CN103232345B - Synthesis method of 8-hydroxyl ethyl caprylate - Google Patents
Synthesis method of 8-hydroxyl ethyl caprylate Download PDFInfo
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Abstract
The invention relates to the synthesis technical field of medical intermediates and discloses a synthesis method of 8-hydroxyl ethyl caprylate. The synthesis method comprises the following steps of: dissolving 6-bromohexanol and diethyl malonate in an azeotropic organic solvent, heating to have reaction under alkaline catalysis to generate an intermediate which is 2-(6-hydroxyl hexyl) diethyl malonate, wherein the molar ratio of 6-bromohexanol to diethyl malonate to alkali is 1:0.95-1.05:1.37-2.73; and dissolving the intermediate in a polar aprotic solvent and water, heating to having reaction under catalytic effect of sodium halide to generate 8-hydroxyl ethyl caprylate, wherein the molar ratio of the intermediate to sodium halide is 1:1-3. According to the technical scheme provided by the invention, the process line is simple and the cost of raw materials is low; therefore and the method is favorable to industrial production.
Description
Technical field
The present invention relates to the synthesis technical field of medicine intermediate, particularly relate to a kind of synthetic method of 8-Hydroxyoctanoic acid ethyl ester.
Background technology
8-Hydroxyoctanoic acid ethyl ester is a kind of compound conventional in medicine is produced.
The synthetic method of the Hydroxyoctanoic acid of 8-disclosed in currently available technology ethyl ester has following several:
The first, the investigator such as Kudo is in " Synlett " periodical (Synlett, 23 (12), 1843-1846; 2012) report on and under sulfuric acid catalysis, be obtained by reacting 8-Hydroxyoctanoic acid ethyl ester with caprylolactone and ethanol, as shown in Figure 1, its yield is 44% to its synthetic route.
The investigator such as the second, Deng is in " Tetrahedron Letters " periodical (Tetrahedron Letters, 38 (45), 7829-7832; 1997) report on and obtain 8-Hydroxyoctanoic acid ethyl ester with 5-hexen-1-ol and 2-methylmercaptan ethyl acetoacetic ester with acetonitrile solvent, its synthetic route as shown in Figure 2.
The third, the investigator such as Dhide is at " Indian Journal of Chemistry " periodical (Indian Journalof Chemistry, Section B:Organic Chemistry Including Medicinal Chemistry, 24B (10), 1081-3, 1985) method of a kind of multi-step synthesis 8-Hydroxyoctanoic acid ethyl ester is reported on, first be adopt dihydropyrane to protect to the hydroxyl of 6-bromine hexanol, generate 6-(bromine hexyloxy) tetrahydrochysene-2H-pyrans, then diethyl malonate and 6-(bromine hexyloxy) under sodium ethylate catalysis, there is condensation reaction in tetrahydrochysene-2H-pyrans, recycling dimethyl sulfoxide (DMSO) (DMSO) makes solvent, decarboxylic reaction is carried out with Potassium ethanoate, obtain 8-Hydroxyoctanoic acid potassium, last under the katalysis of tosic acid, 8-Hydroxyoctanoic acid potassium and ethanol carry out esterification and obtain 8-Hydroxyoctanoic acid ethyl ester, its principal synthetic routes as shown in Figure 3.
Above three kinds of method Problems existing are as follows:
First method reaction yield is low; In second method 5-hexen-1-ol and 2-methylmercaptan ethyl acetoacetic ester cost of material high; In the third method, 6-bromine hexanol is first with dihydropyrane protection, then carries out condensation, decarboxylation and esterification successively, and reaction scheme is long, complex process.
Therefore, in prior art, the preparation process of 8-Hydroxyoctanoic acid ethyl ester is more complicated, and raw materials cost is high.
Summary of the invention
The object of this invention is to provide a kind of synthetic method of 8-Hydroxyoctanoic acid ethyl ester, in order to shorten reaction scheme, reduce production cost.
The synthetic method of 8-Hydroxyoctanoic acid ethyl ester of the present invention, comprising:
6-bromine hexanol and diethyl malonate are dissolved in and can carry out reacting by heating in the organic solvent of azeotropic under base catalysis, generate intermediate, described intermediate is 2-(6-hydroxyl hexyl) diethyl malonate, wherein, the mol ratio of described 6-bromine hexanol, diethyl malonate and alkali is 1:0.95 ~ 1.05:1.37 ~ 2.73;
Be dissolved in polar aprotic solvent and water under the katalysis of sodium halide by described intermediate and carry out reacting by heating, generate 8-Hydroxyoctanoic acid ethyl ester, wherein, the mol ratio of described intermediate and sodium halide is 1:1 ~ 3.
Contriver finds, according to the reaction equation of 6-bromine hexanol and diethyl malonate, the mol ratio of 6-bromine hexanol and diethyl malonate is 1:1, therefore, the 6-bromine hexanol adopted and the mol ratio of diethyl malonate do not depart from 1, be preferably 1:0.95 ~ 1.05, and alkali is as the acid binding agent in this reaction, alkali can promote the carrying out of this reaction with the reaction of hydrogen bromide that generates in reaction, therefore, also the content of alkali is limited, when alkali is more, reaction is very fast, but the alkali retained after having reacted is also more, need to remove remaining alkali after reaction, and be also a kind of waste, when alkali content is less, the hydrogen bromide generated in reaction can not be removed completely.And intermediate 2-(6-hydroxyl hexyl) diethyl malonate carries out reacting by heating under the katalysis of sodium halide, reaction principle is form oxa-ring through transesterify, form 8-Hydroxyoctanoic acid ethyl ester through hydrolysis and decarboxylic reaction more successively.
Preferably, the mol ratio of described intermediate and sodium halide is 1:1.2 ~ 1.5.
Preferably, described sodium halide is sodium-chlor or Sodium Bromide.
Preferably, be dissolved in polar aprotic solvent and water under the katalysis of sodium halide by described intermediate and carry out reacting by heating, its temperature of reaction is 100 ~ 150 DEG C.
Preferably, be dissolved in polar aprotic solvent and water under the katalysis of sodium halide by described intermediate and carry out reacting by heating, its temperature of reaction is 140 ~ 145 DEG C.
Preferably, be dissolved in polar aprotic solvent and water by described intermediate and carry out reacting by heating under the katalysis of sodium halide, reaction duration is 8 ~ 10 hours.
In synthetic method for above-mentioned 8-Hydroxyoctanoic acid ethyl ester, described polar aprotic solvent is dimethyl sulfoxide (DMSO).
Preferably, described alkali is sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium ethylate, sodium methylate, sodium tert-butoxide or potassium tert.-butoxide.
Preferably, 6-bromine hexanol and diethyl malonate are dissolved in and can carry out reacting by heating in the organic solvent of azeotropic under base catalysis, its temperature of reaction is 50 ~ 150 DEG C.
Preferably, describedly the organic solvent of azeotropic can comprise two kinds of organic solvents, wherein a kind of organic solvent is protic solvent, N can be selected from, dinethylformamide, N, one in N-diethylformamide, N-Methyl pyrrolidone and dimethyl sulfoxide (DMSO), is preferably DMF or N-Methyl pyrrolidone; Another kind of organic solvent can be selected from the one in hexanaphthene, normal hexane, sherwood oil and ethyl acetate, is preferably hexanaphthene or benzene.
In the synthetic method of 8-Hydroxyoctanoic acid ethyl ester of the present invention, first 6-bromine hexanol and diethyl malonate are reacted as raw material, engaging vibrating bromize hydrogen generates intermediate, then is reacted under sodium halide catalysis by intermediate, generate 8-Hydroxyoctanoic acid ethyl ester, adopt two steps can prepare 8-Hydroxyoctanoic acid ethyl ester, and raw material sources are convenient, cost is low, therefore, enormously simplify processing step, and greatly reduce the cost of product, be conducive to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the first synthetic route chart of prior art 8-Hydroxyoctanoic acid ethyl ester;
Fig. 2 is the second synthetic route chart of prior art 8-Hydroxyoctanoic acid ethyl ester;
Fig. 3 is the third synthetic route chart of prior art 8-Hydroxyoctanoic acid ethyl ester;
Fig. 4 is the synthetic method schematic flow sheet of 8-Hydroxyoctanoic acid ethyl ester of the present invention;
Fig. 5 is the synthetic route chart of 8-Hydroxyoctanoic acid ethyl ester of the present invention.
Embodiment
In order to shorten reaction scheme, reducing production cost, the invention provides a kind of preparation method of 8-Hydroxyoctanoic acid ethyl ester.In this scenario, first 6-bromine hexanol and diethyl malonate are reacted as raw material, engaging vibrating bromize hydrogen generates intermediate, again intermediate is reacted under sodium halide catalysis, generation 8-Hydroxyoctanoic acid ethyl ester, in technical solution of the present invention, raw material sources are convenient, cost is low, operational path is simple, is beneficial to suitability for industrialized production.For making the object, technical solutions and advantages of the present invention clearly, below lifting specific embodiment and the present invention is described in further detail.
The synthetic method of 8-Hydroxyoctanoic acid ethyl ester of the present invention, as shown in Figure 4, Fig. 4 is the synthetic method schematic flow sheet of 8-Hydroxyoctanoic acid ethyl ester of the present invention, comprising:
Step 101,6-bromine hexanol and diethyl malonate are dissolved in and can carry out reacting by heating in the organic solvent of azeotropic under base catalysis, generate intermediate, described intermediate is 2-(6-hydroxyl hexyl) diethyl malonate, wherein, the mol ratio of described 6-bromine hexanol, diethyl malonate and alkali is 1:0.95 ~ 1.05:1.37 ~ 2.73;
Step 102, to be dissolved in polar aprotic solvent and water by described intermediate and to carry out reacting by heating under the katalysis of sodium halide, generate 8-Hydroxyoctanoic acid ethyl ester, wherein, the mol ratio of described intermediate and sodium halide is 1:1 ~ 3.
In embodiments of the present invention, first 6-bromine hexanol and diethyl malonate are reacted under base catalysis, engaging vibrating bromize hydrogen generates intermediate 2-(6-hydroxyl hexyl) diethyl malonate, again 2-(6-hydroxyl hexyl) diethyl malonate is reacted under sodium halide catalysis, generate 8-Hydroxyoctanoic acid ethyl ester, adopt two steps can prepare 8-Hydroxyoctanoic acid ethyl ester, and, raw material sources are convenient, cost is low, therefore, simplify processing step, and reduce the production cost of product, be conducive to suitability for industrialized production.
Contriver finds, preferably, the mol ratio of described intermediate and sodium halide is 1:1 ~ 3.Further optimization, the mol ratio of described intermediate and sodium halide is 1:1.2 ~ 1.5.
Preferably, described sodium halide is sodium-chlor or Sodium Bromide.
Preferably, reacted by described intermediate under the katalysis of sodium halide, be dissolved in polar aprotic solvent and water under the katalysis of sodium halide by described intermediate and carry out reacting by heating, its temperature of reaction is 100 ~ 150 DEG C.
Preferably, be dissolved in polar aprotic solvent and water under the katalysis of sodium halide by described intermediate and carry out reacting by heating, its temperature of reaction is 140 ~ 145 DEG C.
Preferably, be dissolved in polar aprotic solvent and water by described intermediate and carry out reacting by heating under the katalysis of sodium halide, reaction duration is 8 ~ 10 hours.
In synthetic method for above-mentioned 8-Hydroxyoctanoic acid ethyl ester, described polar aprotic solvent is dimethyl sulfoxide (DMSO).
Contriver finds, preferably, described alkali is sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium ethylate, sodium methylate, sodium tert-butoxide or potassium tert.-butoxide.
Preferably, 6-bromine hexanol and diethyl malonate are dissolved in and can carry out reacting by heating in the organic solvent of azeotropic under base catalysis, its temperature of reaction is 50 ~ 150 DEG C.
Preferably, describedly the organic solvent of azeotropic can comprise two kinds of organic solvents, wherein a kind of organic solvent is protic solvent, N can be selected from, dinethylformamide, N, one in N-diethylformamide, N-Methyl pyrrolidone and dimethyl sulfoxide (DMSO), is preferably DMF or N-Methyl pyrrolidone; Another kind of organic solvent can be selected from the one in hexanaphthene, normal hexane, sherwood oil and ethyl acetate, is preferably hexanaphthene or benzene.
The synthetic route chart of 8-Hydroxyoctanoic acid ethyl ester of the present invention as shown in Figure 5,6-bromine hexanol and diethyl malonate react under base catalysis, engaging vibrating bromize hydrogen generates intermediate, by intermediate under sodium halide catalysis through transesterify, hydrolysis, decarboxylic reaction, generate 8-Hydroxyoctanoic acid ethyl ester.
Below enumerate the preparation method of specific embodiment to 8-Hydroxyoctanoic acid ethyl ester of the present invention and do explanation detailed further, but the present invention is not limited to following embodiment.In following examples, raw material is all convenient source, is buied by commercially available.In following examples, the weight taking 6-bromine hexanol and diethyl malonate is respectively 132.5g and 119g, certain the present invention is not limited in this numerically, the proportional increase of weight of both or reduction can, corresponding other materials following also proportional increase or reduction, as taken 6-bromine hexanol 265g, diethyl malonate 238g, corresponding alkali, the organic solvent of azeotropic, sodium halide, dimethyl sulfoxide (DMSO) and water etc. also can all become original 2 times; As taken 6-bromine hexanol 66.25g, diethyl malonate 59.5g, corresponding alkali, the organic solvent of azeotropic, sodium halide, dimethyl sulfoxide (DMSO) and water etc. also can all become original 1/2; And 6-bromine hexanol 132.5g(0.732mol) and diethyl malonate 119g(0.744mol) mol ratio be 1:1.016, certain the present invention is not limited to this mol ratio, and the mol ratio of 6-bromine hexanol and diethyl malonate is at 1:0.95 ~ 1.05(such as 1:0.95,1:1.02,1:1.05).
Embodiment 1
Step one, 6-bromine hexanol 132.5g is added in the four-hole boiling flask of 1000ml, diethyl malonate 119g, alkali selects salt of wormwood 195g, wherein, 6-bromine hexanol, the mol ratio of diethyl malonate and salt of wormwood is 1:1.016:1.93, the organic solvent of azeotropic can select the N of 120ml, dinethylformamide (DMF) and 250ml hexanaphthene, be warming up to 80 DEG C of back flow reaction, after adopting vapor-phase chromatography to judge that reaction completes, be down to room temperature, suction filtration obtains filter cake and filtrate, by concentrated for filtrate dry, use 200ml diluted ethyl acetate, wash with water again, concentrated, obtain 175g yellow oily liquid, i.e. intermediate 2-(6-hydroxyl hexyl) diethyl malonate, molar yield is 90%,
Step 2, upper step products therefrom is dissolved in the dimethyl sulfoxide (DMSO) of 300ml, add the sodium-chlor of 46g and the water of 23g, be warming up to 145 DEG C, insulation reaction, after 9 hours, is cooled to 20 DEG C, with the extraction into ethyl acetate of 200ml, use the washing ethyl acetate layer of 100ml again, concentrate and obtain product 118g, adopt vapor-phase chromatography and standard control to locate and judge that this product is as 8-Hydroxyoctanoic acid ethyl ester, purity is 98.5%, and molar yield is 95%.
Obtain 8-Hydroxyoctanoic acid ethyl ester through step one and step 2, total molar yield is 86%.
Embodiment 2
Step one, 6-bromine hexanol 132.5g is added in the four-hole boiling flask of 1000ml, diethyl malonate 119g, alkali selects sodium carbonate 212g, wherein, 6-bromine hexanol, the mol ratio of diethyl malonate and sodium carbonate is 1:1.016:2.73, the organic solvent of azeotropic can select 150mlN, N-diethylformamide and 250ml normal hexane, be warming up to 150 DEG C of backflows, after adopting vapor-phase chromatography to judge that reaction completes, be down to room temperature, suction filtration obtains filter cake and filtrate, by concentrated for filtrate dry, use 200ml diluted ethyl acetate, wash with water again, concentrated, obtain 167g yellow oily liquid, i.e. intermediate 2-(6-hydroxyl hexyl) diethyl malonate, molar yield is 86%,
Step 2, upper step products therefrom is dissolved in the dimethyl sulfoxide (DMSO) of 250ml, add the Sodium Bromide of 78g and the water of 30g, be warming up to 100 DEG C, insulation reaction, after 8 hours, is cooled to 20 DEG C, with the extraction into ethyl acetate of 200ml, use the washing ethyl acetate layer of 100ml again, concentrate and obtain product 111g, adopt vapor-phase chromatography and standard control to locate and judge that this product is as 8-Hydroxyoctanoic acid ethyl ester, purity is 98%, and molar yield is 94%.
8-Hydroxyoctanoic acid ethyl ester is obtained, total molar yield 81% through step one and step 2.
Embodiment 3
Step one, 6-bromine hexanol 132.5g is added in the four-hole boiling flask of 1000ml, diethyl malonate 119g, alkali selects sodium hydroxide 45g, wherein, 6-bromine hexanol, the mol ratio of diethyl malonate and sodium hydroxide is 1:1.016:1.54, the organic solvent of azeotropic can select 200ml N-Methyl pyrrolidone and 350ml sherwood oil, be warming up to 100 DEG C of back flow reaction, after adopting vapor-phase chromatography to judge that reaction completes, be down to room temperature, suction filtration obtains filter cake and filtrate, by concentrated for filtrate dry, use 200ml diluted ethyl acetate, wash with water again, concentrated, obtain 145g yellow oily liquid, i.e. intermediate 2-(6-hydroxyl hexyl) diethyl malonate, molar yield about 77%,
Step 2, upper step products therefrom is dissolved in the dimethyl sulfoxide (DMSO) of 200ml, add the sodium-chlor of 99g and the water of 15g, be warming up to 143 DEG C, insulation reaction, after 10 hours, is cooled to 20 DEG C, with the extraction into ethyl acetate of 200ml, use the washing ethyl acetate layer of 100ml again, concentrate and obtain product 96g, adopt vapor-phase chromatography and standard control to locate and judge that this product is as 8-Hydroxyoctanoic acid ethyl ester, purity is 97.5%, and molar yield is 90%.
Obtain 8-Hydroxyoctanoic acid ethyl ester through step one and step 2, total molar yield is 69%.
Embodiment 4
Step one, 6-bromine hexanol 132.5g is added in the four-hole boiling flask of 1000ml, diethyl malonate 119g, alkali selects potassium hydroxide 56g, wherein, 6-bromine hexanol, the mol ratio of diethyl malonate and potassium hydroxide is 1:1.016:1.37, the organic solvent of azeotropic can select 200ml dimethyl sulfoxide (DMSO) and 350ml ethyl acetate, be warming up to 80 DEG C of back flow reaction, after adopting vapor-phase chromatography to judge that reaction completes, be down to room temperature, suction filtration obtains filter cake and filtrate, by concentrated for filtrate dry, use 200ml diluted ethyl acetate, wash with water again, concentrated, obtain 155g yellow oily liquid, i.e. intermediate 2-(6-hydroxyl hexyl) diethyl malonate, molar yield is 82%,
Step 2, upper step products therefrom is dissolved in the dimethyl sulfoxide (DMSO) of 200ml, add the sodium-chlor of 36g and the water of 15g, be warming up to 150 DEG C, insulation reaction 9 hours, is cooled to 20 DEG C, with the extraction into ethyl acetate of 200ml, use the washing ethyl acetate layer of 100ml again, concentrate and obtain product 104g, adopt vapor-phase chromatography and standard control to locate and judge that this product is as 8-Hydroxyoctanoic acid ethyl ester, purity is 98.5%, and molar yield is 92%.
Obtain 8-Hydroxyoctanoic acid ethyl ester through step one and step 2, total molar yield is 75%.
Embodiment 5
Step one, 6-bromine hexanol 132.5g is added in the four-hole boiling flask of 1000ml, diethyl malonate 119g, alkali selects sodium ethylate 68g, wherein, 6-bromine hexanol, the mol ratio of diethyl malonate and sodium ethylate is 1:1.016:1.37, the organic solvent of azeotropic can select 200mlDMF and 350ml hexanaphthene, be warming up to 80 DEG C of back flow reaction, after adopting vapor-phase chromatography to judge that reaction completes, be down to room temperature, suction filtration obtains filter cake and filtrate, by concentrated for filtrate dry, use 200ml diluted ethyl acetate, wash with water again, concentrated, obtain 126g yellow oily liquid, i.e. intermediate 2-(6-hydroxyl hexyl) diethyl malonate, molar yield is 67%,
Step 2, upper step products therefrom is dissolved in the dimethyl sulfoxide (DMSO) of 200ml, add the sodium-chlor of 57g and the water of 25g, be warming up to 145 DEG C, insulation reaction, after 9 hours, is cooled to 20 DEG C, with the extraction into ethyl acetate of 200ml, use the washing ethyl acetate layer of 100ml again, concentrate and obtain product 89g, adopt vapor-phase chromatography and standard control to locate and judge that this product is as 8-Hydroxyoctanoic acid ethyl ester, purity is 97.5% molar yield is 96%.
Obtain 8-Hydroxyoctanoic acid ethyl ester through step one and step 2, total molar yield is 64%.
Embodiment 6
Step one, 6-bromine hexanol 132.5g is added in the four-hole boiling flask of 1000ml, diethyl malonate 119g, alkali selects sodium methylate 60g, wherein, 6-bromine hexanol, the mol ratio of diethyl malonate and sodium methylate is 1:1.016:1.52, the organic solvent of azeotropic can select 200ml N-Methyl pyrrolidone and 250ml normal hexane, be warming up to 80 DEG C of back flow reaction, after adopting vapor-phase chromatography to judge that reaction completes, be down to room temperature, suction filtration obtains filter cake and filtrate, by concentrated for filtrate dry, use 200ml diluted ethyl acetate, wash with water again, concentrated, obtain 130g yellow oily fluid cpds, i.e. intermediate 2-(6-hydroxyl hexyl) diethyl malonate, molar yield is 69%,
Step 2, upper step products therefrom is dissolved in the dimethyl sulfoxide (DMSO) of 200ml, add the sodium-chlor of 48g and the water of 25g, be warming up to 145 DEG C, insulation reaction, after 9 hours, is cooled to 20 DEG C, with the extraction into ethyl acetate of 200ml, use the washing ethyl acetate layer of 100ml again, concentrate and obtain product 92g, adopt vapor-phase chromatography and standard control to locate and judge that this product is as 8-Hydroxyoctanoic acid ethyl ester, purity is 98%, and molar yield is 96%.
8-Hydroxyoctanoic acid ethyl ester is obtained, total molar yield 66% through step one and step 2.
Embodiment 7
Step one, 6-bromine hexanol 132.5g is added in the four-hole boiling flask of 1000ml, diethyl malonate 119g, alkali selects potassium tert.-butoxide 120g, wherein, 6-bromine hexanol, the mol ratio of diethyl malonate and potassium tert.-butoxide is 1:1.016:1.46, the organic solvent of azeotropic can select 200ml N-Methyl pyrrolidone and 250ml toluene, be warming up to 80 DEG C of back flow reaction, after adopting vapor-phase chromatography to judge that reaction completes, be down to room temperature, suction filtration obtains filter cake and filtrate, by concentrated for filtrate dry, use 200ml diluted ethyl acetate, wash with water again, concentrated, obtain 150g yellow oily liquid, i.e. intermediate 2-(6-hydroxyl hexyl) diethyl malonate, molar yield is 79%,
Step 2, upper step products therefrom is dissolved in the dimethyl sulfoxide (DMSO) of 200ml, add the sodium-chlor of 60g and the water of 30g, be warming up to 145 DEG C, insulation reaction, after 9 hours, is cooled to 20 DEG C, with the extraction into ethyl acetate of 200ml, use the washing ethyl acetate layer of 100ml again, concentrate and obtain product 101g, adopt vapor-phase chromatography and standard control to locate and judge that this product is as 8-Hydroxyoctanoic acid ethyl ester, purity is 98.5%, and molar yield is 92%.
8-Hydroxyoctanoic acid ethyl ester is obtained, total molar yield 73% through step one and step 2.
Embodiment 8
Step one, 6-bromine hexanol 132.5g is added in the four-hole boiling flask of 1000ml, diethyl malonate 119g, alkali selects sodium tert-butoxide 100g, wherein, 6-bromine hexanol, the mol ratio of diethyl malonate and sodium tert-butoxide is 1:1.016:1.42, the organic solvent of azeotropic can select 200ml N-Methyl pyrrolidone and 250ml benzene, be warming up to 80 DEG C of back flow reaction, after adopting vapor-phase chromatography to judge that reaction completes, be down to room temperature, suction filtration obtains filter cake and filtrate, by concentrated for filtrate dry, use 200ml diluted ethyl acetate, wash with water again, concentrated, obtain 140g yellow oily liquid, i.e. intermediate 2-(6-hydroxyl hexyl) diethyl malonate, molar yield is 74%,
Step 2, upper step products therefrom is dissolved in the dimethyl sulfoxide (DMSO) of 200ml, add the sodium-chlor of 60g and the water of 30g, be warming up to 145 DEG C, insulation reaction, after 9 hours, is cooled to 20 DEG C, with the extraction into ethyl acetate of 200ml, use the washing ethyl acetate layer of 100ml again, concentrate and obtain product 94g, adopt vapor-phase chromatography and standard control to locate and judge that this product is as 8-Hydroxyoctanoic acid ethyl ester, purity is 97.5%, and molar yield is 92%.
Obtain 8-Hydroxyoctanoic acid ethyl ester through step one and step 2, total molar yield is 68%.
In embodiment 1 to embodiment 8, the 8-Hydroxyoctanoic acid ethyl ester standard substance in adopting vapor-phase chromatography and standard control to locate purchased from lark prestige (J & K), production code member EN300-79047, purity 95%.
In embodiment 1 to embodiment 8, the condition of gas-chromatography is as follows:
Detector: FID;
Chromatographic column: DB-624,30m × 0.53mm × 3.0 μm;
Carrier gas: nitrogen;
Flow velocity: 3.0ml/min;
Injector temperature: 280 DEG C;
Detect mouth temperature: 300 DEG C;
Column temperature: 70 DEG C keep 1 minute, rise to 250 DEG C, keep 11 minutes, total run time 30 minutes with 10 DEG C/min.
Splitting ratio: 30:1;
Sample size: 0.2 μ L.
8-Hydroxyoctanoic acid ethyl ester prepared by the present invention is called for short SNAC can be applied to the novel delivery agent Salcaprozat Sodium(of a kind of oral insulin as a kind of pharmaceutical excipient) preparation among.
State in embodiment 1 to embodiment 8 on the invention, total molar yield is all more than 60%, and purity is all more than 97%, and the total molar yield wherein in embodiment 1 reaches 86%, purity reaches 98.5%, visible employing preparation method of the present invention, yield is higher, and purity is very high, and raw materials used wide material sources, low price in technical solution of the present invention, and reactions steps is simple, and two steps can obtain 8-Hydroxyoctanoic acid ethyl ester, are beneficial to suitability for industrialized production.
Obviously, those skilled in the art can carry out various change and modification to the present invention and not depart from the spirit and scope of the present invention.Like this, if these amendments of the present invention and modification belong within the scope of the claims in the present invention and equivalent technologies thereof, then the present invention is also intended to comprise these change and modification.
Claims (9)
1. a synthetic method for 8-Hydroxyoctanoic acid ethyl ester, is characterized in that, comprising:
6-bromine hexanol and diethyl malonate are dissolved in and can carry out reacting by heating in the organic solvent of azeotropic under base catalysis, generate intermediate, described intermediate is 2-(6-hydroxyl hexyl) diethyl malonate, wherein, the mol ratio of described 6-bromine hexanol, diethyl malonate and alkali is 1:0.95 ~ 1.05:1.37 ~ 2.73, and described alkali is sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium ethylate, sodium methylate, sodium tert-butoxide or potassium tert.-butoxide;
Be dissolved in polar aprotic solvent and water under the katalysis of sodium halide by described intermediate and carry out reacting by heating, generate 8-Hydroxyoctanoic acid ethyl ester, wherein, the mol ratio of described intermediate and sodium halide is 1:1 ~ 3.
2. the synthetic method of 8-Hydroxyoctanoic acid ethyl ester as claimed in claim 1, it is characterized in that, the mol ratio of described intermediate and sodium halide is 1:1.2 ~ 1.5.
3. the synthetic method of 8-Hydroxyoctanoic acid ethyl ester as claimed in claim 1, it is characterized in that, described sodium halide is sodium-chlor or Sodium Bromide.
4. the synthetic method of 8-Hydroxyoctanoic acid ethyl ester as claimed in claim 1, it is characterized in that, be dissolved in polar aprotic solvent and water under the katalysis of sodium halide by described intermediate and carry out reacting by heating, its temperature of reaction is 100 ~ 150 DEG C.
5. the synthetic method of 8-Hydroxyoctanoic acid ethyl ester as claimed in claim 4, it is characterized in that, be dissolved in polar aprotic solvent and water under the katalysis of sodium halide by described intermediate and carry out reacting by heating, its temperature of reaction is 140 ~ 145 DEG C.
6. the synthetic method of 8-Hydroxyoctanoic acid ethyl ester as claimed in claim 1, is characterized in that, be dissolved in polar aprotic solvent and water by described intermediate and carry out reacting by heating under the katalysis of sodium halide, and reaction duration is 8 ~ 10 hours.
7. the synthetic method of the 8-Hydroxyoctanoic acid ethyl ester according to any one of claim 1 ~ 6, is characterized in that, described polar aprotic solvent is dimethyl sulfoxide (DMSO).
8. the synthetic method of 8-Hydroxyoctanoic acid ethyl ester as claimed in claim 1, it is characterized in that, 6-bromine hexanol and diethyl malonate are dissolved in and can carry out reacting by heating in the organic solvent of azeotropic under base catalysis, its temperature of reaction is 50 ~ 150 DEG C.
9. the synthetic method of 8-Hydroxyoctanoic acid ethyl ester as claimed in claim 1, it is characterized in that, describedly the organic solvent of azeotropic can comprise two kinds of organic solvents, wherein a kind of organic solvent is N, one in dinethylformamide, N, N-diethylformamide, N-Methyl pyrrolidone and dimethyl sulfoxide (DMSO); Another kind of organic solvent is the one in hexanaphthene, normal hexane, sherwood oil and ethyl acetate.
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| CN113087623A (en) * | 2021-04-13 | 2021-07-09 | 苏州昊帆生物股份有限公司 | Synthesis method of 8-bromoethyl octanoate |
| CN115611740A (en) * | 2022-10-09 | 2023-01-17 | 扬州市普林斯医药科技有限公司 | Production method of 8-chloro ethyl caprylate |
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