JPS62212352A - Production of carnitine intermediate - Google Patents
Production of carnitine intermediateInfo
- Publication number
- JPS62212352A JPS62212352A JP5521586A JP5521586A JPS62212352A JP S62212352 A JPS62212352 A JP S62212352A JP 5521586 A JP5521586 A JP 5521586A JP 5521586 A JP5521586 A JP 5521586A JP S62212352 A JPS62212352 A JP S62212352A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- chloromethyloxirane
- carnitine
- trimethylamine
- mathematical
- 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
- 229960004203 carnitine Drugs 0.000 title claims abstract description 19
- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 title claims abstract 3
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 239000005703 Trimethylamine hydrochloride Substances 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 5
- SZYJELPVAFJOGJ-UHFFFAOYSA-N trimethylamine hydrochloride Chemical compound Cl.CN(C)C SZYJELPVAFJOGJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000004367 Lipase Substances 0.000 claims abstract description 4
- 102000004882 Lipase Human genes 0.000 claims abstract description 4
- 108090001060 Lipase Proteins 0.000 claims abstract description 4
- 238000004821 distillation Methods 0.000 claims abstract description 4
- 235000019421 lipase Nutrition 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims abstract 3
- 150000002314 glycerols Chemical class 0.000 claims abstract 2
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- -1 ester compound Chemical class 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 3
- CSPHGSFZFWKVDL-UHFFFAOYSA-M (3-chloro-2-hydroxypropyl)-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)CCl CSPHGSFZFWKVDL-UHFFFAOYSA-M 0.000 abstract 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 abstract 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 abstract 1
- 230000003287 optical effect Effects 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 244000005700 microbiome Species 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- RIAJTMUAPNIDSS-UHFFFAOYSA-N 3-aminopropan-1-ol;hydron;chloride Chemical compound Cl.NCCCO RIAJTMUAPNIDSS-UHFFFAOYSA-N 0.000 description 1
- YNOWULSFLVIUDH-UHFFFAOYSA-N 3-dehydrocarnitine Chemical compound C[N+](C)(C)CC(=O)CC([O-])=O YNOWULSFLVIUDH-UHFFFAOYSA-N 0.000 description 1
- UCTNTYHJFWMUBD-UHFFFAOYSA-N 4-chloro-3-oxobutanoic acid Chemical compound OC(=O)CC(=O)CCl UCTNTYHJFWMUBD-UHFFFAOYSA-N 0.000 description 1
- 206010058892 Carnitine deficiency Diseases 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229960000678 carnitine chloride Drugs 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 238000001032 ion-exclusion chromatography Methods 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 208000016505 systemic primary carnitine deficiency disease Diseases 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分身〕
本発明は（ＩＱ−力ルニチンの合成中間体の製造方法に
関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application] The present invention relates to a method for producing a synthetic intermediate of IQ-lunithine.
カルニチン（３−ヒドロキシ−γ−トリメチルアミノ酪
酸）は１ケの不斉中心を有するため、（２）及び（８）
体、２種の光学異性体が存在する。（１）−力ルニチン
はビタミンＢＴとして知られ、生体内に広く分布してお
り、長鎖脂肪酸のキャリアーとして重要な化合物である
。カルニチン欠乏症の治療には従来（ｄ＃）−カルニチ
ンが用いられて来たが、近年＜１＞体のみを使用する方
が治療上はるかに効果的であることが明らかとなり、（
Ｏ−カルニチンの重要性が注目されて来ている。更に詳
しくは、本発明は、（Ｓ）−クロルメチルオキシランよ
（Ｖ０１）カルニチンに誘導される。Carnitine (3-hydroxy-γ-trimethylaminobutyric acid) has one asymmetric center, so (2) and (8)
There are two types of optical isomers. (1) - Rurnitine is known as vitamin BT, is widely distributed in living organisms, and is an important compound as a carrier of long-chain fatty acids. Conventionally, (d#)-carnitine has been used to treat carnitine deficiency, but in recent years it has become clear that using only <1> carnitine is much more effective therapeutically.
The importance of O-carnitine has been attracting attention. More specifically, the present invention is derived from (S)-chloromethyloxirane to (V01)carnitine.
従来の＜１）−力ルニチンの製造法としては、（イ）（
ｄＩＩ）−カルニチン、あるいは中間体である（几Ｓ）
−カルニチノニトリルの化学的光学分′剖法（特開昭５
９−１９９６６６、同５９−２８１０４８）、（ｒ：４
微生物を利用する分割法（特開昭６Ｏ−２１４８９
８）、（ハ） ｒ−ブチロベタイン、あるいはｒ−クロ
トノベタインの微生物による不斉水酸化（特開昭５７−
８９７９１．同５９−１８８６９４゜同５９−１９２０
２５．同６０−１８７２９５゜同６０−２１４８９０．
同６Ｏ−２２４４８８）、に） γ−クロルーβ−ケト
酪酸及びその誘導体、あるいは３−デヒドロカルニチン
の微生物による不斉ｉ′近元（′特開昭５９−１１８０
７８．ＵＳＰ−４，２２１，８６９）、（ホ）の）−マ
ンニトールからの合成（待）０昭５７−１６５３５２）
などが知られているが、（イ）は高価な光学分割剤の使
用と回収の問題があり、微生物を利用する（口）（ハ）
に）の方法は反応率が概して不充分である欠点を有し、
Ｑ的の方法は１俣が極めて長い上に、四酢酸鉛、トリフ
ェニルホスフィンなど取り扱いにくい、あるいは高価な
反応試剤を使用しなければならない不利な点があって、
いずれも人里有利な生産を目的とする工業的製造法には
適していない。Conventional <1)-methods for producing lurnithine include (a) (
dII)-carnitine or intermediate (几S)
- Chemical optical dissection method of carnitinonitrile (Japanese Patent Application Laid-open No. 5
9-199666, 59-281048), (r:4
Division method using microorganisms (JP-A-6O-21489
8), (c) Asymmetric hydroxylation of r-butyrobetaine or r-crotonobetaine by microorganisms (JP-A-57-
89791. 59-188694゜59-1920
25. 60-187295゜60-214890.
6O-224488), 2) Asymmetric i' neighborhood of γ-chloro-β-ketobutyric acid and its derivatives, or 3-dehydrocarnitine caused by microorganisms ('JP 59-1180
78. USP-4,221,869), Synthesis from (e)-mannitol (wait)0 1984-165352)
are known, but (b) has problems with the use and recovery of expensive optical resolution agents, and the use of microorganisms (mouth) (c)
The method of (2) has the disadvantage that the reaction rate is generally insufficient;
Q's method has the disadvantage that one block is extremely long and requires the use of difficult or expensive reaction reagents such as lead tetraacetate and triphenylphosphine.
None of these methods are suitable for industrial manufacturing methods aimed at profitable production.
本発明者等は、先に高光学純度の（Ｓ）−クロルメチル
オキシランｌを高収率で極めて容易に、かつ大量に調製
する方法を明らかにした（特願昭６Ｏ−２９８４８１）
。この光学活性（Ｓ）−クロルメチルオキシランを原料
にして次式に示す経路で（ノーカルニチンの合成を試み
た。The present inventors previously revealed a method for preparing (S)-chloromethyloxirane l with high optical purity in high yield, extremely easily, and in large quantities (Japanese Patent Application No. 6O-298481).
. Using this optically active (S)-chloromethyloxirane as a raw material, an attempt was made to synthesize no-carnitine by the route shown in the following formula.
既に（Ｒ８）−クロルメチルオキシランを用い、２ある
いは５のラセミ体を経て（ｄＩり一カルニチンへ導びく
方法（特公昭３７−５１７１．同４２−１５５２８、同
５ｌ−４１６１７）は公知である。A method of using (R8)-chloromethyloxirane to lead to dI-carnitine via the racemic form of 2 or 5 (Japanese Patent Publications No. 37-5171, No. 42-15528, No. 51-41617) is known.
同じ＜（Ｒ８）−クロルメチルオキシランから出発して
光学分割によって得られる（Ｓ） −２、あるいは（Ｓ
）−２から導びかれる（Ｓ）−５を経て（Ｏ−カルニチ
ンを合成する方法も知られている（特開昭６Ｏ−２８１
６８２）。しかし光学活性（Ｓ）−クロルメチルオキシ
ランを出発原料として（の−カルニチンへ誘導した報告
はなく、また光学活性が各工程に於いて保持されるかど
うかも未知であった。クロルメチルオキシランは反応活
性部位を２ケ所有し、その光学活性体を用いる場合は、
位置選択的に反応させないとラセミ化する懸念があった
。（Ｓ）−クロルメチルオキシランから完全に立体保持
で（Ｓ） −２または（８）−５に誘導できれば、それ
から（→−カルニチンへは立体保持で導びけることは知
られているので、従来法に比べ極めて短い工程で、かっ
高収率で（の−カルニチンを製造できる。(S)-2 obtained by optical resolution starting from the same <(R8)-chloromethyloxirane, or (S)
)-2 is derived from (S)-5 to synthesize (O-carnitine).
682). However, there has been no report on the derivation of optically active (S)-chloromethyloxirane into (-carnitine) as a starting material, and it was also unknown whether the optical activity was maintained in each step. When using an optically active substance that has two active sites,
There was a concern that racemization would occur unless the reaction was carried out regioselectively. It is known that if (S)-2 or (8)-5 can be derived from (S)-chloromethyloxirane with complete steric retention, then it can be derived from (→-carnitine) with steric retention. It is possible to produce (-carnitine) with a high yield in an extremely short process compared to the conventional method.
〔問題を解決する為の手段１作用効果〕本発明は光学活
性（Ｓ）−クロルメチルオキシラン１を原料として用い
、塩酸トリメチルアミンと反応させて（ｔ）−カルニチ
ンの光学活性中間体である（８） −８−クロル−２−
ヒドロキシプロピルアンモニウムクロリド２の製造方法
に関するものである。[Means to Solve the Problem 1 Effects] The present invention uses optically active (S)-chloromethyloxirane 1 as a raw material and reacts it with trimethylamine hydrochloride to produce an optically active intermediate of (t)-carnitine (8 ) -8-chlor-2-
The present invention relates to a method for producing hydroxypropylammonium chloride 2.
本発明者等は、特願昭６０−２９８４８１に於いて、一
般式
％式％）
（式中、几は０１〜Ｃ８の脂肪族炭化水素基、几′は芳
香族炭化水素基）で表わされるラセミ体基質（Ｒ８）−
８を不斉加水分解能を有するリパーゼで処理する事によ
り、一般式
（式中、Ｒ，Ｒ’は上記に同じ）で表わされる未反応光
学活性エステル体（２）−８と、一般式（式中、几′は
上記に同じ）で表わされる光学活性アルコール体（８）
−４の等モル量混合物を得、次いでこの混合物に塩基
処理を施すと（Ｓ）−４のみが選択的にエポキシ化し、
（Ｓ）−クロルメチルオキシラン１に変換され、このも
のは蒸留操作により容易に■−８と分離され、しかも極
めて高光学純度を有する事を明らかにした。残渣として
得られるエステル体（２）−８は別途、同じく（０−カ
ルニチンへ導びかれる。In Japanese Patent Application No. 60-298481, the present inventors proposed the following formula: Racemic substrate (R8)-
By treating 8 with a lipase having asymmetric hydrolyzing ability, unreacted optically active ester (2)-8 represented by the general formula (wherein R and R' are the same as above) and the general formula (formula an optically active alcohol (8) represented by
-4 is obtained, and then this mixture is treated with a base, so that only (S)-4 is selectively epoxidized,
It was revealed that it was converted to (S)-chloromethyloxirane 1, which was easily separated from (1)-8 by distillation and had extremely high optical purity. The ester (2)-8 obtained as a residue is separately led to (0-carnitine).
（Ｓ）−クロルメチルオキシランを塩酸トリメチルアミ
ンの１から２等量、好ましくは１．１〜１．５等量を含
む、１０％から５０％、好ましくは８０％から５０％の
水溶液に１５゛Ｃから１００゛Ｃ１好ましくは４０゛Ｃ
から５０°Ｃの温度で滴下すると反応は速やかに進行す
る。ガスクロマトグラフィーで１の消失を確認した後、
減圧上濃縮し、次いでアルコール、好ましくはエタノー
ルから晶析させることにより光学活性（Ｓ） −Ｓ−ク
ロル−２−ヒドロキシプロピルトリメチルアンモニウム
クロリド２が高収率、高光学純度で得られる。■）−２
は公知の方法によって（０−カルニチンへ導びかれる（
特開昭５７−１６５ｆ１１５２．同６Ｏ−２８１６８２
）。(S)-Chloromethyloxirane is dissolved in a 10% to 50%, preferably 80% to 50% aqueous solution containing 1 to 2 equivalents, preferably 1.1 to 1.5 equivalents, of trimethylamine hydrochloride at 15°C. From 100゛C1 preferably 40゛C
When added dropwise at a temperature of 50°C to 50°C, the reaction proceeds rapidly. After confirming the disappearance of 1 by gas chromatography,
By concentrating under reduced pressure and then crystallizing from alcohol, preferably ethanol, optically active (S)-S-chloro-2-hydroxypropyltrimethylammonium chloride 2 is obtained in high yield and high optical purity. ■)-2
is derived from (0-carnitine) by a known method (
JP-A-57-165f1152. 6O-281682
).
■）−クロルメチルオキシランから出発して途中の工程
で精製することなく（ｊ’）−カルニチンクロリドまで
誘導し、過剰に用いた反応試剤及び副生する無機塩をイ
オン排除クロマトグラフィーで除き精製してもよい。■) Starting from -chloromethyloxirane, it is derived to (j')-carnitine chloride without purification in intermediate steps, and the excess reaction reagent and by-product inorganic salts are removed and purified by ion exclusion chromatography. It's okay.
以上説明したように、本発明によれば容易に得られる高
光学純度の（Ｓ）−クロルメチルオキシラン１を原料に
用いることにより、光学分−刀などの繁雑な工程を伴う
ことなく（クーカルニチンへ誘導できる高光学純度の中
間体を有利に製造できる。As explained above, according to the present invention, by using (S)-chloromethyloxirane 1 of high optical purity, which is easily obtained, as a raw material, there is no need for complicated processes such as optical spectroscopy (Cucarnitin It is possible to advantageously produce intermediates of high optical purity that can be induced into .
以下、実施例で説明するが、本発明はこれ等の実施例に
限定されるものではない。なお、実施例１及び参考例２
で得られた化合物については特開昭６０−２３１６８２
記載の各種データと比較し同定した。Examples will be described below, but the present invention is not limited to these examples. In addition, Example 1 and Reference Example 2
Regarding the compound obtained in JP-A-60-231682,
Identification was made by comparing with the various data listed.
実施例１ （Ｓ）−８−クロル−２−ヒドロキシプロ
ピルトリメチルアンモニウムクロリド２の合成塩酸トリ
メチルアミン９．５ＦＭを水１０ｓ＋ｌに溶解し、４０
°Ｃに加温する。撹拌下、温度が５０″Ｃを越えないよ
う、９．２５１の（Ｓ）−クロルメチルオキシラン（参
考例１参照）を滴下し、！西下終了後４０〜５０°Ｃで
２時間反応させる。減圧上濃縮し、残渣を２５ｍ１のエ
タノールに加熱溶解し、放冷、晶析させた。収量１５．
２Ｆ（８１％）融点２１４〜２１５°Ｃ
（ａ−］ ”ｏ ＝２９．５’ （ａ−１，０８、Ｒ２
０）〔文献ｌｌ［Ｉ（特開昭６Ｏ−２８１６８２）；融
点２１４°Ｃ，（α’）”＝−２９，５°（ａ＝１．Ｒ
２０） ）〈参考例１＞（Ｓ）−クロルメチルオキシラ
ンの調製（Ｒ８）−８−クロル−２−アセトキシブロピ
ルギノサ（Ｐｓｅｕｄｏｍｏｎａｓ ａｅｒｕｇｉｎｏ
ｓａ ）起源の市販リパーゼ［アマノＰＪ（大野製薬（
（７）製）Ｏ−８９゜及び水１５０＋ｔを含む反応液を
４０°Ｃ，５Ｎ−ＮａＯＨでｐＨを７．２に床ちながら
不斉加水分解を行う。反応は約４時間で終了し、冷却後
１５０Ｊ１／のエーテルで２回抽出する。エーテル７１
を硫酸ソーダーで脱水し、α０−８−クロル−２−７セ
トキシブロビルーｐ−トルエンスルホネート２−ヒドロ
キシプロピル−ｐ−トルエンスルホネエーテル溶液を得
る。Example 1 Synthesis of (S)-8-chloro-2-hydroxypropyltrimethylammonium chloride 2 Trimethylamine hydrochloride (9.5 FM) was dissolved in 10 s+l of water.
Warm to °C. While stirring, 9.251 (S)-chloromethyloxirane (see Reference Example 1) was added dropwise so that the temperature did not exceed 50''C, and the reaction was carried out at 40-50°C for 2 hours after completion of heating. It was concentrated under reduced pressure, and the residue was heated and dissolved in 25 ml of ethanol, allowed to cool, and crystallized. Yield: 15.
2F (81%) melting point 214-215 °C (a-] ”o = 29.5' (a-1,08, R2
0) [Reference ll [I (JP-A-6O-281682); melting point 214°C, (α')" = -29.5° (a = 1.R
20) ) <Reference Example 1> Preparation of (S)-chloromethyloxirane (R8)-8-chloro-2-acetoxybropyrginosa (Pseudomonas aerugino)
sa ) origin commercially available lipase [Amano PJ (Ohno Pharmaceutical Co., Ltd.
(7)) A reaction solution containing O-89° and 150+ tons of water is subjected to asymmetric hydrolysis at 40°C while adjusting the pH to 7.2 with 5N-NaOH. The reaction was completed in about 4 hours, and after cooling, the mixture was extracted twice with 150 J/l of ether. ether 71
is dehydrated with sodium sulfate to obtain a solution of α0-8-chloro-2-7cetoxybroby-p-toluenesulfonate 2-hydroxypropyl-p-toluenesulfone ether.
このエーテル溶液を約１００ＪＩ／まで製品し、水５０
ｇ／を加え、ａｏ’ｃで撹拌下５ Ｎ −Ｎａ０Ｅｌを
滴下する。ｐＨは１２．０になるよう滴下速度を調整す
る。反応はＨＰＬＯで（Ｓ） −８−クロル−２−ヒド
ロキシプロピル−ｐ−トルエンスルホネートの消失を追
跡すると、約４時間で終了する。エーテル層を硫酸ソー
ダーで脱水し、（Ｓ）−クロルメチルオキシランの含量
をガスクロマトグラフィーで分析すると１３．９８ｖ（
８５％）相当量であった。エーテルをバス温５０°Ｃで
溜去した後、パス温１４０°Ｃで（Ｓ）−クロルメチル
オキシランを蒸留した。このものはガスクロマトグラフ
ィーで９８％の純度であった。収ｆ１８．２８ｇ（７０
％）（α）”＝＋ ８８．４°（Ｃ＝１．８９．ＭｅＯ
Ｈ）〔文献値（Ｊ、 Ｏｒｇ、 Ｏｈｅｍ、、４８．４
８７６（１９７Ｂ））；〔ａゾ８−一ト ８８．０°
（０＝１．２６． ＭｅＯＨ））蒸留残渣から光学純
度１００％の（６）−８−クロル−２−アセトキシプロ
ピル−ｐ−トルエンスルホネートが結晶として得られ、
このものは別途（１り一カルニチンへ誘導される。This ether solution is processed to about 100 JI/
g/, and 5 N-Na0El is added dropwise while stirring ao'c. Adjust the dropping rate so that the pH is 12.0. The reaction was completed in about 4 hours when the disappearance of (S)-8-chloro-2-hydroxypropyl-p-toluenesulfonate was monitored by HPLO. The ether layer was dehydrated with sodium sulfate, and the content of (S)-chloromethyloxirane was analyzed by gas chromatography to find that it was 13.98v (
85%). After distilling off the ether at a bath temperature of 50°C, (S)-chloromethyloxirane was distilled at a bath temperature of 140°C. This product was found to be 98% pure by gas chromatography. Yield f18.28g (70
%)(α)”=+88.4°(C=1.89.MeO
H) [Literature value (J, Org, Ohem, 48.4
876 (197B)); [azo 8-1 88.0°
(0=1.26.MeOH)) (6)-8-chloro-2-acetoxypropyl-p-toluenesulfonate with 100% optical purity was obtained as crystals from the distillation residue,
This product is separately derived (one by one) to carnitine.
＜参考例２〉 （の−カルニチノニトリルの合成実施例
１で得られた（Ｓ）−ａ−クロル−２−ヒドロキシプロ
ピルトリメチルアンモニウムクロリド８７．６Ｆを９５
％メタノール５０ｍ１に５０°Ｃで加熱溶解させ、次い
で１６ｇ／の水に溶解したシアン化ナトリウム１０．８
ｇを撹拌下１５分で滴下し、さらに３０分同温度で反応
させる。加熱を止めた後６Ｎ−Ｈ０１でｐＨ４〜５にし
、次いで氷冷する。<Reference Example 2> (S)-a-chloro-2-hydroxypropyltrimethylammonium chloride 87.6F obtained in Synthesis Example 1 of -carnitinonitrile was 95
10.8% sodium cyanide dissolved in 50ml methanol heated at 50°C and then dissolved in 16g/water
g was added dropwise over 15 minutes with stirring, and the mixture was allowed to react for an additional 30 minutes at the same temperature. After stopping the heating, adjust the pH to 4 to 5 with 6N-H01, and then cool on ice.
沈澱したＭａｉｌを濾過した後、減圧乾固し、残渣をメ
タノールに加温溶解する。不溶物を濾過して放冷晶析さ
せる。収率２８．２Ｆ（７８，７％）融点２４１〜２４
８°ＣAfter filtering the precipitated Mail, it is dried under reduced pressure, and the residue is dissolved in methanol with heating. Insoluble matter is filtered and crystallized while cooling. Yield 28.2F (78,7%) Melting point 241-24
8°C
Claims (3)
学式、表等があります▼）を出発原料として塩酸トリメ
チルアミンと反応させ、（Ｓ）−３−クロル−２−ヒド
ロキシトリメチルアンモニウムクロリド■ （▲数式、化学式、表等があります▼）を得ることを特
徴と するカルニチン中間体の製造方法。(1) (S)-Chloromethyloxirane■ (▲Mathematical formula, chemical formula, table, etc. are available▼) is reacted with trimethylamine hydrochloride as a starting material to produce (S)-3-chloro-2-hydroxytrimethylammonium chloride■ (▲ A method for producing a carnitine intermediate, which is characterized by obtaining a mathematical formula, a chemical formula, a table, etc. ▼).
ｌＣＨ＿２ＣＨ（ＯＣＯＲ）ＣＨ＿２ＯＳＯ＿２Ｒ′・
・・（ＲＳ）−■（式中、ＲはＣ＿１〜Ｃ＿８の脂肪族
炭化水素基、Ｒ′は芳香族炭化水素基） で表わされるグリセロール誘導体を基質として（Ｓ）体
を選択的に加水分解する能力を有するリパーゼを作用さ
せ、一般式 ▲数式、化学式、表等があります▼・・・（Ｒ）−■ （式中、Ｒ、Ｒ′は前記に同じ）で表わされる未反応エ
ステル体（Ｒ）−■と、一般式 ▲数式、化学式、表等があります▼・・・（Ｓ）−■ （式中、Ｒ′は前記に同じ）で表わされるアルコール体
（Ｓ）−■との等モル量の混合物を生成せしめ、次いで
塩基処理を施すことにより（Ｓ）−■のみをエポキシ化
させ、更に蒸留分離することにより調製される特許請求
の範囲第１項記載の製造方法。(2) (S)-Chloromethyloxirane ■ has the general formula C
lCH_2CH(OCOR)CH_2OSO_2R'・
Selective hydrolysis of the (S) form using a glycerol derivative represented by (RS)-■ (in the formula, R is an aliphatic hydrocarbon group of C_1 to C_8, R' is an aromatic hydrocarbon group) as a substrate. The unreacted ester compound (R)-■ (wherein R and R' are the same as above) is treated with a lipase that has the ability to R)-■ and the alcohol compound (S)-■ represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(S)-■ (in the formula, R' is the same as above), etc. 2. The manufacturing method according to claim 1, which is prepared by forming a molar mixture, then treating with a base to epoxidize only (S)-■, and further separating by distillation.
チルアミンを無溶媒下に反応させる特許請求の範囲第１
項記載の製造方法。(3) Claim 1 in which (S)-chloromethyloxirane ■ and anhydrous trimethylamine are reacted without a solvent.
Manufacturing method described in section.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5521586A JPS62212352A (en) | 1986-03-11 | 1986-03-11 | Production of carnitine intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5521586A JPS62212352A (en) | 1986-03-11 | 1986-03-11 | Production of carnitine intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62212352A true JPS62212352A (en) | 1987-09-18 |
Family
ID=12992397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5521586A Pending JPS62212352A (en) | 1986-03-11 | 1986-03-11 | Production of carnitine intermediate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62212352A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02295952A (en) * | 1989-05-10 | 1990-12-06 | Daiso Co Ltd | Production of aqueous solution of 3-chloro-2-hydroxypropyltrimethylammonium chloride |
| JP2008133198A (en) * | 2006-11-27 | 2008-06-12 | Mitsubishi Rayon Co Ltd | Method for producing l-carnitine |
| CN115636771A (en) * | 2022-11-01 | 2023-01-24 | 宁夏坤正生物科技有限公司 | Optimized synthesis method for cyanidation reaction in L-carnitine production process |
| CN115850113A (en) * | 2022-12-16 | 2023-03-28 | 山东阳谷华泰化工股份有限公司 | Synthetic method of L-Carlactonitrile |
-
1986
- 1986-03-11 JP JP5521586A patent/JPS62212352A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02295952A (en) * | 1989-05-10 | 1990-12-06 | Daiso Co Ltd | Production of aqueous solution of 3-chloro-2-hydroxypropyltrimethylammonium chloride |
| JP2008133198A (en) * | 2006-11-27 | 2008-06-12 | Mitsubishi Rayon Co Ltd | Method for producing l-carnitine |
| CN115636771A (en) * | 2022-11-01 | 2023-01-24 | 宁夏坤正生物科技有限公司 | Optimized synthesis method for cyanidation reaction in L-carnitine production process |
| CN115850113A (en) * | 2022-12-16 | 2023-03-28 | 山东阳谷华泰化工股份有限公司 | Synthetic method of L-Carlactonitrile |
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