JP6858011B2 - Method for producing hexyl 4-hydroxybenzoate - Google Patents
Method for producing hexyl 4-hydroxybenzoate Download PDFInfo
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- JP6858011B2 JP6858011B2 JP2016240132A JP2016240132A JP6858011B2 JP 6858011 B2 JP6858011 B2 JP 6858011B2 JP 2016240132 A JP2016240132 A JP 2016240132A JP 2016240132 A JP2016240132 A JP 2016240132A JP 6858011 B2 JP6858011 B2 JP 6858011B2
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- hydroxybenzoate
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- hexyl
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- 238000004519 manufacturing process Methods 0.000 title claims description 41
- WEMCWZGCSRGJGW-UHFFFAOYSA-N [3-fluoro-5-(trifluoromethyl)phenyl]boronic acid Chemical compound OB(O)C1=CC(F)=CC(C(F)(F)F)=C1 WEMCWZGCSRGJGW-UHFFFAOYSA-N 0.000 title claims description 35
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 72
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 67
- 239000000203 mixture Substances 0.000 claims description 58
- 239000012044 organic layer Substances 0.000 claims description 42
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- 239000003377 acid catalyst Substances 0.000 claims description 22
- 239000007864 aqueous solution Substances 0.000 claims description 22
- 238000002425 crystallisation Methods 0.000 claims description 16
- 230000008025 crystallization Effects 0.000 claims description 16
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 15
- 239000012535 impurity Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000010410 layer Substances 0.000 claims description 12
- 238000004821 distillation Methods 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 8
- DUKPKQFHJQGTGU-UHFFFAOYSA-N Hexyl salicylic acid Chemical compound CCCCCCOC(=O)C1=CC=CC=C1O DUKPKQFHJQGTGU-UHFFFAOYSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 description 34
- 238000004817 gas chromatography Methods 0.000 description 15
- 239000013078 crystal Substances 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 238000000746 purification Methods 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- 239000006227 byproduct Substances 0.000 description 9
- 238000000605 extraction Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 150000007514 bases Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000005292 vacuum distillation Methods 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 101100133339 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) NHP6B gene Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- ULULAZKOCFNOIM-UHFFFAOYSA-N hexyl 4-hydroxybenzoate Chemical compound CCCCCCOC(=O)C1=CC=C(O)C=C1 ULULAZKOCFNOIM-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052743 krypton Inorganic materials 0.000 description 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- RLJWTAURUFQFJP-UHFFFAOYSA-N propan-2-ol;titanium Chemical compound [Ti].CC(C)O.CC(C)O.CC(C)O.CC(C)O RLJWTAURUFQFJP-UHFFFAOYSA-N 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、４−ヒドロキシ安息香酸ヘキシルの製造方法に関する。 The present invention relates to a method for producing hexyl 4-hydroxybenzoate.
パラベンは４−ヒドロキシ安息香酸のエステル類の総称であり、化粧品、医薬品、食品等の防腐剤または抗菌剤として幅広く用いられている。 Paraben is a general term for esters of 4-hydroxybenzoic acid, and is widely used as a preservative or antibacterial agent for cosmetics, pharmaceuticals, foods, and the like.
パラベンとしては、４−ヒドロキシ安息香酸メチル（メチルパラベン）、４−ヒドロキシ安息香酸エチル（エチルパラベン）、４−ヒドロキシ安息香酸プロピル（プロピルパラベン）、４−ヒドロキシ安息香酸ヘキシル（ヘキシルパラベン）などが知られており、中でも４−ヒドロキシ安息香酸ヘキシルは抗菌力が強く、更なる抗菌用途への展開が期待されている。 Known parabens include methyl 4-hydroxybenzoate (methylparaben), ethyl 4-hydroxybenzoate (ethylparaben), propyl 4-hydroxybenzoate (propylparaben), and hexyl 4-hydroxybenzoate (hexylparaben). Among them, hexyl 4-hydroxybenzoate has strong antibacterial activity and is expected to be further applied to antibacterial applications.
これらのパラベン類は、通常、酸触媒の存在下、ヒドロキシ安息香酸と脂肪族アルコールとを反応させることによって製造されるが、この反応は平衡反応であるため、原料のいずれか一方を過剰となるように反応に供することによって、目的物の生成率を向上させることが知られている。例えば、ヒドロキシ安息香酸のカルボン酸１モルに対して脂肪族アルコール２０〜６０モル当量を反応に供することで、高い生成率で目的物を得る方法が提案されている（特許文献１）。 These parabens are usually produced by reacting hydroxybenzoic acid with an aliphatic alcohol in the presence of an acid catalyst, but since this reaction is an equilibrium reaction, one of the raw materials becomes excessive. It is known that the production rate of the target product is improved by subjecting the reaction to such a reaction. For example, a method has been proposed in which a target product is obtained at a high production rate by subjecting 20 to 60 mol equivalents of an aliphatic alcohol to 1 mol of the carboxylic acid of hydroxybenzoic acid in the reaction (Patent Document 1).
しかしながら、過剰量の脂肪族アルコールを反応に供すると、大容積の反応装置が必要になるとともに、生産効率の低下や、後処理における脂肪族アルコールの除去工程に長時間を要するという問題があった。 However, when an excessive amount of fatty alcohol is subjected to the reaction, there are problems that a large volume reactor is required, production efficiency is lowered, and a long time is required for the step of removing the fatty alcohol in the post-treatment. ..
また、４−ヒドロキシ安息香酸ヘキシルの製造に際しては、目的物である４−ヒドロキシ安息香酸ヘキシルと反応に使用する１−ヘキサノールとが溶解性等の物性が類似するため、１−ヘキサノールの除去がより困難であるという問題があった。 Further, in the production of hexyl 4-hydroxybenzoate, the removal of 1-hexanol is more effective because the target product, hexyl 4-hydroxybenzoate, and 1-hexanol used in the reaction have similar physical properties such as solubility. There was a problem that it was difficult.
さらに、特許文献１の方法によって得られる４−ヒドロキシ安息香酸ヘキシルは、１−ヘキサノールの他、触媒や原料などの不純物が残存するため、低純度のものであった。したがって、生産性に優れ、高収率かつ高純度で４−ヒドロキシ安息香酸ヘキシルが得られる製造方法が求められていた。 Further, the hexyl 4-hydroxybenzoate obtained by the method of Patent Document 1 has a low purity because impurities such as a catalyst and a raw material remain in addition to 1-hexanol. Therefore, there has been a demand for a production method capable of obtaining hexyl 4-hydroxybenzoate with excellent productivity, high yield and high purity.
本発明の目的は、生産性に優れるとともに、副生物の生成を抑制し、高収率で４−ヒドロキシ安息香酸ヘキシルが得られる製造方法を提供することにある。また、本発明の別の目的は、高純度の４−ヒドロキシ安息香酸ヘキシルが得られる製造方法を提供することにある。 An object of the present invention is to provide a production method which is excellent in productivity, suppresses the production of by-products, and can obtain hexyl 4-hydroxybenzoate in a high yield. Another object of the present invention is to provide a production method for obtaining high-purity hexyl 4-hydroxybenzoate.
本発明者らは、４−ヒドロキシ安息香酸ヘキシルの製造方法について鋭意検討した結果、酸触媒の存在下、４−ヒドロキシ安息香酸と所定量の１−ヘキサノールを反応させることによって、４−ヒドロキシ安息香酸ヘキシルが高収率かつ高生産効率で得られることを見出し、本発明を完成させるに至った。 As a result of diligent studies on a method for producing hexyl 4-hydroxybenzoate, the present inventors have made 4-hydroxybenzoic acid react with a predetermined amount of 1-hexanol in the presence of an acid catalyst. We have found that hexyl can be obtained in high yield and high production efficiency, and have completed the present invention.
本発明者らは、また、酸触媒の存在下、４−ヒドロキシ安息香酸と１−ヘキサノールを反応させることによって得られる、４−ヒドロキシ安息香酸ヘキシルを含む粗組成物に、塩基性水溶液を添加して粗組成物を中和した後、有機層と水層に分離し、有機層を抽出することによって、未反応のカルボン酸や酸触媒などを除去し得ることを見出し、本発明を完成させるに至った。 The present inventors also added a basic aqueous solution to a crude composition containing hexyl 4-hydroxybenzoate obtained by reacting 4-hydroxybenzoic acid with 1-hexanol in the presence of an acid catalyst. After neutralizing the crude composition, it was separated into an organic layer and an aqueous layer, and by extracting the organic layer, it was found that unreacted carboxylic acid, acid catalyst, etc. could be removed, and the present invention was completed. I arrived.
すなわち本発明は、酸触媒の存在下、４−ヒドロキシ安息香酸１モル当量と１−ヘキサノール０．８〜３．０モル当量とを反応させる工程を含む、式（１）で表される４−ヒドロキシ安息香酸ヘキシルの製造方法を提供する。
また本発明は、酸触媒の存在下、４−ヒドロキシ安息香酸と１−ヘキサノールとを反応させることにより、式（１）で表される４−ヒドロキシ安息香酸ヘキシルを含む粗組成物を得る工程、次いで前記粗組成物に塩基性水溶液を添加して粗組成物を中和する工程、次いで有機層と水層に分離し、有機層を抽出する工程を含む、式（１）で表される４−ヒドロキシ安息香酸ヘキシルの製造方法を提供する。
本発明によれば、生産性に優れるとともに、副生物の生成を抑制し、高収率で４−ヒドロキシ安息香酸ヘキシルを得ることができる。 According to the present invention, hexyl 4-hydroxybenzoate can be obtained in high yield by suppressing the production of by-products while being excellent in productivity.
また、本発明によれば、簡易な方法でより高純度の４−ヒドロキシ安息香酸ヘキシルを得ることができる。 Further, according to the present invention, higher-purity hexyl 4-hydroxybenzoate can be obtained by a simple method.
本発明において、反応原料として使用される４−ヒドロキシ安息香酸および１−ヘキサノールは、市販のものを用いてもよく、また当業者に知られた方法で製造したものを用いてもよい。 In the present invention, 4-hydroxybenzoic acid and 1-hexanol used as reaction raw materials may be commercially available ones or those produced by a method known to those skilled in the art.
本発明で使用される１−ヘキサノールは、４−ヒドロキシ安息香酸１モル当量に対し、０．８〜３．０モル当量、好ましくは０．９〜２．５モル当量、より好ましくは１．０〜２．０モル当量、さらに好ましくは１．１〜１．８モル当量反応させるのがよい。 The 1-hexanol used in the present invention is 0.8 to 3.0 molar equivalents, preferably 0.9 to 2.5 molar equivalents, more preferably 1.0, relative to 1 molar equivalent of 4-hydroxybenzoic acid. It is preferable to react with ~ 2.0 molar equivalents, more preferably 1.1 to 1.8 molar equivalents.
４−ヒドロキシ安息香酸１モル当量に対し、１−ヘキサノールの量が０．８モル当量を下回る場合、得られる４−ヒドロキシ安息香酸ヘキシルの収率が低下する。また、１−ヘキサノールの量が３．０モル当量を上回る場合、過剰量の１−ヘキサノールが残存し、生産効率が低下するとともに、後処理工程において、１−ヘキサノールの除去に長時間を要する。 When the amount of 1-hexanol is less than 0.8 molar equivalents with respect to 1 molar equivalent of 4-hydroxybenzoic acid, the yield of the obtained hexyl 4-hydroxybenzoate decreases. When the amount of 1-hexanol exceeds 3.0 molar equivalents, an excess amount of 1-hexanol remains, the production efficiency is lowered, and it takes a long time to remove 1-hexanol in the post-treatment step.
本発明では、例えば４−ヒドロキシ安息香酸１モル当量と１−ヘキサノール１．５モル当量とを反応させることは、４−ヒドロキシ安息香酸１モル当量に対し、１−ヘキサノールが１．５モル当量となるような量で存在させて反応させることを意味する。 In the present invention, for example, reacting 1 molar equivalent of 4-hydroxybenzoic acid with 1.5 molar equivalent of 1-hexanol results in 1.5 molar equivalent of 1-hexanol with respect to 1 molar equivalent of 4-hydroxybenzoic acid. It means to make it exist and react in such an amount.
本発明に使用される酸触媒としては、ｐ−トルエンスルホン酸、硫酸、塩酸、リン酸および硝酸からなる群から選択される１種以上が挙げられ、入手容易性および反応性に優れる点で、硫酸またはｐ−トルエンスルホン酸が好ましく、特に、反応性および副生物抑制効果に優れる点でｐ−トルエンスルホン酸が好ましい。ｐ−トルエンスルホン酸は水和物であってもよい。 Examples of the acid catalyst used in the present invention include one or more selected from the group consisting of p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid and nitric acid, and are excellent in availability and reactivity. Sulfuric acid or p-toluenesulfonic acid is preferable, and p-toluenesulfonic acid is particularly preferable because it is excellent in reactivity and by-product suppressing effect. The p-toluenesulfonic acid may be a hydrate.
これらの触媒は、単独で用いてもよく、２種以上を組み合わせて用いてもよい。 These catalysts may be used alone or in combination of two or more.
本発明に使用される酸触媒の量は特に限定されないが、４−ヒドロキシ安息香酸１００重量部に対し、好ましくは０．１〜１０重量部、より好ましくは０．３〜６重量部、さらに好ましくは０．５〜３重量部である。 The amount of the acid catalyst used in the present invention is not particularly limited, but is preferably 0.1 to 10 parts by weight, more preferably 0.3 to 6 parts by weight, still more preferably 100 parts by weight, based on 100 parts by weight of 4-hydroxybenzoic acid. Is 0.5 to 3 parts by weight.
４−ヒドロキシ安息香酸１００重量部に対し、酸触媒の量が０．１重量部を下回る場合、反応が十分に進行しない傾向がある。酸触媒の量が１０重量部を上回る場合、１−ヘキサノールの２量化エーテル体等の副生物が生成する傾向があるとともに、経済的にも不利となる。 When the amount of the acid catalyst is less than 0.1 part by weight with respect to 100 parts by weight of 4-hydroxybenzoic acid, the reaction tends not to proceed sufficiently. If the amount of the acid catalyst exceeds 10 parts by weight, by-products such as a dimerized etheric body of 1-hexanol tend to be produced, which is economically disadvantageous.
４−ヒドロキシ安息香酸と１−ヘキサノールとの反応における反応温度は特に限定されないが、１００℃以上が好ましく、１３５℃以上がより好ましい。反応温度が１００℃を下回る場合、反応が十分に進行しない傾向がある。 The reaction temperature in the reaction of 4-hydroxybenzoic acid and 1-hexanol is not particularly limited, but is preferably 100 ° C. or higher, more preferably 135 ° C. or higher. When the reaction temperature is lower than 100 ° C., the reaction tends not to proceed sufficiently.
反応時間は、反応温度等の条件によって変動するため特に限定されないが、１〜２０時間、好ましくは２〜１４時間、より好ましくは４〜８時間の間で適宜選択される。 The reaction time is not particularly limited because it varies depending on conditions such as the reaction temperature, but is appropriately selected from 1 to 20 hours, preferably 2 to 14 hours, and more preferably 4 to 8 hours.
本発明において、４−ヒドロキシ安息香酸と１−ヘキサノールとの反応は、不活性ガス気流下またはバブリング下、もしくは減圧条件下で行うのが好ましい。このような条件下で反応させることによって、酸素や水分による反応阻害や触媒失活を回避し、反応を円滑に進行させることが可能となる。 In the present invention, the reaction of 4-hydroxybenzoic acid with 1-hexanol is preferably carried out under an inert gas stream, bubbling, or under reduced pressure conditions. By reacting under such conditions, it is possible to avoid reaction inhibition and catalyst deactivation due to oxygen and water, and to allow the reaction to proceed smoothly.
不活性ガスとしては、４−ヒドロキシ安息香酸と１−ヘキサノールとの反応を阻害しないガスであればよく、具体的には、窒素、二酸化炭素、アルゴン、ヘリウム、ネオン、キセノンおよびクリプトンからなる群から選択される１種以上が挙げられる。これらの中で、入手容易性および経済性に優れる点で、窒素が好ましい。 The inert gas may be a gas that does not inhibit the reaction between 4-hydroxybenzoic acid and 1-hexanol, and specifically, it is composed of a group consisting of nitrogen, carbon dioxide, argon, helium, neon, xenon and krypton. One or more selected. Among these, nitrogen is preferable because it is excellent in availability and economy.
不活性ガスは、原料である４−ヒドロキシ安息香酸および１−ヘキサノールを収容する反応容器の反応液上部の空間部に吹き込んでもよく、あるいは、反応液中に直接吹き付けてもよい。 The inert gas may be blown into the space above the reaction solution of the reaction vessel containing the raw materials 4-hydroxybenzoic acid and 1-hexanol, or may be blown directly into the reaction solution.
酸触媒の存在下、４−ヒドロキシ安息香酸と１−ヘキサノールとを反応させる工程によって得られる、式（１）で表される４−ヒドロキシ安息香酸ヘキシルを含む粗組成物は、精製により、純度を高めることができる。 The crude composition containing hexyl 4-hydroxybenzoate represented by the formula (1) obtained by reacting 4-hydroxybenzoic acid with 1-hexanol in the presence of an acid catalyst can be purified to obtain purity. Can be enhanced.
精製は、前記粗組成物に塩基性水溶液を添加して粗組成物を中和する工程、次いで有機層と水層に分離し、有機層を抽出する工程を含むのが、生成物の純度を効率よく高められる点で好ましい。上記反応後の粗組成物は、反応温度から４０〜１００℃冷却した後、続く精製方法に供するのがよい。 Purification includes a step of adding a basic aqueous solution to the crude composition to neutralize the crude composition, and then a step of separating the crude composition into an organic layer and an aqueous layer and extracting the organic layer to determine the purity of the product. It is preferable because it can be efficiently enhanced. The crude composition after the reaction is preferably cooled from the reaction temperature at 40 to 100 ° C. and then subjected to the subsequent purification method.
式（１）で表される４−ヒドロキシ安息香酸ヘキシルを含む粗組成物とは、目的物である４−ヒドロキシ安息香酸ヘキシル以外に、反応原料や触媒および反応副生物などの不純物を含む組成物を意味する。 The crude composition containing hexyl 4-hydroxybenzoate represented by the formula (1) is a composition containing impurities such as a reaction raw material, a catalyst and a reaction by-product in addition to the target hexyl 4-hydroxybenzoate. Means.
粗組成物中に含まれる不純物の例としては、原料である４−ヒドロキシ安息香酸や１−ヘキサノール、触媒等が挙げられる。また、不純物には、１−ヘキサノールの２量化エーテルや、１−ヘキサノールと酸触媒との反応による硫酸エステル等の反応副生物も包含される。 Examples of impurities contained in the crude composition include 4-hydroxybenzoic acid, 1-hexanol, a catalyst and the like, which are raw materials. Impurities also include reaction by-products such as 1-hexanol dimerized ethers and sulfate esters produced by the reaction of 1-hexanol with an acid catalyst.
粗組成物中に塩基性水溶液を添加して粗組成物を中和する工程（以下、中和工程という）、および有機層と水層に分離し、有機層を抽出する工程（以下、抽出工程という）は、具体的には、反応後の粗組成物を冷却した後、中和工程において、粗組成物中に塩基性水溶液を添加し、攪拌を継続することによって酸触媒を失活させる。その後、抽出工程において反応系を静置して有機層と水層に分離し、有機層を回収することにより行われる。 A step of adding a basic aqueous solution to the crude composition to neutralize the crude composition (hereinafter referred to as a neutralization step), and a step of separating the organic layer into an aqueous layer and extracting the organic layer (hereinafter referred to as an extraction step). Specifically, after cooling the crude composition after the reaction, in the neutralization step, a basic aqueous solution is added to the crude composition and stirring is continued to inactivate the acid catalyst. Then, in the extraction step, the reaction system is allowed to stand to separate into an organic layer and an aqueous layer, and the organic layer is recovered.
塩基性水溶液に含まれる塩基性化合物としては、トリエチルアミン、モノエチルアミン、ジエチルアミン、トリメチルアミン、モノメチルアミン、ジメチルアミン、エチレンジアミン、トリエタノールアミン、テトラメチルエチレンジアミン、ピロリジン、ピペリジン、ピリジン、水酸化ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、水酸化カリウム、炭酸カリウムおよび炭酸水素カリウムからなる群から選択される１種以上が挙げられる。これらの中で、有機層と水層との分離性および入手容易性に優れる点で炭酸水素ナトリウムが好ましい。 Examples of the basic compounds contained in the basic aqueous solution include triethylamine, monoethylamine, diethylamine, trimethylamine, monomethylamine, dimethylamine, ethylenediamine, triethanolamine, tetramethylethylenediamine, pyrrolidine, piperidine, pyridine, sodium hydroxide and sodium hydrogen carbonate. , One or more selected from the group consisting of sodium carbonate, potassium hydroxide, potassium carbonate and potassium hydrogen carbonate. Of these, sodium hydrogencarbonate is preferable because it is excellent in separability and availability between the organic layer and the aqueous layer.
塩基性化合物の添加量は、酸触媒を中和できる量以上であればよく、通常、塩基性水溶液全量に対して１〜１０重量％である。 The amount of the basic compound added may be an amount that can neutralize the acid catalyst or more, and is usually 1 to 10% by weight based on the total amount of the basic aqueous solution.
塩基性水溶液全量に対し塩基性化合物の添加量が１重量％を下回る場合、中和が不完全となる傾向がある。塩基性化合物の添加量が１０重量％を上回る場合、過剰な塩基性物質が不純物として目的物に残存する傾向があるとともに、経済的にも不利となる。 When the amount of the basic compound added is less than 1% by weight based on the total amount of the basic aqueous solution, neutralization tends to be incomplete. When the amount of the basic compound added exceeds 10% by weight, the excess basic substance tends to remain in the target product as an impurity, which is economically disadvantageous.
抽出工程における水の量は、原料である４−ヒドロキシ安息香酸１００重量部に対して１００重量部以上であるのが好ましい。４−ヒドロキシ安息香酸１００重量部に対して水の量が１００重量部を下回る場合、不純物となる原料の４−ヒドロキシ安息香酸や触媒、金属分が目的物中に残存して品質が低下する。抽出工程における水の量を調節するために、抽出工程において水を更に添加してもよい。 The amount of water in the extraction step is preferably 100 parts by weight or more with respect to 100 parts by weight of 4-hydroxybenzoic acid as a raw material. When the amount of water is less than 100 parts by weight with respect to 100 parts by weight of 4-hydroxybenzoic acid, the raw material 4-hydroxybenzoic acid, the catalyst, and the metal content, which are impurities, remain in the target product and the quality is deteriorated. Further water may be added in the extraction step to control the amount of water in the extraction step.
中和工程および抽出工程は、更に精製効果を高めるために繰返し行ってもよく、また、金属除去のために水洗浄を行ってもよい。 The neutralization step and the extraction step may be repeated in order to further enhance the purification effect, or may be washed with water to remove the metal.
抽出工程において回収された有機層は、更に下記精製工程ＡまたはＢに供するのが好ましい。精製工程ＡおよびＢは、精製後に求められる４−ヒドロキシ安息香酸ヘキシルの品質等によって適宜選択される。また、これらの精製工程は、単独でまたは組み合わせて行うことができる。 The organic layer recovered in the extraction step is preferably further subjected to the following purification step A or B. Purification steps A and B are appropriately selected depending on the quality of hexyl 4-hydroxybenzoate obtained after purification and the like. In addition, these purification steps can be performed alone or in combination.
［精製工程Ａ］
精製工程Ａは、抽出された有機層の不純物を留去する工程（以下、不純物留去工程という）、次いで有機層に溶媒を添加して晶析する工程（以下、晶析工程という）を含む。
[Purification step A]
The purification step A includes a step of distilling off impurities in the extracted organic layer (hereinafter referred to as an impurity distilling step), and then a step of adding a solvent to the organic layer for crystallization (hereinafter referred to as a crystallization step). ..
不純物留去工程において、留去される不純物としては、原料である１−ヘキサノールの他に、反応で副生した１−ヘキサノールの二量化エーテルのような低沸点の化合物も含まれる。 In the impurity distillation step, the impurities distilled include not only 1-hexanol which is a raw material but also a compound having a low boiling point such as a dimerized ether of 1-hexanol produced as a by-product in the reaction.
不純物の留去は、有機層を加熱および／または減圧することによって行われる。加熱および減圧における温度および圧力は、同時に実施する場合、６０〜１６０℃および４０〜８０Ｔｏｒｒであるのが好ましく、８０〜１４０℃および５０〜７０Ｔｏｒｒであるのがより好ましい。加熱のみで留去する場合は、水を添加し、９０〜１３０℃で共沸することが好ましい。 Impurities are distilled off by heating and / or reducing the pressure of the organic layer. The temperatures and pressures for heating and depressurization are preferably 60-160 ° C and 40-80 Torr, more preferably 80-140 ° C and 50-70 Torr when performed simultaneously. When distilling off only by heating, it is preferable to add water and azeotrope at 90 to 130 ° C.
加熱および／または減圧時間は特に限定されないが、上記条件において不純物が有機層から留去されなくなるまで行うのがよい。 The heating and / or depressurizing time is not particularly limited, but it is preferable to carry out until impurities are no longer distilled from the organic layer under the above conditions.
次いで晶析工程において、有機層に溶媒を添加し、加熱して溶解させた後、冷却することによって４−ヒドロキシ安息香酸ヘキシルを晶析させることができる。析出した結晶を濾過等により固液分離し、洗浄、乾燥することによって、高純度の４−ヒドロキシ安息香酸ヘキシルを得ることができる。 Next, in the crystallization step, hexyl 4-hydroxybenzoate can be crystallized by adding a solvent to the organic layer, heating to dissolve it, and then cooling it. High-purity hexyl 4-hydroxybenzoate can be obtained by solid-liquid separation of the precipitated crystals by filtration or the like, washing and drying.
晶析工程で使用される溶媒としては、メタノール、エタノール、１−プロパノール、２−プロパノールおよびエチレングリコール等からなる群から選択される１種以上のアルコールを含むアルコール水溶液が挙げられ、精製効率および入手容易性の観点からメタノール水溶液が好ましい。 Examples of the solvent used in the crystallization step include an aqueous alcohol solution containing one or more alcohols selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, ethylene glycol and the like, for purification efficiency and availability. An aqueous solution of methanol is preferable from the viewpoint of ease.
アルコール水溶液の濃度は１０〜５０重量％が好ましく、さらに好ましくは２０〜４０重量％である。アルコール水溶液の濃度が１０重量％を下回る場合、得られる４−ヒドロキシ安息香酸ヘキシルの結晶の純度が低下する傾向があり、アルコール水溶液の濃度が５０重量％を上回る場合、得られる４−ヒドロキシ安息香酸ヘキシルの収率が低下する傾向がある。 The concentration of the aqueous alcohol solution is preferably 10 to 50% by weight, more preferably 20 to 40% by weight. When the concentration of the aqueous alcohol solution is less than 10% by weight, the purity of the crystals of the obtained 4-hydroxybenzoate hexyl tends to decrease, and when the concentration of the aqueous alcohol solution exceeds 50% by weight, the obtained 4-hydroxybenzoic acid tends to decrease. The yield of hexyl tends to decrease.
晶析工程で使用される溶媒の量は、用いる溶媒の種類によって変動するため特に限定されないが、原料の４−ヒドロキシ安息香酸に対し１〜２０倍重量、好ましくは２〜１５倍重量、より好ましくは３〜１０倍重量である。 The amount of the solvent used in the crystallization step varies depending on the type of solvent used and is not particularly limited, but is 1 to 20 times by weight, preferably 2 to 15 times by weight, more preferably with respect to the raw material 4-hydroxybenzoic acid. Is 3 to 10 times heavier.
溶媒の量が１倍重量を下回る場合、晶析時に撹拌不良が生じる傾向があり、２０倍重量を超える場合、収率が低下する傾向があるとともに、経済的にも不利となる。 If the amount of the solvent is less than 1 times the weight, stirring failure tends to occur at the time of crystallization, and if it exceeds 20 times the weight, the yield tends to decrease and it is economically disadvantageous.
晶析工程は、溶媒を添加した後、加熱して有機層中の有機物を完全に溶解させた後、撹拌を継続しながら、ゆっくりと冷却して晶析させることにより行われる。 The crystallization step is carried out by adding a solvent, heating to completely dissolve the organic matter in the organic layer, and then slowly cooling and crystallization while continuing stirring.
晶析の際に過飽和現象が生じた場合は、種結晶を適宜添加して結晶化を促進させても良い。 If a supersaturation phenomenon occurs during crystallization, seed crystals may be appropriately added to promote crystallization.
晶析工程によって析出した結晶は濾過等の常套手段により固液分離し、目的物である４−ヒドロキシ安息香酸ヘキシルを回収する。固液分離に際し、適宜溶媒を注いで結晶を洗浄するのが好ましい。固液分離の際に用いる溶媒としては、晶析工程で使用される溶媒と同様のものが使用される。 The crystals precipitated by the crystallization step are solid-liquid separated by conventional means such as filtration, and the target product, hexyl 4-hydroxybenzoate, is recovered. At the time of solid-liquid separation, it is preferable to pour a solvent as appropriate to wash the crystals. As the solvent used for the solid-liquid separation, the same solvent as that used in the crystallization step is used.
固液分離によって回収された結晶は、加熱および／または減圧して溶媒を留去することによって、高純度の４−ヒドロキシ安息香酸ヘキシルを得ることができる。 Crystals recovered by solid-liquid separation can be heated and / or reduced in pressure to distill off the solvent to obtain high-purity hexyl 4-hydroxybenzoate.
加熱温度は、４−ヒドロキシ安息香酸ヘキシルが融解せず溶媒を留去できる範囲であれば特に限定されないが、通常４０〜５０℃であるのがよい。 The heating temperature is not particularly limited as long as the hexyl 4-hydroxybenzoate does not melt and the solvent can be distilled off, but it is usually preferably 40 to 50 ° C.
減圧時の圧力は、残存する溶媒の種類や量によって異なるため特に限定されないが、通常１０Ｔｏｒｒ以下で行うのがよい。 The pressure at the time of depressurization is not particularly limited because it varies depending on the type and amount of the remaining solvent, but it is usually preferably 10 Torr or less.
［精製工程Ｂ］
精製工程Ｂは、抽出された有機層を蒸留する工程を含む。
[Purification step B]
Purification step B includes a step of distilling the extracted organic layer.
蒸留としては、常圧蒸留、減圧蒸留、水蒸気蒸留等が挙げられ、特に加熱および減圧を含む蒸留が好ましい。加熱および減圧における温度および圧力は、１３０〜１８０℃および０．１〜１０Ｔｏｒｒであるのが好ましく、１４０〜１７０℃および０．１〜３Ｔｏｒｒであるのがより好ましい。加熱および減圧を上記範囲内で行うことにより、４−ヒドロキシ安息香酸ヘキシルの分解が抑制される。また、中和された有機層を用いることで、蒸留中の副反応を抑制することができる。 Examples of the distillation include atmospheric distillation, vacuum distillation, steam distillation and the like, and distillation including heating and reduced pressure is particularly preferable. The temperatures and pressures for heating and depressurization are preferably 130-180 ° C. and 0.1-10 Torr, more preferably 140-170 ° C. and 0.1-3 Torr. Decomposition of 4-hydroxybenzoate hexyl is suppressed by heating and depressurizing within the above range. In addition, by using a neutralized organic layer, side reactions during distillation can be suppressed.
加熱および減圧時間は特に限定されないが、上記蒸留条件において４−ヒドロキシ安息香酸ヘキシルが有機層から抽出されなくなるまで行うのがよい。 The heating and depressurizing time is not particularly limited, but it is preferable to carry out until the hexyl 4-hydroxybenzoate is no longer extracted from the organic layer under the above distillation conditions.
以下、実施例により本発明を詳細に説明するが、本発明はこれに限定されるものではない。 Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.
粗組成物の組成および得られた結晶の組成は、以下の条件にて高速液体クロマトグラフィー（ＨＰＬＣ）およびガスクロマトグラフィー（ＧＣ）による定量分析により求めた。 The composition of the crude composition and the composition of the obtained crystals were determined by quantitative analysis by high performance liquid chromatography (HPLC) and gas chromatography (GC) under the following conditions.
［高速液体クロマトグラフィー（ＨＰＬＣ）］
装置： Ｗａｔｅｒｓ アライアンス ２６９０／２９９６
カラム型番： Ｌ−Ｃｏｌｕｍｎ
液量： １．０ｍＬ／ｍｉｎ
溶媒比： Ｈ２Ｏ（ｐＨ２．３）／ＣＨ３ＯＨ＝８０／２０（８ｍｉｎ）→３０／７０（２１ｍｉｎ）→１０／９０（１４ｍｉｎ）、グラジエント分析
波長： ２５４ｎｍ
カラム温度： ４０℃
[High Performance Liquid Chromatography (HPLC)]
Equipment: Waters Alliance 2690/2996
Column model number: L-Column
Liquid volume: 1.0 mL / min
Solvent ratio: H 2 O (pH 2.3) / CH 3 OH = 80/20 (8 min) → 30/70 (21 min) → 10/90 (14 min), gradient analysis Wavelength: 254 nm
Column temperature: 40 ° C
［ガスクロマトグラフィー（ＧＣ）］
装置： 株式会社島津製作所製ＧＣ−２０１４／ＧＣ−１４Ａ
カラム型番： Ｇ−９５０
注入量： １．０μＬ
オーブン温度： ２２５℃
キャリアガス： ヘリウム
検出器： ＦＩＤ
[Gas Chromatography (GC)]
Equipment: GC-2014 / GC-14A manufactured by Shimadzu Corporation
Column model number: G-950
Injection volume: 1.0 μL
Oven temperature: 225 ° C
Carrier gas: Helium detector: FID
実施例１
撹拌機、温度センサーおよびディーンスターク装置を備えた３００ｍＬスケールの４つ口フラスコ（反応容器）に、４−ヒドロキシ安息香酸（ＰＯＢ）９１．２ｇ（０．６６モル）、１−ヘキサノール（ＨｅｘＯＨ）１０１．１ｇ（０．９９モル）および触媒としてｐ−トルエンスルホン酸一水和物（ＰＴＳ・Ｈ２Ｏ）１．８ｇを加え、３８ｍＬ／ｍｉｎの窒素気流下、１４５℃まで昇温し、同温度で６時間反応させ、粗組成物を得た。得られた粗組成物をＨＰＬＣおよびＧＣにて定量分析を行った。結果を表１に記す。
Example 1
91.2 g (0.66 mol) of 4-hydroxybenzoic acid (POB), 1-hexanol (HexOH) 101 in a 300 mL scale four-necked flask (reaction vessel) equipped with a stirrer, temperature sensor and Dean-Stark apparatus. .1g (0.99 mol) and a catalytic as p- toluenesulfonic acid monohydrate (PTS · H 2 O) 1.8g was added, under a nitrogen flow of 38 mL / min, the temperature was raised to 145 ° C., this temperature Was reacted for 6 hours to obtain a crude composition. The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.
実施例２
１−ヘキサノールを６０．７ｇ（０．５９モル）とした以外は、実施例１と同様にして粗組成物を得た。得られた粗組成物をＨＰＬＣおよびＧＣにて定量分析を行った。結果を表１に記す。
Example 2
A crude composition was obtained in the same manner as in Example 1 except that the amount of 1-hexanol was 60.7 g (0.59 mol). The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.
実施例３
１−ヘキサノールを８０．９ｇ（０．７９モル）とした以外は、実施例１と同様にして粗組成物を得た。得られた粗組成物をＨＰＬＣおよびＧＣにて定量分析を行った。結果を表１に記す。
Example 3
A crude composition was obtained in the same manner as in Example 1 except that the amount of 1-hexanol was 80.9 g (0.79 mol). The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.
実施例４（参考例）
１−ヘキサノールを１３４．８ｇ（１．３２モル）とした以外は、実施例１と同様にして粗組成物を得た。得られた粗組成物をＨＰＬＣおよびＧＣにて定量分析を行った。結果を表１に記す。
Example 4 (reference example)
A crude composition was obtained in the same manner as in Example 1 except that the amount of 1-hexanol was 134.8 g (1.32 mol). The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.
実施例５（参考例）
ｐ−トルエンスルホン酸一水和物を濃硫酸とした以外は、実施例１と同様にして粗組成物を得た。得られた粗組成物をＨＰＬＣおよびＧＣにて定量分析を行った。結果を表１に記す。
Example 5 (reference example)
A crude composition was obtained in the same manner as in Example 1 except that the p-toluenesulfonic acid monohydrate was concentrated sulfuric acid. The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.
比較例１
１−ヘキサノールを３３７．２ｇ（３．３０モル）とし、反応容器を１Ｌの４つ口フラスコとした以外は、実施例１と同様にして粗組成物を得た。得られた粗組成物をＨＰＬＣおよびＧＣにて定量分析を行った。結果を表１に記す。
Comparative Example 1
A crude composition was obtained in the same manner as in Example 1 except that 1-hexanol was 337.2 g (3.30 mol) and the reaction vessel was a 1 L four-necked flask. The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.
比較例２
ｐ−トルエンスルホン酸一水和物１．８ｇをテトライソプロポキシチタン７．４ｇとした以外は、実施例２と同様にして粗組成物を得た。得られた粗組成物をＨＰＬＣおよびＧＣにて定量分析を行った。結果を表１に記す。
Comparative Example 2
A crude composition was obtained in the same manner as in Example 2 except that 1.8 g of p-toluenesulfonic acid monohydrate was changed to 7.4 g of tetraisopropoxytitanium. The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.
比較例３
１−ヘキサノールを３３．７ｇ（０．３３モル）とした以外は、実施例１と同様にして粗組成物を得ようとしたが、ＰＯＢが溶解せず撹拌不良となったため、反応を中断した。
Comparative Example 3
An attempt was made to obtain a crude composition in the same manner as in Example 1 except that the amount of 1-hexanol was 33.7 g (0.33 mol), but the reaction was interrupted because POB did not dissolve and stirring was poor. ..
実施例６
撹拌機、温度センサーおよび冷却管を備え、底部にコック付きの排出口を設けた１Ｌスケールの底抜き４つ口フラスコに、実施例１で得られた粗組成物１７９．９ｇを８０℃まで冷却した後に加えた。ここに、５ｗｔ％炭酸水素ナトリウム水溶液１２７．７ｇを加え、８０℃で１時間撹拌し中和させた。その後撹拌を停止して同温度で３０分間静置することにより有機層と水層に分離し、下層の水層を底部の排出口から廃棄し、有機層を抽出した。この抽出工程を更に３回実施し、有機層１７５．７ｇを得た。得られた有機層をＨＰＬＣおよびＧＣにて定量分析を行った。結果を表２に記す。
Example 6
Cooling 179.9 g of the crude composition obtained in Example 1 to 80 ° C. in a 1 L-scale bottomless four-necked flask equipped with a stirrer, a temperature sensor and a cooling tube and provided with a discharge port with a cock at the bottom. Added after. To this, 127.7 g of a 5 wt% sodium hydrogen carbonate aqueous solution was added, and the mixture was neutralized by stirring at 80 ° C. for 1 hour. After that, stirring was stopped and the mixture was allowed to stand at the same temperature for 30 minutes to separate into an organic layer and an aqueous layer, the lower aqueous layer was discarded from the bottom discharge port, and the organic layer was extracted. This extraction step was carried out three more times to obtain 175.7 g of an organic layer. The obtained organic layer was quantitatively analyzed by HPLC and GC. The results are shown in Table 2.
実施例７
撹拌機、温度センサー、リービッヒ冷却管、その先にアダプターと留出液を溜めるフラスコを備えた１Ｌスケールの減圧蒸留装置に、実施例６で得られた有機層１７５．７ｇを加え、６０Ｔｏｒｒの減圧下で８０℃から１４５℃に昇温しながら２時間溶媒の留去を行った。留去された溶媒量は２３．５ｇであった。
Example 7
175.7 g of the organic layer obtained in Example 6 was added to a 1 L-scale vacuum distillation apparatus equipped with a stirrer, a temperature sensor, a Liebig condenser, and an adapter and a flask for storing distillate, and the pressure was reduced by 60 Torr. The solvent was distilled off for 2 hours while raising the temperature from 80 ° C. to 145 ° C. below. The amount of solvent distilled off was 23.5 g.
溶媒留去後の残留液を５０℃まで冷却し、３０ｗｔ％メタノール水溶液１２７．７ｇを加え、５０℃のまま３０分間保持し、溶解させた後、２５℃まで冷却し、純度９９．５ｗｔ％のＮＨＰＢ１．８ｇを加え、１５℃まで冷却し晶析させた。晶析で得られた固形物を濾別によって取り出し、３０ｗｔ％メタノール水溶液９１．２ｇで洗浄した後、４０℃および４．５Ｔｏｒｒの条件下で乾燥させて、結晶８４．５ｇを得た（収率５７．１ｍｏｌ％）。 The residual liquid after distilling off the solvent was cooled to 50 ° C., 127.7 g of a 30 wt% methanol aqueous solution was added, the mixture was kept at 50 ° C. for 30 minutes to dissolve, and then cooled to 25 ° C. to a purity of 99.5 wt%. 1.8 g of NHPB was added, and the mixture was cooled to 15 ° C. and crystallized. The solid obtained by crystallization was taken out by filtration, washed with 91.2 g of a 30 wt% methanol aqueous solution, and then dried under the conditions of 40 ° C. and 4.5 Torr to obtain 84.5 g of crystals (yield). 57.1 mol%).
得られた結晶を、ＨＰＬＣおよびＧＣにて定量分析を行った。結果を表２に記す。 The obtained crystals were quantitatively analyzed by HPLC and GC. The results are shown in Table 2.
実施例８
撹拌機、温度センサー、リービッヒ冷却管、その先にアダプターと留出液を溜めるフラスコを備えた１Ｌスケールの減圧蒸留装置に、実施例６で得られた有機層１７５．７ｇおよび水２７３．６ｇを加え、１１０℃で３時間溶媒の留去を行った。留去された溶媒量は２９１．３ｇであった。
Example 8
175.7 g of the organic layer and 273.6 g of water obtained in Example 6 were placed in a 1 L-scale vacuum distillation apparatus equipped with a stirrer, a temperature sensor, a Liebig condenser, and an adapter and a flask for storing distillate. In addition, the solvent was distilled off at 110 ° C. for 3 hours. The amount of the solvent distilled off was 291.3 g.
溶媒留去後の残留液を５０℃まで冷却し、３０ｗｔ％メタノール水溶液１２７．７ｇを加え、５０℃のまま３０分間保持し、溶解させた後、２５℃まで冷却し、純度９９．５ｗｔ％のＮＨＰＢ１．８ｇを加え、１５℃まで冷却し晶析させた。晶析で得られた固形物を濾別によって取り出し、３０ｗｔ％メタノール水溶液９１．２ｇで洗浄した後、４０℃および４．５Ｔｏｒｒの条件で乾燥させて、結晶１１５．８ｇを得た（収率７８．９ｍｏｌ％）。 The residual liquid after distilling off the solvent was cooled to 50 ° C., 127.7 g of a 30 wt% methanol aqueous solution was added, the mixture was kept at 50 ° C. for 30 minutes to dissolve, and then cooled to 25 ° C. to a purity of 99.5 wt%. 1.8 g of NHPB was added, and the mixture was cooled to 15 ° C. and crystallized. The solid obtained by crystallization was taken out by filtration, washed with 91.2 g of a 30 wt% methanol aqueous solution, and then dried under the conditions of 40 ° C. and 4.5 Torr to obtain 115.8 g of crystals (yield 78). .9 mol%).
得られた結晶を、ＨＰＬＣおよびＧＣにて定量分析を行った。結果を表２に記す。 The obtained crystals were quantitatively analyzed by HPLC and GC. The results are shown in Table 2.
実施例９
撹拌機、温度センサー、リービッヒ冷却管、その先にアダプターと留出液を溜めるフラスコを備えた１Ｌスケールの減圧蒸留装置に、実施例６で得られた有機層１７５．７ｇを加え、１５７℃および１．５Ｔｏｒｒで蒸留した結晶１３８．９ｇを得た（収率９４．７ｍｏｌ％）。得られた結晶をＨＰＬＣおよびＧＣにて定量分析を行った。結果を表２に記す。
Example 9
175.7 g of the organic layer obtained in Example 6 was added to a 1 L-scale vacuum distillation apparatus equipped with a stirrer, a temperature sensor, a Liebig condenser, and an adapter and a flask for storing distillate, and the temperature was increased to 157 ° C. 138.9 g of crystals distilled at 1.5 Torr was obtained (yield 94.7 mol%). The obtained crystals were quantitatively analyzed by HPLC and GC. The results are shown in Table 2.
このように、表１から分かる通り、本発明によれば、副生物や余分な残存アルコール量を低減できるため、高収率かつ高生産効率で４−ヒドロキシ安息香酸ヘキシルが得られる。 As described above, as can be seen from Table 1, according to the present invention, the amount of by-products and excess residual alcohol can be reduced, so that hexyl 4-hydroxybenzoate can be obtained in high yield and high production efficiency.
さらに、表２から分かる通り、本発明によれば、４−ヒドロキシ安息香酸ヘキシルを含む粗組成物を精製することで、反応原料や副生物などが除去され、高純度の４−ヒドロキシ安息香酸ヘキシルが得られる。
本発明の好ましい態様は以下を包含する。
〔１〕酸触媒の存在下、４−ヒドロキシ安息香酸１モル当量と１−ヘキサノール０．８〜３．０モル当量とを反応させる工程を含む、式（１）で表される４−ヒドロキシ安息香酸ヘキシルの製造方法。
〔３〕酸触媒が、ｐ−トルエンスルホン酸、硫酸、塩酸、リン酸および硝酸からなる群から選択される１種以上である、〔１〕または〔２〕に記載の製造方法。
〔４〕酸触媒がｐ−トルエンスルホン酸である、〔１〕〜〔３〕のいずれかに記載の製造方法。
〔５〕前記工程が式（１）で表される４−ヒドロキシ安息香酸ヘキシルを含む粗組成物を得る工程である、〔１〕〜〔４〕のいずれかに記載の製造方法。
〔６〕前記粗組成物に塩基性水溶液を添加して粗組成物を中和する工程、次いで有機層と水層に分離し、有機層を抽出する工程を更に含む、〔５〕に記載の製造方法。
〔７〕抽出した有機層の不純物を留去する工程、次いで有機層に溶媒を添加して晶析する工程を更に含む、〔６〕に記載の製造方法。
〔８〕留去を６０〜１６０℃の温度下および４０〜８０Ｔｏｒｒの圧力下で行う、〔７〕に記載の製造方法。
〔９〕溶媒がアルコール水溶液である、〔７〕に記載の製造方法。
〔１０〕アルコール水溶液が１０〜５０％メタノール水溶液である、〔９〕に記載の製造方法。
〔１１〕抽出した有機層を蒸留する工程を更に含む、〔６〕に記載の製造方法。
〔１２〕蒸留を１３０〜１８０℃の温度下および０．１〜１０Ｔｏｒｒの圧力下で行う、〔１１〕に記載の製造方法。
〔１３〕酸触媒の存在下、４−ヒドロキシ安息香酸と１−ヘキサノールとを反応させることにより、式（１）で表される４−ヒドロキシ安息香酸ヘキシルを含む粗組成物を得る工程、
次いで前記粗組成物に塩基性水溶液を添加して粗組成物を中和する工程、
次いで有機層と水層に分離し、有機層を抽出する工程
を含む、式（１）で表される４−ヒドロキシ安息香酸ヘキシルの製造方法。
Preferred embodiments of the present invention include:
[1] 4-Hydroxybenzoic acid represented by the formula (1), which comprises a step of reacting 1 molar equivalent of 4-hydroxybenzoic acid with 0.8 to 3.0 molar equivalent of 1-hexanol in the presence of an acid catalyst. Method for producing hexyl acid.
[3] The production method according to [1] or [2], wherein the acid catalyst is at least one selected from the group consisting of p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid and nitric acid.
[4] The production method according to any one of [1] to [3], wherein the acid catalyst is p-toluenesulfonic acid.
[5] The production method according to any one of [1] to [4], wherein the step is a step of obtaining a crude composition containing hexyl 4-hydroxybenzoate represented by the formula (1).
[6] The step according to [5], further comprising a step of adding a basic aqueous solution to the crude composition to neutralize the crude composition, and then a step of separating the crude composition into an organic layer and an aqueous layer and extracting the organic layer. Production method.
[7] The production method according to [6], further comprising a step of distilling off impurities in the extracted organic layer and then a step of adding a solvent to the organic layer for crystallization.
[8] The production method according to [7], wherein the distillation is carried out under a temperature of 60 to 160 ° C. and a pressure of 40 to 80 Torr.
[9] The production method according to [7], wherein the solvent is an aqueous alcohol solution.
[10] The production method according to [9], wherein the alcohol aqueous solution is a 10 to 50% methanol aqueous solution.
[11] The production method according to [6], further comprising a step of distilling the extracted organic layer.
[12] The production method according to [11], wherein the distillation is carried out under a temperature of 130 to 180 ° C. and a pressure of 0.1 to 10 Torr.
[13] A step of reacting 4-hydroxybenzoic acid with 1-hexanol in the presence of an acid catalyst to obtain a crude composition containing hexyl 4-hydroxybenzoate represented by the formula (1).
Next, a step of adding a basic aqueous solution to the crude composition to neutralize the crude composition.
Next, a step of separating into an organic layer and an aqueous layer and extracting the organic layer.
A method for producing hexyl 4-hydroxybenzoate represented by the formula (1), which comprises.
Claims (11)
次いで前記粗組成物に塩基性水溶液を添加して粗組成物を中和する工程、
次いで有機層と水層に分離し、有機層を抽出する工程
を含む、式（１）で表される４−ヒドロキシ安息香酸ヘキシルの製造方法。
Next, a step of adding a basic aqueous solution to the crude composition to neutralize the crude composition.
A method for producing hexyl 4-hydroxybenzoate represented by the formula (1), which comprises a step of separating into an organic layer and an aqueous layer and extracting the organic layer.
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