JP2008001631A - Reduction reaction by borohydride compound using tetrahydropyran as solvent - Google Patents
Reduction reaction by borohydride compound using tetrahydropyran as solvent Download PDFInfo
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- JP2008001631A JP2008001631A JP2006172566A JP2006172566A JP2008001631A JP 2008001631 A JP2008001631 A JP 2008001631A JP 2006172566 A JP2006172566 A JP 2006172566A JP 2006172566 A JP2006172566 A JP 2006172566A JP 2008001631 A JP2008001631 A JP 2008001631A
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- borohydride
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- tetrahydropyran
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- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 title claims abstract description 25
- 238000006722 reduction reaction Methods 0.000 title claims description 18
- 239000002904 solvent Substances 0.000 title abstract description 15
- -1 alcohol compound Chemical class 0.000 claims abstract description 25
- 150000001728 carbonyl compounds Chemical class 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 6
- 150000001768 cations Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 15
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 13
- 238000000605 extraction Methods 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 description 4
- 239000012448 Lithium borohydride Substances 0.000 description 4
- 235000002597 Solanum melongena Nutrition 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000004292 cyclic ethers Chemical class 0.000 description 3
- 239000003822 epoxy resin Substances 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229920000647 polyepoxide Polymers 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 description 2
- ADZUEEUKBYCSEY-UHFFFAOYSA-N 1h-indole-5-carbaldehyde Chemical compound O=CC1=CC=C2NC=CC2=C1 ADZUEEUKBYCSEY-UHFFFAOYSA-N 0.000 description 2
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 2
- 241000819038 Chichester Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- XPNGNIFUDRPBFJ-UHFFFAOYSA-N alpha-methylbenzylalcohol Natural products CC1=CC=CC=C1CO XPNGNIFUDRPBFJ-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- HJOVHMDZYOCNQW-UHFFFAOYSA-N isophorone Chemical compound CC1=CC(=O)CC(C)(C)C1 HJOVHMDZYOCNQW-UHFFFAOYSA-N 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 2
- OTKCEEWUXHVZQI-UHFFFAOYSA-N 1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(=O)CC1=CC=CC=C1 OTKCEEWUXHVZQI-UHFFFAOYSA-N 0.000 description 1
- CCVWCDBPHTVORF-UHFFFAOYSA-N 1,3-thiazolidine-3-carbaldehyde Chemical compound O=CN1CCSC1 CCVWCDBPHTVORF-UHFFFAOYSA-N 0.000 description 1
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- BNPJNOLDKSAJSD-UHFFFAOYSA-N C(C)[N+](CC)(CC)CC.[B+3] Chemical class C(C)[N+](CC)(CC)CC.[B+3] BNPJNOLDKSAJSD-UHFFFAOYSA-N 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- IZALUMVGBVKPJD-UHFFFAOYSA-N benzene-1,3-dicarbaldehyde Chemical compound O=CC1=CC=CC(C=O)=C1 IZALUMVGBVKPJD-UHFFFAOYSA-N 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- YOUGRGFIHBUKRS-UHFFFAOYSA-N benzyl(trimethyl)azanium Chemical compound C[N+](C)(C)CC1=CC=CC=C1 YOUGRGFIHBUKRS-UHFFFAOYSA-N 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- FLLNLJJKHKZKMB-UHFFFAOYSA-N boron;tetramethylazanium Chemical compound [B].C[N+](C)(C)C FLLNLJJKHKZKMB-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical compound C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 description 1
- MLUCVPSAIODCQM-UHFFFAOYSA-N crotonaldehyde Natural products CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 description 1
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclo-pentanone Natural products O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 1
- UHBZEAPZATVYKV-UHFFFAOYSA-N cyclohexylacetone Chemical compound CC(=O)CC1CCCCC1 UHBZEAPZATVYKV-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- YLQWCDOCJODRMT-UHFFFAOYSA-N fluoren-9-one Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C2=C1 YLQWCDOCJODRMT-UHFFFAOYSA-N 0.000 description 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- SNWQUNCRDLUDEX-UHFFFAOYSA-N inden-1-one Chemical compound C1=CC=C2C(=O)C=CC2=C1 SNWQUNCRDLUDEX-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- WMPJPAMWRAOQSU-UHFFFAOYSA-N naphthalene-1,2-dicarbaldehyde Chemical compound C1=CC=CC2=C(C=O)C(C=O)=CC=C21 WMPJPAMWRAOQSU-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- HTKPDYSCAPSXIR-UHFFFAOYSA-N octyltrimethylammonium ion Chemical compound CCCCCCCC[N+](C)(C)C HTKPDYSCAPSXIR-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229940100595 phenylacetaldehyde Drugs 0.000 description 1
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- DXBWJLDFSICTIH-UHFFFAOYSA-N pyrazine-2-carbaldehyde Chemical compound O=CC1=CN=CC=N1 DXBWJLDFSICTIH-UHFFFAOYSA-N 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- FREJAOSUHFGDBW-UHFFFAOYSA-N pyrimidine-5-carbaldehyde Chemical compound O=CC1=CN=CN=C1 FREJAOSUHFGDBW-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- KUCOHFSKRZZVRO-UHFFFAOYSA-N terephthalaldehyde Chemical compound O=CC1=CC=C(C=O)C=C1 KUCOHFSKRZZVRO-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本発明は、カルボニル化合物をテトラヒドロピラン中で水素化ホウ素化合物により還元し、アルコール化合物を製造する方法に関する。 The present invention relates to a method for producing an alcohol compound by reducing a carbonyl compound with a borohydride compound in tetrahydropyran.
従来、水素化ホウ素化合物によるカルボニル化合物の還元反応は水、アルコールなどのプロトン性溶媒中で行われるのが一般的であった（Reduction in Organic Chemistry, Ellis Horwood Ltd., Chichester (1984)：非特許文献１）。
しかし、原料化合物が水に溶解しにくい有機化合物である場合には、まず水と相溶する有機溶媒に溶解させた後に、水を添加して還元反応を行う方法を用いる。このような水と相溶する有機溶媒としては、例えばテトラヒドロフラン（Bull. Chem. Soc. Jpn., 78 p307 (2005)：非特許文献２）、ジエチレングリコールジメチルエーテル（ジグライム）などが挙げられる。
このように、水と相溶する有機溶媒を用いた水素化ホウ素化合物の還元反応の場合には、反応により生成したアルコール化合物は、反応溶媒を濃縮し、酢酸エチルなどの抽出溶媒を加え、抽出分離することにより得られる。これらの操作においては、蒸発潜熱の高い水を留去した後に、さらに反応溶媒と異なる抽出溶媒を用いなければならないため、反応工程の煩雑化やエネルギーコストの点が問題となっている。
Conventionally, the reduction reaction of a carbonyl compound by a borohydride compound is generally performed in a protic solvent such as water or alcohol (Reduction in Organic Chemistry, Ellis Horwood Ltd., Chichester (1984): Non-patent Reference 1).
However, in the case where the raw material compound is an organic compound that is difficult to dissolve in water, a method is used in which a reduction reaction is performed by first adding water to an organic solvent that is compatible with water and then adding water. Examples of such an organic solvent compatible with water include tetrahydrofuran (Bull. Chem. Soc. Jpn., 78 p307 (2005): Non-Patent Document 2), diethylene glycol dimethyl ether (diglyme), and the like.
Thus, in the case of a reduction reaction of a borohydride compound using an organic solvent compatible with water, the alcohol compound produced by the reaction is extracted by concentrating the reaction solvent and adding an extraction solvent such as ethyl acetate. It is obtained by separating. In these operations, after distilling off water having a high latent heat of vaporization, an extraction solvent different from the reaction solvent must be used, which complicates the reaction process and increases energy costs.
また、特開平１−１０８２１８号公報（特許文献１）には、有機塩素を含有するエポキシ樹脂に、環状エーテルを主体とする溶媒中で、アルカリ金属および金属水酸化物を作用させてエポキシ樹脂を精製する方法が記載されている。
上記特許文献１には環状エーテルの例示中にテトラヒドロピランも挙げられているが、テトラヒドロピランを実際に用いた例は開示されていない。また、この文献に記載の発明では、環状エーテルはエポキシ樹脂に含まれる有機塩素などの不純物を精製するための目的で使用されており、カルボニル化合物の還元反応に用いることは知られていない。
JP-A-1-108218 (Patent Document 1) discloses an epoxy resin prepared by allowing an alkali metal and a metal hydroxide to act on an epoxy resin containing organic chlorine in a solvent mainly composed of cyclic ether. A method of purification is described.
In the above-mentioned Patent Document 1, tetrahydropyran is also mentioned in the examples of cyclic ethers, but an example in which tetrahydropyran is actually used is not disclosed. In the invention described in this document, the cyclic ether is used for the purpose of purifying impurities such as organic chlorine contained in the epoxy resin, and is not known to be used for the reduction reaction of the carbonyl compound.
本発明は、カルボニル化合物をプロトン性溶媒存在下で水素化ホウ素化合物により還元する方法における上記の問題点を解決し、安全かつ効率的にアルコール化合物を製造する方法を提供することを目的とする。 An object of the present invention is to solve the above-mentioned problems in a method of reducing a carbonyl compound with a borohydride compound in the presence of a protic solvent, and to provide a method for producing an alcohol compound safely and efficiently.
本発明者らは、上記課題に鑑み鋭意努力した結果、カルボニル化合物と水素化ホウ素化合物の還元反応において、溶媒として毒性の低いテトラヒドロピランを使用することによって生体への安全性が高まり、また、反応溶媒と抽出溶媒を同一のものとすることができるので反応工程の簡素化、エネルギーコストの低減などが実現できるようになることを見出し、本発明を完成させた。 As a result of diligent efforts in view of the above problems, the present inventors have increased the safety to living bodies by using tetrahydropyran having low toxicity as a solvent in the reduction reaction of a carbonyl compound and a borohydride compound, and the reaction It has been found that since the solvent and the extraction solvent can be the same, the reaction process can be simplified, energy costs can be reduced, and the present invention has been completed.
すなわち、本発明は以下のアルコール化合物の製造方法に関するものである。
［１］下記式（１）
で示されるカルボニル化合物をテトラヒドロピラン中、
下記式（２）
で示される水素化ホウ素化合物で還元することを特徴とする
下記式（３）
で示されるアルコール化合物の製造方法。
［２］前記式（２）におけるＭが、リチウム、ナトリウム、カリウムまたは４級アンモニウム化合物である前記１に記載のアルコール化合物の製造方法。
［３］水素化ホウ素化合物が、水素化ホウ素ナトリウムまたは水素化ホウ素カリウムであり、還元反応を水の存在下にて行う前記１に記載のアルコール化合物の製造方法。
［４］水を０．１質量％以上存在させて還元反応を行う前記３に記載のアルコール化合物の製造方法。
That is, this invention relates to the manufacturing method of the following alcohol compounds.
[1] The following formula (1)
In a tetrahydropyran, the carbonyl compound represented by
Following formula (2)
Reduction with a borohydride compound represented by the following formula (3)
The manufacturing method of the alcohol compound shown by these.
[2] The method for producing an alcohol compound according to 1 above, wherein M in the formula (2) is a lithium, sodium, potassium, or quaternary ammonium compound.
[3] The method for producing an alcohol compound according to 1 above, wherein the borohydride compound is sodium borohydride or potassium borohydride, and the reduction reaction is performed in the presence of water.
[4] The method for producing an alcohol compound as described in 3 above, wherein the reduction reaction is carried out in the presence of 0.1% by mass or more of water.
本発明のテトラヒドロピランを反応溶媒とするアルコール化合物の製造方法においては、反応溶媒と抽出溶媒を同一のものとすることが可能となるため、反応工程の簡素化、エネルギーコストの低減などが実現できるようになる。また、反応溶媒に毒性の低いテトラヒドロピランを用いることにより、生体への安全性も高まる。 In the method for producing an alcohol compound using tetrahydropyran as a reaction solvent of the present invention, the reaction solvent and the extraction solvent can be made the same, so that the reaction process can be simplified and the energy cost can be reduced. It becomes like this. Moreover, the safety | security to a biological body also increases by using tetrahydropyran with low toxicity as a reaction solvent.
以下に、本発明の具体的内容について詳細に説明する。
本発明は、下記式（１）
で示されるカルボニル化合物をテトラヒドロピラン中で水素化ホウ素化合物により還元し、下記式（３）
で示されるアルコール化合物を製造する方法であり、反応溶媒であるテトラヒドロピランを抽出溶媒としても用いることを特徴とする。
Hereinafter, the specific contents of the present invention will be described in detail.
The present invention provides the following formula (1)
Is reduced with a borohydride compound in tetrahydropyran, and the following formula (3)
In which tetrahydropyran, which is a reaction solvent, is also used as an extraction solvent.
[カルボニル化合物]
本発明で使用されるカルボニル化合物については、特に制限はない。
また、上記式（１）におけるＲ1及びＲ2は同一でも異なっていても良い。従って、本発明が適用されるカルボニル化合物には、Ｒ1及びＲ2の少なくとも一方が水素原子であるアルデヒド類、両者が炭化水素基であるケトン類がすべて含まれる。炭化水素基は、例えば、アルキル基、アルケニル基（還元反応による影響が問題とならない場合はアルキニル基でもよい。）、アリール基を含み、また、これらの組み合わせ（例えば、アラルキル基）であってもよい。
[Carbonyl compounds]
There is no restriction | limiting in particular about the carbonyl compound used by this invention.
R 1 and R 2 in the above formula (1) may be the same or different. Accordingly, the carbonyl compounds to which the present invention is applied include all aldehydes in which at least one of R 1 and R 2 is a hydrogen atom, and ketones in which both are hydrocarbon groups. The hydrocarbon group includes, for example, an alkyl group, an alkenyl group (which may be an alkynyl group when the influence of the reduction reaction does not matter), an aryl group, and a combination thereof (for example, an aralkyl group). Good.
なお、本発明において炭化水素基とは、還元反応を妨げない限りにおいて異種元素を含んでもよい。異種元素としては、特に限定されず、同じ異種元素を複数含んでもよいし、異なる種類の元素を複数含んでもよい。異種元素は、例えば、Ｏ、Ｎ、Ｓ、ハロゲン等であるが、エーテル結合（還元反応による影響が問題とならない場合に限る）やスルフィド結合等のように炭素鎖中の炭素を置換したものでもよいし、＞Ｃ＝Ｏや水酸基等のように炭素鎖状の水素を置換したものでもよい。従って、本発明が適用されるカルボニル化合物には、カルボニル基を分子中に２個以上含む化合物も含まれる。また、Ｒ1及びＲ2は結合して環を形成してもよい。 In the present invention, the hydrocarbon group may contain a different element as long as the reduction reaction is not hindered. The different elements are not particularly limited and may include a plurality of the same different elements or a plurality of different types of elements. Heterogeneous elements are, for example, O, N, S, halogen, etc., but may be those in which carbon in the carbon chain is substituted such as an ether bond (only when the effect of the reduction reaction does not matter) or a sulfide bond. Alternatively, a carbon chain-like hydrogen may be substituted such as> C═O or a hydroxyl group. Accordingly, the carbonyl compound to which the present invention is applied includes a compound containing two or more carbonyl groups in the molecule. R 1 and R 2 may combine to form a ring.
具体的には、例えば、ホルムアルデヒド、アセトアルデヒド、ブチルアルデヒド、クロトンアルデヒド、３−フェニルプロピオンアルデヒド、プロピオンアルデヒド、バレルアルデヒド、シクロヘキサンカルボアルデヒド、フェニルアセトアルデヒドなどの脂肪族アルデヒド化合物、グリオキザール、マロンアルデヒド、スクシンアルデヒド、グルタルアルデヒドなどの多価脂肪族アルデヒド化合物、ベンズアルデヒド、アニスアルデヒド、ｐ−クロロベンズアルデヒド、ｐ−メチルベンズアルデヒド、バニリン、２−ナフタレンアルデヒドなどの芳香族アルデヒド化合物、テレフタルアルデヒド、フタルアルデヒド、イソフタルアルデヒド、１，２−ナフタレンジカルボアルデヒドなどの芳香族多価アルデヒド、フルフリルアルデヒド、ピリジンアルデヒド、ニコチンアルデヒド、２−ホルミルチオフェン、５−ホルミルインドール、３−ホルミルチアゾリジン、５−ホルミルピリミジン、２−ホルミルピラジンなどの複素環式アルデヒド化合物、アセトン、メチルエチルケトン、ジエチルケトン、イソホロン、シクロペンタノン、シクロヘキサノン、シクロヘキシルアセトン、アセチルアセトン、アセト酢酸メチルなどの脂肪族ケトン化合物、アセトフェノン、プロピオフェノン、ベンゾフェノンデオキシベンゾイン、アセトナフトフェノン、ブチロナフトフェノン、インデン−１−オン、フルオレン−９−オンなどの芳香族ケトン化合物などを用いることができる。 Specifically, for example, aliphatic aldehyde compounds such as formaldehyde, acetaldehyde, butyraldehyde, crotonaldehyde, 3-phenylpropionaldehyde, propionaldehyde, valeraldehyde, cyclohexanecarbaldehyde, phenylacetaldehyde, glyoxal, malonaldehyde, succinaldehyde , Polyhydric aliphatic aldehyde compounds such as glutaraldehyde, benzaldehyde, anisaldehyde, p-chlorobenzaldehyde, p-methylbenzaldehyde, vanillin, 2-naphthalenealdehyde and other aromatic aldehyde compounds, terephthalaldehyde, phthalaldehyde, isophthalaldehyde, 1 , 2-Naphthalenedicarbaldehyde and other polyvalent aromatic aldehydes, furfuryl aldehyde, Heterocyclic aldehyde compounds such as ginaldehyde, nicotinaldehyde, 2-formylthiophene, 5-formylindole, 3-formylthiazolidine, 5-formylpyrimidine, 2-formylpyrazine, acetone, methyl ethyl ketone, diethyl ketone, isophorone, cyclopentanone Aliphatic ketone compounds such as cyclohexanone, cyclohexylacetone, acetylacetone, methyl acetoacetate, acetophenone, propiophenone, benzophenone deoxybenzoin, acetonaphthophenone, butyronaphthophenone, inden-1-one, fluoren-9-one, etc. An aromatic ketone compound or the like can be used.
[水素化ホウ素化合物]
本発明で使用される水素化ホウ素化合物は、下記式（２）
で示される水素化ホウ素化合物である。
[Boron hydride compounds]
The borohydride compound used in the present invention has the following formula (2):
It is a borohydride compound shown by these.
このような水素化ホウ素化合物としては、Ｍが金属である水素化ホウ素化合物としては、水素化ホウ素リチウム、水素化ホウ素ナトリウム、水素化ホウ素カリウムなどが挙げられる。また、Ｍが１価の陽イオンとなり得る水素化ホウ素化合物としては、有機アンモニウムを有する水素化ホウ素化合物（本願において水素化ホウ素アンモニウム等と言う。）、例えば、水素化ホウ素テトラメチルアンモニウム、水素化ホウ素テトラエチルアンモニウム、水素化ホウ素テトラブチルアンモニウム、水素化ホウ素トリメチルオクチルアンモニウム、水素化ホウ素トリメチルベンジルアンモニウムなどを用いることができる。
これらの中でも特に、水を共存させる系においては水素化ホウ素ナトリウム、水素化ホウ素カリウムが好ましく、水を共存させない系においては水素化ホウ素リチウムが好ましい。
Examples of such borohydride compounds include lithium borohydride, sodium borohydride, potassium borohydride, and the like as borohydride compounds in which M is a metal. In addition, as a borohydride compound in which M can be a monovalent cation, a borohydride compound having organic ammonium (referred to as ammonium borohydride in the present application), for example, tetramethylammonium borohydride, hydrogenated Boron tetraethylammonium borohydride, tetrabutylammonium hydride, trimethyloctylammonium borohydride, trimethylbenzylammonium borohydride, and the like can be used.
Among these, sodium borohydride and potassium borohydride are preferable in a system in which water coexists, and lithium borohydride is preferable in a system in which water does not coexist.
水素化ホウ素化合物の添加量としては、水素化ホウ素化合物は４つのヒドリドを有するので、カルボニル化合物に対して、少なくとも０．２５ｍｏｌ当量必要である。 As the amount of the borohydride compound added, the borohydride compound has four hydrides, so that it must be at least 0.25 mol equivalent to the carbonyl compound.
[反応溶媒]
本発明では、反応溶媒としてテトラヒドロピランを用いる。但し、反応の妨げにならない限りにおいて他の溶媒を含んでもよい。例えば、テトラヒドロピランと水との混合溶媒を用いることができる。水素化ホウ素リチウムなど水と激しく反応する水素化ホウ素化合物は使用できないが、水素化ホウ素ナトリウム、水素化ホウ素カリウム、水素化ホウ素アンモニウム化合物などは用いることができる。
[Reaction solvent]
In the present invention, tetrahydropyran is used as a reaction solvent. However, other solvents may be included as long as they do not interfere with the reaction. For example, a mixed solvent of tetrahydropyran and water can be used. Although borohydride compounds that react violently with water, such as lithium borohydride, cannot be used, sodium borohydride, potassium borohydride, ammonium borohydride compounds, and the like can be used.
テトラヒドロピランと水の量比としては、テトラヒドロピランに対して、水を０．１質量％以上存在させることにより反応促進効果が認められ、５〜５０００質量％使用することが好ましく、１０〜１０００質量％使用することがさらに好ましい。
テトラヒドロピランと水との混合溶媒系では、カルボニル化合物の還元反応の反応速度を向上させることができ、また、生成したアルコール化合物を含む反応溶媒を濃縮したり、別途抽出溶媒を加えたりすることなしに直接抽出分離することができる。
As the quantity ratio of tetrahydropyran and water, the reaction promoting effect is recognized by the presence of 0.1% by mass or more of water with respect to tetrahydropyran, and it is preferable to use 5 to 5000% by mass, and 10 to 1000% by mass. % Is more preferable.
In the mixed solvent system of tetrahydropyran and water, the reaction rate of the reduction reaction of the carbonyl compound can be improved, and the reaction solvent containing the generated alcohol compound is not concentrated or a separate extraction solvent is not added. Can be directly extracted and separated.
反応温度は、テトラヒドロピランと水との混合溶媒が固化しない温度から共沸温度までの間で行うことができ、好適には０〜７５℃である。 The reaction temperature can be from a temperature at which the mixed solvent of tetrahydropyran and water does not solidify to an azeotropic temperature, and is preferably 0 to 75 ° C.
以下、代表的な例を示して本発明を具体的に説明するが、本発明はこれらに何ら制限されるものではない。
なお、実施例における各成分の分析は、ガスクロマトグラフィー装置として６８９０Ｎ（アジレント・テクノロジー（株）製）を用い、分析カラムとしてＤＢ−１カラム（Ｊ＆Ｗ Ｓｃｉｅｎｔｉｆｉｃ社製，長さ３０ｍ、直径０．３２ｍｍ、膜厚１μｍ）を用いた。
Hereinafter, the present invention will be specifically described with reference to representative examples, but the present invention is not limited thereto.
In addition, the analysis of each component in an Example uses 6890N (made by Agilent Technologies) as a gas chromatography apparatus, DB-1 column (made by J & W Scientific, length 30m, diameter 0.32mm) as an analysis column. , A film thickness of 1 μm) was used.
［実施例１］
容量１００ｍｌのナスフラスコに撹拌子、３−フェニルプロピオンアルデヒド１．３４ｇ（１０ｍｍｏｌ）、水素化ホウ素ナトリウム０．１９ｇ（５ｍｍｏｌ）を加え、表１に示す割合で水とテトラヒドロピラン（ＴＨＰ）の量比を変え、室温で２０分反応させた。反応後、生成した３−フェニルプロパノールをＧＣで定量した。結果を表１に示す。
[Example 1]
A stirring bar, 1.34 g (10 mmol) of 3-phenylpropionaldehyde and 0.19 g (5 mmol) of sodium borohydride were added to a 100 ml volume eggplant flask, and the ratio of water and tetrahydropyran (THP) in the proportions shown in Table 1 And allowed to react at room temperature for 20 minutes. After the reaction, the produced 3-phenylpropanol was quantified by GC. The results are shown in Table 1.
［実施例２］
容量１００ｍｌのナスフラスコに撹拌子、カルボニル化合物１０ｍｍｏｌ、テトラヒドロピラン２０ｍｌ、水２０ｍｌ、水素化ホウ素ナトリウム（ＳＢＨ）を加え、室温で激しく撹拌反応させた。反応後、生成したアルコールをＧＣで定量した。結果を表２に示す。
[Example 2]
A stirring bar, 10 mmol of a carbonyl compound, 20 ml of tetrahydropyran, 20 ml of water, and sodium borohydride (SBH) were added to an eggplant flask having a capacity of 100 ml, and the mixture was vigorously stirred at room temperature. After the reaction, the produced alcohol was quantified by GC. The results are shown in Table 2.
［実施例３］
容量１００ｍｌのナスフラスコに撹拌子、アセトフェノン１．２０ｇ（１０ｍｍｏｌ）、テトラヒドロピラン２０ｍｌ、水２０ｍｌ、水素化ホウ素ナトリウム０．３８ｇ（１０ｍｍｏｌ）を加え室温で激しく撹拌しながら６時間反応させた。反応液を分液ロートに移し、水を分離し、飽和食塩水２０ｍｌで分液した。ＴＨＰ溶液を濃縮、乾固し１−フェニルエタノール１．０８ｇ（収率８８％）を得た。
[Example 3]
A stirring bar, 1.20 g (10 mmol) of acetophenone, 20 ml of tetrahydropyran, 20 ml of water, and 0.38 g (10 mmol) of sodium borohydride were added to a eggplant flask having a capacity of 100 ml and reacted at room temperature with vigorous stirring for 6 hours. The reaction solution was transferred to a separatory funnel, water was separated, and the solution was separated with 20 ml of saturated brine. The THP solution was concentrated and dried to obtain 1.08 g of 1-phenylethanol (yield 88%).
［実施例４］
容量１００ｍｌのナスフラスコに撹拌子、アセトフェノン１．２０ｇ（１０ｍｍｏｌ）、テトラヒドロピラン２０ｍｌ、水素化ホウ素リチウム０．２１ｇ（１０ｍｍｏｌ）を加え還流下、２時間反応させた。反応後、ＧＣで定量すると１−フェニルエタノールの収率は９５％であった。
[Example 4]
A stirring bar, 1.20 g (10 mmol) of acetophenone, 20 ml of tetrahydropyran, and 0.21 g (10 mmol) of lithium borohydride were added to an eggplant flask having a volume of 100 ml and reacted for 2 hours under reflux. After the reaction, the yield of 1-phenylethanol was 95% as determined by GC.
本発明のテトラヒドロピランを反応溶媒とするアルコール化合物の製造方法においては、反応溶媒と抽出溶媒を同一のものとすることが可能となるため、反応工程の簡素化、エネルギーコストの低減などが実現できるようになる。また、反応溶媒に毒性の低いテトラヒドロピランを用いることにより、生体への安全性も高まる。
In the method for producing an alcohol compound using tetrahydropyran as a reaction solvent of the present invention, the reaction solvent and the extraction solvent can be made the same, so that the reaction process can be simplified and the energy cost can be reduced. It becomes like this. Moreover, the safety | security to a biological body also increases by using tetrahydropyran with low toxicity as a reaction solvent.
Claims (4)
で示されるカルボニル化合物をテトラヒドロピラン中、
下記式（２）
で示される水素化ホウ素化合物で還元することを特徴とする
下記式（３）
で示されるアルコール化合物の製造方法。 Following formula (1)
In a tetrahydropyran, the carbonyl compound represented by
Following formula (2)
Reduction with a borohydride compound represented by the following formula (3)
The manufacturing method of the alcohol compound shown by these.
The method for producing an alcohol compound according to claim 3, wherein the reduction reaction is carried out in the presence of 0.1% by mass or more of water.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020248127A1 (en) * | 2019-06-11 | 2020-12-17 | 凯莱英医药集团（天津）股份有限公司 | Borohydride reduction stabilizing system and method for reducing ester to alcohol |
| WO2022082337A1 (en) * | 2020-10-19 | 2022-04-28 | Nikang Therapeutics, Inc. | Process of preparing 3-fluoro-5 ( ( (1r, 2ar) -3, 3, 4, 4-tetrafluoro-1, 2a-dihydroxy-2, 2a, 3, 4-tetrahydro-1h-cyclopenta [cd] inden-7-yl) oxy) benzonitrile |
-
2006
- 2006-06-22 JP JP2006172566A patent/JP2008001631A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020248127A1 (en) * | 2019-06-11 | 2020-12-17 | 凯莱英医药集团（天津）股份有限公司 | Borohydride reduction stabilizing system and method for reducing ester to alcohol |
| US12351544B2 (en) | 2019-06-11 | 2025-07-08 | Asymchem Laboratories (Tianjin) Co., Ltd. | Borohydride reduction stabilizing system and method for reducing ester to alcohol |
| WO2022082337A1 (en) * | 2020-10-19 | 2022-04-28 | Nikang Therapeutics, Inc. | Process of preparing 3-fluoro-5 ( ( (1r, 2ar) -3, 3, 4, 4-tetrafluoro-1, 2a-dihydroxy-2, 2a, 3, 4-tetrahydro-1h-cyclopenta [cd] inden-7-yl) oxy) benzonitrile |
| US11634382B2 (en) | 2020-10-19 | 2023-04-25 | Nikang Therapeutics, Inc. | Process of preparing 3-fluoro-5(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)-oxy)benzonitrile |
| US12435034B2 (en) | 2020-10-19 | 2025-10-07 | Nikang Therapeutics, Inc. | Process of preparing 3-fluoro-5(((1R,2AR)-3,3,4,4-tetrafluoro-1,2A-dihydroxy-2,2A,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)-oxy)benzonitrile |
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