CN115385786B - Method for synthesizing vitamin K2 - Google Patents
Method for synthesizing vitamin K2 Download PDFInfo
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- CN115385786B CN115385786B CN202211129233.2A CN202211129233A CN115385786B CN 115385786 B CN115385786 B CN 115385786B CN 202211129233 A CN202211129233 A CN 202211129233A CN 115385786 B CN115385786 B CN 115385786B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
- C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures
- C07C46/06—Preparation of quinones by oxidation giving rise to quinoid structures of at least one hydroxy group on a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
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Abstract
The invention provides a method for synthesizing vitamin K2, which is characterized in that common phthalic acid in industry is used as a starting material to synthesize the vitamin K2, the intermediate raw material is cheap and easy to obtain mostly, the selectivity of intermediate products and products is high, the total yield is more than 63%, if the yield is calculated from the intermediate beta-menadione and is more than 70%, the whole reaction condition is mild, and the method is easy for industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of vitamin K2.
Background
Vitamin K2, also known as menadione, is a fat-soluble vitamin and also one of the essential vitamins for the human body. In the human body, vitamin K2 is mainly synthesized by intestinal bacteria and is also present in some animal meat products and fermented products, such as animal livers, fermented dairy products, cheese and the like, and the most abundant source is natto.
There are three major types of vitamin K2, MK-4, MK-7, MK-9.MK-4 and MK-7 are widely used throughout the world, and in particular MK-7, is produced primarily in Europe, china and Japan, and MK-4 is produced primarily in China and Japan. All-trans menaquinone-7 (MK-7) is the most active structure of vitamin K2. Research shows that the Bone Mineral Density (BMD) can be obviously improved by taking 45 mu g of vitamin K2 (MK-7) every day, and the effect on the activation of osteoblasts and the inhibition of bone resorption is also realized. Therefore, the vitamin K2 (MK-7) is more suitable for accurate nutrition and accurate treatment.
Most of the methods reported in the literature start to react from the middle step, and have low yield and selectivity, and many side reactions, so the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a method for synthesizing vitamin K2, which overcomes the defects of the prior art, synthesizes vitamin K2 by using phthalic acid which is common in industry as a starting material, and has the advantages of low cost and easy obtainment of most raw materials required in the middle, high selectivity of intermediate products and products, and provides a synthetic route which is easy to industrialize.
In order to achieve the above object, the present invention provides a method for synthesizing vitamin K2 (formula 1), comprising the steps of:
(1) Adding bis (trichloromethyl) carbonate into an autoclave, and adding diethyl ether for dissolving;
(2) Slowly adding phthalic acid powder into the solution obtained in the step (1) to perform acylation reaction to generate phthaloyl chloride;
the reaction formula is as follows:
the solubility of phthalic acid as a raw material in diethyl ether is low, and the solubility of phthaloyl chloride as a product in diethyl ether is high, so that the generated product can be transferred into a solvent by utilizing the characteristic, the reaction is facilitated, and meanwhile, phthalic acid powder is added into diethyl ether solution of bis (trichloromethyl) carbonate, so that the bis (trichloromethyl) carbonate is always in an excessive state, the generation of byproducts is reduced, and the reaction selectivity is improved.
(3) And (3) adding zinc powder and cuprous chloride into the reaction liquid obtained in the step (2), introducing propylene gas, keeping the pressure in the reaction kettle at 0.05-0.3 MPa, filtering to remove the catalyst and solid particles after the reaction is finished, removing the solvent to obtain crude beta-menadione, and recrystallizing the crude beta-menadione to obtain pure beta-menadione.
The reaction formula is as follows:
side reaction is easy to occur when the reaction pressure is too high, the yield is lower when the pressure is too low, and the pressure in the reaction kettle is preferably between 0.05 and 0.3 MPa.
(4) Adding tin powder and beta-menadione into a three-neck flask, adding ethanol, heating to dissolve the beta-menadione, dropwise adding hydrochloric acid, carrying out reduction reaction, adding water into a reaction solution after the reaction is finished, separating out a product, washing with water, and drying to obtain 2-methyl-1, 4-naphthalenediol;
the reaction formula is as follows:
(5) Dissolving the 2-methyl-1, 4-naphthalenediol obtained in the step 4 into chloroform, then adding a catalyst of anhydrous aluminum trichloride in batches, slowly adding long-chain terpene primary alcohol into the chloroform, keeping the reaction temperature between 75 and 85 ℃, maintaining the pressure of the whole reaction system between-0.03 and-0.01 MPa, and reacting for 3 to 5 hours;
the reaction formula is as follows:
certain negative pressure is kept in the reaction process, which is beneficial to the forward proceeding of the reaction.
(6) Adding a mixed solution of dilute hydrochloric acid and hydrogen peroxide into the reaction solution obtained in the step 5 to perform acidolysis oxidation reaction, and after the acidolysis oxidation reaction is finished, filtering, washing and drying to obtain a crude product of the compound shown in the formula 1;
(7) Recrystallizing the crude product of the compound shown in the formula 1 obtained in the step 6 by using a mixed solution of ethanol and acetone to obtain a pure product of the compound shown in the formula 1, namely vitamin K2.
Preferably, the molar ratio of the bis (trichloromethyl) carbonate in the step 1 to the phthalic acid in the step 2 is 1: 1.0-1.5.
Preferably, the adding amount of the zinc powder and the cuprous chloride in the step 3 is 5-25% of the mass of the solution.
Preferably, the purity of the crude product beta-menadione in the step 3 is 82-95%.
Preferably, the mole ratio of the hydrogen chloride and the tin powder contained in the beta-menadione, the ethanol and the hydrochloric acid in the step 4 is 1: 8-50: 2-5: 2-4.
Preferably, the mole ratio of the 2-methyl-1, 4-naphthalenediol to the anhydrous aluminum trichloride in the step 5 is 1: 2-3.
Preferably, in said formulae 1 and 2, n is 2, 4, 7 or 9.
Preferably, in the formula 1 and the formula 2, n is 2, and the long-chain terpene primary alcohol is geraniol.
Preferably, in the step 6, the content of the hydrochloric acid in the mixed solution is 3-8%, and the content of the hydrogen peroxide in the mixed solution is 6-10%.
Preferably, the volume ratio of the ethanol to the acetone in the step 7 is 1: 0.5-10
The invention provides a method for synthesizing vitamin K2, which is characterized in that common phthalic acid in industry is used as a starting material to synthesize the vitamin K2, the intermediate raw material is cheap and easy to obtain mostly, the selectivity of intermediate products and products is high, the total yield is more than 63%, if the yield is calculated from the intermediate beta-menadione and is more than 70%, the whole reaction condition is mild, and the method is easy for industrial production.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
A method for preparing a compound represented by formula 1, comprising the steps of:
(1) 148.4g (0.5 mol) of bis (trichloromethyl) carbonate is added into an autoclave, and 1kg of diethyl ether is added for dissolution;
(2) 83.07g (0.5 mol) of phthalic acid powder is slowly added into the solution in the step 1 to carry out acylation reaction to generate phthaloyl chloride;
(3) And (3) adding 70g of zinc powder and cuprous chloride into the reaction solution obtained in the step (2), introducing propylene gas, keeping the pressure in the reaction kettle at 0.1MPa, filtering to remove the catalyst and solid particles after the reaction is finished, removing the solvent to obtain 80.9g of crude beta-menadione with the purity of 85%, and recrystallizing the crude beta-menadione to obtain 75.8g (0.44 mol) of pure beta-menadione with the purity of more than 97%. The yield of the first three steps is 88.1 percent
(4) Adding 104.5 g (0.88 mol) of tin powder and 75.8g of beta-menadione into a three-neck flask, then adding 202.7g (4.4 mol) of ethanol, heating to dissolve the beta-menadione, then dropwise adding hydrochloric acid (containing 0.88mol of hydrogen chloride) to carry out reduction reaction, after the reaction is finished, adding water into the reaction liquid to precipitate a product, washing with water, and drying to obtain 71.4g (0.41 mol) of 2-methyl-1, 4-naphthalenediol;
(5) Dissolving the 2-methyl-1, 4-naphthalenediol obtained in the step 4 in chloroform, then adding 109.3g (0.82 mol) of anhydrous aluminum trichloride serving as a catalyst in batches, simultaneously slowly adding 64.78g (0.42 mol) of geraniol into the chloroform, keeping the reaction temperature between 75 and 85 ℃, and maintaining the pressure of the whole reaction system between-0.03 and-0.02 MPa for 3 hours;
(6) Adding a mixed solution of dilute hydrochloric acid with the hydrochloric acid content of 3% and hydrogen peroxide with the hydrogen peroxide content of 6% into the reaction solution obtained in the step 5 to perform acidolysis oxidation reaction, and after the acidolysis oxidation reaction is finished, filtering, washing and drying to obtain 118.2g of a crude product of the compound shown in the formula 1, wherein n =2;
(7) Recrystallizing the crude product of the compound shown in the formula 1 obtained in the step 6 by using a mixed solution of ethanol and acetone, wherein the volume ratio of the ethanol to the acetone is 1: 0.5, so as to obtain 101.8g (0.33 mol) of a pure product of the compound shown in the formula 1, namely vitamin K2 (10), and the total yield is 66%.
Example 2
A method for preparing a compound represented by formula 1, comprising the steps of:
(1) 100.9g (0.34 mol) of bis (trichloromethyl) carbonate is added into an autoclave, and 1kg of diethyl ether is added for dissolution;
(2) Slowly adding 83.07g (0.5 mol) of phthalic acid powder into the solution obtained in the step (1) to perform acylation reaction to generate phthaloyl chloride;
(3) And (3) adding 200g of zinc powder and cuprous chloride into the reaction solution obtained in the step (2), introducing propylene gas, keeping the pressure in the reaction kettle at 0.25MPa, filtering to remove the catalyst and solid particles after the reaction is finished, and removing the solvent to obtain 82.3g of crude beta-menadione with the purity of 95%, and recrystallizing the crude beta-menadione to obtain 79.2g (0.46 mol) of pure beta-menadione with the purity of more than 97%. The yield of the first three steps is 92.0 percent
(4) Adding 218.4 g (1.84 mol) of tin powder and 79.2g of beta-menadione into a three-neck flask, then adding 1059.6g (23 mol) of ethanol, heating to dissolve the beta-menadione, then dropwise adding hydrochloric acid (containing 2.3mol of hydrogen chloride) to carry out reduction reaction, after the reaction is finished, adding water into the reaction solution to precipitate a product, washing with water, and drying to obtain 74.9g (0.43 mol) of 2-methyl-1, 4-naphthalenediol;
(5) Dissolving the 2-methyl-1, 4-naphthalenediol obtained in the step 4 in chloroform, then adding 172.0g (1.29 mol) of anhydrous aluminum trichloride serving as a catalyst in batches, simultaneously slowly adding 67.86g (0.44 mol) of geraniol into the chloroform, keeping the reaction temperature between 75 and 85 ℃, and maintaining the pressure of the whole reaction system between-0.02 MPa and-0.01 MPa for 5 hours;
(6) Adding a mixed solution of dilute hydrochloric acid and hydrogen peroxide, the hydrochloric acid content of which is 8% and the hydrogen peroxide content of which is 10%, into the reaction solution obtained in the step 5 to perform acidolysis oxidation reaction, and after the acidolysis oxidation reaction is finished, filtering, washing and drying to obtain 123.5g of a crude product of the compound shown in the formula 1, wherein n =2;
(7) Recrystallizing the crude product of the compound shown in the formula 1 obtained in the step 6 by using a mixed solution of ethanol and acetone, wherein the volume ratio of the ethanol to the acetone is 1: 0.5, and obtaining 107.9g (0.34 mol) of a pure product of the compound shown in the formula 1, namely vitamin K2 (10), wherein the total yield is 68%.
Example 3
A method for preparing a compound represented by formula 1, comprising the steps of:
(1) 100.9g (0.34 mol) of bis (trichloromethyl) carbonate is added into an autoclave, and 1kg of diethyl ether is added for dissolution;
(2) 83.07g (0.5 mol) of phthalic acid powder is slowly added into the solution in the step 1 to carry out acylation reaction to generate phthaloyl chloride;
(3) And (3) adding 200g of zinc powder and cuprous chloride into the reaction solution obtained in the step (2), introducing propylene gas, keeping the pressure in the reaction kettle at 0.25MPa, filtering to remove the catalyst and solid particles after the reaction is finished, and removing the solvent to obtain 82.3g of crude beta-menadione with the purity of 95%, and recrystallizing the crude beta-menadione to obtain 79.2g (0.46 mol) of pure beta-menadione with the purity of more than 97%. The yield of the first three steps is 92.0 percent
(4) Adding 218.4 (1.84 mol) of tin powder and 79.2g of beta-menadione into a three-neck flask, then adding 1059.6g (23 mol) of ethanol, heating to dissolve the beta-menadione, then dropwise adding hydrochloric acid (containing 2.3mol of hydrogen chloride) to carry out reduction reaction, after the reaction is finished, adding water into the reaction liquid to precipitate a product, washing with water, and drying to obtain 74.9g (0.43 mol) of 2-methyl-1, 4-naphthalenediol;
(5) Dissolving the 2-methyl-1, 4-naphthalenediol obtained in the step 4 into chloroform, then adding 172.0g (1.29 mol) of anhydrous aluminum trichloride serving as a catalyst in batches, simultaneously slowly adding 128.5g (0.44 mol) of long-chain terpene primary alcohol (formula 2) into the chloroform, keeping the reaction temperature between 75 and 85 ℃, maintaining the pressure of the whole reaction system between-0.02 MPa and-0.01 MPa, and keeping the reaction time for 5 hours;
(6) Adding a mixed solution of dilute hydrochloric acid with the hydrochloric acid content of 8% and hydrogen peroxide with the hydrogen peroxide content of 10% into the reaction solution obtained in the step 5 to perform acidolysis oxidation reaction, and after the acidolysis oxidation reaction is finished, filtering, washing and drying to obtain 167.4g of a crude product of the compound shown in the formula 1, wherein n =4;
(7) Recrystallizing the crude product of the compound shown in the formula 1 obtained in the step 6 by using a mixed solution of ethanol and acetone, wherein the volume ratio of the ethanol to the acetone is 1: 10, so as to obtain 148.9g (0.335 mol) of a pure product of the compound shown in the formula 1, namely vitamin K2 (20), and the total yield is 67%.
Example 4
A method for preparing a compound represented by formula 1, comprising the steps of:
(1) 100.9g (0.34 mol) of bis (trichloromethyl) carbonate is added into an autoclave, and 1kg of diethyl ether is added for dissolution;
(2) Slowly adding 83.07g (0.5 mol) of phthalic acid powder into the solution obtained in the step (1) to perform acylation reaction to generate phthaloyl chloride;
(3) And (3) adding 200g of zinc powder and cuprous chloride into the reaction solution obtained in the step (2), introducing propylene gas, keeping the pressure in the reaction kettle at 0.25MPa, filtering to remove the catalyst and solid particles after the reaction is finished, and removing the solvent to obtain 82.3g of crude beta-menadione with the purity of 95%, and recrystallizing the crude beta-menadione to obtain 79.2g (0.46 mol) of pure beta-menadione with the purity of more than 97%. The yield of the first three steps is 92.0 percent
(4) Adding 218.4 g (1.84 mol) of tin powder and 79.2g of beta-menadione into a three-neck flask, then adding 1059.6g (23 mol) of ethanol, heating to dissolve the beta-menadione, then dropwise adding hydrochloric acid (containing 2.3mol of hydrogen chloride) to carry out reduction reaction, after the reaction is finished, adding water into the reaction solution to precipitate a product, washing with water, and drying to obtain 74.9g (0.43 mol) of 2-methyl-1, 4-naphthalenediol;
(5) Dissolving the 2-methyl-1, 4-naphthalenediol obtained in the step 4 into chloroform, then adding 172.0g (1.29 mol) of anhydrous aluminum trichloride serving as a catalyst in batches, simultaneously slowly adding 219.5g (0.44 mol) of long-chain terpene primary alcohol (formula 2) into the chloroform, keeping the reaction temperature between 75 and 85 ℃, maintaining the pressure of the whole reaction system between-0.02 MPa and-0.01 MPa, and keeping the reaction time for 5 hours;
(6) Adding a mixed solution of dilute hydrochloric acid with the hydrochloric acid content of 8% and hydrogen peroxide with the hydrogen peroxide content of 10% into the reaction solution obtained in the step 5 to perform acidolysis oxidation reaction, and after the acidolysis oxidation reaction is finished, filtering, washing and drying to obtain 242.3g of a crude product of the compound shown in the formula 1, wherein n =7;
(7) Recrystallizing the crude product of the compound shown in the formula 1 obtained in the step 6 by using a mixed solution of ethanol and acetone, wherein the volume ratio of the ethanol to the acetone is 1: 5, so as to obtain 213.6g (0.329 mol) of a pure product of the compound shown in the formula 1, namely vitamin K2 (35), and the total yield is 65.8%.
Example 5
A method for preparing a compound represented by formula 1, comprising the steps of:
(1) 100.9g (0.34 mol) of bis (trichloromethyl) carbonate is added into an autoclave, and 1kg of diethyl ether is added for dissolution;
(2) 83.07g (0.5 mol) of phthalic acid powder is slowly added into the solution in the step 1 to carry out acylation reaction to generate phthaloyl chloride;
(3) And (3) adding 200g of zinc powder and cuprous chloride into the reaction solution obtained in the step (2), introducing propylene gas, keeping the pressure in the reaction kettle at 0.25MPa, filtering to remove the catalyst and solid particles after the reaction is finished, and removing the solvent to obtain 82.3g of crude beta-menadione with the purity of 95%, and recrystallizing the crude beta-menadione to obtain 79.2g (0.46 mol) of pure beta-menadione with the purity of more than 97%. The yield of the first three steps is 92.0 percent
(4) Adding 218.4 g (1.84 mol) of tin powder and 79.2g of beta-menadione into a three-neck flask, then adding 1059.6g (23 mol) of ethanol, heating to dissolve the beta-menadione, then dropwise adding hydrochloric acid (containing 2.3mol of hydrogen chloride) to carry out reduction reaction, after the reaction is finished, adding water into the reaction solution to precipitate a product, washing with water, and drying to obtain 74.9g (0.43 mol) of 2-methyl-1, 4-naphthalenediol;
(5) Dissolving the 2-methyl-1, 4-naphthalenediol obtained in the step 4 into chloroform, then adding 172.0g (1.29 mol) of anhydrous aluminum trichloride serving as a catalyst in batches, simultaneously slowly adding 267.5g (0.44 mol) of long-chain terpene primary alcohol (shown as a formula 2) into the chloroform, keeping the reaction temperature between 75 and 85 ℃, maintaining the pressure of the whole reaction system between-0.02 MPa and-0.01 MPa, and keeping the reaction time for 5 hours;
(6) Adding a mixed solution of dilute hydrochloric acid with the hydrochloric acid content of 8% and hydrogen peroxide with the hydrogen peroxide content of 10% into the reaction solution obtained in the step 5 to perform acidolysis oxidation reaction, and after the acidolysis oxidation reaction is finished, filtering, washing and drying to obtain 283.4g of a crude product of the compound shown in the formula 1, wherein n =9;
(7) Recrystallizing the crude product of the compound shown in the formula 1 obtained in the step 6 by using a mixed solution of ethanol and acetone, wherein the volume ratio of the ethanol to the acetone is 1: 5, so as to obtain 250.5g (0.318 mol) of a pure product of the compound shown in the formula 1, namely vitamin K2 (45), and the total yield is 63.6%.
Comparative example 1
The difference between the embodiment and the embodiment 2 is that in the step 6, hydrochloric acid is added for acidolysis, and hydrogen peroxide is added for oxidation after the acidolysis is completed; the rest is the same as embodiment 2, and will not be described again. The final vitamin K2 (10) has a total yield of 36.8%, which is significantly reduced. Because the structure before acidolysis is different from the structure after acidolysis, the reactivity of the substrate is different, and the rate and the yield are influenced.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and all modifications, equivalents and applications made by the present invention in the spirit of the present invention or other related fields are included in the scope of the present invention.
Claims (9)
1. A method for preparing a compound represented by formula 1, comprising the steps of:
(1) Adding bis (trichloromethyl) carbonate into an autoclave, and adding diethyl ether for dissolving;
(2) Slowly adding phthalic acid powder into the solution obtained in the step (1) to perform acylation reaction to generate phthaloyl chloride;
(3) Adding zinc powder and cuprous chloride into the reaction liquid obtained in the step (2), introducing propylene gas, keeping the pressure in the reaction kettle at 0.05-0.3 MPa, filtering to remove the catalyst and solid particles after the reaction is finished, removing the solvent to obtain a crude product beta-menadione, and recrystallizing the crude product beta-menadione to obtain a pure product beta-menadione;
(4) Adding tin powder and beta-menadione into a three-neck flask, adding ethanol, heating to dissolve the beta-menadione, dropwise adding hydrochloric acid, carrying out reduction reaction, adding water into a reaction solution after the reaction is finished, separating out a product, washing with water, and drying to obtain 2-methyl-1, 4-naphthalenediol;
(5) Dissolving the 2-methyl-1, 4-naphthalenediol obtained in the step (4) in chloroform, then adding anhydrous aluminum trichloride serving as a catalyst in batches, slowly adding long-chain terpene primary alcohol shown in a formula 2 into the chloroform at the same time, keeping the reaction temperature between 75 and 85 ℃, and keeping the pressure of the whole reaction system between-0.03 and-0.01 MPa for 3 to 5 hours;
(6) Adding a mixed solution of dilute hydrochloric acid and hydrogen peroxide into the reaction solution obtained in the step (5) to perform acidolysis oxidation reaction, and after the acidolysis oxidation reaction is finished, filtering, washing and drying to obtain a crude product of the compound shown in the formula 1;
(7) Recrystallizing the crude product of the compound shown in the formula 1 obtained in the step (6) by using a mixed solution of ethanol and acetone to obtain a pure product of the compound shown in the formula 1, namely vitamin K2;
in the formulas 1 and 2, n is 2, 4, 7 or 9.
2. The method according to claim 1, wherein the molar ratio of bis (trichloromethyl) carbonate in step (1) to phthalic acid in step (2) is 1: 1.0 to 1.5.
3. The method according to claim 1, wherein the zinc powder and the cuprous chloride are added in an amount of 5 to 25% by mass of the solution in step (3).
4. The preparation method according to claim 1, wherein the purity of the crude beta-menadione in the step (3) is 82 to 95%.
5. The preparation method according to claim 1, wherein the molar ratio of the beta-menadione to the hydrogen chloride to the tin powder contained in the ethanol and the hydrochloric acid in the step (4) is 1: 8 to 50: 2 to 5: 2 to 4.
6. The process according to claim 1, wherein the molar ratio of 2-methyl-1, 4-naphthalenediol to anhydrous aluminum trichloride in the step (5) is 1: 2 to 3.
7. The method according to claim 1, wherein in the formula 1 and the formula 2, n is 2, and the long-chain terpene primary alcohol is geraniol.
8. The production method according to claim 1, wherein the content of hydrochloric acid in the mixed solution in the step (6) is 3 to 8%, and the content of hydrogen peroxide in the mixed solution is 6 to 10%.
9. The method according to claim 1, wherein the volume ratio of ethanol to acetone in the step (7) is 1: 0.5 to 10.
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| CN104744230A (en) * | 2015-02-13 | 2015-07-01 | 安徽万和制药有限公司 | Method for synthesizing vitamin K1 |
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