JPS61129159A - Purification of protected amino acid amide compound - Google Patents
Purification of protected amino acid amide compoundInfo
- Publication number
- JPS61129159A JPS61129159A JP59249762A JP24976284A JPS61129159A JP S61129159 A JPS61129159 A JP S61129159A JP 59249762 A JP59249762 A JP 59249762A JP 24976284 A JP24976284 A JP 24976284A JP S61129159 A JPS61129159 A JP S61129159A
- Authority
- JP
- Japan
- Prior art keywords
- solution
- amino acid
- acid amide
- protected amino
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 30
- 150000001413 amino acids Chemical class 0.000 title claims abstract description 29
- 238000000746 purification Methods 0.000 title description 3
- 239000003960 organic solvent Substances 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 239000012535 impurity Substances 0.000 claims abstract description 10
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 8
- 238000005406 washing Methods 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 17
- 230000003213 activating effect Effects 0.000 claims description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 8
- 239000013078 crystal Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 3
- 230000004913 activation Effects 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 229940024606 amino acid Drugs 0.000 description 24
- 235000001014 amino acid Nutrition 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- 238000002425 crystallisation Methods 0.000 description 14
- 230000008025 crystallization Effects 0.000 description 13
- 239000002904 solvent Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- -1 aliphatic amines Chemical class 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000006482 condensation reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003495 polar organic solvent Substances 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 2
- 229960003136 leucine Drugs 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- HCDLAJHOIWLVLK-JTQLQIEISA-N (2s)-2-amino-4-methyl-n-(3-methylbutyl)pentanamide Chemical compound CC(C)CCNC(=O)[C@@H](N)CC(C)C HCDLAJHOIWLVLK-JTQLQIEISA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000002862 amidating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は保護化アミノ酸アミド化合物の精製法に関し、
さらに詳しくは、各種医薬などを合成するための中間体
として有用な保護化アミノ酸アミド化合物を間車な操作
で効率よく精製する方法に関する。[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a method for purifying a protected amino acid amide compound,
More specifically, the present invention relates to a method for efficiently purifying protected amino acid amide compounds, which are useful as intermediates for synthesizing various medicines, through slow operations.
ロイシン、イソロイシン、アラニン、バリンなどのごと
きアミノ酸を脂肪族アミン、芳香族アミンなどでアミド
化したアミノ酸アミド化合物は、従来から医薬用の原料
として有用なことが知られている（例えば特開昭５５−
１１５８７８号）。Amino acid amide compounds, which are made by amidating amino acids such as leucine, isoleucine, alanine, and valine with aliphatic amines and aromatic amines, have long been known to be useful as raw materials for pharmaceuticals (for example, in JP-A-55 −
No. 115878).
かかる化合物は、一般にアミノ酸のアミノ基を保護した
のち、縮合剤や活性化剤の存在下にアミンと反応させ、
次いで保護基を除去することによって合成されるが、こ
の方法の場合、縮合反応の過程で縮合剤や活性化剤に由
来する不純物が副生ずるためそれを除去することが必要
である。Such compounds are generally prepared by protecting the amino group of an amino acid and then reacting it with an amine in the presence of a condensing agent or activating agent.
The compound is then synthesized by removing the protecting group, but in this method, impurities derived from the condensing agent and activating agent are produced as by-products during the condensation reaction, so it is necessary to remove them.
しかし、生成したアミノ酸アミド化合物は一般に高沸点
であり、かつ常温で油状のため、蒸留精製あるいは晶析
精製ができないという問題があった。However, the produced amino acid amide compound generally has a high boiling point and is oily at room temperature, so there is a problem that it cannot be purified by distillation or crystallization.
そこで本発明者らは、アミノ酸アミド化合物の中間体で
ある保護化アミノ酸アミド化合物が常温で個体であるこ
とに着目し、この段階での晶析精製を試みた。しかし、
保護化アミノ酸アミド化合物は一般に有機溶媒に溶解し
やすく、そのため通常の晶析法が適用できないことが判
明した。Therefore, the present inventors focused on the fact that the protected amino acid amide compound, which is an intermediate of the amino acid amide compound, is a solid at room temperature, and attempted crystallization purification at this stage. but,
It has been found that protected amino acid amide compounds are generally easily soluble in organic solvents, and therefore normal crystallization methods cannot be applied.
そこで本発明者らは、かがる問題点を解決すべく鋭意検
討を進めた結果、溶剤転換の手法と水系溶剤での晶析と
を組合わせることが有効なことを見い出し本発明を完成
するに到った。Therefore, the present inventors conducted intensive studies to solve these problems, and as a result, they discovered that it is effective to combine the solvent conversion method and crystallization using an aqueous solvent, and completed the present invention. reached.
かくして本発明によれば、縮合剤及び／又は活性化剤に
由来する不純物を含む粗製保護化アミノ酸アミド化合物
の疎水性有機溶剤溶液を水で洗浄したのち、親水性有機
溶剤溶液に転換し、水と親水性有機溶剤の混合系で保護
化アミノ酸アミド化合物を晶析することを特徴とする保
護化アミノ酸アミド化合物の精製法が提供される。Thus, according to the present invention, a solution of a crude protected amino acid amide compound in a hydrophobic organic solvent containing impurities derived from a condensing agent and/or an activating agent is washed with water, and then converted into a hydrophilic organic solvent solution. Provided is a method for purifying a protected amino acid amide compound, which comprises crystallizing the protected amino acid amide compound in a mixed system of a hydrophilic organic solvent and a hydrophilic organic solvent.
本発明によって精製される保護化アミノ酸アミド化合物
は下記一般式（１）で示されるものである。The protected amino acid amide compound purified by the present invention is represented by the following general formula (1).
式中のＸはアミノ基の保護基で通常ハイドロカルビルオ
キシカルボニル基であり、例えばｔ−ブトキシカルボニ
ル基で代表される。Ｒは低級アルキル基であり、例えば
メチル基、イソプロピル基、イソブチル基、５ｅｃ−ブ
チル基などである。Ｙは１級あるいは２級アミノ残基で
あり、例えばジエチルアミノ基、イソアミルアミノ基、
ピロリジノ基、Ｎ−メチルアニリノ基などである。かか
る保護化アミノ酸アミド化合物は、通常、下記一般式（
ＩＩ）で示される保護化アミノ酸化合物と下記一般式〔
■〕で示されるアミン化合物とを、有機溶剤中、Ｎ 、
Ｎ’−ジシクロへキシルカルボジイミド、１−エチル
−３−（３−ジメチル−アミノプロピル）カルボジイミ
ド等の縮合剤の存在下に反応させて得られる。In the formula, X is a protecting group for an amino group and is usually a hydrocarbyloxycarbonyl group, represented by, for example, a t-butoxycarbonyl group. R is a lower alkyl group, such as a methyl group, isopropyl group, isobutyl group, 5ec-butyl group, etc. Y is a primary or secondary amino residue, such as a diethylamino group, an isoamylamino group,
Examples include pyrrolidino group and N-methylanilino group. Such protected amino acid amide compounds usually have the following general formula (
The protected amino acid compound represented by II) and the following general formula [
■] in an organic solvent with N,
It is obtained by reaction in the presence of a condensing agent such as N'-dicyclohexylcarbodiimide and 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide.
喜
（ｎ〕（Ｉ［［）
（式中、Ｘ、Ｒ及びＹは前記と同じである）この反応に
あたっては、通常、Ｎ−ヒドロキシコハク酸イミド、１
−ヒドロキシベンゾトリアゾール等の活性化剤が使用さ
れる。そのため反応生成物中にはこれらの縮合剤及び／
又は活性化剤に由来する不純物が必然的に付随している
。In this reaction, N-hydroxysuccinimide, 1
-Activating agents such as hydroxybenzotriazole are used. Therefore, these condensing agents and/or
Or, impurities derived from the activator are inevitably present.
本発明においては、このような不純物を含む粗製保護化
アミノ酸アミド化合物の疎水性有機溶剤溶液がまず調製
される。この溶液は単離した粗製保護化アミノ酸アミド
化合物に溶剤を加えて調製してもよいが、通常は、縮合
反応後に濾過等の適当な処理を施した反応液が用いられ
る。In the present invention, a hydrophobic organic solvent solution of a crude protected amino acid amide compound containing such impurities is first prepared. This solution may be prepared by adding a solvent to the isolated crude protected amino acid amide compound, but usually a reaction solution that has been subjected to appropriate treatment such as filtration after the condensation reaction is used.
用いられる有機溶剤は疎水性の極性溶剤であることが好
ましく、その具体的な例として酢酸エチル、ジエチルエ
ーテル、クロロホルム、ジクロロメタンなどが例示され
る。極性溶剤に代えてベンゼン、トルエンなどのごとき
非極性溶剤を使用することも可能であるが、これらの溶
剤は前記式〔■〕で示した保護化アミノ酸の溶解度が低
いため、縮合反応溶剤としては好ましくなく、一旦他の
溶剤を使用して縮合反応を実施した後、溶剤転換を行な
う必要がある。The organic solvent used is preferably a hydrophobic polar solvent, and specific examples thereof include ethyl acetate, diethyl ether, chloroform, and dichloromethane. It is also possible to use non-polar solvents such as benzene and toluene instead of polar solvents, but these solvents have low solubility for the protected amino acid shown in the above formula [■], so they are not suitable as condensation reaction solvents. Undesirably, it is necessary to carry out the solvent conversion once the condensation reaction has been carried out using another solvent.
かかる粗製保護化アミノ酸アミド化合物の溶液は、次い
で水で洗浄することにより、溶液中に含まれる不純物の
除去が行われる。水洗の条件は適宜選択しうるが、通常
は溶液に対し０．５〜２倍量の水を数回接触させ、水相
中に不純物を抽出する方法が用いられる。使用する水は
、必要に応じて食塩水や酸の水溶液であってもよいが、
酸の水溶液で洗浄した場合には、その後、塩基の水溶液
で中和することが好ましい。The solution of the crude protected amino acid amide compound is then washed with water to remove impurities contained in the solution. Conditions for washing with water can be selected as appropriate, but usually a method is used in which the solution is brought into contact with 0.5 to 2 times the amount of water several times to extract impurities into the aqueous phase. The water used may be a saline solution or an acid aqueous solution if necessary, but
When washing with an aqueous acid solution, it is preferable to neutralize with an aqueous base solution afterwards.
水洗後の溶液は、次いで親水性有機溶剤に溶剤転換がな
される。溶剤転換は、疎水性有機溶剤を留去したのち親
水性有機溶剤を加える方法、疎水性有機溶剤溶液に親水
性有機溶剤を加え共沸により溶剤を転換する方法のいず
れを採用することもできる。用いられる親水性有機溶剤
は水と自由に相溶しうるちのであり、その具体例として
メタノール、エタノール、イソプロパツール、アセトン
、テトラヒドロフラン、ジオキサン、アセトニトリル、
ジメチルホルムアミドなどが例示される。また、保護化
アミノ酸アミド化合物が均一に溶解可能な範囲内であれ
ば、親水性有機溶剤とともに水を混合して用いることも
できる。The solution after washing with water is then converted into a hydrophilic organic solvent. For solvent conversion, either a method of distilling off a hydrophobic organic solvent and then adding a hydrophilic organic solvent, or a method of adding a hydrophilic organic solvent to a hydrophobic organic solvent solution and converting the solvent by azeotropy can be adopted. The hydrophilic organic solvent used is one that is freely compatible with water, and specific examples include methanol, ethanol, isopropanol, acetone, tetrahydrofuran, dioxane, acetonitrile,
Examples include dimethylformamide. Furthermore, water may be mixed with a hydrophilic organic solvent as long as the protected amino acid amide compound can be uniformly dissolved.
この操作中に不溶物が形成される場合には、濾過等の手
段により除去することが必要である。If insoluble matter is formed during this operation, it is necessary to remove it by means such as filtration.
次いでこの親水性有機溶剤溶液と水を混合することによ
って保護化アミノ酸アミド化合物の晶析が行われる。混
合法は適宜選択することができ、親水性有機溶剤溶液に
水を加える方法またはその逆の方法のいずれでもよい。Next, the protected amino acid amide compound is crystallized by mixing this hydrophilic organic solvent solution with water. The mixing method can be selected as appropriate, and may be either a method of adding water to a hydrophilic organic solvent solution or the reverse method.
また水の添加量は晶析が起こる範囲内で選択すればよい
が、通常は４０〜８０容量％である。また晶析にあたっ
ての溶液の温度は１０℃以下にすることが好ましく、と
くに−２０〜５℃にすることが適切である。この際、温
度が過度に高くなると結晶が生成しにくくなる。Further, the amount of water added may be selected within a range in which crystallization occurs, but it is usually 40 to 80% by volume. Further, the temperature of the solution during crystallization is preferably 10°C or lower, and particularly suitably -20 to 5°C. At this time, if the temperature becomes too high, it becomes difficult to form crystals.
晶析操作によって蒸発乾固法に比べ操作性のよい結晶が
得られ、この結晶を濾別し、減圧乾燥することにより精
製された保護化アミノ酸アミドが得られる。ここで濾過
操作は常温で行なっても差しつかえない。The crystallization operation yields crystals that are easier to handle than the evaporation to dryness method, and the purified protected amino acid amide is obtained by filtering the crystals and drying under reduced pressure. Here, the filtration operation may be performed at room temperature.
また、粗製保護化アミノ酸アミド化合物の疎水性有機溶
剤溶液が極性有機溶剤の溶液である場合には、晶析操作
に移る前に必要に応じて非極性有機溶剤に溶剤転換し、
溶剤に不溶の不純物を濾過等の手段を使用して除去する
ことにより精製効果を上げることができる。用いられる
非極性有機溶剤の具体例としては、ヘキサン、ヘプタン
、オクタン、シクロヘキサン、ベンゼン、トルエン、キ
シレン、石油エーテルなどのごとき炭化水素溶剤が例示
され、また溶剤転換の手法としては前記した方法と同様
の手法が採用される。In addition, if the hydrophobic organic solvent solution of the crude protected amino acid amide compound is a polar organic solvent solution, the solvent may be converted to a non-polar organic solvent as necessary before proceeding to the crystallization operation.
The purification effect can be improved by removing impurities that are insoluble in the solvent using means such as filtration. Specific examples of non-polar organic solvents to be used include hydrocarbon solvents such as hexane, heptane, octane, cyclohexane, benzene, toluene, xylene, petroleum ether, etc., and the solvent conversion method is similar to the method described above. method will be adopted.
かくして本発明によれば、簡単な装置および簡易な操作
により、保護化アミノ酸アミド化合物を純度よくしかも
操作性のよい結晶として得ることができる。Thus, according to the present invention, a protected amino acid amide compound can be obtained in the form of crystals with high purity and good operability using a simple device and simple operation.
以下に実施例を挙げて本発明をさらに具体的に説明する
。The present invention will be explained in more detail with reference to Examples below.
１今史上
Ｎ−（ｔ−ブトキシカルボニル）−Ｌ−ロイシン１永和
物２４．９ ｇ、イソアミルアミン８．７ｇ、Ｎ−ヒド
ロキシコハク酸イミド１１．５ｇを酢酸エチル７５ｍ１
に溶解し、これを水冷攪拌しなからＮＮ ／ −ジシク
ロへキシルカルボジイミド２０．６ｇを酢酸エチル４０
ｍ１に溶解した溶液を滴下した。1 Currently, 24.9 g of N-(t-butoxycarbonyl)-L-leucine 1 hydrate, 8.7 g of isoamylamine, and 11.5 g of N-hydroxysuccinimide were added to 75 ml of ethyl acetate.
20.6 g of NN/-dicyclohexylcarbodiimide was dissolved in ethyl acetate and 40 g of ethyl acetate was dissolved in water-cooled and stirred.
A solution dissolved in m1 was added dropwise.
温度をそのままに保って２時間攪拌し、更に室温で３時
間攪拌した。生成した沈澱物を濾別し、Ｎ−（１−ブト
キシカルボニル）−Ｌ−ロイシルイソアミルアミド（以
下、ＢＬＡと称する）の酢酸エチル溶液を得た。この溶
液中にはＮ−ヒドロキシコハク酸イミド及びＮ 、 Ｎ
’ −ジシクロへキシルカルボジイミドに由来する不純
物が含まれていた。The mixture was stirred for 2 hours while maintaining the same temperature, and further stirred for 3 hours at room temperature. The generated precipitate was filtered to obtain an ethyl acetate solution of N-(1-butoxycarbonyl)-L-leucylisoamylamide (hereinafter referred to as BLA). This solution contains N-hydroxysuccinimide and N,N
' -Contained impurities derived from dicyclohexylcarbodiimide.
刃】１生１
参考例１で得たＢＬＡの酢酸エチル溶液を５％塩酸水、
５％食塩水、飽和重曹水、５％食塩水各２００ｍ１で順
次洗浄し、無水硫酸ナトリウム上で乾燥後、溶媒を留去
して純度９６．９％の粗製Ｎ−（ｔ−ブトキシカルボニ
ル）−Ｌ−ロイシルイソアミルアミド２９．５ ｇを得
た。この粗製物８．０ｇをヘキサン２７ｍ１に溶解し、
不溶物を濾別し、濾液を乾固して固体７．８ｇを得た。[Blade] 1 Raw 1 The ethyl acetate solution of BLA obtained in Reference Example 1 was mixed with 5% hydrochloric acid water,
Washed sequentially with 200 ml each of 5% brine, saturated sodium bicarbonate solution, and 5% brine, dried over anhydrous sodium sulfate, and distilled off the solvent to obtain crude N-(t-butoxycarbonyl)- with a purity of 96.9%. 29.5 g of L-leucylisoamylamide was obtained. 8.0 g of this crude product was dissolved in 27 ml of hexane,
Insoluble matter was filtered off, and the filtrate was dried to obtain 7.8 g of solid.
これにアセトン３０ｍ１、水１０ｍ１を室温で加え溶解
させた後、−１０℃に冷却し攪拌しながら水２０ｍ１を
徐々に加え晶析を行った。生成した結晶を濾別し、減圧
乾燥してＢＬＡ６．５ｇを得た。検量線を使用する高速
液体クロマトグラフ（以下ＨＰＬＣと称する）分析の結
果によると、晶析前の純度は９８．１％であるが、晶析
後の純度は９９．８％であった。After adding and dissolving 30 ml of acetone and 10 ml of water at room temperature, the mixture was cooled to -10 DEG C., and while stirring, 20 ml of water was gradually added to perform crystallization. The generated crystals were filtered and dried under reduced pressure to obtain 6.5 g of BLA. According to the results of high performance liquid chromatography (hereinafter referred to as HPLC) analysis using a calibration curve, the purity before crystallization was 98.1%, but the purity after crystallization was 99.8%.
大旌斑主
ヘキサンによる処理操作を行なわないこと以外は実施例
１と同様にして晶析操作を行ない、ＢＬＡ６．６ｇを得
た。ＨＰＬＣ分析の結果、晶析前の純度は９６．９％、
晶析後の純度は９９．１％であった。Crystallization was carried out in the same manner as in Example 1 except that the treatment with hexane was not carried out to obtain 6.6 g of BLA. As a result of HPLC analysis, the purity before crystallization was 96.9%.
The purity after crystallization was 99.1%.
Claims (1)
保護化アミノ酸アミド化合物の疎水性有機溶剤溶液を水
で洗浄したのち、親水性有機溶剤溶液に転換し、水と親
水性有機溶剤の混合系で保護化アミノ酸アミド化合物を
晶析することを特徴とする保護化アミノ酸アミド化合物
の精製法。After washing the hydrophobic organic solvent solution of the crude protected amino acid amide compound containing impurities derived from the condensing agent and/or activating agent with water, it is converted to a hydrophilic organic solvent solution, and the water and the hydrophilic organic solvent are mixed. A method for purifying a protected amino acid amide compound, the method comprising crystallizing the protected amino acid amide compound in a system.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59249762A JPS61129159A (en) | 1984-11-28 | 1984-11-28 | Purification of protected amino acid amide compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59249762A JPS61129159A (en) | 1984-11-28 | 1984-11-28 | Purification of protected amino acid amide compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS61129159A true JPS61129159A (en) | 1986-06-17 |
Family
ID=17197850
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59249762A Pending JPS61129159A (en) | 1984-11-28 | 1984-11-28 | Purification of protected amino acid amide compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61129159A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998008806A1 (en) * | 1996-08-28 | 1998-03-05 | Ajinomoto Co., Inc. | Method for purifying n-acylamino acid amides |
| JP2006525247A (en) * | 2003-05-06 | 2006-11-09 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Method for crystallizing guanidine salts |
| WO2007083620A1 (en) * | 2006-01-20 | 2007-07-26 | Kaneka Corporation | PROCESS FOR PRODUCTION OF β-AMINO-α-HYDROXY ACID AMIDE DERIVATIVE |
| WO2009081608A1 (en) * | 2007-12-21 | 2009-07-02 | Kaneka Corporation | Process for producing n-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride |
-
1984
- 1984-11-28 JP JP59249762A patent/JPS61129159A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998008806A1 (en) * | 1996-08-28 | 1998-03-05 | Ajinomoto Co., Inc. | Method for purifying n-acylamino acid amides |
| JP2006525247A (en) * | 2003-05-06 | 2006-11-09 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Method for crystallizing guanidine salts |
| WO2007083620A1 (en) * | 2006-01-20 | 2007-07-26 | Kaneka Corporation | PROCESS FOR PRODUCTION OF β-AMINO-α-HYDROXY ACID AMIDE DERIVATIVE |
| US8183413B2 (en) | 2006-01-20 | 2012-05-22 | Kaneka Corporation | Process for production of β-amino-α-hydroxy carboxamide derivative |
| JP5260062B2 (en) * | 2006-01-20 | 2013-08-14 | 株式会社カネカ | Process for producing β-amino-α-hydroxy acid amide derivative |
| WO2009081608A1 (en) * | 2007-12-21 | 2009-07-02 | Kaneka Corporation | Process for producing n-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride |
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