ring [3.3.1.1
3,7] post-treating method of decane-1-acetic acid, comprise the steps:
1) the alpha-brominated three ring [3.3.1.1 existing method prepared
3,7] decane-1-acetic acidreaction liquid (containing THF, water, alpha-brominated three ring [3.3.1.1
3,7] decane-1-acetic acid) be concentrated into white solid;
2) be heated to by the white solid that step 1) obtains in a solvent dissolve, solution becomes cooling crystallization after clarification, filters, dry pure alpha-brominated three ring [3.3.1.1
3,7] decane-1-acetic acid solid;
3) by step 2) filter after mother liquor concentrations to solid, be heated to dissolve, solution become clarification after cooling crystallization, obtain pure alpha-brominated three ring [3.3.1.1
3,7] decane-1-acetic acid solid.
Above-mentioned alpha-brominated three ring [3.3.1.1
3,7] post-treating method of decane-1-acetic acid, described solvent refers to ethyl acetate (EtOAc), methyl acetate, methyl-formiate, ethyl formate, propyl formate, methyl propionate, methylene dichloride, tetrahydrofuran (THF), methyl alcohol, ethanol equal solvent.All processes is not all the solvent having the toxicity such as acetonitrile higher.
Above-mentioned alpha-brominated three ring [3.3.1.1
3,7] post-treating method of decane-1-acetic acid, the mode of the water-oil bath reflux of 30-95 DEG C can be adopted during described heating for dissolving.
Beneficial effect of the present invention:
The present invention is at the alpha-brominated three ring [3.3.1.1 of preparation
3,7] take the post-treating method of recrystallization after decane-1-acetic acid, compared with the conventional method, its technical progress is the method:
1) by three ring [3.3.1.1 alpha-brominated in existing treatment process
3,7] productive rate of decane-1-acetic acid is increased to 92% by 82%, and improves raw material and solvent utilization ratio simultaneously;
2) with ethyl acetate, tetrahydrofuran (THF), n-propyl formate, methyl alcohol etc. replace acetonitrile, and not only price is low, and toxicity is also much lower, and can directly recycle, and greatly reduces the three wastes and production cost;
3) the present invention has operationally deducted the operation of adding crystal seed and grinding mother liquor, makes program in the industrial production simple, easy to operate, is more suitable for suitability for industrialized production.
Illustrate content of the present invention further below in conjunction with embodiment, these embodiments are not the restrictions to the scope of the invention and spirit.
Embodiment
Alpha-brominated three ring [3.3.1.1 are prepared according to the method for patent documentation (CN1791401) 63-64 page embodiment 17
3,7] decane-1-acetic acid:
Raw material 1-adamantane acetic acid 288g drops in 3000mL four-hole boiling flask and reacts, and through three steps, chloride, bromo, hydrolysis obtain object product.The present embodiment is taked and existing patent documentation diverse ways in the aftertreatment of product:
Embodiment 1
1) will be hydrolyzed completely reaction solution (containing THF, water, alpha-brominated three ring [3.3.1.1
3,7] decane-1-acetic acid) be at room temperature concentrated into drying with Rotary Evaporators 35 DEG C-65 DEG C, obtain white solid;
2) with ethyl acetate (EtOAc) for solvent, water-oil bath 35-85 DEG C of heating in 1000mL four-hole boiling flask, backflow is dissolved, use ethyl acetate 250-500mL altogether, solution becomes clarification, is cooled to room temperature, add ice bath to spend the night, crystallization, filters, dry white solid product 318.4g (80%);
3) Rotary Evaporators under the mother liquor room temperature after filtration is concentrated into drying, water-oil bath 35-85 DEG C of heating, backflow is dissolved, use ethyl acetate 35-65mL altogether, solution becomes clarification, is again cooled to room temperature, ice bath spends the night, crystallization, obtains white solid product 52.3g (12%).
Embodiment 2
1) raw material 1-adamantane acetic acid 250g drops into 3000mL four-hole boiling flask, through three steps, chloride, bromo, hydrolysis obtain containing THF, water, alpha-brominated three ring [3.3.1.1
3,7] reaction solution of decane-1-acetic acid, be then at room temperature concentrated into drying, white solid with Rotary Evaporators 35-65 DEG C;
2) take tetrahydrofuran (THF) as solvent, water-oil bath 30-80 DEG C of heating in 1000mL four-hole boiling flask, backflow is dissolved, and uses solvent 200-450mL altogether, solution becomes clarification, after being cooled to room temperature, adding ice bath and spends the night, crystallization, filters, dry white solid product 270.9g (77%);
3) Rotary Evaporators 35-65 DEG C under the mother liquor room temperature after filtration is concentrated into drying, water-oil bath 30-80 DEG C of heating, backflow is dissolved, and uses solvent 30-70mL altogether, solution becomes clarification, is again cooled to room temperature, adds ice bath and spend the night, crystallization, filters, obtains white solid product 52.8g (15%)
Embodiment 3
1) raw material 1-adamantane acetic acid 250g drops into 3000mL four-hole boiling flask, through three steps, chloride, bromo, hydrolysis obtain containing THF, water, alpha-brominated three ring [3.3.1.1
3,7] reaction solution of decane-1-acetic acid, be then at room temperature concentrated into drying, white solid with Rotary Evaporators 35-65 DEG C;
2) take n-propyl formate as solvent, water-oil bath 30-95 DEG C of heating in 1000mL four-hole boiling flask, backflow is dissolved, and uses solvent 250-500mL altogether, solution becomes clarification, after being cooled to room temperature, adding ice bath and spends the night, crystallization, filters, dry white solid product 274.4g (78%);
3) Rotary Evaporators 35-65 DEG C under the mother liquor room temperature after filtration is concentrated into drying, water-oil bath 30-95 DEG C of heating, backflow is dissolved, and uses solvent 30-70mL altogether, solution becomes clarification, is again cooled to room temperature, adds ice bath and spend the night, crystallization, filters, obtains white solid product 49.2g (14%)
Embodiment 4
1) raw material 1-adamantane acetic acid 250g drops into 3000mL four-hole boiling flask, through three steps, chloride, bromo, hydrolysis obtain containing THF, water, alpha-brominated three ring [3.3.1.1
3,7] reaction solution of decane-1-acetic acid, be then at room temperature concentrated into drying, white solid with Rotary Evaporators 35-65 DEG C;
2) take methyl alcohol as solvent, water-oil bath 30-95 DEG C of heating in 1000mL four-hole boiling flask, backflow is dissolved, and uses solvent 200-450mL altogether, solution becomes clarification, after being cooled to room temperature, adding ice bath and spends the night, crystallization, filters, dry white solid product 277.9g (79%);
3) Rotary Evaporators 35-65 DEG C under the mother liquor room temperature after filtration is concentrated into drying, water-oil bath 30-95 DEG C of heating, backflow is dissolved, and uses solvent 30-70mL altogether, solution becomes clarification, is again cooled to room temperature, adds ice bath and spend the night, crystallization, filters, obtains white solid product 45.7g (13%).
Claims (3)
1. alpha-brominated three ring [3.3.1.1
3,7] post-treating method of decane-1-acetic acid, comprise the steps:
1) the alpha-brominated three ring [3.3.1.1 existing method prepared
3,7] decane-1-acetic acidreaction liquid (containing THF, water, alpha-brominated three ring [3.3.1.1
3,7] decane-1-acetic acid) be concentrated into solid;
2) be heated to by the white solid that step 1) obtains in a solvent dissolve, solution becomes cooling crystallization after clarification, filters, dry pure alpha-brominated three ring [3.3.1.1
3,7] decane-1-acetic acid solid;
3) by step 2) filter after mother liquor concentrations to solid, be heated to dissolve, solution become clarification after cooling crystallization, obtain pure alpha-brominated three ring [3.3.1.1
3,7] decane-1-acetic acid solid.
2. alpha-brominated three ring [3.3.1.1 as claimed in claim 1
3,7] post-treating method of decane-1-acetic acid, it is characterized in that described solvent is ethyl acetate, methyl acetate, methyl-formiate, ethyl formate, propyl formate, methyl propionate, methylene dichloride, tetrahydrofuran (THF), methyl alcohol or ethanol.
3. alpha-brominated three ring [3.3.1.1 as claimed in claim 1
3,7] post-treating method of decane-1-acetic acid, adopt the mode of the water-oil bath reflux of 30-95 DEG C when it is characterized in that described heating for dissolving.
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| CN201410048194.2A CN104829444A (en) | 2014-02-12 | 2014-02-12 | Post-treatment method of [alpha]-bromotricycle[3.3.1.13,7]decane-1-acetic acid |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH594603A5 (en) * | 1974-05-16 | 1978-01-13 | Pliva Pharm & Chem Works | |
| CN1791401A (en) * | 2002-12-09 | 2006-06-21 | 布里斯托尔-迈尔斯斯奎布公司 | Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
| CN101531583A (en) * | 2009-02-26 | 2009-09-16 | 泸州万联化工有限公司 | Method for the synthesis of alpha-bromoadamantane acetic acid at high yield |
| WO2013179297A1 (en) * | 2012-05-30 | 2013-12-05 | Rao Davuluri Ramamohan | Process for preparation of (1s, 3s, 5s)-2-[(2s)-2-amino-2-(3-hydroxy-1-adamantyl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile |
-
2014
- 2014-02-12 CN CN201410048194.2A patent/CN104829444A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH594603A5 (en) * | 1974-05-16 | 1978-01-13 | Pliva Pharm & Chem Works | |
| CN1791401A (en) * | 2002-12-09 | 2006-06-21 | 布里斯托尔-迈尔斯斯奎布公司 | Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
| CN102070451A (en) * | 2002-12-09 | 2011-05-25 | 布里斯托尔-迈尔斯斯奎布公司 | Methods and compounds producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
| CN101531583A (en) * | 2009-02-26 | 2009-09-16 | 泸州万联化工有限公司 | Method for the synthesis of alpha-bromoadamantane acetic acid at high yield |
| WO2013179297A1 (en) * | 2012-05-30 | 2013-12-05 | Rao Davuluri Ramamohan | Process for preparation of (1s, 3s, 5s)-2-[(2s)-2-amino-2-(3-hydroxy-1-adamantyl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile |
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