JPH0523256B2 - - Google Patents
Info
- Publication number
- JPH0523256B2 JPH0523256B2 JP15303987A JP15303987A JPH0523256B2 JP H0523256 B2 JPH0523256 B2 JP H0523256B2 JP 15303987 A JP15303987 A JP 15303987A JP 15303987 A JP15303987 A JP 15303987A JP H0523256 B2 JPH0523256 B2 JP H0523256B2
- Authority
- JP
- Japan
- Prior art keywords
- hydroxybutyronitrile
- reaction
- amino
- azide
- azido
- 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.)
- Expired - Fee Related
Links
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical group [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- HBRGVTLYZNPAFJ-UHFFFAOYSA-N 4-azido-3-hydroxybutanenitrile Chemical compound N#CCC(O)CN=[N+]=[N-] HBRGVTLYZNPAFJ-UHFFFAOYSA-N 0.000 claims description 5
- -1 azide salt Chemical class 0.000 claims description 5
- LHBPNZDUNCZWFL-UHFFFAOYSA-N 4-chloro-3-hydroxybutanenitrile Chemical compound ClCC(O)CC#N LHBPNZDUNCZWFL-UHFFFAOYSA-N 0.000 claims description 4
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims 1
- 238000000034 method Methods 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- HBRGVTLYZNPAFJ-SCSAIBSYSA-N (3R)-4-azido-3-hydroxybutanenitrile Chemical compound N#CC[C@@H](O)CN=[N+]=[N-] HBRGVTLYZNPAFJ-SCSAIBSYSA-N 0.000 description 5
- AFSJSMGLWQBMPX-UHFFFAOYSA-N 4-amino-3-hydroxybutanenitrile Chemical compound NCC(O)CC#N AFSJSMGLWQBMPX-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- BRLQWZUYTZBJKN-VKHMYHEASA-N (-)-Epichlorohydrin Chemical compound ClC[C@H]1CO1 BRLQWZUYTZBJKN-VKHMYHEASA-N 0.000 description 4
- YQGDEPYYFWUPGO-GSVOUGTGSA-N (3r)-4-amino-3-hydroxybutanoic acid Chemical compound NC[C@H](O)CC(O)=O YQGDEPYYFWUPGO-GSVOUGTGSA-N 0.000 description 4
- LHBPNZDUNCZWFL-SCSAIBSYSA-N (3r)-4-chloro-3-hydroxybutanenitrile Chemical compound ClC[C@H](O)CC#N LHBPNZDUNCZWFL-SCSAIBSYSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- BYJAJQGCMSBKPB-UHFFFAOYSA-N 3-hydroxybutanenitrile Chemical compound CC(O)CC#N BYJAJQGCMSBKPB-UHFFFAOYSA-N 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BAPRUDZDYCKSOQ-RITPCOANSA-N (2s,4r)-1-acetyl-4-hydroxypyrrolidine-2-carboxylic acid Chemical compound CC(=O)N1C[C@H](O)C[C@H]1C(O)=O BAPRUDZDYCKSOQ-RITPCOANSA-N 0.000 description 1
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-HWQSCIPKSA-N L-arabinopyranose Chemical compound O[C@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-HWQSCIPKSA-N 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- MHRSSQGDFHPZPL-SNVBAGLBSA-N [(2r)-3-cyano-2-hydroxypropyl] 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OC[C@H](O)CC#N)C=C1 MHRSSQGDFHPZPL-SNVBAGLBSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- YQGDEPYYFWUPGO-UHFFFAOYSA-N gamma-amino-beta-hydroxybutyric acid Chemical class [NH3+]CC(O)CC([O-])=O YQGDEPYYFWUPGO-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は医薬品である（Ｒ）−４−アジド−３
−ヒドロキシ酪酸を合成するための中間体として
有用な（Ｒ）−４−アジド−３−ヒドロキシブチ
ロニトリルの製法に関する。Detailed Description of the Invention (Industrial Field of Application) The present invention is a pharmaceutical product (R)-4-azido-3
- A method for producing (R)-4-azido-3-hydroxybutyronitrile useful as an intermediate for synthesizing hydroxybutyric acid.
（従来の技術とその問題点）
（Ｒ）−４−アミノ−３−ヒドロキシ酪酸は、
その薬効として脳代謝改善作用、脳血流量増加作
用、血圧降下作用、鎮静作用等がある。現在ラセ
ミ体で使用されているが、生物活性を示すのは
（Ｒ）体であり、したがつて（Ｒ）体のみを高純
度で得ることが重要である。（Ｒ）−４−アミノ−
３−ヒドロキシ酪酸の製法として従来知られてい
るのは次のごとくである。(Prior art and its problems) (R)-4-Amino-3-hydroxybutyric acid is
Its medicinal effects include improving brain metabolism, increasing cerebral blood flow, lowering blood pressure, and sedating. Although it is currently used in racemic form, it is the (R) form that exhibits biological activity, and therefore it is important to obtain only the (R) form in high purity. (R)-4-amino-
Conventionally known methods for producing 3-hydroxybutyric acid are as follows.
Ｌ−アスコルビン酸を出発原料とする方法
（J.Am.Chem.Soc.，第102巻，6304頁
（1980））。 A method using L-ascorbic acid as a starting material (J.Am.Chem.Soc., Vol. 102, p. 6304 (1980)).
Ｌ−アラビノーズを出発原料とする方法
（Acta.Chem.Scand.B，第37巻，344頁
（1983））。 A method using L-arabinose as a starting material (Acta.Chem.Scand.B, Vol. 37, p. 344 (1983)).
シヤープレス酸化により不斉合成する方法
（J.Org.Chem.，第49巻、3707頁（1984））。 A method for asymmetric synthesis by shear press oxidation (J.Org.Chem., Vol. 49, p. 3707 (1984)).
酸素及び微生物を利用する方法
（Tetrahedron Lett，第25巻、5235頁（1984），
Tetrahedron Lett，第26巻、101頁（1985），
J.Bull.Soc.Chem：Fr，103頁（1980），J.Am.
Chem.Soc，第105巻、5925頁（1983），
Angew.Chem.Int.Ed.Engl，第23巻151頁
（1984），J.Am.Chem.Soc，第107巻、4028頁
（1985））。 Methods using oxygen and microorganisms (Tetrahedron Lett, Vol. 25, p. 5235 (1984),
Tetrahedron Lett, Vol. 26, p. 101 (1985),
J.Bull.Soc.Chem: Fr, 103 pages (1980), J.Am.
Chem.Soc, vol. 105, p. 5925 (1983),
Angew.Chem.Int.Ed.Engl, Vol. 23, p. 151 (1984), J.Am.Chem.Soc, Vol. 107, p. 4028 (1985)).
（2S，4R）−Ｎ−アセチル−４−ヒドロキシ
プロリンを出発原料とする方法（Synthesis424
頁（1986））。 A method using (2S,4R)-N-acetyl-4-hydroxyproline as a starting material (Synthesis424
(1986)).
カルニチン及び４−アミノ−３−ヒドロキシ
酪酸誘導体の分割による方法（特公昭40−
3891、特公昭43−8248、特公昭43−26849、特
公昭43−26850、特公昭47−6609、特開昭51−
100026、特開昭52−133920、特開昭52−
133933、特開昭55−13299、特開昭59−
199666）。 Method by resolution of carnitine and 4-amino-3-hydroxybutyric acid derivatives (Special Publication 1979-
3891, Special Publication No. 43-8248, Special Publication No. 43-26849, Special Publication No. 43-26850, Special Publication No. 47-6609, No. 51- Publication of Special Publication
100026, JP-A-52-133920, JP-A-52-
133933, JP-A-55-13299, JP-A-59-
199666).
以上の方法のうち））は工程数が多いこ
と、）は生成物の光学純度の低いこと）は反
応濃度の低いこと、あるいは光学純度の低いこ
と、）は出発原料が高価であること、）は最
高収率が50％であつて得られた物質の50％は失わ
れること等の点でそれぞれ問題が残る。 Among the above methods, )) has a large number of steps, ) has low optical purity of the product,) has low reaction concentration or low optical purity, ) has expensive starting materials, ) The maximum yield is 50%, and 50% of the obtained substance is lost, so each method has its own problems.
（問題点を解決するための手段）
本発明者らは上記の問題点を解決するために鋭
意検討を行つた結果、本発明を完成した。(Means for Solving the Problems) The present inventors have completed the present invention as a result of intensive studies to solve the above problems.
すなわち本発明は４−クロル−３−ヒドロキシ
ブチロニトリルをアジド塩と反応させることを特
徴とする４−アジド−３−ヒドロキシブチロニト
リルの製法である。 That is, the present invention is a method for producing 4-azido-3-hydroxybutyronitrile, which is characterized by reacting 4-chloro-3-hydroxybutyronitrile with an azide salt.
本発明によつて得られた（Ｒ）−４−アジド−
３−ヒドロキシブチロニトリルは水素添加した
後、加水分解することにより、（Ｒ）−４−アミノ
−３−ヒドロキシ酪酸に変換できる点で有用な中
間体である。 (R)-4-Azide obtained by the present invention
3-hydroxybutyronitrile is a useful intermediate in that it can be converted to (R)-4-amino-3-hydroxybutyric acid by hydrogenation and then hydrolysis.
本発明方法はラセミ体の４−クロル−３−ヒド
ロキシブチロニトリルを用いてラセミ体の４−ア
ジド−３−ヒドロキシブチロニトリルを得ること
もできるが、光学活性体の原料を用いて光学活性
体の生成物を得ることが以上の理由により特に有
用である。 In the method of the present invention, racemic 4-azido-3-hydroxybutyronitrile can be obtained using racemic 4-chloro-3-hydroxybutyronitrile, but optically active It is particularly useful for these reasons to obtain body products.
ここで用いられる（Ｒ）−４−クロル−３−ヒ
ドロキシブチロニトリルは（Ｒ）−エピクロルヒ
ドリンに青酸を付加することによつて得られる。 (R)-4-chloro-3-hydroxybutyronitrile used here can be obtained by adding hydrocyanic acid to (R)-epichlorohydrin.
（Ｒ）−エピクロルヒドリンより（Ｒ）−４−ア
ミノ−３−ヒドロキシ酪酸を製造する概要を示す
と次のごとくである。 The outline of the production of (R)-4-amino-3-hydroxybutyric acid from (R)-epichlorohydrin is as follows.
本発明方法、すなわち（Ｒ）−４−クロル−３
−ヒドロキシブチロニトリル（Ｂ）より（Ｒ）−
４−アジド−３−ヒドロキシブチロニトリル
（Ｃ）を合成する反応は塩素とアジドの置換反応
である。 The method of the present invention, namely (R)-4-chloro-3
-Hydroxybutyronitrile (B) to (R)-
The reaction for synthesizing 4-azido-3-hydroxybutyronitrile (C) is a substitution reaction between chlorine and azide.
本発明法の反応に用いるアジド塩はナトリウム
アジド、カリウムアジドが好ましく、溶媒はジメ
チルホルムアミドあるいはアセトニトリル等の極
性溶媒が好ましい。反応は80〜90℃、２〜3.5時
間で終了する。 The azide salt used in the reaction of the present invention is preferably sodium azide or potassium azide, and the solvent is preferably a polar solvent such as dimethylformamide or acetonitrile. The reaction is completed in 2 to 3.5 hours at 80 to 90°C.
反応後溶液をエーテルで抽出し、このエーテル
層を洗浄、乾燥後、溶媒を留去して得られた残渣
を減圧蒸留して無色油状の（Ｒ）−４−アジド−
３−ヒドロキシブチロニトリルが得られる。その
収率は85〜90％である。 After the reaction, the solution was extracted with ether, the ether layer was washed and dried, the solvent was distilled off, and the resulting residue was distilled under reduced pressure to obtain (R)-4-azide as a colorless oil.
3-hydroxybutyronitrile is obtained. Its yield is 85-90%.
本発明方法によつて得られた（Ｒ）−４−アジ
ド−３−ヒドロキシブチロニトリル（Ｃ）より
（Ｒ）−４−アミノ−３−ヒドロキシブチロニトリ
ル（Ｄ）を合成する還元反応は水素還元用触媒の
存在で水素添加することによつて行われる。触媒
としては金属系触媒、例えばパラジウム、白金等
がよく、収率及び経済性の面でパラジウムが好ま
しい。特にパラジウムの含有量が10重量％程度の
パラジウム−炭素粉末が優れている。触媒の使用
量は原料化合物に対して0.5〜50重量％の範囲が
適当であり、溶媒中で通常室温（20〜25℃）、常
圧で３〜７時間反応を行う。収率は約94％程度で
ある。反応に際し用いられる溶媒としては、アル
コール類例えばメタノール、エタノール、ｎ−プ
ロパノール、イソプロパノール、ｔ−ブタノール
等あるいはこれらと水との混合物、エーテル類、
例えばエチルエーテル、テトラヒドロフラン、ジ
オキサン等が挙げられるが通常メタノールが好ま
しい。得られた（Ｒ）−４−アミノ−３−ヒドロ
キシブチロニトリル（Ｄ）は精製することなく次
の加水分解工程に用いられ目的の（Ｒ）−４−ア
ミノ−３−ヒドロキシ酪酸（Ｅ）に変換すること
ができる。 The reduction reaction for synthesizing (R)-4-amino-3-hydroxybutyronitrile (D) from (R)-4-azido-3-hydroxybutyronitrile (C) obtained by the method of the present invention is It is carried out by hydrogenation in the presence of a catalyst for hydrogen reduction. The catalyst is preferably a metal catalyst such as palladium or platinum, with palladium being preferred in terms of yield and economy. In particular, palladium-carbon powder with a palladium content of about 10% by weight is excellent. The appropriate amount of the catalyst used is 0.5 to 50% by weight based on the starting compound, and the reaction is usually carried out in a solvent at room temperature (20 to 25°C) and normal pressure for 3 to 7 hours. The yield is about 94%. Solvents used in the reaction include alcohols such as methanol, ethanol, n-propanol, isopropanol, t-butanol, etc. or mixtures of these with water, ethers,
Examples include ethyl ether, tetrahydrofuran, dioxane, etc., but methanol is usually preferred. The obtained (R)-4-amino-3-hydroxybutyronitrile (D) is used in the next hydrolysis step without purification to obtain the desired (R)-4-amino-3-hydroxybutyronitrile (E). can be converted to .
なお上記水素還元反応を加圧下で行う方法、及
び加水分解反応自体は公知であり、J.Am.Chem.
Soc.102、6304（1980）には水素還元反応を水素ガ
ス３気圧下、パラジウム−炭素粉末を触媒として
エタノール−クロロホルムの混合溶媒中1.5時間
で行う方法、及び加水分解反応についての記載が
ある。 The method of carrying out the above hydrogen reduction reaction under pressure and the hydrolysis reaction itself are well known, and are described in J.Am.Chem.
Soc. 102 , 6304 (1980) describes a method in which a hydrogen reduction reaction is carried out under 3 atmospheres of hydrogen gas in a mixed solvent of ethanol and chloroform using palladium-carbon powder as a catalyst for 1.5 hours, and a hydrolysis reaction.
実施例
この実施例において原料とした（Ｒ）−エピク
ロルヒドリンは本出願人の出願に係る特開昭61−
132196号、特公平１−55879号に記載の方法によ
り得られたものである。上記（Ｒ）−エピクロル
ヒドリンを弱塩基条件下でシアン化カリウム溶液
と反応させることにより（Ｒ）−４−クロル−３
−ヒドロキシブチロニトリルを得る。この（Ｒ）
−４−クロル−３−ヒドロキシブチロニトリル
（1.19ｇ、10mmol）をジメチルホルムアミド（20
ml）に溶かし、室温でナトリウムアジド（1.3ｇ，
20mmol）を加えた後、80〜90℃で３時間攪拌し
た。反応溶液を室温まで冷却後水を加え、エーテ
ルにより抽出し、このエーテル層を飽和食塩水で
洗浄、さらに硫酸マグネシウムで乾燥した後、溶
媒を減圧留去した。得られた残渣を減圧蒸留し
（135℃／1mmHg）、無色油状の（Ｒ）−４−アジ
ド−３−ヒドロキシブチロニトリル1.12ｇを得た
（収率86％）。そのスペクトルデータは次のとおり
である。Example The (R)-epichlorohydrin used as the raw material in this example is
It was obtained by the method described in No. 132196 and Japanese Patent Publication No. 1-55879. By reacting the above (R)-epichlorohydrin with a potassium cyanide solution under weak basic conditions, (R)-4-chloro-3
-Hydroxybutyronitrile is obtained. This (R)
-4-chloro-3-hydroxybutyronitrile (1.19 g, 10 mmol) was dissolved in dimethylformamide (20
ml) and at room temperature sodium azide (1.3 g,
After adding 20 mmol), the mixture was stirred at 80 to 90°C for 3 hours. After cooling the reaction solution to room temperature, water was added and extracted with ether. The ether layer was washed with saturated brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was distilled under reduced pressure (135° C./1 mmHg) to obtain 1.12 g of (R)-4-azido-3-hydroxybutyronitrile as a colorless oil (yield: 86%). The spectrum data is as follows.
〔α〕D−0.24（Ｃ，1.23，EtOH）
Ｈ−NMR（CDcl3）δ
2.63（2H，ｄ，Ｊ＝6.0Hz，−ＣH2 −CN）
3.44（2H，ｄ，Ｊ＝5.8Hz，−ＣH2 −N3）
3.85〜4.30（1H，ｍ−ＣＨ（OH））
3.30〜3.70（1H，br，exchangeable with D2Ｏ
−ＯＨ）
IR υCm-1：3460（OH），2260（CN），2112（N3）
参考例
（Ｒ）−４−アジド−３−ヒドロキシブチロニ
トリル（0.98ｇ，7.8mmol）をメタノール（20
ml）に溶かし、パラジウム−炭素粉末（パラジウ
ム含量10重量％、500mg）を加え、水素雰囲気下
室温で７時間攪拌させながら反応を行つた。反応
後、反応溶液をセライト濾過し、溶媒を減圧下留
去させて油状の（Ｒ）−４−アミノ−３−ヒドロ
キシブチロニトリル（0.73ｇ，収率94％）を得
た。（Ｒ）−４−アミノ−３−ヒドロキシブチロニ
トリル塩酸塩のスペクトルデータは次のとおりで
ある。[α] D −0.24 (C, 1.23, EtOH) H-NMR (CDcl 3 ) δ 2.63 (2H, d, J=6.0Hz, −CH 2 −CN) 3.44 (2H, d, J=5.8Hz, -C H 2 -N 3 ) 3.85-4.30 (1H, m-C H (OH)) 3.30-3.70 (1H, br, exchangeable with D 2 O
-OH ) IR υCm -1 : 3460 (OH), 2260 (CN), 2112 (N 3 ) Reference example (R) -4-azido-3-hydroxybutyronitrile (0.98 g, 7.8 mmol) was dissolved in methanol ( 20
ml), palladium-carbon powder (palladium content 10% by weight, 500 mg) was added, and the reaction was carried out with stirring at room temperature under a hydrogen atmosphere for 7 hours. After the reaction, the reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain oily (R)-4-amino-3-hydroxybutyronitrile (0.73 g, yield 94%). The spectral data of (R)-4-amino-3-hydroxybutyronitrile hydrochloride are as follows.
NMR（D2Ｏ，acetone−d6）
δ5.75（ｍ，2H，−ＣH2 −CN）
3.10（ｍ，2H，−ＣH2 −NH2）
4.10（ｍ，1H，−ＣＨ（OH）−）
4.60（Ｓ，HOD）
1R Cm-1：3400−2900（OH），2252（CN）
次に得られた（Ｒ）−４−アミノ−３−ヒドロ
キシブチロニトリルを“J.Am.Chem.Soc.102，
6304（1980）”記載の方法で加水分解を行つたとこ
ろ、〔α〕D−7.80°（Ｃ，100，H2Ｏ）の（Ｒ）−４
−アミノ−３−ヒドロキシ酪酸が得られ、文献値
の〔α〕D−7.09°（Ｃ，3.5，H2Ｏ）とほぼ一致して
いる。NMR (D 2 O, acetone-d 6 ) δ5.75 (m, 2H, -C H 2 -CN) 3.10 (m, 2H, -C H 2 -NH 2 ) 4.10 (m, 1H, -C H ( OH)-) 4.60 (S, HOD) 1R Cm -1 : 3400-2900 (OH), 2252 (CN) Next, the obtained (R)-4-amino-3-hydroxybutyronitrile was .Chem.Soc. 102 ,
6304 (1980)", (R)-4 of [α] D -7.80° (C, 100, H 2 O)
-Amino-3-hydroxybutyric acid is obtained, which is in close agreement with the literature value of [α] D -7.09° (C, 3.5, H2O ).
（発明の効果）
本発明によつて得られた（Ｒ）−４−アジド−
３−ヒドロキシブチロニトリルは、前記のごとく
高純度の（Ｒ）−４−アミノ−３−ヒドロキシ酪
酸に変換できる。(Effect of the invention) (R)-4-azide obtained by the present invention
3-hydroxybutyronitrile can be converted to highly purified (R)-4-amino-3-hydroxybutyric acid as described above.
この（Ｒ）−４−アジド−３−ヒドロキシブチ
ロニトリルは、従来（Ｒ）−４−（トシロキシ）−
３−ヒドロキシブチロニトリル、又は（Ｒ）−４
−（メシロキシ）−３−ヒドロキシブチロニトリル
をカルウムアジド、18−クラウン−６とアセトニ
トリル中で反応させ63〜77％で得る方法が知られ
ているが（J.Am.Chem.Soc.102、6304（1980））、
本発明方法はこれら従来法と比較して、試薬が安
価であること、収率が良いこと、さらに（Ｒ）−
エピクロルヒドリンを出発物質として２段階で得
られる等の点でより優れた方法である。 This (R)-4-azido-3-hydroxybutyronitrile is conventionally (R)-4-(tosyloxy)-
3-hydroxybutyronitrile, or (R)-4
A method is known in which -(mesyloxy)-3-hydroxybutyronitrile is reacted with potassium azide, 18-crown-6, in acetonitrile to obtain a concentration of 63 to 77% (J.Am.Chem.Soc. 102 , 6304 (1980)),
Compared to these conventional methods, the method of the present invention has inexpensive reagents, high yield, and (R)-
This method is superior in that it can be obtained in two steps using epichlorohydrin as a starting material.
Claims (1)
をアジド塩と反応させることを特徴とする４−ア
ジド−３−ヒドロキシブチロニトリルの製法。 ２ ４−クロル−３−ヒドロキシブチロニトリル
及び４−アジド−３−ヒドロキシブチロニトリル
が光学活性体である特許請求の範囲第１項記載の
製法。 ３ アジド塩がナトリウムアジド、カリウムアジ
ドである特許請求の範囲第１項もしくは第２項記
載の製法。[Scope of Claims] 1. A method for producing 4-azido-3-hydroxybutyronitrile, which comprises reacting 4-chloro-3-hydroxybutyronitrile with an azide salt. 2. The manufacturing method according to claim 1, wherein 4-chloro-3-hydroxybutyronitrile and 4-azido-3-hydroxybutyronitrile are optically active substances. 3. The manufacturing method according to claim 1 or 2, wherein the azide salt is sodium azide or potassium azide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15303987A JPS63316759A (en) | 1987-06-18 | 1987-06-18 | Production of 4-azide-3-hydroxybutyronitrile |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15303987A JPS63316759A (en) | 1987-06-18 | 1987-06-18 | Production of 4-azide-3-hydroxybutyronitrile |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63316759A JPS63316759A (en) | 1988-12-26 |
| JPH0523256B2 true JPH0523256B2 (en) | 1993-04-02 |
Family
ID=15553638
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15303987A Granted JPS63316759A (en) | 1987-06-18 | 1987-06-18 | Production of 4-azide-3-hydroxybutyronitrile |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63316759A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5210031A (en) * | 1989-07-20 | 1993-05-11 | Nitto Chemical Industry Co., Ltd. | Process for the production of R(-)-4-halo-3-hydroxybutyronitrile |
-
1987
- 1987-06-18 JP JP15303987A patent/JPS63316759A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63316759A (en) | 1988-12-26 |
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