CN109988064B - Selective cyclization method of pseudo ionone - Google Patents
Selective cyclization method of pseudo ionone Download PDFInfo
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
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Abstract
The invention provides a selective cyclization method of pseudo ionone, which is characterized by comprising the following raw materials: 20-35 parts of concentrated sulfuric acid, 15-25 parts of phosphorus pentoxide, 10-15 parts of petroleum ether, 5-8 parts of methanol and 25-40 parts of pseudo ionone. The invention adds a mixture of concentrated sulfuric acid and phosphorus pentoxide in a certain proportion as a cyclization agent into the rectified pseudo-ionone, adds petroleum ether and methanol as solvents, and uniformly stirs at low temperature, so that the selectivity of beta-ionone in the cyclization process is obviously increased, the content reaches more than 97 percent, and the separation difficulty is reduced.
Description
Technical Field
The invention belongs to the field of chemical industry, and relates to a technology for increasing the selectivity of main reaction in the preparation process, in particular to a technology for increasing the selectivity of main reaction for a drug intermediate with high purity requirement, such as beta-ionone.
Background
The current methods for cyclizing pseudoionone in the cyclization process include the following methods:
1.98% concentrated sulfuric acid (density 1.84g/mL), the temperature can not be lower than-20 ℃ (mixed with petroleum ether), otherwise the concentrated sulfuric acid will solidify, the selectivity of beta-ionone in the cyclization does not exceed 85%, and great difficulty is brought to the subsequent separation and purification.
2.85% concentrated phosphoric acid (density 1.84), the temperature can not be lower than-10 ℃ (mixed with petroleum ether), otherwise the concentrated phosphoric acid will solidify, the selectivity of beta-ionone in the cyclization does not exceed 55%, which brings great difficulty to the subsequent separation and purification and can only be used as spice.
As a medical intermediate for preparing vitamin A, the purity of beta-ionone must reach 94%, the higher the selectivity of beta-ionone in production and synthesis is, the easier the separation and purification is, the higher the yield is, the selectivity is improved by one percentage point in synthesis, and finally the yield is improved by at least five percentage points (within the range of 90-99%). Otherwise, it can only be discarded or used as a much less expensive perfume raw material, causing significant losses.
Disclosure of Invention
The invention aims to provide a selective cyclization method of pseudo-ionone to improve the yield of beta-ionone.
In order to achieve the aim, the invention provides a selective cyclization method of pseudo ionone, which is characterized in that the raw materials comprise:
preferably, the raw materials of the selective cyclization method of the pseudoionone also comprise dry ice, and the raw materials are properly added according to the temperature in the reaction kettle and higher than-30 ℃.
Preferably, the petroleum ether has a boiling point of 30-60 ℃. The petroleum ether contains various pentanes, hexanes and the like.
Preferably, the concentration of the concentrated sulfuric acid is 96-98%.
Preferably, the specific steps of the selective cyclization method of pseudo-ionone comprise:
step 1: dissolving 15-25 parts by weight of phosphorus pentoxide into 20-35 parts by weight of concentrated sulfuric acid, stirring and mixing, pumping the mixture into a reaction kettle, adding 5-8 parts by weight of methanol and 8-10 parts by weight of petroleum ether, and cooling to-30-35 ℃ under stirring;
step 2: adding petroleum ether into 25-40 parts by weight of pseudo ionone to obtain a mixture, wherein the sum of the petroleum ether and the petroleum ether in the step 1 is 10-15 parts by weight, and dropwise adding the obtained mixture into a reaction kettle;
and step 3: and after the dropwise addition is finished, continuing stirring for 5-15 minutes, gradually heating to-5-15 ℃, then putting the mixture obtained by the reaction into ice water which is added with petroleum ether and has the temperature of-8-12 ℃, stirring and extracting, wherein the volume ratio of the petroleum ether to the ice water is 1: and 5-15, separating the liquid, and evaporating the solvent petroleum ether from the obtained organic phase to obtain the beta-ionone.
Preferably, during the dropping process of the step 2, the temperature is controlled not to exceed-30 ℃.
Preferably, in the step 2, if the temperature exceeds-30 ℃ in the dropping process, the dropping is stopped, and dry ice is added to reduce the temperature to below-30 ℃.
Preferably, the ice water in step 3 contains 30-50% of sulfuric acid.
Preferably, the ice water in the step 3 is the water phase obtained by the liquid separation in the step 3 in the previous preparation method of the beta-ionone, and contains 30-50% of sulfuric acid, so that the wastewater discharge is reduced and the energy is saved.
The mixture of concentrated sulfuric acid and phosphorus pentoxide can remove one molecule of water in pseudo-ionone with high efficiency, so that molecules are cyclized, the probability of cyclizing beta-ionone at low temperature is high, the freezing point of the concentrated sulfuric acid mixture can be reduced by adding methanol, the concentrated sulfuric acid mixture is kept in a liquid state at low temperature and is fully contacted and reacted with the pseudo-ionone, and the addition of dry ice can ensure that the low temperature is maintained in the reaction process (the reaction is strongly exothermic) and impurities are not mixed (the dry ice is completely volatilized by heating).
Compared with the prior art, the invention has the beneficial effects that:
the invention adds a mixture of concentrated sulfuric acid and phosphorus pentoxide in a certain proportion as a cyclization agent into the rectified pseudo-ionone, adds petroleum ether and methanol as solvents, and uniformly stirs at low temperature, so that the selectivity of beta-ionone in the cyclization process is obviously increased, the content reaches more than 97 percent, and the separation difficulty is reduced.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
Each raw material used in the following examples is a commercially available product.
Example 1
A selective cyclization method of pseudo ionone comprises the following raw materials: concentrated sulfuric acid (98%, density 1.84g/mL), phosphorus pentoxide, petroleum ether (boiling point 30-60 deg.C), methanol, pseudoionone, the specific amounts are shown in Table 1.
The method for selective cyclization of the pseudo ionone comprises the following specific steps:
step 1: dissolving 15Kg of phosphorus pentoxide into 22Kg of concentrated sulfuric acid, stirring and mixing, pumping the mixture into a reaction kettle, adding 8Kg of methanol and 8Kg of petroleum ether, stirring and cooling to-30 to-35 ℃, and stirring at the rotation speed of 200-;
step 2: adding petroleum ether into 40Kg of pseudo-ionone to obtain a mixture, wherein the sum of the petroleum ether and the petroleum ether in the step 1 is 15Kg, and dropwise adding the obtained mixture into a reaction kettle; paying attention to the temperature rise condition, if the temperature exceeds-30 ℃, stopping dripping and adding dry ice to reduce the temperature;
and step 3: after the dropwise addition, the mixture is continuously stirred for 10 minutes, the temperature is gradually increased to-10 ℃, then the mixture obtained by the reaction is put into 1000L of ice water (containing 30-50% of sulfuric acid) with petroleum ether and at the temperature of-10 ℃, the water phase obtained by the liquid separation in the step 3 in the previous batch of preparation method of beta-ionone is adopted, and the volume ratio of the petroleum ether to the ice water is 1: 10, separating the liquid, and evaporating the solvent petroleum ether from the obtained organic phase to obtain the beta-ionone. The chromatogram showed a content of 98.1% (deduction of the solvent petroleum ether).
Example 2
A selective cyclization method of pseudo ionone comprises the following raw materials: concentrated sulfuric acid (98%, density 1.84g/mL), phosphorus pentoxide, petroleum ether (boiling point 30-60 deg.C), methanol, pseudoionone, the specific amounts are shown in Table 1.
The method for selective cyclization of the pseudo ionone comprises the following specific steps:
step 1: dissolving 25Kg of phosphorus pentoxide into 25g of concentrated sulfuric acid, stirring and mixing, pumping the mixture into a reaction kettle, adding 7Kg of methanol and 10Kg of petroleum ether, stirring and cooling to-30 to-35 ℃, and stirring at the rotation speed of 200-;
step 2: adding petroleum ether into 28Kg of pseudo ionone to obtain a mixture, wherein the sum of the petroleum ether and the petroleum ether in the step 1 is 15Kg, and dropwise adding the obtained mixture into a reaction kettle; paying attention to the temperature rise condition, if the temperature exceeds-30 ℃, stopping dripping and adding dry ice to reduce the temperature;
and step 3: after the dropwise addition, the mixture is continuously stirred for 10 minutes and heated to-10 ℃, and then the mixture obtained by the reaction is put into 1000L of ice water (containing 30-50% of sulfuric acid) with petroleum ether and at the temperature of-10 ℃, wherein the water phase obtained by liquid separation in the step 3 in the previous preparation method of the beta-ionone is adopted, and the volume ratio of the petroleum ether to the ice water is 1: 10, separating the liquid, and evaporating the solvent petroleum ether from the obtained organic phase to obtain the beta-ionone. The chromatogram showed a content of 98.3% (deduction of the solvent petroleum ether).
Example 3
A selective cyclization method of pseudo ionone comprises the following raw materials: concentrated sulfuric acid (98%, density 1.84g/mL), phosphorus pentoxide, petroleum ether (boiling point 30-60 deg.C), methanol, pseudoionone, the specific amounts are shown in Table 1.
The method for selective cyclization of the pseudo ionone comprises the following specific steps:
step 1: dissolving 20Kg of phosphorus pentoxide into 30Kg of concentrated sulfuric acid, stirring and mixing, pumping the mixture into a reaction kettle, adding 6Kg of methanol and 8g of petroleum ether, stirring and cooling to-30 to-35 ℃, and stirring at the rotation speed of 200-;
step 2: adding petroleum ether into 31Kg of pseudo ionone to obtain a mixture, wherein the sum of the petroleum ether and the petroleum ether in the step 1 is 13Kg, and dropwise adding the obtained mixture into a reaction kettle; paying attention to the temperature rise condition, if the temperature exceeds-30 ℃, stopping dripping and adding dry ice to reduce the temperature;
and step 3: after the dropwise addition, the mixture is continuously stirred for 10 minutes and heated to-10 ℃, and then the mixture obtained by the reaction is put into 1000L of ice water (containing 30-50% of sulfuric acid) with petroleum ether at the temperature of-10 ℃ for stirring and extraction, wherein the volume ratio of the petroleum ether to the ice water is 1: 10, separating the liquid, and evaporating the solvent petroleum ether from the obtained organic phase to obtain the beta-ionone. The chromatogram showed a content of 99.5% (deduction of the solvent petroleum ether).
Example 4
A selective cyclization method of pseudo ionone comprises the following raw materials: concentrated sulfuric acid (98%, density 1.84g/mL), phosphorus pentoxide, petroleum ether (boiling point 30-60 deg.C), methanol, pseudoionone, the specific amounts are shown in Table 1.
The method for selective cyclization of the pseudo ionone comprises the following specific steps:
step 1: dissolving 25Kg of phosphorus pentoxide into 35Kg of concentrated sulfuric acid, stirring and mixing, pumping the mixture into a reaction kettle, adding 6Kg of methanol and 7Kg of petroleum ether, stirring and cooling to-30 to-35 ℃, and stirring at the rotation speed of 200-;
step 2: adding petroleum ether into 25Kg of pseudo ionone to obtain a mixture, wherein the sum of the petroleum ether and the petroleum ether in the step 1 is 10Kg, and dropwise adding the obtained mixture into a reaction kettle; paying attention to the temperature rise condition, if the temperature exceeds-30 ℃, stopping dripping and adding dry ice to reduce the temperature;
and step 3: after the dropwise addition, the mixture is continuously stirred for 10 minutes and heated to-10 ℃, and then the mixture obtained by the reaction is put into 1000L of ice water (containing 30-50% of sulfuric acid) with petroleum ether at the temperature of-10 ℃ for stirring and extraction, wherein the volume ratio of the petroleum ether to the ice water is 1: 10, separating the liquid, and evaporating the solvent petroleum ether from the obtained organic phase to obtain the beta-ionone. The chromatogram showed a content of 99.7% (deduction of the solvent petroleum ether).
Comparative example 1: a method for synthesizing beta-ionone by using pseudoionone ring comprises the following steps of:
pumping 55Kg of concentrated sulfuric acid into a reaction kettle, adding 10Kg of petroleum ether, cooling to-20 ℃ under high-speed stirring, and stirring at the rotation speed of 200 and 250 revolutions per minute; adding 5Kg of petroleum ether into 30Kg of pseudo-ionone, slowly and dropwise adding into a reaction kettle, and stopping dropwise adding and adding dry ice to reduce the temperature and then dropwise adding when the temperature is increased to be higher than-10 ℃ and the temperature is increased. After the dropwise addition, the reaction mixture is stirred for 10 minutes and slightly heated to-5 ℃, then the reaction mixture is put into-10 ℃ ice water (aqueous phase obtained by the liquid separation in the step 3 in the previous batch of preparation method of the beta-ionone) added with 1000L of petroleum ether and stirred for extraction, and the organic phase is evaporated to remove the solvent petroleum ether to obtain crude beta-ionone with low selectivity.
TABLE 1 purity of beta-ionone (subtraction of mass of solution during analysis)
Claims (5)
1. A selective cyclization method of pseudo ionone is characterized in that the raw materials comprise:
the raw material of the selective cyclization method of the pseudo ionone also comprises dry ice;
the method for selectively cyclizing the pseudoionone comprises the following specific steps:
step 1: dissolving 15-25 parts by weight of phosphorus pentoxide into 20-35 parts by weight of concentrated sulfuric acid, stirring and mixing, pumping the obtained mixture into a reaction kettle, adding 5-8 parts by weight of methanol and 8-10 parts by weight of petroleum ether, and cooling to-30-35 ℃ under stirring;
step 2: adding petroleum ether into 25-40 parts by weight of pseudo ionone to obtain a mixture, wherein the sum of the petroleum ether and the petroleum ether in the step 1 is 10-15 parts by weight, and dropwise adding the obtained mixture into a reaction kettle;
and step 3: and after the dropwise addition is finished, continuing stirring for 5-15 minutes, gradually heating to-5-15 ℃, then putting the mixture obtained by the reaction into ice water which is added with petroleum ether and has the temperature of-8-12 ℃, stirring and extracting, wherein the volume ratio of the petroleum ether to the ice water is 1: and 5-15, separating the liquid, and evaporating the solvent petroleum ether from the obtained organic phase to obtain the beta-ionone.
2. The selective cyclization process of pseudoionone according to claim 1, wherein said petroleum ether has a boiling point of 30-60 ℃.
3. The selective cyclization process of pseudo-ionone according to claim 1, wherein the concentrated sulfuric acid has a concentration of 96% to 98%.
4. The selective cyclization process of pseudoionone according to claim 1, wherein the temperature is controlled not to exceed-30 ℃ during the dropwise addition in step 2.
5. The selective cyclization process of pseudo ionone according to claim 1, wherein in step 2, if the temperature during the dropwise addition exceeds-30 ℃, the dropwise addition is stopped and dry ice is added to reduce the temperature to below-30 ℃.
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Citations (6)
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|---|---|---|---|---|
| US4565894A (en) * | 1983-08-06 | 1986-01-21 | Basf Aktiengesellschaft | Preparation of ionones |
| CN1109462A (en) * | 1994-10-08 | 1995-10-04 | 中标标准技术研究所 | Synthesis for high purity beta ionone |
| CN1129209A (en) * | 1995-10-05 | 1996-08-21 | 复旦大学 | Process for production of beta-jonone |
| CN1508113A (en) * | 2002-12-19 | 2004-06-30 | 上海应用技术学院 | Industrial method for preparing beta-ionone |
| EP1921058A1 (en) * | 2006-11-10 | 2008-05-14 | DSMIP Assets B.V. | Process for the preparation of ionones and vitamin A, vitamin A derivatives, carotenes and carotenoids |
| CN101333154A (en) * | 2007-06-28 | 2008-12-31 | 拜耳技术工程（上海）有限公司 | Method for synthesizing beta-ionone |
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- 2019-04-28 CN CN201910349736.2A patent/CN109988064B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4565894A (en) * | 1983-08-06 | 1986-01-21 | Basf Aktiengesellschaft | Preparation of ionones |
| CN1109462A (en) * | 1994-10-08 | 1995-10-04 | 中标标准技术研究所 | Synthesis for high purity beta ionone |
| CN1129209A (en) * | 1995-10-05 | 1996-08-21 | 复旦大学 | Process for production of beta-jonone |
| CN1508113A (en) * | 2002-12-19 | 2004-06-30 | 上海应用技术学院 | Industrial method for preparing beta-ionone |
| EP1921058A1 (en) * | 2006-11-10 | 2008-05-14 | DSMIP Assets B.V. | Process for the preparation of ionones and vitamin A, vitamin A derivatives, carotenes and carotenoids |
| CN101333154A (en) * | 2007-06-28 | 2008-12-31 | 拜耳技术工程（上海）有限公司 | Method for synthesizing beta-ionone |
Non-Patent Citations (1)
| Title |
|---|
| β-紫罗兰的制备;王兰明;《中国医药工业杂志》;19900531;第21卷(第5期);第230-234页 * |
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