CN115215802A - Method for purifying vitamin H intermediate cyclic acid - Google Patents
Method for purifying vitamin H intermediate cyclic acid Download PDFInfo
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- CN115215802A CN115215802A CN202110416118.2A CN202110416118A CN115215802A CN 115215802 A CN115215802 A CN 115215802A CN 202110416118 A CN202110416118 A CN 202110416118A CN 115215802 A CN115215802 A CN 115215802A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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Abstract
The invention provides a method for purifying a vitamin H intermediate cyclic acid. The method comprises the following steps: (1) Adding triphosgene solution and potassium hydroxide solution dropwise into the compound water solution of the formula 2; (2) After the reaction is finished, adjusting the pH value of the reaction solution to be acidic, and filtering to obtain a crude product of the compound shown in the formula 3; (3) Adding isopropanol and water into the crude product of the compound shown in the formula 3, mixing, heating, dissolving, dripping hydrochloric acid, cooling, filtering, washing and drying to obtain the intermediate cyclic acid of the vitamin H.
Description
Technical Field
The invention relates to the technical field of production of vitamin H, in particular to a method for purifying a vitamin H intermediate cyclic acid.
Background
Vitamin H, also known as d-biotin, coenzyme R, is a water-soluble vitamin, also belonging to the vitamin B group, B7. It is an indispensable substance for the normal metabolism of fat and protein, and is also a necessary nutrient for maintaining the natural growth and development of human bodies and the normal functional health of human bodies.
To date, several routes for the synthesis of vitamin H have been developed, but the most industrially recognized route currently is that disclosed in the Hoffmann-La Roche (US 2489238):
in the route, the compound of formula 2 is subjected to cyclization reaction to the compound of formula 3, the traditional synthesis method is that triphosgene solution and potassium hydroxide solution are dropwise added into potassium hydroxide aqueous solution of the compound of formula 2 in a reaction kettle, after the reaction is finished, the pH of the reaction solution is adjusted to be acidic, and the compound of formula 3 is obtained after filtering, washing and drying, wherein the purity of HPLC is normally 95.5% -96.5%.
The purification method of the patent method comprises the steps of dropwise adding a triphosgene solution and a potassium hydroxide solution into a compound water solution in a formula 2 in a reaction kettle, adjusting the pH of a reaction solution to be acidic after the reaction is finished, filtering to obtain a crude product in a formula 3, adding isopropanol and water, mixing, heating, dissolving to be clear, dropwise adding hydrochloric acid, cooling, filtering, washing and drying to obtain the compound in the formula 3, wherein the purity of HPLC is 98.5-99.5%.
Disclosure of Invention
In order to solve the problems, the invention provides a method for purifying the vitamin H intermediate cyclic acid, which has the advantages of safe process, high reaction yield and low production cost and is suitable for industrial production.
The invention provides a method for purifying a compound of formula 3, which is characterized by comprising the following steps:
1) Adding triphosgene solution and potassium hydroxide solution into potassium hydroxide solution of the compound shown in the formula 2;
2) After the reaction is finished, adjusting the pH value of the reaction solution to be acidic, and filtering to obtain a crude product of the compound shown in the formula 3;
3) Adding isopropanol and water into the crude product of the formula 3, mixing, heating, dissolving, dripping hydrochloric acid, cooling, filtering, washing and drying to obtain the compound of the formula 3.
Preferably, the molar ratio of the compound of formula 3 to isopropanol in step (3) is 1.
Preferably, the molar ratio of the compound of formula 3 to water in step (3) is 1.
Preferably, in the dissolving and clearing process in the step (3), the temperature is controlled to be less than or equal to 40 ℃.
Preferably, the stirring time after the solution in the step (3) is controlled to be 10-15 min.
Preferably, the temperature of the hydrochloric acid dropped in the step (3) is controlled to be 20-28 ℃.
Preferably, the amount of the dropwise added hydrochloric acid in the step (3) is controlled to be 1:0.78 to 1:0.87.
preferably, the temperature of the cooling end point in the step (3) is 0-10 ℃.
A compound of formula 3, prepared according to the method of claim 1.
In another aspect of the present invention, there is provided the use of any one of the methods described above for the preparation of vitamin H.
In another aspect of the present invention, there is provided a compound represented by formula 3, wherein the compound is prepared according to the method of claim 1.
Compared with the prior art, the vitamin H prepared by using the compound of the formula 3 purified by the purification method has higher quality. Meanwhile, the process operation is simple, the technical requirement is low, the generation of three wastes is avoided, and the method is easy to apply to industrial production.
Detailed Description
The present invention will be described in detail with reference to examples. It should be noted that the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention; various modifications and improvements can be made to the present invention without departing from the spirit and scope of the invention. The content in the present invention refers to a mass percentage content unless otherwise specified.
The following cases were carried out by a conventional method unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1
35.0g (0.100 mol) of the compound of formula 2, 20g of potassium hydroxide and 133.3g of water are put into a reaction flask, stirred to be dissolved and clear, and cooled to 10-15 ℃. Simultaneously dropwise adding 40.0g (0.135 mol) of triphosgene into 160.0g of toluene (mass concentration is 20%) to obtain a solution B and a 25% potassium hydroxide aqueous solution C, wherein the pH is controlled to be 8-9 in the process, and the reaction temperature is 10-30 ℃. After about 1 to 1.5 hours of dripping, keeping the temperature and reacting for 0.5 hour. And then adjusting the pH value of the reaction solution to 1-2 by using acid, filtering, adding 16.6g of isopropanol and water into a filter cake, heating to 38 ℃ for clearing, keeping the temperature and stirring for 25min, cooling to 20-28 ℃, dropwise adding 27ml of common hydrochloric acid, cooling to 0-10 ℃, filtering, and washing the filter cake to be nearly neutral. 34.22g of solid is obtained after air-blast drying, the mass yield is 97.8 percent, and the purity of liquid phase analysis is 98.5 percent.
Example 2
35.0g (0.100 mol) of the compound of formula 2, 20g of potassium hydroxide and 133.3g of water are put into a reaction flask, stirred to be dissolved and clear, and cooled to 10-15 ℃. Simultaneously dropwise adding 40.0g (0.135 mol) of triphosgene into 160.0g of toluene (mass concentration is 20%) to obtain a solution B and a 25% potassium hydroxide aqueous solution C, wherein the pH is controlled to be 8-9 in the process, and the reaction temperature is 10-30 ℃. After about 1 to 1.5 hours of dripping, keeping the temperature and reacting for 0.5 hour. And then adjusting the pH value of the reaction solution to 1-2 by using acid, filtering, adding 28ml of isopropanol and 16.6g of water into a filter cake, heating to 37 ℃ for dissolving, keeping the temperature, stirring for 25min, cooling to 20-28 ℃, dropwise adding 27ml of common hydrochloric acid, cooling to 0-10 ℃, filtering, and washing the filter cake to be nearly neutral. 34.13g of solid is obtained after air-blast drying, the mass yield is 97.5 percent, and the liquid phase analysis purity is 98.8 percent.
Example 3
52.5g (0.100 mol) of the compound of formula 2, 30g of potassium hydroxide and 200g of water are put into a reaction flask, stirred to be dissolved and clear, and cooled to 10-15 ℃. Simultaneously dropwise adding 40.0g (0.135 mol) of triphosgene into 160.0g of toluene (mass concentration is 20%) to obtain a solution B and a 25% potassium hydroxide aqueous solution C, wherein the pH is controlled to be 8-9 in the process, and the reaction temperature is 10-30 ℃. After about 1 to 1.5 hours of dripping, keeping the temperature and reacting for 0.5 hour. And then adjusting the pH of the reaction solution to 1-2 by using acid, filtering, adding 39ml of isopropanol and 24.9g of water into a filter cake, heating to 38 ℃ for dissolving, keeping the temperature and stirring for 25min, cooling to 20-28 ℃, dropwise adding 27ml of common hydrochloric acid, cooling to 0-10 ℃, filtering, and washing the filter cake to be nearly neutral. After air-blast drying, 51.39g of solid is obtained, the mass yield is 97.9%, and the liquid phase analysis purity is 98.6%.
Example 4
35.0g (0.100 mol) of the compound of formula 2, 20g of potassium hydroxide and 133.3g of water are put into a reaction flask, stirred to be dissolved and clear, and cooled to 10-15 ℃. Simultaneously dropwise adding 40.0g (0.135 mol) of triphosgene into 160.0g of toluene (mass concentration is 20%) to obtain a solution B and a 25% potassium hydroxide aqueous solution C, wherein the pH is controlled to be 8-9 in the process, and the reaction temperature is 10-30 ℃. After about 1 to 1.5 hours of dripping, keeping the temperature and reacting for 0.5 hour. And then adjusting the pH value of the reaction solution to 1-2 by using acid, filtering, adding 16.6g of isopropanol and water into a filter cake, heating to 38 ℃ for clearing, keeping the temperature and stirring for 10min, cooling to 20-28 ℃, dropwise adding 27ml of common hydrochloric acid, cooling to 0-10 ℃, filtering, and washing the filter cake to be nearly neutral. 34.19g of solid is obtained after air-blast drying, the mass yield is 97.7 percent, and the purity of liquid phase analysis is 98.5 percent.
Example 5
35.0g (0.100 mol) of the compound of formula 2, 20g of potassium hydroxide and 133.3g of water are put into a reaction flask, stirred to dissolve the mixture, and cooled to 10-15 ℃. Simultaneously dropwise adding 40.0g (0.135 mol) of triphosgene into 160.0g of toluene (mass concentration is 20%) to obtain a solution B and a 25% potassium hydroxide aqueous solution C, wherein the pH is controlled to be 8-9 in the process, and the reaction temperature is 10-30 ℃. After about 1 to 1.5 hours of dripping, keeping the temperature and reacting for 0.5 hour. And then adjusting the pH value of the reaction solution to 1-2 by using acid, filtering, adding 31ml of isopropanol and 16.6g of water into a filter cake, heating to 38 ℃ for clearing, keeping the temperature and stirring for 25min, cooling to 20-28 ℃, dropwise adding 27ml of common hydrochloric acid, cooling to 0-10 ℃ for filtering, and washing the filter cake to be nearly neutral. 34.16g of solid is obtained after air blowing and drying, the mass yield is 97.6%, and the liquid phase analysis purity is 99.2%.
Comparative example 1
35.0g (0.100 mol) of the compound of formula 2, 20g of potassium hydroxide and 133.3g of water are put into a reaction flask, stirred to be dissolved and clear, and cooled to 10-15 ℃. Simultaneously dropwise adding 40.0g (0.135 mol) of triphosgene into 160.0g of toluene (mass concentration is 20%) to obtain a solution B and a 25% potassium hydroxide aqueous solution C, wherein the pH is controlled to be 8-9 in the process, and the reaction temperature is 10-30 ℃. After about 1 to 1.5 hours of dripping, keeping the temperature and reacting for 0.5 hour. Then adjusting the pH value of the reaction solution to 1-2 by acid, filtering, and washing a filter cake to be nearly neutral. After air-blast drying, 35.28g of solid is obtained, the mass yield is 100.8%, and the liquid phase analysis purity is 95.9%.
Comparative example 2
52.5g (0.160 mol) of the compound of formula 2, 30g of potassium hydroxide and 200g of water are put into a reaction flask, stirred to be dissolved and clear, and cooled to 10-15 ℃. And simultaneously dropwise adding 60.0g (0.202 mol) of triphosgene into 240.0g of toluene (mass concentration is 20%) to obtain a solution B and a 25% potassium hydroxide aqueous solution C, wherein the pH is controlled to be 8-9 in the process, and the reaction temperature is 10-30 ℃. After about 1 to 1.5 hours of dripping, keeping the temperature and reacting for 0.5 hour. Then adjusting the pH value of the reaction solution to 1-2 by acid, filtering, and washing a filter cake to be nearly neutral. 52.96g of solid is obtained after air-blast drying, the mass yield is 100.9 percent, and the purity of liquid phase analysis is 96.1 percent.
As can be seen from comparison of examples 1-5 with comparative examples 1-2, the compound of formula 3 purified in the examples of the present invention has high purity and small single impurity, and can be used for production of cyclic acid as vitamin H intermediate.
Claims (10)
1. A method for purifying a cyclic acid as a vitamin H intermediate is characterized by comprising the following steps:
1) Mixing the crude compound of formula 3, isopropanol and water produced by the traditional process in proportion respectively;
2) Heating the mixed materials to control the dissolution;
3) Cooling, and beginning to dropwise add hydrochloric acid;
4) Cooling, filtering, washing and drying to obtain the compound shown in the formula 3.
2. The method of claim 1,
the molar ratio of the compound of formula 3 to isopropanol is 1.
3. The method of claim 1,
the molar ratio of the compound of formula 3 to water is 1.
4. The method of claim 2,
in the process of dissolving and cleaning, the temperature is controlled to be less than or equal to 40 ℃.
5. The method of claim 2,
the stirring time is controlled to be 10-15 min after the dissolution and the cleaning.
6. The method of claim 3,
the temperature of the hydrochloric acid is reduced and dropped is controlled to be 20-28 ℃.
7. The method of claim 3,
the mass ratio of the compound of formula 3 and the hydrochloric acid is controlled to be 1:0.78 to 1:0.87.
8. the method of claim 4,
the temperature of the cooling end point is 0-10 ℃.
9. Use of a process according to any one of claims 1 to 8 for the preparation of vitamin H.
10. A compound of formula 3, prepared according to the method of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202110416118.2A CN115215802A (en) | 2021-04-16 | 2021-04-16 | Method for purifying vitamin H intermediate cyclic acid |
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| CN202110416118.2A CN115215802A (en) | 2021-04-16 | 2021-04-16 | Method for purifying vitamin H intermediate cyclic acid |
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