JPH0381262A - Production of optically active substance of dihydropyridine-based calcium antagonist - Google Patents
Production of optically active substance of dihydropyridine-based calcium antagonistInfo
- Publication number
- JPH0381262A JPH0381262A JP21657889A JP21657889A JPH0381262A JP H0381262 A JPH0381262 A JP H0381262A JP 21657889 A JP21657889 A JP 21657889A JP 21657889 A JP21657889 A JP 21657889A JP H0381262 A JPH0381262 A JP H0381262A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- optically active
- carbamate
- formulas
- dihydropyridine
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 title abstract description 7
- 229940127291 Calcium channel antagonist Drugs 0.000 title abstract description 5
- 239000000480 calcium channel blocker Substances 0.000 title abstract description 5
- 239000013543 active substance Substances 0.000 title description 3
- 239000001913 cellulose Substances 0.000 claims abstract description 23
- 229920002678 cellulose Polymers 0.000 claims abstract description 23
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical class NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 239000007983 Tris buffer Substances 0.000 claims description 11
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 claims description 11
- -1 di-substituted phenyl Chemical group 0.000 claims description 10
- 230000003287 optical effect Effects 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- KBRZBBOTZJFKFH-UHFFFAOYSA-N (3,5-dichlorophenyl) carbamate Chemical compound NC(=O)OC1=CC(Cl)=CC(Cl)=C1 KBRZBBOTZJFKFH-UHFFFAOYSA-N 0.000 claims description 3
- CCENBZDJMALWCH-UHFFFAOYSA-N (4-chlorophenyl) carbamate Chemical compound NC(=O)OC1=CC=C(Cl)C=C1 CCENBZDJMALWCH-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 8
- CGAWJRUQVUFKNM-UHFFFAOYSA-N (4-tert-butylphenyl) carbamate Chemical compound CC(C)(C)C1=CC=C(OC(N)=O)C=C1 CGAWJRUQVUFKNM-UHFFFAOYSA-N 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 229920001221 xylan Polymers 0.000 abstract description 16
- 150000004823 xylans Chemical class 0.000 abstract description 11
- 238000011914 asymmetric synthesis Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 150000002367 halogens Chemical class 0.000 abstract description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract 2
- 230000002411 adverse Effects 0.000 abstract 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- 230000004048 modification Effects 0.000 abstract 1
- 238000012986 modification Methods 0.000 abstract 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 abstract 1
- 229960001783 nicardipine Drugs 0.000 description 15
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 14
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 6
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 6
- 230000005526 G1 to G0 transition Effects 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- ZBBHBTPTTSWHBA-XMMPIXPASA-N (R)-nicardipine Chemical compound C1([C@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)OCCN(C)CC=2C=CC=CC=2)=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-XMMPIXPASA-N 0.000 description 2
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 2
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 2
- 229960001597 nifedipine Drugs 0.000 description 2
- 229960005425 nitrendipine Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 description 1
- XNRBLQMJVXSCAJ-UHFFFAOYSA-N (2-chlorophenyl) carbamate Chemical compound NC(=O)OC1=CC=CC=C1Cl XNRBLQMJVXSCAJ-UHFFFAOYSA-N 0.000 description 1
- JRCHSAHJTCLPDB-UHFFFAOYSA-N (2-tert-butylphenyl) carbamate Chemical compound CC(C)(C)C1=CC=CC=C1OC(N)=O JRCHSAHJTCLPDB-UHFFFAOYSA-N 0.000 description 1
- RRNGFPNDTJUIGS-UHFFFAOYSA-N (3,4-dichlorophenyl) carbamate Chemical compound NC(=O)OC1=CC=C(Cl)C(Cl)=C1 RRNGFPNDTJUIGS-UHFFFAOYSA-N 0.000 description 1
- SBTVLCPCSXMWIQ-UHFFFAOYSA-N (3,5-dimethylphenyl) carbamate Chemical compound CC1=CC(C)=CC(OC(N)=O)=C1 SBTVLCPCSXMWIQ-UHFFFAOYSA-N 0.000 description 1
- HGVPQJLGBGKLNF-UHFFFAOYSA-N (4-bromophenyl) carbamate Chemical compound NC(=O)OC1=CC=C(Br)C=C1 HGVPQJLGBGKLNF-UHFFFAOYSA-N 0.000 description 1
- ANJYDSPMBISEHY-UHFFFAOYSA-N (4-fluorophenyl) carbamate Chemical compound NC(=O)OC1=CC=C(F)C=C1 ANJYDSPMBISEHY-UHFFFAOYSA-N 0.000 description 1
- 229950005981 (s)-nicardipine Drugs 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960004916 benidipine Drugs 0.000 description 1
- QZVNQOLPLYWLHQ-ZEQKJWHPSA-N benidipine Chemical compound C1([C@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@H]2CN(CC=3C=CC=CC=3)CCC2)=CC=CC([N+]([O-])=O)=C1 QZVNQOLPLYWLHQ-ZEQKJWHPSA-N 0.000 description 1
- SRBFZHDQGSBBOR-KKQCNMDGSA-N beta-D-xylose Chemical group O[C@@H]1CO[C@@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-KKQCNMDGSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000002866 dihydropyridine calcium channel blocker Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004427 isradipine Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000012495 reaction gas Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、ジヒドロピリジン系カルシウム拮抗薬の光学
活性異性体混合物を光学分割し、光学活性なカルシウム
拮抗薬を製造する方法に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing an optically active calcium antagonist by optically resolving a mixture of optically active isomers of a dihydropyridine calcium antagonist.
（従来の技術および発明が解決しようとする課題） ジヒドロピリジン系カルシウム拮抗薬は。(Problems to be solved by conventional technology and invention) Dihydropyridine calcium channel blockers.
１．４−ジヒドロピリジン骨格を有するＣａ＋＋拮抗作
用を示す化合物であり２強力な血管拡張作用。1. A compound with a 4-dihydropyridine skeleton that exhibits Ca++ antagonistic action and 2. Strong vasodilatory action.
脳血流障害に基づく諸症状の改善作用、血圧降下作用等
を示す薬物である。この中、ニフェジピンおよびニカル
ジピンが臨床的に広く用いらており、このほか数種が治
験中である。これらのジヒドロピリジン系化合物は、ニ
フェジピンを除き、１．４−ジヒドロピリジン環の４位
に不斉炭素原子を持っており、立体異性体が存在する。It is a drug that improves various symptoms caused by cerebral blood flow disorders, lowers blood pressure, etc. Among these, nifedipine and nicardipine are widely used clinically, and several others are under clinical trials. These dihydropyridine compounds, except nifedipine, have an asymmetric carbon atom at the 4-position of the 1,4-dihydropyridine ring, and stereoisomers exist.
そして、それらの異性体は、（＋）体と（−）体では体
内動態や薬理効果において相違が認めめられることが報
告されているが、現在のところ臨床開発されているもの
は、大部分がラセミ体である。しかし、異性体の一方の
みを治療薬として用いることは、投与量が少なくてすむ
こと及び副作用の低減といった点から、非常に好ましい
ことであると考えられる。It has been reported that there are differences in pharmacokinetics and pharmacological effects between the (+) and (-) isomers of these isomers, but most of the isomers currently in clinical development are is racemic. However, using only one of the isomers as a therapeutic agent is considered to be highly preferable from the viewpoints of requiring less dosage and reducing side effects.
本発明者らは、ジヒドロピリジン系カルシウム拮抗薬の
光学活性異性体混合物、即ちラセ□体又は不斉合成法で
作られた一方の異性体を過剰に含む混合物から、純粋な
一種類の光学活性異性体を採取する方法について鋭意研
究した結果。The present inventors obtained a pure optically active isomer from a mixture of optically active isomers of a dihydropyridine calcium antagonist, that is, from a mixture containing an excess of one isomer made by racemic isomer or an asymmetric synthesis method. The result of intensive research on how to collect the body.
特定のキシラン誘導体又はセルロース誘導体を用いると
、かかる目的が達成できることを知見し９本発明に到達
し、た。The inventors have discovered that such objects can be achieved by using specific xylan derivatives or cellulose derivatives, and have arrived at the present invention.
（課題を解決するための手段） すなわち９本発明は、一般式（Ｉ） で示される基をまた。(Means for solving problems) That is, 9 the present invention provides general formula (I) Also the group shown in .
Ｒ２はメチル基又はシア
示される基を意味するときは Ｒ２はシアノ基を意味す
る。また本口は不斉炭素原子を示す。）で表わされるジ
ヒドロピリジン系カルシウム拮抗薬の光学活性異性体混
合物を、一般式（ＩＩ）（式中Ｒ３は、１〜３個のハロ
ゲン原子、低級アルキル基又は）・ロゲン化低級アルキ
ル基を表わす。Ｒ４は、水素原子又は式
−ＣＨ，−０−Ｃ０ＮＨ−（）′（（式中Ｒ３は、前記
と同じ意味を表わす））で示される基を表わす。）で表
わされる構造単位を有するキシラン ジ置換フェニルカ
ルバメート又はセルロース トリ置換フェニルカルバメ
ートを用いて光学分割することを特徴とする光学活性な
ジヒドロピリジン系カルシウム拮抗薬の製造法である。When R2 means a methyl group or a group represented by cya, R2 means a cyano group. In addition, honguchi indicates an asymmetric carbon atom. A mixture of optically active isomers of a dihydropyridine calcium antagonist represented by formula (II) (wherein R3 represents 1 to 3 halogen atoms, a lower alkyl group, or a halogenated lower alkyl group) is used. R4 represents a hydrogen atom or a group represented by the formula -CH, -0-C0NH-()' ((in the formula, R3 represents the same meaning as above)). ) is a method for producing an optically active dihydropyridine calcium antagonist characterized by optical resolution using xylan di-substituted phenyl carbamate or cellulose tri-substituted phenyl carbamate having the structural unit represented by:
本発明において用いられるジヒドロピリジン系カルシウ
ム拮抗薬としては、以下のものが挙げられる。The dihydropyridine calcium antagonists used in the present invention include the following.
また。Also.
本発明において用いられるキシラン
ジ置換フ
ェニルカルバメー
ト
またはセルロース
トリ置換フェニルカルバメートは、夫々キシランまたは
セルロースに置換フェニルインシアネートを反応させる
ことによって容易に得られる。The xylan di-substituted phenyl carbamate or cellulose tri-substituted phenyl carbamate used in the present invention can be easily obtained by reacting xylan or cellulose, respectively, with a substituted phenyl incyanate.
この反応で、キシランの基本単位であるβ−キシロピラ
ノース環に存在する２個の水酸基又はセルロースの基本
単位であるグルコース環に存在する３つの水酸基が、実
質的に全部置換フェニルカルバメート化される。本発明
におけるフェニル基の置換基とは、１〜３個のハロゲン
。In this reaction, substantially all of the two hydroxyl groups present in the β-xylopyranose ring, which is the basic unit of xylan, or the three hydroxyl groups present in the glucose ring, which is the basic unit of cellulose, are converted to substituted phenyl carbamate. The substituent of the phenyl group in the present invention is 1 to 3 halogens.
即ち、フッ素、塩素、臭素、ヨウ素又は炭素数が１〜４
個の１〜３個の低級アルキル基、又は１〜３個のハロゲ
ン化された低級アルキル基である。そして９本発明にお
いて好ましく用いられるキシラン ジ置換フェニルカル
バメートの例としては、キシラン ビス（３，５−ジク
ロロフェニルカルバメート）、キシラン ビス（クロロ
フェニルカルバメート）、キシラン ビス（４−ｔｅｒ
ｔ−ブチルフェニルカルバメート）。That is, fluorine, chlorine, bromine, iodine or carbon number is 1 to 4
1 to 3 lower alkyl groups, or 1 to 3 halogenated lower alkyl groups. 9 Examples of xylan disubstituted phenyl carbamates preferably used in the present invention include xylan bis(3,5-dichlorophenyl carbamate), xylan bis(chlorophenyl carbamate), xylan bis(4-ter
t-butylphenyl carbamate).
キシラン ビス（ｐ−１リルカルバメ−１・）である。It is xylan bis(p-1 lylcarbame-1.).
また、セルロース トリ置換フェニルカルバメートの例
は、セルロース トリス（３，４−ジクロロフェニルカ
ルバメート）、セルロース トリス（ｐ−１０ロフエニ
ルカルバメート）、セルロース トリス（ｐ −） Ｉ
Ｊルカルバメート）。Further, examples of cellulose tri-substituted phenyl carbamates include cellulose tris (3,4-dichlorophenyl carbamate), cellulose tris (p-10 lophenyl carbamate), cellulose tris (p-) I
J carbamate).
セルロース トリス（ｐ−フルオロフェニルカルバメー
ト）、セルロース トリス（α、α、α−トリフルオロ
トリルカルバメート、セルローストリス（ｐ−ブロモフ
ェニルカルバメート）。Cellulose Tris (p-fluorophenyl carbamate), Cellulose Tris (α, α, α-trifluorotolyl carbamate), Cellulose Tris (p-bromophenyl carbamate).
セルロース トリス（３，５−ジメチルフェニルカルバ
メート）である。Cellulose tris(3,5-dimethylphenylcarbamate).
本発明においては、かかるキシラン ジ置換フェニルカ
ルバメートまたはセルロース トリ置換フェニルカルバ
メートを用いてジヒドロピリジン系カルシウム拮抗薬の
光学活性異性体を光学分割する具体的手段・方法は、何
ら限定されるものではなく、公知のいかなる手段・方法
を採用してもよい。例えば、キシラン ジ置換フェニル
カルバメート又はセルロース トリ置換フェニルカルバ
メートをシリカゲルに担持させ。In the present invention, the specific means and method for optically resolving optically active isomers of dihydropyridine calcium antagonists using xylan di-substituted phenyl carbamate or cellulose tri-substituted phenyl carbamate are not limited in any way, and are known in the art. Any means or method may be used. For example, xylan di-substituted phenyl carbamate or cellulose tri-substituted phenyl carbamate is supported on silica gel.
これをカラムに充填してキラル固定相カラムとなし、無
極性溶媒や、含水有機溶媒のような極性の高い溶媒系を
用（・て、光学活性異性体を分割することができる。This is packed into a column to form a chiral stationary phase column, and optically active isomers can be resolved using a highly polar solvent system such as a nonpolar solvent or a water-containing organic solvent.
以下、実施例により本発明を詳述する。Hereinafter, the present invention will be explained in detail with reference to Examples.
実施例 １゜
キシラン ビス（３，５−ジクロロフェニルカルバメー
ト）を、３−アミノプロピルトリメトキシシラン処理し
た大孔径シリカゲル（粒子径１０μ、孔径１０００−４
０００Ａ ’）に２５ｗｔ％担持させて。Example 1 Large pore silica gel (particle size 10μ, pore size 1000-4
000A') was loaded at 25 wt%.
キラ段々固定相を調製し、これを長さ２５ｃｍ、内径０
．４６ ＣｍＯカラムに充填した。Prepare a Kira stepwise stationary phase, which is 25 cm long and has an inner diameter of 0.
．． It was packed into a 46 CmO column.
ヘキサン−イソプロパツール（ｓ：ｌ混ｉ）に０．１％
ジエチルアミンを加えた溶液を溶離液とし。0.1% in hexane-isopropanol (s:l mixture)
Use a solution containing diethylamine as the eluent.
ニカルジピン（ラセミ体）１．０Ｑ！を、２５℃、流速
０．５ｍＺ／分 で上記カラムを通した。クロマトグラ
フとして島津製作所ＬＣ−５Ａを用い、検出器としては
日本分光ＵＶＵＶ−１Ｏ０−波長２５４ ｎｍ ）を使
用して光学分割した。得られた流出パターンを第１図に
示した。第１図から明らかな通り９本発明の光学分割に
より、（＋）体（右旋性）が先に流出し１次いで（−）
体（左旋性）が流出する。Nicardipine (racemic) 1.0Q! was passed through the above column at 25°C and a flow rate of 0.5 mZ/min. Optical resolution was performed using Shimadzu LC-5A as a chromatograph and JASCO UV-1O0 (wavelength 254 nm) as a detector. The resulting outflow pattern is shown in Figure 1. As is clear from FIG. 1, due to the optical separation of the present invention, the (+) body (dextrorotatory) flows out first, and the (-) body flows out first.
The body (levorotatory) flows out.
実施例 ２゜
実ｍ例１のキシラン ビス（３，５−ジクロロ７エニル
カルバメート）の代すに、セルロース トリス（４−ｔ
ｅｒｔ−ブチルフェニルカルバメート）を用い、また、
ヘキサン−インプロパツール（８：１混液）に０．１％
ジエチルアミンを加えた溶液の代りにヘキサンーイング
ロバノール（９：ｘｉｉ）を用いて、ニトレンジピン（
ラセミ体）を、（＋）体と（−）体に分離した。結果を
第２図に示した。Example 2゜In place of xylan bis(3,5-dichloro7enylcarbamate) in Example 1, cellulose tris(4-t
ert-butylphenyl carbamate), and
0.1% in hexane-improper tool (8:1 mixture)
Nitrendipine (
racemic body) was separated into (+) body and (-) body. The results are shown in Figure 2.
実施例 ３゜
実施例１において、ヘキサン−イソプロパツール（８：
１混液）に０．１％ジエチルアミンを加えた溶液の代り
にヘキサン−イソプロパツール（８５： １５混液）に
０．１％ジエチルアミンを加えた溶液を溶離液として、
ニカルジピン（ラセミ体）を（＋）体と（−）体に分離
した。結果を第３図に示した。Example 3 In Example 1, hexane-isopropanol (8:
Instead of a solution of 0.1% diethylamine added to 1 mixture), a solution of 0.1% diethylamine added to hexane-isopropanol (85:15 mixture) was used as the eluent.
Nicardipine (racemic form) was separated into (+) and (-) forms. The results are shown in Figure 3.
実施例４゜
実施例１において、ヘキサンーイングロバノール（８：
ｌ混液）に０．１％ジエチルアミンを加えた溶液の代り
に、ヘキサン−イソプロパツール（８：２混液）に０１
％ジエチルア□ンを加えた溶液を溶離液としてベニジビ
ン（ラセミ体）を（＋）体と（−）体に分離した。結果
を第４図に示した。Example 4 In Example 1, hexane-inglobanol (8:
0.1% diethylamine in hexane-isopropanol (8:2 mixture).
Benigibin (racemic form) was separated into (+) form and (-) form using a solution containing % diethylamine as an eluent. The results are shown in Figure 4.
実施例５
実施例１において、キシラン ビス（３，５−ジクロロ
フェニルカルバメート）の代りに、セルロース トリス
（４−クロロフェニルカルバメート）を用い、また、ヘ
キサン−インプロパツール（８：ｌ混液）に０．１％ジ
エチルアミンを加えた溶液の代りに２ヘキサン−イソプ
ロパツール（８５：１５混液）に０．１％ジエチルアミ
ンを加えた溶液を溶臨液としてベニジピン（ラセミ体）
を（＋）体と（−）体に分離した。結果を第５図に示し
た。Example 5 In Example 1, cellulose tris(4-chlorophenylcarbamate) was used instead of xylan bis(3,5-dichlorophenylcarbamate), and 0.1% of hexane-impropatol (8:1 mixture) was used. Benidipine (racemic form) was prepared using a solution of 0.1% diethylamine in 2-hexane-isopropanol (85:15 mixture) instead of a solution containing 0.1% diethylamine.
was separated into (+) and (-) bodies. The results are shown in Figure 5.
（発明の効果）
以上、キラル固定相カラムを用いた本発明のジヒドロピ
リジン系カルシウム拮抗薬の光学活性体の製造法を説明
したが、この製造法は、ニカルジピン、ニトレンジピン
、ニルノクシヒン、ベニジヒ。(Effects of the Invention) The method for producing an optically active dihydropyridine calcium antagonist of the present invention using a chiral stationary phase column has been described above.
ンの光学活性体の製造法として好適であるほか。In addition, it is suitable as a method for producing an optically active substance of.
その条件を適宜選択することにより、これら以外にイス
ラジピンやニモジピンの光学活性体の製造法としても利
用できる。By appropriately selecting the conditions, it can also be used as a method for producing optically active forms of isradipine and nimodipine in addition to these.
本発明の製造法は、ニカルジピンの如く、これまでラセ
ミ体の分割技術が確立されていなかったため、不斉合成
によらなければＡらなかった化合物については、その光
学活性体の製造法として特に有用である。The production method of the present invention is particularly useful as a method for producing the optically active form of compounds such as nicardipine, for which A cannot be obtained without asymmetric synthesis because the technology for resolving racemates has not been established. It is.
また９本発明のギラル固定相カラムを用いた直接光学分
割法は、ジヒドロピリジン系化合物の定量法と組合せる
ことにより、血中の光学活性体を容易に分離定量できる
から、ラセミ体でヒトに投与されたジヒドロピリジン系
カルシウム拮抗薬について、光学活性体刑の血中濃度測
定にも応用できる。In addition, the direct optical resolution method using the Giral stationary phase column of the present invention can be combined with the method for quantifying dihydropyridine compounds to easily separate and quantify optically active substances in blood, so it can be administered to humans in racemic form. The dihydropyridine calcium antagonists can also be applied to the measurement of optically active blood concentration.
つぎに、ラセミ体としてヒトに投与されたニカルジピン
の光学活性体刑の血中濃度の経時変化を本発明の直接光
学分割技術とガスクロマトグラフイー・マススペクトロ
メトリー（Ｇ ＣＭ Ｓ ）とを組合せた分離・定量法
により測定する場合について、さらに具体的に説明する
。Next, the time course of the blood concentration of the optically active form of nicardipine administered to humans as a racemate was analyzed by separation and analysis using a combination of the direct optical resolution technology of the present invention and gas chromatography mass spectrometry (GCMS). The case of measurement by quantitative method will be explained in more detail.
血中ニカルジピンの抽出操作および定量法血漿１ ｍｌ
に内部標準物質（Ｄ、−ニカルジピン）飽和塩化ナトリ
ウム水溶液１ ｒｎｌおよび１規定苛性カリ水溶液０．
５ｍｌを加えた後、トルエン３．５ｍｌで抽出した（１
５分間攪拌後＋ ３５０Ｏｒｐｍで３０分間遠心分離
）。トルエン層を５０℃で減圧留去したのち、残渣に０
．１％ジエチルアミン含有ヘキサンイソプロパツール（
８：１混液）１０ｍｌを加えて溶解し、この溶解液の全
量なＨＰ Ｌ Ｃのカラムに注入した。溶離液として０
．１％ジエチルアミン含有ヘキサン−イソプロパツール
（８：１混液）を用い、ニカルジピンの各光学異性体の
保持時間に基づき、各分割を分取した。各分画を５０’
Ｃで減圧濃縮し、残渣を１％酢酸エチル含有ヘキサン１
０μｌにとかし、全量をＧ Ｃ−Ｍ Ｓに注入した。Extraction procedure and assay method for nicardipine in blood 1 ml of plasma
An internal standard (D, -nicardipine) was added to 1 rnl of a saturated aqueous solution of sodium chloride and 0.0 rnl of a 1N aqueous solution of caustic potassium.
After adding 5 ml, it was extracted with 3.5 ml of toluene (1
After stirring for 5 minutes + centrifugation at 350 rpm for 30 minutes). After the toluene layer was distilled off under reduced pressure at 50°C, the residue was
．． Hexane isopropanol containing 1% diethylamine (
8:1 mixture) was added to dissolve the solution, and the entire amount of this solution was injected into an HPLC column. 0 as eluent
．． Using hexane-isopropanol (8:1 mixture) containing 1% diethylamine, each fraction was separated based on the retention time of each optical isomer of nicardipine. Each fraction is 50'
The residue was dissolved in hexane containing 1% ethyl acetate.
The mixture was diluted to 0 μl and the entire volume was injected into GC-MS.
ＧＣ−ＭＳによる測定条件はつぎの通りである。The measurement conditions by GC-MS are as follows.
測定装置： ＪＥＯＬ ＤＸ３０３−ＤＡ５０００（
日本電子製ガスクロマトグラフ・
マススペクトロメトリー）
カ ラ ム ： ＤＢ−５，５ｍＸ０．３２ｍｍ
１．Ｄ。Measuring device: JEOL DX303-DA5000 (
JEOL gas chromatograph/mass spectrometry) Column: DB-5,5mX0.32mm
1. D.
（Ｈｅｗｌｅｔｔ Ｐａｃｋａｒｄ社）温 度：イン
ジェクション部
カラム
セパレーター
イオン源
反応ガス二メタン
担体ガス：ヘリウム
３２０ ’Ｃ
３００’Ｃ
３１０°Ｃ
３００°Ｃ
光学活性体刑のニカルジピン血中濃度
の経時変化
ニカルジピン普通錠（商品名：ベルジビン）および徐放
性製剤（商品名：ペルジビンＬＡ）をニカルジピンとし
て４０■成人に投与し、血中濃度の経時変化を上記方法
で測定した。その測定結果を第６図および第７図に示す
。なお、 ＮＩＣＩ−ＧＣＭＳ法による定量法によるニ
カルジピン（＋）体と（−）体の検量線は０．２５〜４
０ ＋ｎｇ ／ ｍｌ の範囲で共に良好々直線性を
示した（第８図および第９図）。(Hewlett Packard Company) Temperature: Injection section Column separator Ion source Reaction gas Dimethane Carrier gas: Helium 320'C 300'C 310°C 300°C Time course change in blood concentration of optically active nicardipine Nicardipine regular tablets (product) Pergivin) and a sustained-release preparation (trade name: Pergivin LA) were administered as nicardipine to 40 adults, and changes in blood concentration over time were measured using the method described above. The measurement results are shown in FIGS. 6 and 7. In addition, the calibration curve of nicardipine (+) and (-) isomers determined by the quantitative method using the NICI-GCMS method is 0.25 to 4.
Both showed good linearity in the range of 0 + ng/ml (Figures 8 and 9).
第１図は、ニカルジピン（ラセミ体）の流出パターンを
示す。
第２図は、ニトレンジピン（ラセミ体）の流出パターン
を示す。
第３図は、ニルバジビン（ラセミ体）の流出パターンを
示す。
第４図および第５図は、ベニジビン（ラセミ体）の流出
パターンを示す。
第６図および第７図は、ニカルジピン普通錠および徐放
性製剤を夫々ヒトに投与した場合の血中濃度変化を示す
。
第８図および第９図は、 ＮＩＣＩ−ＧＣＭＳ法で定量
したニカルジピン（＋）体と（−）体の検量線を示す。
第
を
図
第２図
第３
図
第４
図
第５
図
第６図
第７図
第８図
第９図
Ａｒｅａ ｒａ↑１０FIG. 1 shows the efflux pattern of nicardipine (racemic form). Figure 2 shows the efflux pattern of nitrendipine (racemic form). Figure 3 shows the efflux pattern of nilvazibin (racemic form). Figures 4 and 5 show the efflux pattern of benizibine (racemate). FIGS. 6 and 7 show blood concentration changes when nicardipine regular tablets and sustained release preparations were administered to humans, respectively. Figures 8 and 9 show the calibration curves of nicardipine (+) and (-) nicardipine quantified by the NICI-GCMS method. Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Area ra↑10
Claims (1)
、式−ＣＨ＿２ＣＨ＿３、式▲数式、化学式、表等があ
ります▼又は式▲数式、化学式、表等があります▼で示
され る基を、また、Ｒ＾２はメチル基又はシアノ基を意味す
る。ただし、Ｒ＾１が▲数式、化学式、表等があります
▼で示される基を意味するときは、Ｒ＾２はシアノ基を
意味する。また、＊印は不斉炭素原子を意味する。）で
表わされるジヒドロピリジン系カルシウム拮抗薬の光学
活性異性体混合物を、一般式（II）▲数式、化学式、表
等があります▼（II）（式中Ｒ＾３は、１〜３個のハロ
ゲン原子、低級アルキル基又はハロゲン化低級アルキル
基を表わす。Ｒ＾４は、水素原子又は式 ▲数式、化学式、表等があります▼（（式中Ｒ′は前記
と同じ 意味を表わす））で示される基を表わす。）で表わされ
る構造単位を有するキシランジ置換フェニルカルバメー
ト又はセルローストリ置換フェニルカルバメートを用い
て光学分割することを特徴とする光学活性なジヒドロピ
リジン系カルシウム拮抗薬の製造法。 ２、Ｒ＾１が式▲数式、化学式、表等があります▼で示
される基であ る請求項１記載の製造法。 ３、一般式（II）で表わされる構造単位を有するキシラ
ンジ置換フェニルカルバメートが、キランビス（３，５
−ジクロロフェニルカルバメート）である請求項１記載
の製造法。４、一般式（II）で表わされる構造単位を有
するセルローストリ置換フェニルカルバメートが、セル
ローストリス（４−ｔｅｒｔ−ブチルフェニルカルバメ
ート）又はセルローストリス（４−クロロフェニルカル
バメート）である請求項１記載の製造法。[Claims] 1. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 is the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼
, formula -CH_2CH_3, a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and R^2 means a methyl group or a cyano group. However, when R^1 means a group represented by ▲a numerical formula, chemical formula, table, etc.▼, R^2 means a cyano group. Further, the * mark means an asymmetric carbon atom. ) is a mixture of optically active isomers of a dihydropyridine calcium antagonist represented by the general formula (II) ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ (II) (wherein R^3 is 1 to 3 halogen atoms , represents a lower alkyl group or a halogenated lower alkyl group. R^4 is a hydrogen atom or is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ ((in the formula, R' represents the same meaning as above)) 1. A method for producing an optically active dihydropyridine calcium antagonist, which comprises optical resolution using a xyrane di-substituted phenyl carbamate or a cellulose tri-substituted phenyl carbamate having a structural unit represented by the following formula: 2. The manufacturing method according to claim 1, wherein R^1 is a group represented by the formula ▲A mathematical formula, a chemical formula, a table, etc. are available. 3. A xyrane di-substituted phenyl carbamate having a structural unit represented by general formula (II) is a xylane bis(3,5
-dichlorophenyl carbamate). 4. The production method according to claim 1, wherein the cellulose trisubstituted phenyl carbamate having a structural unit represented by general formula (II) is cellulose tris (4-tert-butylphenyl carbamate) or cellulose tris (4-chlorophenyl carbamate). .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21657889A JPH0381262A (en) | 1989-08-23 | 1989-08-23 | Production of optically active substance of dihydropyridine-based calcium antagonist |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21657889A JPH0381262A (en) | 1989-08-23 | 1989-08-23 | Production of optically active substance of dihydropyridine-based calcium antagonist |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0381262A true JPH0381262A (en) | 1991-04-05 |
Family
ID=16690614
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP21657889A Pending JPH0381262A (en) | 1989-08-23 | 1989-08-23 | Production of optically active substance of dihydropyridine-based calcium antagonist |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0381262A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0663822A1 (en) * | 1992-10-06 | 1995-07-26 | Sepracor, Inc. | Methods and compositions for treating hypertension, angina and other disorders using optically pure s(-) nitrendipine |
| US8236347B2 (en) | 2007-10-05 | 2012-08-07 | Alzheimer's Institute Of America, Inc. | Pharmaceutical compositions for reducing amyloid deposition, amyloid neurotoxicity, and microgliosis |
| WO2016182083A1 (en) * | 2015-05-14 | 2016-11-17 | 株式会社ダイセル | Separating agent for optical isomers |
-
1989
- 1989-08-23 JP JP21657889A patent/JPH0381262A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0663822A1 (en) * | 1992-10-06 | 1995-07-26 | Sepracor, Inc. | Methods and compositions for treating hypertension, angina and other disorders using optically pure s(-) nitrendipine |
| EP0663822A4 (en) * | 1992-10-06 | 1997-04-23 | Sepracor Inc | Methods and compositions for treating hypertension, angina and other disorders using optically pure s(-) nitrendipine. |
| US8236347B2 (en) | 2007-10-05 | 2012-08-07 | Alzheimer's Institute Of America, Inc. | Pharmaceutical compositions for reducing amyloid deposition, amyloid neurotoxicity, and microgliosis |
| US8236346B2 (en) | 2007-10-05 | 2012-08-07 | Alzheimer's Institute of America, Inc | Method for reducing amyloid deposition, amyloid neurotoxicity, and microgliosis with (-)-nilvadipine enantiomer |
| WO2016182083A1 (en) * | 2015-05-14 | 2016-11-17 | 株式会社ダイセル | Separating agent for optical isomers |
| CN107615060A (en) * | 2015-05-14 | 2018-01-19 | 株式会社大赛璐 | Agent for separating optical isomers |
| JPWO2016182083A1 (en) * | 2015-05-14 | 2018-03-01 | 株式会社ダイセル | Separating agent for optical isomers |
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