CN110467544A - A kind of preparation method of gram of vertical boron sieve intermediate - Google Patents
A kind of preparation method of gram of vertical boron sieve intermediate Download PDFInfo
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- CN110467544A CN110467544A CN201910763009.0A CN201910763009A CN110467544A CN 110467544 A CN110467544 A CN 110467544A CN 201910763009 A CN201910763009 A CN 201910763009A CN 110467544 A CN110467544 A CN 110467544A
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- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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Abstract
The invention discloses a kind of preparation methods of gram vertical boron sieve intermediate, gram vertical boron sieve intermediate has structure shown in formula IV, the preparation method includes: to carry out haptoreaction in the presence of the first organic solvent and the first alkali by type I compound and to fluorobenzonitrile, obtain II compound of formula；In the presence of the second solvent, II compound of formula and alkali metal borohydride are subjected to haptoreaction, obtain III compound of formula；In the presence of third organic solvent and catalyst, III compound of formula and brominated reagent are subjected to haptoreaction, obtain IV compound of formula；Preparation method of the invention uses reaction raw materials, as an ortho position steric group, to eliminate the use of protecting group to fluorobenzonitrile, improves bromo-reaction selectivity, process costs are low, and cost of material is cheap, can preferably be applied to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, more particularly, to a kind of preparation method of gram vertical boron sieve intermediate.
Background technique
Eczema is the allergic inflammation dermatoses as caused by a variety of internal and external factors, multiform damage symmetrical with skin lesion,
Acute pruritus has exudation tendency, recurrent exerbation etc. for notable feature.This disease is touching refractory, and clinical treatment is intractable, to the body of patient
Heart health causes larger impact.
Currently, western medicine is based on Loratadine, glucocorticoid and convergence, the protection symptomatic treatments such as preparation,
Though such drug can control symptom, easy to recur after being discontinued, and for a long time, repeatedly, large area use can cause infant part capillary
The adverse reactions such as blood vessel dilatation, cutaneous pigmentation.Gram vertical boron sieve is non-hormone drug, has easy to use, adverse reaction
The small, advantages such as recurrence rate is low, and clinical value with higher.
In order to preferably prepare gram vertical boron sieve, people conduct extensive research a gram synthesis for vertical boron sieve intermediate；Example
Such as, the synthetic route for two kinds of grams of vertical boron sieve intermediates being shown respectively such as formula 1 and formula 2；Wherein, used in method shown in formula 1
The bromo- 5- hydroxy benzaldehyde of reaction raw materials 2- it is expensive, increase a gram preparation cost for vertical boron sieve intermediate；Shown in formula 2
The selectivity of method, the bromo-reaction in the bromo- 5- hydroxy benzaldehyde preparation process of 2- is low, and yield is low.
Summary of the invention
The object of the present invention is to provide a kind of gram vertical boron sieve intermediate 4-4- bromo- 3- (hydroxymethyl) phenoxy groups) benzyl formonitrile HCN
New preparation process, which is raw material using cheap m-hydroxybenzaldehyde, and reaction step is short, and selectivity is high,
It is suitble to industrialized production.
To achieve the goals above, the present invention provides a kind of preparation method of gram vertical boron sieve intermediate, which is characterized in that institute
Stating gram vertical boron sieve intermediate has structure shown in formula IV,
The preparation method includes the following steps:
(1) in the presence of the first organic solvent and the first alkali, by compound shown in formula I and fluorobenzonitrile contact anti-
It answers, obtains compound shown in formula II；
(2) in the presence of the second solvent, compound shown in the formula II and alkali metal borohydride contact anti-
It answers, obtains compound shown in formula III；
(3) in the presence of third organic solvent and catalyst, compound shown in the formula III and brominated reagent are carried out
Haptoreaction obtains compound shown in formula IV；
Technical solution of the present invention has the advantages that
(1) preparation step of the invention is short, and any protecting group, raw material m-hydroxybenzaldehyde price are not used in whole process
It is cheap, and the bromo- 5- hydroxy benzaldehyde of 2- used in the prior art is expensive.
(2) preparation method high income of the invention, bromo-reaction selectivity is high, and the o-brominated of phenoxy group is not detected
Object, and bromo-reaction is selectively low in the preparation process of the bromo- 5- hydroxy benzaldehyde of prior art route 2-, yield is low.
(3) a preparation method of the invention ortho position steric group of the reaction raw materials to fluorobenzonitrile as phenoxy group saves
The use of protecting group has been gone, has improved bromo-reaction selectivity, process costs are low, and cost of material is cheap, can preferably be applied to
Industrialized production.
Other features and advantages of the present invention will then part of the detailed description can be specified.
Detailed description of the invention
Exemplary embodiment of the invention is described in more detail in conjunction with the accompanying drawings, it is of the invention above-mentioned and its
Its purpose, feature and advantage will be apparent, wherein in exemplary embodiment of the invention, identical reference label
Typically represent same parts.
Fig. 1 shows the HPLC method purity test figure of gram vertical boron sieve intermediate of the preparation of embodiment according to the present invention 1.
Specific embodiment
The preferred embodiment of the present invention is described in more detail below.Although the following describe preferred implementations of the invention
Mode, however, it is to be appreciated that may be realized in various forms the present invention without that should be limited by the embodiments set forth herein.Phase
Instead, these embodiments are provided so that the present invention is more thorough and complete, and can be by the scope of the present invention completely
It is communicated to those skilled in the art.
The present invention provides a kind of preparation method of gram vertical boron sieve intermediate, described gram of vertical boron sieve intermediate has IV institute of formula
Show structure,
The preparation method includes the following steps:
(1) in the presence of the first organic solvent and the first alkali, by compound shown in formula I and fluorobenzonitrile contact anti-
It answers, obtains compound shown in formula II；
(2) in the presence of the second solvent, compound shown in the formula II and alkali metal borohydride contact anti-
It answers, obtains compound shown in formula III；
(3) in the presence of third organic solvent and catalyst, compound shown in the formula III and brominated reagent are carried out
Haptoreaction obtains compound shown in formula IV；
In accordance with the present invention it is preferred that first organic solvent is n,N dimethylformamide, dimethyl in step (1)
Sulfoxide, at least one of sulfolane and NMP；
First alkali be potassium carbonate, sodium carbonate, sodium bicarbonate, saleratus, sodium methoxide, sodium ethoxide, sodium tert-butoxide and
At least one of potassium tert-butoxide.
In accordance with the present invention it is preferred that the dosage to fluorobenzonitrile is compound shown in the formula I in step (1)
1.5-3 equivalent.
In the present invention, as a preferred embodiment, reaction temperature is 80-150 DEG C, further excellent in step (1)
It is selected as 80-110 DEG C, reaction time 8-24h.
In accordance with the present invention it is preferred that the alkali metal borohydride is sodium borohydride and/or hydroboration in step (2)
Potassium；
Second solvent is at least one of methanol, ethyl alcohol, isopropanol, water and tetrahydrofuran.
In accordance with the present invention it is preferred that the dosage of the alkali metal borohydride is chemical combination shown in the formula II in rapid (2)
The 0.5-3 equivalent of object.
In the present invention, as a preferred embodiment, catalytic temperature is -10 to 80 DEG C in step (2),
Further preferably 20-30 DEG C, reaction time 1-10h.
In accordance with the present invention it is preferred that in step (3), the third organic solvent is acetonitrile, ethyl acetate, methylene chloride,
Glacial acetic acid, methanol, at least one of ethyl alcohol and n,N-Dimethylformamide；
The catalyst is the toluenesulfonic acid to sulfuric acid, acetic acid, trifluoroacetic acid, thiocarbamide, in trifluoromethanesulfonic acid and methanesulfonic acid
It is at least one；
The brominated reagent is NBS (N-bromosuccinimide), dibromo sea English or bromine.
In accordance with the present invention it is preferred that the dosage of the brominated reagent is compound shown in the formula III in step (3)
0.5-2 equivalent.
In the present invention, as a preferred embodiment, in step (3), reaction temperature is -10 to 100 DEG C, when reaction
Between be 0.5-48h.
The present invention is further illustrated by the following examples:
Embodiment 1
As shown in Equation 3, the present embodiment provides a kind of preparation method of gram vertical boron sieve intermediate, it is specific the preparation method is as follows:
(1) preparation of 4- (3- (formoxyl) phenoxy group) cyanophenyl (compound shown in formula II)
By 122g (1mol) m-hydroxybenzaldehyde (compound shown in formula I), 400mlDMF, potassium carbonate 276g (2mol) are added
Into reaction kettle, it is added with stirring to fluorobenzonitrile 182g (2mol), 110 DEG C of reaction 16h, it is cooling, add 2000ml water, ethyl acetate
Extraction three times, recycles ethyl acetate, methanol mashing, filtering, dry brown solid 203g, yield 91%；
(2) preparation of 4- (3- (methylol) phenoxy group) cyanophenyl (compound shown in formula III)
By 4- (3- (formoxyl) phenoxy group) cyanophenyl (compound shown in formula II) 223g (1mol), 2000ml methanol is added to
In reaction kettle, reaction kettle then is added portionwise in 18.9g (1mol) sodium borohydride, is finished, continues to stir 2h at 25 DEG C to raw material
Methanol is recycled in fully reacting, and the mashing of 1000ml water is added, filters, dry, obtains solid 220g, yield 98%；
(3) preparation of 4- (4- bromine 3- (methylol) phenoxy group) cyanophenyl (compound shown in formula IV) is by 225g (1mol) 4-
(3- (methylol) phenoxy group) cyanophenyl (compound shown in formula III), 1000ml acetonitrile, 17.2g (0.1mol) p-methyl benzenesulfonic acid are added
Into reaction kettle, reaction kettle is added portionwise in 196g (1.1mol) NBS at 25 DEG C, is added, flow back 6h, recycles acetonitrile, adds water, mistake
Filter, dry white solid 290g, yield 95%；Nuclear-magnetism is composed1H-NMR (300MHz, CDCl3): δ 7.62 (2H, d, Ph-H),
7.56 (1H, d, Ph-H), 7.26 (1H, d, Ph-H), 7.02 (2H, d, Ph-H), 6.88 (1H, dd, Ph-H), 4.75 (2H, s,
CH2-H)。
Embodiment 2
As shown in Equation 3, the present embodiment provides a kind of preparation method of gram vertical boron sieve intermediate, it is specific the preparation method is as follows:
(1) preparation of 4- (3- (formoxyl) phenoxy group) cyanophenyl (compound shown in formula II)
By 122g (1mol) m-hydroxybenzaldehyde (compound shown in formula I), 400mlDMF, potassium carbonate 276g (2mol) are added
Into reaction kettle, it is added with stirring to fluorobenzonitrile 182g (2mol), 110 DEG C of reaction 16h, it is cooling, add 2000ml water, ethyl acetate
Extraction three times, recycles ethyl acetate, methanol mashing, filtering, dry brown solid 203g, yield 91%；
(2) preparation of 4- (3- (methylol) phenoxy group) cyanophenyl (compound shown in formula III)
By 4- (3- (formoxyl) phenoxy group) cyanophenyl (compound shown in formula II) 223g (1mol), 2000ml methanol is added to
In reaction kettle, reaction kettle then is added portionwise in 18.9g (1mol) sodium borohydride, is finished, continues to stir 2h at 25 DEG C to raw material
Methanol is recycled in fully reacting, and the mashing of 1000ml water is added, filters, dry, obtains solid 220g, yield 98%；
3) preparation of 4- (4- bromine 3- (methylol) phenoxy group) cyanophenyl (compound shown in formula IV)
By 225g (1mol) 4- (3- (methylol) phenoxy group) cyanophenyl (compound shown in formula III), 1000ml acetonitrile, 7.6g
(0.1mol) thiocarbamide is added in reaction kettle, and reaction kettle is added portionwise in 196g (1.1mol) NBS at 25 DEG C, adds reflux 10h,
Acetonitrile is recycled, water is added, is filtered, dry white solid 276g, yield 91%；Nuclear-magnetism is composed1H-NMR (300MHz, CDCl3): δ
7.62 (2H, d, Ph-H), 7.56 (1H, d, Ph-H), 7.26 (1H, d, Ph-H), 7.02 (2H, d, Ph-H), 6.88 (1H, dd,
Ph-H), 4.75 (2H, s, CH2-H)。
Embodiment 3
As shown in Equation 3, the present embodiment provides a kind of preparation method of gram vertical boron sieve intermediate, it is specific the preparation method is as follows:
(1) preparation of 4- (3- (formoxyl) phenoxy group) cyanophenyl (compound shown in formula II)
By 122g (1mol) m-hydroxybenzaldehyde (compound shown in formula I), 400mlDMF, potassium carbonate 276g (2mol) are added
Into reaction kettle, it is added with stirring to fluorobenzonitrile 182g (2mol), 110 DEG C of reaction 16h, it is cooling, add 2000ml water, ethyl acetate
Extraction three times, recycles ethyl acetate, methanol mashing, filtering, dry brown solid 203g, yield 91%；
(2) preparation of 4- (3- (methylol) phenoxy group) cyanophenyl (compound shown in formula III)
By 4- (3- (formoxyl) phenoxy group) cyanophenyl (compound shown in formula II) 223g (1mol), 2000ml methanol is added to
In reaction kettle, reaction kettle then is added portionwise in 18.9g (1mol) sodium borohydride, is finished, continues to stir 2h at 25 DEG C to raw material
Methanol is recycled in fully reacting, and the mashing of 1000ml water is added, filters, dry, obtains solid 220g, yield 98%；
3) preparation of 4- (4- bromine 3- (methylol) phenoxy group) cyanophenyl (compound shown in formula IV)
By 225g (1mol) 4- (3- (methylol) phenoxy group) cyanophenyl (compound shown in formula III), 1000ml methylene chloride,
25 DEG C are added dropwise the concentrated sulfuric acid that 20g mass concentration is 98% into reaction kettle, by 156g (0.55mol) dibromo sea scruple batch at 25 DEG C
Reaction kettle is added, adds reflux 8h, recycles methylene chloride, water on the rocks, filtering, dry white solid 284g；Yield 93%；Core
Magnetic spectrum is1H-NMR (300MHz, CDCl3): δ 7.62 (2H, d, Ph-H), 7.56 (1H, d, Ph-H), 7.26 (1H, d, Ph-H),
7.02 (2H, d, Ph-H), 6.88 (1H, dd, Ph-H), 4.75 (2H, s, CH2-H)。
Wherein, MBH4 refers to alkali metal borohydride.
Test case
According to the purity of gram vertical boron sieve intermediate (compound shown in formula IV) prepared by HPLC method testing example 1, lead to
Test is crossed, the purity of gram vertical boron sieve intermediate (compound shown in formula IV) prepared by embodiment 1 is 99.5%.
Wherein, the liquid-phase condition of HPLC method is as follows:
Chromatographic column is Agilent interma C18 (250*4.6mm, 5um)
A phase: 10mmol/L KH2PO4B phase: methanol
Wavelength X=254nm flow velocity v=1ml/min t=30min T=30 DEG C, is specifically shown in Table 1；
Table 1
| Time/min | A phase | B phase | Flow velocity/ml/min |
| 0 | 45 | 55 | 1 |
| 15 | 20 | 80 | 1 |
| 25 | 20 | 80 | 1 |
| 26 | 45 | 55 | 1 |
| 30 | 45 | 55 | 1 |
Various embodiments of the present invention are described above, above description is exemplary, and non-exclusive, and
It is not limited to disclosed each embodiment.Without departing from the scope and spirit of illustrated each embodiment, for this skill
Many modifications and changes are obvious for the those of ordinary skill in art field.
Claims (7)
1. a kind of preparation method of gram vertical boron sieve intermediate, which is characterized in that described gram of vertical boron sieve intermediate has shown in formula IV
Structure,
The preparation method includes the following steps:
(1) in the presence of the first organic solvent and the first alkali, haptoreaction is carried out by compound shown in formula I and to fluorobenzonitrile,
Obtain compound shown in formula II；
(2) in the presence of the second solvent, compound shown in the formula II and alkali metal borohydride is subjected to haptoreaction, obtained
Compound shown in formula III；
(3) in the presence of third organic solvent and catalyst, compound shown in the formula III and brominated reagent are contacted
Reaction, obtains compound shown in formula IV；
2. preparation method according to claim 1, wherein in step (1), first organic solvent is N, N dimethyl
Formamide, dimethyl sulfoxide, at least one of sulfolane and NMP；
First alkali is potassium carbonate, sodium carbonate, sodium bicarbonate, saleratus, sodium methoxide, sodium ethoxide, sodium tert-butoxide and tertiary fourth
At least one of potassium alcoholate.
3. preparation method according to claim 1, wherein in step (1), the dosage to fluorobenzonitrile is the formula I
The 1.5-3 equivalent of shown compound.
4. preparation method according to claim 1, wherein in step (2), the alkali metal borohydride is sodium borohydride
And/or potassium borohydride；
Second solvent is at least one of methanol, ethyl alcohol, isopropanol, water and tetrahydrofuran.
5. preparation method according to claim 1, wherein in step (2), the dosage of the alkali metal borohydride is institute
State the 0.5-3 equivalent of compound shown in formula II.
6. preparation method according to claim 1, wherein in step (3), the third organic solvent is acetonitrile, acetic acid
Ethyl ester, methylene chloride, glacial acetic acid, methanol, at least one of ethyl alcohol and n,N-Dimethylformamide；
The catalyst is sulfuric acid, p-methyl benzenesulfonic acid, acetic acid, trifluoroacetic acid, thiocarbamide, in trifluoromethanesulfonic acid and methanesulfonic acid at least
It is a kind of；
The brominated reagent is NBS, dibromo sea English or bromine.
7. preparation method according to claim 1, wherein in step (3), the dosage of the brominated reagent is the formula III
The 0.5-2 equivalent of shown compound.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114702408A (en) * | 2022-02-22 | 2022-07-05 | 南京康川济医药科技有限公司 | Preparation method and application of Kelibaro impurity |
| CN114716349A (en) * | 2022-04-29 | 2022-07-08 | 武汉绿合医药科技有限公司 | Preparation method of Kelibaro impurity |
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