CN108997399A - The preparation method of gram vertical boron sieve intermediate - Google Patents
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- CN108997399A CN108997399A CN201810819282.6A CN201810819282A CN108997399A CN 108997399 A CN108997399 A CN 108997399A CN 201810819282 A CN201810819282 A CN 201810819282A CN 108997399 A CN108997399 A CN 108997399A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Abstract
The invention discloses a kind of preparation method of gram vertical boron sieve intermediate, gram vertical boron sieve intermediate has structure shown in formula VI, including type I compound and halogenation benzyl haptoreaction, obtains II compound of formula；II compound of formula and alkali metal borohydride haptoreaction obtain III compound of formula；III compound of formula and compound a haptoreaction or III compound of formula and dihydropyran haptoreaction, obtain IV compound of formula；Compound a is trim,ethylchlorosilane, tert-butyl chloro-silicane, chloromethyl methyl ether；IV compound of formula and isopropylmagnesium chloride solution haptoreaction；Haptoreaction acquired solution is added in compound b and the 4th organic solvent mixed liquor and carries out haptoreaction, hydrochloric acid haptoreaction is added, obtains V compound of formula；Compound b is penta ring of 2- alkoxy -4,4,5,5- tetramethyl -1,3,2- dioxy boron, triisopropyl borate or trimethyl borate；V compound of formula carries out hydrogenation, obtains VI compound of formula；
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.
CN106928264 reports the synthetic route (as shown in Figure 1) of gram vertical boron sieve, it is disclosed that 1,3- dihydro -1,5-
The synthetic route of penta ring of dihydroxy -2,1- benzoxaborole (gram vertical boron sieve intermediate).This method has used organic palladium catalyst
With duplex pinacol borate, starting material is expensive
Summary of the invention
The object of the present invention is to provide a kind of gram vertical boron sieve intermediate 1,3- dihydro -1,5- dihydroxy -2,1- benzo oxa-s
The new preparation process of penta ring of boron, the preparation method are not related to the reaction condition of organic palladium catalyst and harshness, and process costs are low, energy
It is enough to be preferably applied to industrialized production.
To achieve the goals above, the present invention provides a kind of preparation method of gram vertical boron sieve intermediate, described gram of vertical boron sieve
Intermediate has structure shown in formula VI,
The preparation method includes the following steps:
(1) in the presence of the first organic solvent and the first alkali, compound shown in formula I and halogenation benzyl 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 are subjected to haptoreaction,
Obtain compound shown in formula III；
(3) in the presence of third organic solvent and the second alkali, compound shown in the formula III and compound a are contacted
Reaction, obtains compound shown in formula IV；It, will be shown in the formula III or in the presence of third organic solvent and the first catalyst
Compound and dihydropyran carry out haptoreaction, obtain compound shown in formula IV；Wherein, the compound a is trimethylchloro-silicane
Alkane, tert-butyl chloro-silicane or chloromethyl methyl ether；
Wherein, R1For trimethylsilyl, t-butyldimethylsilyi,
Dimethyl cellosolve base or THP trtrahydropyranyl；
(4) in the presence of the 4th organic solvent and protective gas, by compound and isopropylmagnesium chloride shown in the formula IV
Solution carries out haptoreaction；Then haptoreaction acquired solution is added in the mixed liquor of compound b and the 4th organic solvent into
Row haptoreaction adds hydrochloric acid haptoreaction, obtains compound shown in formula V；Wherein, the compound b is 2- alkoxy-
Penta ring of 4,4,5,5- tetramethyl -1,3,2- dioxy boron, triisopropyl borate or trimethyl borate；
(5) in the presence of the 5th solvent and the second catalyst, compound shown in the formula V is subjected to hydrogenation, is obtained
To compound shown in formula VI；
Technical solution of the present invention has the advantages that
(1) boric acid for preparing of the invention uses grignard reagent to substitute organic palladium catalyst in the process, cheap, reacts item
Part is mild, will not generate palladium residual.
(2) preparation method of the invention does not need to be reacted under harsh Cryogenic Conditions.
(3) preparation method process costs of the invention are low, and cost of material is cheap, can preferably be applied to industrial metaplasia
It produces.
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 a kind of synthetic route chart of gram vertical boron sieve in the prior art.
Fig. 2 shows the synthetic route charts of according to an embodiment of the invention gram of vertical boron sieve intermediate.
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 VI 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, compound shown in formula I and halogenation benzyl 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 are subjected to haptoreaction,
Obtain compound shown in formula III；
(3) in the presence of third organic solvent and the second alkali, compound shown in the formula III and compound a are contacted
Reaction, obtains compound shown in formula IV；It, will be shown in the formula III or in the presence of third organic solvent and the first catalyst
Compound and dihydropyran carry out haptoreaction, obtain compound shown in formula IV；Wherein, the compound a is trimethylchloro-silicane
Alkane, tert-butyl chloro-silicane or chloromethyl methyl ether；
Wherein, R1For trimethylsilyl, t-butyldimethylsilyi,
Dimethyl cellosolve base or THP trtrahydropyranyl；
(4) in the presence of the 4th organic solvent and protective gas, by compound and isopropylmagnesium chloride shown in the formula IV
Solution carries out haptoreaction；Then haptoreaction acquired solution is added in the mixed liquor of compound b and the 4th organic solvent into
Row haptoreaction adds hydrochloric acid haptoreaction, obtains compound shown in formula V；Wherein, the compound b is 2- alkoxy-
Penta ring of 4,4,5,5- tetramethyl -1,3,2- dioxy boron, triisopropyl borate or trimethyl borate；
(5) in the presence of the 5th solvent and the second catalyst, compound shown in the formula V is subjected to hydrogenation, is obtained
To compound shown in formula VI；
In accordance with the present invention it is preferred that there is also third catalyst, the third catalyst is potassium iodide in step (1),
At least one of sodium iodide and tetrabutylammonium iodide.
In accordance with the present invention it is preferred that the dosage of the halogenation benzyl is that the 1-1.5 of compound shown in formula I works as in step (1)
Amount；The halogenation benzyl is benzyl chloride and/or cylite；First organic solvent is n,N dimethylformamide, and dimethyl is sub-
At least one of sulfone, methanol, ethyl alcohol, isopropanol, acetone, butanone and acetonitrile；First alkali is triethylamine, pyridine, N, N-
In diisopropylethylamine, tri-n-butylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide and potassium hydroxide extremely
Few one kind；As a preferred embodiment, reaction temperature is 30-150 DEG C, and further preferably 60-100 DEG C, when reaction
Between be 8-12h..
In accordance with the present invention it is preferred that the dosage of the alkali metal borohydride is II shownization of formula in step (2)
Close the 0.5-3 equivalent of object；The alkali metal borohydride is sodium borohydride and/or potassium borohydride；Second solvent be methanol,
At least one of ethyl alcohol, isopropanol, water and tetrahydrofuran；As a preferred embodiment, catalytic temperature be-
10 to 80 DEG C, preferably 20-30 DEG C, reaction time 1-10h.
In accordance with the present invention it is preferred that the third organic solvent is methylene chloride, tetrahydrofuran, toluene in step (3)
At least one of with N,N-dimethylformamide；Second alkali is organic base and/or inorganic base, and the organic base is three second
At least one of amine, tri-n-butylamine, diisopropylethylamine and imidazoles, the inorganic base are sodium hydride, sodium hydroxide, hydroxide
Potassium, at least one of sodium carbonate and potassium carbonate；First catalyst is p-methyl benzenesulfonic acid；Embodiment party as one preferred
Formula, reaction temperature are -10 to 110 DEG C, reaction time 2-48h.
In accordance with the present invention it is preferred that in step (4), by compound shown in the formula IV and isopropylmagnesium chloride solution into
The catalytic reaction condition of row includes: that the isopropylmagnesium chloride solution is added dropwise to IV institute of formula in the presence of protective gas
In the mixed liquor for showing compound and the 4th organic solvent, it is -20-0 DEG C that temperature is kept during being added dropwise.
In accordance with the present invention it is preferred that the reaction condition of compound shown in preparation formula V includes: that contact is anti-in step (4)
Acquired solution is answered to be added dropwise in the mixed liquor of the compound b and the 4th organic solvent, haptoreaction acquired solution is in 1-2h
It has been added that, 10-30 DEG C of reaction 6-12h, it is 3 hereinafter, the reaction was continued 1-3h that hydrochloric acid to pH value is then added under condition of ice bath；As
A kind of preferred embodiment, the reaction temperature of the reaction was continued the 1-3h are 20-100 DEG C, further preferably 50-100 DEG C；
Preferably, the mass concentration of the hydrochloric acid is 10-37.5%.
In accordance with the present invention it is preferred that in step (4), the amount of the isopropylmagnesium chloride in the isopropylmagnesium chloride solution
For the 1-2.5 equivalent of compound shown in the formula IV；The dosage of the compound b is the 1- of the haptoreaction acquired solution
2.5 equivalent；4th organic solvent is at least one in tetrahydrofuran, ether, methyltetrahydrofuran and glycol dimethyl ether
Kind.
In accordance with the present invention it is preferred that in step (4), the 2- alkoxy -4,4,5,5- tetramethyls -1,3,2- dioxy boron
Alkoxy in penta ring is preferably the alkoxy of C1-C4；2- alkoxy -4,4,5,5- tetramethyl -1,3,2- dioxy the boron penta
Ring is more preferably penta ring of 2- methoxyl group -4,4,5,5- tetramethyl -1,3,2- dioxy boron and/or 2- isopropyl alkoxy -4,4,
Penta ring of 5,5- tetramethyl -1,3,2- dioxy boron.
In accordance with the present invention it is preferred that the 5th solvent is methanol, ethyl alcohol, isopropanol, n-butanol, water in step (5)
At least one of with tetrahydrofuran；Second catalyst is palladium carbon.Preferably, the additive amount of palladium carbon is chemical combination shown in formula V
The 5-10wt% of the dosage of object；Fully reacting is hydrogenated under 1-5bar pressure.
Inventor is the study found that after coupling reaction using organic palladium catalyst borate, and organic palladium catalyst is not
It is recyclable, and it be easy to cause palladium in gram vertical boron sieve drug of preparation exceeded；And grignard reagent is used to substitute organic palladium catalyst
Boric acid is prepared, reaction condition is mild, will not generate palladium residual, and catalyst used is cheap.
The present invention is further illustrated by the following examples:
Embodiment
As shown in Fig. 2, 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 the bromo- benzaldehyde of 5- benzyloxy -2- (compound shown in formula II)
By the bromo- 5- hydroxy-benzaldehyde of 201g (1mol) 2- (compound shown in formula I), 1000ml acetone, potassium carbonate 276g
(1.1mol) is added in reaction kettle, is added with stirring benzyl chloride 152g (1.2mol), and flow back 10h, and recycling design adds 1000ml
Water is beaten, and filtering is dried under reduced pressure to obtain solid 279g, yield 96%；
(2) preparation of the bromo- benzyl alcohol of 5- benzyloxy -2- (compound shown in formula III)
By the bromo- benzaldehyde of 145g (0.5mol) 5- benzyloxy -2-, 2000ml methanol is added in reaction kettle, is added portionwise
18.9g (1mol) sodium borohydride, finishes, and continues to stir 4h at 25 DEG C to raw material fully reacting, recycles methanol, 1000ml water is added
Mashing is filtered, dry, obtains solid 143g, yield 98%；
(3) [(the bromo- benzene of 5- benzyloxy -2-) methoxyl group] (compound shown in formula IV, R1 are trimethyl silicane to-trimethyl silane
Alkyl) preparation
By the bromo- benzyl alcohol of 145g (0.5mol) 5- benzyloxy -2-, 500ml methylene chloride, 60.6g triethylamine (0.6mol)
It is added in reaction kettle, is cooled to 0-10 DEG C, 65g trim,ethylchlorosilane is added dropwise, control temperature is no more than 10 DEG C, 25 DEG C of stirrings
For 24 hours, add water quenching reaction, methylene chloride extraction is washed, and anhydrous magnesium sulfate dries, filters, and recycling design obtains grease 171g；
(4) preparation of penta ring (compound shown in formula V) of 5- benzyloxy 1,3- dihydro -1- hydroxyl -2,1- benzoxaborole
Reaction is added in [(the bromo- benzene of 5- benzyloxy -2-) methoxyl group]-trimethyl silane 36.5g (0.1mol), THF300ml
In kettle, under nitrogen protection, be cooled to -10 DEG C, be added dropwise 2.0mol/L isopropylmagnesium chloride tetrahydrofuran solution (75ml,
0.15mol), temperature is no more than 0 DEG C, and about dropwise addition 3h drop finishes, 20 DEG C of stirring 1h, solution for standby；
THF300ml, 23.7g (0.15mol) 2- methoxyl group -4,4,5,5- tetramethyls -1,3,2- bis- are added in reaction flask
Penta ring of oxygen boron, is cooled to 0-10 DEG C, and above-mentioned stock solution is added dropwise, and about dropwise addition 1.5h, drop finish, and 25 DEG C of reaction 9h, ice bath is added
Hydrochloric acid to pH value is 3 hereinafter, continuing back flow reaction 2 hours, recycles organic solvent, 0-10 DEG C of crystallization, and filtration drying obtains chemical combination
Object 21g, yield 81%；
(5) preparation of penta ring of 1,3- dihydro -1,5- dihydroxy -2,1- benzoxaborole (compound shown in formula VI)
By 5- benzyloxy 1, penta ring (25.6g, 0.1mol) of 3- dihydro -1- hydroxyl -2,1- benzoxaborole, ethyl alcohol 500ml,
5%Pd/C is added in reaction kettle, 3bar pressure hydrogenation to fully reacting, and the temperature of reaction is 25 DEG C, time 6h, is filtered, and returns
Ethyl alcohol is received, water is added, is filtered, dry solid 13.8g, yield 92%；1HNMR DMSO-d6 9.32(s,1H)7,23(d,1H),
7.12(d,1H),6.90(dd,1H)4.96(S,2H),ESI M-H 149
The embodiment of the present invention is described above, above description is exemplary, and non-exclusive, and also not
It is limited to disclosed embodiment.Without departing from the scope and spirit of embodiment described, for the art
Those of ordinary skill for many modifications and changes are obvious.
Claims (10)
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 VI
Structure,
The preparation method includes the following steps:
(1) in the presence of the first organic solvent and the first alkali, compound shown in formula I and halogenation benzyl is subjected to haptoreaction, obtained
To 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, obtain formula
Compound shown in III；
(3) in the presence of third organic solvent and the second alkali, compound shown in the formula III and compound a contact anti-
It answers, obtains compound shown in formula IV；Or in the presence of third organic solvent and the first catalyst, it will change shown in the formula III
It closes object and dihydropyran carries out haptoreaction, obtain compound shown in formula IV；Wherein, the compound a be trim,ethylchlorosilane,
Tert-butyl chloro-silicane or chloromethyl methyl ether；
Wherein, R1For trimethylsilyl, t-butyldimethylsilyi, methyl first
Ether or THP trtrahydropyranyl；
(4) in the presence of the 4th organic solvent and protective gas, by compound shown in the formula IV and isopropylmagnesium chloride solution
Carry out haptoreaction；Then haptoreaction acquired solution is added in compound b and the mixed liquor of the 4th organic solvent and is connect
Touching reaction, adds hydrochloric acid haptoreaction, obtains compound shown in formula V；Wherein, the compound b is 2- alkoxy -4,4,
Penta ring of 5,5- tetramethyl -1,3,2- dioxy boron, triisopropyl borate or trimethyl borate；
(5) in the presence of the 5th solvent and the second catalyst, compound shown in the formula V is subjected to hydrogenation, obtains formula
Compound shown in VI；
2. preparation method according to claim 1, wherein in step (1), there is also third catalyst, the third is urged
Agent is potassium iodide, at least one of sodium iodide and tetrabutylammonium iodide.
3. preparation method according to claim 1, wherein in step (1), the dosage of the halogenation benzyl is I shownization of formula
Close the 1-1.5 equivalent of object；The halogenation benzyl is benzyl chloride and/or cylite；First organic solvent is N, N dimethyl formyl
Amine, at least one of dimethyl sulfoxide, methanol, ethyl alcohol, isopropanol, acetone, butanone and acetonitrile；First alkali is three second
Amine, pyridine, n,N-diisopropylethylamine, tri-n-butylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide and hydrogen
At least one of potassium oxide.
4. 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；The alkali metal borohydride is sodium borohydride and/or potassium borohydride；Described
Two solvents are at least one of methanol, ethyl alcohol, isopropanol, water and tetrahydrofuran.
5. preparation method according to claim 1, wherein in step (3), the third organic solvent is methylene chloride,
Tetrahydrofuran, at least one of toluene and n,N-Dimethylformamide；Second alkali is organic base and/or inorganic base, institute
Stating organic base is at least one of triethylamine, tri-n-butylamine, diisopropylethylamine and imidazoles, and the inorganic base is sodium hydride, hydrogen
Sodium oxide molybdena, potassium hydroxide, at least one of sodium carbonate and potassium carbonate；First catalyst is p-methyl benzenesulfonic acid.
6. preparation method according to claim 1, wherein in step (4), by compound and isopropyl shown in the formula IV
It includes: in the presence of protective gas, by the isopropylmagnesium chloride solution that magnesium chloride solution, which carries out catalytic reaction condition,
It is added dropwise in the mixed liquor of compound shown in formula IV and the 4th organic solvent, it is -20-0 DEG C that temperature is kept during being added dropwise.
7. preparation method according to claim 1, wherein in step (4), the reaction condition of compound shown in preparation formula V
It include: to be added dropwise to haptoreaction acquired solution in the mixed liquor of the compound b and the 4th organic solvent, obtained by haptoreaction
Solution has added in 1-2h, 10-30 DEG C of reaction 6-12h, and it is 3 hereinafter, continuing that hydrochloric acid to pH value is then added under condition of ice bath
React 1-3h.
8. preparation method according to claim 1, wherein the isopropyl in step (4), in the isopropylmagnesium chloride solution
The amount of base magnesium chloride is the 1-2.5 equivalent of compound shown in the formula IV；The dosage of the compound b is the haptoreaction institute
Obtain the 1-2.5 equivalent of solution；4th organic solvent is tetrahydrofuran, ether, methyltetrahydrofuran and glycol dimethyl ether
At least one of.
9. preparation method according to claim 1, wherein in step (4), the 2- alkoxy -4,4,5,5- tetramethyls -
Penta ring of 1,3,2- dioxy boron is penta ring of 2- methoxyl group -4,4,5,5- tetramethyl -1,3,2- dioxy boron and/or 2- isopropyl alkoxy -
Penta ring of 4,4,5,5- tetramethyl -1,3,2- dioxy boron.
10. preparation method according to claim 1, wherein in step (5), the 5th solvent is methanol, ethyl alcohol, different
At least one of propyl alcohol, n-butanol, water and tetrahydrofuran；Second catalyst is palladium carbon.
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| CN113387971A (en) * | 2021-04-19 | 2021-09-14 | 安徽普利药业有限公司 | Synthesis method of Kriboro |
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| CN112174989B (en) * | 2019-07-02 | 2023-06-20 | 江西同和药业股份有限公司 | Preparation method of clenbuterol |
| CN113387971A (en) * | 2021-04-19 | 2021-09-14 | 安徽普利药业有限公司 | Synthesis method of Kriboro |
| CN113387971B (en) * | 2021-04-19 | 2023-10-27 | 安徽普利药业有限公司 | Synthesis method of clenbuterol |
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Application publication date: 20181214 |