CN111153765B - Vitamin K with different cis-trans isomer ratios1Preparation method of halogenated plant alcohol as intermediate thereof - Google Patents
Vitamin K with different cis-trans isomer ratios1Preparation method of halogenated plant alcohol as intermediate thereof Download PDFInfo
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- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
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- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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Abstract
The invention discloses vitamin K with different cis-trans isomer ratios1The preparation method of halogenated plant alcohol as intermediate comprises the steps of carrying out halogenation reaction on raw material plant alcohol and phosphorus trihalide under the catalysis of phosphoric acid to obtain halogenated plant alcohol, carrying out high-temperature depolymerization after the reaction of the halogenated plant alcohol and cyclopentadiene menadione to obtain vitamin K1. Vitamin K obtained by the method of the invention1The vitamin K can be obtained by controlling the adding amount of phosphoric acid in the halogenation reaction1The cis isomer ratio can be regulated and controlled between 1% and 21%.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to vitamin K with different cis-trans isomer ratios1And a preparation method of halogenated plant alcohol as an intermediate thereof.
Background
Vitamin K1(Vitamin K1) The chemical name of the derivative is 2-methyl-3- (3,7,11, 15-tetramethyl hexadec-2-alkenyl) -1, 4-naphthoquinone, belongs to vitamin medicaments, and a molecular side chain has a double bond, so cis-trans isomers exist. Chemical synthesis of vitamin K1Is a mixture of cis and trans isomers, and the cis isomer has little physiological activity. Therefore, after the 80 s in the 20 th century, all the pharmacopoeias of various countries have registered vitamin K1The cis-isomer of (A) defines the limit (cis-isomer. ltoreq.21).0％)。
At present, domestic vitamin K1The preparation method mainly comprises 1) a Friedel-crafts alkylation method; 2) menadione-cyclopentadiene method. The Friedel-crafts alkylation method has the defects of low yield, more product impurities and difficult purification; the menadione-cyclopentadiene method has the advantages of simple step operation, high product yield, lower product purification difficulty and industrial production value.
Quaternary fly et al (Ya-Fei Ji, et al. improved Synthesis of Vitamin K)1SYNTHETIC COMMUNICA-TIONS, Vol.33, No.5, pp.763-772,2003) reported that isophytol was used as a raw material to synthesize vitamin K1The cis-trans ratio of the chlorinated phytol product obtained by reacting the isophytol with the hydrogen chloride solution is 19.5:80.5, and the cis-trans ratio of the brominated phytol product obtained by synthesizing the chlorinated phytol product with the hydrogen bromide solution is 24.5: 75.5; the cis-trans example of the bromophytol product obtained by the reaction with phosphorus tribromide is 30: 70; natural plant alcohol is used as a raw material, and the cis-trans ratio of the natural plant alcohol to a bromophytol product obtained by synthesizing phosphorus tribromide is 10: 85-15: 90. Because of vitamin K1The ratio of cis-trans isomers is consistent with that of halogenated plant alcohol, so that the ratio of cis-isomers obtained by the method is more than 10%.
Zhang Shi just et al (vitamin K with different cis-trans isomer ratio)1The synthesis of (1) is reported in journal of Chinese medicine industry, 47(2), pp.147-148, 2016). Natural plant alcohol is brominated by phosphorus tribromide under the action of different amounts of water media to obtain leaf-based bromine with different cis-trans isomer ratios, and then condensed with cyclopentadienylmenadione to obtain vitamin K1Precursor, finally depolymerizing to obtain vitamin K with the cis-isomer ratio of 10-21% or less than or equal to 1%1。
Thus, it is often difficult to control the product vitamin K by these prior art methods1The proportion of the medium cis-isomer is controllable within a large range of 1-21%, and particularly, vitamin K with the proportion of the cis-isomer of 1-10% is difficult to obtain1。
Therefore, there is still a need in the art to develop vitamin K with simple operation and adjustable isomer ratio1A preparation method.
Disclosure of Invention
Objects of the inventionProvides vitamin K with different cis-trans isomer ratios1And a preparation method of halogenated plant alcohol as an intermediate thereof, which solves the problem of uncontrollable isomer ratio in the prior art.
One of the purposes of the invention adopts the following scheme:
vitamin K with different cis-trans isomer ratios1The preparation method of the intermediate halogenated plant alcohol comprises the following steps of carrying out halogenation reaction on plant alcohol and phosphorus trihalide under the conditions of an organic solvent and phosphoric acid at a certain temperature to obtain the halogenated plant alcohol, wherein the reaction is as follows:
as a further improvement of the invention, the organic solvent is one of saturated aliphatic hydrocarbon or ether solvent.
As a further improvement of the invention, the saturated aliphatic hydrocarbon is preferably selected from one of n-pentane, n-hexane, n-heptane and petroleum ether; the ether solvent is preferably one of diethyl ether and tetrahydrofuran, and the selected organic solvent has simple post-treatment and low cost; wherein, saturated aliphatic hydrocarbon solvent is more preferable, such as n-hexane, which has better solubility to phytol, halogenated phytol and vitamin K1, and can effectively reduce impurities in the reaction.
As a further improvement of the invention, the phosphorus trihalide is one of phosphorus trichloride or phosphorus tribromide, and more preferably phosphorus tribromide, because the brominated plant alcohol used as the starting material in the subsequent reaction has higher activity than chlorinated plant alcohol.
As a further improvement of the invention, the mass ratio of phosphoric acid to plant alcohol in the halogenation reaction is 0.05: 1-0.6: 1, and when the mass ratio of phosphoric acid to plant alcohol is less than 0.05:1, the reaction is slow, and the impurity content and impurity types are more; more preferably 0.2: 1-0.5: 1, and when the mass ratio of the phosphoric acid to the plant alcohol is between 0.2: 1-0.5: 1, the obtained vitamin K1The product has high purity and less impurity content and impurity types, and the cis-isomer ratio is lower than 21.0 percent; when in useWhen the mass ratio of phosphoric acid to plant alcohol exceeds 0.6:1, the cis-isomer ratio exceeds 21.0%, purification is required to remove the cis-isomer, which causes cost increase, and the impurity content and impurity species are significantly increased.
As a further improvement of the method, the reaction temperature in the halogenation reaction is-20 ℃, more preferably-10 ℃, and when the temperature exceeds 10 ℃, relatively more impurities are generated.
The second object of the present invention is to provide vitamin K with different cis-trans isomer ratios1The method for preparing the compound (A) is as follows,
1) carrying out halogenation reaction on plant alcohol and phosphorus trihalide at a certain temperature under the conditions of an organic solvent and phosphoric acid to obtain halogenated plant alcohol;
2) condensing halogenated plant alcohol with cyclopentadiene menadione under the condition of potassium tert-butoxide and tetrahydrofuran, cooling to-20 ℃ to obtain vitamin K1A precursor;
3) the obtained vitamin K1Dissolving the precursor with glacial acetic acid, heating to 90-110 ℃, and performing depolymerization reaction to obtain vitamin K1The reaction formula is shown as follows:
as a further improvement of the invention, in the step 1), the organic solvent is one of n-pentane, n-hexane, n-heptane, petroleum ether, diethyl ether and tetrahydrofuran, and the phosphorus trihalide is one of phosphorus trichloride or phosphorus tribromide.
As a further improvement of the method, in the step 1), the reaction temperature is-20 ℃, and the mass ratio of phosphoric acid to plant alcohol is 0.05: 1-0.6: 1.
The raw materials of the invention are all conventional and commercially available.
The invention adopts liquid chromatography to detect vitamin K1The cis isomer ratio of (1).
Compared with the prior art, the invention has the following advantages: mixing plant alcohol inReacting with phosphorus trihalide under the conditions of organic solvent and phosphoric acid at a certain temperature, and controlling the addition of phosphoric acid in the halogenation reaction to obtain the vitamin K1The cis-isomer ratio can be controlled in a large range of 1-21%, and especially vitamin K with the cis-isomer ratio of 1-10% can be easily obtained1. Vitamin K obtained by adopting the technology of the invention1The purity is basically equivalent to the prior art, and the isomer is less than or equal to 21.0 percent and meets the pharmacopoeia standards of various countries. The technology of the invention overcomes the defect of the prior domestic vitamin K1The production can only control the cis-isomer ratio to be less than or equal to 1 percent under the condition of no water addition; the method has the advantages of lower purity, more impurities, difficult purification of the product and uncontrollable cis-isomer under the action of adding different water media, and the method is simpler and more convenient to operate, lower in purification difficulty and beneficial to industrial production and application.
Drawings
FIG. 1 shows the cis-trans isomer of vitamin K obtained in example 11HPLC profile of (a).
FIG. 2 shows the cis-trans isomer of vitamin K obtained in example 21HPLC profile of (a).
FIG. 3 shows the cis-trans isomer of vitamin K obtained in example 31HPLC profile of (a).
FIG. 4 shows the cis-trans isomer of vitamin K obtained in example 41HPLC profile of (a).
FIG. 5 shows the cis-trans isomer of vitamin K obtained in example 51HPLC profile of (a).
FIG. 6 shows the cis-trans isomer of vitamin K obtained in example 61HPLC profile of (a).
FIG. 7 shows the cis-trans isomer of vitamin K obtained in example 71HPLC profile of (a).
FIG. 8 shows the cis-trans isomer of vitamin K obtained in example 81HPLC profile of (a).
FIG. 9 shows the cis-trans isomer of vitamin K obtained in example 91HPLC profile of (a).
FIG. 10 shows the cis-trans isomer of vitamin K obtained in example 101HPLC profile of (a).
FIG. 11 is a pairCis-trans isomer vitamin K obtained in ratio 11HPLC profile of (a).
FIG. 12 is the cis-trans isomer vitamin K obtained in comparative example 21HPLC profile of (a).
Detailed Description
To facilitate understanding of the present invention by those skilled in the art, the technical solutions of the present invention will be further described below with reference to specific examples, but the following contents are not intended to limit the scope and spirit of the present invention as claimed in the claims.
Example 1
Adding 200g of plant alcohol and 10g of phosphoric acid into 1.2L of n-hexane, stirring, cooling to-10-0 ℃, dropwise adding 240g of phosphorus tribromide, and controlling the temperature at an internal temperature not higher than 0 ℃. And (3) after TLC monitoring for 3 hours, completely reacting the raw materials, adding methanol for quenching, layering, and removing the solvent by spin-drying to obtain the brominated phytol.
Adding 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into a reaction bottle, stirring, cooling to-20-10 ℃, adding 60g of cyclopentadienylmethylnaphthoquinone, and slowly dropwise adding brominated phytol. TLC monitoring for 2 hr, adding hydrochloric acid to quench, rotary distilling to remove tetrahydrofuran, extracting the residual water phase with 0.5L methyl tert-butyl ether, separating, and rotary distilling to remove solvent to obtain oily substance. Dissolving the oily substance with 0.5L of glacial acetic acid, adding the dissolved oily substance into a reaction bottle, stirring, heating to 95-100 ℃, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, spin-drying, adding 0.5L of n-hexane for dissolving, washing with water, and spin-drying an organic phase to obtain vitamin K1. As shown in figure 1, the peak with the retention time of 20.682min is cis-isomer through HPLC detection, and the peak area percentage is 5.47%; the peak with the retention time of 31.629min is trans isomer, and the peak area percentage is 92.99 percent; thus the cis-trans isomer ratio was 5.6: 94.4; the chromatographic purity of the final product, cis-trans isomer, was 98.46% with a total impurity content of 1.54%, containing 3 impurities.
Example 2
Adding 200g of plant alcohol and 40g of phosphoric acid into 1.2L of n-hexane, stirring, cooling to-10-0 ℃, dropwise adding 240g of phosphorus tribromide, and controlling the temperature at an internal temperature not higher than 0 ℃. And (3) after 2.5 hours of TLC monitoring, completely reacting the raw materials, adding methanol for quenching, layering, and removing the solvent by spin-drying to obtain the brominated phytol.
Adding 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into a reaction bottle, stirring, cooling to-20-10 ℃, adding 60g of cyclopentadienylmethylnaphthoquinone, and slowly dropwise adding brominated phytol. TLC monitoring for 2 hr, adding hydrochloric acid to quench, rotary distilling to remove tetrahydrofuran, extracting the residual water phase with 0.5L methyl tert-butyl ether, separating, and rotary distilling to remove solvent to obtain oily substance. Dissolving the oily substance with 0.5L of glacial acetic acid, adding the dissolved oily substance into a reaction bottle, stirring, heating to 95-100 ℃, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, spin-drying, adding 0.5L of n-hexane for dissolving, washing with water, and spin-drying an organic phase to obtain vitamin K1. As shown in FIG. 2, the peak with a retention time of 20.509min is cis-isomer through HPLC detection, and the peak area percentage is 9.93%; the peak with the retention time of 30.295min is trans isomer, and the peak area percentage is 89.98%; thus the cis-trans isomer ratio was 9.9: 90.1; the chromatographic purity of the final product, cis-trans isomer, was 99.91% with a total impurity content of 0.09%, containing only 1 impurity.
Example 3
Adding 200g of plant alcohol and 60g of phosphoric acid into 1.2L of n-hexane, stirring, cooling to-10-0 ℃, dropwise adding 240g of phosphorus tribromide, and controlling the temperature at an internal temperature not higher than 0 ℃. And (3) after TLC monitoring for 2 hours, completely reacting the raw materials, adding methanol for quenching, layering, and removing the solvent by spin-drying to obtain the brominated phytol.
Adding 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into a reaction bottle, stirring, cooling to-20-10 ℃, adding 60g of cyclopentadienylmethylnaphthoquinone, and slowly dropwise adding brominated phytol. TLC monitoring for 2 hr, adding hydrochloric acid to quench, rotary distilling to remove tetrahydrofuran, extracting the residual water phase with 0.5L methyl tert-butyl ether, separating, and rotary distilling to remove solvent to obtain oily substance. Dissolving the oily substance with 0.5L of glacial acetic acid, adding the dissolved oily substance into a reaction bottle, stirring, heating to 95-100 ℃, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, spin-drying, adding 0.5L of n-hexane for dissolving, washing with water, and spin-drying an organic phase to obtain vitamin K1. As shown in FIG. 3, the peak with the retention time of 26.173min is cis-isomer through HPLC detection, and the peak area percentage is 15.10%; the peak with retention time of 35.960min is trans isomer, and its peak area percentage is84.85 percent; thus the cis-trans isomer ratio is 15.1: 84.9; the chromatographic purity of the final product, cis-trans isomer, was 99.95% with a total impurity content of 0.05%, containing only 1 impurity.
Example 4
Adding 200g of plant alcohol and 100g of phosphoric acid into 1.2L of n-hexane, stirring, cooling to-10-0 ℃, dropwise adding 240g of phosphorus tribromide, and controlling the temperature at an internal temperature not higher than 0 ℃. And (3) after 1 hour of TLC monitoring, completely reacting the raw materials, adding methanol for quenching, layering, and removing the solvent by spin-drying to obtain the brominated phytol.
Adding 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into a reaction bottle, stirring, cooling to-20-10 ℃, adding 60g of cyclopentadienylmethylnaphthoquinone, and slowly dropwise adding brominated phytol. TLC monitoring for 2 hr, adding hydrochloric acid to quench, rotary distilling to remove tetrahydrofuran, extracting the residual water phase with 0.5L methyl tert-butyl ether, separating, and rotary distilling to remove solvent to obtain oily substance. Dissolving the oily substance with 0.5L of glacial acetic acid, adding the dissolved oily substance into a reaction bottle, stirring, heating to 95-100 ℃, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, spin-drying, adding 0.5L of n-hexane for dissolving, washing with water, and spin-drying an organic phase to obtain vitamin K1. As shown in FIG. 4, the peak with a retention time of 36.364min was cis-isomer by HPLC detection, and its peak area percentage was 18.52%; the peak with the retention time of 46.364min is trans isomer, and the peak area percentage is 81.42%; thus the cis-trans isomer ratio was 18.5: 81.5; the chromatographic purity of the final product, cis-trans isomer, was 99.94% with a total impurity content of 0.06%, containing only 1 impurity.
Example 5
Adding 200g of plant alcohol and 120g of phosphoric acid into 1.2L of n-hexane, stirring, cooling to-10-0 ℃, dropwise adding 240g of phosphorus tribromide, and controlling the temperature at an internal temperature not higher than 0 ℃. And monitoring the complete reaction of the raw materials after TLC for 1 hour, adding methanol for quenching, layering, and removing the solvent by spin-drying to obtain the brominated phytol.
Adding 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into a reaction bottle, stirring, cooling to-20-10 ℃, adding 60g of cyclopentadienylmethylnaphthoquinone, and slowly dropwise adding brominated phytol. TLC monitoring for 2 hr to complete the reaction, adding hydrochloric acid to quench, rotary evaporating to remove tetrahydrofuran, and adding 0 for the residual water phase5L of methyl tert-butyl ether was extracted, separated, and the solvent was removed by rotary evaporation to give an oil. Dissolving the oily substance with 0.5L of glacial acetic acid, adding the dissolved oily substance into a reaction bottle, stirring, heating to 95-100 ℃, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, spin-drying, adding 0.5L of n-hexane for dissolving, washing with water, and spin-drying an organic phase to obtain vitamin K1. As shown in FIG. 5, the peak with a retention time of 20.449min was cis-isomer with a peak area percentage of 20.33% by HPLC; the peak with the retention time of 30.055min is trans isomer, and the peak area percentage is 75.82%; thus the cis-trans isomer ratio was 21.1: 78.9; the chromatographic purity of the final product, cis-trans isomer, was 96.15% with a total impurity content of 3.85%, containing 8 impurities.
As can be seen from the comparison of the above examples 1 to 5, under the condition that other process parameters are completely consistent, the influence of different addition amounts of phosphoric acid on the ratio of cis-trans isomers in the product, the product purity and the impurities is studied, and in example 1, when the mass ratio of phosphoric acid to plant alcohol is less than 0.05:1, the reaction is slow, and the impurity content and the impurity types are more; in examples 2 to 4, when the mass ratio of phosphoric acid to plant alcohol is 0.2:1 to 0.5:1, vitamin K is obtained1The product has high purity and less impurity content and impurity types, and the cis-isomer ratio is lower than 21.0 percent; in example 5, when the mass ratio of phosphoric acid to plant alcohol exceeds 0.6:1, the cis-isomer ratio exceeds 21.0%, purification is required to remove the cis-isomer, resulting in an increase in cost and a significant increase in impurity content and impurity species.
Example 6
Adding 200g of plant alcohol and 60g of phosphoric acid into 1.2L of n-hexane, stirring, cooling to 10-20 ℃, dropwise adding 240g of phosphorus tribromide, and controlling the temperature and the internal temperature to be not higher than 20 ℃. And (3) after 1 hour of TLC monitoring, completely reacting the raw materials, adding methanol for quenching, layering, and removing the solvent by spin-drying to obtain the brominated phytol.
Adding 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into a reaction bottle, stirring, cooling to 0-10 ℃, adding 60g of cyclopentadienylmethylnaphthoquinone, and slowly dropwise adding brominated phytol. TLC monitoring for 1 hr, adding hydrochloric acid to quench, rotary distilling to remove tetrahydrofuran, extracting the residual water phase with 0.5L methyl tert-butyl ether, separating, and rotary distillingThe solvent was evaporated to give an oil. Dissolving the oily substance with 0.5L of glacial acetic acid, adding the dissolved oily substance into a reaction bottle, stirring, heating to 95-100 ℃, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, spin-drying, adding 0.5L of n-hexane for dissolving, washing with water, and spin-drying an organic phase to obtain vitamin K1. As shown in FIG. 6, the peak with retention time of 23.792min was cis-isomer by HPLC detection, and the peak area percentage was 13.65%; the peak with the retention time of 36.605min is trans isomer, and the peak area percentage is 83.41%; thus the cis-trans isomer ratio is 14.0: 86.0; the chromatographic purity of the final product, cis-trans isomer, was 97.06%, the total impurity content was 2.94%, and 5 impurities were included.
As can be seen from the comparison of example 3 and example 6, under the condition of completely consistent other process parameters, the influence of the reaction temperature on the ratio of cis-trans isomers in the product, the product purity and impurities is studied, and when the temperature of the bromination reaction and the condensation reaction does not exceed 10 ℃, relatively less impurity content and types are generated, and the product purity is higher.
Example 7
Adding 200g of plant alcohol and 60g of phosphoric acid into 1.2L of n-hexane, stirring, cooling to-10-0 ℃, dropwise adding 130g of phosphorus trichloride, and controlling the temperature to be not higher than 10 ℃. And (3) after 2 hours of TLC monitoring, completely reacting the raw materials, adding methanol for quenching, layering, and removing the solvent by spin-drying to obtain the chlorinated plant alcohol.
Adding 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into a reaction bottle, stirring, cooling to-20-10 ℃, adding 60g of cyclopentadienylmethylnaphthoquinone, and slowly dropwise adding chlorinated plant alcohol. TLC monitoring is carried out for 6 hours, then the raw materials are completely reacted, hydrochloric acid is added for quenching, tetrahydrofuran is removed by rotary evaporation, the residual water phase is extracted by 0.5L of methyl tert-butyl ether, liquid separation is carried out, and the solvent is removed by rotary evaporation, thus obtaining oily matter. Dissolving the oily substance with 0.5L of glacial acetic acid, adding the dissolved oily substance into a reaction bottle, stirring, heating to 95-100 ℃, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, spin-drying, adding 0.5L of n-hexane for dissolving, washing with water, and spin-drying an organic phase to obtain vitamin K1. As shown in FIG. 7, the peak with a retention time of 20.775min was cis-isomer with a peak area percentage of 15.13% by HPLC; the peak with the retention time of 31.201min is trans isomer, and the peak area percentage is 84.25%;thus the cis-trans isomer ratio is 15.2: 84.8; the chromatographic purity of the final product, cis-trans isomer, was 99.38% with a total impurity content of 0.62%, containing only 2 impurities.
As can be seen from a comparison of examples 3 and 7, the influence of the type of substituents in the phosphorus trihalide on the reaction was investigated under conditions in which the other process parameters were completely identical, and the results show that: the brominated phytol serving as the starting material in the subsequent condensation reaction has higher reactivity and shorter reaction time than the chlorinated phytol; the ratio of cis-trans isomers, the purity of the product and the content of impurities of the final product are equivalent, and the influence is small.
Example 8
Adding 200g of plant alcohol and 100g of phosphoric acid into 1.2L of tetrahydrofuran, stirring, cooling to-10-0 ℃, dropwise adding 240g of phosphorus tribromide, and controlling the temperature and the internal temperature to be not higher than 0 ℃. And (3) after 1 hour of TLC monitoring, completely reacting the raw materials, adding methanol for quenching, layering, and removing the solvent by spin-drying to obtain the brominated phytol.
Adding 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into a reaction bottle, stirring, cooling to-20-10 ℃, adding 60g of cyclopentadienylmethylnaphthoquinone, and slowly dropwise adding brominated phytol. TLC monitoring for 2 hr, adding hydrochloric acid to quench, rotary distilling to remove tetrahydrofuran, extracting the residual water phase with 0.5L methyl tert-butyl ether, separating, and rotary distilling to remove solvent to obtain oily substance. Dissolving the oily substance with 0.5L of glacial acetic acid, adding the dissolved oily substance into a reaction bottle, stirring, heating to 95-100 ℃, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, spin-drying, adding 0.5L of tetrahydrofuran for dissolving, washing with water, and spin-drying an organic phase to obtain vitamin K1. As shown in FIG. 8, the peak with a retention time of 22.522min was cis-isomer with a peak area percentage of 17.18% by HPLC; the peak with the retention time of 35.162min is trans isomer, and the peak area percentage is 81.73%; thus the cis-trans isomer ratio was 17.4: 82.6; the chromatographic purity of the final product, cis-trans isomer, was 98.91% with a total impurity content of 1.09%, containing 8 impurities.
As can be seen from the comparison of example 4 with example 8, the influence of the type of halogenated reaction solvent on the reaction was investigated under conditions where the other process parameters were completely consistent, and the results show that: the n-hexane has better solubility to the plant alcohol, the halogenated plant alcohol and the vitamin K1, can effectively reduce the content and the variety of impurities in the reaction, and has higher product purity.
Example 9
Adding 200g of plant alcohol and 30g of phosphoric acid into 1.2L of n-pentane, stirring, cooling to-5 ℃, dropwise adding 240g of phosphorus tribromide, and controlling the temperature and the internal temperature to be not higher than 0 ℃. And (3) after 2.5 hours of TLC monitoring, completely reacting the raw materials, adding methanol for quenching, layering, and removing the solvent by spin-drying to obtain the brominated phytol.
Adding 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into a reaction bottle, stirring, cooling to-20-10 ℃, adding 60g of cyclopentadienylmethylnaphthoquinone, and slowly dropwise adding brominated phytol. TLC monitoring for 2 hr, adding hydrochloric acid to quench, rotary distilling to remove tetrahydrofuran, extracting the residual water phase with 0.5L methyl tert-butyl ether, separating, and rotary distilling to remove solvent to obtain oily substance. Dissolving the oily substance with 0.5L of glacial acetic acid, adding the dissolved oily substance into a reaction bottle, stirring, heating to 95-100 ℃, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, spin-drying, adding 0.5L of n-pentane for dissolving, washing with water, and spin-drying an organic phase to obtain vitamin K1. As shown in FIG. 9, the peak with a retention time of 24.886min was cis-isomer with a peak area percentage of 7.16% by HPLC; the peak with the retention time of 37.452min is trans isomer, and the peak area percentage is 92.34%; thus the cis-trans isomer ratio was 7.2: 92.8; the chromatographic purity of the final product, cis-trans isomer, was 99.50% with a total impurity content of 0.5%, containing 10 impurities.
Example 10
Adding 200g of plant alcohol and 40g of phosphoric acid into 1.2L of n-heptane, stirring, cooling to-5 ℃, dropwise adding 240g of phosphorus tribromide, and controlling the temperature to be not higher than 10 ℃. And (3) after TLC monitoring for 3 hours, completely reacting the raw materials, adding methanol for quenching, layering, and removing the solvent by spin-drying to obtain the brominated phytol.
Adding 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into a reaction bottle, stirring, cooling to-20-10 ℃, adding 60g of cyclopentadienylmethylnaphthoquinone, and slowly dropwise adding brominated phytol. TLC monitoring for 2 hr, adding hydrochloric acid to quench, rotary distilling to remove tetrahydrofuran, extracting the residual water phase with 0.5L methyl tert-butyl ether, separating, and rotary distillingThe solvent was removed to give an oil. Dissolving the oily substance with 0.5L of glacial acetic acid, adding the dissolved oily substance into a reaction bottle, stirring, heating to 95-100 ℃, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, spin-drying, adding 0.5L of n-heptane for dissolving, washing with water, and spin-drying an organic phase to obtain vitamin K1. As shown in FIG. 10, the peak with a retention time of 22.478min was cis-isomer with a peak area percentage of 11.63% by HPLC; the peak with the retention time of 34.885min is trans isomer, and the peak area percentage is 87.88%; thus the cis-trans isomer ratio was 11.7: 88.3; the chromatographic purity of the final product, cis-trans isomer, was 99.51%, the total impurity content was 0.49%, and 7 impurities were included.
As can be seen from the comparison of example 2, example 9 and example 10, the results show that the change of the types of the aliphatic hydrocarbon solvents, the small change of the feeding amount of the phosphoric acid (the mass ratio of the phosphoric acid to the plant alcohol is controlled to be changed within the range of 0.2: 1-0.5: 1) and the slight increase of the reaction temperature in the halogenation reaction have no obvious influence on the purity of the product, but can cause the impurity types of the final product to be obviously increased, probably because the impurity types are relatively sensitive to the temperature.
Comparative example 1
Adding 200g of plant alcohol into 1.2L of n-hexane, stirring, cooling to-10-0 ℃, dropwise adding 240g of phosphorus tribromide, and controlling the temperature at the internal temperature not higher than 0 ℃. And (4) carrying out TLC monitoring, completely reacting the raw materials after 4 hours, adding methanol for quenching, layering, and carrying out spin-drying to remove the solvent to obtain the brominated phytol.
Adding 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into a reaction bottle, stirring, cooling to-20-10 ℃, adding 60g of cyclopentadienylmethylnaphthoquinone, and slowly dropwise adding brominated phytol. TLC monitoring for 2 hr, adding hydrochloric acid to quench, rotary distilling to remove tetrahydrofuran, extracting the residual water phase with 0.5L methyl tert-butyl ether, separating, and rotary distilling to remove solvent to obtain oily substance. Dissolving the oily substance with 0.5L of glacial acetic acid, adding the dissolved oily substance into a reaction bottle, stirring, heating to 95-100 ℃, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, spin-drying, adding 0.5L of n-hexane for dissolving, washing with water, and spin-drying an organic phase to obtain vitamin K1. As shown in FIG. 11, the peak with a retention time of 20.714min was cis-isomer with a peak area percentage of 1.13% by HPLC; the retention time is 30.254minThe peak of (A) is a trans isomer, and the peak area percentage thereof is 98.43%; the cis-trans isomer ratio was therefore 1.1: 98.9. When no phosphoric acid or water is added in the reaction, the cis-isomer ratio is always low, approaching 1% content.
Comparative example 2
Adding 200g of plant alcohol and 6g of purified water into 1.2L of n-hexane, stirring, cooling to-10-0 ℃, dropwise adding 240g of phosphorus tribromide, and controlling the temperature at an internal temperature not higher than 0 ℃. And (4) carrying out TLC monitoring, completely reacting the raw materials after 4 hours, adding methanol for quenching, layering, and carrying out spin-drying to remove the solvent to obtain the brominated phytol.
Adding 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into a reaction bottle, stirring, cooling to-20-10 ℃, adding 60g of cyclopentadienylmethylnaphthoquinone, and slowly dropwise adding brominated phytol. TLC monitoring for 2 hr, adding hydrochloric acid to quench, rotary distilling to remove tetrahydrofuran, extracting the residual water phase with 0.5L methyl tert-butyl ether, separating, and rotary distilling to remove solvent to obtain oily substance. Dissolving the oily substance with 0.5L of glacial acetic acid, adding the dissolved oily substance into a reaction bottle, stirring, heating to 95-100 ℃, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, spin-drying, adding 0.5L of n-hexane for dissolving, washing with water, and spin-drying an organic phase to obtain vitamin K1. As shown in FIG. 12, the peak with a retention time of 24.392min was cis-isomer with a peak area percentage of 5.54% by HPLC; the peak with the retention time of 38.225min is trans isomer, and the peak area percentage is 86.29%; the cis-trans isomer ratio was thus 6.0: 94.0. Meanwhile, when the feeding amount of other components is unchanged, different adding amounts of purified water are controlled, for example, the adding amount of the purified water is respectively 1g or 4g, the cis-trans isomer ratios obtained by the method are respectively 4.3:95.7 and 5.9:94.1, namely the cis-isomer ratio is below 6%, and the isomer ratio cannot be reported.
The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which are intended to fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (11)
1. Vitamin K with different cis-trans isomer ratios1The preparation method of the intermediate halogenated plant alcohol is characterized by comprising the following steps: reacting plant alcohol with phosphorus trihalide under the conditions of an organic solvent and phosphoric acid at a certain temperature to obtain halogenated plant alcohol, wherein the reaction is as follows:
2. vitamin K of different cis-trans isomer ratios according to claim 11The preparation method of the intermediate halogenated plant alcohol is characterized by comprising the following steps: the organic solvent is one of saturated aliphatic hydrocarbon or ether solvent.
3. Vitamin K according to claim 2 in different cis-trans isomer ratios1The preparation method of the intermediate halogenated plant alcohol is characterized by comprising the following steps: the saturated aliphatic hydrocarbon is selected from one of n-pentane, n-hexane, n-heptane and petroleum ether; the ether solvent is one of diethyl ether and tetrahydrofuran.
4. Vitamin K of different cis-trans isomer ratios according to claim 11The preparation method of the intermediate halogenated plant alcohol is characterized by comprising the following steps: the phosphorus trihalide is one of phosphorus trichloride or phosphorus tribromide.
5. Vitamin K of different cis-trans isomer ratios according to claim 11The preparation method of the intermediate halogenated plant alcohol is characterized by comprising the following steps: the reaction temperature is-20 to 20 ℃.
6. Vitamin K according to claim 5 in different cis-trans isomer ratios1Preparation of intermediate halogenated plant alcoholThe preparation method is characterized by comprising the following steps: the reaction temperature is-10 to 10 ℃.
7. Vitamin K of different cis-trans isomer ratios according to claim 11The preparation method of the intermediate halogenated plant alcohol is characterized by comprising the following steps: the mass ratio of the phosphoric acid to the plant alcohol is 0.05: 1-0.6: 1.
8. Vitamin K of different cis-trans isomer ratios according to claim 71The preparation method of the intermediate halogenated plant alcohol is characterized by comprising the following steps: the mass ratio of the phosphoric acid to the plant alcohol is 0.2: 1-0.5: 1.
9. Vitamin K with different cis-trans isomer ratios1The preparation method is characterized by comprising the following steps:
1) the preparation method of the halogenated plant alcohol according to claim 1, namely, the plant alcohol and phosphorus trihalide are subjected to halogenation reaction under the conditions of an organic solvent and phosphoric acid at a certain temperature to obtain the halogenated plant alcohol;
2) condensing halogenated plant alcohol with cyclopentadiene menadione under the condition of potassium tert-butoxide and tetrahydrofuran, cooling to-20 ℃ to obtain vitamin K1A precursor;
3) the obtained vitamin K1Dissolving the precursor with glacial acetic acid, heating to 90-110 ℃, and performing depolymerization reaction to obtain vitamin K with the cis-isomer ratio of 1-21%1；
The reaction formula is shown as follows:
10. vitamin K of different cis-trans isomer ratios according to claim 91The preparation method is characterized by comprising the following steps: the organic solvent in the step 1) is one of n-pentane, n-hexane, n-heptane, petroleum ether, diethyl ether and tetrahydrofuran, and the phosphorus trihalide is phosphorus trichloride or tribromideOne of phosphorus compounds.
11. Vitamin K of different cis-trans isomer ratios according to claim 91The preparation method is characterized by comprising the following steps: in the step 1), the reaction temperature is-20 ℃, and the mass ratio of phosphoric acid to plant alcohol is 0.05: 1-0.6: 1.
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| CN114965742B (en) * | 2022-04-21 | 2023-08-18 | 广西铭磊维生制药有限公司 | Method for measuring related substances of vitamin K1 drops |
| CN116990402A (en) * | 2023-06-25 | 2023-11-03 | 南京汉欣医药科技有限公司 | Vitamin K determination 1 Analysis method of isomer content in injection |
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