CN113087623A - Synthesis method of 8-bromoethyl octanoate - Google Patents
Synthesis method of 8-bromoethyl octanoate Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- BKJFDZSBZWHRNH-UHFFFAOYSA-N 8-bromooctanoic acid Chemical compound OC(=O)CCCCCCCBr BKJFDZSBZWHRNH-UHFFFAOYSA-N 0.000 claims abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 31
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 24
- UBTQVPMVWAEGAC-UHFFFAOYSA-N ethyl 8-bromooctanoate Chemical compound CCOC(=O)CCCCCCCBr UBTQVPMVWAEGAC-UHFFFAOYSA-N 0.000 claims abstract description 22
- SGRHVVLXEBNBDV-UHFFFAOYSA-N 1,6-dibromohexane Chemical compound BrCCCCCCBr SGRHVVLXEBNBDV-UHFFFAOYSA-N 0.000 claims abstract description 16
- -1 6-bromohexyl Chemical group 0.000 claims abstract description 16
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 15
- 238000006467 substitution reaction Methods 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000010931 ester hydrolysis Methods 0.000 claims abstract description 13
- 238000005886 esterification reaction Methods 0.000 claims abstract description 13
- 238000010189 synthetic method Methods 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 28
- 239000002585 base Substances 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- CTRYHWQCGHKCMM-UHFFFAOYSA-N 2-(6-bromohexyl)propanedioic acid Chemical compound OC(=O)C(C(O)=O)CCCCCCBr CTRYHWQCGHKCMM-UHFFFAOYSA-N 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- UEOSPPIPGYKPTO-UHFFFAOYSA-N diethyl 2-(6-bromohexyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)CCCCCCBr UEOSPPIPGYKPTO-UHFFFAOYSA-N 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 4
- 239000000920 calcium hydroxide Substances 0.000 claims description 4
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 claims description 3
- 229940007718 zinc hydroxide Drugs 0.000 claims description 3
- 229910021511 zinc hydroxide Inorganic materials 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 26
- 238000007086 side reaction Methods 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000012043 crude product Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000004817 gas chromatography Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- HNHPPZMCJLFGRP-UHFFFAOYSA-N ethyl 8-chlorooctanoate Chemical group CCOC(=O)CCCCCCCCl HNHPPZMCJLFGRP-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- YYZUSRORWSJGET-UHFFFAOYSA-N octanoic acid ethyl ester Natural products CCCCCCCC(=O)OCC YYZUSRORWSJGET-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- OVISMSJCKCDOPU-UHFFFAOYSA-N 1,6-dichlorohexane Chemical compound ClCCCCCCCl OVISMSJCKCDOPU-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
-
- 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
Abstract
The invention provides a synthetic method of 8-bromoethyl octanoate, which comprises the following steps: step S1, carrying out substitution reaction on 1, 6-dibromohexane and diethyl malonate to obtain a compound 2- (6-bromohexyl) -diethyl malonate; step S2, carrying out ester hydrolysis and decarboxylation on the 2- (6-bromohexyl) -diethyl malonate to obtain 8-bromooctanoic acid; step S3, carrying out esterification reaction on the 8-bromooctanoic acid and absolute ethyl alcohol to obtain the 8-bromooctanoic acid ethyl ester. According to the synthesis method of the ethyl 8-bromooctanoate provided by the embodiment of the invention, 1, 6-dibromohexane initial raw material is firstly used for carrying out substitution reaction with diethyl malonate to generate 2- (6-bromohexyl) diethyl malonate, and then ester hydrolysis and decarboxylation reaction are carried out to obtain the 8-bromooctanoic acid; and finally, esterification reaction is carried out to generate the compound 8-bromoethyl octanoate, the scheme has the advantages of easily obtained raw materials, less side reactions in the reaction, simple process, suitability for industrial production and very wide application prospect.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthetic method of 8-bromoethyl octanoate.
Background
The 8-bromooctanoic acid ethyl ester is an excellent solvent and an important intermediate of medicines and pesticides. The CAS number of the 8-bromoethyl octanoate is 105484-55-7, and the structural formula is shown as the following formula (1):
at present, little literature is available on the synthesis of ethyl 8-bromooctanoate. For reference. Known reports about the synthesis of ethyl 8-chlorooctanoate include that 1, 6-dichlorohexane and diethyl malonate are used as initial raw materials, tetramethyl ammonium bromide (TMAC) is used as an auxiliary catalyst for phase transfer, powdered potassium carbonate is used as a base to synthesize diethyl 2- (6-chlorohexyl) malonate, and then the diethyl 2- (6-chlorohexyl) malonate is selectively reacted under the condition of sulfuric acid to obtain ethyl 8-chlorooctanoate, wherein the synthetic route is shown as the following formula (2):
however, in the first step of the above reports, the raw material 1, 6-dichlorohexane reacts with diethyl malonate to synthesize diethyl 2- (6-chlorohexyl) malonate, so that the yield is low due to the easily generated multi-substituted impurities, and the second step of the high-temperature decarboxylation process of diethyl 2- (6-chlorohexyl) malonate and sulfuric acid has more side reactions, so that the route is not suitable for industrial production.
Disclosure of Invention
In view of the above, the synthesis method of the ethyl 8-bromooctanoate provided by the invention has the advantages of less side reaction, high yield, high product content and suitability for industrial production.
In order to solve the technical problems, the invention adopts the following technical scheme:
the synthesis method of ethyl 8-bromooctanoate according to this embodiment includes the following steps:
step S1, carrying out substitution reaction on 1, 6-dibromohexane and diethyl malonate to obtain a compound 2- (6-bromohexyl) -diethyl malonate;
step S2, carrying out ester hydrolysis and decarboxylation on the 2- (6-bromohexyl) -diethyl malonate to obtain 8-bromooctanoic acid;
step S3, carrying out esterification reaction on the 8-bromooctanoic acid and absolute ethyl alcohol to obtain the 8-bromooctanoic acid ethyl ester.
Further, in step S1, the substitution reaction is performed in a first solvent under the action of a first base, wherein the first base is any one selected from sodium ethoxide, sodium methoxide, potassium carbonate, and potassium tert-butoxide, and the first solvent is any one selected from acetonitrile, toluene, xylene, and carbon disulfide.
Further, the reaction temperature of the step S1 is 25 to 70 ℃, and the ratio of the 1, 6-dibromohexane: diethyl malonate: the molar ratio of the first base is 1: (0.8-1.2): (1-3).
Further, the step S2 includes:
step S21, carrying out ester hydrolysis reaction on the 2- (6-bromohexyl) -malonic acid diethyl ester under the action of a second alkali to obtain 2- (6-bromohexyl) -malonic acid;
step S22, the 2- (6-bromohexyl) -malonic acid is subjected to decarboxylation reaction under the heating condition to obtain the 8-bromooctanoic acid.
Still further, in step S21, the second base is any one selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, and zinc hydroxide, and the ratio of 2- (6-bromohexyl) -malonic acid diethyl ester: the molar ratio of the second base is 1: (2-6).
Further, the reaction temperature in the step S21 is 25-50 ℃, and the reaction temperature in the step S22 is 105-135 ℃.
Further, the step S3 includes:
and carrying out reflux esterification reaction on the 8-bromooctanoic acid in the anhydrous ethanol under the catalysis of acid to obtain the 8-bromooctanoic acid ethyl ester.
Still further, the acid is any one selected from the group consisting of toluenesulfonic acid, concentrated sulfuric acid, phosphoric acid.
Still further, the acid: the molar ratio of the 8-bromooctanoic acid is 1 (40-100).
Further, the reaction temperature of the step S3 is 60 to 85 ℃.
The technical scheme of the invention at least has one of the following beneficial effects:
according to the synthesis method of the 8-bromoethyl octanoate provided by the embodiment of the invention, the synthesis route of the 8-chloroethyl octanoate is improved, the original two-step synthesis is changed into a three-step method, firstly, 1, 6-dibromohexane initial raw material and diethyl malonate are subjected to substitution reaction to generate 2- (6-bromohexyl) diethyl malonate, and then the 2- (6-bromohexyl) diethyl malonate is subjected to ester hydrolysis and decarboxylation reaction to obtain 8-bromooctanoic acid; and finally, the 8-bromooctanoic acid and absolute ethyl alcohol are subjected to esterification reaction to generate a compound 8-bromooctanoic acid ethyl ester, the raw materials are easy to obtain, the product can be obtained through three steps of reaction, the side reaction in the reaction is less, the process is simple, the method is suitable for industrial production, and the method has a very wide application prospect.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention, are within the scope of the invention.
The following first describes a method for synthesizing ethyl 8-bromooctanoate according to an embodiment of the present invention.
The synthesis method of the ethyl 8-bromooctanoate provided by the embodiment of the invention comprises the following steps:
in step S1, 1, 6-dibromohexane and diethyl malonate are subjected to substitution reaction to obtain a compound 2- (6-bromohexyl) -diethyl malonate.
That is, first, 1, 6-dibromohexane was used to carry out a substitution reaction with diethyl malonate to obtain 2- (6-bromohexyl) -diethyl malonate as an intermediate.
The reaction formula is shown as the following formula (3):
further, in step S1, the substitution reaction is performed in a first solvent under the action of a first base, wherein the first base is any one selected from sodium ethoxide, sodium methoxide, potassium carbonate, and potassium tert-butoxide, and the first solvent is any one selected from acetonitrile, toluene, xylene, and carbon disulfide.
That is, the substitution reaction of the first step may be carried out under basic conditions in a solvent. Under alkaline conditions, the above substitution reaction is advantageously promoted. In addition, the raw materials used in the reaction have good solubility in acetonitrile, toluene, xylene and carbon disulfide, and are beneficial to promoting the reaction.
Further, the reaction temperature of the step S1 is 25 to 70 ℃, and the ratio of the 1, 6-dibromohexane: diethyl malonate: the molar ratio of the first base is 1: (0.8-1.2): (1-3). That is, the substitution reaction described above can be carried out at a relatively low temperature, and an excess amount of base is preferably added.
Step S2, carrying out ester hydrolysis and decarboxylation on the 2- (6-bromohexyl) -diethyl malonate to obtain 8-bromooctanoic acid.
That is, after the substitution reaction is completed, the obtained intermediate, diethyl 2- (6-bromohexyl) -malonate, is further subjected to ester hydrolysis and decarboxylation reaction to obtain 8-bromooctanoic acid.
The reaction formula is shown as the following formula (4):
in the present invention, in order to overcome the problem of low yield of side reactions in the second part of the selective reaction in the synthesis route of ethyl 8-chlorooctanoate, after the intermediate diethyl 2- (6-bromohexyl) -malonate is obtained, it is first subjected to ester hydrolysis and decarboxylation to obtain 8-bromooctanoic acid.
Further, the step S2 includes:
step S21, carrying out ester hydrolysis reaction on the 2- (6-bromohexyl) -malonic acid diethyl ester under the action of a second alkali to obtain 2- (6-bromohexyl) -malonic acid;
step S22, the 2- (6-bromohexyl) -malonic acid is subjected to decarboxylation reaction under the heating condition to obtain the 8-bromooctanoic acid.
That is, 2- (6-bromohexyl) -malonic acid diethyl ester is first subjected to ester hydrolysis reaction under the action of a second base to produce 2- (6-bromohexyl) -malonic acid, and thereafter, the acid is subjected to decarboxylation reaction to obtain 8-bromooctanoic acid.
Further, in the step S21, the second base is any one selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, and zinc hydroxide, and the diethyl 2- (6-bromohexyl) -malonate: the molar ratio of the second base is 1: (2-6).
The reaction temperature in the step S21 is 25-50 ℃, and the reaction temperature in the step S22 is 105-135 ℃.
In the above reaction, after the reaction of step S21 is completed, the pH of the reaction system is adjusted to be acidic, and after impurities are removed by filtration, the decarboxylation reaction can be directly performed by heating.
Step S3, carrying out esterification reaction on the 8-bromooctanoic acid and absolute ethyl alcohol to obtain the 8-bromooctanoic acid ethyl ester.
Namely, after 8-bromooctanoic acid is obtained, the esterification reaction is further carried out on the 8-bromooctanoic acid and ethanol to obtain the target product of 8-bromooctanoic acid ethyl ester.
The reaction formula is shown as the following formula (5):
further, the step S3 includes: and carrying out reflux esterification reaction on the 8-bromooctanoic acid in the anhydrous ethanol under the catalysis of acid to obtain the 8-bromooctanoic acid ethyl ester.
That is, the esterification reaction occurs under acid-catalyzed conditions with reflux.
Preferably, the acid is any one selected from the group consisting of toluenesulfonic acid, concentrated sulfuric acid, phosphoric acid. Compared with sulfuric acid used for synthesizing 8-chloro ethyl caprylate, the acid has strong operability, fewer side reactions, low requirement on equipment and fewer three wastes.
Further, the acid: the molar ratio of the 8-bromooctanoic acid is 1 (40-100). The acid is present as a catalyst and only the above-mentioned very small amount is required to promote the esterification reaction.
Further, the reaction temperature of the step S3 is 60 to 85 ℃. Compared with the method for preparing the 8-chloro ethyl caprylate by high-temperature selective reaction under the condition of sulfuric acid in the synthesis of the 8-chloro ethyl caprylate, the method has the advantage that the reaction temperature is also obviously reduced.
According to the synthesis method of the 8-bromoethyl octanoate provided by the embodiment of the invention, the synthesis route of the 8-chloroethyl octanoate is improved, the original two-step synthesis is changed into a three-step method, firstly, 1, 6-dibromohexane initial raw material and diethyl malonate are subjected to substitution reaction to generate 2- (6-bromohexyl) diethyl malonate, and then the 2- (6-bromohexyl) diethyl malonate is subjected to ester hydrolysis and decarboxylation reaction to obtain 8-bromooctanoic acid; and finally, the 8-bromooctanoic acid and absolute ethyl alcohol are subjected to esterification reaction to generate a compound 8-bromooctanoic acid ethyl ester, the raw materials are easy to obtain, the product can be obtained through three steps of reaction, the side reaction in the reaction is less, the process is simple, the method is suitable for industrial production, and the method has a very wide application prospect.
Next, the synthesis method of ethyl 8-bromooctanoate according to the present invention is further explained in detail by specific examples.
Example 1
S1: pouring raw materials of diethyl malonate (100g of 1.0eq), 1, 6-dibromohexane (458kg of 3.0eq), sodium ethoxide (46.7g of 1.1eq) and solvent ethanol (500mL) into a reaction bottle, then starting stirring, controlling the temperature to react at 30-40 ℃ for 8 hours.
After the GC pilot reaction is completed, the solvent is removed by decompression and rotation, the reaction is poured into ice water (200mL), an organic layer is extracted by dichloromethane (200mL), the raw material is recovered by decompression distillation after drying, and then the raw material is distilled and purified to obtain 155g of compound diethyl 2- (6-bromohexyl) malonate with the yield of 50%.
1H NMR(400MHz,CDCl3)δ3.77(s,4H),3.40(m,J＝10.9,4.1Hz,3H),2.00-1.77(m,6H),1.57-1.04(m,10H)。
S2: the compound diethyl 2- (6-bromohexyl) malonate (155g, 1.0eq) and sodium hydroxide (38.4g, 2.0eq) are subjected to hydrolysis reaction for 2 hours at a controlled temperature, and the reaction temperature is controlled to be 25-40 ℃.
And (4) after no raw material is detected by central control, adjusting the pH value to acidity, filtering, and controlling the temperature of the intermediate 2- (6-bromohexyl) malonic acid to 120 ℃ and 135 ℃ for reacting for 8 hours.
After cooling, the reaction system is poured into ethyl acetate (500mL) as a solvent, washed twice (200mL x 2) with water, washed once with saturated sodium chloride, dried with anhydrous sodium sulfate as an organic layer, and the solvent is removed by rotary removal under reduced pressure to obtain a crude product of 8-bromooctanoic acid. The crude product is distilled under reduced pressure by an oil pump to obtain 72.7g of 8-bromooctanoic acid with the yield of 68 percent.
1HNMR(400MHz,CDCl3)δ11.0(s,1H)3.41(m,2H),2.36(m,2H),1.85(m,2H),1.64(m,2H)，1.45(m,2H)，1.35(m,4H)。
S3: the compound 8-bromooctanoic acid (72.7g), absolute ethyl alcohol (363g) and concentrated sulfuric acid (0.32g) are catalyzed to carry out reflux reaction for 8 hours, water and azeotropic ethanol solvent generated in the reaction are separated out, after the middle control detection reaction is completed and no raw material exists, the solvent is removed by rotation under reduced pressure to obtain a crude product, and the crude product is rectified under reduced pressure to obtain a transparent liquid, namely 66.3g of ethyl 8-bromooctanoate, wherein the yield is 81%.
1HNMR(400MHz,CDCl3)δ4.13(m,2H)3.51(m,2H),2.32(m,2H),1.82(m,2H),1.64(m,2H)，1.29(m,9H)。
Example 2
S1: pouring raw materials of diethyl malonate (320g, 1.0eq), 1, 6-dibromohexane (1.46kg, 3.0eq) and potassium carbonate (303g, 1.1eq) into a reaction bottle, then starting stirring, raising the temperature to control the reaction temperature to 65-75 ℃ and carrying out reaction for 10 hours.
And (3) controlling the reaction to be complete by GC, pouring the reaction solution into water to separate an organic layer, drying the organic layer, then carrying out reduced pressure distillation, firstly recovering the raw material, and then carrying out distillation and purification to obtain 510g of the compound diethyl 2- (6-bromohexyl) malonate with the yield of 79%.
S2: and (3) carrying out temperature-controlled hydrolysis reaction on the prepared compound diethyl 2- (6-bromohexyl) malonate (510g, 1.0eq) and potassium hydroxide (177g, 2.0eq) for 2 hours, and controlling the reaction temperature to be 25-40 ℃.
After no raw material is detected by the central control, the pH value is adjusted to acidity, the filtration is carried out, and the intermediate 2- (6-bromohexyl) malonic acid is reacted for 8 hours at the temperature of 120 ℃ and 135 ℃.
After cooling, the reaction system is poured into ethyl acetate (1000mL) as a solvent, washed twice (500mL x 2) with water, washed once with saturated sodium chloride, dried with anhydrous sodium sulfate as an organic layer, and the solvent is removed by rotary removal under reduced pressure to obtain a crude product of 8-bromooctanoic acid.
The crude product is distilled under reduced pressure by an oil pump to obtain 257g of 8-bromooctanoic acid with the yield of 73 percent.
S3: the compound 8-bromooctanoic acid (257g), absolute ethyl alcohol (478g) and concentrated sulfuric acid (1.13g) are catalyzed to carry out reflux reaction for 9 hours, water and azeotropic ethanol solvent generated in the reaction are separated out, after the middle control GC detection reaction is completed and no raw material exists, the solvent is removed by rotation under reduced pressure to obtain a crude product, and the crude product is rectified under reduced pressure to obtain transparent liquid 8-bromooctanoic acid ethyl ester 246g, wherein the yield is 85%.
Example 3
S1: pouring raw materials of diethyl malonate (400g, 1.0eq), 1, 6-dibromohexane (1.83kg, 3.0eq) and sodium methoxide (148g, 1.1eq) and solvent methanol (2000mL) into a reaction bottle, then starting stirring, controlling the temperature to react at 25-35 ℃ for 8 h.
After the reaction is completely controlled by GC, the solvent is removed by rotary removal under reduced pressure, the reaction is poured into ice water (1000mL), an organic layer is extracted by dichloromethane (1000mL), the raw material 1, 6-dibromohexane is recovered by reduced pressure distillation after drying, and then the compound 2- (6-bromohexyl) diethyl malonate is obtained by distillation and purification, wherein the yield is 83 percent.
S2: the compound diethyl 2- (6-bromohexyl) malonate (500g, 1.0eq) and sodium hydroxide (123g, 2.0eq) are subjected to temperature-controlled hydrolysis reaction for 3 hours, and the reaction temperature is controlled to be 30-40 ℃.
And (3) after no raw material is detected by central control, adjusting the pH value to acidity, filtering, and reacting the intermediate compound 2- (6-bromohexyl) malonic acid at the temperature of 120 ℃ and 135 ℃ for 8 hours.
After cooling, the reaction system is poured into ethyl acetate (1000mL) as a solvent, washed twice (500mL x 2) with water, washed once with saturated sodium chloride, the organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by rotary removal under reduced pressure to obtain a crude product of 8-bromooctanoic acid. The crude product is distilled under reduced pressure by an oil pump to obtain 259g of 8-bromooctanoic acid with the yield of 75 percent.
S3: putting the compound 8-bromooctanoic acid (259g of 1.0eq), absolute ethyl alcohol (425g) and phosphoric acid (2.3g) into a reaction bottle for reflux reaction for 9 hours, separating out water and an azeotropic ethanol solvent generated in the reaction, performing central control detection to obtain a crude product after the reaction is completely free of raw materials and performing reduced pressure rotary removal on the solvent, and performing reduced pressure rectification to obtain a transparent liquid, namely, ethyl 8-bromooctanoate (110.3 g) with the yield of 89%.
Example 4
S1: the raw materials of diethyl malonate (656g, 1.0eq), 1, 6-dibromohexane (3.0kg, 3.0eq) and potassium carbonate (680g, 1.2eq) are poured into a reaction bottle, stirred, heated and reacted for 10 hours at the temperature of 65-75 ℃.
The GC control reaction is complete, water is poured into the reaction kettle to separate an organic layer, the organic layer is dried and then subjected to reduced pressure distillation, raw materials are firstly recovered, and then the raw materials are distilled and purified to obtain 1.02kg of compound 2- (6-bromohexyl) diethyl malonate with the yield of 77 percent.
S2: the compound diethyl 2- (6-bromohexyl) malonate (1020g 1.0eq) and calcium hydroxide (468g2.0eq) are hydrolyzed for 2 hours under the controlled temperature, and the reaction temperature is controlled to be 25-40 ℃.
And (4) after no raw material is detected by central control, adjusting the pH value to acidity, filtering, and controlling the temperature of the intermediate 2- (6-bromohexyl) malonic acid to 120 ℃ and 135 ℃ for reaction for 9 hours.
After cooling, the reaction system is poured into ethyl acetate (2000mL) as a solvent, washed twice (500mL x 2) with water, washed once with saturated sodium chloride, dried with anhydrous sodium sulfate as an organic layer, and the solvent is removed by rotary removal under reduced pressure to obtain a crude product of 8-bromooctanoic acid. The crude product is distilled under reduced pressure by an oil pump to obtain 437g of 8-bromooctanoic acid with the yield of 62 percent.
S3: the compound 8-bromooctanoic acid (109.6g, 1.0eq) is catalyzed by absolute ethyl alcohol (600mL) and concentrated sulfuric acid (2.2g) to carry out reflux reaction for 9 hours, water and azeotropic ethanol solvent generated in the reaction are separated out, the solvent is removed by rotation under reduced pressure after the reaction is completely detected by GC (gas chromatography), a crude product is obtained, and a transparent liquid, namely, 110.3g of ethyl 8-bromooctanoate, is obtained by rectification under reduced pressure, wherein the yield is 89%.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. A synthetic method of 8-bromoethyl octanoate is characterized by comprising the following steps:
step S1, carrying out substitution reaction on 1, 6-dibromohexane and diethyl malonate to obtain a compound 2- (6-bromohexyl) -diethyl malonate;
step S2, carrying out ester hydrolysis and decarboxylation on the 2- (6-bromohexyl) -diethyl malonate to obtain 8-bromooctanoic acid;
step S3, carrying out esterification reaction on the 8-bromooctanoic acid and absolute ethyl alcohol to obtain the 8-bromooctanoic acid ethyl ester.
2. The synthesis method according to claim 1, wherein in step S1, the substitution reaction is performed in a first solvent under the action of a first base, wherein the first base is any one selected from sodium ethoxide, sodium methoxide, potassium carbonate, and potassium tert-butoxide, and the first solvent is any one selected from acetonitrile, toluene, xylene, and carbon disulfide.
3. The synthesis method according to claim 2, wherein the reaction temperature of step S1 is 25 to 70 ℃, and the molar ratio of 1, 6-dibromohexane: diethyl malonate: the molar ratio of the first base is 1: (0.8-1.2): (1-3).
4. The synthesis method according to claim 1, wherein the step S2 includes:
step S21, carrying out ester hydrolysis reaction on the 2- (6-bromohexyl) -malonic acid diethyl ester under the action of a second alkali to obtain 2- (6-bromohexyl) -malonic acid;
step S22, the 2- (6-bromohexyl) -malonic acid is subjected to decarboxylation reaction under the heating condition to obtain the 8-bromooctanoic acid.
5. The synthesis method according to claim 4, wherein in the step S21, the second base is any one selected from sodium hydroxide, potassium hydroxide, calcium hydroxide and zinc hydroxide, and the ratio of diethyl 2- (6-bromohexyl) -malonate: the molar ratio of the second base is 1: (2-6).
6. The synthesis method as claimed in claim 4, wherein the reaction temperature in step S21 is 25-50 ℃, and the reaction temperature in step S22 is 105-135 ℃.
7. The synthesis method according to claim 1, wherein the step S3 includes:
and carrying out reflux esterification reaction on the 8-bromooctanoic acid in the anhydrous ethanol under the catalysis of acid to obtain the 8-bromooctanoic acid ethyl ester.
8. The synthesis method according to claim 7, wherein the acid is any one selected from toluene sulfonic acid, concentrated sulfuric acid and phosphoric acid.
9. The method of synthesis according to claim 7, wherein the acid: the molar ratio of the 8-bromooctanoic acid is 1 (40-100).
10. The synthesis method according to claim 7, wherein the reaction temperature of step S3 is 60-85 ℃.
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