CN103483300B - Preparation method of 5-cyanogen-1-(4-fluobenzene)-1,3-dihydrogenated-isobenzofuranone - Google Patents
Preparation method of 5-cyanogen-1-(4-fluobenzene)-1,3-dihydrogenated-isobenzofuranone Download PDFInfo
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Abstract
The invention provides a preparation method of 5-cyanogen-1-(4-fluobenzene)-1,3-dihydrogenated-isobenzofuranone. The preparation method comprises the following steps: reducing fluorobenzoic acid ester through hydrazine hydrate to obtain fluorobenzene formylhydrazine; enabling the fluorobenzene formylhydrazine to react with 5-bromine-2-hydroxybenzaldehyde under acidic conditions to obtain 4-fluorine-[(5-bromine-2- hydroxy phenyl) methene] hydrazide benzoic acid; oxidizing the 4-fluorine-[(5-bromine-2- hydroxy phenyl) methene] hydrazide benzoic acid through an oxidizing agent to obtain 5-bromine-2-(4-fluorine benzoyl)-benzaldehyde; reducing the 5-bromine-2-(4-fluorine benzoyl)-benzaldehyde through a reducing agent to obtain 4-bromine-Alpha 1-(4-fluorine phenyl)-1,2-xylyl alcohol; performing condensation reaction on the 4-bromine-Alpha 1-(4-fluorine phenyl)-1,2-xylyl alcohol by using toluenesulfonic acid as a catalyst to obtain 1-(4-fluobenzene)-5-bromine-1,3-dihydro- isobenzofuranone; enabling the 1-(4-fluobenzene)-5-bromine-1,3-dihydro- isobenzofuranone to react with copper cyanide to obtain the product. The method is low in cost, simple in technology, easy-operated in reaction, high in yield and suitable for industrialized production.
Description
Technical field
The invention belongs to organic chemistry filed, particularly a kind of preparation method of S-escitalopram intermediate 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran.
Background technology
It is general that S-escitalopram (Escitalopram) has another name called to come scholar, chemistry (+)-(s)-1-[3-(dimethylamino)-propyl group]-1-(4-fluorophenyl)-1 by name, 3-dihydroisobenzofuran-5-nitrile is the S-isomer of racemic modification citalopram.Escitalopram is developed, on March 15th, 2002 in Switzerland's Initial Public Offering by Lundbeck company of Denmark.This product is used for the treatment of dysthymia disorders, can promote the re-uptake of central nervous system serotonin, and compared with citalopram, this product is stronger to the selection of serotonin, and rapid-action, and security is high.
5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran is a kind of important intermediate of synthesis citalopram.In prior art, the synthetic method of relevant 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran mainly contains following several operational path.
One, US6291689 discloses a kind of synthetic method of 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran:
Be specially: 4-fluorophenylhalide (being obtained in the tetrahydrofuran (THF) of drying by 4-bromofluoro benzene and magnesium) dropwise instills 5-Cyano-phthalide at 5 DEG C; Reaction terminates the ethanolic soln stirred overnight at room temperature of the excessive sodium borohydride of rear dropping, adds water after vacuum concentration, and adopt ethyl acetate to extract, ethyl acetate extract vacuum concentration obtains oily matter, and oily matter obtains pure solid through chromatography column.By the solid 80 DEG C of reaction 3h in 60% phosphoric acid solution obtained, make its cyclization; Methylbenzene extraction twice, organic layer in vacuo concentrates, the oily matter obtained recrystallization in ethanol, namely obtained pure compound 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran.
But the major defect of the method is
1., in industrial production, the higher and more difficult recovery of anhydrous tetrahydro furan cost uses;
2. different reactions steps solvent for use is different, makes it comparatively loaded down with trivial details in the industrial production;
3. need a large amount of sodium borohydrides in reaction process, this makes to react has certain danger;
4. yield is lower.
In addition, GB2385051A, WO02066453A1, WO2004011450A1, WO2004016602A1, WO2004080988A1 also with this route for major design route, for wherein Problems existing, corresponding research has been done respectively from solvent, temperature of reaction aspect, compared with route in US6291689, there is change to a certain degree, but still fundamentally do not changed the problems referred to above.
Its two, EP1095926A2 synthetic method disclosing a kind of 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran:
Be specially: compound 4-halogen-1,3-xylyl alcohol (X is Cl, Br, I) is first converted into Grignard reagent or lithium compound, be combined with p-Fluorobenzenecarboxaldehyde afterwards, gained compound obtains compound [1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-base] methyl alcohol through amination, cyclization; Compound [1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-base] methyl alcohol is containing oxidizable group, under hypochlorite and nitrogen oxygen-cent red radical catalysts conditions, the methylol selective oxidation that it contains, generate compound [1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-base] formaldehyde; Compound [1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-base] formaldehyde dewaters with after azanol or inorganic salt reaction, can obtain compound 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran.
In addition, WO2006057261A1, JP2007045807A are respectively to [1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-base] formaldehyde carries out dehydration reaction and generates 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran is studied, and is particularly studied in detail with regard to solvent required in its dehydration.
But this method treating processes is comparatively loaded down with trivial details, is only applicable to laboratory operation, is not suitable for industrial production, its total recovery is also lower simultaneously, does not have commercial value.
Its three, EP1125907A2 synthetic method disclosing a kind of 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran:
Be specially: 2,4-dimethylbenzaldehyde and 4-bromofluoro benzene Grignard reagent react obtained (4-fluorophenyl)-2,4-dimethylphenylcarbinols; (4-fluorophenyl)-2,4-dimethylphenylcarbinols generate 4-(4-fluoro benzoyl)-1,3-phthalic acid through oxidation, the reaction of Kerafyrm thatch; 4-(4-fluoro benzoyl)-1,3-phthalic acid generates 1-(4-fluorophenyl)-1,3-dihydro-5-cumarone methyl alcohol through reduction, cyclization, the reaction of Kerafyrm thatch; 1-(4-fluorophenyl)-1,3-dihydro-5-cumarone methyl alcohol generates 1-(4-fluorophenyl)-1 using Manganse Dioxide as oxygenant generation oxidizing reaction, 3-dihydro-5-cumarone formaldehyde, through oximate, dehydration, obtain target product 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran.
But loaded down with trivial details, the required reagent of the method technique is expensive, yield is low, is unsuitable for suitability for industrialized production.
EP1428813A1 has done corresponding improvement for problem existing in EP1125907A2, attempt the different reaction solvent of change and a series of research has been carried out to temperature, although slightly improve its Problems existing, but still there is open defect, essential defect can not be solved.
Its four, WO2005066185A1 synthetic method disclosing a kind of 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran:
Be specially: after compound 4-fluorophenylhalide carries out grignard reaction, extraction, organic layer ethanolic soln dilutes; Add sodium borohydride to obtain boron-containing compound, there is cyclization and get final product in product under acidic conditions.
Although the operation of this synthetic method is comparatively simple, the sodium borohydride amount required for it is comparatively large, and operation has certain danger, and total recovery is lower.
Summary of the invention
Goal of the invention: the preparation method that the object of the present invention is to provide S-escitalopram intermediate 5-cyano group-1-(4-fluorophenyl)-1, the 3-dihydro-isobenzofuran that a kind of synthesis technique is simple, yield is high, cost is low.
Technical scheme: the preparation method of a kind of 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran provided by the invention, comprises the following steps:
(1) starting raw material parafluorobenzoic acid ester, through hydrazine hydrate reduction, obtained to fluorobenzoyl hydrazine;
(2) fluorobenzoyl hydrazine and the bromo-Benzaldehyde,2-hydroxy of 5-are reacted in acid condition, obtained 4-fluoro-[(the bromo-2-hydroxy phenyl of 5-) methylene radical] hydrazides phenylformic acid;
(3) 4-fluoro-[(5-bromo-2-hydroxy phenyl) methylene radical] hydrazides phenylformic acid is through oxidizing, the obtained bromo-2-of 5-(4-fluoro benzoyl)-phenyl aldehyde;
(4) the bromo-2-of 5-(4-fluoro benzoyl)-phenyl aldehyde reduces through reductive agent, the obtained bromo-α 1-of 4-(4-fluorophenyl)-1,2-xylyl alcohol;
(5) take tosic acid as catalyzer, the bromo-α 1-of 4-(4-fluorophenyl)-1,2-xylyl alcohol generation condensation reaction, obtained bromo-1, the 3-dihydroisobenzofuran of 1-(4-fluorophenyl)-5-;
(6) bromo-1, the 3-dihydroisobenzofuran of 1-(4-fluorophenyl)-5-and cuprous cyanide react, and obtain 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran.
Reaction equation is as follows:
Wherein, R is methyl or ethyl.
In step (1), described parafluorobenzoic acid ester is parafluorobenzoic acid methyl esters or parafluorobenzoic acid ethyl ester, and the mol ratio of parafluorobenzoic acid ester and hydrazine hydrate is 1: (1 ~ 5), and temperature of reaction is 80 ~ 100 DEG C, and the reaction times is 1 ~ 1.5h.
In step (2), the bromo-Benzaldehyde,2-hydroxy of 5-be (1 ~ 2) to the mol ratio of fluorobenzoyl hydrazine: 1, temperature of reaction is 30 ~ 40 DEG C, and the reaction times is 10 ~ 20min, and pH value is 3 ~ 4.
In step (3), the mol ratio of fluoro-[(the bromo-2-hydroxy phenyl of 5-) methylene radical] the hydrazides phenylformic acid of 4-and lead tetraacetate is (1 ~ 2): 1, and temperature of reaction is-5 ~ 5 DEG C, and the reaction times is 1 ~ 3h.
In step (4), described reductive agent is sodium borohydride or lithium aluminium hydride, and the mol ratio of the bromo-2-of 5-(4-fluoro benzoyl)-phenyl aldehyde and reductive agent is 1: (1 ~ 2), and temperature of reaction is room temperature, and the reaction times is 1 ~ 2h.
In step (5), temperature of reaction is room temperature, and the reaction times is 1 ~ 3h, and catalyzer is Lewis acid; Preferred tosic acid, hydrochloric acid or boron trifluoride diethyl etherate.
In step (6), the mol ratio of bromo-1, the 3-dihydroisobenzofuran of 1-(4-fluorophenyl)-5-and cuprous cyanide is 1: (1 ~ 2), and temperature of reaction is 120 ~ 180 DEG C, and the reaction times is 5 ~ 7h.
Beneficial effect: S-escitalopram intermediate 5-cyano group-1-(4-fluorophenyl)-1 provided by the invention, the preparation method of 3-dihydro-isobenzofuran with parafluorobenzoic acid ethyl ester for starting raw material, with low cost, technique is simple, and reaction easily manipulates, and yield is high, be suitable for suitability for industrialized production; Meanwhile, in reaction process, the discharge of unharmful substance, pollution-free.
Embodiment
According to following embodiment, the present invention may be better understood.But those skilled in the art will readily understand, concrete material proportion, processing condition and result thereof described by embodiment only for illustration of the present invention, and should can not limit the present invention described in detail in claims yet.
Embodiment 1
The preparation of 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran, comprises the following steps:
(1) to the synthesis of fluorobenzoyl hydrazine
Reaction equation is:
Parafluorobenzoic acid ethyl ester (115g, 683.8mmol) adds in 1500ml ethanolic soln, is stirred to solution clarification, dropwise adds hydrazine hydrate 1.7mol, 90 DEG C of back flow reaction 1h in solution.TLC monitors, hold over night after completion of the reaction, separates out solid 95g, is fluorobenzoyl hydrazine (compound 2), yield 89.7%.
1H-NMR(300M,CDCl
3)：8.12(m，2H),7.42(t，2H)，8.0(s，1H)，2.0(s，2H)。
(2) 4-fluoro-[(5-bromo-2-hydroxy phenyl) methylene radical] the benzoic synthesis of hydrazides
Reaction equation is:
It is in the 50ml aqueous acetic acid of 3.5 that the bromo-Benzaldehyde,2-hydroxy (21g, 100mmol) of 5-is dissolved in pH, adds fluorobenzoyl hydrazine (15.4g, 100mmol), 35 DEG C of reaction 15min, after completion of the reaction, pour into reaction solution in cold water, separate out white-yellowish solid, filter, normal hexane is washed, and obtains white-yellowish solid 34g, be 4-fluoro-[(the bromo-2-hydroxy phenyl of 5-) methylene radical] hydrazides phenylformic acid (compound 3), yield 96%.
1H-NMR(300M,d
6-DMSO)：12.21(s，1H)，11.29(s，1H)，8.63(s，1H)，8.02(m，2H)，7.80(s，1H)，7.41(m，3H)，6.90(d，1H)。
(3) synthesis of the bromo-α 1-of 4-(4-fluorophenyl)-1,2-xylyl alcohol
Reaction equation is:
4-fluoro-[(the bromo-2-hydroxy phenyl of 5-) methylene radical] hydrazides phenylformic acid (100g, 297mmol) is dissolved in THF, after being down to 0 DEG C, dropwise adds Pd (OAc)
4(200g) THF solution, 0 DEG C of reaction 2h.Add ethyl acetate suction filtration after reaction solution is concentrated, the saturated potassium hydroxide aqueous solution of organic layer is washed, anhydrous sodium sulfate drying, concentrated, obtains solid 77g, is the bromo-2-of 5-(4-fluoro benzoyl)-phenyl aldehyde (compound 4), yield 86%.
1H-NMR(300M,CDCl
3)：9.97(s，1H)，8.15(s，1H)，7.80-7.82(m，3H)，7.38(d，1H)，7.14(t，1H)。
Get the bromo-2-of 5-(4-fluoro benzoyl)-phenyl aldehyde 50g, be dissolved in dehydrated alcohol, be down to 0 DEG C, add 15ml pyridine as catalyzer, then add 10g sodium borohydride, room temperature reaction 1.5h; Be concentrated into dry, add ethyl acetate, water, be adjusted to acidity with 1N hydrochloric acid, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrate to obtain solid 48g, be the bromo-α 1-of 4-(4-fluorophenyl)-1,2-xylyl alcohol (compound 5), yield 95%.
1H-NMR(300M,CDCl
3)：7.52(s，1H)，7.44(m，1H)，7.31(m，2H)，7.16(d，1H)，7.03(t，2H)，6.01(s，1H)，5.45(s，1H)，4.66(d，2H)，3.52(s，1H)。
(4) synthesis of bromo-1, the 3-dihydroisobenzofuran of 1-(4-fluorophenyl)-5-
Reaction equation is:
With tosic acid (2g, 0.01mol) be catalyzer, the bromo-α 1-of 4-(4-fluorophenyl)-1,2-xylyl alcohol (30g, 0.1mol) is room temperature reaction 2h in toluene solution, uses saturated sodium carbonate solution, extraction into ethyl acetate successively, anhydrous sodium sulfate drying, concentrate to obtain solid 26.7g, be synthesis (compound 6) yield 93% of bromo-1, the 3-dihydroisobenzofuran of 1-(4-fluorophenyl)-5-.
1H-NMR(300M,CDCl
3)：7.80(m，1H)，7.34(d，1H)，7.24(m，2H)，7.17(t，3H),5.69(s，1H)，4.78(s，1H)，4.34(s，1H)。
(5) synthesis of 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran
Reaction equation is:
Bromo-1, the 3-dihydroisobenzofuran (35.7g, 120mmol) of 1-(4-fluorophenyl)-5-is dissolved in DMF, adds CuCN (12.9g, 144mmol), 150 DEG C of back flow reaction 6h; Be cooled to room temperature, pour in 50ml ammoniacal liquor, benzene extracts, and ammoniacal liquor, saturated common salt are washed, anhydrous sodium sulfate drying, concentrated, obtains 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran 23g, yield 83%.
1H-NMR(300M,CDCl
3):8.01(s，1H)，7.48(m，2H)，7.28(m，2H)，7.17(t，2H)，5.56(s，1H)，4.88(d，1H)，4.58(d，1H)。
Embodiment 2
The preparation of 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran, comprises the following steps:
(1) to the synthesis of fluorobenzoyl hydrazine
Parafluorobenzoic acid methyl esters 0.5mol adds in 1500ml ethanolic soln, is stirred to solution clarification, dropwise adds hydrazine hydrate 0.5mol, 100 DEG C of back flow reaction 1.5h in solution.TLC monitors, hold over night after completion of the reaction, separates out solid, obtains fluorobenzoyl hydrazine 0.45mol, yield 90.0%.
(2) 4-fluoro-[(5-bromo-2-hydroxy phenyl) methylene radical] the benzoic synthesis of hydrazides
It is in the 50ml aqueous acetic acid of 3.0 that the bromo-Benzaldehyde,2-hydroxy 0.2mol of 5-is dissolved in pH, add fluorobenzoyl hydrazine 0.2mol, 40 DEG C of reaction 10min, after completion of the reaction, pour into reaction solution in cold water, separate out white-yellowish solid, filter, normal hexane is washed, and obtains white-yellowish solid 190mmol, be 4-fluoro-[(the bromo-2-hydroxy phenyl of 5-) methylene radical] hydrazides phenylformic acid, yield 95%.
(3) synthesis of the bromo-α 1-of 4-(4-fluorophenyl)-1,2-xylyl alcohol
4-fluoro-[(the bromo-2-hydroxy phenyl of 5-) methylene radical] hydrazides phenylformic acid 100mmol is dissolved in THF, after being down to 0 DEG C, dropwise adds containing Pd (OAc)
4the THF solution of 100mmol ,-5 DEG C of reaction 3h.Add ethyl acetate suction filtration after reaction solution is concentrated, the saturated potassium hydroxide aqueous solution of organic layer is washed, anhydrous sodium sulfate drying, concentrated, obtains the bromo-2-of 5-(4-fluoro benzoyl)-phenyl aldehyde 89.4mmol, yield 89.4%.
Get the bromo-2-of 5-(4-fluoro benzoyl)-phenyl aldehyde 80mmol, be dissolved in dehydrated alcohol, be down to 0 DEG C, add 15ml pyridine as catalyzer, then add 160mmol lithium aluminium hydride, room temperature reaction 1h; Be concentrated into dry, add ethyl acetate, water, be adjusted to acidity with 1N hydrochloric acid, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrate to obtain the bromo-α 1-of 4-(4-fluorophenyl)-1,2-xylyl alcohol 74mmol, yield 92.5%.
(4) synthesis of bromo-1, the 3-dihydroisobenzofuran of 1-(4-fluorophenyl)-5-
With boron trifluoride diethyl etherate 0.02mol for catalyzer, the bromo-α 1-of 4-(4-fluorophenyl)-1,2-xylyl alcohol 60mmol room temperature reaction 1h in toluene solution, use saturated sodium carbonate solution, extraction into ethyl acetate successively, anhydrous sodium sulfate drying, the synthesis 54mmol of concentrated bromo-1, the 3-dihydroisobenzofuran of 1-(4-fluorophenyl)-5-, yield 90%.
(5) synthesis of 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran
Bromo-1, the 3-dihydroisobenzofuran 50mmol of 1-(4-fluorophenyl)-5-is dissolved in DMF, adds CuCN50mmol, 180 DEG C of back flow reaction 7h; Be cooled to room temperature, pour in 50ml ammoniacal liquor, benzene extracts, and ammoniacal liquor, saturated common salt are washed, anhydrous sodium sulfate drying, concentrated, obtains 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran 41mmol, yield 82%.Embodiment 3
The preparation of 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran, comprises the following steps:
(1) to the synthesis of fluorobenzoyl hydrazine
Parafluorobenzoic acid ethyl ester 0.5mol adds in 1500ml ethanolic soln, is stirred to solution clarification, dropwise adds hydrazine hydrate 2.5mol, 80 DEG C of back flow reaction 1h in solution.TLC monitors, hold over night after completion of the reaction, separates out solid, obtains fluorobenzoyl hydrazine 0.46mol, yield 92.0%.
(2) 4-fluoro-[(5-bromo-2-hydroxy phenyl) methylene radical] the benzoic synthesis of hydrazides
It is in the 50ml aqueous acetic acid of 4.0 that the bromo-Benzaldehyde,2-hydroxy 0.4mol of 5-is dissolved in pH, add fluorobenzoyl hydrazine 0.2mol, 30 DEG C of reaction 20min, after completion of the reaction, pour into reaction solution in cold water, separate out white-yellowish solid, filter, normal hexane is washed, and obtains white-yellowish solid 195mmol, be 4-fluoro-[(the bromo-2-hydroxy phenyl of 5-) methylene radical] hydrazides phenylformic acid, yield 97.5%.
(3) synthesis of the bromo-α 1-of 4-(4-fluorophenyl)-1,2-xylyl alcohol
4-fluoro-[(the bromo-2-hydroxy phenyl of 5-) methylene radical] hydrazides phenylformic acid 100mol is dissolved in THF, after being down to 0 DEG C, dropwise adds containing Pd (OAc)
4the THF solution of 50mmol, 5 DEG C of reaction 1h.Add ethyl acetate suction filtration after reaction solution is concentrated, the saturated potassium hydroxide aqueous solution of organic layer is washed, anhydrous sodium sulfate drying, concentrated, obtains the bromo-2-of 5-(4-fluoro benzoyl)-phenyl aldehyde 85.2mmol, yield 85.2%.
Get the bromo-2-of 5-(4-fluoro benzoyl)-phenyl aldehyde 80mmol, be dissolved in dehydrated alcohol, be down to 0 DEG C, add 15ml pyridine as catalyzer, then add 80mmol sodium borohydride, room temperature reaction 2h; Be concentrated into dry, add ethyl acetate, water, be adjusted to acidity with 1N hydrochloric acid, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrate to obtain the bromo-α 1-of 4-(4-fluorophenyl)-1,2-xylyl alcohol 78mmol, yield 97.5%.
(4) synthesis of bromo-1, the 3-dihydroisobenzofuran of 1-(4-fluorophenyl)-5-
With the aqueous hydrochloric acid containing HCl0.01mol for catalyzer, the bromo-α 1-of 4-(4-fluorophenyl)-1,2-xylyl alcohol 60mmol room temperature reaction 3h in toluene solution, use saturated sodium carbonate solution, extraction into ethyl acetate successively, anhydrous sodium sulfate drying, the synthesis 57mmol of concentrated bromo-1, the 3-dihydroisobenzofuran of 1-(4-fluorophenyl)-5-, yield 95%.
(5) synthesis of 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran
Bromo-1, the 3-dihydroisobenzofuran 50mmol of 1-(4-fluorophenyl)-5-is dissolved in DMF, adds CuCN100mmol, 120 DEG C of back flow reaction 5h; Be cooled to room temperature, pour in 50ml ammoniacal liquor, benzene extracts, and ammoniacal liquor, saturated common salt are washed, anhydrous sodium sulfate drying, concentrated, obtains 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran 44mmol, yield 88%.
Claims (1)
1. the preparation method of 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran, is characterized in that: comprise the following steps:
(1) starting raw material parafluorobenzoic acid ester, through hydrazine hydrate reduction, obtained to fluorobenzoyl hydrazine; Described parafluorobenzoic acid ester is parafluorobenzoic acid methyl esters or parafluorobenzoic acid ethyl ester, and the mol ratio of parafluorobenzoic acid ester and hydrazine hydrate is 1:(1 ~ 5), temperature of reaction is 80 ~ 100 DEG C, and the reaction times is 1 ~ 1.5h;
(2) fluorobenzoyl hydrazine and the bromo-Benzaldehyde,2-hydroxy of 5-are reacted in acid condition, obtained 4-fluoro-[(the bromo-2-hydroxy phenyl of 5-) methylene radical] hydrazides phenylformic acid; The bromo-Benzaldehyde,2-hydroxy of 5-be (1 ~ 2) to the mol ratio of fluorobenzoyl hydrazine: 1, temperature of reaction is 30 ~ 40 DEG C, and the reaction times is 10 ~ 20min, and pH value is 3 ~ 4;
(3) 4-fluoro-[(the bromo-2-hydroxy phenyl of 5-) methylene radical] hydrazides phenylformic acid is oxidized through lead tetraacetate, the obtained bromo-2-of 5-(4-fluoro benzoyl)-phenyl aldehyde; The mol ratio of fluoro-[(the bromo-2-hydroxy phenyl of 5-) methylene radical] the hydrazides phenylformic acid of 4-and lead tetraacetate is (1 ~ 2): 1, and temperature of reaction is-5 ~ 5 DEG C, and the reaction times is 1 ~ 3h;
(4) the bromo-2-of 5-(4-fluoro benzoyl)-phenyl aldehyde reduces through reductive agent, obtained
described reductive agent is sodium borohydride or lithium aluminium hydride, and the mol ratio of the bromo-2-of 5-(4-fluoro benzoyl)-phenyl aldehyde and reductive agent is 1:(1 ~ 2), temperature of reaction is room temperature, and the reaction times is 1 ~ 2h;
(5) take tosic acid as catalyzer,
there is condensation reaction, obtained bromo-1, the 3-dihydroisobenzofuran of 1-(4-fluorophenyl)-5-; Temperature of reaction is room temperature, and the reaction times is 1 ~ 3h;
(6) bromo-1, the 3-dihydroisobenzofuran of 1-(4-fluorophenyl)-5-and cuprous cyanide react, and obtain 5-cyano group-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran; The mol ratio of bromo-1, the 3-dihydroisobenzofuran of 1-(4-fluorophenyl)-5-and cuprous cyanide is 1:(1 ~ 2), temperature of reaction is 120 ~ 180 DEG C, and the reaction times is 5 ~ 7h.
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| CN111018740B (en) * | 2019-12-20 | 2022-04-05 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester |
| CN111646922B (en) * | 2020-07-21 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid |
| CN112250599B (en) * | 2020-11-24 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester |
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