CN104744230A - Method for synthesizing vitamin K1 - Google Patents
Method for synthesizing vitamin K1 Download PDFInfo
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- CN104744230A CN104744230A CN201510079473.XA CN201510079473A CN104744230A CN 104744230 A CN104744230 A CN 104744230A CN 201510079473 A CN201510079473 A CN 201510079473A CN 104744230 A CN104744230 A CN 104744230A
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Abstract
The invention discloses a method for synthesizing vitamin K1, relating to the field of synthesis of organics. The method comprises the following steps: reducing 2-methyl1,4-naphthalenediol in a certain solvent in the presence of a reducing agent under certain conditions to generate 2-methyl-1,4-hydronaphthoquinone; then, adding pohytol and reacting under certain conditions in the presence of a proper catalyst to synthesize 2-methyl3-phytyl1,4-naphthalenediol; oxidizing with a proper oxidizing agent to generate vitamin K1; and carrying out vacuum concentration to obtain finished vitamin K1. When the method is used for synthesizing vitamin K1, 2-methyl1,4-naphthoquinone is used as a raw material, no hydroxyl group protection is needed. Therefore, the method disclosed by the invention has the characteristics of simple process, mild reaction conditions, high yield, high product purity and high product yield; and in addition, the production cost is low, and therefore the method is very suitable for industrial production.
Description
Technical field
The present invention relates to organic synthetic method, more specifically, is a kind of method of synthesise vitamins K1.
Background technology
Vitamin K1, chemical name 2-methyl-3-(3,7,11,15-tetramethyl-16-2-thiazolinyl)-1,4-naphthoquinone, vitamin k 1 belongs to vitamin medicaments, is the necessary material of liver composition-factor II, VII, Ⅸ, Ⅹ.Vitamin K 1 injection is 2009 editions National essential drugs list kinds, is mainly used in the treatment of the hemorrhagic diseases that various vitamin K deficiency causes.Vitamin K1 is as pharmaceutical preparation, be applied to the too low disease of zymoplasm, vitamin K1 deficiency disease, newborn infant's nature control of hemorrhage and obstructive jaundice, leak, chronic diarrhoea etc. clinically caused hemorrhage, the Hypoprothrombinemia that coumarins, sodium salicylate etc. are caused.VITAMIN also has analgesia, alleviates the effect of bronchospasm, has obvious effect to the angina that visceral smooth muscle angina, cholepathia spastica, enterospasm cause.
The synthesis of vitamin K1 receives the concern of people day by day, according to current literature, the synthesis of most economical vitamin K1 require be: (1) is carried out the productive rate that condensation reaction is and is wanted high, can not waste too many pohytol; (2) raw material is easy to get; (3) technique is relatively simple, and reaction conditions is gentle, and product purity is high, and side reaction is less, is beneficial to purification; (4) the large production of suitability for industrialized.Comprehensive literature can draw, the method for various synthesise vitamins K1 respectively has quality, and vitamin k4-cyclopentadiene method step is relatively simple, and product yield is higher, but the separation and purification difficulty of subsequent products is large, the not too large production of suitability for industrialized; One kettle way has good stereoselectivity, but severe reaction conditions, and reagent difficulty is asked, and yield is not high, is unfavorable for suitability for industrialized production; The disadvantage that direct F-C reaction is sent out is that yield is low, and by product is many, but experiment condition is simple, and subsequent products separation and purification difficulty is little, and the value of suitability for industrialized production is large.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of and has that technique is simple, yield is high and the method for the synthesise vitamins K1 that production cost is low.
The present invention is realized by following technique means: according to F-C alkylated reaction characteristic, select suitable catalyzer, by 2 methyl isophthalic acids, 4 naphthalenediols and pohytol high yield be condensed into 2-methyl 3-phytyl 1,4-naphthalenediol, then select suitable oxidizing one-tenth vitamin K1.
A method of synthesise vitamins K1, is characterized in that: comprise the steps:
(1) 2-methyl isophthalic acid, the synthesis of 4 naphthalenediols: first add 2-methyl isophthalic acid in ether solvent, 4 naphthoquinones, stir temperature rising reflux, slowly add reductive agent again, after adding people, stirring reaction 1-5 hour, wherein, go back original reagent and 2-methyl isophthalic acid, the ratio of the molar weight of 4 naphthoquinones is greater than 2:1; After reaction terminates, after being cooled by reaction solution, then through washing, after saturated brine washing, obtain 2-methyl isophthalic acid, 4 naphthalenediol solution;
Chemical equation is as follows:
(2) F-C alkylated reaction: under nitrogen protection, add catalyzer and acetic acid to above-mentioned 2-methyl isophthalic acid, in 4 naphthalenediol solution, stir, be warming up to 45 DEG C-50 DEG C, start the pohytol that dropping solvent cut is crossed, after dropwising, insulation reaction 2-6 hour, is cooled to less than 25 DEG C, obtain 2-methyl 3-phytyl 1,4-Naphthohydroquinone solution;
Chemical equation is as follows:
(3) oxidizing reaction: in the solution of above-mentioned steps 2, add 2-methyl 3-phytyl 1, the oxygenant of 4-naphthalenediol solution 1.5-2 times of mol ratio, carry out stirring reaction 2-5 hour at normal temperatures, point plate is determined to be oxidized terminal, after oxidation terminates, uses saturated brine to wash, and then adding after dewatering agent, flocculation agent and discoloring agent carry out decolorization filtering, decompression and solvent recovery obtains vitamin K1.
Chemical equation is as follows:
Described ether solvent is the one in the mixed solution of anhydrous diethyl ether, isopropyl ether, anhydrous diethyl ether and sherwood oil.
Described reductive agent is V-Brite B, S-WAT, zinc powder add one in acetic acid, hydrogen.
Described catalyzer is the one in aluminum chloride, zinc chloride, tin protochloride, boron trifluoride, trifluoromethanesulfonic acid samarium.
Described oxygenant is the one in iron(ic) chloride, oxygen, hydrogen peroxide, air.
Described dewatering agent is anhydrous sodium sulphate, and flocculation agent is aluminum oxide, and discoloring agent is gac.
According to method synthesise vitamins K1 of the present invention, 2-methyl 1,4-naphthoquinone is utilized to be reduced into 2-methyl isophthalic acid, 4-naphthalenediol with reductive agent under solvent, this reduction process is simple to operate, reaction conditions is gentle, and yield is more than 93%, and the solvent phase of solvent and later step is same, do not need to extract, directly can enter the next step, greatly reduce working hour and 2-methyl isophthalic acid, 4-naphthalenediol exposes probability oxidized in atmosphere; Add pohytol again, under certain condition, use the Lewis acid of suitable water tolerance as catalyzer, catalyst failure can not be made because of system water generation reaction, greatly can improve 2-methyl 3-phytyl 1, the productive rate of 4-naphthalenediol, reach more than 75%, re-use suitable oxygenant to carry out being oxidized to vitamin K1, vitamin K1 is obtained through concentrating under reduced pressure, whole operating process reaction conditions is gentle, reaction preference is high, product purity is high, yield is high and cost-saving, is very applicable to suitability for industrialized production.
Embodiment
The technique means realized to make the present invention, creation characteristic, reaching object and effect is easy to understand, below in conjunction with specific embodiment, setting forth the present invention further.
Embodiment 1:
Synthesise vitamins K1 as follows:
(1) 2-methyl 1 is synthesized, 4 naphthalenediols: add 120g anhydrous diethyl ether in the round-bottomed flask of 500ml, add 20g 2-methyl Isosorbide-5-Nitrae naphthoquinones again, after stirring and dissolving, add 80g sherwood oil, be warming up to backflow, then drip the hydrogensulfite solution of 200g25% slowly, within about 1 hour, dropwise, after dropwising, insulation backflow 3 hours; After reaction terminates, reaction solution is cooled to less than 25 DEG C, stops stirring, point sub-cloud water layer, use saturated brine to wash 2 times, add 10g anhydrous sodium sulfate dehydration, filter, filtrate is 2-methyl Isosorbide-5-Nitrae naphthalenediol solution.
(2) synthesise vitamins K1: under nitrogen protection; 2g trifluoromethanesulfonic acid samarium and 2g acetic acid is added in above-mentioned solution; stirring is warming up to backflow; slow dropping contains the pohytol petroleum ether solution of 60g50%; after dropwising, insulation backflow 4 hours, after completion of the reaction; be cooled to room temperature; add 50g iron(ic) chloride, stirring reaction 5 hours, some plate is determined to be oxidized terminal; after filtration; filtrate is washed with saturated brine, adds 4g anhydrous sodium sulphate, 3g aluminum oxide; 3g activated carbon decolorizing filters, and filtrate reduced in volume obtains vitamin K1 26.5g.
Embodiment 2:
Synthesizing trichloro-6-ethyl ester as follows:
(1) 2-methyl 1 is synthesized, 4 naphthalenediols: add 150g anhydrous diethyl ether in the round-bottomed flask of 500ml, add 22g 2-methyl Isosorbide-5-Nitrae naphthoquinones again, after stirring and dissolving, add 90g sherwood oil, be warming up to backflow, then drip the hydrogensulfite solution of 230g25% slowly, within about 1 hour, dropwise, after dropwising, insulation backflow 3.5 hours; After reaction terminates, reaction solution is cooled to less than 25 DEG C, stops stirring, point sub-cloud water layer, use saturated brine to wash 2 times, add 8g anhydrous sodium sulfate dehydration, filter, filtrate is 2-methyl Isosorbide-5-Nitrae naphthalenediol solution.
(2) synthesise vitamins K1: under nitrogen protection; 2.2g trifluoromethanesulfonic acid samarium and 2.5g acetic acid is added in above-mentioned solution; stirring is warming up to backflow; slow dropping contains the pohytol petroleum ether solution of 60g50%; after dropwising, insulation backflow 4.5 hours, after completion of the reaction; be cooled to room temperature; add 50g iron(ic) chloride, stirring reaction 5.5 hours, some plate is determined to be oxidized terminal; after filtration; filtrate is washed with saturated brine, adds 4g anhydrous sodium sulphate, 3g aluminum oxide; 3g activated carbon decolorizing filters, and filtrate reduced in volume obtains vitamin K1 28.3g.
In order to progressive of the present invention is described, the finished product of Example 1 and embodiment 2 carries out productive rate, purity, yield and the test of production cycle, and meanwhile, adopt the common level of prior art as a comparison, result is as shown in table 1:
Table 1
In sum, the method of synthesise vitamins K1 of the present invention, compared to prior art, has the advantages that technique is simple, reaction conditions is gentle, productive rate is high, with short production cycle, product purity is high and yield is high, and production cost is low, be very applicable to suitability for industrialized production.
More than show and describe ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.
Claims (6)
1. a method of synthesise vitamins K1, is characterized in that: comprise the steps:
(1) 2-methyl isophthalic acid, the synthesis of 4 naphthalenediols: first add 2-methyl isophthalic acid in ether solvent, 4 naphthoquinones, stir temperature rising reflux, slowly add reductive agent again, after adding people, stirring reaction 1-5 hour, wherein, go back original reagent and 2-methyl isophthalic acid, the ratio of the molar weight of 4 naphthoquinones is greater than 2:1; After reaction terminates, after being cooled by reaction solution, then through washing, after saturated brine washing, obtain 2-methyl isophthalic acid, 4 naphthalenediol solution;
Chemical equation is as follows:
(2) F-C alkylated reaction: under nitrogen protection, add catalyzer and acetic acid to above-mentioned 2-methyl isophthalic acid, in 4 naphthalenediol solution, stir, be warming up to 45 DEG C-50 DEG C, start the pohytol that dropping solvent cut is crossed, after dropwising, insulation reaction 2-6 hour, is cooled to less than 25 DEG C, obtain 2-methyl 3-phytyl 1,4-Naphthohydroquinone solution;
Chemical equation is as follows:
(3) oxidizing reaction: in the solution of above-mentioned steps 2, add 2-methyl 3-phytyl 1, the oxygenant of 4-naphthalenediol solution 1.5-2 times of mol ratio, carry out stirring reaction 2-5 hour at normal temperatures, point plate is determined to be oxidized terminal, after oxidation terminates, uses saturated brine to wash, and then adding after dewatering agent, flocculation agent and discoloring agent carry out decolorization filtering, decompression and solvent recovery obtains vitamin K1.
Chemical equation is as follows:
2. the method for a kind of synthesise vitamins K1 according to claim 1, is characterized in that: described ether solvent is the one in the mixed solution of anhydrous diethyl ether, isopropyl ether, anhydrous diethyl ether and sherwood oil.
3. the method for a kind of synthesise vitamins K1 according to claim 1, is characterized in that: described reductive agent is V-Brite B, S-WAT, zinc powder add one in acetic acid, hydrogen.
4. the method for a kind of synthesise vitamins K1 according to claim 1, is characterized in that: described catalyzer is the one in aluminum chloride, zinc chloride, tin protochloride, boron trifluoride, trifluoromethanesulfonic acid samarium.
5. the method for a kind of synthesise vitamins K1 according to claim 1, is characterized in that: described oxygenant is the one in iron(ic) chloride, oxygen, hydrogen peroxide, air.
6. the method for a kind of synthesise vitamins K1 according to claim 1, it is characterized in that: described dewatering agent is anhydrous sodium sulphate, flocculation agent is aluminum oxide, and discoloring agent is gac.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111153765A (en) * | 2019-12-21 | 2020-05-15 | 南京汉欣医药科技有限公司 | Vitamin K with different cis-trans isomer ratios1Preparation method of halogenated plant alcohol as intermediate thereof |
| CN112778114A (en) * | 2021-01-21 | 2021-05-11 | 杭州浙中医药科技有限公司 | Efficient and environment-friendly method for synthesizing vitamin K1 |
| CN113135820A (en) * | 2021-04-22 | 2021-07-20 | 江苏慈星药业有限公司 | High-efficiency preparation of pharmaceutical-grade vitamin K1And intermediates thereof |
| CN114149314A (en) * | 2021-11-26 | 2022-03-08 | 安徽先和医药研究有限公司 | Synthetic method of VK2 |
| CN114262264A (en) * | 2021-10-29 | 2022-04-01 | 太阳树(莆田)生物医药有限公司 | Vitamin K1Heck reaction synthesis method |
| CN114276225A (en) * | 2021-10-29 | 2022-04-05 | 太阳树(莆田)生物医药有限公司 | Vitamin K1Synthetic method of organic zinc reagent |
| CN115151524A (en) * | 2020-02-25 | 2022-10-04 | 帝斯曼知识产权资产管理有限公司 | Vitamin K2 synthesis |
| CN115385786A (en) * | 2022-09-16 | 2022-11-25 | 新拓洋生物工程有限公司 | Method for synthesizing vitamin K2 |
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| JPS6281347A (en) * | 1985-10-02 | 1987-04-14 | Mitsubishi Gas Chem Co Inc | Production of quinone compound |
| CN102351677A (en) * | 2011-09-16 | 2012-02-15 | 重庆大学 | Method for chemical synthesis of vitamin K2 |
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2015
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| CN102351677A (en) * | 2011-09-16 | 2012-02-15 | 重庆大学 | Method for chemical synthesis of vitamin K2 |
Non-Patent Citations (2)
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| RALPH HIRSCHMANN ET AL.: "The Synthesis of Vitamin K1", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| YOSHITOMO SUHARA ET AL.: "Synthesis of Novel Vitamin K2 Analogues with Modification at the ω-Terminal Position and Their Biological Evaluation as Potent Steroid and Xenobiotic Receptor (SXR) Agonists", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111153765A (en) * | 2019-12-21 | 2020-05-15 | 南京汉欣医药科技有限公司 | Vitamin K with different cis-trans isomer ratios1Preparation method of halogenated plant alcohol as intermediate thereof |
| CN111153765B (en) * | 2019-12-21 | 2020-10-20 | 南京汉欣医药科技有限公司 | Vitamin K with different cis-trans isomer ratios1Preparation method of halogenated plant alcohol as intermediate thereof |
| CN115151524A (en) * | 2020-02-25 | 2022-10-04 | 帝斯曼知识产权资产管理有限公司 | Vitamin K2 synthesis |
| CN115151524B (en) * | 2020-02-25 | 2024-01-19 | 帝斯曼知识产权资产管理有限公司 | Vitamin K2 synthesis |
| CN112778114A (en) * | 2021-01-21 | 2021-05-11 | 杭州浙中医药科技有限公司 | Efficient and environment-friendly method for synthesizing vitamin K1 |
| CN113135820A (en) * | 2021-04-22 | 2021-07-20 | 江苏慈星药业有限公司 | High-efficiency preparation of pharmaceutical-grade vitamin K1And intermediates thereof |
| CN114262264A (en) * | 2021-10-29 | 2022-04-01 | 太阳树(莆田)生物医药有限公司 | Vitamin K1Heck reaction synthesis method |
| CN114276225A (en) * | 2021-10-29 | 2022-04-05 | 太阳树(莆田)生物医药有限公司 | Vitamin K1Synthetic method of organic zinc reagent |
| CN114276225B (en) * | 2021-10-29 | 2024-03-19 | 太阳树(莆田)生物医药有限公司 | Vitamin K 1 Method for synthesizing organic zinc reagent |
| CN114149314A (en) * | 2021-11-26 | 2022-03-08 | 安徽先和医药研究有限公司 | Synthetic method of VK2 |
| CN114149314B (en) * | 2021-11-26 | 2024-05-28 | 安徽先和医药研究有限公司 | Synthesis method of VK2 |
| CN115385786A (en) * | 2022-09-16 | 2022-11-25 | 新拓洋生物工程有限公司 | Method for synthesizing vitamin K2 |
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