JPS6152826B2 - - Google Patents
Info
- Publication number
- JPS6152826B2 JPS6152826B2 JP53079189A JP7918978A JPS6152826B2 JP S6152826 B2 JPS6152826 B2 JP S6152826B2 JP 53079189 A JP53079189 A JP 53079189A JP 7918978 A JP7918978 A JP 7918978A JP S6152826 B2 JPS6152826 B2 JP S6152826B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- formula
- acid
- defined above
- same meaning
- 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
- 238000000034 method Methods 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 12
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- -1 chloroformic acid ester Chemical class 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- IULDWWUGMGLWOB-UHFFFAOYSA-N piperazin-1-yl(pyridin-2-yl)methanone Chemical compound C=1C=CC=NC=1C(=O)N1CCNCC1 IULDWWUGMGLWOB-UHFFFAOYSA-N 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 229910017053 inorganic salt Inorganic materials 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 150000001875 compounds Chemical class 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 238000004508 fractional distillation Methods 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NZVZVGPYTICZBZ-UHFFFAOYSA-N 1-benzylpiperidine Chemical compound C=1C=CC=CC=1CN1CCCCC1 NZVZVGPYTICZBZ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 1
- BTJRKNUKPQBLAL-UHFFFAOYSA-N hydron;4-methylmorpholine;chloride Chemical compound Cl.CN1CCOCC1 BTJRKNUKPQBLAL-UHFFFAOYSA-N 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Description
【発明の詳細な説明】
本発明はピリジンカルボン酸ピペラジドおよび
それらの酸付加塩の新規な製造方法に関する。本
発明に従い製造される化合物は一般式
（式中R′はメチルまたはベンジル基を表わす）で
示され、その酸付加塩とともに価値ある心臓血管
作用および抗うつ作用（antidepressant）を有す
る。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing pyridinecarboxylic acid piperazides and their acid addition salts. Compounds produced according to the invention have the general formula (wherein R' represents a methyl or benzyl group) and together with its acid addition salts have valuable cardiovascular and antidepressant effects.
一般式の化合物は当技術で既知であり、「フ
アーマシア」（Farmacia）〔ブカレスト
（Bucuresti）〕、10、35、81（1962）およびハンガ
リー特許第162396号明細書にすでに記載されてい
る。 Compounds of the general formula are known in the art and have already been described in "Farmacia" (Bucuresti), 10 , 35, 81 (1962) and in Hungarian Patent No. 162,396.
一般式（式中R′は前記定義と同じ意味を有
する）を有する化合物の製造には、今迄次の３つ
の方法が使用されていた：
(a) ピリジンカルボン酸を一般式
（式中R′は前記定義と同じ意味を有する）を有
する相当するピペラジン誘導体と溶融状態で
140℃ないし250℃の温度で20ないし25時間反応
させる。 To date, the following three methods have been used for the production of compounds having the general formula (in which R' has the same meaning as defined above): (a) Pyridinecarboxylic acid is converted into (wherein R′ has the same meaning as defined above) in the molten state.
React at a temperature of 140°C to 250°C for 20 to 25 hours.
(b) ピリジンカルボン酸を対応するエステルまた
はアミド誘導体に変換し、次に一般式（式中
R′は前記定義と同じ意味を有する）のピペラ
ジン誘導体と上記(a)法に関して記載したとおり
のやり方で反応させる。(b) Converting the pyridine carboxylic acid to the corresponding ester or amide derivative, then the general formula
R' has the same meaning as defined above) in the same manner as described for process (a) above.
(c) ピリジンカルボン酸を対応する酸クロリドに
変換し、次に一般式Ｖ（式中R′は前記定義と
同じ意味を有する）の化合物と０℃ないし100
℃の温度で反応させる。(c) Converting the pyridinecarboxylic acid into the corresponding acid chloride and then adding the compound of the general formula V (wherein R' has the same meaning as defined above) from 0°C to 100°C.
React at a temperature of °C.
(c)法では理論量の68％に相当する収率が達成さ
れ、一方(a)法および(b)法では約40ないし60％の収
率が達成できる。上記方法のいずれか１つにより
製造された生成物は真空蒸留により精製する。 With method (c), yields corresponding to 68% of theory are achieved, while with methods (a) and (b), yields of about 40 to 60% can be achieved. The product produced by any one of the above methods is purified by vacuum distillation.
(a)法により処理した場合に得られる比較的低収
率に関する妥当な説明を見出すために、この反応
を熱重量分析により追跡する。ピリジン−２−カ
ルボン酸の溶融物をＮ−ベンジルピペリジンと反
応させた場合に、またはピリジン−２−カルボン
酸およびＮ−ペンジルピペラジンを一緒に溶融し
た場合に、顕著な重量損失を脱カルボキシル化副
反応により120℃ですでに観察しうることが見出
された。換言すれば、最適温度範囲で行なつた場
合に、主反応は最終生成物の顕著な損失をもたら
す副反応を伴なう。 The reaction is followed by thermogravimetric analysis in order to find a plausible explanation for the relatively low yields obtained when treated by method (a). Decarboxylation causes significant weight loss when a melt of pyridine-2-carboxylic acid is reacted with N-benzylpiperidine or when pyridine-2-carboxylic acid and N-benzylpiperazine are melted together. It has been found that side reactions can already be observed at 120°C. In other words, when carried out in the optimum temperature range, the main reaction is accompanied by side reactions that result in significant loss of final product.
上記(b)法では、理論的に幾分より良好な収率を
予期しうるが、この原料化合物の製造に追加の反
応工程が必要であることを考慮すれば、その総収
率は(a)法の場合と同じかまたはより低いことさえ
ある。 Although a somewhat better yield could theoretically be expected with method (b) above, taking into account the additional reaction steps required for the production of this starting compound, the total yield is (a ) law may be the same or even lower.
一方、(b)法および(c)法は追加の欠点を有する、
すなわち(b)法では原料物質の製造および反応中に
発生する重大量のアンモニアが汚染問題を包含
し、また(c)法では形成された塩酸の捕束および排
除が非常に困難である。 On the other hand, methods (b) and (c) have additional drawbacks,
That is, in the method (b), the significant amount of ammonia generated during the production and reaction of the raw materials involves pollution problems, and in the method (c), it is very difficult to capture and eliminate the hydrochloric acid formed.
本発明は一般式を有する化合物を前記の欠
点、すなわち低いまたは中程度の収率、長い反応
時間、高温、真空中での分別蒸留による精製およ
び環境を汚染する副生成物の形成を回避して製造
する方法を提供することを目的とする。 The present invention provides compounds having the general formula which avoid the above-mentioned drawbacks, namely low or moderate yields, long reaction times, high temperatures, purification by fractional distillation in vacuum and the formation of by-products that pollute the environment. The purpose is to provide a method for manufacturing.
本発明により、一般式
のピリジンカルボン酸の有機または鉱物塩を一般
式
Cl−CO2−Ｒ （）
（式中Ｒは炭素原子１ないし３個を有するアルキ
ル基を表わす）を有するクロルギ酸と不活性溶媒
中で反応させ、次に得られた一般式
（式中Ｒは前記と同じ意味を有する）のピリジン
カルボン酸誘導体を好ましくは分離することなく
一般式（式中R′は前記定義と同じ意味を有す
る）を有するピペラジン誘導体と反応させ、所望
により得られた一般式の化合物を適当な有機ま
たは無機酸との反応によりその酸付加塩に変換す
ることにより、前記欠点の全部を排除でき、また
極めて純粋な最終生成物を得ることができること
が驚くべきことに見出された。 According to the invention, the general formula An organic or mineral salt of pyridinecarboxylic acid is reacted with chloroformic acid having the general formula Cl- CO2 -R () in which R represents an alkyl group having 1 to 3 carbon atoms in an inert solvent. , then the general formula obtained (wherein R has the same meaning as defined above) is preferably reacted without separation with a piperazine derivative having the general formula (wherein R' has the same meaning as defined above), optionally It is surprising that by converting the compounds of the general formula obtained into their acid addition salts by reaction with suitable organic or inorganic acids, it is possible to eliminate all of the above-mentioned drawbacks and to obtain extremely pure final products. It was discovered that it should be done.
不活性溶媒としては、与えられた条件下に化学
反応に関与せず、従つて反応の進行に対して作用
しないいずれの溶媒も使用できる。たとえば、テ
トラヒドロフラン、ジメチルホルムアミド、ジメ
チルスルホキシド、ジオキサンおよび酢酸エチル
はこの目的に有用であることが判つた。 As inert solvent it is possible to use any solvent which does not take part in the chemical reaction under the given conditions and therefore does not have any effect on the progress of the reaction. For example, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dioxane and ethyl acetate have been found useful for this purpose.
原料物質として使用するピリジンカルボン酸の
塩は３級アミン、たとえばトリエチルアミンまた
はＮ−メチルモルホリンあるいは水酸化カリウム
のごとき無機塩基を用いて製造できるが、その他
のアルカリ金属塩もまた有利に使用できる。 The salts of pyridinecarboxylic acids used as starting materials can be prepared using tertiary amines such as triethylamine or N-methylmorpholine or inorganic bases such as potassium hydroxide, but other alkali metal salts can also be used with advantage.
有機塩基を用いて製造した塩から出発する場合
には、反応は一般に均質媒質中で生起し、塩を予
め製造する必要はないが、一方塩を無機塩基によ
り製造する場合には、反応は不均質媒質中で進行
し、この塩は予め製造せねばならない。 When starting from a salt prepared using an organic base, the reaction generally takes place in a homogeneous medium and there is no need to pre-prepare the salt, whereas when the salt is prepared using an inorganic base, the reaction takes place in a homogeneous medium. Proceeding in a homogeneous medium, the salt must be prepared beforehand.
反応は得られる収率の実質的な変化をともなわ
ず広い温度範囲で実施できる。この温度は一般に
−20℃ないし＋40℃、好ましくは、−５℃ないし
＋20℃である。 The reaction can be carried out over a wide temperature range without substantial change in the yield obtained. This temperature is generally between -20°C and +40°C, preferably between -5°C and +20°C.
反応混合物を水で処理した場合に、生成物の２
水和物が結晶形で沈澱し、後続の真空分別蒸留に
よる精製は省略できる。 When the reaction mixture is treated with water, the product 2
The hydrate precipitates in crystalline form and subsequent purification by vacuum fractional distillation can be omitted.
本発明による方法の従来公知の技術に優る主な
利点は次のとおりである：
反応が短時間で終了する；
高められた温度が不必要である；
特殊な装置が不必要である；
副生成物が環境に対して有害でない；
一般式の化合物をほゞ定量的に優れた純度で
得ることができる。 The main advantages of the process according to the invention over the previously known technology are: the reaction is completed in a short time; elevated temperatures are not required; special equipment is not required; by-products The compound is not harmful to the environment; compounds of the general formula can be obtained almost quantitatively in excellent purity.
本発明を次の非限定的例によつてさらに詳細に
説明する。 The invention will be explained in further detail by the following non-limiting examples.
例 １
１−ベンジル−４−（2′−ピコリル）−ピペラジ
ンの製造
ピリジン−２−カルボン酸246.2ｇ（2.0モル）
を酢酸エチル中トリエチルアミン202.4ｇ（2.0モ
ル）と反応させる。エチルクロルホ−メート
217.1ｇ（２モル）を次に−５゜ないし０℃で加
え、反応混合物をこの温度で30分間撹拌する。そ
の後、混合物を酢酸エチル400ml中のＮ−ベンジ
ルピペラジン352.5ｇ（2.0モル）で半時間処理す
る。上記溶液の添加が完了した時、反応混合物を
を続く２時間10℃で撹拌する。この酢酸エチル溶
液を真空で蒸発させ、次に残留物をメタノール中
に溶解し、水で沈澱させる。Example 1 Production of 1-benzyl-4-(2'-picolyl)-piperazine 246.2 g (2.0 mol) of pyridine-2-carboxylic acid
is reacted with 202.4 g (2.0 mol) of triethylamine in ethyl acetate. Ethyl chloroformate
217.1 g (2 mol) are then added at -5° to 0° C. and the reaction mixture is stirred at this temperature for 30 minutes. The mixture is then treated with 352.5 g (2.0 mol) of N-benzylpiperazine in 400 ml of ethyl acetate for half an hour. When the addition of the above solution is complete, the reaction mixture is stirred for the next 2 hours at 10°C. The ethyl acetate solution is evaporated in vacuo, then the residue is dissolved in methanol and precipitated with water.
収量：615ｇ（97％）。Yield: 615g (97%).
相当する２水和物の融点：81℃〜82℃。 Melting point of the corresponding dihydrate: 81°C to 82°C.
C17H23N30.2H2Oに対する分析値：
計算値：
Ｃ＝64.33％；Ｈ＝7.30％；Ｎ＝13.24％；
実測値：
Ｃ＝64.25％；Ｈ＝7.42％；Ｎ＝13.15％。Analytical value for C 17 H 23 N 3 0.2H 2 O: Calculated value:
C=64.33%; H=7.30%; N=13.24%; Actual value:
C=64.25%; H=7.42%; N=13.15%.
相当する水素フマル酸塩の融点：165℃〜166℃ （文献融点：164℃）。 Melting point of equivalent hydrogen fumarate: 165℃~166℃ (Literature melting point: 164°C).
例 ２
１−メチル−４−（3′−ニコチノイル）−ピペラ
ジンの製造
ニコチン酸のカリウム塩16.1ｇ（0.1モル）を
ジメチルホルムアミドとテトラヒドロフランとの
混合物中−５℃ないし０℃でエチルクロホーメー
ト10.8ｇ（0.1モル）と反応させ、次にこの反応
混合物に同じ温度でメチルピペラジンの酢酸エチ
ル溶液10.0ｇ（0.1モル）を加える。混合物を続
く２時間＋10℃で撹拌し、次に真空で蒸発させ
る。残留物をジクロルエタンに溶解し、得られた
溶液を水で洗浄し、蒸発させ、次に残留物を真空
で分留する。Example 2 Preparation of 1-methyl-4-(3'-nicotinoyl)-piperazine 16.1 g (0.1 mol) of the potassium salt of nicotinic acid were mixed with ethyl chloroformate 10.8 g (0.1 mol) in a mixture of dimethylformamide and tetrahydrofuran at -5°C to 0°C. g (0.1 mol) and then 10.0 g (0.1 mol) of a solution of methylpiperazine in ethyl acetate is added to the reaction mixture at the same temperature. The mixture is stirred for the next 2 hours at +10°C and then evaporated in vacuo. The residue is dissolved in dichloroethane, the resulting solution is washed with water, evaporated and the residue is then fractionated in vacuo.
収量：18.25ｇ（89.0％）。Yield: 18.25g (89.0%).
沸点：146℃〜149℃／0.1mmHg。Boiling point: 146℃~149℃/0.1mmHg.
C11H15N3Oに対する分析値：
計算値：
Ｃ＝64.36％；Ｈ＝7.3％；Ｎ＝20.47％；
実測値：
Ｃ＝64.15％；Ｈ＝7.43％；Ｎ＝20.56％。Analytical values for C 11 H 15 N 3 O: Calculated values:
C=64.36%; H=7.3%; N=20.47%; Actual value:
C=64.15%; H=7.43%; N=20.56%.
相当するジクロルハイドレートの融点：130
℃。 Melting point of equivalent dichlorohydrate: 130
℃.
例 ３
１−メチル−４−（4′−イソニコチノイル）−ピ
ペラジンの製造
イソニコチン酸12.3ｇ（0.1モル）をＮ−メチ
ルモルホリン10.1ｇ（0.1モル）の酢酸エチル溶
液と室温で反応させることにより塩に変換する。
この反応混合物に−５℃ないし０℃の温度でメチ
ルクロルホーメート9.40ｇ（0.1モル）を加え、
次いで同じ温度で酢酸エチル中のＮ−メチルピペ
ラジン10.0ｇ（0.1モル）を加える。添加が完了
した時に、反応混合物を＋10℃で２時間撹拌す
る。得られたＮ−メチルモルホリン塩酸塩を去
し、液を蒸発させ、残留物を真空で分留する。Example 3 Preparation of 1-methyl-4-(4'-isonicotinoyl)-piperazine The salt is prepared by reacting 12.3 g (0.1 mol) of isonicotinic acid with a solution of 10.1 g (0.1 mol) of N-methylmorpholine in ethyl acetate at room temperature. Convert to
9.40 g (0.1 mol) of methyl chloroformate was added to the reaction mixture at a temperature of -5°C to 0°C,
Then, at the same temperature, 10.0 g (0.1 mol) of N-methylpiperazine in ethyl acetate are added. When the addition is complete, the reaction mixture is stirred at +10°C for 2 hours. The N-methylmorpholine hydrochloride obtained is removed, the liquid is evaporated and the residue is fractionated in vacuo.
収量：17.2ｇ（84％） 沸点：147℃〜149℃／0.2mmHg。Yield: 17.2g (84%) Boiling point: 147℃~149℃/0.2mmHg.
C11H15N3Oに対する分析値：
計算値：
Ｃ＝64.36％；Ｈ＝7.37％；Ｎ＝20.47％；
実測値：
Ｃ＝64.52％；Ｈ＝7.48％；Ｎ＝20.31％。Analytical values for C 11 H 15 N 3 O: Calculated values:
C=64.36%; H=7.37%; N=20.47%; Actual value:
C=64.52%; H=7.48%; N=20.31%.
相当するジクロルハイドレートの融点：271
℃。 Melting point of equivalent dichlorohydrate: 271
℃.
Claims (1)
により予め分離することなく一般式 Cl−CO2−Ｒ （式中Ｒは炭素原子１ないし３個を有するアルキ
ル基を表わす）のクロルギ酸エステルと、均質ま
たは不均質反応系で不活性溶媒の存在下に反応さ
せ、得られた式 （式中Ｒは前記定義と同じ意味を有する）のピリ
ジン−カルボン酸誘導体を好ましくは分離するこ
となく一般式 （式中R′はメチルまたはベンジル基を表わす）を
有する置換ピペラジンとさらに反応させ、所望に
より得られた塩基をそれ自体既知のやり方でその
酸付加塩に変換することよりなる一般式 （式中R′は前記定義と同じ意味を有する）で示さ
れるピリジンカルボン酸ピペラジドおよびその酸
付加塩の製造方法。 ２ 有機塩基として３級アミン、好ましくはトリ
エチルアミンまたはＮ−メチル−モルホリンを使
用する特許請求の範囲第１項に記載の方法。 ３ 無機塩基としてアルカリ金属水酸化物、好ま
しくは水酸化カリウムを使用する特許請求の範囲
第１項に記載の方法。[Claims] 1 formula An organic or inorganic salt of pyridinecarboxylic acid, optionally without prior separation, can be homogeneously prepared with a chloroformic acid ester of the general formula Cl- CO2 -R, in which R represents an alkyl group having 1 to 3 carbon atoms. Or react in the presence of an inert solvent in a heterogeneous reaction system, and the obtained formula (wherein R has the same meaning as defined above), preferably without separation, of the general formula (R' represents a methyl or benzyl group) and optionally converts the base obtained into its acid addition salt in a manner known per se. A method for producing pyridinecarboxylic acid piperazide and its acid addition salt represented by the formula (wherein R' has the same meaning as defined above). 2. Process according to claim 1, in which a tertiary amine, preferably triethylamine or N-methyl-morpholine, is used as organic base. 3. Process according to claim 1, in which an alkali metal hydroxide, preferably potassium hydroxide, is used as inorganic base.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU77EE2510A HU175075B (en) | 1977-06-30 | 1977-06-30 | Process for preparing pyridine-carboxylic acid piperazides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5414985A JPS5414985A (en) | 1979-02-03 |
| JPS6152826B2 true JPS6152826B2 (en) | 1986-11-14 |
Family
ID=10995734
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7918978A Granted JPS5414985A (en) | 1977-06-30 | 1978-06-29 | Production of pyridinecarboxylic acid piperazide |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS5414985A (en) |
| AT (1) | AT365172B (en) |
| CA (1) | CA1103252A (en) |
| CH (1) | CH634572A5 (en) |
| CS (1) | CS199212B2 (en) |
| DD (1) | DD136136A5 (en) |
| DE (1) | DE2828888A1 (en) |
| DK (1) | DK148771C (en) |
| FI (1) | FI66174C (en) |
| GB (1) | GB2001062B (en) |
| HU (1) | HU175075B (en) |
| PL (1) | PL110336B1 (en) |
| SE (1) | SE429042B (en) |
| SU (1) | SU715023A3 (en) |
| YU (1) | YU40711B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3985066A (en) * | 1975-05-15 | 1976-10-12 | S&S Corrugated Paper Machinery Co., Inc. | Single point means for slotter adjustment |
| DE10035908A1 (en) * | 2000-07-21 | 2002-03-07 | Asta Medica Ag | New heteroaryl derivatives and their use as medicines |
| WO2002094799A2 (en) | 2001-05-22 | 2002-11-28 | Neurogen Corporation | Melanin concentrating hormone receptor ligands: substituted 1-benzyl-4-aryl piperazine analogues |
| EP2470182B1 (en) * | 2009-08-24 | 2014-06-04 | Neuralstem, Inc. | Synthesis of a neurostimulative piperazine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5033073A (en) * | 1973-07-20 | 1975-03-31 | ||
| JPS5144957A (en) * | 1974-10-14 | 1976-04-16 | Matsushita Electric Works Ltd | DEJITARU TOKEI |
| JPS5246080A (en) * | 1975-10-06 | 1977-04-12 | Taiho Yakuhin Kogyo Kk | Preparation of pyridinecarbonyl aminoalkyl thiols |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3865828A (en) * | 1972-03-22 | 1975-02-11 | Egyt Gyogyszervegyeszeti Gyar | Pyridine derivatives having antidepressant activity |
-
1977
- 1977-06-30 HU HU77EE2510A patent/HU175075B/en not_active IP Right Cessation
-
1978
- 1978-06-20 CA CA305,894A patent/CA1103252A/en not_active Expired
- 1978-06-21 AT AT0453178A patent/AT365172B/en active
- 1978-06-26 DK DK285178A patent/DK148771C/en not_active IP Right Cessation
- 1978-06-26 SU SU782628948A patent/SU715023A3/en active
- 1978-06-26 FI FI782031A patent/FI66174C/en not_active IP Right Cessation
- 1978-06-26 YU YU1499/78A patent/YU40711B/en unknown
- 1978-06-28 GB GB7828118A patent/GB2001062B/en not_active Expired
- 1978-06-28 DD DD78206341A patent/DD136136A5/en not_active IP Right Cessation
- 1978-06-29 PL PL1978208009A patent/PL110336B1/en unknown
- 1978-06-29 CS CS784300A patent/CS199212B2/en unknown
- 1978-06-29 JP JP7918978A patent/JPS5414985A/en active Granted
- 1978-06-29 CH CH709078A patent/CH634572A5/en not_active IP Right Cessation
- 1978-06-29 SE SE7807383A patent/SE429042B/en not_active IP Right Cessation
- 1978-06-30 DE DE19782828888 patent/DE2828888A1/en active Granted
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5033073A (en) * | 1973-07-20 | 1975-03-31 | ||
| JPS5144957A (en) * | 1974-10-14 | 1976-04-16 | Matsushita Electric Works Ltd | DEJITARU TOKEI |
| JPS5246080A (en) * | 1975-10-06 | 1977-04-12 | Taiho Yakuhin Kogyo Kk | Preparation of pyridinecarbonyl aminoalkyl thiols |
Also Published As
| Publication number | Publication date |
|---|---|
| PL208009A1 (en) | 1979-05-07 |
| FI782031A (en) | 1978-12-31 |
| PL110336B1 (en) | 1980-07-31 |
| SE7807383L (en) | 1978-12-31 |
| DD136136A5 (en) | 1979-06-20 |
| YU40711B (en) | 1986-04-30 |
| DK285178A (en) | 1978-12-31 |
| DK148771C (en) | 1986-03-10 |
| CH634572A5 (en) | 1983-02-15 |
| GB2001062B (en) | 1982-02-24 |
| ATA453178A (en) | 1981-05-15 |
| DE2828888C2 (en) | 1987-10-29 |
| CS199212B2 (en) | 1980-07-31 |
| GB2001062A (en) | 1979-01-24 |
| DK148771B (en) | 1985-09-23 |
| JPS5414985A (en) | 1979-02-03 |
| FI66174C (en) | 1984-09-10 |
| DE2828888A1 (en) | 1979-01-18 |
| HU175075B (en) | 1980-05-28 |
| FI66174B (en) | 1984-05-31 |
| SE429042B (en) | 1983-08-08 |
| YU149978A (en) | 1982-10-31 |
| CA1103252A (en) | 1981-06-16 |
| SU715023A3 (en) | 1980-02-05 |
| AT365172B (en) | 1981-12-28 |
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