JPH0320392B2 - - Google Patents
Info
- Publication number
- JPH0320392B2 JPH0320392B2 JP18660886A JP18660886A JPH0320392B2 JP H0320392 B2 JPH0320392 B2 JP H0320392B2 JP 18660886 A JP18660886 A JP 18660886A JP 18660886 A JP18660886 A JP 18660886A JP H0320392 B2 JPH0320392 B2 JP H0320392B2
- Authority
- JP
- Japan
- Prior art keywords
- pyrrolidine
- group
- distilled
- reduced pressure
- benzyl
- 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
Links
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 29
- 239000003054 catalyst Substances 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical class C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- -1 monochloroacetyl group Chemical group 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000009835 boiling Methods 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 5
- 239000012346 acetyl chloride Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical class NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 3
- CMSWETNAAPYFSH-UHFFFAOYSA-N n-(1-benzylpyrrolidin-3-yl)acetamide Chemical compound C1C(NC(=O)C)CCN1CC1=CC=CC=C1 CMSWETNAAPYFSH-UHFFFAOYSA-N 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- HBVNLKQGRZPGRP-UHFFFAOYSA-N 1-benzylpyrrolidin-3-amine Chemical compound C1C(N)CCN1CC1=CC=CC=C1 HBVNLKQGRZPGRP-UHFFFAOYSA-N 0.000 description 2
- CMZSIQCZAFAEDH-UHFFFAOYSA-N 2,2,2-trifluoro-n-pyrrolidin-3-ylacetamide;hydrochloride Chemical compound Cl.FC(F)(F)C(=O)NC1CCNC1 CMZSIQCZAFAEDH-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NDMHLYRDMWCIOE-UHFFFAOYSA-N N-(1-benzylpyrrolidin-3-yl)propanamide Chemical compound C1C(NC(=O)CC)CCN1CC1=CC=CC=C1 NDMHLYRDMWCIOE-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- HFZWIEKMCFJKFB-UHFFFAOYSA-N n-(1-benzylpyrrolidin-3-yl)-2,2,2-trifluoroacetamide Chemical compound C1C(NC(=O)C(F)(F)F)CCN1CC1=CC=CC=C1 HFZWIEKMCFJKFB-UHFFFAOYSA-N 0.000 description 2
- HDCCJUCOIKLZNM-UHFFFAOYSA-N n-pyrrolidin-3-ylacetamide Chemical compound CC(=O)NC1CCNC1 HDCCJUCOIKLZNM-UHFFFAOYSA-N 0.000 description 2
- BWKZDJZUJVBDOX-UHFFFAOYSA-N n-pyrrolidin-3-ylbutanamide Chemical compound CCCC(=O)NC1CCNC1 BWKZDJZUJVBDOX-UHFFFAOYSA-N 0.000 description 2
- JTOGNXBWLDRNON-UHFFFAOYSA-N n-pyrrolidin-3-ylpropanamide Chemical compound CCC(=O)NC1CCNC1 JTOGNXBWLDRNON-UHFFFAOYSA-N 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 150000003235 pyrrolidines Chemical class 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 1
- FCLZCOCSZQNREK-UHFFFAOYSA-N Pyrrolidine, hydrochloride Chemical compound Cl.C1CCNC1 FCLZCOCSZQNREK-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 125000002339 acetoacetyl group Chemical group O=C([*])C([H])([H])C(=O)C([H])([H])[H] 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- BHEXKVGLZMEJRQ-UHFFFAOYSA-N n,1-dibenzylpyrrolidin-3-amine Chemical compound C=1C=CC=CC=1CNC(C1)CCN1CC1=CC=CC=C1 BHEXKVGLZMEJRQ-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical class CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OPCPWFHLFKAUEA-UHFFFAOYSA-N n-ethylpyrrolidin-3-amine Chemical compound CCNC1CCNC1 OPCPWFHLFKAUEA-UHFFFAOYSA-N 0.000 description 1
- OHLXXFUDMGUKCG-UHFFFAOYSA-N n-methylpyrrolidin-1-amine Chemical compound CNN1CCCC1 OHLXXFUDMGUKCG-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical class NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【発明の詳細な説明】
〔産業上の利用分野〕
この発明は合成原料として有用な、殊に農薬・
医薬のような生理活性物質をつくる構成要素とし
て適合する３−アミノプロリジン化合物のうち、
３−（アシルアミノ）ピロリジン又はその塩の製
造法に関する。[Detailed description of the invention] [Industrial application field] This invention is useful as a raw material for synthesis, especially agricultural chemicals.
Among 3-aminoprolidine compounds that are suitable as components for producing physiologically active substances such as pharmaceuticals,
The present invention relates to a method for producing 3-(acylamino)pyrrolidine or a salt thereof.
従来、３−アミノピロリジン化合物の中でも３
−（アシルアミノ）ピロリジン化合物は、その潜
在的な広汎な用途にもかかわらず、その物性も製
法も全く知られていない。近年僅かにそれらの使
用例が報告されているのみである。
Conventionally, among 3-aminopyrrolidine compounds, 3
Despite its potential wide range of uses, -(acylamino)pyrrolidine compounds have no known physical properties or methods of preparation. Only a few examples of their use have been reported in recent years.
本発明の目的は、他の方法では困難な３−アミ
ノピロリジンの３−位の窒素原子にアシル基を持
ち、合成的に有用な３−（アシルアミノ）ピロリ
ジン化合物の一般的、かつ工業的な製造方法を提
供する事である。
The purpose of the present invention is to provide general and industrial production of synthetically useful 3-(acylamino)pyrrolidine compounds having an acyl group at the 3-position nitrogen atom of 3-aminopyrrolidine, which is difficult to achieve using other methods. It is to provide a method.
本発明により得られる化合物は、一般式：
（式中、R1は水素原子、C1〜C5の低級アルキル
基、ベンジル、置換ベンジンなどのアリールアル
キル基を、またR2はC1〜C10のアシル基を表す。
HKは塩酸、臭化水素酸及び酢酸などのプロトン
酸を表す。）で表される３−（アシルアミノ）ピロ
リジンのプロトン酸塩、又は一般式：
（式中、R1及びR2は前記に同じく定義される）
で表される遊離の３−（アシルアミノ）ピロリジ
ンである。
The compound obtained by the present invention has the general formula: (In the formula, R 1 represents a hydrogen atom, a C 1 to C 5 lower alkyl group, an arylalkyl group such as benzyl or substituted benzine, and R 2 represents a C 1 to C 10 acyl group.
HK represents protic acids such as hydrochloric acid, hydrobromic acid and acetic acid. ) 3-(acylamino)pyrrolidine protonate salt represented by or general formula: (wherein R 1 and R 2 are defined as above)
It is free 3-(acylamino)pyrrolidine represented by
ここでアシル基としては、ホルミル基、アセチ
ル基、モノクロロアセチル基、ジクロロアセチル
基、トリクロロアセチル基、トリフロオロアセチ
ル基、アセトアセチル基、フエニルアセチル基、
フエノキシアセチル基、プロピオニル基、３−フ
エニルプロピオニル基、３−クロロプロピオニル
基、ブチリル基、イソプチリル基、２−メチルプ
チリル基、４−クロロプチリル基、ベンゾイル基
及びｐ−アニソイル基等を表す。 Here, the acyl group includes a formyl group, an acetyl group, a monochloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a trifluoroacetyl group, an acetoacetyl group, a phenylacetyl group,
It represents a phenoxyacetyl group, a propionyl group, a 3-phenylpropionyl group, a 3-chloropropionyl group, a butyryl group, an isoptyryl group, a 2-methylbutyryl group, a 4-chlorobutyryl group, a benzoyl group, a p-anisoyl group, and the like.
本発明によれば、かかる３−（アシルアミノ）
ピロリジン塩、又は遊離の３−（アシルアミノ）
ピロリジンは、一般式：
（式中、R1、R2、及びHXは上と同じく定義さ
れる。また、R3はフエニル基、又は置換フエニ
ル基を表し、R4は水素原子、アルキル基、フエ
ニル基又は置換フエニル基を表す）で表される
Ｎ，N'，N'−置換−３−アミノピロリジンのプ
ロトン酸塩を、温和な条件下、還元触媒の存在下
に水素によつて接触還元すること、及びそれを更
に温和な条件下で当量のアルカリと処理すること
によつて得ることができる。 According to the invention, such 3-(acylamino)
Pyrrolidine salt or free 3-(acylamino)
Pyrrolidine has the general formula: (In the formula, R 1 , R 2 , and HX are defined as above. Also, R 3 represents a phenyl group or a substituted phenyl group, and R 4 represents a hydrogen atom, an alkyl group, a phenyl group, or a substituted phenyl group. catalytic reduction of a protonate salt of N,N',N'-substituted-3-aminopyrrolidine represented by It can also be obtained by treatment with an equivalent amount of alkali under milder conditions.
尚、本発明に使用される原料のＮ，N'，N'−
置換−３−アミノピロリジンは、本発明者等が見
出した反応、即ち一般式：XCH2CHYCH2CH2Z
〔式中、Ｘ、Ｙ及びＺはそれぞれ塩素、臭素、
ヨウ素のようなハロゲン原子、又はOR基（ここ
でＲは、メタンスルホニルのようなアルカンスル
ホニル基、或いはトルエンスルホニルのような芳
香族スルホニル基）を表す〕で表される三置換ブ
タンに、一般式：R3（R4）CHNH2
（式中、R3及びR4は前記と同じく定義される）
で表される第一アミンと、一般式：R1NH2
（式中、R1は前記に同じく定義される）で表
される第一アミンを逐次反応させ、一般式：
で表されるＮ，N'−二置換−３−アミノピロリ
ジンをつくり、これを常法によりアシル化し、更
にプロトン酸との塩にする事によつて得ることが
できる。 In addition, N, N', N'- of the raw materials used in the present invention
Substituted-3-aminopyrrolidine is produced by the reaction discovered by the present inventors, that is, the general formula: XCH 2 CHYCH 2 CH 2 Z [wherein,
The general formula :R 3 (R 4 )CHNH 2 (wherein R 3 and R 4 are defined as above)
A primary amine represented by the formula: R 1 NH 2 (wherein R 1 is defined as above) is sequentially reacted with the primary amine represented by the general formula: It can be obtained by preparing N,N'-disubstituted-3-aminopyrrolidine represented by, acylating it by a conventional method, and further converting it into a salt with a protonic acid.
本発明者等は、Ｎ，N'−置換−３−アミノピ
ロリジン化合物について、各種反応条件化で接触
環元による１−位の窒素原子上の置換基の除去に
ついて検討した結果、Ｎ，N'−置換−３−アミ
ノピロリジンを一旦そのプロトン酸塩に変えてか
ら還元を行う事により、温和な条件で３−位の窒
素原子上のアシル基を損なう事なく反応を進行さ
せ得ることを見出し、収率の良い実用的な製造法
を完成させた。 The present inventors investigated the removal of the substituent on the 1-position nitrogen atom using a catalytic ring element under various reaction conditions for N,N'-substituted-3-aminopyrrolidine compounds, and found that N,N' We have discovered that by first converting -substituted-3-aminopyrrolidine into its protonate salt and then reducing it, the reaction can proceed under mild conditions without damaging the acyl group on the 3-position nitrogen atom, A practical manufacturing method with good yield was completed.
以下、本発明の具体的な方法について説明す
る。 Hereinafter, a specific method of the present invention will be explained.
Ｎ，N'−置換−３−アミノピロリジンのプロ
トン酸塩の接触水素還元反応は、通常オートクレ
ーブ中で、水、メタノール、エタノール、イソプ
ロピルアルコール、テトラドロフラン、ジオキサ
ン、ジメトキシエタンなどの単一、或いは混合溶
媒系中で行うことができる。触媒としては５％
Pd‐Ｃ、５％Pd‐BaSO4、PdO及びPtO2等が有
効であり、通常これらの触媒を原料に対して５〜
20（ｗ／ｗ）％用いる。還元反応は20〜70℃の温
度範囲で、水素圧１〜30Kg／cm2で行うことが望ま
しく、通常30分〜24時間で完結する。後処理は常
法によるが、できるだけ低い温度で素早く行うな
ど、通常の注意を払う事がましい。 The catalytic hydrogen reduction reaction of the protonate salt of N,N'-substituted-3-aminopyrrolidine is usually carried out in an autoclave using a single or It can be carried out in a mixed solvent system. 5% as a catalyst
Pd-C, 5% Pd-BaSO 4 , PdO and PtO 2 etc. are effective, and these catalysts are usually added at 5% to 5% to the raw material.
Use 20 (w/w)%. The reduction reaction is preferably carried out at a temperature range of 20 to 70°C and a hydrogen pressure of 1 to 30 kg/cm 2 , and is usually completed in 30 minutes to 24 hours. Post-treatment is carried out using conventional methods, but it is recommended to take the usual precautions, such as performing it quickly and at the lowest possible temperature.
３−（アシルアミノ）ピロリジン或いはその塩
類の製法は、これまで全く知られていない。最
近、本発明者等が三置換ブタンとアンモニアとの
反応によつて得る方法を開発した母核の３−アミ
ノピロリジン（特願昭60−226041号参照）を用
い、選択的にこのものの３−位のアミノ基をアシ
ル化する方法を種々検討したが可能ではなかつ
た。例えば３−アミノピロリジンを各種溶媒中で
１当量の無水酢酸、或いは塩化アセチルと１当量
のルイス酸或いは鉱酸の存在或いは非存在下に反
応させると１−アセチル及び３−（Ｎ−アセチル）
アミノピロリジンの混合物が得られた。また、３
−アミノピロリジンを２当量のトリメチルシリル
クロリドとトリエチルアミンで処理した後アセチ
ル化を行い、次いで脱シリル化を行つても目的と
する３−（Ｎ−アセチル）アミノピロリジンは得
られなかつた。３−（アシルアミノ）ピロリジン
類は１−位に置換基、３−位の窒素原子上にアシ
ル基をもつた前駆体の１−位の窒素上の置換基を
穏やかな条件下の水素還元によつて除去する、本
発明の方法によつて初めて純粋な状態で効果的に
得ることができた。
Until now, no method for producing 3-(acylamino)pyrrolidine or its salts has been known. Recently, the present inventors have developed a method for obtaining 3-aminopyrrolidine by reacting trisubstituted butane with ammonia (see Japanese Patent Application No. 60-226041). Various methods of acylating the amino group at this position were investigated, but none were possible. For example, when 3-aminopyrrolidine is reacted with 1 equivalent of acetic anhydride or acetyl chloride in various solvents in the presence or absence of 1 equivalent of Lewis acid or mineral acid, 1-acetyl and 3-(N-acetyl) are produced.
A mixture of aminopyrrolidines was obtained. Also, 3
-Aminopyrrolidine was treated with 2 equivalents of trimethylsilyl chloride and triethylamine, then acetylated, and then desilylated, but the desired 3-(N-acetyl)aminopyrrolidine could not be obtained. 3-(Acylamino)pyrrolidines are obtained by reducing the substituent on the 1-position nitrogen of a precursor having a substituent at the 1-position and an acyl group on the 3-position nitrogen atom by hydrogen reduction under mild conditions. By using the method of the present invention, which removes the oxidizing agent by heating, it was possible to effectively obtain it in a pure state for the first time.
尚、この３−（アシルアミノ）ピロリジン化合
物は、その構造から予想されるように、合成原料
として農薬・医薬のような生理活性物質を作るの
に用いられるが、とりわけ抗菌作用を有する医
薬・原薬類の合成原料として使用できる（J.
Matsumoto et al.，J.Med.Chem.，27，1543
（1984））。 As expected from its structure, this 3-(acylamino)pyrrolidine compound is used as a synthetic raw material to produce physiologically active substances such as agricultural chemicals and pharmaceuticals, but it is especially useful for pharmaceuticals and drug substances with antibacterial effects. (J.
Matsumoto et al., J.Med.Chem., 27, 1543
(1984)).
以下本発明の製造法の実施例を示すが、本発明
の方法はこれらの実施例に限定されるものではな
い。
Examples of the production method of the present invention will be shown below, but the method of the present invention is not limited to these Examples.
実施例１（３−アセチルアミノ）ピロリジンの
合成）
１−ベンジル−３−アミノピロリジン（bp107
〜108℃／２mmHg）8.8gをTHF30mlに溶かし、
氷冷下かき混ぜながらアセチルクロリド4.3gを
THF10mlに溶かした溶液を滴下した。溶媒を減
圧下留去し、粗製の１−ベンジル−３−（アセチ
ルアミノ）ピロリジン・塩酸塩を得た。これをベ
ンゼン30mlに懸濁させ、カセイソーダ4.4gを水15
mlに溶かした溶液を加えた。分液し、ベンゼン層
を硫酸マグネシウム上で乾燥してから濃縮し、残
分を減圧下蒸留して沸点171〜172℃／２mmHgの
１−ベンジル−３−（アセチルアミノ）ピロリジ
ン7.5g（68.3％）を得た。 Example 1 (Synthesis of 3-acetylamino)pyrrolidine) 1-benzyl-3-aminopyrrolidine (bp107
~108℃/2mmHg) Dissolve 8.8g in 30ml of THF,
Add 4.3g of acetyl chloride while stirring under ice cooling.
A solution dissolved in 10 ml of THF was added dropwise. The solvent was distilled off under reduced pressure to obtain crude 1-benzyl-3-(acetylamino)pyrrolidine hydrochloride. Suspend this in 30ml of benzene, add 4.4g of caustic soda to 15ml of water.
ml solution was added. The benzene layer was dried over magnesium sulfate, concentrated, and the residue was distilled under reduced pressure to 7.5 g of 1-benzyl-3-(acetylamino)pyrrolidine (68.3% ) was obtained.
融点 62〜64％
NMR（CDCI3）；δ＝7.37（ｓ，5H），6.00〜
6.57
（broad，1H），4.17〜4.73（ｍ，1H），3.63
（ｓ，2H），1.93（ｓ，3H），1.23〜3.17（ｍ，6H）
IR（neat）；3250，3050，1640，1540cm-1
元素分析
計算値(%)；C71.53 H8.31 N12.83
実測値(%)；C71.52 H8.47 N12.64
１−ベンジル−３−（アセチルアミノ）ピロリ
ジン7.0gをメタノール20mlに溶かし、氷冷下かき
混ぜながら、6N塩酸水5.3mlを滴下した。減圧下
で溶媒を留去し、１−ベンジル−３−（アセチル
アミノ）ピロリジン．塩酸塩を得た。これをオー
トクレーブ中でメタノール160mlと水40mlの混合
液に溶かし、５％Pd−Ｃ触媒1gを加え、温度30
〜40℃、水素圧11Kg／cm2で3.5時間かき混ぜた、
触媒を濾別し、大部分の溶媒を減圧下留去し、少
量の水を含む残分にエタノールを加えて水をエタ
ノールと共に留去して、３−（アセチルアミノ）
ピロリジン・塩酸塩4.6g（85.9％）を得た。これ
を、エタノール10mlに溶かし、氷冷下かき混ぜな
がら、カセイソーダ1.1gをエタノール15mlに溶か
した溶液を滴下した。析出晶を濾別し、濾液を減
圧下濃縮後蒸留して沸点131〜132℃／２mmHgの
３−（アセチルアミノ）ピロリジン3.1g（89.6％）
を得た。 Melting point 62~64% NMR ( CDCI3 ); δ=7.37 (s, 5H), 6.00~
6.57 (broad, 1H), 4.17-4.73 (m, 1H), 3.63
(s, 2H), 1.93 (s, 3H), 1.23-3.17 (m, 6H) IR (neat); 3250, 3050, 1640, 1540cm -1 Elemental analysis Calculated value (%); C71.53 H8.31 N12 .83 Actual value (%); C71.52 H8.47 N12.64 7.0 g of 1-benzyl-3-(acetylamino)pyrrolidine was dissolved in 20 ml of methanol, and 5.3 ml of 6N hydrochloric acid water was added dropwise while stirring under ice cooling. . The solvent was distilled off under reduced pressure to give 1-benzyl-3-(acetylamino)pyrrolidine. The hydrochloride was obtained. This was dissolved in a mixture of 160 ml of methanol and 40 ml of water in an autoclave, 1 g of 5% Pd-C catalyst was added, and the temperature was 30 ml.
Stirred for 3.5 hours at ~40℃ and hydrogen pressure of 11Kg/ cm2 .
The catalyst was filtered off, most of the solvent was distilled off under reduced pressure, ethanol was added to the residue containing a small amount of water, and the water was distilled off together with the ethanol to give 3-(acetylamino).
4.6 g (85.9%) of pyrrolidine hydrochloride was obtained. This was dissolved in 10 ml of ethanol, and a solution of 1.1 g of caustic soda dissolved in 15 ml of ethanol was added dropwise while stirring under ice cooling. The precipitated crystals were separated by filtration, and the filtrate was concentrated under reduced pressure and distilled to obtain 3.1 g (89.6%) of 3-(acetylamino)pyrrolidine with a boiling point of 131-132°C/2 mmHg.
I got it.
n20 D 1.5048
NMR（CDCI3）；δ＝6.8〜7.53（ｓ，broad，IH），
4.01〜4.67（ｍ，IH），2.57〜3.50（ｍ，4H），
1.33〜2.53（ｍ，3H），2.00（ｓ，3H）
IR（neat）；3250，3050，1545cm- 1
実施例２（３−（Ｎ−メチルアセチルアミノ）ピロ
リジンの合成）
１−ベンジル−３−（メチルアミノ）ピロリジ
ン8.5ｇをベンゼン20mlに溶かし、氷冷下かき混
ぜながらアセチルクロリド3.9gを滴下した。水10
mlを加えて分液し、水層にカセインソーダ2.1gを
加え、ベンゼン30mlと振り混ぜた、ベンゼン層を
分け、硫酸マグネシウム上で乾燥し、減圧下濃縮
し、残分（8.3g，80％）を減圧下蒸留して沸点
154〜155℃／mmHgの１−ベンジル−３−（Ｎ−メ
チルアセチルアミノ）ピロリジン4.7g（44.6％）
を得た。 n 20 D 1.5048 NMR (CDCI 3 ); δ = 6.8 to 7.53 (s, broad, IH), 4.01 to 4.67 (m, IH), 2.57 to 3.50 (m, 4H),
1.33-2.53 (m, 3H), 2.00 (s, 3H) IR (neat); 3250, 3050, 1545cm - 1 Example 2 (Synthesis of 3-(N-methylacetylamino)pyrrolidine) 1-benzyl-3- 8.5 g of (methylamino)pyrrolidine was dissolved in 20 ml of benzene, and 3.9 g of acetyl chloride was added dropwise while stirring under ice cooling. water 10
Add 2.1 g of casein soda to the aqueous layer and shake and mix with 30 ml of benzene. Separate the benzene layer, dry over magnesium sulfate, and concentrate under reduced pressure. Residue (8.3 g, 80%) Distilled under reduced pressure to find the boiling point
1-benzyl-3-(N-methylacetylamino)pyrrolidine 4.7g (44.6%) at 154-155℃/mmHg
I got it.
n20 D．5397
NMR（CDCI3）；δ＝7.40（ｓ，5H），4.13〜5.60
（ｍ，1H），3.60（ｄ，Ｊ＝４Hz，2H），2.97（ｄ，
Ｊ＝４Hz，3H），2.07（ｄ，Ｊ＝４Hz，3H）1.43
〜3.30（ｍ，6H）
IR（neat）；1635，1450cm-1
元素分析
計算値(%)；C72.38 H8.68 N12.06
実測値(%)；C72.45 H8.95 N11.87
１−ベンジル−３−（Ｎ−メチルアセチルアミ
ノ）ピロリジン4.0gをメタノール20mlに溶かし、
氷冷下6N塩酸水2.9mlを滴下した。減圧下で溶媒
を留去し、１−ベンジル−３−（Ｎ−メチルアセ
チルアミノ）ピロリジン・塩酸塩を得た。これを
オートクレープ中でメタノール160mlと水40mlの
混合液に溶かし、５％Pd−Ｃ触媒1.0gを加え、
温度30〜40℃、水素圧11Kg／cm2で２時間かき混ぜ
た。触媒を濾別し、大部分の溶媒を減圧下留去
し、少量の水を含む残分にエタノールを加えて水
をエタノールと共に留去し、３−（Ｎ−メチルア
セチルアミノ）ピロリジン・塩酸塩2.8g（85.1％）
を得た。これをエタノール15mlに溶かし、氷冷
下、カセイソーダ0.6gをエタノール10mlに溶かし
た溶液を滴下した。析出晶を濾別し、濾液を減圧
下濃縮し、残分（2.2g，100％）を減圧下蒸留し
て、沸点109〜110％／１mmHgの３−（Ｎ−メチル
アセチルアミノ）ピロリジン1.7g（76.8％）を得
た。 n 20 D. 5397 NMR ( CDCI3 ); δ=7.40 (s, 5H), 4.13-5.60
(m, 1H), 3.60 (d, J=4Hz, 2H), 2.97 (d,
J = 4Hz, 3H), 2.07 (d, J = 4Hz, 3H) 1.43
~3.30 (m, 6H) IR (neat); 1635, 1450 cm -1 Elemental analysis Calculated value (%); C72.38 H8.68 N12.06 Actual value (%); C72.45 H8.95 N11.87 1 -Dissolve 4.0 g of benzyl-3-(N-methylacetylamino)pyrrolidine in 20 ml of methanol,
2.9 ml of 6N hydrochloric acid solution was added dropwise under ice-cooling. The solvent was distilled off under reduced pressure to obtain 1-benzyl-3-(N-methylacetylamino)pyrrolidine hydrochloride. This was dissolved in a mixture of 160 ml of methanol and 40 ml of water in an autoclave, and 1.0 g of 5% Pd-C catalyst was added.
The mixture was stirred for 2 hours at a temperature of 30 to 40°C and a hydrogen pressure of 11 kg/cm 2 . The catalyst was filtered off, most of the solvent was distilled off under reduced pressure, ethanol was added to the residue containing a small amount of water, the water was distilled off together with the ethanol, and 3-(N-methylacetylamino)pyrrolidine hydrochloride was obtained. 2.8g (85.1%)
I got it. This was dissolved in 15 ml of ethanol, and a solution of 0.6 g of caustic soda dissolved in 10 ml of ethanol was added dropwise under ice cooling. The precipitated crystals were filtered off, the filtrate was concentrated under reduced pressure, and the residue (2.2 g, 100%) was distilled under reduced pressure to obtain 1.7 g of 3-(N-methylacetylamino)pyrrolidine with a boiling point of 109-110%/1 mmHg. (76.8%).
n20 1D ．5028
NMR（CDCI3）；δ＝4.13〜5.37（ｍ，1H），2.92
（ｄ，Ｊ＝４Hz，3H），2.50〜3.40（ｍ，4H），２，
13（ｄ，Ｊ＝４Hz，3H），1.33〜2.37（ｍ，3H）
IR（neat）；3300，1630cm-1
実施例３（３−（Ｎ−エチルアセチルアミノ）ピ
ロリジンの合成）
１−ベンジル−３−（エチルアミノ）ピロリジ
ン6.1gをベンゼン38mlに溶かし、氷冷下かき混ぜ
ながらアセチルクロリド2.6gをベンゼン２mlに溶
かした溶液を滴下した。一旦室温まで昇温させた
のち再び氷冷し、カセイゾーダ2.4gを水15mlに溶
かした溶液を加えた。分液し、ベンゼン層を硫酸
マグネシウム上で乾燥し、減圧下濃縮して、粗製
の１−ベンジル−３−（Ｎ−エチルアセチルアミ
ノ）ピロリジン7.0g（94.0％）を油状物として得
た。 n 20 1D . 5028 NMR ( CDCI3 ); δ=4.13-5.37 (m, 1H), 2.92
(d, J=4Hz, 3H), 2.50~3.40 (m, 4H), 2,
13 (d, J = 4 Hz, 3H), 1.33-2.37 (m, 3H) IR (neat); 3300, 1630 cm -1 Example 3 (Synthesis of 3-(N-ethylacetylamino)pyrrolidine) 1-benzyl- 6.1 g of 3-(ethylamino)pyrrolidine was dissolved in 38 ml of benzene, and a solution of 2.6 g of acetyl chloride dissolved in 2 ml of benzene was added dropwise while stirring under ice cooling. The temperature was once raised to room temperature, then cooled on ice again, and a solution of 2.4 g of Kaseizoda dissolved in 15 ml of water was added. The layers were separated, and the benzene layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 7.0 g (94.0%) of crude 1-benzyl-3-(N-ethylacetylamino)pyrrolidine as an oil.
n20 D 1.5338
NMR（CDCI3）；δ＝7.37（ｓ，5H），3.17〜
5.33（ｍ，1H），3.63（ｓ，2H），3.20〜3.60（ｑ，
2H），2.10（ｓ，3H），1.53〜3.10（ｍ，6H），1.67
（ｔ，Ｊ＝６Hz，3H）
IR（neat）；1630，1420cm-1
元素分析
計算値(%)；C73.13 H9.00 N11.37
実側値(%)；C72.90 H9.05 N11.13
１−ベンジル−３−（Ｎ−エチルアセチルアミ
ノ）ピロリジン3.7gをメタノール20mlに溶かし、
氷冷下かき混ぜながら6N塩酸水2.5mlを滴下し
た。減圧下で溶媒を留去し、１−ベンジル−３−
（Ｎ−エチルアセチルアミノ）ピロリジン・塩酸
塩を得た。これをオートクレーブ中でメタノール
160mlと水40mlの混合液に溶かし、５％Pd−Ｃ触
媒1gを加え、温度40℃で、水素圧11Kg／cm2で２
時間かき混ぜた。触媒を濾別し、大部分の溶媒を
減圧下留去し、少量の水を含む残分にエタノール
を加えて水をエタノールと共に留去し、３−（Ｎ
−エチルアセチルアミノ）ピロリジン・塩酸塩
2.7g（89.0％）を得た。これをエタノール15mlに
溶かし、氷冷下、カセイソーダ0.6gをエタノール
10mlに溶かした溶液を滴下した。析出晶を濾別
し、濾液を減圧下濃縮し、残分を減圧下蒸留し、
沸点106〜107℃／１mmHgの３−（Ｎ−エチルアセ
チルアミノ）ピロリジン1.7g（80.4％）を得た。 n 20 D 1.5338 NMR (CDCI 3 ); δ = 7.37 (s, 5H), 3.17 ~
5.33 (m, 1H), 3.63 (s, 2H), 3.20~3.60 (q,
2H), 2.10 (s, 3H), 1.53-3.10 (m, 6H), 1.67
(t, J=6Hz, 3H) IR (neat); 1630, 1420cm -1 Elemental analysis Calculated value (%); C73.13 H9.00 N11.37 Actual value (%); C72.90 H9.05 N11 .13 Dissolve 3.7 g of 1-benzyl-3-(N-ethylacetylamino)pyrrolidine in 20 ml of methanol,
While stirring under ice-cooling, 2.5 ml of 6N hydrochloric acid water was added dropwise. The solvent was distilled off under reduced pressure, and 1-benzyl-3-
(N-ethylacetylamino)pyrrolidine hydrochloride was obtained. This was mixed with methanol in an autoclave.
Dissolved in a mixture of 160 ml and 40 ml of water, added 1 g of 5% Pd-C catalyst, and heated at a temperature of 40°C and a hydrogen pressure of 11 kg/cm 2 .
Stirred for an hour. The catalyst was filtered off, most of the solvent was distilled off under reduced pressure, ethanol was added to the residue containing a small amount of water, the water was distilled off together with the ethanol, and 3-(N
-ethylacetylamino)pyrrolidine hydrochloride
2.7g (89.0%) was obtained. Dissolve this in 15ml of ethanol, and add 0.6g of caustic soda to ethanol under ice cooling.
A solution dissolved in 10 ml was added dropwise. The precipitated crystals were separated by filtration, the filtrate was concentrated under reduced pressure, and the residue was distilled under reduced pressure.
1.7 g (80.4%) of 3-(N-ethylacetylamino)pyrrolidine having a boiling point of 106-107°C/1 mmHg was obtained.
n20 D 1.4945
NMR（CDCI3）；δ＝4.07〜4.63（ｍ，1H），
2.50〜3.60（ｍ，6H），2.13（ｓ，3H），1.53〜2.43
（ｍ，3H），1.02（ｔ，Ｊ＝６Hz，3H）
IR（neat）；3250，1630，31420cm-1
実施例４（３−（Ｎ−ベンジルアセチルアミノ）
ピロリジンの合成）
Ｎ，N'−ジベンジル−３−アミノピロリジン
302.8gを塩化メチレン600mlに溶かし、氷令下ア
セチルクロリド94.4gを滴下した。室温まで昇温
させ、同温度で30分間かき混ぜた。再び氷冷し、
カセイソーダ48gを水200mlに溶かした溶液を加
え、かき混ぜた後分液した。有機層をとり、硫酸
マグネシウム上で乾燥してから濃縮し、残分を蒸
留して沸点204〜208℃／２mmHgの１−ベンジル
−３−（Ｎ−ベンジルアセチルアミノ）ピロリジ
ン310.4g（88.5％）を得た。 n 20 D 1.4945 NMR (CDCI 3 ); δ = 4.07 to 4.63 (m, 1H),
2.50~3.60 (m, 6H), 2.13 (s, 3H), 1.53~2.43
(m, 3H), 1.02 (t, J = 6Hz, 3H) IR (neat); 3250, 1630, 31420cm -1 Example 4 (3-(N-benzylacetylamino)
Synthesis of pyrrolidine) N,N'-dibenzyl-3-aminopyrrolidine
302.8 g was dissolved in 600 ml of methylene chloride, and 94.4 g of acetyl chloride was added dropwise under ice. The mixture was heated to room temperature and stirred at the same temperature for 30 minutes. Cool again on ice,
A solution of 48 g of caustic soda dissolved in 200 ml of water was added, stirred, and then separated. The organic layer was separated, dried over magnesium sulfate, concentrated, and the residue was distilled to give 310.4 g (88.5%) of 1-benzyl-3-(N-benzylacetylamino)pyrrolidine with a boiling point of 204-208°C/2 mmHg. I got it.
n20 . 1.5731
NMR（CCI4）；δ＝1.3〜3.0（9H，ｍ），3.4（ｓ）
〜3.5（ｓ）（合計2H），4.6（2H，ｓ）4.2〜5.2
（broad ｓ，1H），7.1（ｓ，10H）
IR（neat）；1640，1410cm-1
１−ベンジル−３−（Ｎ−ベンジルアセチルア
ミノ）ピロリジン224.1gを塩化水素26.5gを含む
酢酸エチル170ml中に徐々に加えた。溶媒を減圧
下留去し、１−ベンジル−３−（Ｎ−ベンジルア
セチルアミノ）ピロリジン・塩酸塩270gを得た。
これをオートクレーブ中、メタノール500mlと水
125mlの混合液に溶かし、５％Pd−Ｃ触媒27gを
加え、温度60〜70℃、水素圧11Kg／cm2で3.5時間
かき混ぜた。触媒を濾別し、反応液にカセイソー
ダ31gを加え室温で１時間かき混ぜた。析出晶を
濾別し、濾液を濃縮乾固し、濃縮物に水300mlと
ベンゼン300mlを加え分液した。ベンゼン層を飽
和食塩水で洗い、硫酸ナトリウム上で乾燥した後
濃縮し、残分を減圧下蒸留し、沸点164〜166℃／
1.5mmHgの３−（Ｎ−ベンジルアセチルアミノ）
ピロリジン101.4g（64.2％）を得た。 n20.1.5731 NMR ( CCI4 ); δ=1.3~3.0 (9H, m), 3.4 (s)
~3.5 (s) (total 2H), 4.6 (2H, s) 4.2 ~ 5.2
(broad s, 1H), 7.1 (s, 10H) IR (neat); 1640, 1410 cm -1 224.1 g of 1-benzyl-3-(N-benzylacetylamino)pyrrolidine in 170 ml of ethyl acetate containing 26.5 g of hydrogen chloride was added gradually. The solvent was distilled off under reduced pressure to obtain 270 g of 1-benzyl-3-(N-benzylacetylamino)pyrrolidine hydrochloride.
In an autoclave, add 500ml of methanol and water.
The mixture was dissolved in 125 ml of mixed liquid, 27 g of 5% Pd-C catalyst was added, and the mixture was stirred for 3.5 hours at a temperature of 60 to 70°C and a hydrogen pressure of 11 kg/cm 2 . The catalyst was filtered off, 31 g of caustic soda was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were filtered off, the filtrate was concentrated to dryness, and 300 ml of water and 300 ml of benzene were added to the concentrate to separate the layers. The benzene layer was washed with saturated brine, dried over sodium sulfate, concentrated, and the residue was distilled under reduced pressure to obtain a boiling point of 164-166℃/
3-(N-benzylacetylamino) at 1.5 mmHg
101.4 g (64.2%) of pyrrolidine was obtained.
n20 1.5594
NMR（CCI4）；δ＝7.13（ｓ，5H），4.50（ｓ，
2H），4.01〜5.00（broad，1H）2.37〜3.53（ｍ，
4H），1.37〜2.27（ｍ，6H）
IR（neat）；1635cm-1
実施例５（３−（Ｎ−トリフルオロアセチルアミ
ノ）ピロリジン・塩酸塩の合成）
１−ベンジル−３−アミノピロリジン33.9gを
ベンゼン120mlに溶かし、氷冷下かき混ぜながら
無水トリフルオロ酢酸40.0gを滴下した。徐々に
室温まで昇温させて２時間反応させた。水200ml
と重炭酸ナトリウム16.2gを少しずつ加えた。更
にベンゼン50mlと飽和重炭酸ナトリウム水溶液50
mlを加えて、振り混ぜ分液した。ベンゼン層を硫
酸ナトリウム上で乾燥し、濃縮した後、減圧下蒸
留して沸点130〜131℃／１mmHgの１−ベンジル
−３−（Ｎ−トリフルオロアセチルアミノ）ピロ
リジン41.2g（78.8％）を得た。これは室温で固化
した。 n 20 1.5594 NMR (CCI 4 ); δ = 7.13 (s, 5H), 4.50 (s,
2H), 4.01~5.00 (broad, 1H) 2.37~3.53 (m,
4H), 1.37-2.27 (m, 6H) IR (neat); 1635cm -1 Example 5 (Synthesis of 3-(N-trifluoroacetylamino)pyrrolidine hydrochloride) 1-benzyl-3-aminopyrrolidine 33.9g was dissolved in 120 ml of benzene, and 40.0 g of trifluoroacetic anhydride was added dropwise while stirring under ice cooling. The temperature was gradually raised to room temperature and the mixture was reacted for 2 hours. 200ml water
and 16.2 g of sodium bicarbonate were added little by little. Additionally, 50 ml of benzene and 50 ml of saturated aqueous sodium bicarbonate solution.
ml and shaken to separate the liquids. The benzene layer was dried over sodium sulfate, concentrated, and then distilled under reduced pressure to obtain 41.2 g (78.8%) of 1-benzyl-3-(N-trifluoroacetylamino)pyrrolidine with a boiling point of 130-131°C/1 mmHg. Ta. This solidified at room temperature.
NMR（CDCI3）；δ＝7.40（ｓ，5H），6.73〜
7.33（broad，1H）4.23〜4.80（ｍ，1H），3.67（ｓ，
2H），1.03〜3.23（ｍ，6H）
IR（neat）；1700，1550，1210cm-1
１−ベンジル−３−（Ｎ−トリフルオロアセチ
ルアミノ）ピロリジン41.2gをメタノール200mlに
溶かし、氷冷下かき混ぜながら6N塩酸水25.3ml
を滴下した。大部分の溶媒を減圧下留去し、残分
にエタノールを加えて濃縮乾固し、１−ベンジル
−３−（Ｎ−トリフルオロアセチルアミノ）ピロ
リジン・塩酸塩46.6（100％，融点141〜143℃）を
得た。これをオートクレーブ中でメタノール160
ml、水40mlの混合液に溶かし、５％Pd−Ｃ触媒
4.6gを加え、温度30℃、水素圧５Kg／cm2で４時間
かき混ぜた。触媒を濾別し、大部分の溶媒を減圧
下で留去し、残分にエタノールを加えて水をエタ
ノールと共に留去し、３−（Ｎ−トリフルオロア
セチルアミノ）ピロリジン・塩酸塩30・2g（91・
５％）を白色結晶として得た。 NMR (CDCI 3 ); δ=7.40 (s, 5H), 6.73~
7.33 (broad, 1H) 4.23-4.80 (m, 1H), 3.67 (s,
2H), 1.03-3.23 (m, 6H) IR (neat); 1700, 1550, 1210cm -1 Dissolve 41.2g of 1-benzyl-3-(N-trifluoroacetylamino)pyrrolidine in 200ml of methanol and stir under ice cooling. 6N hydrochloric acid water 25.3ml
was dripped. Most of the solvent was distilled off under reduced pressure, ethanol was added to the residue, and the residue was concentrated to dryness. °C) was obtained. Methanol 160% in an autoclave
ml, dissolved in a mixture of 40 ml of water, 5% Pd-C catalyst
4.6g was added and stirred for 4 hours at a temperature of 30°C and a hydrogen pressure of 5Kg/cm 2 . The catalyst was filtered off, most of the solvent was distilled off under reduced pressure, ethanol was added to the residue, water was distilled off along with the ethanol, and 30.2 g of 3-(N-trifluoroacetylamino)pyrrolidine hydrochloride was obtained. (91・
5%) was obtained as white crystals.
融点 178〜182℃（dec） IR（KBr）；1710，1210，1180，1150cm-1。 Melting point 178-182℃ (dec) IR (KBr); 1710, 1210, 1180, 1150cm -1 .
Claims (1)
リールアルキル基を、R2はアシル基を表す。ま
たR3はフエニル基、又は置換フエニル基を表し、
R4は水素原子、アルキル基、フエニル基又は置
換フエニル基を表す。またHXはプロトン酸を表
す。）で表されるＮ，N'，N'−置換−３−アミノ
ピロリジンの塩を還元触媒の存在下に水素によつ
て接触還元することを特徴とする一般式： （式中、R1及びR2は前記に同じく定義される）
で表される３−（アシルアミノ）ピロリジン又は
その塩の製造法。 ２ プロトン酸が塩酸、臭化水素酸又は酢酸であ
る特許請求の範囲第１項記載の製造法。[Claims] 1. General formula: (In the formula, R 1 represents a hydrogen atom, an alkyl group, or an arylalkyl group, R 2 represents an acyl group, and R 3 represents a phenyl group or a substituted phenyl group,
R 4 represents a hydrogen atom, an alkyl group, a phenyl group or a substituted phenyl group. Moreover, HX represents protonic acid. ) A general formula characterized in that a salt of N,N',N'-substituted-3-aminopyrrolidine represented by is catalytically reduced with hydrogen in the presence of a reduction catalyst: (wherein R 1 and R 2 are defined as above)
A method for producing 3-(acylamino)pyrrolidine or a salt thereof represented by: 2. The production method according to claim 1, wherein the protonic acid is hydrochloric acid, hydrobromic acid, or acetic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18660886A JPS6341453A (en) | 1986-08-08 | 1986-08-08 | Production of 3-(acylamino)pyrrolidine and salt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18660886A JPS6341453A (en) | 1986-08-08 | 1986-08-08 | Production of 3-(acylamino)pyrrolidine and salt thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6341453A JPS6341453A (en) | 1988-02-22 |
| JPH0320392B2 true JPH0320392B2 (en) | 1991-03-19 |
Family
ID=16191548
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18660886A Granted JPS6341453A (en) | 1986-08-08 | 1986-08-08 | Production of 3-(acylamino)pyrrolidine and salt thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6341453A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4859776A (en) * | 1988-03-11 | 1989-08-22 | Abbott Laboratories | (S)-7-(3-aminopyrrolidin-1-yl)-1-(ortho, para-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid and method for its preparation |
| JP4057088B2 (en) * | 1996-04-22 | 2008-03-05 | 株式会社カネカ | Method for producing pyrrolidine derivative |
-
1986
- 1986-08-08 JP JP18660886A patent/JPS6341453A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6341453A (en) | 1988-02-22 |
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