CN108250177B - A kind of preparation method of 1,4- benzdioxan -2- formic acid - Google Patents

A kind of preparation method of 1,4- benzdioxan -2- formic acid Download PDF

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CN108250177B
CN108250177B CN201810225851.4A CN201810225851A CN108250177B CN 108250177 B CN108250177 B CN 108250177B CN 201810225851 A CN201810225851 A CN 201810225851A CN 108250177 B CN108250177 B CN 108250177B
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benzdioxan
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nitrae
isosorbide
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CN108250177A (en
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柴腾
黄龙龙
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SHANGHAI BALMXY PHARMACEUTICAL Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The present invention provides one kind 1, the preparation method of 4- benzdioxan -2- formic acid, the preparation method includes using benzyloxy glycidol ether and adjacent halobenzene phenol as raw material, by cyclization reaction, debenzylation and oxidation reaction obtain described 1, 4- benzdioxan -2- formic acid, preparation method provided by the invention, reaction process is simple, it is reacted using benzyloxy glycidol ether and adjacent halobenzene phenol as raw material, pollutant will not be generated, it is non-stimulated without easy allergy object, compared to other existing routes, it is environmental-friendly, total recovery is high, it is readily mass-produced, 1 be finally prepared, 4- benzdioxan -2- formic acid ee value is greater than 99%, chiral purity is high.

Description

A kind of preparation method of 1,4- benzdioxan -2- formic acid
Technical field
The invention belongs to medicine intermediates to synthesize field, be related to a kind of preparation method of Isosorbide-5-Nitrae-benzdioxan -2- formic acid.
Background technique
(R) -1,4- benzdioxan -2- formic acid or (S) -1,4- benzdioxan -2- formic acid are a kind of important medicine Intermediate can be used as the intermediate for preparing Carclura, before having a wide range of applications in chipal compounds field Scape, about its synthetic method, there are mainly two types of routes at present:
The first route is from chiral benzyl group glycerol ether, finally through double tosylations, cyclization, hydrogenation and oxidation Obtain target product, the route of reaction approximately as:
But in this route, double tosylation brings pollution of first step reaction is larger, and yield is also relatively low；
Second of route is to split to obtain final product by double brominations, cyclization, hydrolysis and enzyme from acrylate, Its react route approximately as:
But in this route, there is also the bromines during double bromos, used to the disagreeableness problem of environment, and after When continuous bioconversion, the purity of chipal compounds is not high, influences yield.
Therefore, how to develop a new route, solve the problems, such as environmental pollution and purity and yield, this for expanding production, Cost is reduced to have great importance.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of 1,4- benzdioxan -2- formic acid.
To achieve this purpose, the present invention adopts the following technical scheme:
The present invention provides a kind of Isosorbide-5-Nitrae-benzdioxan -2- formic acid preparation methods, and the preparation method includes with benzyl Oxygen glycidol ether and adjacent halobenzene phenol are raw material, obtain the Isosorbide-5-Nitrae-benzene by cyclization reaction, debenzylation and oxidation reaction And dioxanes -2- formic acid.
Isosorbide-5-Nitrae provided by the invention-benzdioxan -2- formic acid preparation method, reaction process is simple, is shunk with benzyloxy sweet Oily ether and adjacent halobenzene phenol are that raw material is reacted, and will not generate pollutant, non-stimulated without easy allergy object, compared to it is existing other Route, environmental-friendly, total recovery is high, is readily mass-produced, the Isosorbide-5-Nitrae being finally prepared-benzdioxan -2- formic acid ee value is greater than 99%, chiral purity is high.
The present invention is to provide a completely new synthetic routes, carry out Isosorbide-5-Nitrae-using route of the invention currently without research The synthesis of benzdioxan -2- formic acid.
Preferably, the Isosorbide-5-Nitrae-benzdioxan -2- formic acid includes (R)-Isosorbide-5-Nitrae-benzdioxan -2- formic acid and (S) -1, 4- benzdioxan -2- formic acid.
Preferably, the preparation method comprises the following steps:
(1) by benzyloxy glycidol ether and adjacent halobenzene phenol in the presence of alkaline reagent, heating, cyclization reaction are obtained in solvent To 2- benzyloxymethyl -2,3- dihydrobenzo dioxanes, specific reaction equation is as follows:
(2) the 2- benzyloxymethyl -2,3- dihydrobenzo dioxanes that step (1) obtains carries out debenzylation in the presence of a catalyst Reaction obtains Isosorbide-5-Nitrae-benzdioxan -2- methanol, and specific reaction equation is as follows:
(3) the 1,4- benzdioxan -2- methanol that step (2) obtains and oxidant carry out oxidation reaction and obtain the 1,4- Benzdioxan -2- formic acid, specific reaction equation are as follows:
In the present invention, " * " represents chiral atom in structural formula.
Preferably, neighbour's halobenzene phenol described in step (1) includes any one in 2- fluorophenol, 2- bromophenol or 2- chlorophenol Kind, preferably 2- fluorophenol；
Preferably, the molar ratio of benzyloxy glycidol ether described in step (1) and adjacent halogen phenol reactant is 1:1-1.3, example It such as can be 1:1,1:1.1,1:1.2 or 1:1.3.
Preferably, alkaline reagent described in step (1) includes potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate or bicarbonate In potassium any one or at least two combination, preferably potassium carbonate.
Preferably, solvent described in step (1) is n,N-Dimethylformamide.
Preferably, the temperature of cyclization reaction described in step (1) be 100-130 DEG C, such as can be 100 DEG C, 105 DEG C, 110 DEG C, 115 DEG C, 120 DEG C, 125 DEG C or 130 DEG C.
Preferably, the time of cyclization reaction described in step (1) be 15-20h, such as can be 15h, 16h, 17h, 18h, 19h or 20h.
In the present invention, it by the reaction in step (1), successfully avoids and generates pollution in reaction process, compared to mesh Preceding existing synthetic method is more environmentally-friendly, low in raw material price, and reaction yield is high, and chiral purity is high, and ee value is greater than 99%, It during cyclization reaction, only needs to heat, so that it may which directly cyclization, reaction is easy, easy to operate, is conducive to largely be prepared.
Preferably, the mass ratio of 2- benzyloxymethyl -2,3- dihydrobenzo dioxanes and catalyst described in step (2) is (8-12): 1, such as can be 8:1,8.5:1,9:1,9.5:1,10:1,10.5:1,11:1,11.5:1 or 12:1.
Preferably, step (2) catalyst is palladium carbon.
Preferably, the solvent of reaction described in step (2) be methanol, ethyl acetate or chloroform in any one or at least Two kinds of combination, preferably methanol.
Preferably, it reacts described in step (2) and carries out in a hydrogen atmosphere.
Preferably, the temperature of reaction described in step (2) is 35-45 DEG C, such as can be 35 DEG C, 36 DEG C, 37 DEG C, 38 DEG C, 39 DEG C, 40 DEG C, 41 DEG C, 42 DEG C, 43 DEG C, 44 DEG C or 45 DEG C.
Preferably, the time of reaction described in step (2) be 12-18h, such as can be 12h, 13h, 14h, 15h, 16h, 17h or 18h.
Preferably, oxidant described in step (3) is sodium hypochlorite.
Preferably, in step (3) Isosorbide-5-Nitrae-benzdioxan -2- methanol and oxidant molar ratio 1:1.5-2.5, such as can To be 1:1.5,1:1.7,1:1.9,1:2,1:2.3 or 1:2.5.
Preferably, step (3) described oxidation reaction carries out in the presence of a catalyst, and the catalyst is preferably 2,2,6,6- Tetramethyl piperidine oxides (Tempo).
Preferably, relative to 0.5mol Isosorbide-5-Nitrae-benzdioxan -2- methanol, the dosage of catalyst described in step (3) is 0.01-0.03mol, such as can be 0.01mol, 0.015mol, 0.02mol, 0.025mol or 0.0.3mol.
Preferably, step (3) described oxidation reaction carries out in the presence of alkaline reagent.
Preferably, the alkaline reagent be potassium carbonate, saleratus, cesium carbonate, in sodium bicarbonate any one or extremely Few two kinds of combination, preferably saleratus.
Preferably, relative to 0.5mol Isosorbide-5-Nitrae-benzdioxan -2- methanol, the dosage of alkaline reagent described in step (3) For 1-2mol, for example, can be 1mol, 1.1mol, 1.2mol, 1.3mol, 1.4mol, 1.5mol, 1.6mol, 1.7mol, 1.8mol, 1.9mol or 2mol.
Preferably, oxidation reaction described in step (3) carries out in the presence of halide.
Preferably, the halide includes any one in potassium bromide, sodium bromide, potassium iodide or sodium iodide or at least two The combination of kind, preferably potassium bromide.
Preferably, relative to 0.5mol Isosorbide-5-Nitrae-benzdioxan -2- methanol, the dosage of the halide is 0.1- 0.3mol, such as can be 0.1mol, 0.15mol, 0.2mol, 0.25mol or 0.3mol.
Preferably, the solvent of oxidation reaction described in step (3) is any one in methylene chloride, chloroform or ethyl acetate Kind or at least two combination, preferably methylene chloride；
Preferably, the time of oxidation reaction described in step (3) be 9-15h, such as can be 9h, 10h, 11h, 12h, 13h, 14h or 15h.
Preferably, the method for oxidation reaction described in step (3) specifically: by Isosorbide-5-Nitrae-benzdioxan -2- methanol and oxygen Agent, catalyst, halide, saleratus are mixed in solvent, are stirred and evenly mixed, and sodium hypochlorite is then added dropwise and is reacted, low Temperature reaction obtains the 1,4- benzdioxan -2- formic acid again after temperature reaction.
In the present invention, it when sodium hypochlorite is added dropwise, needs slowly to be added dropwise, oxidation effectiveness can be made more preferable in this way.
Preferably, the temperature of the mixing is 0-5 DEG C, such as can be 0 DEG C, 1 DEG C, 2 DEG C, 3 DEG C, 4 DEG C or 5 DEG C.
Preferably, the temperature of the low-temp reaction is 0-10 DEG C, such as can be 0 DEG C, 1 DEG C, 2 DEG C, 3 DEG C, 4 DEG C, 5 DEG C, 6 DEG C, 7 DEG C, 8 DEG C, 9 DEG C or 10 DEG C.
Preferably, the time of the low-temp reaction is 2-4h, such as can be 2h, 2.5h, 3h, 3.5h or 4h.
Preferably, the temperature of the temperature reaction is 20-35 DEG C, such as can be 20 DEG C, 22 DEG C, 25 DEG C, 27 DEG C, 29 DEG C, 30 DEG C, 32 DEG C, 33 DEG C, 34 DEG C or 35 DEG C.
Preferably, the time of the temperature reaction is 7-11h, such as can be 7h, 8h, 9h, 10h or 11h.
In the present invention, by controlling to adjust reaction temperature, oxidation reaction can be made to carry out more abundant, yield is higher.
Compared with the existing technology, the invention has the following advantages:
Isosorbide-5-Nitrae provided by the invention-benzdioxan -2- formic acid preparation method, reaction process is simple, is shunk with benzyloxy sweet Oily ether and adjacent halobenzene phenol are that raw material is reacted, and will not generate pollutant, non-stimulated without easy allergy object, compared to it is existing other Route, environmental-friendly, total recovery is high, is readily mass-produced, the Isosorbide-5-Nitrae being finally prepared-benzdioxan -2- formic acid ee value is greater than 99%, chiral purity is high.
Specific embodiment
The technical scheme of the invention is further explained by means of specific implementation.Those skilled in the art should be bright , the described embodiments are merely helpful in understanding the present invention, should not be regarded as a specific limitation of the invention.
Embodiment 1
The present embodiment prepares (S) -1,4- benzdioxan -2- formic acid by following steps
(1) preparation of (R) -2- benzyloxymethyl -2,3- dihydrobenzo dioxanes, reaction equation are as follows:
(S)-glycidol benzyl oxide (164g, 1mol) is dissolved in n,N-Dimethylformamide (2L), is added with stirring 2- fluorobenzene Phenol (123g, 1.1mol), potassium carbonate (276g, 2mol) room temperature are warming up to 40 DEG C overnight after ten minutes.TLC detects raw material and disappears Afterwards, temperature rises to 110 DEG C, and the reaction was continued 18 hours.5L water is added in reaction solution, then (600 milliliters, 5 times) of ethyl acetate extractions, Merge organic phase, the caustic washing of 1N 2 times, three times, saturated common salt washing is dry for washing, is concentrated.Obtain colorless oil liquid (R) -2- benzyloxymethyl -2,3- dihydrobenzo dioxanes 212g, yield 83.4%.
1H NMR(d6- DMSO, 400MHz) δ: 7.26-7.43 (m, 5H), 6.88-7.14 (m, 4H), 4.59 (s, 2H), 4.25 (ddd, 1H), 4.05-4.15 (m, 2H), 3.65-3.75 (m, 2H).
(2) preparation of (R)-Isosorbide-5-Nitrae-benzdioxan -2- methanol, reaction equation are as follows:
(R) -2- benzyloxymethyl -2,3- dihydrobenzo dioxanes 200g is dissolved in methanol (2L), is added palladium carbon (5%, 20g), Three times, hydrogen atmosphere hydrogenation, reaction temperature is controlled at 40 DEG C air under stirring in displacement reaction flask, reacts 15 hours.It crosses Filter, drying are concentrated to get (R)-Isosorbide-5-Nitrae-benzdioxan -2- methanol, white powder 123g, yield 95%.
1H NMR(d6- DMSO, 400MHz) δ: 6.80-6.94 (m, 4H), 4.20-4.33 (m, 2H), 4.13 (dd, 1H), 3.78-3.95(m,2H)。
(3) preparation of (S)-Isosorbide-5-Nitrae-benzdioxan -2- formic acid, reaction equation are as follows:
(R)-Isosorbide-5-Nitrae-benzene dioxanes -2- methanol (100g, 0.6mol) is dissolved in methylene chloride (1L), and kbr aqueous solution is added (14g, 0.12mol, water 500mL), Tempo (1.8g, 0.012mol), potassium bicarbonate aqueous solution (120g, 1.2mol), after adding Stirring 10 minutes, reaction system ice bath is cooled to 0-5 DEG C, and aqueous sodium hypochlorite solution (10%, 860mL), keeping body is slowly added dropwise Be temperature less than 10 DEG C hereinafter, keeping 3 hours of temperature after dripping off, heating naturally, room temperature reacts 10 hours again.Fully reacting Afterwards, excessive sodium hypochlorite is quenched with sodium thiosulfate solution (74g, 0.3mol, water 100mL).Reaction system is with 50% Sodium hydrate aqueous solution adjusts pH value and is greater than 12, and layering, water phase is extracted with dichloromethane 1 time again.Methylene chloride twice is mutually abandoned It goes.Water phase hydrochloride adjusts pH value less than 2, and then methylene chloride extraction three times, merges this organic phase three times, and drying is dense It contracts to get object (S)-Isosorbide-5-Nitrae-benzdioxan -2- formic acid 92g, yield 85% is arrived.
1H NMR(CDCl3, 400MHz) and δ: 12.3 (Brs, 1H), 6.96-7.02 (m, 1H), 6.85-6.94 (m, 3H), 4.87-4.91 (m, 2H), 4.35-4.48 (m, 2H), chiral purity ee value > 99%.
Embodiment 2
The present embodiment prepares (R) -1,4- benzdioxan -2- formic acid by following steps
(1) preparation of (S) -2- benzyloxymethyl -2,3- dihydrobenzo dioxanes, reaction equation are as follows:
(R)-glycidol benzyl oxide (164g, 1mol) is dissolved in n,N-Dimethylformamide (2L), is added with stirring 2- fluorobenzene Phenol (123g, 1.1mol), potassium carbonate (276g, 2mol) room temperature are warming up to 40 DEG C overnight after ten minutes.TLC detects raw material and disappears Afterwards, temperature rises to 110 DEG C, and the reaction was continued 18 hours.5L water is added in reaction solution, then (600 milliliters, 5 times) of ethyl acetate extractions, Merge organic phase, the caustic washing of 1N 2 times, three times, saturated common salt washing is dry for washing, is concentrated.Obtain colorless oil liquid (S) -2- benzyloxymethyl -2,3- dihydrobenzo dioxanes 210g, yield 82.2%.
1H NMR(d6- DMSO, 400MHz) δ: 7.26-7.43 (m, 5H), 6.88-7.14 (m, 4H), 4.59 (s, 2H), 4.25 (ddd, 1H), 4.05-4.15 (m, 2H), 3.65-3.75 (m, 2H).
(2) preparation of (S)-Isosorbide-5-Nitrae-benzdioxan -2- methanol, reaction equation are as follows:
(S) -2- benzyloxymethyl -2,3- dihydrobenzo dioxanes 200g is dissolved in methanol (2L), is added palladium carbon (5%, 20g), Three times, hydrogen atmosphere hydrogenation, reaction temperature is controlled at 40 DEG C air under stirring in displacement reaction flask, reacts 15 hours.It crosses Filter, drying are concentrated to get (S)-Isosorbide-5-Nitrae-benzdioxan -2- methanol, white powder 123g, yield 95%.
1H NMR(d6- DMSO, 400MHz) δ: 6.80-6.94 (m, 4H), 4.20-4.33 (m, 2H), 4.13 (dd, 1H), 3.78-3.95(m,2H)。
(3) preparation of (R)-Isosorbide-5-Nitrae-benzdioxan -2- formic acid, reaction equation are as follows:
(S)-Isosorbide-5-Nitrae-benzene dioxanes -2- methanol (80g, 0.48mol) is dissolved in methylene chloride (1L), and kbr aqueous solution is added (11g, 0.1mol, water 400mL), Tempo (1.4g, 0.01mol), potassium bicarbonate aqueous solution (96g, 1mol) stir after adding 10 minutes, reaction system ice bath was cooled to 0-5 DEG C, was slowly added dropwise aqueous sodium hypochlorite solution (10%, 690mL), kept system temperature Degree is less than 10 DEG C hereinafter, keep 3 hours of temperature after dripping off, heating, room temperature react 10 hours again naturally.After fully reacting, Excessive sodium hypochlorite is quenched with sodium thiosulfate solution (59g, 0.24mol, water 100mL).Reaction system with 50% hydrogen Aqueous solution of sodium oxide adjusts pH value and is greater than 12, and layering, water phase is extracted with dichloromethane 1 time again.Methylene chloride twice mutually discards. Water phase hydrochloride adjusts pH value less than 2, and then methylene chloride extraction three times, merges this organic phase three times, dry to be concentrated, i.e., Obtain object (R)-Isosorbide-5-Nitrae-benzdioxan -2- formic acid 75g, yield 87%.
1H NMR(CDCl3, 400MHz) and δ: 12.3 (Brs, 1H), 6.96-7.02 (m, 1H), 6.85-6.94 (m, 3H), 4.87-4.91 (m, 2H), 4.35-4.48 (m, 2H), chiral purity ee value > 99%.
Embodiment 3
The present embodiment prepares (S) -1,4- benzdioxan -2- formic acid by following steps
(1) preparation of (R) -2- benzyloxymethyl -2,3- dihydrobenzo dioxanes, reaction equation are as follows:
(S)-glycidol benzyl oxide (164g, 1mol) is dissolved in n,N-Dimethylformamide (2L), is added with stirring 2- chlorobenzene Phenol (167g, 1.3mol), potassium carbonate (276g, 2mol) room temperature are warming up to 40 DEG C overnight after ten minutes.TLC detects raw material and disappears Afterwards, temperature rises to 130 DEG C, and the reaction was continued 20 hours.5L water is added in reaction solution, then (600 milliliters, 5 times) of ethyl acetate extractions, Merge organic phase, the caustic washing of 1N 2 times, three times, saturated common salt washing is dry for washing, is concentrated.Obtain colorless oil liquid (R) -2- benzyloxymethyl -2,3- dihydrobenzo dioxanes 209g, yield 82.2%.
1H NMR(d6- DMSO, 400MHz) δ: 7.26-7.43 (m, 5H), 6.88-7.14 (m, 4H), 4.59 (s, 2H), 4.25 (ddd, 1H), 4.05-4.15 (m, 2H), 3.65-3.75 (m, 2H).
(2) preparation of (R)-Isosorbide-5-Nitrae-benzdioxan -2- methanol, reaction equation are as follows:
(R) -2- benzyloxymethyl -2,3- dihydrobenzo dioxanes 200g is dissolved in methanol (2L), addition palladium carbon (5%, 16.7g), three times, hydrogen atmosphere hydrogenation, reaction temperature is controlled at 45 DEG C the air under stirring in displacement reaction flask, reacts 18 Hour.Filtering, drying are concentrated to get (R)-Isosorbide-5-Nitrae-benzdioxan -2- methanol, white powder 119g, yield 92%.
1H NMR(d6- DMSO, 400MHz) δ: 6.80-6.94 (m, 4H), 4.20-4.33 (m, 2H), 4.13 (dd, 1H), 3.78-3.95(m,2H)。
(3) preparation of (S)-Isosorbide-5-Nitrae-benzdioxan -2- formic acid, reaction equation are as follows:
(R)-Isosorbide-5-Nitrae-benzene dioxanes -2- methanol (83.3g, 0.5mol) is dissolved in methylene chloride (1L), and it is water-soluble that potassium bromide is added Liquid (14g, 0.12mol, water 500mL), Tempo (4.5g, 0.03mol), potassium bicarbonate aqueous solution (200g, 2mol), after adding Stirring 10 minutes, reaction system ice bath is cooled to 0-5 DEG C, and aqueous sodium hypochlorite solution (10%, 860mL), keeping body is slowly added dropwise Be temperature less than 10 DEG C hereinafter, keeping 4 hours of temperature after dripping off, heating naturally, room temperature reacts 11 hours again.Fully reacting Afterwards, excessive sodium hypochlorite is quenched with sodium thiosulfate solution (74g, 0.3mol, water 100mL).Reaction system is with 50% Sodium hydrate aqueous solution adjusts pH value and is greater than 12, and layering, water phase is extracted with dichloromethane 1 time again.Methylene chloride twice is mutually abandoned It goes.Water phase hydrochloride adjusts pH value less than 2, and then methylene chloride extraction three times, merges this organic phase three times, and drying is dense It contracts to get object (S)-Isosorbide-5-Nitrae-benzdioxan -2- formic acid 73g, yield 81.1% is arrived.
1H NMR(CDCl3, 400MHz) and δ: 12.3 (Brs, 1H), 6.96-7.02 (m, 1H), 6.85-6.94 (m, 3H), 4.87-4.91 (m, 2H), 4.35-4.48 (m, 2H), chiral purity ee value > 99%.
Embodiment 4
The present embodiment prepares (S) -1,4- benzdioxan -2- formic acid by following steps
(1) preparation of (R) -2- benzyloxymethyl -2,3- dihydrobenzo dioxanes, reaction equation are as follows:
(S)-glycidol benzyl oxide (164g, 1mol) is dissolved in n,N-Dimethylformamide (2L), is added with stirring 2- fluorobenzene Phenol (112g, 1mol), potassium carbonate (276g, 2mol) room temperature are warming up to 40 DEG C overnight after ten minutes.After TLC detects raw material disappearance, Temperature rises to 100 DEG C, and the reaction was continued 15 hours.5L water is added in reaction solution, then (600 milliliters, 5 times) of ethyl acetate extractions, closes And organic phase, the caustic washing of 1N 2 times, three times, saturated common salt washing is dry for washing, is concentrated.Obtain colorless oil liquid (R)- 2- benzyloxymethyl -2,3- dihydrobenzo dioxanes 205g, yield 80.6%.
1H NMR(d6- DMSO, 400MHz) δ: 7.26-7.43 (m, 5H), 6.88-7.14 (m, 4H), 4.59 (s, 2H), 4.25 (ddd, 1H), 4.05-4.15 (m, 2H), 3.65-3.75 (m, 2H).
(2) preparation of (R)-Isosorbide-5-Nitrae-benzdioxan -2- methanol, reaction equation are as follows:
(R) -2- benzyloxymethyl -2,3- dihydrobenzo dioxanes 200g is dissolved in methanol (2L), is added palladium carbon (5%, 25g), Three times, hydrogen atmosphere hydrogenation, reaction temperature is controlled at 35 DEG C air under stirring in displacement reaction flask, reacts 12 hours.It crosses Filter, drying are concentrated to get (R)-Isosorbide-5-Nitrae-benzdioxan -2- methanol, white powder 114g, yield 88%.
1H NMR(d6- DMSO, 400MHz) δ: 6.80-6.94 (m, 4H), 4.20-4.33 (m, 2H), 4.13 (dd, 1H), 3.78-3.95(m,2H)。
(3) preparation of (S)-Isosorbide-5-Nitrae-benzdioxan -2- formic acid, reaction equation are as follows:
(R)-Isosorbide-5-Nitrae-benzene dioxanes -2- methanol (83.3g, 0.5mol) is dissolved in methylene chloride (1L), and it is water-soluble that potassium bromide is added Liquid (14g, 0.12mol, water 500mL), Tempo (1.5g, 0.01mol), potassium bicarbonate aqueous solution (100g, 1mol), after adding Stirring 10 minutes, reaction system ice bath is cooled to 0-5 DEG C, and aqueous sodium hypochlorite solution (10%, 860mL), keeping body is slowly added dropwise Be temperature less than 10 DEG C hereinafter, keeping 2 hours of temperature after dripping off, heating naturally, room temperature reacts 7 hours again.Fully reacting Afterwards, excessive sodium hypochlorite is quenched with sodium thiosulfate solution (62g, 0.25mol, water 100mL).Reaction system is with 50% Sodium hydrate aqueous solution adjusts pH value and is greater than 12, and layering, water phase is extracted with dichloromethane 1 time again.Methylene chloride twice is mutually abandoned It goes.Water phase hydrochloride adjusts pH value less than 2, and then methylene chloride extraction three times, merges this organic phase three times, and drying is dense It contracts to get object (S)-Isosorbide-5-Nitrae-benzdioxan -2- formic acid 69g, yield 76.7% is arrived.
1H NMR(CDCl3, 400MHz) and δ: 12.3 (Brs, 1H), 6.96-7.02 (m, 1H), 6.85-6.94 (m, 3H), 4.87-4.91 (m, 2H), 4.35-4.48 (m, 2H), chiral purity ee value > 99%.
The Applicant declares that the present invention is explained by the above embodiments Isosorbide-5-Nitrae-benzdioxan -2- formic acid of the invention Preparation method, but the invention is not limited to above-mentioned method detaileds, that is, do not mean that the present invention must rely on above-mentioned method detailed It could implement.It should be clear to those skilled in the art, any improvement in the present invention, to each raw material of product of the present invention Equivalence replacement and addition, the selection of concrete mode of auxiliary element etc., all fall within protection scope of the present invention and the open scope Within.

Claims (33)

1. a kind of Isosorbide-5-Nitrae-benzdioxan -2- formic acid preparation method, which is characterized in that the preparation method includes being contracted with benzyloxy Water glycerin ether and adjacent halobenzene phenol are raw material, obtain the Isosorbide-5-Nitrae-benzo two by cyclization reaction, debenzylation and oxidation reaction Oxane -2- formic acid；
The preparation method comprises the following steps:
(1) by benzyloxy glycidol ether and adjacent halobenzene phenol in the presence of alkaline reagent, heating, cyclization reaction obtain 2- in solvent Benzyloxymethyl -2,3- dihydrobenzo dioxanes, specific reaction equation are as follows:
(2) the 2- benzyloxymethyl -2,3- dihydrobenzo dioxanes that step (1) obtains carries out debenzylation in the presence of a catalyst Isosorbide-5-Nitrae-benzdioxan -2- methanol is obtained, specific reaction equation is as follows:
(3) the 1,4- benzdioxan -2- methanol that step (2) obtains and oxidant carry out oxidation reaction and obtain the 1,4- benzo Dioxanes -2- formic acid, specific reaction equation are as follows:
The molar ratio of benzyloxy glycidol ether described in step (1) and adjacent halogen phenol reactant is 1:1-1.3；
The temperature of cyclization reaction described in step (1) is 100-130 DEG C；
The time of cyclization reaction described in step (1) is 15-20h；
Step (3) described oxidation reaction carries out in the presence of a catalyst, and the catalyst is the oxidation of 2,2,6,6- tetramethyl piperidines Object；
Relative to 0.5mol Isosorbide-5-Nitrae-benzdioxan -2- methanol, the dosage of catalyst described in step (3) is 0.01- 0.03mol。
2. preparation method according to claim 1, which is characterized in that the Isosorbide-5-Nitrae-benzdioxan -2- formic acid includes (R) -1,4- benzdioxan -2- formic acid and (S) -1,4- benzdioxan -2- formic acid.
3. preparation method according to claim 1, which is characterized in that neighbour's halobenzene phenol described in step (1) be 2- fluorophenol, Any one in 2- bromophenol or 2- chlorophenol.
4. preparation method according to claim 3, which is characterized in that neighbour's halobenzene phenol described in step (1) is 2- fluorophenol.
5. preparation method according to claim 1, which is characterized in that alkaline reagent described in step (1) is potassium carbonate, carbon In sour caesium, sodium carbonate, sodium bicarbonate or saleratus any one or at least two combination.
6. preparation method according to claim 5, which is characterized in that alkaline reagent described in step (1) is potassium carbonate.
7. preparation method according to claim 1, which is characterized in that solvent described in step (1) is N, N- dimethyl methyl Amide.
8. preparation method according to claim 1, which is characterized in that 2- benzyloxymethyl -2,3- dihydro described in step (2) The mass ratio of benzdioxan and catalyst is (8-12): 1.
9. preparation method according to claim 1, which is characterized in that step (2) catalyst is palladium carbon.
10. preparation method according to claim 1, which is characterized in that the solvent of reaction described in step (2) be methanol, In ethyl acetate or chloroform any one or at least two combination.
11. preparation method according to claim 10, which is characterized in that the solvent of reaction described in step (2) is methanol.
12. preparation method according to claim 1, which is characterized in that reacted described in step (2) in a hydrogen atmosphere into Row.
13. preparation method according to claim 1, which is characterized in that the temperature of reaction described in step (2) is 35-45 ℃。
14. preparation method according to claim 1, which is characterized in that the time of reaction described in step (2) is 12- 18h。
15. preparation method according to claim 1, which is characterized in that oxidant described in step (3) is sodium hypochlorite.
16. preparation method according to claim 1, which is characterized in that Isosorbide-5-Nitrae-benzdioxan -2- methanol in step (3) With the molar ratio 1:1.5-2.5 of oxidant.
17. preparation method according to claim 1, which is characterized in that step (3) described oxidation reaction is deposited in alkaline reagent In lower progress.
18. preparation method according to claim 17, which is characterized in that the alkaline reagent be potassium carbonate, saleratus, In cesium carbonate, sodium bicarbonate any one or at least two combination.
19. preparation method according to claim 18, which is characterized in that the alkaline reagent is saleratus.
20. preparation method according to claim 19, which is characterized in that relative to 0.5mol Isosorbide-5-Nitrae-benzdioxan -2- Methanol, the dosage of alkaline reagent described in step (3) are 1-2mol.
21. preparation method according to claim 1, which is characterized in that oxidation reaction described in step (3) is deposited in halide In lower progress.
22. preparation method according to claim 21, which is characterized in that the halide is potassium bromide, sodium bromide, iodate In potassium or sodium iodide any one or at least two combination.
23. preparation method according to claim 22, which is characterized in that the halide is potassium bromide.
24. preparation method according to claim 23, which is characterized in that relative to 0.5mol Isosorbide-5-Nitrae-benzdioxan -2- Methanol, the dosage of the halide are 0.1-0.3mol.
25. preparation method according to claim 1, which is characterized in that the solvent of oxidation reaction described in step (3) is two In chloromethanes, chloroform or ethyl acetate any one or at least two combination.
26. preparation method according to claim 25, which is characterized in that the solvent of oxidation reaction described in step (3) is Methylene chloride.
27. preparation method according to claim 1, which is characterized in that the time of oxidation reaction described in step (3) is 9- 15h。
28. preparation method according to claim 1, which is characterized in that the method for oxidation reaction described in step (3) is specific Are as follows: Isosorbide-5-Nitrae-benzdioxan -2- methanol and oxidant, catalyst, halide, saleratus are mixed in solvent, stirring is mixed It is even, sodium hypochlorite is then added dropwise and is reacted, temperature reaction obtains the Isosorbide-5-Nitrae-benzdioxan -2- first again after low-temp reaction Acid.
29. the method according to claim 28, which is characterized in that the temperature of the mixing is 0-5 DEG C.
30. the method according to claim 28, which is characterized in that the temperature of the low-temp reaction is 0-10 DEG C.
31. the method according to claim 28, which is characterized in that the time of the low-temp reaction is 2-4h.
32. the method according to claim 28, which is characterized in that the temperature of the temperature reaction is 20-35 DEG C.
33. the method according to claim 28, which is characterized in that the time of the temperature reaction is 7-11h.
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