CN102485709B - Preparation method of vitamin K2 compound - Google Patents
Preparation method of vitamin K2 compound Download PDFInfo
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- CN102485709B CN102485709B CN201010568730.3A CN201010568730A CN102485709B CN 102485709 B CN102485709 B CN 102485709B CN 201010568730 A CN201010568730 A CN 201010568730A CN 102485709 B CN102485709 B CN 102485709B
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Abstract
The invention provides a preparation method of a vitamin K2 compound. The preparation method comprises the following steps that a compound shown by the formula 2, a carbonyl protective agent and a bromination agent undergo a reaction to produce a compound shown in the formula 3; the compound shown in the formula 3 and a long-chain olefin metal compound undergo a reaction in the presence of catalysts to produce a compound shown in the formula 4; and the compound shown in the formula 4 reacts under an acid catalysis condition to produce a compound shown in the formula 1, wherein n represents an integer of 0 to 10, such as 1, 3, 6 or 8; and R represents C1-C4 of O,O-, O,S- and S,S-ketal and acetal (comprising annular ketal and acetal), O,O,O-orthoester, O,S,S-orthoester, S,S,S-orthoester, alkenyl ether, sulfo-alkenyl ether and enamine. The preparation method has the advantages of mild reaction conditions, less side reactions, poor product decomposability, relatively simple deprotection reaction conditions and high yield.
Description
Technical field
The invention belongs to the synthetic field of organic drug, specifically, relate to the synthetic method of vitamin K 2 compound.
Background technology
1934, first Denmark scientist found vitamin K and is confirmed that it is liposoluble vitamin.Vitamin K is that a class has the bioactive naphthoquinone derivatives of phylloquinone, is one of indispensable important VITAMIN in human body.Naturally occurring have vitamin K1, a K2, and wherein vitamin K1 is extensively present in green plants, is the important sources of vitamin K in food; Multiprenylmenaquinone is mainly synthesized by intestinal bacteria.
Multiprenylmenaquinone can be used for treatment and preventing osteoporosis disease, increases bone density, prevents fracture; Prevention liver cirrhosis develops into liver cancer; Treatment multiprenylmenaquinone shortage property hemorrhage, promotes the formation of thrombogen, accelerates blood coagulation, maintains the normal clotting time; Also there is the function of detoxification of diuresis, strengthening liver, and can reduce blood pressure.Multiprenylmenaquinone is series compound, is light yellow crystal or oily liquids, according to the length difference of the upper isoprene side chains of C3, has various ways, with MK-n, represents, n represents the number of isoprene unit on side chain, wherein the strongest with the activity of MK4, MK7.
1958, Isler etc. first chemosynthesis went out multiprenylmenaquinone series compound, but its method productive rate is lower.1994, Hamamura etc. applied for the patent that vitamin k4-cyclopentadiene adduction synthesis method is produced multiprenylmenaquinone.The method need be carried out under strong alkaline condition, easily causes the decomposition of multiprenylmenaquinone, and the long-chain terpenes tertiary alcohol changes primary alconol into after chlorination is reset, and side reaction is many, and yield is very low.It is raw material that acute bright and beautiful bright grade be take 2-MNQ and geranyl Linalool, and anhydrous ZnCl2, as catalyzer, adopts Fu-Ke alkylated reaction to synthesize multiprenylmenaquinone.The condition of the method is harsh, complex operation, and yield is lower, is not suitable for suitability for industrialized production.The people such as Xavier Garcias are with 2-methyl-3-bromo-1; 4-naphthalenediol and geranyl geranic acid are raw material; through reaction synthesise vitamins K2 such as condensation, elimination, deprotections; the method has been used sensitive chemical product n-Butyl Lithium; in operating process, needing to carry out column chromatography,, there is larger potential safety hazard in complex operation; yield is very low, is not suitable for industrial production.
Summary of the invention
Therefore, the object of the invention is to overcome the shortcoming of prior art, the method for simple to operate, reaction conditions is gentle and yield is higher synthesise vitamins K2 a kind of is provided.The method is first protected two carbonyls of 2-MNQ on synthesizing, bromo, then carries out condensation with geranyl spiceleaf bromine organometallic compound.Therefore; reaction conditions is gentle, and side reaction is few, and product is difficult for decomposing; deprotection reaction condition is also relatively simple; in acidic aqueous solution, get final product deprotection base, yield is higher, has overcome the shortcoming of Fu-Ke alkylated reaction; when realizing suitability for industrialized production smoothly; reduce environmental pollution, reduced production cost, embodied the aim of green reaction.
As follows for realizing the technical scheme of above-mentioned purpose:
A preparation method for compound shown in formula I, this preparation method comprises the following steps:
(1) compound shown in formula 2 reacts compound shown in the formula of obtaining 3 with carbonyl protective agent and brominated reagent;
(2) under catalyzer exists, compound shown in formula 3 reacts compound shown in the formula of obtaining 4 with long-chain olefin metallic compound;
(3) compound shown in formula 4 reacts and obtains compound shown in formula 1 under acid catalysis;
Wherein, the integer that n is 0～10, for example 1,3,6 or 8;
Specifically, n=1, multiprenylmenaquinone (10), i.e. MK2; N=3, multiprenylmenaquinone (20) is MK4; N=6, multiprenylmenaquinone (35), i.e. MK7; N=8, multiprenylmenaquinone (45), i.e. MK9.
The structural formula of MK2, MK4, MK7 and MK9 is as follows:
R is selected from C
1-C
4o, O-, O, S-and S, S-ketal, acetal (comprising cyclic ketal, acetal), O, O, O-ortho ester, O, S, S-ortho ester, S, S, S-ortho ester, alkene ether, sulfo-alkene ether, enamine.
When R selects different substituted radicals, it is one of following that the structural formula of compound shown in formula 3 can be selected from:
In above-mentioned preparation method, carbonyl protective agent in step (1) can be selected from hydroxyoxime, phenylhydrazone, methyl alcohol, ethylene glycol, 1,3 propylene glycol, dithioglycol, 1,3-dimercaptopropane and 4-methyl-2, one or more in 6,7-, tri-oxygen dicyclo [2.2.2] octanes; Brominated reagent can be selected from one or more in phosphorus tribromide, phosphorus pentabromide, tribromo oxygen phosphorus, acetyl bromide and N-bromo-succinimide.
In above-mentioned preparation method, preferably, the long-chain olefin metallic compound in step (2) is compound shown in formula 5,
Wherein, M is MgBr, ZnBr, (CH
2cH
2cH
2cH
2)
3sn;
Preferably, catalyzer is the title complex of Ni salt, Ni and title complex and the salt thereof of salt, Pd salt or Pd thereof, is preferably title complex and the salt thereof of Pd salt or Pd, more preferably triphenyl phosphorus palladium chloride or palladium chloride.
In above-mentioned preparation method, preferably, the reaction in step (1) is carried out in one or more are selected from the organic solvent of methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, methylene dichloride, toluene, tetrahydrofuran (THF), ether, methyl tertiary butyl ether and trichloromethane; Preferably, the reaction of step (2) is carried out in one or more are selected from the organic solvent of tetrahydrofuran (THF), methyl alcohol, ethanol, methylene dichloride, ether, toluene, methyl tertiary butyl ether and trichloromethane; Preferably, reaction in step (3) is selected from methyl alcohol at one or more, ethanol, propyl alcohol, Virahol, acetone, tetrahydrofuran (THF), in the water-containing organic solvent of DMF and dimethyl sulfoxide (DMSO), carry out, acid can be selected from one or more in hydrochloric acid, the vitriol oil, phosphoric acid, sulfonic acid, methylsulfonic acid, formic acid and glacial acetic acid.
In above-mentioned preparation method, preferably, step (1) one of comprises the following steps:
A. compound shown in formula 2 is dissolved in to organic solvent, drips the bromine of 1～2.5 equivalent at 0～30 ℃, drip and finish reaction at 10～70 ℃, be then concentrated into 1/2 volume, crystallization obtains compound shown in formula 3 at 0～10 ℃; Or
B. by compound organic solvent dissolution shown in formula 2, the acid that adds 0.01～4.5 equivalent, one or more in dry hydrogen chloride, dry hydrogen bromide, formic acid, glacial acetic acid, sulfuric acid, phosphoric acid, sulfonic acid and methylsulfonic acid for example, at 0～30 ℃, drip hydroxyoxime or the phenylhydrazone of 1～2.5 equivalent, at 30～70 ℃, react completely, drip 1～2.5 equivalent brominated reagent, concentratedly at the complete vacuum tightness at P≤0.8Mpa of question response and 30-80 ℃ desolventize to obtain compound shown in formula 3.
In above-mentioned preparation method, preferably, step (2) comprises the following steps:
By compound organic solvent dissolution shown in formula 3, add the catalyzer of 0.01～1.5 equivalent, the cuprous bromide of 0.01～2 equivalent, 1 of 2～5 times of volumes, 4 dioxane, the long-chain olefin metallic compound of 1～3 equivalent, at 20～80 ℃, react complete filtration, concentratedly at the vacuum tightness of P≤0.8Mpa and 30-80 ℃ desolventize to obtain compound shown in formula 4.
In above-mentioned preparation method, preferably, the preparation method of the long-chain olefin metallic compound in step (1) comprises the following steps:
To the metal reagent that adds 1～10 equivalent in the organic solvent of 1～3 times of volume, for example metal simple-substance magnesium, metal simple-substance zinc or three normal-butyl hydrogen tin, with-10 ℃～30 ℃ at splash into 5 times of volumes that comprise geranyl spiceleaf bromine and enclose organic solvents, and add iodine or the Grignard reagent of 0.01～1 equivalent, for example C
1-C
10organo-magnesium compound, as iodate methyl magnesium, methylmagnesium-bromide, ethyl-magnesium-bromide, brominated hexyl magnesium etc., reaction is to completely at 10～80 ℃.
In above-mentioned preparation method, preferably, step (3) comprises the following steps:
Compound 4 is dissolved in the organic solvent of 3-10 times of volume, at 0-30 ℃, drip the aqueous acid of the 0.5-12mol/l of 0.5-5 equivalent, at 10-70 ℃, reaction is to completely, concentrated except organic solvent at the vacuum tightness of P≤0.8Mpa and 30-80 ℃, filters and obtain compound shown in formula 1.
In above-mentioned preparation method, shown in formula 4, the preparation method of compound comprises the following steps:
(1) by compound organic solvent dissolution shown in formula 3, add the catalyzer of 0.01～1.5 equivalent, the cuprous bromide of 0.01～2 equivalent, 1 of 2～5 times of volumes, 4 dioxane, the organometallic compound of the spiceleaf bromine of 1～3 equivalent, at 30～80 ℃, react complete, cold filtration, filtrate is concentrated under vacuum tightness P≤0.8Mpa desolventizes to obtain compound shown in the formula 4 of n=1;
(2) compound organic solvent dissolution shown in the formula 4 of the n=1 being prepared by step (1), tindioxide-the peroxy tert-butyl alcohol that adds 1～25 equivalent, at 0～35 ℃, react complete, filter, concentrated, use again the organic solvent dissolution of 1～15 times of volume, add the sodium borohydride of 0.2～4 equivalent or POTASSIUM BOROHYDRIDE to reacting completely, obtain compound shown in formula 6;
(3) by compound organic solvent dissolution shown in formula 6, at-10～30 ℃, drip tribromo oxygen phosphorus or the phosphorus tribromide solution of 0.5～5 equivalent, reaction, obtains compound shown in formula 7 at 0～30 ℃;
(4) by compound organic solvent dissolution shown in formula 7, add the catalyzer of 0.01～1.5 equivalent, the cuprous bromide of 0.01～2 equivalent, 1 of 2～5 times of volumes, 4 dioxane, the organometallic compound of the spiceleaf bromine of 1～3 equivalent, at 30～80 ℃, react complete, cold filtration, filtrate is concentrated at vacuum tightness P≤0.8Mpa and 30-80 ℃ desolventizes to obtain compound shown in the formula 4 of n=3;
Wherein, R is selected from C
1-C
4o, O-, O, S-and S, S-ketal, acetal (comprising cyclic ketal, acetal), O, O, O-ortho ester, O, S, S-ortho ester, S, S, S-ortho ester, alkene ether, sulfo-alkene ether, enamine.
In step (the 1)～step (4) of compound shown in preparation formula 4, organic solvent is selected from one or more in tetrahydrofuran (THF), methyl alcohol, ethanol, methylene dichloride, ether, methyl tertiary butyl ether and trichloromethane.
In the step (1) and step (4) of compound shown in preparation formula 4, catalyzer is the title complex of Ni salt, Ni and title complex and the salt thereof of salt, Pd salt or Pd thereof; Be preferably title complex and the salt thereof of Pd salt or Pd; More preferably triphenyl phosphorus palladium chloride or palladium chloride.
The organometallic compound of spiceleaf bromine is that the azoviolet of spiceleaf bromine is, the tri-n-butyl tin of the zincon of spiceleaf bromine or spiceleaf bromine.
The preparation method of the organometallic compound of described spiceleaf bromine comprises the steps:
To the metal reagent that adds 1～10 equivalent in the organic solvent of 1～3 times of volume, for example metal simple-substance magnesium, metal simple-substance zinc or three normal-butyl hydrogen tin, at-10 ℃～30 ℃, splash into 5 times of volume organic solvent dissolution spiceleaf bromines, and add the iodine of 0.01～1 equivalent or Grignard reagent as initiator, C for example
1-C
10organo-magnesium compound, as iodate methyl magnesium, methylmagnesium-bromide, ethyl-magnesium-bromide, brominated hexyl magnesium etc., 10～80 ℃ of reactions are to complete.
At this, prepare in the organometallic compound of spiceleaf bromine, described organic solvent is selected from one or more in tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane and methyl tertiary butyl ether.
Most reaction of the present invention is all carried out under the condition of low temperature or room temperature, has effectively controlled the decomposition of product and the conversion of configuration, has improved the yield of reaction, has simplified actually operating.In addition, reaction conditions of the present invention is gentle, and easy and simple to handle, product is easy to separation and purification, and yield is higher, and solvent can be reclaimed to greatest extent, is very suitable for suitability for industrialized production.Meanwhile, solvent for use is all more common, and catalyst levels is also less, has effectively reduced the pollution to environment.
Embodiment
Below in conjunction with embodiment, the present invention is further described in detail, the embodiment providing is only in order to illustrate the present invention, rather than in order to limit the scope of the invention.
embodiment 1
(1) compound shown in formula 3 is synthetic
The 2-MNQ that adds 500ml methyl alcohol and 100g in the four-hole bottle of 1L, is cooled to 0 ℃, drips bromine 111.7g at temperature control 0-10 ℃, notes connecting alkali absorption unit.Drip to finish, be incubated 3-5 hour at 10-30 ℃, be slowly warming up to backflow and react again 3 hours, be naturally cooled to room temperature, then be cooled to 0-5 ℃ of natural crystallization 10 hours, suction filtration, drying under reduced pressure at 25-30 ℃, obtains 124.4g white solid, and yield is 91%.
(2) compound shown in formula 4 is synthetic
A. in the dry four-hole bottle of 1L, add 87g tri-n-butyl tin hydrogen, 200ml tetrahydrofuran (THF), be cooled to-10 ℃, temperature control-10 are to 10 ℃ of 300ml tetrahydrofuran solutions that drip geranyl spiceleaf bromine 100g, naturally rise again to 20-25 ℃ of reaction to complete, suction filtration is to doing to obtain yellow solid 163.2g, be the tri-n-butyl tin compound of geranyl spiceleaf bromine, yield is 98%.
B. to being equipped with in the 2L four-hole bottle of reflux, add 500ml tetrahydrofuran (THF), be heated to reflux 30 minutes, be cooled to room temperature, add compound shown in formula 3 prepared by 100g step (1), it is dissolved completely, be filled with nitrogen and remove the oxygen in system, add 2.1g triphenyl phosphorus palladium chloride, 20.8g cuprous bromide, Isosorbide-5-Nitrae-dioxane of 200ml, the tri-n-butyl tin compound of 180.6g geranyl spiceleaf bromine, at 25-30 ℃, reaction, to completely, is filtered.At the vacuum tightness of P≤0.8Mpa and 40-45 ℃, concentrated desolventizing, obtains 125.2g yellow solid, and yield is 80.2%.
(3) compound shown in formula 1 is synthetic
In the four-hole bottle of 2L, add compound, 600ml methyl alcohol shown in formula 4 prepared by 100g step (2), be cooled to 0 ℃, at temperature control 0-10 ℃, drip 1mol/L dilute hydrochloric acid 150ml, naturally rise again to 25-30 ℃ of reaction to complete, most of methyl alcohol in concentration response system, filter to obtain the crude product of compound shown in formula 1, with acetone recrystallization, obtain light yellow crystal 73.7g, yield is 89%.
embodiment 2
(1) compound shown in formula 3 is synthetic
In the four-hole bottle of 1L, add 500ml toluene, the 2-MNQ of 100g, ethylene glycol 49.5g, after backflow 3h, is cooled to 0 ℃, drips the tetrahydrofuran solution 100ml containing tribromo oxygen phosphorus 200g at temperature control 0-10 ℃, notes connecting alkali absorption unit.Drip to finish, be incubated 3-5 hour at 10-30 ℃, be slowly warming up to backflow and react again 3 hours, be naturally cooled to room temperature, then be cooled to 0-5 ℃ of natural crystallization 10 hours, suction filtration, drying under reduced pressure at 25-30 ℃, obtains 120.3g white solid, and yield is 89%.
(2) compound shown in formula 4 is synthetic
A. in the dry four-hole bottle of 1L, add 50g simple substance magnesium, iodine 1g, 600ml tetrahydrofuran (THF) and geranyl spiceleaf bromine 100g, be slowly heated to the 10h that refluxes, and is naturally cooled to room temperature, i.e. the tetrahydrofuran solution of geranyl spiceleaf magnesium bromide.
B. to being equipped with in the 2L four-hole bottle of reflux, add 500ml tetrahydrofuran (THF), triphenyl phosphorus palladium chloride 10g, compound shown in formula 3 prepared by 100g step (1), be filled with nitrogen and remove the oxygen in system, drip the tetrahydrofuran solution of the geranyl spiceleaf magnesium bromide of above-mentioned preparation, at 25-30 ℃, reaction is to complete, temperature control drips ammonium chloride solution and destroys unnecessary Grignard reagent, with methylene dichloride 300ml * 2, extract, concentrated desolventizing at the vacuum tightness of P≤0.8Mpa and 40-45 ℃, obtain 130.2g yellow solid, yield is 83.4%.
(3) compound shown in formula 1 is synthetic
In the four-hole bottle of 2L, add compound, 600ml tetrahydrofuran (THF) shown in formula 4 prepared by 100g step (2), be cooled to 0 ℃, at temperature control 0-10 ℃, drip 3mol/L dilute phosphoric acid 150ml, naturally rise again to 25-30 ℃ of reaction to complete, most of solvent in concentration response system, filter to obtain the crude product of compound shown in formula 1, with acetone recrystallization, obtain light yellow crystal 73.7g, yield is 89%.
embodiment 3
(1) compound shown in formula 3 is synthetic
In the four-hole bottle of 1L, add 500ml toluene, the 2-MNQ of 100g, dithioglycol 75.5g, after backflow 3h, is cooled to 0 ℃, drips the tetrahydrofuran solution 100ml containing tribromo oxygen phosphorus 200g at temperature control 0-10 ℃, notes connecting alkali absorption unit.Drip to finish, be incubated 3-5 hour at 10-30 ℃, be slowly warming up to backflow and react again 3 hours, be naturally cooled to room temperature, then be cooled to 0-5 ℃ of natural crystallization 10 hours, suction filtration, drying under reduced pressure at 25-30 ℃, obtains 143g white solid, and yield is 89%.
(2) compound shown in formula 4 is synthetic
A. in the dry four-hole bottle of 1L, add 50g simple substance zinc, iodine 1g, 600ml toluene and geranyl spiceleaf bromine 100g, be slowly heated to the 10h that refluxes, and is naturally cooled to room temperature, i.e. the toluene solution of geranyl spiceleaf magnesium bromide.
B. to being equipped with in the 2L four-hole bottle of reflux, add 500ml tetrahydrofuran (THF), triphenyl phosphorus palladium chloride 10g, compound shown in formula 3 prepared by 100g step (1), be filled with nitrogen and remove the oxygen in system, drip the tetrahydrofuran solution of the geranyl spiceleaf magnesium bromide of above-mentioned preparation, at 25-30 ℃, reaction is to complete, temperature control drips ammonium chloride solution and destroys unnecessary Grignard reagent, with methyl tertiary butyl ether 300ml * 2, extract, concentrated desolventizing at the vacuum tightness of P≤0.8Mpa and 40-45 ℃, obtain 120.2g yellow solid, yield is 77%.
(3) compound shown in formula 1 is synthetic
In the four-hole bottle of 2L, add compound, 600ml methyl alcohol shown in formula 4 prepared by 100g step (2), be cooled to 0 ℃, at temperature control 0-10 ℃, drip 1mol/L dilute hydrochloric acid 150ml, naturally rise again to 25-30 ℃ of reaction to complete, most of methyl alcohol in concentration response system, filter to obtain the crude product of compound shown in formula 1, with acetone recrystallization, obtain light yellow crystal 73.7g, yield is 89%.
embodiment 4
(1) compound shown in formula 4 (n=1) is synthetic
A. in the dry four-hole bottle of 1L, add 171g tri-n-butyl tin hydrogen, 200ml tetrahydrofuran (THF), be cooled to-10 ℃, temperature control-10 are to 10 ℃ of 300ml tetrahydrofuran solutions that drip spiceleaf bromine 100g, naturally rise again to 20-25 ℃ of reaction to complete, suction filtration is to doing to obtain yellow solid 192.8g, be the tri-n-butyl tin compound of spiceleaf bromine, yield is 97.8%.
B. to being equipped with in the 2L four-hole bottle of reflux, add 500ml tetrahydrofuran (THF), be heated to reflux 30 minutes, be cooled to room temperature, add compound shown in 100g formula 3 (being prepared by embodiment 1), it is dissolved completely, be filled with nitrogen and remove the oxygen in system, add 2.1g triphenyl phosphorus palladium chloride, 20.8g cuprous bromide, Isosorbide-5-Nitrae-dioxane of 200ml, the tri-n-butyl tin compound of 124.6g spiceleaf bromine, at 25-30 ℃, reaction, to completely, is filtered.At the vacuum tightness of P≤0.8Mpa and 40-45 ℃, concentrated desolventizing, obtains 108.5g yellow solid, and yield is 93%.
(2) compound shown in formula 6 (n=1) is synthetic
In the dry four-hole bottle of 1L, add compound shown in 100g formula 4 (n=1), 600ml tetrahydrofuran (THF), be cooled to-5-0 ℃, add 8.5g tindioxide, the superoxol of the 30g trimethyl carbinol, naturally rise again to 20-25 ℃ of reaction to complete, 45 ℃ of decompressions steam solvent, add methyl alcohol 600ml to make its dissolving, filtering residual solids, be cooled to 0 ℃, add sodium borohydride 12g in batches, stabilize to room temperature, reaction is to complete, 30 ℃ of following 1mol/L hydrochloric acid solns that drip of temperature control destroy unreacted sodium borohydride, water extracts with methyl tertiary butyl ether, 45 ℃ of concentrating under reduced pressure go out solvent, obtain faint yellow solid 95.7g, it is compound shown in formula 6, yield: 92.3%.
(3) compound shown in formula 7 (n=1) is synthetic
In the dry four-hole bottle of 1L, add compound shown in 100g formula 6 (n=1), 400ml methylene dichloride, temperature control 0-10 ℃ of dichloromethane solution 200ml that drips tribromo oxygen phosphorus 78g, naturally rise again to room temperature, react complete, reaction system is slowly poured in frozen water, with the sodium hydroxide solution of 10mol/l, adjust pH to 7-8, separatory, water extracts with methyl tertiary butyl ether, and decompression steams solvent and obtains milk yellow solid 110.5, be compound shown in formula 7 (n=1), yield 96%.
(4) compound shown in formula 4 (n=3) is synthetic
To being equipped with in the 2L four-hole bottle of reflux, add 500ml tetrahydrofuran (THF), be heated to reflux 30 minutes, be cooled to room temperature, add compound shown in formula 7 prepared by 100g step (3), it is dissolved completely, be filled with nitrogen and remove the oxygen in system, add 2.1g triphenyl phosphorus palladium chloride, 20.8g cuprous bromide, Isosorbide-5-Nitrae-dioxane of 200ml, the tri-n-butyl tin compound of 107g spiceleaf bromine, at 25-30 ℃, reaction, to completely, is filtered.At the vacuum tightness of P≤0.8Mpa and 40-45 ℃, concentrated desolventizing, obtains 116g yellow solid, and yield is 90%.
embodiment 5
(1) compound shown in formula 4 (n=1) is synthetic
A. in the dry four-hole bottle of 1L, add 171g tri-n-butyl tin hydrogen, 200ml tetrahydrofuran (THF), be cooled to-10 ℃, temperature control-10 are to 10 ℃ of 300ml tetrahydrofuran solutions that drip spiceleaf bromine 100g, naturally rise again to 20-25 ℃ of reaction to complete, suction filtration is to doing to obtain yellow solid 192.8g, be the tri-n-butyl tin compound of spiceleaf bromine, yield is 97.8%.
B. to being equipped with in the 2L four-hole bottle of reflux, add 500ml tetrahydrofuran (THF), be heated to reflux 30 minutes, be cooled to room temperature, add compound shown in 98.8g formula 3 (being prepared by embodiment 2), it is dissolved completely, be filled with nitrogen and remove the oxygen in system, add 2.1g palladium chloride, 20.8g cuprous bromide, Isosorbide-5-Nitrae-dioxane of 150ml, the tri-n-butyl tin compound of 124.6g spiceleaf bromine, at 25-30 ℃, reaction, to completely, is filtered.At the vacuum tightness of P≤0.8Mpa and 40-45 ℃, concentrated desolventizing, obtains 128.5g yellow solid, and yield is 92%.
(2) compound shown in formula 6 (n=1) is synthetic
In the dry four-hole bottle of 1L, add compound shown in 100g formula 4 (n=1), 600ml tetrahydrofuran (THF), be cooled to-5-0 ℃, add 7.5g tindioxide, the superoxol of the 20g trimethyl carbinol, naturally rise again to 20-25 ℃ of reaction to complete, 45 ℃ of decompressions steam solvent, add ethanol 600ml to make its dissolving, filtering residual solids, be cooled to 0 ℃, add POTASSIUM BOROHYDRIDE 14g in batches, stabilize to room temperature, reaction is to complete, 30 ℃ of following 1mol/L hydrochloric acid solns that drip of temperature control destroy unreacted POTASSIUM BOROHYDRIDE, water extracts with methyl tertiary butyl ether, 45 ℃ of concentrating under reduced pressure go out solvent, obtain faint yellow solid 95.7g, it is compound shown in formula 6, yield: 92.3%.
(3) compound shown in formula 7 (n=1) is synthetic
In the dry four-hole bottle of 1L, add compound shown in 100g formula 6 (n=1), 400ml methylene dichloride, temperature control 0-10 ℃ of dichloromethane solution 200ml that drips tribromo oxygen phosphorus 78g, naturally rise again to room temperature, react complete, reaction system is slowly poured in frozen water, with the sodium hydroxide solution of 10mol/l, adjust pH to 7-8, separatory, water extracts with methyl tertiary butyl ether, and decompression steams solvent and obtains milk yellow solid 110.5, be compound shown in formula 7 (n=1), yield 96%
(4) compound shown in formula 4 (n=3) is synthetic
To being equipped with in the 2L four-hole bottle of reflux, add 500ml tetrahydrofuran (THF), be heated to reflux 30 minutes, be cooled to room temperature, add compound shown in formula 7 prepared by 100g step (3), it is dissolved completely, be filled with nitrogen and remove the oxygen in system, add 2.1g triphenyl phosphorus palladium chloride, 20.8g cuprous bromide, Isosorbide-5-Nitrae-dioxane of 200ml, the tri-n-butyl tin compound of 107g spiceleaf bromine, at 25-30 ℃, reaction, to completely, is filtered.At the vacuum tightness of P≤0.8Mpa and 40-45 ℃, concentrated desolventizing, obtains 114.7g yellow solid, and yield is 89.8%.
embodiment 6
Synthesizing of compound shown in formula 4
A. in the dry four-hole bottle of 1L, add 50g simple substance magnesium, iodine 1g, 600ml tetrahydrofuran (THF) and spiceleaf bromine 100g, be slowly heated to the 10h that refluxes, and is naturally cooled to room temperature, i.e. the tetrahydrofuran solution of spiceleaf magnesium bromide.
B. to being equipped with in the 2L four-hole bottle of reflux, add 500ml tetrahydrofuran (THF), triphenyl phosphorus palladium chloride 10g, compound shown in 100g formula 7 (being prepared by embodiment 4), be filled with nitrogen and remove the oxygen in system, drip the tetrahydrofuran solution of the spiceleaf magnesium bromide of above-mentioned preparation, at 25-30 ℃, reaction is to complete, temperature control drips ammonium chloride solution and destroys unnecessary Grignard reagent, with methylene dichloride 300ml * 2, extract, concentrated desolventizing at the vacuum tightness of P≤0.8Mpa and 40-45 ℃, obtain 130.2g yellow solid, yield is 83.4%.
Claims (12)
1. a preparation method for compound shown in formula 1, this preparation method comprises the following steps:
(1) compound shown in formula 2 reacts compound shown in the formula of obtaining 3 with carbonyl protective agent and brominated reagent; Described carbonyl protective agent is selected from one or more in methyl alcohol, ethylene glycol and dithioglycol;
(2) under catalyzer exists, compound shown in formula 3 reacts compound shown in the formula of obtaining 4 with long-chain olefin metallic compound;
(3) compound shown in formula 4 reacts and obtains compound shown in formula 1 under acid catalysis;
Wherein, the integer that n is 0～10;
The structural formula of compound shown in formula 3 is one of following:
2. preparation method according to claim 2, is characterized in that, described n is 1,3,6 or 8.
3. preparation method according to claim 1, is characterized in that, the brominated reagent in described step (1) is selected from one or more in phosphorus tribromide, phosphorus pentabromide, tribromo oxygen phosphorus, acetyl bromide and N-bromo-succinimide.
4. preparation method according to claim 1, is characterized in that, the long-chain olefin metallic compound in described step (2) is compound shown in formula 5,
Wherein, M is MgBr, ZnBr, (CH
2cH
2cH
2cH
2)
3sn;
Described catalyzer is Ni salt or Pd salt.
5. preparation method according to claim 4, is characterized in that, the title complex that described Ni salt is Ni, the title complex that described Pd salt is Pd.
6. preparation method according to claim 4, is characterized in that, the title complex that described catalyzer is Pd.
7. preparation method according to claim 4, is characterized in that, described catalyzer is triphenyl phosphorus palladium chloride or palladium chloride.
8. according to the preparation method described in any one in claim 1 to 7, it is characterized in that, the reaction in described step (1) is carried out in one or more are selected from the organic solvent of methylene dichloride, toluene, tetrahydrofuran (THF), ether, methyl tertiary butyl ether and trichloromethane; The reaction of described step (2) is carried out in one or more are selected from the organic solvent of tetrahydrofuran (THF), methylene dichloride, ether, toluene, methyl tertiary butyl ether and trichloromethane; Reaction in described step (3) is selected from methyl alcohol at one or more, ethanol, propyl alcohol, Virahol, acetone, tetrahydrofuran (THF), N, in the water-containing organic solvent of dinethylformamide and dimethyl sulfoxide (DMSO), carry out, described acid is selected from one or more in hydrochloric acid, the vitriol oil, phosphoric acid, sulfonic acid, methylsulfonic acid, formic acid and glacial acetic acid.
9. according to the preparation method described in any one in claim 1 to 7, it is characterized in that, the preparation method of the long-chain olefin metallic compound in described step (2) comprises the following steps:
Metal reagent to adding 1～10 equivalent in the organic solvent of 1～3 times of volume splashes into 5 times of volume organic solvents that comprise geranyl spiceleaf bromine, and adds iodine or the Grignard reagent of 0.01～1 equivalent at-10 ℃～30 ℃, and reaction is to completely at 10～80 ℃.
10. preparation method according to claim 9, is characterized in that, described metal reagent is metal simple-substance magnesium, metal simple-substance zinc and three normal-butyl hydrogen tin.
11. preparation methods according to claim 9, is characterized in that, described Grignard reagent is C
1-C
10organo-magnesium compound.
12. preparation methods according to claim 9, is characterized in that, described Grignard reagent is iodate methyl magnesium, methylmagnesium-bromide, ethyl-magnesium-bromide or brominated hexyl magnesium.
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| Bertrand L.Chenard.Organocopper chemistry of quinone bisketals.application to the synthesis of isoprenoid quinone systems.《J.Org.Chem.》.1980,第45卷(第3期),第378-384页. |
| Organocopper chemistry of quinone bisketals.application to the synthesis of isoprenoid quinone systems;Bertrand L.Chenard;《J.Org.Chem.》;19801231;第45卷(第3期);第378-384页 * |
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