JP6002603B2 - Method for producing high-purity optically active dialkyl ester of tartaric acid - Google Patents
Method for producing high-purity optically active dialkyl ester of tartaric acid Download PDFInfo
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- JP6002603B2 JP6002603B2 JP2013040644A JP2013040644A JP6002603B2 JP 6002603 B2 JP6002603 B2 JP 6002603B2 JP 2013040644 A JP2013040644 A JP 2013040644A JP 2013040644 A JP2013040644 A JP 2013040644A JP 6002603 B2 JP6002603 B2 JP 6002603B2
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- optically active
- tartaric acid
- active tartaric
- acid
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 title claims description 91
- 235000002906 tartaric acid Nutrition 0.000 title claims description 91
- 239000011975 tartaric acid Substances 0.000 title claims description 89
- 150000002148 esters Chemical class 0.000 title claims description 25
- 238000004519 manufacturing process Methods 0.000 title claims description 25
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 104
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 65
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 49
- 238000000746 purification Methods 0.000 claims description 48
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 32
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 31
- 238000005886 esterification reaction Methods 0.000 claims description 31
- 239000001630 malic acid Substances 0.000 claims description 31
- 235000011090 malic acid Nutrition 0.000 claims description 31
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 30
- 239000007788 liquid Substances 0.000 claims description 28
- 239000001530 fumaric acid Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- 230000032050 esterification Effects 0.000 claims description 22
- YSAVZVORKRDODB-UHFFFAOYSA-N Diethyl tartrate Chemical compound CCOC(=O)C(O)C(O)C(=O)OCC YSAVZVORKRDODB-UHFFFAOYSA-N 0.000 claims description 18
- 239000012452 mother liquor Substances 0.000 claims description 18
- 238000000926 separation method Methods 0.000 claims description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- -1 tartrate ester Chemical class 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- 229940095064 tartrate Drugs 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 4
- XLYMOEINVGRTEX-ONEGZZNKSA-N (e)-4-ethoxy-4-oxobut-2-enoic acid Chemical class CCOC(=O)\C=C\C(O)=O XLYMOEINVGRTEX-ONEGZZNKSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- 229960001367 tartaric acid Drugs 0.000 description 69
- 238000006243 chemical reaction Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 229960001270 d- tartaric acid Drugs 0.000 description 11
- 239000012535 impurity Substances 0.000 description 8
- IEPRKVQEAMIZSS-AATRIKPKSA-N diethyl fumarate Chemical compound CCOC(=O)\C=C\C(=O)OCC IEPRKVQEAMIZSS-AATRIKPKSA-N 0.000 description 7
- VKNUORWMCINMRB-UHFFFAOYSA-N diethyl malate Chemical group CCOC(=O)CC(O)C(=O)OCC VKNUORWMCINMRB-UHFFFAOYSA-N 0.000 description 7
- YSAVZVORKRDODB-WDSKDSINSA-N diethyl tartrate Chemical compound CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC YSAVZVORKRDODB-WDSKDSINSA-N 0.000 description 7
- 238000006386 neutralization reaction Methods 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 238000004817 gas chromatography Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- DCEMCPAKSGRHCN-UHFFFAOYSA-N oxirane-2,3-dicarboxylic acid Chemical compound OC(=O)C1OC1C(O)=O DCEMCPAKSGRHCN-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003377 acid catalyst Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000010409 thin film Substances 0.000 description 3
- XXMFJKNOJSDQBM-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;hydrate Chemical compound [OH3+].[O-]C(=O)C(F)(F)F XXMFJKNOJSDQBM-UHFFFAOYSA-N 0.000 description 2
- ZUDZWKJBYZAGBS-UHFFFAOYSA-N 4-ethoxy-2,3-dihydroxy-4-oxobutanoic acid Chemical compound CCOC(=O)C(O)C(O)C(O)=O ZUDZWKJBYZAGBS-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000012159 carrier gas Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000010408 film Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HNNJFUDLLWOVKZ-UHFFFAOYSA-N 2-aminobutanamide Chemical compound CCC(N)C(N)=O HNNJFUDLLWOVKZ-UHFFFAOYSA-N 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- 101150077194 CAP1 gene Proteins 0.000 description 1
- 101100493710 Caenorhabditis elegans bath-40 gene Proteins 0.000 description 1
- 208000006558 Dental Calculus Diseases 0.000 description 1
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 101100245221 Mus musculus Prss8 gene Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- XEBCWEDRGPSHQH-UHFFFAOYSA-N diisopropyl tartrate Chemical compound CC(C)OC(=O)C(O)C(O)C(=O)OC(C)C XEBCWEDRGPSHQH-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000011982 enantioselective catalyst Substances 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 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
- 238000012827 research and development Methods 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 238000001577 simple distillation Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、光学活性酒石酸と脂肪族アルコールを反応させて、高純度光学活性酒石酸ジアルキルエステルを製造する方法に関する。 The present invention relates to a method for producing a highly pure optically active tartaric acid dialkyl ester by reacting optically active tartaric acid with an aliphatic alcohol.
光学活性酒石酸ジアルキルエステルは、多くの医薬品製造に使用される有用な化合物であることが知られている。例えば、不斉触媒としての使用例では、光学活性酒石酸ジエチルエステルあるいは光学活性酒石酸ジイソプロピルエステル触媒の存在下、非対称スルフィドの不斉酸化による光学活性スルホキシドの合成例（非特許文献１、非特許文献２）や光学活性酒石酸ジイソプロピルエステル触媒存在下、アリルアルコールの不斉エポキシ化反応例（非特許文献３）が報告されている。 Optically active tartaric acid dialkyl esters are known to be useful compounds used in many pharmaceutical manufactures. For example, in the use example as an asymmetric catalyst, an optically active sulfoxide is synthesized by asymmetric oxidation of an asymmetric sulfide in the presence of an optically active tartaric acid diethyl ester or optically active diisopropyl ester catalyst (Non-patent Document 1, Non-patent Document 2). ) And an optically active tartaric acid diisopropyl ester catalyst in the presence of an asymmetric epoxidation reaction of allyl alcohol (Non-patent Document 3) has been reported.
酒石酸ジアルキルエステルの製造法は、種々の酸触媒共存下、酒石酸と脂肪族アルコールとのエステル反応が公知である。この反応は平衡反応であるため、副生する水を減圧下、濃縮する方法や、大量の原料アルコールを用いる方法により、平衡を生成物側に片寄らせる事で酒石酸ジアルキルの収率を高める事が出来る。例えば、副生する水をクロロホルムとの共沸脱水により除去する方法（非特許文献４）や酸触媒存在下、オルトギ酸エステルをエステル化剤として使用する方法（非特許文献５）が報告されている。さらに、工業的にも実用的な方法として、酒石酸と低級アルコールに塩化チオニルを添加することにより、アルコール使用量を最小限に抑えて高収率で酒石酸ジアルキルエステルを取得する方法が知られている（特許文献１）。 As a method for producing a tartaric acid dialkyl ester, an ester reaction between tartaric acid and an aliphatic alcohol in the presence of various acid catalysts is known. Since this reaction is an equilibrium reaction, the yield of dialkyl tartrate can be increased by shifting the equilibrium to the product side by concentrating the by-produced water under reduced pressure or by using a large amount of raw alcohol. I can do it. For example, a method of removing by-product water by azeotropic dehydration with chloroform (Non-Patent Document 4) and a method of using orthoformate as an esterifying agent in the presence of an acid catalyst (Non-Patent Document 5) have been reported. Yes. Furthermore, as an industrially practical method, a method of obtaining a tartaric acid dialkyl ester in a high yield by adding thionyl chloride to tartaric acid and lower alcohol and minimizing the amount of alcohol used is known. (Patent Document 1).
しかしながら、原料として使用される酒石酸は多くの方法により製造されている。例えば、Ｌ−酒石酸（天然型）の製造法としては、ワイン製造時に析出する酒石から得る方法やエポキシコハク酸の不斉加水分解が知られている。一方、Ｄ−酒石酸（非天然型）の製造法としては、発酵による方法（特許文献２）、エポキシコハク酸の不斉加水分解（特許文献３）、ラセミ体を２−アミノブタンアミドによりジアステレオマー塩分割する方法（特許文献４）等が公知である。 However, tartaric acid used as a raw material is produced by many methods. For example, as a method for producing L-tartaric acid (natural type), a method obtained from tartar precipitated during wine production and asymmetric hydrolysis of epoxy succinic acid are known. On the other hand, as a method for producing D-tartaric acid (non-natural type), a fermentation method (Patent Document 2), an asymmetric hydrolysis of epoxy succinic acid (Patent Document 3), and a racemate is diastereomerized with 2-aminobutanamide. A method of splitting a Mer salt (Patent Document 4) is known.
光学活性酒石酸ジアルキルエステルを医薬中間体に用いる場合、微量不純物の混入は大きな問題であり、不純物の副生を抑制した効率的な光学活性酒石酸ジアルキルエステルの製造方法の創出が強く求められている。しかしながら、従来技術では、原料に用いる光学活性酒石酸に含まれる有機酸、特にジカルボン酸は、エステル化の際にリンゴ酸ジアルキルエステルやフマル酸ジアルキルエステル等のカルボン酸ジアルキルエステルに誘導化され、目的の光学活性酒石酸ジアルキルエステルから除去することが困難である。近年、安価な中国品を光学活性酒石酸に用いる機会が増え、微量不純物が光学活性酒石酸に混入していることがしばしば見られる。特に、リンゴ酸やフマル酸は光学活性酒石酸中に含まれることが多い。現在までに、０．１％オーダーの微量不純物を含む光学活性酒石酸を使用して、該不純物から誘導される不純物の光学活性酒石酸ジアルキルエステル中への混入量を抑制した製造方法に関する報告例はなく、高純度酒石酸ジアルキルエステルの製造方法の創出が強く望まれてきた。 When optically active dialkyl tartrate is used as a pharmaceutical intermediate, the incorporation of trace impurities is a major problem, and the creation of an efficient method for producing optically active dialkyl tartrate that suppresses by-product impurities is strongly demanded. However, in the prior art, an organic acid contained in the optically active tartaric acid used as a raw material, in particular a dicarboxylic acid, is derivatized into a carboxylic acid dialkyl ester such as malic acid dialkyl ester or fumaric acid dialkyl ester during esterification. It is difficult to remove from optically active dialkyl esters of tartaric acid. In recent years, opportunities to use inexpensive Chinese products for optically active tartaric acid have increased, and it is often seen that trace impurities are mixed in optically active tartaric acid. In particular, malic acid and fumaric acid are often contained in optically active tartaric acid. To date, there has been no report on a production method using optically active tartaric acid containing a trace amount of impurities of the order of 0.1% and suppressing the amount of impurities derived from the impurities in the optically active tartaric acid dialkyl ester. Therefore, creation of a method for producing a high-purity dialkyl ester of tartaric acid has been strongly desired.
本発明の目的は、光学活性酒石酸ジアルキルエステルの製造方法において、高い生産性で、且つ、高純度光学活性酒石酸ジアルキルを製造する方法を提供することにある。 An object of the present invention is to provide a method for producing optically active dialkyl tartrate with high productivity and high purity in a method for producing an optically active dialkyl tartrate.
本発明者等は、前記課題を解決するために鋭意検討を重ねた結果、本発明を見出すに至った。即ち、第１の本発明の高純度光学活性酒石酸ジアルキルエステルの製造方法は、下記の（第一精製工程）、（エステル化工程）を含む酒石酸ジエチルエステルの製造方法であって、下記一般式（２）で表されるリンゴ酸ジエチルエステルの含有量が０．１％以下、且つ下記一般式（３）で表されるフマル酸ジエチルエステルの含有量が０．１％以下であることを特徴とする。
（第一精製工程）：リンゴ酸および／またはフマル酸を０．１％以上含む光学活性酒石酸に、エタノールを添加し、固液二相系で撹拌した後、固液分離により光学活性酒石酸を回収する精製工程
（エステル化工程）：前記第一精製工程で取得した光学活性酒石酸と、エタノールを反応させるエステル化工程
(First purification step): After adding ethanol to optically active tartaric acid containing 0.1% or more of malic acid and / or fumaric acid and stirring in a solid-liquid two-phase system, optically active tartaric acid is recovered by solid-liquid separation. purification step of (esterification step): and the optically active tartaric acid obtained in the first purification step, as the ester modified reacting ethanol
第２の本発明の高純度光学活性酒石酸ジアルキルエステルの製造方法は、下記の（第一精製工程）（第二精製工程）（エステル化工程）を含む酒石酸ジエチルエステルの製造方法であって、前記式（２）で表されるリンゴ酸ジエチルエステルの含有量が０．１％以下、且つ前記式（３）で表されるフマル酸ジエチルエステルの含有量が０．１％以下であることを特徴とする。
（第一精製工程）：０．１％以上のリンゴ酸および／またはフマル酸を含む光学活性酒石酸に、エタノールを添加し、固液二相系で撹拌した後、固液分離により光学活性酒石酸と母液に分離する精製工程
（第二精製工程）：リンゴ酸および／またはフマル酸を０．１％以上含む光学活性酒石酸に、前記第一精製工程で分離した母液を添加し、固液二相系で撹拌した後、固液分離により光学活性酒石酸と母液に分離し、光学活性酒石酸を回収する精製工程
（エステル化工程）：前記第二精製工程で取得した光学活性酒石酸と、エタノールを反応させるエステル化工程
Process for producing a high-purity optically active tartaric acid dialkyl esters of the second invention is a manufacturing method of tartaric diethyl ester containing (first purification step) (Second purification step) (esterification step) below, formula (2) in a content of malic acid di-ethyl ester is 0.1% or less, expressed, and the content of the formula (3) represented by fumarate ethyl ester is less than 0.1% It is characterized by that.
(First purification step): After adding ethanol to optically active tartaric acid containing 0.1% or more of malic acid and / or fumaric acid and stirring in a solid-liquid two-phase system, the optically active tartaric acid is separated by solid-liquid separation. Purification step for separating into mother liquor (second purification step): adding the mother liquor separated in the first purification step to optically active tartaric acid containing 0.1% or more of malic acid and / or fumaric acid, and solid-liquid two-phase system After being stirred in step 2, the optically active tartaric acid and the mother liquor are separated by solid-liquid separation, and the optically active tartaric acid obtained in the second purification step is reacted with ethanol. Process
本発明によれば、光学活性酒石酸にエタノールを添加して固液二相系で撹拌、固液分離して精製した光学活性酒石酸と、エタノールとのエステル化反応を行うようにしたので、リンゴ酸および／またはフマル酸を０．１％以上含む光学活性酒石酸を用いながら、効率的に高純度光学活性酒石酸ジエチルエステルを製造することが出来る。 According to the present invention, since ethanol is added to optically active tartaric acid and stirred in a solid-liquid two-phase system, the optically active tartaric acid purified by solid-liquid separation is subjected to an esterification reaction with ethanol. and / or with an optically active tartaric acid containing 0.1% or more of fumaric acid, can be efficiently producing high-purity optically active tartaric acid di-ethyl ester.
また第２の本発明において、リンゴ酸および／またはフマル酸を０．１％以上含む光学活性酒石酸に、第一精製工程または第二精製工程で分離した母液を添加し、光学活性酒石酸を回収するようにしたので、光学活性酒石酸の回収率をより高くすることができる。さらに精製工程の固液分離により得られる母液は、精製工程に用いる溶媒として複数回使用することができる。 In the second invention, the mother liquor separated in the first purification step or the second purification step is added to the optically active tartaric acid containing 0.1% or more of malic acid and / or fumaric acid, and the optically active tartaric acid is recovered. Since it did in this way, the collection | recovery rate of optically active tartaric acid can be made higher. Furthermore, the mother liquor obtained by solid-liquid separation in the purification process can be used multiple times as a solvent used in the purification process.
前記式（２）で表されるリンゴ酸ジエチルの含有量は０．０５％以下、且つ前記式（３）で表されるフマル酸ジエチルエステルの含有量は０．０５％以下であることが好ましい。 Formula (2) the content of malic acid di ethyl represented 0.05% or less, and said content of fumarate ester represented by the formula (3) is less than 0.05% Is preferred.
前記第一または第二精製工程によって得られた光学活性酒石酸を、乾燥せずにエステル化反応を行うことができる。 The optically active tartaric acid obtained by the first or second purification step can be subjected to an esterification reaction without drying.
前記第一精製工程において、エタノールの使用量は、光学活性酒石酸の使用量に対して０．２〜１．０重量倍にすることが好ましい。 In the first purification step, the amount of ethanol used is preferably 0.2 to 1.0 times the amount of optically active tartaric acid.
前記エステル化工程において、塩化チオニルを用いることが好ましい。 In the esterification step, thionyl chloride is preferably used.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
第１の本発明の高純度光学活性酒石酸ジアルキルエステルの製造方法は、次の２工程、（第一精製工程）および（エステル化工程）を含む。 The method for producing a highly pure optically active tartaric acid dialkyl ester of the first invention includes the following two steps, (first purification step) and (esterification step).
（第一精製工程）：０．１％以上のリンゴ酸、及び／またはフマル酸を含む光学活性酒石酸に、エタノールを添加し、固液二相系で撹拌した後、固液分離により光学活性酒石酸と母液に分離し、光学活性酒石酸を回収する光学活性酒石酸の精製工程、 (First purification step): After adding ethanol to optically active tartaric acid containing at least 0.1% malic acid and / or fumaric acid and stirring in a solid-liquid two-phase system, optically active tartaric acid is obtained by solid-liquid separation. And purification step of optically active tartaric acid, which is separated into mother liquor and recovers optically active tartaric acid ,
（エステル化工程）第一精製工程で取得した光学活性酒石酸と、第一精製工程と同じ種類の脂肪族アルコールを反応させるエステル化工程。 (Esterification step) An esterification step in which the optically active tartaric acid obtained in the first purification step is reacted with the same type of aliphatic alcohol as in the first purification step.
本発明の高純度光学活性酒石酸ジアルキルエステルの製造方法は、下記一般式（２）で表されるリンゴ酸ジエチルエステルの含有量が０．１％以下、且つ下記一般式（３）で表されるフマル酸ジエチルエステルの含有量が０．１％以下である高純度光学活性酒石酸ジエチルエステルを製造することができる。
本発明の製造方法で使用する光学活性酒石酸は、Ｌ体でもＤ体でも良い。また、その光学純度は脂肪族アルコールを用いて精製することを考慮すると、好ましくは９０％ｅｅ以上であり、さらに好ましくは９５％ｅｅ以上である。工業品で入手可能な光学活性酒石酸は９９％ｅｅのものがある。光学活性酒石酸の製造方法も特に限定されない。本発明の製造方法は、リンゴ酸および／またはフマル酸を０．１％以上含む光学活性酒石酸に対して有効である。すなわち、リンゴ酸、フマル酸のいずれか一方を０．１％以上含む酒石酸、並びにリンゴ酸とフマル酸を両方とも０．１％以上含む酒石酸に対して有効である。特に、後者においても本発明の製造方法により、リンゴ酸とフマル酸を効率的に除去することができ、得られる酒石酸ジアルキルエステル中のリンゴ酸ジアルキルエステルおよびフマル酸ジアルキルエステルの含量を０．１％以下に低減することができる。 The optically active tartaric acid used in the production method of the present invention may be L-form or D-form. Moreover, the optical purity is preferably 90% ee or more, more preferably 95% ee or more, in consideration of purification using an aliphatic alcohol. The optically active tartaric acid available as an industrial product is 99% ee. The method for producing optically active tartaric acid is not particularly limited. The production method of the present invention is effective for optically active tartaric acid containing 0.1% or more of malic acid and / or fumaric acid. That is, it is effective for tartaric acid containing 0.1% or more of either malic acid or fumaric acid, and tartaric acid containing 0.1% or more of both malic acid and fumaric acid. Particularly in the latter case, malic acid and fumaric acid can be efficiently removed by the production method of the present invention, and the content of dialkyl malate and dialkyl fumarate in the resulting tartaric acid dialkyl ester is 0.1%. The following can be reduced.
本発明の製造方法では、エタノールを使用する。 In the production method of the present invention , ethanol is used .
第一精製工程では、光学活性酒石酸にエタノールを添加して固液二相系で撹拌する。固液二相系での撹拌により、光学活性酒石酸の回収率を高くすることができる。そのため、エタノールの使用量は、光学活性酒石酸に対して、撹拌可能なスラリーを形成するのに必要な量から、光学活性酒石酸が完全に溶解しない量の範囲となる。例えば、溶媒がエタノールの場合、エタノールは、光学活性酒石酸の重量に対し０．１〜４．０重量倍であり、好ましくは０．１〜２．０重量倍、より好ましくは０．２〜１．０重量倍である。一般に、固液二相系での撹拌は室温〜溶媒の沸点以下で実施するが、固液分離は室温以下まで冷却してから行えば、光学活性酒石酸の回収率を高くするのに有効と言える。 In the first purification step, ethanol is added to optically active tartaric acid and stirred in a solid-liquid two-phase system. The recovery rate of optically active tartaric acid can be increased by stirring in a solid-liquid two-phase system. Therefore, the amount of ethanol used is in the range from the amount necessary to form a stirrable slurry to the optically active tartaric acid, so that the optically active tartaric acid is not completely dissolved. For example, when the solvent is ethanol, the ethanol is 0.1 to 4.0 times by weight, preferably 0.1 to 2.0 times by weight, more preferably 0.2 to 1 times the weight of the optically active tartaric acid. 0.0 weight times. In general, stirring in a solid-liquid two-phase system is carried out at room temperature to the boiling point of the solvent, but solid-liquid separation can be said to be effective for increasing the recovery rate of optically active tartaric acid after cooling to room temperature or lower. .
第一精製工程によって回収された光学活性酒石酸は、次にエステル化工程でエステル化される。このとき回収された光学活性酒石酸は、乾燥せずにエステル化反応を行うことができる。これにより作業を省略し生産日数を短縮することができる。 The optically active tartaric acid recovered by the first purification step is then esterified in the esterification step. The optically active tartaric acid recovered at this time can be esterified without drying. Thereby, work can be omitted and the number of production days can be shortened.
エステル化工程では、第一精製工程で取得した光学活性酒石酸と、エタノールを反応させ、光学活性酒石酸をエステル化する。エタノールを第一精製工程とエステル化工程で使用する理由としては、目的とする光学活性酒石酸ジエチルエステル（エステル化工程生成物）に微量不純物が混入するのを抑制するためである。 In the esterification step, the optically active tartaric acid obtained in the first purification step is reacted with ethanol to esterify the optically active tartaric acid. Ethanol as a reason to use in the first purification step and an esterification step, in order to prevent the trace impurities are mixed into the optically active tartaric acid di-ethyl ester (esterification step) A mixture of interest.
光学活性酒石酸とエタノールのエステル化は酸触媒を用いて行うと、反応が効率的に進行する。例えば、濃塩酸、塩化水素、硫酸等のブレンステッド酸や、塩化鉄、塩化アルミニウム、ホウ酸等のルイス酸を挙げることができるが、好ましくは濃塩酸、塩化水素、硫酸である。 When esterification of optically active tartaric acid and ethanol is carried out using an acid catalyst, the reaction proceeds efficiently. Examples thereof include Bronsted acids such as concentrated hydrochloric acid, hydrogen chloride, and sulfuric acid, and Lewis acids such as iron chloride, aluminum chloride, and boric acid, and concentrated hydrochloric acid, hydrogen chloride, and sulfuric acid are preferred.
エステル化工程において、エタノールの使用量に特に制限はなく、多いほど反応が進み易くて良いが、原料費が高くなり経済性の面では好ましくない。エステル化のためのエタノールの使用量は、具体的には、光学活性酒石酸のモル量に対して１〜５モル倍が良く、好ましくは１〜４モル倍であり、さらに好ましくは１〜２モル倍である。光学活性酒石酸の溶解度を考慮して、エタノールを化学両論量である２モル倍より多く使用するのが好ましいが、安価な工業的製造方法としては、化学両論量である２モル倍で反応させることが良い。この場合、反応液の粘性を考慮して、光学活性酒石酸は一度に添加するよりも、２回以上に分割して系内のスラリー濃度を２０〜３０重量％にするのが撹拌の安定性や設備の負荷を考慮すると好ましい。 In the esterification step, the amount of ethanol used is not particularly limited, and the more the reaction, the easier the reaction proceeds. However, the raw material cost increases, which is not preferable in terms of economy. Specifically, the amount of ethanol used for esterification is preferably 1 to 5 times, preferably 1 to 4 times, more preferably 1 to 2 times the molar amount of optically active tartaric acid. Is double. In consideration of the solubility of optically active tartaric acid, it is preferable to use ethanol in an amount of more than 2 moles, which is a stoichiometric amount. However, as an inexpensive industrial production method, the reaction is carried out in 2 mole times, which is a stoichiometric amount. Is good. In this case, considering the viscosity of the reaction solution, the optically active tartaric acid is divided into two or more times so that the slurry concentration in the system is 20 to 30% by weight, rather than being added all at once. It is preferable in view of the load on the equipment.
反応温度は、室温〜エタノールの沸点以下であることが好ましく、減圧下で行うこともできる。この場合、熱による不純化、例えば、酒石酸ジエチルエステルの二量体を抑制するのに有効である。反応をより完結させるためには、このエステル化反応を２回以上繰り返し実施するもできるし、少量の塩化チオニルを添加すると反応を完結させることもできる。塩化チオニルの添加は、エステル化反応液中の水分を除去することにより、水分率が１．０重量％以下である状態で添加するとよく、塩化チオニルが水により無駄に分解することが少なくなる。 The reaction temperature is preferably room temperature to the boiling point of ethanol or lower, and can also be performed under reduced pressure. In this case, adulteration by heat, for example, is effective in inhibiting dimer of tartaric diethyl ester. In order to complete the reaction, this esterification reaction can be repeated twice or more, or the reaction can be completed by adding a small amount of thionyl chloride. Thionyl chloride may be added in a state where the water content is 1.0% by weight or less by removing water in the esterification reaction solution, and thionyl chloride is less likely to be decomposed by water.
また、第２の本発明の製造方法において、リンゴ酸および／またはフマル酸を０．１％以上含む光学活性酒石酸に、上述した第一精製工程で固液分離した母液を添加し、固液二相系で撹拌することにより、リンゴ酸およびフマル酸を除去する。第一精製工程の固液分離で光学活性酒石酸を除去した母液中にも溶解度分の光学活性酒石酸が存在する。その母液に、新たに光学活性酒石酸を添加し、固液二相系で撹拌した後、固液分離すれば、光学活性酒石酸を回収率９０％以上で効率的に回収することが可能である。この母液を使用したリンゴ酸およびフマル酸の除去および光学活性酒石酸の回収を行う操作は繰り返し実施することも可能である。 In the production method of the second invention, the mother liquor separated in the first purification step is added to the optically active tartaric acid containing 0.1% or more of malic acid and / or fumaric acid. Malic acid and fumaric acid are removed by stirring in the phase system. Optically active tartaric acid corresponding to the solubility is also present in the mother liquor from which optically active tartaric acid has been removed by solid-liquid separation in the first purification step. If optically active tartaric acid is newly added to the mother liquor, stirred in a solid-liquid two-phase system, and solid-liquid separated, the optically active tartaric acid can be efficiently recovered at a recovery rate of 90% or more. The operations of removing malic acid and fumaric acid and recovering optically active tartaric acid using this mother liquor can be repeated.
エステル化反応液には副生した塩化水素や亜硫酸ガスが溶存しており、中和後、濃縮するのが良い。一般に、中和は、得られた酒石酸ジエチルエステルの加水分解が起こらない様にアルカリ金属の重炭酸塩を用いることができる。アルカリ金属の重炭酸塩としては、好ましくは、炭酸水素ナトリウムや炭酸水素カリウムであり、また水溶液ではなく固体状、好ましくは粉末状のものを用いるのが好ましい。アルカリ金属の重炭酸塩の水溶液を用いると、トルエン等の有機溶媒を用いた抽出により酒石酸ジエチルエステルを回収する必要が生じ、有機溶媒由来の不純物が製品に混入するリスクがある。アルカリ金属の重炭酸塩の使用量は、エステル化工程で仕込んだ酒石酸使用量に対して０．０５〜０．３モル倍が好ましく、より好ましくは０．０５〜０．２モル倍である。中和に要する時間は５〜７２時間が好ましく、より好ましくは１０〜５０時間であり、さらに好ましくは２０〜４０時間である。中和は、副生した塩化水素や亜硫酸ガスの中和に加え、酒石酸モノエチルエステルを中和して酒石酸モノエチルエステルのナトリウム塩に変換し、結晶にするために重要な工程である。中和後、濾過や遠心分離などの方法により、中和で生じた食塩や過剰な塩基性化合物を除くことが出来る。得られた濾液を濃縮してエタノールを除き、さらに蒸留により、高純度酒石酸ジエチルエステルを得ることが出来る。蒸留の方法は、単蒸留でも薄膜蒸留でも構わないが、熱による不純化を抑制するには、薄膜蒸留が好ましく用いられる。蒸留温度は、品質への影響を考慮すると、低温の方が好ましく、通常、減圧下で実施される。 By-product hydrogen chloride and sulfurous acid gas are dissolved in the esterification reaction solution, and it is better to concentrate after neutralization. In general, neutralization can be used alkali metal bicarbonates as hydrolysis of tartaric diethyl ester does not occur was obtained. The alkali metal bicarbonate is preferably sodium hydrogen carbonate or potassium hydrogen carbonate, and it is preferable to use a solid, preferably powdered, not an aqueous solution. Using an aqueous solution of an alkali metal bicarbonate, extracted with it is necessary to recover the tartaric acid di-ethyl ester using an organic solvent such as toluene, with the risk of impurities derived from the organic solvent is mixed into the product. The amount of alkali metal bicarbonate used is preferably 0.05 to 0.3 mol times, more preferably 0.05 to 0.2 mol times the amount of tartaric acid used in the esterification step. The time required for neutralization is preferably 5 to 72 hours, more preferably 10 to 50 hours, and still more preferably 20 to 40 hours. Neutralization, in addition to the neutralization of by-product hydrogen chloride and sulfur dioxide, by neutralizing the tartrate monoethyl ester was converted to the sodium salt of tartaric acid monoethyl ester, is an important step for the crystal. After neutralization, the salt and excess basic compound produced by neutralization can be removed by methods such as filtration and centrifugation. The resulting filtrate was concentrated remove ethanol, by further distillation, can be obtained high purity tartaric diethyl ester. The distillation method may be simple distillation or thin film distillation, but thin film distillation is preferably used in order to suppress the impureness due to heat. The distillation temperature is preferably lower when the influence on quality is taken into consideration, and it is usually carried out under reduced pressure.
以上の方法により得られる光学活性酒石酸ジエチルエステルは、下記一般式（２）で表されるリンゴ酸ジエチルエステルの含有量が０．１％以下であり、好ましくは０．０５％以下である。
また、本発明によって得られる酒石酸ジエチルエステルは、下記一般式（３）で表されるフマル酸ジエチルエステルの含有量が０．１％以下であり、好ましくは０．０５％以下である。
以下、実施例により本発明をさらに詳細に説明するが、本発明はこれに限定されるものではない。ここでは、酒石酸ジエチルエステルの合成に関する結果を挙げて記載する。分析法は以下の通りである。光学活性酒石酸ジエチルエステル、フマル酸ジエチルエステルの含有量は、分析法は高速液体クロマトグラフィー（ＨＰＬＣ）により、ＨＰＬＣにおける面積％として分析した。また、リンゴ酸ジエチルエステルは、高速液体クロマトグラフィー（ＨＰＬＣ）では酒石酸ジエチルエステル中の副生物とピークが重なるため、ガスクロマトグラフィー（ＧＣ）により分析した。 EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to this. Here, the results relating to the synthesis of diethyl tartrate are listed. The analysis method is as follows. The contents of optically active tartaric acid diethyl ester and fumaric acid diethyl ester were analyzed by high performance liquid chromatography (HPLC) as an area% in HPLC. Further, malic acid diethyl ester was analyzed by gas chromatography (GC) because high-performance liquid chromatography (HPLC) overlapped with a by-product in the tartaric acid diethyl ester.
（光学活性酒石酸ジエチルエステル、フマル酸ジエチルエステルの分析法）
分析装置 ＨＰＬＣ
カラム Ｚｏｒｂａｘ Ｃ８、４．６ｍｍφ×１５０ｍｍ
恒温槽 ４０℃
検出器 ＵＶ（２１２ｎｍ）
流量 １．５ｍｌ／分
移動相 Ａ／Ｂ＝１００／０（０〜４分）→０／１００（２５〜３５分）
Ａ：アセトニトリル／水／１％トリフルオロ酢酸水＝５／９４／１
Ｂ：アセトニトリル／水／１％トリフルオロ酢酸水＝９０／９／１
(Analytical method of optically active tartaric acid diethyl ester and fumaric acid diethyl ester)
Analyzer HPLC
Column Zorbax C8, 4.6mmφ × 150mm
Constant temperature bath 40 ℃
Detector UV (212nm)
Flow rate 1.5 ml / min Mobile phase A / B = 100/0 (0-4 minutes) → 0/100 (25-35 minutes)
A: Acetonitrile / water / 1% trifluoroacetic acid water = 5/94/1
B: Acetonitrile / water / 1% trifluoroacetic acid water = 90/9/1
（リンゴ酸ジエチルエステルの分析法）
分析装置 ＧＣ
カラム Ｉｎｅｒｔ Ｃａｐ１、０．２５ｍｍφ×６０ｍ、膜厚０．４０μｍ
キャリアガス Ｈｅ（６０ｋＰａ）
分析温度 １００℃（２分）→５℃／分昇温→２５０℃（８分）
注入口温度 ２５０℃
検出器 ＦＩＤ（２５０℃）
(Analytical method for malic acid diethyl ester)
Analyzer GC
Column Inert Cap1, 0.25 mmφ × 60 m, film thickness 0.40 μm
Carrier gas He (60kPa)
Analysis temperature 100 ° C. (2 minutes) → 5 ° C./minute temperature increase → 250 ° C. (8 minutes)
Inlet temperature 250 ℃
Detector FID (250 ° C)
（酒石酸ジエチルエステルの光学純度分析法）
分析装置 ＧＣ
カラム Ｃｈｒｏｍｐａｃｋ ＣＰ−Ｃｈｉｒａｌｓｉｌ−ＤＥＸ ＣＢ
０．３２ｍｍφ×２５ｍ、膜厚０．２５μｍ
キャリアガス Ｈｅ（６０ｋＰａ）
分析温度 １５０℃
注入口温度 ２００℃
検出器 ＦＩＤ（３００℃）
(Optical purity analysis of tartaric acid diethyl ester)
Analyzer GC
Column Chrompack CP-Chiralsil-DEX CB
0.32mmφ × 25m, film thickness 0.25μm
Carrier gas He (60kPa)
Analysis temperature 150 ° C
Inlet temperature 200 ° C
Detector FID (300 ° C)
実施例１
温度計、攪拌機を装着したフラスコに、Ｄ−酒石酸（リンゴ酸０．２０％、フマル酸０．０７％）６０．０ｇとエタノール３６．０ｇを仕込み、１０℃で２時間撹拌した後、濾過によりＤ−酒石酸４８．１ｇを回収した［第一精製工程］。このＤ−酒石酸を乾燥せずに、エタノール２８．８ｇを添加し、３５％塩酸１．９ｇを加え、８０℃で反応させる。次に、７０℃以下で濃縮し、先と同量のエタノールと３５％塩酸を加えて反応後、同様に濃縮する。エタノールを添加し撹拌した後、塩化チオニル１１．４ｇを加えて３０〜４０℃で反応させた[エステル化工程]。濃縮後、炭酸水素ナトリウムで中和後、濾過して得られた濾液を濃縮した（Ｄ−酒石酸ジエチルエステル反応収率９７％）。最後に、減圧下、薄膜蒸留（熱媒温度１４５℃）により単離したＤ−酒石酸ジエチルエステルの光学純度は９９．８％ｅｅ、リンゴ酸ジエチルエステル及びフマル酸ジエチルエステルの含有量は、いずれも０．０１％未満であった。
Example 1
A flask equipped with a thermometer and a stirrer was charged with 60.0 g of D-tartaric acid (malic acid 0.20%, fumaric acid 0.07%) and ethanol 36.0 g, stirred at 10 ° C for 2 hours, and then filtered. 48.1 g of D-tartaric acid was recovered [first purification step]. Without drying this D-tartaric acid, 28.8 g of ethanol is added, and 1.9 g of 35% hydrochloric acid is added and reacted at 80 ° C. Next, the mixture is concentrated at 70 ° C. or less, and after adding the same amount of ethanol and 35% hydrochloric acid as above, the reaction is concentrated in the same manner. After adding ethanol and stirring, 11.4 g of thionyl chloride was added and reacted at 30 to 40 ° C. [esterification step]. After concentration, the filtrate obtained by filtering after neutralizing with sodium bicarbonate was concentrated (D-tartaric acid diethyl ester reaction yield 97%). Finally, the optical purity of D-tartaric acid diethyl ester isolated by thin-film distillation under reduced pressure (heating medium temperature 145 ° C.) is 99.8% ee, and the contents of malic acid diethyl ester and fumaric acid diethyl ester are all It was less than 0.01%.
実施例２
実施例１の［第一精製工程］の固液分離で発生した母液に、Ｄ−酒石酸（リンゴ酸０．２０％、フマル酸０．０７％）６０．０ｇを加え、実施例１と同様の方法により、Ｄ−酒石酸５５．３ｇを回収した［第二精製工程］。さらに、この［第二精製工程］の操作で発生した母液にＤ−酒石酸６０．０ｇを添加し、同様の、洗浄、固液分離によりＤ−酒石酸５６．１ｇを回収した。その後、実施例１と同様のエステル化反応によってＤ−酒石酸ジエチルエステルを単離した。その光学純度は９９．８％ｅｅ、リンゴ酸ジエチルエステル及びフマル酸ジエチルエステルの含有量は、それぞれ０．０３％、及び０．０１％未満であった。
Example 2
60.0 g of D-tartaric acid (malic acid 0.20%, fumaric acid 0.07%) was added to the mother liquor generated in the solid-liquid separation in [First purification step] of Example 1, and the same as in Example 1 By the method, 55.3 g of D-tartaric acid was recovered [second purification step]. Furthermore, 60.0 g of D-tartaric acid was added to the mother liquor generated by the operation of [Second Purification Step], and 56.1 g of D-tartaric acid was recovered by the same washing and solid-liquid separation. Thereafter, D-tartaric acid diethyl ester was isolated by the same esterification reaction as in Example 1. Its optical purity was 99.8% ee, and the contents of malic acid diethyl ester and fumaric acid diethyl ester were 0.03% and less than 0.01%, respectively.
実施例３
Ｄ−酒石酸（リンゴ酸０．１０％、フマル酸０．１７％）を、実施例１と同様の方法により精製、反応および単離して得られたＤ−酒石酸ジエチルエステルの光学純度は９９．８％ｅｅ、リンゴ酸ジエチルエステル及びフマル酸ジエチルエステルの含有量は、それぞれ０．０１％未満、及び０．０２％であった。
Example 3
The optical purity of D-tartaric acid diethyl ester obtained by purifying, reacting and isolating D-tartaric acid (malic acid 0.10%, fumaric acid 0.17%) in the same manner as in Example 1 was 99.8. The contents of% ee, malic acid diethyl ester and fumaric acid diethyl ester were less than 0.01% and 0.02%, respectively.
比較例１
Ｄ−酒石酸（リンゴ酸０．２０％、フマル酸０．０７％）を精製することなしに、実施例１と同様の方法によりエステル化反応を行い、単離したＤ−酒石酸ジエチルエステルの光学純度は９９．８％ｅｅ、リンゴ酸ジエチルエステル及びフマル酸ジエチルエステルの含有量は、それぞれ０．２６％、及び０．０９％であった。
Comparative Example 1
Optical purity of D-tartaric acid diethyl ester isolated by conducting esterification reaction in the same manner as in Example 1 without purifying D-tartaric acid (malic acid 0.20%, fumaric acid 0.07%). Was 99.8% ee, and the contents of malic acid diethyl ester and fumaric acid diethyl ester were 0.26% and 0.09%, respectively.
比較例２
Ｄ−酒石酸（リンゴ酸０．１０％、フマル酸０．１７％）を精製することなしに、実施例１と同様の方法によりエステル化反応を行い、単離したＤ−酒石酸ジエチルエステルの光学純度は９９．８％ｅｅ、リンゴ酸ジエチルエステル及びフマル酸ジエチルエステルの含有量は、それぞれ０．１２％、及び０．１７％であった。
Comparative Example 2
Optical purity of D-tartaric acid diethyl ester isolated by conducting esterification reaction in the same manner as in Example 1 without purifying D-tartaric acid (malic acid 0.10%, fumaric acid 0.17%). Was 99.8% ee, and the contents of malic acid diethyl ester and fumaric acid diethyl ester were 0.12% and 0.17%, respectively.
Claims (7)
（第一精製工程）：リンゴ酸および／またはフマル酸を０．１％以上含む光学活性酒石酸に、エタノールを添加し、固液二相系で撹拌した後、固液分離により光学活性酒石酸と母液に分離し、光学活性酒石酸を回収する精製工程
（エステル化工程）：前記第一精製工程で取得した光学活性酒石酸と、エタノールを反応させるエステル化工程
(First purification step): After adding ethanol to optically active tartaric acid containing 0.1% or more of malic acid and / or fumaric acid and stirring in a solid-liquid two-phase system, optically active tartaric acid and mother liquor are separated by solid-liquid separation. separating the purification step to recover the optically active tartaric acid (esterification step): and the optically active tartaric acid obtained in the first purification step, as the ester modified reacting ethanol
（第一精製工程）：０．１％以上のリンゴ酸および／またはフマル酸を含む光学活性酒石酸に、エタノールを添加し、固液二相系で撹拌した後、固液分離により光学活性酒石酸と母液に分離する精製工程
（第二精製工程）：リンゴ酸および／またはフマル酸を０．１％以上含む光学活性酒石酸に、前記第一精製工程で分離した母液を添加し、固液二相系で撹拌した後、固液分離により光学活性酒石酸と母液に分離し、光学活性酒石酸を回収する精製工程
（エステル化工程）：前記第二精製工程で取得した光学活性酒石酸と、エタノールを反応させるエステル化工程
(First purification step): After adding ethanol to optically active tartaric acid containing 0.1% or more of malic acid and / or fumaric acid and stirring in a solid-liquid two-phase system, the optically active tartaric acid is separated by solid-liquid separation. Purification step for separating into mother liquor (second purification step): adding the mother liquor separated in the first purification step to optically active tartaric acid containing 0.1% or more of malic acid and / or fumaric acid, and solid-liquid two-phase system After being stirred in step 2, the optically active tartaric acid and the mother liquor are separated by solid-liquid separation, and the optically active tartaric acid obtained in the second purification step is reacted with ethanol. as the Chemical
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