JPH0330596B2 - - Google Patents
Info
- Publication number
- JPH0330596B2 JPH0330596B2 JP57122800A JP12280082A JPH0330596B2 JP H0330596 B2 JPH0330596 B2 JP H0330596B2 JP 57122800 A JP57122800 A JP 57122800A JP 12280082 A JP12280082 A JP 12280082A JP H0330596 B2 JPH0330596 B2 JP H0330596B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- sodium
- basic condensing
- potassium
- 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 - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- 238000007363 ring formation reaction Methods 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- -1 Anthranilic acid ester Chemical class 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 4
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- RWZYAGGXGHYGMB-UHFFFAOYSA-N o-aminobenzenecarboxylic acid Natural products NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 claims description 2
- MIRBIZDDMSFTKY-UHFFFAOYSA-N 5,11-dihydropyrido[2,3-b][1,4]benzodiazepin-6-one Chemical compound O=C1NC2=CC=CN=C2NC2=CC=CC=C12 MIRBIZDDMSFTKY-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- MEQBJJUWDCYIAB-UHFFFAOYSA-N 2-chloropyridin-3-amine Chemical compound NC1=CC=CN=C1Cl MEQBJJUWDCYIAB-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- WNAJXPYVTFYEST-UHFFFAOYSA-N 2-Amino-3-methylbenzoate Chemical compound CC1=CC=CC(C(O)=O)=C1N WNAJXPYVTFYEST-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- RELMFMZEBKVZJC-UHFFFAOYSA-N 1,2,3-trichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1Cl RELMFMZEBKVZJC-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 229960004633 pirenzepine Drugs 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- YXFAOWYMDGUFIQ-UHFFFAOYSA-N 2-methoxypyridin-3-amine Chemical compound COC1=NC=CC=C1N YXFAOWYMDGUFIQ-UHFFFAOYSA-N 0.000 description 1
- BWWHTIHDQBHTHP-UHFFFAOYSA-N 2-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1C(Cl)=O BWWHTIHDQBHTHP-UHFFFAOYSA-N 0.000 description 1
- MMGYNSSWEUQWAS-UHFFFAOYSA-N Cl.Cl.N1=CC=NC=C2C(=O)C=CC=C21 Chemical compound Cl.Cl.N1=CC=NC=C2C(=O)C=CC=C21 MMGYNSSWEUQWAS-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000000026 anti-ulcerogenic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 150000005440 nitrobenzoic acid derivatives Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は一般式
（式中Ｒは水素もしくはハロゲン原子又はメチ
ル基を表わす）なる５，11−ジヒドロ−6H−ピ
リド〔２，３−ｂ〕〔１，４〕−ベンゾジアゼピン
−６−オンの新規製造方法に関する。これらの化
合物は薬剤組成物の製造に、たとえばピレンゼピ
ン（５，11−ジヒドロ−11−〔（４−メチル−１−
ピペラジニル）−アセチル−6H−ピリド−〔２，
３−ｂ〕〔１，４〕ベンゾジアゼピン−６−オン
二塩酸塩）（強力な抗潰瘍形成作用および胃液の
分泌を抑える作用を有する物質）の製造に有用な
出発生成物である。
本発明の方法は一般式
式中Halはハロゲン原子、好ましくは塩素原
子、を表わす）なる２−ハロ−３−アミノピリジ
ンを一般式
（式中Ｒは上記定義と同じであり、R1は１な
いし３個の炭素原子を有するアルキル基、好まし
くはメチル基、を表わす）なるアントラニル酸エ
ステルと、塩基性縮合剤の存在下に反応させてま
ず一般式
（式中ＲおよびHalは上記定義と同じである）
なる化合物を得、次にこの化合物を中性もしくは
酸性媒質中にて、好ましくは硫酸の存在下に、
100から200℃までの温度で環化する。
新規方法を一容器法として行うのが特に適当で
あり、式なる化合物を単離せずに環化を同じ反
応容器中にて、反応混合物を７もしくはそれ以下
のPHまで酸性とした後に行う。
式なる化合物と式なるアントラニル酸エス
テルとの反応は、有機溶媒の存在下に、上記の如
く、塩基性縮合剤の存在下に10と120℃との間の
温度で行われる。塩基性縮合剤としては、水酸化
テトラブチルアンモニウム、ナトリウムもしくは
カリウムメトキシド、ナトリウムもしくはカリウ
ムイソプロポキシド、ナトリウムもしくはカリウ
ムｔ−ブトキシド、水素化ナトリウム、リチウ
ム、ナトリウムもしくはカリウムアミド又は水酸
化ナトリウムの如き化合物を用いることができ
る。適当な溶媒としては、たとえば、エタノー
ル、トルエン、キシレン、ジメチルスルホキド、
スルホランもしくはトリクロロベンゼンが含まれ
るが、過剰のアルキルアントラニル酸塩を溶媒と
して用いることもできる。
式なる化合物を単離するか又は本法を一容器
反応として行うかどうかににかかわらず、生成さ
れた式なる化合物の環化は、100−200℃の温度
で溶媒、好ましくはトリクロロベンゼンおよびス
ルホラン、中にて中性もしくは酸性PHにて行われ
る。もしも一容器反応を用いるなら、化合物を
含有するアルカリ反応の反応混合物を、好ましく
は硫酸で、酸性とし、次に環化を上記温度まで加
熱することによつて行う。
一般式およびなる化合物ならびに塩基性縮
合剤はモル量を用いるか又は過剰量の式なる化
合物および（もしくは）塩基性縮合剤を用いる。
式なる化合物の収量は98％までであり、一方式
なる終末生成物の収量は87％までである。
式なる化合物の製造方法はドイツ特許第
1179943号からすでに知られている。この既知方
法は３工程法であり、まず式なる２−ハロ−３
−アミノ−ピリジンを反応性ニトロ安息香酸誘導
体、好ましくはその酸ハロゲン化物、と反応さ
せ、次に得られたニトロ化合物を還元し、こうし
て得られた式なる化合物を融成物中にて又は高
沸点溶媒、たとえばパラフインもしくはデカリ
ン、の存在下に、場合によつては塩基性触媒もし
くは粉末銅の存在下でもよく、環化させる。
収量がこの方法では低いという事実とは別に、
この方法はまた取り扱いがむずかしく、そして危
険である２−ニトロ−ベンゾイルクロリドを用い
るのに対し、アントラニル酸エステルは特に安価
な出発物質である。また、この方法は３工程法で
あるが、本発明の方法では化合物を１容器反応で
得ることができる。さらに、環化は中性もしくは
酸性媒質中で明記された溶媒の存在下に行われる
と、媒質中で行う既知方法よりも実質上より良好
であり、かつより高収量を生ずる。既知方法にお
ける環化の収量は本発明の方法の収量（総収量は
87％に達する）よりも低い。
さらに、式なる所望の化合物は一般式なる
化合物を一般式なる化合物と、強塩基の存在下
に反応させることによつて得られるということに
驚くが、これは２−もしくは４−位にハロゲン原
子を有するピリジンは、特にアルカル媒質中に
て、非常に速く相当するピリジノールに変換する
からである。これは、たとえば、アルコール性水
酸化ナトリウムもしくは水性水酸化カリウム溶液
又は水性水酸化カリウム溶液とおよそ90℃の温度
のみを必要とする。さらに、かかる反応は文献か
ら知られている；たとえば、２−クロロ−３−ア
ミノピリジンとナトリウムメトキシド溶液から２
−メトキシ−３−アミノピリジンを得る反応はオ
ー・ボン・シツク（O.von..Schickh）等により
Ber.Dtsch.Chem.Ges.1936、第12号、2594、2600
および2602頁に記載されている。それゆえ、上記
理由のため、本発明の反応では、式の化合物中
のハロゲン原子が塩基性縮合剤の陰イオン基と交
換されるのみならず、またさらに式およびな
る化合物が非常に高い収量で得られることは特に
驚くべきことである。
一般式なる化合物の上記物質ピレンゼピンも
しくは類似ピレンゼピン化合物への変化はドイツ
特許第1795183号に記載されている。
次の例は本発明を例証するものである：
Ａ ２−クロロ−３−（２−アミノベンゾイル）−
アミノピリジンの製造例
例 １ 51.4g（0.4モル）の２−クロロ−３−ア
ミノピリジンを160mlのキシレン中に懸濁させる。
次に58.4g（0.52モル）のカリウムtert.ブトキシド
を加え、そしておよそ25分以内に、78.6g（0.52モ
ル）のメチル２−アミノ安息香酸をも添加する。
次に混合物を１時間還流し、およそ20℃まで冷却
し、そして100mlの水を加える。結晶の懸濁液を
濃塩酸でPH６に調整し、吸引ろ取し、水洗し、減
圧下に一定重量が得られるまで80℃で乾燥させ
る。
収量：94.3g（理論値の95.2％）。
M.p.：169−171℃
同様の反応条件下でのさらに可能な製造方法：
The present invention is based on the general formula The present invention relates to a new method for producing 5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one (wherein R represents hydrogen, a halogen atom, or a methyl group). These compounds can be used in the preparation of pharmaceutical compositions, such as pirenzepine (5,11-dihydro-11-[(4-methyl-1-
piperazinyl)-acetyl-6H-pyrido-[2,
3-b] [1,4]benzodiazepine-6-one dihydrochloride), a substance with strong anti-ulcerogenic and anti-gastric secretion properties. The method of the present invention uses the general formula In the formula, Hal represents a halogen atom, preferably a chlorine atom). (wherein R is the same as defined above and R 1 represents an alkyl group having 1 to 3 carbon atoms, preferably a methyl group) in the presence of a basic condensing agent. First of all, the general formula (In the formula, R and Hal are the same as defined above)
This compound is then mixed in a neutral or acidic medium, preferably in the presence of sulfuric acid.
Cyclizes at temperatures from 100 to 200°C. It is particularly suitable to carry out the new process as a one-pot process, in which the cyclization is carried out in the same reaction vessel, without isolation of the compound of formula, after acidification of the reaction mixture to a pH of 7 or lower. The reaction of the compound of the formula with the anthranilic acid ester of the formula is carried out at a temperature between 10 and 120° C. in the presence of a basic condensing agent, as described above, in the presence of an organic solvent. Basic condensing agents include compounds such as tetrabutylammonium hydroxide, sodium or potassium methoxide, sodium or potassium isopropoxide, sodium or potassium tert-butoxide, sodium hydride, lithium, sodium or potassium amide or sodium hydroxide. can be used. Suitable solvents include, for example, ethanol, toluene, xylene, dimethyl sulfoxide,
Sulfolane or trichlorobenzene are included, but excess alkyl anthranilate can also be used as a solvent. Whether the compound of formula is isolated or the process is carried out as a one-pot reaction, the cyclization of the compound of formula formed is carried out in a solvent, preferably trichlorobenzene and sulfolane, at a temperature of 100-200°C. , at neutral or acidic pH. If a one-vessel reaction is used, the reaction mixture of the alkaline reaction containing the compound is made acidic, preferably with sulfuric acid, and the cyclization is then carried out by heating to the above temperature. The compound of the general formula and the basic condensing agent are used in molar amounts, or the compound of the formula and/or the basic condensing agent is used in an excess amount.
The yield of the compound of the formula is up to 98% and the yield of the final product of the formula is up to 87%. The method for producing the compound of formula is described in German patent no.
Already known from issue 1179943. This known method is a three-step method, first with the formula 2-halo-3
- reacting the amino-pyridine with a reactive nitrobenzoic acid derivative, preferably its acid halide, and then reducing the nitro compound thus obtained, in a melt or in a polymer. The cyclization takes place in the presence of a boiling solvent, such as paraffin or decalin, optionally in the presence of a basic catalyst or powdered copper. Apart from the fact that the yield is lower with this method,
This process also uses 2-nitro-benzoyl chloride, which is difficult and dangerous to handle, whereas anthranilic acid ester is a particularly inexpensive starting material. Furthermore, although this method is a three-step method, the compound can be obtained in a one-vessel reaction in the method of the present invention. Furthermore, when the cyclization is carried out in a neutral or acidic medium in the presence of the specified solvent, it is substantially better and gives higher yields than known methods carried out in a medium. The yield of cyclization in the known method is the yield of the method of the present invention (the total yield is
(reaching 87%). Furthermore, it is surprising that the desired compound of the formula can be obtained by reacting a compound of the general formula with a compound of the general formula in the presence of a strong base; This is because pyridine having a pyridine converts very quickly into the corresponding pyridinol, especially in an alkaline medium. This requires, for example, only alcoholic sodium hydroxide or aqueous potassium hydroxide solution or aqueous potassium hydroxide solution and a temperature of approximately 90°C. Furthermore, such reactions are known from the literature; for example, from 2-chloro-3-aminopyridine and sodium methoxide solution
-The reaction to obtain methoxy-3-aminopyridine was described by O. von Schick et al.
Ber.Dtsch.Chem.Ges. 1936 , No. 12, 2594, 2600
and page 2602. Therefore, for the above reasons, in the reaction of the present invention, not only the halogen atom in the compound of formula is exchanged with the anionic group of the basic condensing agent, but also the compound of formula and What is obtained is particularly surprising. The transformation of the compound of the general formula into the above substance pirenzepine or analogous pirenzepine compounds is described in German Patent No. 1795183. The following example illustrates the invention: A 2-chloro-3-(2-aminobenzoyl)-
Preparation Examples of Aminopyridine Example 1 51.4 g (0.4 mol) of 2-chloro-3-aminopyridine are suspended in 160 ml of xylene.
Next, 58.4 g (0.52 moles) of potassium tert.butoxide are added and, within approximately 25 minutes, 78.6 g (0.52 moles) of methyl 2-aminobenzoic acid are also added.
The mixture is then refluxed for 1 hour, cooled to approximately 20°C and 100ml of water are added. The suspension of crystals is adjusted to pH 6 with concentrated hydrochloric acid, filtered off with suction, washed with water and dried under reduced pressure at 80°C until a constant weight is obtained. Yield: 94.3g (95.2% of theory). Mp: 169−171℃ Further possible preparation methods under similar reaction conditions:
【表】
例 ２
12.85g（0.1モル）の２−クロロ−３−アミノピ
リジンを65mlのジメチルスルホキシド中に溶か
し、環境温度でトルエン中の10.9gの50％ナトリ
ウムアミド懸濁液（＝5.45gのナトリウムアミ
ド；0.14モル）を加える。次に19.7g（0.13モル）
のメチル２−アミノ安息香酸を10分以内に通し、
この混合物を30分間50℃で撹拌する。完成させる
ために、これを20℃まで冷却し、次に窒素雰囲気
下にて100mlの水および十分な濃塩酸を加えてPH
６とする。結晶の懸濁液を吸引ろ取し、水洗し、
そして50℃で乾燥させて一定の重量を得る。
収量：23.9g（理論値の96.4％）
M.p：170−172℃
ナトリウムアミドの代わりに、リチウムアミド
を、たとえば、使用してもよい。
収量：理論値の68.4％
例 ３
25.7g（0.2モル）の２−クロロ−３−アミノピ
リジンおよび16.2g（0.3モル）のナトリウムメト
キシドを160mlのトルエン中にて加熱沸騰させ、
30mlの溶媒を100℃の温度まで留去する。30mlの
トルエンを新たに反応混合物へ入れ、39.6g（0.26
モル）のメチル２−アミノ安息香酸を20分間以内
に入れる（70℃で出発）。次に混合物を４時間90
−95℃で撹拌する。必要ならば、さらに5.4g（0.1
モル）のナトリウムメトキシドをこの後で添加し
てもよく、そして次にこの混合物を放置して90〜
95℃で反応させる。
反応が完了したら、混合物をおよそ15℃まで冷
却し、吸引ろ取し、そしておよそ200mlの石油エ
ーテルで洗う。ろ過残留物を吸引使用により完全
に乾燥させてから250mlの水中に懸濁させ、濃塩
酸でPH６に調整する。結晶スラリーを吸引ろ取
し、水洗し、かつ50℃で乾燥させて一定の重量を
得る。
収量：37.7g（理論値の76.1％）
M.p.：168−170℃
同じ反応条件下でのさらに可能な製造方法：[Table] Example 2 12.85 g (0.1 mol) of 2-chloro-3-aminopyridine are dissolved in 65 ml of dimethyl sulfoxide and a suspension of 10.9 g of 50% sodium amide in toluene (= 5.45 g of Add sodium amide; 0.14 mol). Then 19.7g (0.13mol)
of methyl 2-aminobenzoic acid within 10 minutes,
This mixture is stirred for 30 minutes at 50°C. To complete it, cool it to 20°C and then add 100ml of water and enough concentrated hydrochloric acid under nitrogen atmosphere to pH
Set it to 6. Suction filter the crystal suspension, wash with water,
Then dry at 50°C to obtain a constant weight. Yield: 23.9 g (96.4% of theory) Mp: 170-172°C Instead of sodium amide, lithium amide may be used, for example. Yield: 68.4% of theoretical value Example 3 25.7 g (0.2 mol) of 2-chloro-3-aminopyridine and 16.2 g (0.3 mol) of sodium methoxide were heated to boiling in 160 ml of toluene.
30 ml of solvent are distilled off to a temperature of 100°C. Add 30 ml of toluene to the reaction mixture and add 39.6 g (0.26
mol) of methyl 2-aminobenzoic acid within 20 minutes (starting at 70° C.). Then mix for 4 hours90
Stir at -95°C. If necessary, add an additional 5.4g (0.1
mol) of sodium methoxide may be added after this, and the mixture is then allowed to stand for 90~
React at 95℃. When the reaction is complete, the mixture is cooled to approximately 15° C., filtered off with suction and washed with approximately 200 ml of petroleum ether. The filter residue is completely dried using suction and then suspended in 250 ml of water and adjusted to pH 6 with concentrated hydrochloric acid. The crystal slurry is filtered off with suction, washed with water and dried at 50°C to obtain a constant weight. Yield: 37.7g (76.1% of theory) Mp: 168−170℃ Further possible preparation methods under the same reaction conditions:
【表】
シド 沈澱
[Table] Sid Precipitation
【表】
シド ド 沈澱
[Table] Sidde precipitation
Claims (1)
ル基を表わす）なる５，11−ジヒドロ−6H−ピ
リド−〔２，３−ｂ〕〔１，４〕ベンゾジアゼピン
−６−オンの製造において、一般式 （式中Halはハロゲン原子を表わす） なる２−ハロ−３−アミノピリジンを一般式 （式中Ｒは上記定義と同じであり、R1は１な
いし３個の炭素原子を有するアルキル基を表わ
す）なるアントラニル酸エステルと、有機溶媒中
にて塩基性縮合剤の存在下に10と120℃との間の
温度で反応させ、そして得られた式 （式中ＲおよびHalは上記定義と同じである）
なる化合物を７もしくはそれ以下のPHで、100と
200℃との間の温度で環化することを特徴とする
その製造方法。 ２ 得られた式なる化合物を、単離せずに、無
機酸、好ましくは硫酸、を反応混合物へ添加して
PHを７もしくはそれ以下にした後、100ないし200
℃で式なる化合物に変換することを特徴とする
特許請求の範囲第１項の方法。 ３ 水酸化テトラブチルアンモニウム、ナトリウ
ムもしくはカリウムメトキシド、ナトリウムもし
くはカリウムイソプロポキシド、ナトリウムもし
くはカリウムtert.ブトキシド、水素化ナトリウ
ム、リチウムアミド、カリウムアミド、ナトリウ
ムアミドもしくは水酸化ナトリウムを塩基性縮合
剤として用いることを特徴とする特許請求の範囲
第１もしくは２項のいずれか１つの方法。 ４ モル量の式およびなる化合物ならびに塩
基性縮合剤を用いるか又は過剰の式なる化合物
および（もしくは）塩基性縮合剤を用いることを
特徴とする特許請求の範囲第１項から３項までの
いずれ１つの方法。[Claims] 1. General formula In the production of 5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one (wherein R represents hydrogen, a halogen atom, or a methyl group), the general formula (In the formula, Hal represents a halogen atom) 2-halo-3-aminopyridine with the general formula Anthranilic acid ester (wherein R is the same as defined above and R 1 represents an alkyl group having 1 to 3 carbon atoms) is added to 10 in the presence of a basic condensing agent in an organic solvent. react at a temperature between 120 °C, and the obtained formula (In the formula, R and Hal are the same as defined above)
100 at a pH of 7 or less.
A process for its production characterized by cyclization at a temperature between 200°C. 2 The resulting compound of formula is, without isolation, added to the reaction mixture with an inorganic acid, preferably sulfuric acid.
100 to 200 after reducing the pH to 7 or below
2. A method according to claim 1, characterized in that the compound is converted to a compound of the formula at .degree. 3 Tetrabutylammonium hydroxide, sodium or potassium methoxide, sodium or potassium isopropoxide, sodium or potassium tert.butoxide, sodium hydride, lithium amide, potassium amide, sodium amide or sodium hydroxide are used as basic condensing agents. A method according to claim 1 or 2, characterized in that: 4. Any of claims 1 to 3, characterized in that a molar amount of the compound of the formula and the basic condensing agent is used, or an excess of the compound of the formula and/or the basic condensing agent is used. One way.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3127849.3 | 1981-07-15 | ||
| DE3127849 | 1981-07-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5818383A JPS5818383A (en) | 1983-02-02 |
| JPH0330596B2 true JPH0330596B2 (en) | 1991-04-30 |
Family
ID=6136912
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57122800A Granted JPS5818383A (en) | 1981-07-15 | 1982-07-14 | Novel manufacture of benzodiazepine compound |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS5818383A (en) |
| AT (1) | AT379394B (en) |
| CH (1) | CH649085A5 (en) |
| CS (1) | CS226745B2 (en) |
| DD (1) | DD202571A5 (en) |
| DK (1) | DK157999C (en) |
| ES (1) | ES8307248A1 (en) |
| FI (1) | FI77860C (en) |
| GR (1) | GR76198B (en) |
| HU (1) | HU186090B (en) |
| NL (1) | NL8202145A (en) |
| NO (1) | NO160140C (en) |
| PL (1) | PL237471A1 (en) |
| PT (1) | PT75244B (en) |
| SE (1) | SE449102B (en) |
| YU (1) | YU43724B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0737698A1 (en) * | 1994-10-27 | 1996-10-16 | Polyplastics Co. Ltd. | Modified polyacetal and process for production |
| KR100358667B1 (en) * | 1995-04-27 | 2003-04-16 | 폴리플라스틱스 가부시키가이샤 | Thermoplastic Composition and Manufacturing Method thereof |
-
1982
- 1982-05-26 NL NL8202145A patent/NL8202145A/en not_active Application Discontinuation
- 1982-06-21 ES ES513293A patent/ES8307248A1/en not_active Expired
- 1982-06-28 NO NO822182A patent/NO160140C/en unknown
- 1982-07-06 FI FI822391A patent/FI77860C/en not_active IP Right Cessation
- 1982-07-07 AT AT0263482A patent/AT379394B/en not_active IP Right Cessation
- 1982-07-12 YU YU1519/82A patent/YU43724B/en unknown
- 1982-07-12 CH CH4227/82A patent/CH649085A5/en not_active IP Right Cessation
- 1982-07-12 GR GR68721A patent/GR76198B/el unknown
- 1982-07-12 DK DK311982A patent/DK157999C/en not_active IP Right Cessation
- 1982-07-13 DD DD82241618A patent/DD202571A5/en unknown
- 1982-07-14 JP JP57122800A patent/JPS5818383A/en active Granted
- 1982-07-14 HU HU822292A patent/HU186090B/en not_active IP Right Cessation
- 1982-07-14 PL PL23747182A patent/PL237471A1/en unknown
- 1982-07-14 CS CS825387A patent/CS226745B2/en unknown
- 1982-07-14 SE SE8204330A patent/SE449102B/en not_active IP Right Cessation
- 1982-07-14 PT PT75244A patent/PT75244B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ES513293A0 (en) | 1983-06-16 |
| PT75244B (en) | 1985-10-04 |
| YU43724B (en) | 1989-10-31 |
| FI77860C (en) | 1989-05-10 |
| FI77860B (en) | 1989-01-31 |
| FI822391L (en) | 1983-01-16 |
| DK157999B (en) | 1990-03-12 |
| ATA263482A (en) | 1985-05-15 |
| YU151982A (en) | 1986-04-30 |
| PL237471A1 (en) | 1983-01-17 |
| NO160140B (en) | 1988-12-05 |
| NO160140C (en) | 1989-03-15 |
| NO822182L (en) | 1983-01-17 |
| AT379394B (en) | 1985-12-27 |
| NL8202145A (en) | 1983-02-01 |
| CH649085A5 (en) | 1985-04-30 |
| HU186090B (en) | 1985-05-28 |
| SE8204330L (en) | 1983-01-16 |
| DK157999C (en) | 1990-08-13 |
| SE449102B (en) | 1987-04-06 |
| CS226745B2 (en) | 1984-04-16 |
| SE8204330D0 (en) | 1982-07-14 |
| PT75244A (en) | 1982-08-01 |
| GR76198B (en) | 1984-08-03 |
| DD202571A5 (en) | 1983-09-21 |
| DK311982A (en) | 1983-01-16 |
| FI822391A0 (en) | 1982-07-06 |
| ES8307248A1 (en) | 1983-06-16 |
| JPS5818383A (en) | 1983-02-02 |
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