JP6029729B2 - Method for the synthesis of Na-beta-alaninate and calcium pantothenate - Google Patents
Method for the synthesis of Na-beta-alaninate and calcium pantothenate Download PDFInfo
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- 238000000034 method Methods 0.000 title description 29
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 title description 20
- 229960002079 calcium pantothenate Drugs 0.000 title description 5
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 95
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- 229940000635 beta-alanine Drugs 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 15
- AGSPXMVUFBBBMO-UHFFFAOYSA-N beta-aminopropionitrile Chemical compound NCCC#N AGSPXMVUFBBBMO-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229940115458 pantolactone Drugs 0.000 claims description 8
- 239000011713 pantothenic acid Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229940014662 pantothenate Drugs 0.000 claims 4
- 239000000243 solution Substances 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000010409 thin film Substances 0.000 description 24
- 239000011552 falling film Substances 0.000 description 16
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 15
- 239000011575 calcium Substances 0.000 description 15
- 229910052791 calcium Inorganic materials 0.000 description 15
- QKJPFZCCZMBRFB-UHFFFAOYSA-M sodium;3-aminopropanoate Chemical compound [Na+].NCCC([O-])=O QKJPFZCCZMBRFB-UHFFFAOYSA-M 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 14
- 238000004090 dissolution Methods 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 238000006386 neutralization reaction Methods 0.000 description 9
- GQTHJBOWLPZUOI-FJXQXJEOSA-M sodium D-pantothenate Chemical compound [Na+].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O GQTHJBOWLPZUOI-FJXQXJEOSA-M 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000005342 ion exchange Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 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 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229910001220 stainless steel Inorganic materials 0.000 description 6
- 239000010935 stainless steel Substances 0.000 description 6
- OTOIIPJYVQJATP-BYPYZUCNSA-M (R)-pantoate Chemical compound OCC(C)(C)[C@@H](O)C([O-])=O OTOIIPJYVQJATP-BYPYZUCNSA-M 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 235000019188 sodium D-pantothenate Nutrition 0.000 description 5
- 239000011756 sodium D-pantothenate Substances 0.000 description 5
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 4
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 229940068459 sodium pantothenate Drugs 0.000 description 4
- SERHXTVXHNVDKA-SCSAIBSYSA-N (3s)-3-hydroxy-4,4-dimethyloxolan-2-one Chemical compound CC1(C)COC(=O)[C@H]1O SERHXTVXHNVDKA-SCSAIBSYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000010408 film Substances 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 230000003134 recirculating effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- TXPKUUXHNFRBPS-UHFFFAOYSA-N 3-(2-carboxyethylamino)propanoic acid Chemical compound OC(=O)CCNCCC(O)=O TXPKUUXHNFRBPS-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012527 feed solution Substances 0.000 description 2
- SERHXTVXHNVDKA-UHFFFAOYSA-N pantolactone Chemical compound CC1(C)COC(=O)C1O SERHXTVXHNVDKA-UHFFFAOYSA-N 0.000 description 2
- GHOKWGTUZJEAQD-UHFFFAOYSA-N pantothenic acid Chemical compound OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 1
- -1 2,4-dihydroxy-3,3-dimethylbutyryl Chemical group 0.000 description 1
- DWCSTCCKNZMDHA-UHFFFAOYSA-N 3-(3-aminopropanoylamino)propanoic acid Chemical compound NCCC(=O)NCCC(O)=O DWCSTCCKNZMDHA-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-M alaninate Chemical compound CC(N)C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-M 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- UCMIRNVEIXFBKS-UHFFFAOYSA-M beta-alaninate Chemical compound NCCC([O-])=O UCMIRNVEIXFBKS-UHFFFAOYSA-M 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910001410 inorganic ion Inorganic materials 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000010309 melting process Methods 0.000 description 1
- SIEVQTNTRMBCHO-UHFFFAOYSA-N pantolactone Natural products CC1(C)OC(=O)CC1O SIEVQTNTRMBCHO-UHFFFAOYSA-N 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/26—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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Description
本発明は、β−アミノ−プロピオニトリルからNa−β−アラニネートを製造する方法に関する。 The present invention relates to a process for producing Na-β-alaninate from β-amino-propionitrile.
Na−β−アラニネートは、アラニネートをL−またはDL−パントラクトンと反応させることによってそれぞれNa−またはCa−D−またはDL−パントテネートを製造する際の中間体である。 Na-β-alaninate is an intermediate in the production of Na- or Ca-D- or DL-pantothenate by reacting alaninate with L- or DL-pantolactone, respectively.
米国特許第4,258,210号明細書には、ベータ−アミノプロピオニトリルから結晶性ナトリウムD−パントテネートを製造する方法が記載されている。その方法では、ベータ−アミノプロピオニトリルを水酸化ナトリウム水溶液により鹸化してナトリウムベータ−アラニネート溶液を生成させ、二段乾燥法により水分含量1%の乾燥ナトリウムベータ−アラニネートを得、その乾燥ナトリウムベータ−アラニネートを低級アルカノール溶媒に溶解し、L−パントラクトンと反応させて結晶性ナトリウムD−パントテネートを得る。しかしながら、ヒトが消費するのに適した純度のナトリウムD−パントテネートを得るには、さらなる結晶化が必要であることが判明している。 U.S. Pat. No. 4,258,210 describes a process for producing crystalline sodium D-pantothenate from beta-aminopropionitrile. In that method, beta-aminopropionitrile is saponified with an aqueous sodium hydroxide solution to form a sodium beta-alaninate solution, and dried sodium beta-alaninate having a moisture content of 1% is obtained by a two-stage drying method. -Alaninate is dissolved in a lower alkanol solvent and reacted with L-pantolactone to give crystalline sodium D-pantothenate. However, it has been found that further crystallization is necessary to obtain a sodium D-pantothenate of a purity suitable for human consumption.
従来法のナトリウムベータ−アラニネートに含まれる主な不純物は、無機イオンは別にして、ベータ−アミノプロピオニトリルの水酸化ナトリウム水溶液による鹸化の際に生じるもの、すなわち、ナトリウム塩の形態のジ−(2−カルボキシエチル)−アミン(イミノ−ジ−プロピオン酸(IDPA)とも称する)およびベータ−アラニル−ベータ−アラニン(それぞれ、IおよびII)である。アミンIはパントラクトンと反応しないが、ジペプチドIIはL−パントラクトンと反応してD(+)−N−(2,4−ジヒドロキシ−3,3−ジメチルブチリル)−β−アラニル−β−アラニン(III)を生成する。 The main impurities contained in the conventional sodium beta-alaninate are, apart from inorganic ions, the ones produced during the saponification of beta-aminopropionitrile with an aqueous sodium hydroxide solution, i.e. di- (2-carboxyethyl) -amine (also referred to as imino-di-propionic acid (IDPA)) and beta-alanyl-beta-alanine (I and II, respectively). Amine I does not react with pantolactone, whereas dipeptide II reacts with L-pantolactone to react with D (+)-N- (2,4-dihydroxy-3,3-dimethylbutyryl) -β-alanyl-β-. Alanine (III) is produced.
ヒトが消費するための高純度のD−カルシウムパントテネートの需要が増加していることを考慮すれば、上記方法をさらに改良するニーズ、および、非常に経済的な、すなわち、さらなる結晶化を行う必要がなく、収率の高い高純度結晶質ナトリウムおよびカルシウムD−パントテネート合成法を開発するニーズが存在する。 Given the increasing demand for high purity D-calcium pantothenate for human consumption, there is a need to further improve the method and a very economical, ie further crystallization. There is a need to develop a high purity, high purity crystalline sodium and calcium D-pantothenate synthesis method that does not need to be performed.
したがって、本発明は、R−パントラクトンと縮合させてD−パントテネートを得るのにそのまま使用できるNa−β−アラニネートを、β−アミノ−プロピオニトリルから製造する改良された方法であって、アルコール溶液としてNa−β−アラニネートを得る工程の改良が、
(a)アルカリ性水性媒体またはアルコール/水混合物中で、β−アミノ−プロピオニトリルを加水分解し、その後、
(b)最終のβ−アラニネート混合物に含まれる副生物の量がD−パントテネートの品質に悪影響を及ぼすことのない量となる方法で、溶媒をアルコールに交換すること
を含む方法に関する。鹸化は、水、または水と1種もしくは複数のアルコールとの混合物中で行うことができる。必要ならば、添加溶剤を使用するもしくは使用しない蒸留をそれ自体知られた方法で行うことによって、水を除去することができる。「交換」という用語は、元の1種もしくは複数の溶媒の一部または全部を除去することを含むものとする。これは、L−パントラクトンと直接反応させて高純度のナトリウムD−パントテネート(これも、また、カルシウムD−パントテネートに変換することができ、後者はヒト用食品での使用、または医薬品としての使用における仕様要求を満たす)を得ることができるナトリウムベータ−アラニネートのアルコール溶液が最終的に得られること意味する。これは、より具体的には、例えばカルシウムパントエートの含量が0.80%(w/w)未満で、かつカルシウムパント−β−アラニル−β−アラニネート(IIIのカルシウム塩)の含量が0.10%(w/w)未満であることを意味する。
Accordingly, the present invention is an improved process for producing Na-β-alaninate from β-amino-propionitrile, which can be used as such to condense with R-pantolactone to give D-pantothenate, comprising the steps of: An improvement in the process of obtaining Na-β-alaninate as a solution is
(A) hydrolyzing β-amino-propionitrile in an alkaline aqueous medium or alcohol / water mixture;
(B) relates to a process comprising replacing the solvent with alcohol in such a way that the amount of by-products contained in the final β-alaninate salt is such that it does not adversely affect the quality of D-pantothenate. Saponification can be carried out in water or a mixture of water and one or more alcohols. If necessary, water can be removed by distillation in a manner known per se, with or without added solvents. The term “exchange” is intended to include removing some or all of the original solvent or solvents. This can be directly reacted with L-pantolactone to convert to high purity sodium D-pantothenate (which can also be converted to calcium D-pantothenate, the latter being used in human food or as a pharmaceutical product. This means that an alcohol solution of sodium beta-alaninate can be finally obtained. More specifically, for example, the content of calcium pantoate is less than 0.80% (w / w) and the content of calcium panto-β-alanyl-β-alaninate (the calcium salt of III) is 0.00. It means less than 10% (w / w).
より具体的には、本発明の改良方法は、
(a)β−アミノ−プロピオニトリルを過剰の水酸化ナトリウム水溶液またはアルコール/水溶液に60〜95℃の温度で加え、必要ならばその混合物をさらに加熱し、水を除去する工程;
(b)過剰の水酸化ナトリウムをβ−アラニンにより、β−アラニンが過剰になるのを避けつつ、中和して、所望の濃度の溶液を直接得る工程;
(c)水を除去する工程、および
(d)ナトリウム−β−アラニネートをC1〜8−アルコールに溶解して、所望の濃度のナトリウム−β−アラニネートアルコール溶液を得る工程
を含む。
More specifically, the improved method of the present invention comprises:
(A) adding β-amino-propionitrile to excess aqueous sodium hydroxide or alcohol / water solution at a temperature of 60-95 ° C. and further heating the mixture if necessary to remove water;
(B) neutralizing excess sodium hydroxide with β-alanine while avoiding excess β-alanine to directly obtain a solution with a desired concentration;
(C) removing water, and (d) dissolving sodium-β-alaninate in C 1-8 -alcohol to obtain a desired concentration of sodium-β-alaninate alcohol solution.
β−アミノ−プロピオニトリルは、攪拌しながら、過剰の水酸化ナトリウム水溶液(例えば、約33w/w%溶液)に添加することが有利である。β−アミノ−プロピオニトリルを添加する好ましい温度範囲は、90〜95℃である。生成するアンモニアは、鉱酸水溶液により外部スクラバー中に公知の方法で吸収させることができる。 The β-amino-propionitrile is advantageously added to an excess of aqueous sodium hydroxide (eg, about 33 w / w% solution) with stirring. A preferred temperature range for adding β-amino-propionitrile is 90-95 ° C. The produced ammonia can be absorbed into the external scrubber with a mineral acid aqueous solution by a known method.
β−アミノ−プロピオニトリルと水酸化ナトリウムの好ましいモル量は、1:1.01〜10の範囲であり、より好ましくは1:1.01〜2.0、最も好ましくは1:1.03〜1.1の範囲である。反応終了後、反応混合物をさらに加熱、例えば、還流させて、水の少なくとも一部を蒸留により除去してもよい。この操作中に内部温度は上昇するであろう。反応は、必要ならば不活性ガス雰囲気中、大気圧下、または加圧下で行ってもよい。 The preferred molar amount of β-amino-propionitrile and sodium hydroxide is in the range of 1: 1.01 to 10, more preferably 1: 1.01 to 2.0, most preferably 1: 1.03. It is the range of -1.1. After completion of the reaction, the reaction mixture may be further heated, eg, refluxed, and at least a portion of the water may be removed by distillation. The internal temperature will rise during this operation. If necessary, the reaction may be performed in an inert gas atmosphere, under atmospheric pressure, or under pressure.
残った反応混合物中の過剰な水酸化ナトリウムをβ−アラニンにより中和する。従来技術の方法では、このβ−アラニンを購入していた。しかしながら、本発明では、工程(b)の過剰な水酸化ナトリウムの中和に用いるβ−アラニンを、本方法それ自体の中で、本発明の工程(a)で得られたナトリウムβ−アラニネートの一部をイオン交換することにより得る。この副工程により、経済性の面でプロセス全体がより魅力的になる。多くの適切なイオン交換樹脂が商業的に入手でき、この目的のために使用することができる。 Excess sodium hydroxide in the remaining reaction mixture is neutralized with β-alanine. In the prior art method, this β-alanine was purchased. However, in the present invention, β-alanine used for neutralization of excess sodium hydroxide in step (b) is used in the process itself of the sodium β-alaninate obtained in step (a) of the present invention. Part is obtained by ion exchange. This sub-process makes the entire process more attractive in terms of economy. Many suitable ion exchange resins are commercially available and can be used for this purpose.
適当な寸法のカラム中で、樹脂にβ−アラニネートを通液し、脱イオン水で樹脂を洗浄した後、樹脂を鉱酸水溶液で再生する。言うまでもなく、中和用のβ−アラニンは、また、当量の酸、好ましくは鉱酸水溶液を加えることにより、そのナトリウム塩から得ることができる。 In a column having an appropriate size, β-alaninate is passed through the resin, the resin is washed with deionized water, and then the resin is regenerated with an aqueous mineral acid solution. Needless to say, neutralizing β-alanine can also be obtained from its sodium salt by adding an equivalent amount of acid, preferably an aqueous mineral acid solution.
本方法の中和工程では、過剰なβ−アラニンの使用は避けるべきである。これは、当該技術分野でよく知られた方法、例えば、滴定を行うことにより達成することができる。60%のナトリウムβ−アラニネート水溶液を得ることが好ましい。 In the neutralization step of the method, the use of excess β-alanine should be avoided. This can be achieved by performing methods well known in the art, such as titration. It is preferable to obtain a 60% aqueous solution of sodium β-alaninate.
残留する水のナトリウムβ−アラニネート溶液からの除去は、常圧または減圧下で、当該技術分野でよく知られた方法、例えば、添加溶剤を用いる共沸蒸留、すなわち米国特許第4,258,210号明細書に記載されている方法により行うことができる。この特定の二段水分除去法を使用する場合には、第1の工程において、流下薄膜型蒸発器を使用し、残留水分量が5〜15%(w/w)になるまで減圧下で蒸発させ、そして、第2の工程において、薄膜型蒸発器を使用し、残留水分量が0.5%(w/w)未満、より好ましくは0.20%(w/w)以下になるまで、さらに低い圧力下で蒸発させることが有利である。第2の蒸発工程は、窒素ストリッピングを行うことにより達成することができる。 Removal of residual water from the sodium β-alaninate solution can be accomplished by methods well known in the art, such as azeotropic distillation using added solvents, ie, US Pat. No. 4,258,210, at normal or reduced pressure. It can be carried out by the method described in the specification. When using this specific two-stage moisture removal method, in the first step, a falling film evaporator is used and evaporated under reduced pressure until the residual moisture content is 5-15% (w / w). And in the second step, using a thin film evaporator, until the residual moisture content is less than 0.5% (w / w), more preferably 0.20% (w / w) or less, It is also advantageous to evaporate under a lower pressure. The second evaporation step can be achieved by performing nitrogen stripping.
二段減圧水分除去法の結果として、高純度のナトリウムβ−アラニネート溶解物が得られ、これを、真空解放後、C1〜8アルカノール、好ましくはメタノールまたはエタノールに溶解して、水分含有量が0.5%以下、好ましくは0.2%(w/w)以下である、1〜40%(w/w)のナトリウムβ−アラニネートのアルカノール溶液を得る。「溶解した」および「溶解している」という用語は、それぞれ「分散した」および「分散している」を含む。 As a result of the two-stage vacuum moisture removal method, a high-purity sodium β-alaninate solution is obtained, which is dissolved in a C 1-8 alkanol, preferably methanol or ethanol, after the vacuum is released, and has a moisture content. An alkanol solution of 1-40% (w / w) sodium β-alaninate is obtained that is 0.5% or less, preferably 0.2% (w / w) or less. The terms “dissolved” and “dissolved” include “dispersed” and “dispersed”, respectively.
このようにして得られた、または、得ることができるナトリウムβ−アラニネート溶液は、それ自体、本発明の一態様を示すものであるが、その後、R−パントラクトンと反応させてナトリウムパントテネートを得ることができる。それは、必要に応じて、さらにパントテン酸またはその塩、好ましくはカルシウム塩に、結晶化工程の追加を必要とせずに変換される。「溶液」および「溶解」という用語は「分散」を含む。 The sodium β-alaninate solution thus obtained or obtainable is itself one aspect of the present invention, but is subsequently reacted with R-pantolactone to give sodium pantothenate. Can be obtained. It is optionally converted to pantothenic acid or a salt thereof, preferably a calcium salt, without the need for an additional crystallization step. The terms “solution” and “dissolution” include “dispersion”.
それ自体知られた方法、またはそれに類似した方法で、カルシウムまたはナトリウムD−パントテネートがそれぞれ得られ、後者はカルシウムD−パントテネートへと変換することができる。 Calcium or sodium D-pantothenate is obtained in a manner known per se or in a similar manner, respectively, the latter can be converted to calcium D-pantothenate.
これらの溶液から所望のカルシウムD−パントテネートを、高収率で、かつヒト用食品適用物、ヒト用ビタミン調製物または医薬製剤の調製に使用するための仕様を満たす純度で得ることができる。 From these solutions the desired calcium D-pantothenate can be obtained in high yield and with a purity that meets the specifications for use in the preparation of human food applications, human vitamin preparations or pharmaceutical formulations.
以上説明した方法、および以下の実施例で得られた/得ることができるナトリウムβ−アラニネート溶液およびカルシウムD−パントテネートは、本発明の一態様である。 The methods described above and the sodium β-alaninate solution and calcium D-pantothenate obtained / obtainable in the following examples are an aspect of the present invention.
最後に、ここに記載した方法により得られるカルシウムD−パントテネートの、ヒト用食品および動物用飼料適用物、ビタミン調製物、並びに医薬製剤の製造における使用もまた、本発明の一態様である。 Finally, the use of calcium D-pantothenate obtained by the methods described herein in the manufacture of human food and animal feed applications, vitamin preparations, and pharmaceutical formulations is also an aspect of the present invention.
そのようなヒト用食品および動物用飼料適用物、ビタミン調製物、並びに医薬製剤の製造方法は、当業者にはよく知られている。 Methods for producing such human food and animal feed applications, vitamin preparations, and pharmaceutical formulations are well known to those skilled in the art.
以下の実施例により本発明をさらに詳細に説明する。特に断らない限り、全てのパーセント表示はw/w基準である。 The following examples illustrate the invention in more detail. Unless otherwise indicated, all percentages are on a w / w basis.
[実施例1]
[β−アミノプロピオニトリルからのNa−β−アラニネート]
13.34kgの脱イオン水(MW=18.02、740.29mol、2.6当量)および25.12kgのNaOH水溶液(50%)(NaOH:MW=40.00、314.00mol、1.1当量;水:MW=18.02、697.00mol、2.4当量)の混合物を63Lのステンレス鋼製反応槽中で内部温度(IT)90℃に加熱した。20.02gのベータ−アミノプロピオニトリル(APN)(MW=70.09、99.0w/w%、282.77mol、1.0当量)を、90〜95℃のITで30分かけてこの予備加熱した混合物に加えた。生成したアンモニアを、10%硫酸水溶液を充填した外部スクラバーに吸収させた。
[Example 1]
[Na-β-alaninate from β-aminopropionitrile]
13.34 kg deionized water (MW = 18.02, 740.29 mol, 2.6 eq) and 25.12 kg aqueous NaOH (50%) (NaOH: MW = 40.00, 314.00 mol, 1.1 Equivalent; Water: MW = 18.02, 697.00 mol, 2.4 eq.) Was heated to an internal temperature (IT) of 90 ° C. in a 63 L stainless steel reactor. 20.02 g of beta-aminopropionitrile (APN) (MW = 70.09, 99.0 w / w%, 282.77 mol, 1.0 eq) was added over 30 minutes at 90-95 ° C. IT. Added to the preheated mixture. The produced ammonia was absorbed by an external scrubber filled with 10% aqueous sulfuric acid.
APN添加完了後、反応混合物を90℃のITで45分間攪拌した。その後、反応混合物を加熱還流させた。還流下、反応混合物から6.57kgの水が蒸留された。水の還流/蒸留を3.5時間行った後、HPLCにより反応混合物を分析した。 After complete APN addition, the reaction mixture was stirred for 45 min at 90 ° C. IT. Thereafter, the reaction mixture was heated to reflux. Under reflux, 6.57 kg of water was distilled from the reaction mixture. After refluxing / distilling water for 3.5 hours, the reaction mixture was analyzed by HPLC.
結果:β−アラニン:52.37w/w%;IDPA:0.68w/w%;ジペプチド:0.02w/w%。 Results: β-alanine: 52.37 w / w%; IDPA: 0.68 w / w%; dipeptide: 0.02 w / w%.
46.45kgの反応混合物が得られた(上記分析で収率96.7%)。ITが30℃になるまで反応混合物を冷却し、分割した。40.88kg(88%)を、直接、中和工程に使用し、5.57kg(12%)を、3.55kgの脱イオン水で希釈し、ベータ−アラニンを生成するイオン交換工程に使用した。 46.45 kg of reaction mixture was obtained (96.7% yield in the above analysis). The reaction mixture was cooled until the IT was 30 ° C. and divided. 40.88 kg (88%) was used directly in the neutralization step and 5.57 kg (12%) was diluted in 3.55 kg deionized water and used in the ion exchange step to produce beta-alanine. .
[実施例2]
[イオン交換によるβ−アラニン]
β−アラニン溶液を生成するため、実施例1で得られた希釈反応混合物(9.0kg)をイオン交換工程に使用した。
[Example 2]
[Β-alanine by ion exchange]
In order to produce a β-alanine solution, the diluted reaction mixture (9.0 kg) obtained in Example 1 was used in the ion exchange step.
分析(HPLC):β−アラニン:32.01w/w%;IDPA:0.28w/w%;ジペプチド:0.01w/w%。 Analysis (HPLC): β-alanine: 32.01 w / w%; IDPA: 0.28 w / w%; dipeptide: 0.01 w / w%.
使用前に脱イオン水により洗浄した、直径5.3cmの2.5mステンレス鋼製カラムに、ローム・アンド・ハース(Rohm&Haas)製のAmberlyst 15を4.5L充填した(1.7mol/L、7.65mol)。Na−ベータ−Ala供給溶液を300g/分の流量でカラムに供給した。 A 2.5 m stainless steel column with a diameter of 5.3 cm washed with deionized water before use was packed with 4.5 L of Amberlyst 15 from Rohm & Haas (1.7 mol / L, 7 .65 mol). Na-beta-Ala feed solution was fed to the column at a flow rate of 300 g / min.
この特定の装置により、この供給溶液を用いて5サイクル実行した。各サイクル後、10%の硫酸溶液でカラムを再生し、その後、水で洗浄した。 With this particular apparatus, 5 cycles were carried out with this feed solution. After each cycle, the column was regenerated with 10% sulfuric acid solution and then washed with water.
中和用β−アラニンを含有する5サイクル全ての主フラクションを混合したところ、9.76kgが得られた。ベータ−Alaの回収率:95.6%。 When all the main fractions of 5 cycles containing β-alanine for neutralization were mixed, 9.76 kg was obtained. Beta-Ala recovery: 95.6%.
分析:β−アラニン:28.21w/w%;IDPA:0.35w/w%;ジペプチド:0.01w/w%;ナトリウム(イオンクロマトグラフィ[IC]):438ppm。 Analysis: β-alanine: 28.21 w / w%; IDPA: 0.35 w / w%; dipeptide: 0.01 w / w%; sodium (ion chromatography [IC]): 438 ppm.
[実施例3]
[過剰NaOHの正確な中和]
実施例1に記載したようにして得られた38.57kgの非希釈反応溶液の過剰NaOHを、63Lのステンレス鋼製容器中で、正確に7.12kgの実施例2で得られたβ−アラニン溶液で中和した。IT<27℃で、30分かけてベータ−アラニン溶液を加えた。
[Example 3]
[Exact neutralization of excess NaOH]
Excess NaOH of 38.57 kg of the undiluted reaction solution obtained as described in Example 1 was placed in a 63 L stainless steel container with exactly 7.12 kg of β-alanine obtained in Example 2. Neutralized with solution. The beta-alanine solution was added over 30 minutes at IT <27 ° C.
β−アラニン溶液の必要量は、少量の反応溶液のサンプルを滴定することによって求めた。2.50%のβ−アラニンによる過剰中和が最適であると考えられた。 The required amount of β-alanine solution was determined by titrating a small sample of the reaction solution. 2. Over neutralization with 50% β-alanine was considered optimal.
β−アラニン溶液を添加後、混合物をさらに15分間攪拌した。45.69kgの中和溶液が得られた。 After adding the β-alanine solution, the mixture was stirred for an additional 15 minutes. 45.69 kg of neutralized solution was obtained.
結果:β−アラニン:48.26w/w%;IDPA:0.67w/w%;ジペプチド:0.01w/w%。 Results: β-alanine: 48.26 w / w%; IDPA: 0.67 w / w%; dipeptide: 0.01 w / w%.
その結果、60.19%のNa−ベータ−Ala水溶液が得られた。混合物中のβ−アラニン過剰量は0.22%であった。 As a result, a 60.19% Na-beta-Ala aqueous solution was obtained. The excess amount of β-alanine in the mixture was 0.22%.
[実施例4]
[Na−ベータ−アラニネート水溶液からの水の除去]
実施例3からのNa−ベータ−アラニネート溶液を、5.59kg/時で再循環式流下薄膜型蒸発器に供給した。流下薄膜型蒸発器は以下の条件で運転した。
圧力:175mbar。流下膜温度:150℃。流下膜最下部温度:100℃。流下膜再循環温度:120℃。再循環:20kg/時。
[Example 4]
[Removal of water from aqueous Na-beta-alaninate solution]
The Na-beta-alaninate solution from Example 3 was fed to the recirculating falling film evaporator at 5.59 kg / hr. The falling film evaporator was operated under the following conditions.
Pressure: 175 mbar. Flowing film temperature: 150 ° C. Lowermost temperature of falling film: 100 ° C. Falling film recirculation temperature: 120 ° C. Recirculation: 20 kg / hour.
混合物から1.65kg/時の水が流下膜で蒸留された。濃縮液を、直接、ジャケット付チューブ(温度:130℃)を通して薄膜型蒸発器へ供した。濃縮液は以下の組成であった(ベータ−Alaおよび副生物についてはHPLC、残りは水)。
分析:β−アラニン:66.75w/w%;IDPA:2.11w/w%;ジペプチド:0.01w/w%;水:14.61w/w%。
1.65 kg / hr of water was distilled from the mixture through the falling film. The concentrated solution was directly supplied to the thin film evaporator through a jacketed tube (temperature: 130 ° C.). The concentrate had the following composition (HPLC for beta-Ala and by-products, balance water).
Analysis: β-alanine: 66.75 w / w%; IDPA: 2.11 w / w%; dipeptide: 0.01 w / w%; water: 14.61 w / w%.
濃縮液を3.90kg/時で薄膜型蒸発器へ供給した。薄膜型蒸発器を以下のパラメータで運転した。
圧力:18mbar;薄膜温度:160℃;薄膜最下部温度:150℃。
The concentrate was supplied to the thin film evaporator at 3.90 kg / hour. The thin film evaporator was operated with the following parameters.
Pressure: 18 mbar; thin film temperature: 160 ° C .; thin film bottom temperature: 150 ° C.
Na−ベータ−Alaから0.55kg/時の水が薄膜型蒸発器で蒸留された。 0.55 kg / hr of water from Na-beta-Ala was distilled in a thin film evaporator.
薄膜型蒸発器からの溶融ナトリウムベータ−アラニネートを、5.78kg/時のメタノールで満たされている63Lのステンレス鋼製溶解槽へ直接投入した。溶解槽の温度は5℃に調節し、溶融物の溶解過程で内部温度が<25℃になるようにした。 Molten sodium beta-alaninate from a thin film evaporator was charged directly into a 63 L stainless steel dissolver filled with 5.78 kg / hr of methanol. The temperature of the dissolution tank was adjusted to 5 ° C. so that the internal temperature was <25 ° C. during the melting process of the melt.
溶解槽から9.16kg/時の乾燥Na−ベータ−Alaメタノール溶液が得られた。 A 9.16 kg / hr dry Na-beta-Ala methanol solution was obtained from the dissolution vessel.
分析:β−アラニン:28.67w/w%;IDPA:1.41w/w%;ジペプチド:0.01w/w%;水:0.19w/w%。 Analysis: β-alanine: 28.67 w / w%; IDPA: 1.41 w / w%; dipeptide: 0.01 w / w%; water: 0.19 w / w%.
ベータ−アラニンについて算出した回収率は、二段乾燥プロセス全体で99.0%であった。 The recovery calculated for beta-alanine was 99.0% for the entire two-stage drying process.
この溶液を、直接、次のナトリウムパントテネート縮合反応へ供した。 This solution was directly subjected to the next sodium pantothenate condensation reaction.
[カルパン(Calpan)の調製]
100gの乾燥Na−ベータ−Alaメタノール溶液(321.8mmol)を41.9g(321.8mmol)のR−パントラクトンと反応させ、Na−D−パントテネート溶液を得た。
[Preparation of Calpan]
100 g of dry Na-beta-Ala methanol solution (321.8 mmol) was reacted with 41.9 g (321.8 mmol) of R-pantolactone to obtain a Na-D-pantothenate solution.
ナトリウムからカルシウムへのイオン交換を含む仕上げは、当業者に公知の方法で行った。 Finishing involving ion exchange from sodium to calcium was performed by methods known to those skilled in the art.
カルパン(Calpan)生成物:79.64g、163.93mmol。収率:96.3%。 Calpan product: 79.64 g, 163.93 mmol. Yield: 96.3%.
[分析:]
カルシウムパントテネート:98.09w/w%
カルシウムパントエート:0.59w/w%
カルシウムパント−ベータ−Ala−ベータ−Ala:0.02w/w%
水:100w/w%までの残量
[analysis:]
Calcium pantothenate: 98.09 w / w%
Calcium pantoate: 0.59 w / w%
Calcium panto-beta-Ala-beta-Ala: 0.02 w / w%
Water: remaining amount up to 100w / w%
[実施例5]
[窒素によるNa−ベータ−アラニネート水溶液からの水の除去]
この実験では、別のNa−ベータ−アラニネート水溶液を使用した。この水分除去のための出発物質は、ベータ−アラニンによる過剰中和率は3.4%であり、分析したところ、β−アラニン:46.41w/w%;IDPA:1.69w/w%;ジペプチド:0.06w/w%を含有した。
[Example 5]
[Removal of water from aqueous Na-beta-alaninate solution by nitrogen]
In this experiment, another aqueous Na-beta-alaninate solution was used. The starting material for this water removal has an excess neutralization rate with beta-alanine of 3.4% and analyzed to be β-alanine: 46.41 w / w%; IDPA: 1.69 w / w%; Dipeptide: contained 0.06 w / w%.
この溶液を、5.75kg/時で再循環式流下薄膜型蒸発器に供給した。流下薄膜型蒸発器を以下の条件で運転した。
圧力:175mbar。流下膜温度:150℃。流下膜最下部温度:100℃。流下膜再循環温度:120℃。再循環:20kg/時。
This solution was fed to the recirculating falling film evaporator at 5.75 kg / hr. The falling film evaporator was operated under the following conditions.
Pressure: 175 mbar. Flowing film temperature: 150 ° C. Lowermost temperature of falling film: 100 ° C. Falling film recirculation temperature: 120 ° C. Recirculation: 20 kg / hour.
混合物から1.86kg/時の水が流下膜で蒸留された。濃縮液を、直接、ジャケット付チューブ(温度:130℃)を通して薄膜型蒸発器へ供した。濃縮液は以下の組成であった(ベータ−Alaおよび副生物についてはHPLC、残りは水)。
分析:β−アラニン:68.59w/w%;IDPA:1.94w/w%;ジペプチド:0.09w/w%;水:11.55w/w%。
1.86 kg / hr of water was distilled from the mixture in the falling film. The concentrated solution was directly supplied to the thin film evaporator through a jacketed tube (temperature: 130 ° C.). The concentrate had the following composition (HPLC for beta-Ala and by-products, balance water).
Analysis: β-alanine: 68.59 w / w%; IDPA: 1.94 w / w%; dipeptide: 0.09 w / w%; water: 11.55 w / w%.
濃縮液を3.90kg/時で薄膜型蒸発器へ供給した。薄膜型蒸発器を以下の条件で運転した。
圧力:22mbar;薄膜温度:160℃;薄膜最下部温度:150℃。薄膜型蒸発器最下部における窒素供給量:30L/時。
The concentrate was supplied to the thin film evaporator at 3.90 kg / hour. The thin film evaporator was operated under the following conditions.
Pressure: 22 mbar; thin film temperature: 160 ° C .; thin film bottom temperature: 150 ° C. Nitrogen supply rate at the bottom of the thin film evaporator: 30 L / hour.
0.41kg/時の水が薄膜型蒸発器で蒸留除去された。薄膜型蒸発器からの溶融Na−β−アラニネートは、直接、5.85kg/時のメタノールで満たされている63Lステンレス鋼製溶解槽へ投入した。溶解槽の温度は5℃に調節し、溶融物の溶解過程でITが<25℃になるようにした。 0.41 kg / hr of water was distilled off with a thin film evaporator. The molten Na-β-alaninate from the thin film evaporator was charged directly into a 63L stainless steel dissolution tank filled with 5.85 kg / hr of methanol. The temperature of the dissolution vessel was adjusted to 5 ° C. so that IT was <25 ° C. during the melt dissolution process.
溶解槽から9.27kg/時の乾燥Na−β−Alaメタノール溶液が得られた。 A 9.27 kg / hr dry Na-β-Ala methanol solution was obtained from the dissolution tank.
分析:β−アラニン:28.82w/w%;IDPA:1.28w/w%;ジペプチド:0.04w/w%;水:0.09w/w%。 Analysis: β-alanine: 28.82 w / w%; IDPA: 1.28 w / w%; dipeptide: 0.04 w / w%; water: 0.09 w / w%.
ベータ−アラニンについて算出した回収率は、二段乾燥プロセス全体で量論通りであった。 The recovery calculated for beta-alanine was stoichiometric throughout the two-stage drying process.
この溶液を、直接、次のナトリウムパントテネート縮合反応へ供した。 This solution was directly subjected to the next sodium pantothenate condensation reaction.
[カルパン(Calpan)の調製]
100gの乾燥Na−ベータ−Alaメタノール溶液(323.4mmol)を42.1g(323.4mmol)のR−パントラクトンと反応させ、Na−D−パントテネート溶液を得た。
[Preparation of Calpan]
100 g of dry Na-beta-Ala methanol solution (323.4 mmol) was reacted with 42.1 g (323.4 mmol) of R-pantolactone to obtain a Na-D-pantothenate solution.
ナトリウムからカルシウムへのイオン交換を含む仕上げは、当業者に公知の方法で行った。 Finishing involving ion exchange from sodium to calcium was performed by methods known to those skilled in the art.
カルパン(Calpan)生成物:76.78g、160.68mmol。収率:92.9%。 Calpan product: 76.78 g, 160.68 mmol. Yield: 92.9%.
[分析:]
カルシウムパントテネート:99.73w/w%
カルシウムパントエート:0.25w/w%
カルシウムパント−ベータ−Ala−ベータ−Ala:0.08w/w%
水:100w/w%までの残量
[analysis:]
Calcium pantothenate: 99.73 w / w%
Calcium pantoate: 0.25 w / w%
Calcium punt-beta-Ala-beta-Ala: 0.08 w / w%
Water: remaining amount up to 100w / w%
[実施例6]
[過剰NaOHの過剰中和:]
β−アラニン:51.80w/w%、IDPA:不明、およびジペプチド:0.17w/w%を含有する非希釈反応溶液(実施例1と同じ方法で行った加水分解実験で得られたもの)40.88kg中の過剰NaOHを、63Lのステンレス鋼製容器中で、β−アラニン:26.91w/w%;IDPA:不明、およびジペプチド:0.03w/w%、ナトリウム(IC):380ppmを含有すると分析されたβ−アラニン溶液8.91kgにより中和した。
[Example 6]
[Excess neutralization of excess NaOH:]
Undiluted reaction solution containing β-alanine: 51.80 w / w%, IDPA: unknown, and dipeptide: 0.17 w / w% (obtained in the hydrolysis experiment performed in the same manner as in Example 1) Excess NaOH in 40.88 kg in a 63 L stainless steel container, β-alanine: 26.91 w / w%; IDPA: unknown, and dipeptide: 0.03 w / w%, sodium (IC): 380 ppm The solution was neutralized with 8.91 kg of a β-alanine solution analyzed to contain.
ベータ−アラニン溶液をITを<27℃として120分かけて添加した。 Beta-alanine solution was added over 120 minutes with IT <27 ° C.
滴定によれば、これはベータ−アラニンの21.5%の過剰中和であった。 By titration, this was 21.5% overneutralization of beta-alanine.
β−アラニン溶液を添加した後、混合物をさらに15分間攪拌した。49.49kgの中和溶液が得られた。 After the β-alanine solution was added, the mixture was stirred for an additional 15 minutes. 49.49 kg of neutralized solution was obtained.
結果:β−アラニン:47.37w/w%、IDPA:0.70w/w%、ジペプチド:0.02w/w%。 Results: β-alanine: 47.37 w / w%, IDPA: 0.70 w / w%, dipeptide: 0.02 w / w%.
混合物中における過剰のベータ−アラニンは2.02w/w%であった。 The excess beta-alanine in the mixture was 2.02 w / w%.
[実施例7]
[過剰中和されたNa−ベータ−アラニネート水溶液からの水の除去]
実施例6で得られた過剰中和のNa−ベータ−アラニネート水溶液を7.29kg/時で再循環式流下薄膜型蒸発器に供給した。流下薄膜型蒸発器を以下の条件で運転した。
圧力:175mbar。流下膜温度:150℃。流下膜最下部温度:100℃。流下膜再循環温度:120℃。再循環:20kg/時。
[Example 7]
[Removal of water from over-neutralized Na-beta-alaninate aqueous solution]
The over-neutralized Na-beta-alaninate aqueous solution obtained in Example 6 was fed to the recirculating falling film evaporator at 7.29 kg / hour. The falling film evaporator was operated under the following conditions.
Pressure: 175 mbar. Flowing film temperature: 150 ° C. Lowermost temperature of falling film: 100 ° C. Falling film recirculation temperature: 120 ° C. Recirculation: 20 kg / hour.
混合物から2.23kg/時の水が流下薄膜型蒸発器で蒸留除去された。濃縮液を、直接、ジャケット付チューブ(温度:130℃)を通して、薄膜型蒸発器へ供した。濃縮液は以下の組成であった(ベータ−Alaおよび副生物についてはHPLC、残りは水)。
分析:β−アラニン:64.16w/w%;IDPA:0.34w/w%;ジペプチド:0.05w/w%;水:13.49w/w%。
From the mixture, 2.23 kg / hr of water was distilled off with a falling film evaporator. The concentrated solution was directly supplied to the thin film evaporator through a jacketed tube (temperature: 130 ° C.). The concentrate had the following composition (HPLC for beta-Ala and by-products, balance water).
Analysis: β-alanine: 64.16 w / w%; IDPA: 0.34 w / w%; dipeptide: 0.05 w / w%; water: 13.49 w / w%.
濃縮液を5.06kg/時で薄膜型蒸発器へ供給した。薄膜型蒸発器を以下のパラメータで運転した:
圧力:29mbar;薄膜温度:160℃;薄膜最下部温度:150℃。薄膜型蒸発器下部における窒素供給量:40L/時。
The concentrated solution was supplied to the thin film evaporator at 5.06 kg / hour. The thin film evaporator was operated with the following parameters:
Pressure: 29 mbar; Thin film temperature: 160 ° C .; Thin film bottom temperature: 150 ° C. Nitrogen supply rate at the bottom of the thin film evaporator: 40 L / hour.
0.57kg/時の水が薄膜型蒸発器で蒸留除去された。薄膜型蒸発器からの溶融ナトリウムベータ−アラニネートを、直接、7.39kg/時のメタノールで満たされている溶解槽へ供給した。溶解槽の温度は5℃に調節し、溶融物の溶解過程でITが<25℃になるようにした。 0.57 kg / hr of water was distilled off with a thin film evaporator. Molten sodium beta-alaninate from a thin film evaporator was fed directly into a dissolution tank filled with 7.39 kg / hr of methanol. The temperature of the dissolution vessel was adjusted to 5 ° C. so that IT was <25 ° C. during the melt dissolution process.
溶解槽から11.69kg/時の乾燥Na−ベータ−Alaメタノール溶液が得られた。 A dry Na-beta-Ala methanol solution of 11.69 kg / hr was obtained from the dissolution tank.
分析:β−アラニン:27.02w/w%;IDPA:0.29w/w%;ジペプチド:0.07w/w%;水:0.15w/w%。 Analysis: β-alanine: 27.02 w / w%; IDPA: 0.29 w / w%; dipeptide: 0.07 w / w%; water: 0.15 w / w%.
ベータ−アラニンについて算出した回収率は、二段乾燥プロセス全体で、91.5%であった。 The recovery calculated for beta-alanine was 91.5% for the entire two-stage drying process.
この溶液を、直接、次のナトリウムパントテネート縮合反応へ供した。 This solution was directly subjected to the next sodium pantothenate condensation reaction.
[カルパン(Calpan)の調製]
100gの乾燥Na−ベータ−Alaメタノール溶液(303.3mmol)を39.5g(303.3mmol)のR−パントラクトンと反応させ、Na−D−パントテネート溶液を得た。
[Preparation of Calpan]
100 g of dry Na-beta-Ala methanol solution (303.3 mmol) was reacted with 39.5 g (303.3 mmol) of R-pantolactone to obtain a Na-D-pantothenate solution.
ナトリウムからカルシウムへのイオン交換を含む仕上げは、当業者に公知の方法で行った。 Finishing involving ion exchange from sodium to calcium was performed by methods known to those skilled in the art.
カルパン(Calpan)生成物:79.19g、160.06mmol。収率:94.3%。 Calpan product: 79.19 g, 160.06 mmol. Yield: 94.3%.
[分析:]
カルシウムパントテネート:96.32w/w%
カルシウムパントエート:0.14w/w%
カルシウムパント−ベータ−Ala−ベータ−Ala:0.16w/w%(実施例4および5に比べ極めて高い)
水:100w/w%までの残量
[analysis:]
Calcium pantothenate: 96.32 w / w%
Calcium pantoate: 0.14 w / w%
Calcium punt-beta-Ala-beta-Ala: 0.16 w / w% (very high compared to Examples 4 and 5)
Water: remaining amount up to 100w / w%
[実施例8]
[完全には分解されていないジペプチドとの反応、1.1当量のNaOHによる中和なし]
水酸化ナトリウムペレット21.7g(540.2mmol、1.1当量)を45.1gの脱イオン水(2503.0mmol、5.1当量)に室温で溶解させた。ITが90℃になるまで溶液を加熱した。この温度で35.0gのアミノプロピオニトリル(490.5mmol、1.0当量)の添加を開始した。APNの添加は30分以内に行った。その後、IT90℃で反応混合物を10.5時間攪拌した。
[Example 8]
[Reaction with incompletely degraded dipeptide, no neutralization with 1.1 equivalents of NaOH]
21.7 g (540.2 mmol, 1.1 eq) sodium hydroxide pellets were dissolved in 45.1 g deionized water (2503.0 mmol, 5.1 eq) at room temperature. The solution was heated until the IT was 90 ° C. At this temperature, 35.0 g of aminopropionitrile (490.5 mmol, 1.0 eq) was added. The addition of APN was done within 30 minutes. The reaction mixture was then stirred for 10.5 hours at IT 90 ° C.
分析:β−アラニン:48.54w/w%;IDPA:0.15w/w%;ジペプチド:0.21w/w%。 Analysis: β-alanine: 48.54 w / w%; IDPA: 0.15 w / w%; dipeptide: 0.21 w / w%.
45.11gの反応混合物(全量93.5gから;246.0mmolのNa−ベータ−アラニネート)をロータリーエバポレータに供した。残留アンモニアおよび大部分の水を、浴温度60℃、700〜600mbarの減圧下で除去した。全量147.4gのn−ブタノールを3回に分けて懸濁水に加えた。各n−ブタノール添加後、n−ブタノール/水をロータリーエバポレータで共沸により除去し、68.6gのワックス状固体を得た。固体を49.5gのメタノールに溶解した。 45.11 g of the reaction mixture (from a total amount of 93.5 g; 246.0 mmol Na-beta-alaninate) was subjected to a rotary evaporator. Residual ammonia and most of the water were removed under reduced pressure at a bath temperature of 60 ° C. and 700-600 mbar. A total of 147.4 g of n-butanol was added to the suspension in 3 portions. After each n-butanol addition, n-butanol / water was removed azeotropically on a rotary evaporator, yielding 68.6 g of a waxy solid. The solid was dissolved in 49.5 g of methanol.
分析:β−アラニン:19.13w/w%;IDPA:0.05w/w%;ジペプチド:0.07w/w%;水:0.20w/w%。β−アラニン253.9mmol、収率:103.2%。 Analysis: β-alanine: 19.13 w / w%; IDPA: 0.05 w / w%; dipeptide: 0.07 w / w%; water: 0.20 w / w%. β-alanine 253.9 mmol, yield: 103.2%.
[カルパン(Calpan)の調製]
110.5gの乾燥Na−ベータ−Alaメタノール溶液(237.4mmol)を31.2g(237.3mmol)のR−パントラクトンと反応させ、Na−D−パントテネート溶液を得た。
[Preparation of Calpan]
110.5 g of dry Na-beta-Ala methanol solution (237.4 mmol) was reacted with 31.2 g (237.3 mmol) of R-pantolactone to obtain a Na-D-pantothenate solution.
ナトリウムからカルシウムへのイオン交換を含む仕上げは、当業者に公知の方法で行った。 Finishing involving ion exchange from sodium to calcium was performed by methods known to those skilled in the art.
カルパン(Calpan)生成物:56.71g、110.00mmol。収率:83.2%。 Calpan product: 56.71 g, 110.00 mmol. Yield: 83.2%.
[分析:]
カルシウムパントテネート:92.72w/w%
カルシウムパントエート:3.06w/w%(実施例4、5、7に比べ極めて高い)
カルシウムパント−ベータ−Ala−ベータ−Ala:0.19w/w%(実施例4および5に比べ極めて高い)
水:100w/w%までの残量
[analysis:]
Calcium pantothenate: 92.72 w / w%
Calcium pantoate: 3.06 w / w% (very high compared to Examples 4, 5, and 7)
Calcium punt-beta-Ala-beta-Ala: 0.19 w / w% (very high compared to Examples 4 and 5)
Water: remaining amount up to 100w / w%
Claims (1)
(b)過剰の水酸化ナトリウムをβ−アラニンにより、β−アラニンが過剰になるのを避けつつ、中和して、所望の濃度の溶液を直接得る工程、(B) a step of neutralizing excess sodium hydroxide with β-alanine while avoiding excess β-alanine to directly obtain a solution having a desired concentration;
(c)水を除去する工程、(C) removing water;
(d)Na−β−アラニネートをC(D) Na-β-alaninate to C 1〜81-8 −アルコールに溶解して、所望の濃度のNa−β−アラニネートのアルコール溶液を得る工程、Dissolving in alcohol to obtain a desired concentration of Na-β-alaninate alcohol solution;
(e)Na−β−アラニネートをR−パントラクトンと反応させて、Na−パントテネートを得る工程、および(E) reacting Na-β-alaninate with R-pantolactone to obtain Na-pantothenate; and
(f)Na−パントテネートをCa−パントテネートに変換する工程、を含む、Ca−パントテネートの製造方法。(F) A method for producing Ca-pantothenate, comprising the step of converting Na-pantothenate to Ca-pantothenate.
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