CN115536494B - Synthesis method of 1- (4-bromophenyl) -1, 4-butanediol - Google Patents
Synthesis method of 1- (4-bromophenyl) -1, 4-butanediol Download PDFInfo
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- KRHUFJDZSPFZIP-UHFFFAOYSA-N 1-(4-bromophenyl)butane-1,4-diol Chemical compound OCCCC(O)C1=CC=C(Br)C=C1 KRHUFJDZSPFZIP-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 238000001308 synthesis method Methods 0.000 title claims abstract description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 51
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 21
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 238000005886 esterification reaction Methods 0.000 claims abstract description 16
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 12
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940014800 succinic anhydride Drugs 0.000 claims abstract description 10
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 9
- 239000012265 solid product Substances 0.000 claims abstract description 9
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 7
- 239000012046 mixed solvent Substances 0.000 claims abstract description 6
- 239000003208 petroleum Substances 0.000 claims abstract description 6
- 239000012043 crude product Substances 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- 239000005457 ice water Substances 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000007809 chemical reaction catalyst Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 239000002274 desiccant Substances 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 10
- 239000012280 lithium aluminium hydride Substances 0.000 description 7
- -1 lithium aluminum hydride Chemical compound 0.000 description 7
- 238000000746 purification Methods 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000011403 purification operation Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
- C07C29/78—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by condensation or crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/083—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid anhydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of 1- (4-bromophenyl) -1, 4-butanediol. The method of the invention comprises the following steps: friedel-crafts reaction, namely, bromobenzene and succinic anhydride are used as initial raw materials to react to obtain a compound I; esterification reaction, taking a compound I and methanol as raw materials, and generating an esterification reaction under the catalysis of thionyl chloride to generate a compound II; reducing reaction, using a compound II as a raw material, and reducing under the action of sodium borohydride to generate a 1- (4-bromophenyl) -1, 4-butanediol crude product; recrystallizing and purifying, and recrystallizing and purifying in a mixed solvent of n-heptane and isopropanol or in a mixed solvent of petroleum ether and acetone to obtain a crystalline solid product of 1- (4-bromophenyl) -1, 4-butanediol. The method is suitable for industrial mass production, the operation steps involved in the synthesis process are all feasible operations in industrial production, and raw materials with high risk coefficient are not used, so that the method is a safe, efficient, simple, convenient and economic synthesis method.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of 1- (4-bromophenyl) -1, 4-butanediol, in particular to a synthesis method of 1- (4-bromophenyl) -1, 4-butanediol, which is suitable for industrialized mass production.
Background
1- (4-bromophenyl) -1, 4-butanediol is an important medical intermediate, can be used for synthesizing raw material medicines related to anti-inflammatory and immune diseases, and has wide market demands and large dosage.
The synthesis route of 1- (4-bromophenyl) -1, 4-butanediol has been reported in patent WO2003029245A1, and the target product is obtained by taking bromobenzene and succinic anhydride as starting materials, performing Friedel-crafts reaction, esterifying with methanol and reducing with lithium aluminum hydride. However, the synthesis method has a plurality of defects, and limits the large-scale industrialized popularization and application. Firstly, sulfuric acid is used as a catalyst in the second-step methanol esterification reaction, so that the esterification conversion rate is low, and the reaction time is long (21 hours are required). Secondly, the final step of the reaction for reducing the ester into the alcohol adopts lithium aluminum hydride as a reducing agent, and the lithium aluminum hydride is inflammable and explosive, so that the large-scale application of the lithium aluminum hydride to industrial production brings great potential safety hazard. Again, according to the patent report, the product obtained by the method is oily, has low purity, and needs column chromatography purification, so the method is not suitable for large-scale industrial production.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a novel synthesis method of 1- (4-bromophenyl) -1, 4-butanediol, and aims to search a novel method suitable for industrialized mass production of 1- (4-bromophenyl) -1, 4-butanediol. Specifically, firstly, to overcome the problems of long esterification reaction time and high energy consumption in the existing method, an esterification mode with higher efficiency, higher speed and higher conversion rate is researched; secondly, the problems of easy explosion, easy spontaneous combustion and high danger coefficient of lithium aluminum hydride in the existing method are overcome, and a milder and safer ester reduction process is researched; the method is used for solving the problem that the existing method is unsuitable for industrial application because of column chromatography purification of oily products, and researching a method which can be industrially implemented and can obtain high-purity products.
The synthesis method of the 1- (4-bromophenyl) -1, 4-butanediol provided by the invention synthesizes according to the synthesis path shown in the figure 1, and comprises the following steps:
step one: friedel-crafts reaction, namely, bromobenzene and succinic anhydride are used as initial raw materials to react to obtain a compound I;
step two: esterification reaction, taking a compound I and methanol as raw materials, and generating an esterification reaction under the catalysis of thionyl chloride to generate a compound II;
step three: and (3) reducing the compound II serving as a raw material under the action of sodium borohydride to generate a 1- (4-bromophenyl) -1, 4-butanediol crude product.
Step four: and (3) recrystallizing and purifying the crude 1- (4-bromophenyl) -1, 4-butanediol obtained in the step (III) in a mixed solvent of n-heptane and isopropanol or in a mixed solvent of petroleum ether and acetone to obtain a crystalline solid product of the 1- (4-bromophenyl) -1, 4-butanediol.
Further, in the step one of the synthesis method of 1- (4-bromophenyl) -1, 4-butanediol, the friedel-crafts reaction adopts dichloromethane or dichloroethane as a reaction solvent and aluminum trichloride as a reaction catalyst.
Further, the first step of the synthesis method of 1- (4-bromophenyl) -1, 4-butanediol is as follows:
and adding succinic anhydride and bromobenzene into dichloromethane or dichloroethane, mixing uniformly, adding aluminum trichloride in batches, stirring for reaction, then pouring the mixture obtained by the reaction into dilute hydrochloric acid ice water solution, filtering to obtain a solid, and washing and drying to obtain the compound I.
In the first step of the method for synthesizing 1- (4-bromophenyl) -1, 4-butanediol, the concentration of the diluted hydrochloric acid ice water solution was 9%, and the solid obtained by filtration was washed with n-hexane.
Further, the second step of the synthesis method of 1- (4-bromophenyl) -1, 4-butanediol is operated as follows: and (3) uniformly mixing the compound I and methanol, dropwise adding thionyl chloride under stirring, heating to 65-66 ℃ after adding, preserving heat and refluxing for reaction, monitoring the reaction until no raw material of the compound I remains, concentrating under negative pressure to recover the methanol, adding n-heptane, stirring, cooling to 0-5 ℃, and filtering to obtain the compound II.
Further, the step three of the synthesis method of 1- (4-bromophenyl) -1, 4-butanediol is operated as follows: tetrahydrofuran or tertiary butanol is selected as a solvent, evenly mixed with a compound II, sodium borohydride is added, the temperature is raised to 40-50 ℃, methanol is slowly added dropwise, the mixture is heated and refluxed, the mixture is cooled to room temperature after the reflux is finished, water is slowly added dropwise, then the mixture is concentrated until no liquid is discharged, water and ethyl acetate are added for extraction to obtain an organic phase, a drying agent is added into the organic phase, filtrate is filtered out, and the filtrate is concentrated to obtain oily crude 1- (4-bromophenyl) -1, 4-butanediol.
Further, the synthesis method of the 1- (4-bromophenyl) -1, 4-butanediol comprises the following operation: dissolving the 1- (4-bromophenyl) -1, 4-butanediol crude product in isopropanol or acetone, heating to 50-55 ℃, dropwise adding n-heptane or petroleum ether, stirring and cooling to 0-5 ℃ after adding, filtering to obtain a solid, and vacuum drying at 40-45 ℃ to obtain a crystalline solid product of the 1- (4-bromophenyl) -1, 4-butanediol.
Advantageous effects
The synthesis method of 1- (4-bromophenyl) -1, 4-butanediol provided by the invention takes bromobenzene and succinic anhydride as initial raw materials, and obtains a high-purity 1- (4-bromophenyl) -1, 4-butanediol crystalline solid product through Friedel-crafts reaction, esterification reaction, reduction reaction and recrystallization purification, the operation steps involved in the whole synthesis process are all feasible operations in industrial production, and raw materials with high danger coefficients are not used in the whole synthesis process, so that the synthesis method is a safe, efficient, simple, convenient and economic synthesis method.
According to the synthesis method of 1- (4-bromophenyl) -1, 4-butanediol, the second-step esterification reaction efficiency is obviously improved, the yield and purity of the product reach high levels, and the reaction time is shortened to about 2 hours.
According to the synthesis method of 1- (4-bromophenyl) -1, 4-butanediol, the third-step reduction reaction is carried out without using the easily pyrophoric and explosive dangerous raw material lithium aluminum hydride, the reaction process is milder, the safety is obviously improved, and the safety is the key factor of primary consideration in industrial production.
According to the synthesis method of 1- (4-bromophenyl) -1, 4-butanediol, the fourth purification operation is carried out on the premise of avoiding column chromatography purification operation which is not suitable for industrial implementation, and a high-purity 1- (4-bromophenyl) -1, 4-butanediol crystalline solid product is obtained.
Drawings
FIG. 1 is a schematic diagram of the synthetic route of the present invention.
Detailed Description
The invention is further illustrated by the following specific examples, which are intended to illustrate the problem and to explain the invention, without limiting it.
Example 1
The present example provides a method for synthesizing 1- (4-bromophenyl) -1, 4-butanediol, using a synthetic route as shown in FIG. 1, comprising the following steps.
Step one: friedel-crafts reaction
In a 1L three-necked flask, succinic anhydride (20.0 g,199.9mmol,1.0 eq) and bromobenzene (47.1 g,299.8mmol,1.5 eq) were added to methylene chloride (400 ml, 20V) and stirred well. Cooling in ice water bath, and controlling the internal temperature to 15-25 ℃. Aluminum trichloride (58.6 g,439.7mmol,2.2 eq) was added in portions and stirred at room temperature (15-20 ℃ C.). After the reaction is finished, slowly pouring the reaction solution into 9% dilute hydrochloric acid ice water solution (400 ml, 20V), stirring for 10min, separating out solid from an organic phase, filtering, washing a filter cake with n-hexane, and vacuum drying at 20-25 ℃ to obtain a compound I;42.4g, HPLC:99.6%, yield: 82.6%.
Step two: esterification reaction
Compound I (20 g,77.8mmol,1.0 eq) and methanol (200 ml,10 v) were added to a reaction flask, thionyl chloride (2 g,16.8mmol,0.2 eq) was added dropwise with stirring, and after addition, the mixture was heated to 65-66 ℃ and kept at reflux for 2 hours, TLC analysis was performed without raw material residue, methanol was recovered by negative pressure concentration until no liquid was obtained, n-heptane was added, stirred and cooled to 0-5 ℃, and 0.5g of compound II was obtained by filtration, hplc:99.1%, yield: 97.6%.
Step three: reduction reaction
Adding compound II (20 g,73.8mmol,1.0 eq) and tetrahydrofuran (120 ml, 6V) into a reaction bottle, adding sodium borohydride (5 g,135.1mmol,1.8 eq), heating to 40-50 ℃, slowly dropwise adding methanol (50 ml, 2.5V) for about 2 hours, heating and refluxing for 2 hours, cooling to room temperature, slowly dropwise adding 20g of water, concentrating until no liquid is produced, adding 100g of water and 200ml of ethyl acetate, separating an organic phase, extracting an aqueous phase once with 50ml of ethyl acetate, combining the organic phases, drying anhydrous sodium sulphate, filtering, concentrating the filtrate until the dry oily substance is 18.1g, and obtaining 100% of yield and 92.1% of purity
Step four: recrystallization purification
Dissolving 18.1g of product oily matter in 18.1ml of isopropanol, heating to 50-55 ℃, slowly dripping 90.4g of n-heptane, stirring and cooling to 0-5 ℃ after the dripping is finished, preserving the heat for 2 hours, filtering, and vacuum drying at 40-45 ℃ to obtain a target product; 16.1g, HPLC:99.5%, yield: 89.0%.
1H NMR (d-DMSO，500MHz) δ：1.46-1.55（4H，m，CH 2 ），3.8（2H，m，CH 2 ），4.14-4.17（2H，s，OH），4.41（1H，m，CH），7.17-7.85（4H，d，CH）。FAB-MS(m/z)：246.12 (M+H)。
Example 2
The present example provides a method for synthesizing 1- (4-bromophenyl) -1, 4-butanediol, using a synthetic route as shown in FIG. 1, comprising the following steps.
Step one: friedel-crafts reaction
In a 1L three-necked flask, succinic anhydride (50.0 g,499.8mmol,1.0 eq) and bromobenzene (117.8 g,749.5mmol,1.5 eq) were added to dichloroethane (1000 ml, 20V) and stirred well. Cooling in ice water bath, and controlling the internal temperature to 15-25 ℃. Aluminum trichloride (146.5 g,1.1mol,2.2 eq) was added in portions, and stirring was completed at room temperature (15 to 20 ℃). After the reaction is finished, slowly pouring the reaction solution into 9% dilute hydrochloric acid ice water solution (1000 ml, 20V), stirring for 10min, separating out solid from an organic phase, filtering, washing a filter cake with n-hexane, and vacuum drying at 20-25 ℃ to obtain a compound I;108.8g, HPLC:99.6%, yield: 84.6%.
Step two: esterification reaction
Compound I (50 g,194.5mmol,1.0 eq) and anhydrous methanol (500 ml,10 v) were added to a reaction flask, thionyl chloride (10 g,84mmol,0.4 eq) was added dropwise with stirring, and after the addition, the temperature was raised to 65-66 ℃ and maintained at reflux for 2 hours, TLC analysis was performed without raw material residue, methanol was recovered by negative pressure concentration until no liquid was obtained, n-heptane was added, stirred and cooled to 0-5 ℃, 0.8g of compound II was obtained by filtration, hplc:99.1%, yield: 99.0%.
Step three: reduction reaction
Adding compound II (20 g,73.8mmol,1.0 eq) and tertiary butanol (120 ml, 6V) into a reaction bottle, adding sodium borohydride (5 g,135.1mmol,1.8 eq), heating to 40-50 ℃, slowly dropwise adding methanol (50 ml, 2.5V) for about 2 hours, heating and refluxing for 2 hours, cooling to room temperature, slowly dropwise adding 20g of water, concentrating until no liquid is produced, adding 100g of water and 200ml of ethyl acetate, separating an organic phase, extracting an aqueous phase once with 50ml of ethyl acetate, combining the organic phases, drying anhydrous sodium sulphate, filtering, concentrating the filtrate until the dry oily matter is 17.2g, and obtaining the oily matter with the yield of 95 percent and the purity of 91.9 percent
Step four: recrystallization purification
17.2g of product oily matter is dissolved in 17.2ml of acetone, the temperature is raised to 50-55 ℃, 86.0g of petroleum ether is slowly added dropwise, the mixture is stirred and cooled to 0-5 ℃ after the addition, the mixture is kept for 2 hours, filtered, and vacuum dried at 40-45 ℃ to obtain the target product; 15.6g, HPLC:99.3%, yield: 90.7%.
1H NMR (d-DMSO，500MHz) δ：1.46-1.55（4H，m，CH 2 ），3.8（2H，m，CH 2 ），4.14-4.17（2H，s，OH），4.41（1H，m，CH），7.17-7.85（4H，d，CH）。FAB-MS(m/z)：246.12 (M+H)。
The 1- (4-bromophenyl) -1, 4-butanediol synthesis method adopted in the embodiment takes bromobenzene and succinic anhydride as initial raw materials, and the high-purity 1- (4-bromophenyl) -1, 4-butanediol crystalline solid product is obtained through Friedel-crafts reaction, esterification reaction, reduction reaction and recrystallization purification. The second step of esterification reaction has obviously raised efficiency, high product yield and purity, and shortened reaction time to about 2 hr. The third-step reduction reaction does not need to use lithium aluminum hydride which is a dangerous raw material and is easy to self-ignite and explode, the reaction process is milder, the safety is obviously improved, and the safety is the key factor of primary consideration in industrial production. The fourth step of purification operation is to obtain the high-purity 1- (4-bromophenyl) -1, 4-butanediol crystalline solid product on the premise of avoiding column chromatography purification operation which is not suitable for industrial implementation.
In summary, the operation steps involved in the whole synthesis process of the invention are all feasible operations in industrial production, and raw materials with high risk coefficient are not used in the whole synthesis process, so that the method is a safe, efficient, simple, convenient and economic synthesis method which can be industrially implemented.
The above embodiments are illustrative for the purpose of illustrating the technical concept and features of the present invention so that those skilled in the art can understand the content of the present invention and implement it accordingly, and thus do not limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
Claims (6)
- The synthesis method of 1- (4-bromophenyl) -1, 4-butanediol is characterized by comprising the following steps:the following synthetic route is followed:the method comprises the following steps:step one: friedel-crafts reaction, namely, bromobenzene and succinic anhydride are used as initial raw materials to react to obtain a compound I;step two: esterification reaction, taking a compound I and methanol as raw materials, and generating an esterification reaction under the catalysis of thionyl chloride to generate a compound II;step three: reducing reaction, using a compound II as a raw material, and reducing under the action of sodium borohydride to generate a 1- (4-bromophenyl) -1, 4-butanediol crude product;the operation of the second step is as follows: uniformly mixing a compound I and methanol, dropwise adding thionyl chloride under stirring, heating to 65-66 ℃ after adding, preserving heat and refluxing for reaction, monitoring the reaction until no raw material of the compound I remains, concentrating under negative pressure to recover methanol, adding n-heptane, stirring, cooling to 0-5 ℃, and filtering to obtain a compound II;the operation of the third step is as follows: tetrahydrofuran or tertiary butanol is selected as a solvent, evenly mixed with a compound II, sodium borohydride is added, the temperature is raised to 40-50 ℃, methanol is slowly added dropwise, the mixture is heated and refluxed, the mixture is cooled to room temperature after the reflux is finished, water is slowly added dropwise, then the mixture is concentrated until no liquid is discharged, water and ethyl acetate are added for extraction to obtain an organic phase, a drying agent is added into the organic phase, filtrate is filtered out, and the filtrate is concentrated to obtain oily crude 1- (4-bromophenyl) -1, 4-butanediol.
- 2. The method for synthesizing 1- (4-bromophenyl) -1, 4-butanediol according to claim 1, wherein: and step four, after the step three is finished, performing the following steps: recrystallizing and purifying; and (3) recrystallizing and purifying the crude 1- (4-bromophenyl) -1, 4-butanediol obtained in the step (III) in a mixed solvent of n-heptane and isopropanol or in a mixed solvent of petroleum ether and acetone to obtain a crystalline solid product of the 1- (4-bromophenyl) -1, 4-butanediol.
- 3. The method for synthesizing 1- (4-bromophenyl) -1, 4-butanediol according to claim 1, wherein: in the first step, dichloromethane or dichloroethane is used as a reaction solvent, and aluminum trichloride is used as a reaction catalyst.
- 4. The method for synthesizing 1- (4-bromophenyl) -1, 4-butanediol according to claim 1, wherein: the operation of the first step is as follows:and adding succinic anhydride and bromobenzene into dichloromethane or dichloroethane, mixing uniformly, adding aluminum trichloride in batches, stirring for reaction, then pouring the mixture obtained by the reaction into dilute hydrochloric acid ice water solution, filtering to obtain a solid, and washing and drying to obtain the compound I.
- 5. The method for synthesizing 1- (4-bromophenyl) -1, 4-butanediol according to claim 4, wherein: in the first step, the concentration of the dilute hydrochloric acid ice water solution was 9%, and the solid obtained by filtration was washed with n-hexane.
- 6. The method for synthesizing 1- (4-bromophenyl) -1, 4-butanediol according to claim 2, wherein: the operation of the fourth step is as follows: dissolving the 1- (4-bromophenyl) -1, 4-butanediol crude product in isopropanol or acetone, heating to 50-55 ℃, dropwise adding n-heptane or petroleum ether, stirring and cooling to 0-5 ℃ after adding, filtering to obtain a solid, and vacuum drying at 40-45 ℃ to obtain a crystalline solid product of the 1- (4-bromophenyl) -1, 4-butanediol.
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