TW201136867A - Mono-nitration of aromatic compounds - Google Patents

Mono-nitration of aromatic compounds Download PDF

Info

Publication number
TW201136867A
TW201136867A TW100118559A TW100118559A TW201136867A TW 201136867 A TW201136867 A TW 201136867A TW 100118559 A TW100118559 A TW 100118559A TW 100118559 A TW100118559 A TW 100118559A TW 201136867 A TW201136867 A TW 201136867A
Authority
TW
Taiwan
Prior art keywords
group
acid
solution
doc
mixture
Prior art date
Application number
TW100118559A
Other languages
English (en)
Other versions
TWI374867B (en
Inventor
Miall Cedilote
Thomas P Cleary
Pingsheng Zhang
Original Assignee
Hoffmann La Roche
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of TW201136867A publication Critical patent/TW201136867A/zh
Application granted granted Critical
Publication of TWI374867B publication Critical patent/TWI374867B/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C07B43/02—Formation or introduction of functional groups containing nitrogen of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C07C209/76—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by nitration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • 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
    • C07D471/06—Peri-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

201136867 六、發明說明： 【發明所屬之技術領域】 本發明係關於含有至少一個鹼性氮原子之基質之硝化。 進一步係關於一種方法，該方法包括由基質及石肖酸形成之 硝酸鹽之形成及分離，及此後在酸性條件下該等鹽之硝 化。因此，通常，本發明係關於一種具有驗性氮原子之芳 香族化合物之單硝化的一般方法，且在較特定之實施例 中，本發明係關於一種製備4_嗎啉基_2·硝基苯甲醚之方 法。 【先前技術】 芳香族核之硝化為有機化學中最基本之反應之一，且廣 泛用於製備墙基芳香族化合物。然而，該反應因數種原因 而聲名狼籍且大部分醫藥生產商不願意進行大規模的室内 硝化。主要顧慮到安全問題。兩個主要因素與反應安全性 方面有關。第一為反應本身。最常使用之硝化劑為濃硝酸 與硫酸之混合物。兩者均為強氧化劑。雖然存在替代性硝 化劑，但其之大部分均產生硝酸或其他當場高反應性之中 間體。硝化反應通常放熱劇烈且具有方法誤操作或設備故 障之後失控而爆炸之高風險。第二為硝化產物。其之大部 为具有低熱穩定性及/或低撞擊穩定性且分解之後釋放大 量能量（例如，TNT(三硝基曱苯），一種威力強大的炸 藥）。結果，當進行硝化時必須採取特別的預防措施，包 括專用設備（例如料倉式反應器）及人員之強化訓練。除安 全問題外，另外亦顧慮其副反應。舉例而言，每當硝化劑 156361.doc -4 - 201136867 加载過多時，可發生過硝化。常見為幾何異構物形成及側 鍵上之反應。因此，發展更安全之确化製程及對化學之更 . 好的控制的新穎硝化方法仍為重要的研究目標。 【發明内容】 根據本發明，已發現該方法係適用於多種化合物。理論 上，可在習知條件下硝化且含有鹼性氮原子之任何芳香族 物質均可使用該方案硝化。一些實例係列於表丨至表4中。 對所有列於表1至4中之實例而言，硝化係藉由將硝酸鹽之 溶液或懸浮液添加至約10當量之濃硫酸中施行。可涵蓋於 本發明中之基質係概述於下列群組中。 A.具有通式結構6之苯胺衍生物，其中Ar為可硝化芳香 族王衣，R1及112為氮、院基或芳香族基團。—些實例係列於 表1中。 /R1
Ar-N 6 Β·具有通式結構7之芳香族化合物，其中Αγ為可硝化芳 、裒R、R、R及R4為氫、垸基或芳香族基團，且口 為1至12之整數。一些實例係列於表2中。 r4 C·具有通式結構8之芳香族仆人 香 化合物，彡中Ar為可墙化芳 、袞’G為合適之原子或其圃^2 Α暴團（例如CR】R2、〇、s、SO、 I56361.d〇c 201136867 S〇2等），R為雜環或其他具有鹼性氮原子之基圏 例係列於表3中》
Ar~fGtR 8 D.具有通式結構9之稠合環芳香族化合物，其中笨環係 與具有鹼性氮原子之雜環稠合，R1、R2及R3可為氣或其他 可耐受習知硝化條件之基團。一些實例係列於表4中。
R- 表1 條目基質 鹽之結構 硝化產物
2 Br NO。 產率：鹽 產率： 之形成 硝化 93% 93% 3
.N、 ό
Br
Br
N_2 N-3 98% 96% "•4% 94.6% ^56361.doc -6 · 201136867 條目基質 鹽之結構 硝化產物 產率：鹽 之形成 產率： 确化 4
(75%) N-4 NO.
/N、 (25%) 96.5% 89% N-5
93% 88%
9 97% 95% 92%
95% 156361.doc 201136867 條目基質 鹽之結構 硝化產物 產率：鹽 之形成 產率： 硝化 10 97% 91%
NH, 0一
0一
NO, S-10 + NH, N〇3 NH. N-13 11
NH, NH, NO, S-11
N-14 N-15 n〇2 98% 95% NO, 0%) N-16 12 nh
Cl
96% 96%
N-17 表2 條目基質 鹽之結構硝化產物 產率： 鹽之形 成 產率：硝化 1 1 - , +.ν、ν〇3 1 Γη 广、 I 約 100% ό 1〇 S'13 ίίΊ (67%) ί J (25%) (油） V ^νο2 Ν02 Ν-18 Ν-19 95% 156361.doc 201136867 2 3
94% 89% 條目 表3 基質 鹽之結構 硝化產物 產率： 之形成 產率： 硝化 11
99% 93% 22
95% 33
90% 156361.doc 9 201136867 條目基質 鹽之結構 硝化產物 產率：鹽 產率： 之形成 硝化 44
99% 91% 55
N-28 96% 66
92% 92%
N-31 表4 條目基質 鹽之結構 确化產物 產率： 鹽之形 成 產率： 硝化
N H NO >-Ο
S-22 。'货。舞 (76%) (24%) Ν·32 Ν^3 98% 91% 156361.doc 10 201136867
97.3% 99%
表丨·4之基質之鹽通常可在<20。(：下藉由將1.0當量70°/〇硝 酸添加至基質之溶液中製備。TBME(第三丁基甲基醚）係 用作可溶解基質之反應溶劑。對微溶於TBME中之基質而 s ’添加第二溶劑以幫助溶解。用於反應之溶劑組合包括 TBME/THF(四氫呋喃）、TBME/乙腈、τβμε/乙酸乙酯 等。對鹽形成期間自溶液沉澱析出之鹽而言，分離係藉由 過滤且在周圍溫度下真空乾燥達成。對並不自溶液完全沉 澱析出之鹽而言，添加乙腈直至形成均勻溶液。隨後，將 溶液經MgS〇4乾燥，過濾且濃縮以提供固體鹽。 在<l〇°C下，藉由將鹽之溶液或懸浮液添加至過量硫酸 中進行鹽之硝化。用於反應之溶劑包括二氯甲烷、硝基甲 烧及其他對反應混合物惰性之溶劑。反應完成後，在 <20 C下，藉由將酸層添加至水中使混合物稀釋。隨後， 藉由添加諸如氨水溶液、碳酸鉀水溶液、碳酸鈉水溶液或 碳酸氫鈉水溶液等之鹼將稀混合物鹼化至pH 6-11。在大 多數情況下，此時產物沉澱析出。將固體產物過濾、用水 洗滌且在約50°C下真空乾燥隔夜以產生硝化產物。在產物 156361.doc 201136867 =二物沉颶析出之情況下，將混合物用溶劑(例如，二 /二、乙酸乙醋等)萃取。隨後，將有機溶液用水洗 '、/ gS〇4乾燥，過濾且濃縮以產生粗產物。 方法之應用產生關於製備4_义嗎♦基·2·確基苯▼醚 的方法、當前正開發用於治療抑#症之藥物候選物 的關鍵t間體的發明（wo 01/97786)。該方法概述於 中。 該新穎方法存在數個超越上述申請案中所揭示之原始方 法之主要優點，包括 1) 製程簡化。在5直接自來自第一步驟之粗產物之萃取 物中沉澱之情況下，避免5之游離鹼分離。 2) 穩健性增加。鹽5含1:1精確比率之基質(5之游離鹼)與 硝酸。因A，二石肖化雜質之形成變為不可 精密量測及裝載硝酸之必要，且因此減輕製程操作^ 擔。 、 3) 安全概況改進。該製程消除將5之固體游離鹼添加至 濃硫酸之操作（極危險之大規模操作’因為該過程放熱劇 烈）。實情為，將5於二氣甲烷中之溶液添加至硫酸中。可 容易地控制添加過程以防止產生過多熱量。該製程亦消除 使70%硝酸與濃硫酸混合之操作。 4) 廢棄物產生減少且加工能力增加。該製程中5之使用 使硫酸負％降低60%成為可能，此導致製程中所產生之廢 棄物減少40°/。且能力增加30%。 5) 產率顯著提高。使用新穎方法獲得之總產率為92%， 156361.doc 12 201136867 而原始方法之總產率僅為58%，提高59°/〇。 作為芳香族基團，涵蓋芳基。 "芳基"意謂單價單環或雙環芳香族碳環烴基，較佳為 6-10個成員之芳香族環系統。較佳芳基包括（但不限於）苯 基、萘基、甲苯基及二曱笨基。 "雜環基"意謂經取代或未經取代之5至8員單或雙環芳香 族或非芳香族烴，其中1至3個碳原子係經選自氮、氧或硫 原子之雜原子置換。實例包括°比π各咬-2-基、°比11各咬-3-基、°米°坐-4-基、吼°坐-3-基、嗎琳-4-基及其類似者。 "雜原子"意謂選自Ν、0及S之原子。 術語"烷基”係指具有1至約20個碳原子之直鏈或支鏈飽 和烴基，包括具有1至約7個碳原子之基團。在某些實施例 中，烷基取代基可為低碳烷基取代基。術語"低碳烷基"係 指具有1至6個碳原子之烷基，且在某些實施例中，具有1 至4個碳原子。烷基之實例包括（但不限於）曱基、乙基、正 丙基、異丙基、正丁基、第二丁基、第三丁基、正戊基及 第二戊基。 本發明之方法可如下列流程所述進行。 流程1 1. 溶解於CH2C12中 2. 添加至11^04中0癍 3. 用水稀釋且層分離以 移除ch2ci2 4. 用28%ΝΗ/)Η鹸化 5. 過濾且乾燥
N〇3
〇
νη2 1. 2.0當量之氯乙醚催化劑 Bu,NBr · 42%NaOH Ί10°0 · 8h 2. 萃取至TBME/AcOEt中 3. 1.0當量 70%HNO3 4. 過滤且乾燥 97% 156361.doc -13- 201136867 鹽之硝化亦可在不同條件下進行。舉例而言，反應可藉 由將乙醯氯添加至硝酸鹽於二氣甲烷中之溶液中執行。在 一些情況下，使用不同方法獲得不同產物。舉例而言，當 5之硝化藉由將其溶液添加至硫酸中進行時，產物為％流 程1)。然而，當硝化藉由將2.〇當量之乙醯氣添加至5於乙 酸中之溶液中執行時’以產率91%分離產物10。另一實例 說明於流程2中。該等實例表明苯胺衍生物之硝酸鹽之硝 化的區位選擇性可藉由選擇不同條件來控制。 流程2
Ν-1 93% 93% S-1 11 除硫酸外’其他酸亦可用於硝酸鹽之硝化。此由使用三 氟乙酸、甲烷磺酸於二氣甲烷中之溶液及純甲烷磺酸之S-1之硝化得以例證。結果概述於表5中。 156361.doc -14 - 201136867 表5 基質 酸 條件 產率 產物 S-1 三氟乙酸 〇〇C，1 h 94% 11 S-1 於CH2C12溶液中 之曱烷磺酸 0〇C，4 h 92% 11與N-l，比率為93/7 S-1 甲烷磺酸 17°C 91% 11與N-l ’比率為75/25 各物組成之群之芳香族化 本發明係關於一種選自由以下 合物的硝化製程：
其中
Ar為可硕化芳香族環， R、R、R及R4為氩、烷基或芳香族基團， G係選自由以下各基組成之群：CRiR2 ' 〇、s、s〇及 S〇2， R為雜環或其他具有鹼性氮原子之基團， 且η為1至12之整數； 該方法包含使起始物料與硝酸反應後，形成且分離起始 物料之硝酸鹽’且此後將硝酸鹽之溶液或懸浮液添加至酸 中。所分離之硝酸鹽由1:1比率之硝酸與胺基質組成。因 156361,doc •15- 201136867 此’在該硝化製程中，可容易地防止過硝化及硝化不足， 否則’此情況在大規模生產製程中很難控制。 作為芳香族環/基團，涵蓋芳基。 【實施方式】 提供下列實例及參考以幫助理解本發明，本發明之真實 範疇陳述於附加申請專利範圍中。 實例1 N-嗎啉基苯甲醚，硝酸鹽
使裝配有機械攪拌器及氮氣入口之1L乾燥清潔之4頸圓 底燒瓶裝載有20 g(162.3 mMol)對-甲氧苯胺、48 g(336 氣乙醚、L04 g(3.2 mM〇1)四丁基溴化銨及77 g 42%氫氧化鈉溶液。將混合物在約1丨〇β(：下回流約8 h。確 認反應已完成後，將混合物冷卻至2〇β(：且分別用5〇 mL TBME及50 mL乙酸乙酿萃取。將組合有機溶液用8〇 ^^水 洗滌。將有機溶液冷卻至0±5t且向其中緩慢添加14 6 g(162.3 mMol)70% ΗΝ〇3β添加後期，重質沉澱形成。添 加後，使批料老化至少1 h。將固體過濾，用4〇 mL χΒΜΕ 洗滌且在45 C下真空乾燥隔夜以產生4〇 2 g(97%)呈淺棕色 固體之5。 156361.doc •16· 201136867 實例2 4-N-嗎啉基-2-硝基苯甲醚（4)
使裝配有機械攪拌器及氮氣入口之250 mL乾燥清潔之4 頸圓底燒瓶裝載有80 g(815 mMol)95%硫酸。將酸冷卻至 約〇°C。將20 g(78 mMol)5於125 mL二氯曱院中之溶液緩 慢添加至酸中’同時將批料溫度維持在〇±5°c。添加後， 將混合物授拌3 0分鐘。停止授動且分離底部酸層。將酸溶 液緩慢添加至200 mL水中，同時將溫度維持在< 1 〇〇C。隨 後’向該稀酸溶液中緩慢添加19〇 mL 28% NH4OH溶液’ 同時將溫度維持在< 10。添加結束時，混合物之pH值應 面於10。使批料在5±5°C下老化1 h。將固體過濾’用50 mL水洗滌且在45〇C下真空乾燥隔夜以產生17.5 g(產率 94%)呈橙色固體之4。 實例3 苯胺，硝酸鹽（S-11)
將苯胺（10 g，107 mMol)於1〇〇 mL TBME中之溶液冷卻 156361.doc •17· 201136867 至〇±5t>C °向該溶液中添加70%硝酸（9.7 g，107 mMol)， 同時將溫度維持在<20°C。添加後，將混合物在0±5°C下攪 動約1 h °將固體過濾，用tbmE洗滌且在周圍溫度下在室 内真空下乾燥隔夜以產生164 g(98%)標題化合物。 化合物 S-9、S-12、S-14、S-15、S-16、S-22係使用相同 程序製備。 實例4 對-甲氧笨胺，硝酸鹽（s_1〇) 〇〆
+ nh3 no3 將對·甲氧苯胺（10 g ’ 81.2 mMol)於 80 mL TBME及 20 mL (7.3 THF中之冷液冷部至〇士5〇c。肖該溶液中添加7⑽石肖酸 g’ 81.2福〇1)’同時將溫度維持在<2代。添加後， 將混合物在〇±5°C下授動約1 h。 滌且在周圍溫度下在室内真空 g(97%)標題化合物。 將固體過濾，用TBME洗 下乾燥隔夜以產生14.6 化合物S-19、S-21係伟田士。η 保使用相同程序製備。
實例S Ν，Ν-二甲基苄基胺，硝酸鹽
156361.doc 201136867 ’甲基节基胺（10 g’ 74 mMol)於80 mL TBME及20 中之洛液冷部至〇±5〇c。向該溶液中添加7〇%硝酸 (g 4 mMol) ’同時將溫度維持在<2〇。匸。添加後，將 混口物在0±5 C下攪動約！ h。將乙腈添加至反應混合物中 直至形成均句溶液。將溶液經MgS〇4乾燥，過滤且濃縮以 產生14.7 g(l00%)標題化合物。 S-6 、 S-7 、 S-8 、 S-17 化合物 S-1、S_2、s_3、s_4、s 係使用相同程序製備。 實例6 苯基-2-咪唑啉，硝酸鹽（S18)
將2-苯基-2-味唾琳（10 g，68 4祕〇1)於1〇〇此 及50 mL乙腈+之懸浮液冷卻ι〇±Γ(：。向該懸浮液中添加 70%頌酸（6.2 g，68.4 mMGl)，同時將溫度維持在<耽。 添加後，將混合物在0±5。〇下攪動約1 h。將固體過濾，用 TBME洗滌且在周圍溫度下在室内真空下乾燥隔夜以產生 13,4 g(91%)標題化合物。 化合物S-20、S-23、S-24係使用相同程序製備。 實例7 4，N，N_三曱基-3·硝基苯胺（N-1) 156361.doc -19· 201136867
將S-l(3 g，15.1 mMol)於25 mL二氣甲烷中之溶液緩慢 添加至冷95〇/〇硫酸（14.8 g，151 mMol)f，同時將批料溫 度維持在0±5t。添加後，將混合物在〇dt5^下攪動約3 h。停止攪動且將底部酸層緩慢轉移至30 mL水中，同時將 溫度維持在<20°C。在<20°C下向該稀反應混合物中緩慢添 加氣氧化敍溶液直至PH>10。沉澱形成。使混合物在 <2〇°C下老化約1 h。將固體過濾，用水洗滌且在約45它下 在至内真空下乾燥隔夜以產生2 54 g(93%)標題化合物。 化合物N-3、N-6、N-4/N-5、N-8/N-9、N-10/N-ii、N_ 17、N-32/N-33係使用相同程序製備。 2-(4-硝基苯基）咪唑（N-28)
將S-20(4 g，19.3 mMol)於30 mL二氣曱烷中之懸浮液緩 慢添加至冷95%硫酸（18.9 g，193 mMol)中，同時將批料 度維持在〇±5°C ^添加後，將混合物在〇±5艽下攪動約3 h。停止攪動且將底部酸層緩慢轉移至4〇 mL水中同時將 溫度維持在<2〇°C ^在<20°C下向該稀反應混合物中緩慢添 156361.doc •20· 201136867 加氫氧化銨溶液直至PH>10。沉澱形成。使混合物在 <20°C下老化約1 h。將固體過濾，用水洗滌且在約45。(：下 在室内真空下乾燥隔夜以產生3.5 g(96%)標題化合物。 化合物N-24、N-26、N-27 N-34、N-35係使用相同程序 製備。 實例9 甲氧基-3-硝基-N-甲基苯胺（N-12)
/NH 將S-9(4 g，20 mMol)於4〇 mL二氣甲烷中之溶液緩慢添 加至冷95%硫酸（20 g，200 mMol)中，同時將批料溫度維 持在0±5 C。添加後，將混合物在oyt下授動約3匕。停 止授動且將底部酸層緩慢轉移至4〇 mL水中，同時將溫产 維持在<2〇t ^在<20。〇：下向該稀反應混合物中緩慢添 氧化銨溶液直至pH值為約7。將混合物用二氣甲烷萃取兩 次。將組合有機溶液用鹽水洗滌，經MgS〇4乾燥，過噱且 濃縮以產生3.46 g(95%)標題化合物。 化合物N-9亦使用相同程序製備。 實例10 甲氧基-3-硝基苯胺（N-13) 156361.doc -21. 201136867 nh2 將S-10(4 g，21·5 rnMol)於40 mL二氣甲烷中之懸浮液緩 慢添加至冷95%硫酸（21 g，215 mMol)中，同時將批料溫 度維持在0±5。(：。添加後，將混合物在〇±5〇c下攪動約3 h °停止攪動且將底部酸層緩慢轉移至4〇 mL水中，同時將 溫度維持在<20<>C。在<20°C下向該稀反應混合物中緩慢添 加氫氧化銨溶液直至pH值為6-11 ^將混合物用二氣曱院萃 取兩次。將組合有機溶液用鹽水洗滌，經MgS04乾燥，過 據且濃縮以產生3.3 g(91%)標題化合物。 化合物 N-2、N-9、N-14/N-15/N-16、N-29/N-30/N-31、 Ν·22/Ν-23、N-21係使用相同程序製備。 實例11 Ν-嗎啉基-3-硝基苯甲醚（1〇) 0 在周圍溫度下，向5(2 g，7.8 mMol)於5 mL乙酸中之溶 液中緩慢添加乙醯氣（1.6 g，15.6 mMol)。將混合物攪拌 約30 min。在<2(TC下，將反應混合物緩慢添加至冷氫氧 化鍵溶液中。隨後，將混合物老化約1 h。將固體過滤， 156361.doc •22· 201136867 用水洗滌且在45°C下真空乾燥隔夜以產生1.7 g(產率 91〇/〇)10。 實例12 4，N，N-三甲基-2-硝基苯胺（11)
在約0°C下’向S-l(2 g，10.1 mMol)於1〇 mL二氣曱统中 之溶液中緩慢添加乙酿氣（1 ·6 g，15.6 mMol) »將混合物 攪拌約2 h。在<20°C下’藉由添加氫氧化銨溶液使反應混 合物鹼化至pH>10。將混合物用二氣甲烷萃取兩次。將組 合有機溶液用鹽水洗滌，經MgS〇4乾燥，過濾且濃縮以產 生 1.7 g(93%)ll。 實例13 S -1在三氟乙酸中之石肖化 將s-l(4 g，20_5 mMol)於45 mL二氣甲烷中之溶液緩慢 添加至三氟乙酸（23 g，202 mMol)中，同時將批料溫度維 持在〇±5°C。添加後，將混合物在〇±5χ：下攪動約1匕。將 混合物緩慢轉移至40 mL水中，同時將溫度維持在<2〇它。 在<20°C下向該混合物中緩慢添加28%氫氧化録溶液直至 PH>H)。*離有機相且將水相㈣g二氣甲燒萃*。將植 合有機溶㈣鹽水絲且隨後在旋轉蒸發儀上濃縮至乾燥 以產生 3.44 g(94%)l 1。 156361.doc -23· 201136867 實例14 S-1在甲烷磺酸於二氣甲烷中之溶液中之確化 將S-l(4 g ’ 20.2 mMol)於22 g二氣曱烷中之溶液緩慢添 加至19 g曱烷磺酸與22 g二氣甲烷之混合物中，同時將批 料溫度維持在〇±5°C。添加後，將混合物在〇±5下授動約 4 將混合物緩慢轉移至40 mL水中，同時將溫度維持在 <2〇°C。在<20°C下向該混合物中緩慢添加28%氫氧化銨溶 液直至ρΗ>1〇。分離有機相且將水相用55 g二氣甲烷萃 取《將組合有機溶液用鹽水洗滌且隨後在旋轉蒸發儀上濃 縮至乾燥以產生3.41 g(92%)呈比率為約93:7之丨丨與队丨之 混合物的產物。 實例15 S-1在甲烷磺酸中之硝化 將固體S-l(4 g，20.2 mMol)緩慢添加至19 g甲烷磺酸 中，同時將批料溫度維持在17±5t。添加冑，將混合物在 1 7±5 C下攪動約j h。將混合物緩慢轉移至4〇以水中同 時將/皿度維持在<2〇〇c。在<2〇〇c下向該混合物中緩慢添加 28/。氫氧化銨溶液直至ρΗ>ι〇。將混合物用吕二氣甲烷 卒取。分離有機相且將水相用29 g二氣甲烧萃取。將組合 有機溶液用鹽水m隨後在旋轉蒸發儀上濃縮至乾燥以 產生3 22 g(9l%)呈比率為約75:25之11與N-1之混合物的產 物。 156361.doc •24-

Claims (1)

  1. 201136867 七、申請專利範圍： 1. 一種硝化化合物之方法’該化合物係選自由以下所組成 之群：
    其中 Ar為可硝化芳香族環， 1^、1^2、113及114為氫、烷基或芳香族基團， G係選自由CRiR2、〇、s、SO及S02所組成之群， R為具有驗性氮原子之雜環， 且η為1至12之整數， 且其中基團9之笨環係與具有鹼性氮原子之雜環_ 其限制條件為當G係〇、s、SO及S02時，η為1或2 ; 該方法包括 (a) 使起始物料與硝酸反應後，形成且分離該起始物料之 硝酸鹽，及 (b) 之後，將該硝酸鹽之溶液或懸浮液添加至酸中。 2. 如請求項1之方法，其中該酸係選自由硫酸、三氟乙 酸、甲烷飧酸、三氟乙酸/二氣甲烷、乙醢氯/二氣甲烷 及甲烷磺酸/二氣甲烷所組成之群。 〜 3. 如請求項2之方法，其中該酸為硫酸。 156361.doc 201136867 4.如請求項1之方法，其中 R1 Ar_V 係選自由以下所組成之群：
    係選自由以下所組成之群：
    nh2及
    6.如請求項1之方法，其中 Ar—fGiR 156361.doc 201136867 係選自由以下所組成之群
    及 7.如請求項1之方法，其中 R
    R R 係選自由以下所組成之群：
    156361.doc 201136867 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：
    156361.doc
TW100118559A 2006-04-27 2007-04-24 Mono-nitration of aromatic compounds TWI374867B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US79543106P 2006-04-27 2006-04-27

Publications (2)

Publication Number Publication Date
TW201136867A true TW201136867A (en) 2011-11-01
TWI374867B TWI374867B (en) 2012-10-21

Family

ID=38269011

Family Applications (2)

Application Number Title Priority Date Filing Date
TW100118559A TWI374867B (en) 2006-04-27 2007-04-24 Mono-nitration of aromatic compounds
TW096114461A TWI366558B (en) 2006-04-27 2007-04-24 Mono-nitration of aromatic compounds

Family Applications After (1)

Application Number Title Priority Date Filing Date
TW096114461A TWI366558B (en) 2006-04-27 2007-04-24 Mono-nitration of aromatic compounds

Country Status (12)

Country Link
US (1) US7429589B2 (zh)
EP (2) EP2327677A1 (zh)
JP (1) JP2009534438A (zh)
KR (1) KR101079018B1 (zh)
CN (2) CN102267958A (zh)
AU (1) AU2007245719B2 (zh)
BR (1) BRPI0712901A2 (zh)
CA (2) CA2783281A1 (zh)
IL (1) IL194554A (zh)
MX (1) MX2008013579A (zh)
TW (2) TWI374867B (zh)
WO (1) WO2007125034A2 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8444881B2 (en) * 2007-08-14 2013-05-21 David O.B.A. Adebimpe Methods for making scent simulants of chemical explosives, and compositions thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2002864C (en) * 1988-11-29 1999-11-16 Eddy J. E. Freyne (1h-azol-1-ylmethyl) substituted quinoline, quinazoline or quinoxaline derivatives
US5185346A (en) * 1988-11-29 1993-02-09 Hanssen Pharmaceutica (1H-azol-1-ylmethyl)substituted quinoline derivatives
CA2413086C (en) 2000-06-21 2011-06-28 Alexander Alanine Benzothiazole derivatives
US7087761B2 (en) * 2003-01-07 2006-08-08 Hoffmann-La Roche Inc. Cyclization process for substituted benzothiazole derivatives

Also Published As

Publication number Publication date
US7429589B2 (en) 2008-09-30
CA2783281A1 (en) 2007-11-08
IL194554A (en) 2013-03-24
EP2327677A1 (en) 2011-06-01
KR101079018B1 (ko) 2011-11-01
IL194554A0 (en) 2009-08-03
CA2649784C (en) 2012-10-02
EP2016034A2 (en) 2009-01-21
BRPI0712901A2 (pt) 2013-01-08
JP2009534438A (ja) 2009-09-24
AU2007245719B2 (en) 2012-10-11
MX2008013579A (es) 2008-10-31
US20070255057A1 (en) 2007-11-01
CA2649784A1 (en) 2007-11-08
WO2007125034A3 (en) 2008-01-31
WO2007125034A2 (en) 2007-11-08
TWI366558B (en) 2012-06-21
AU2007245719A1 (en) 2007-11-08
CN101432246A (zh) 2009-05-13
TWI374867B (en) 2012-10-21
CN102267958A (zh) 2011-12-07
KR20080108567A (ko) 2008-12-15
TW200808680A (en) 2008-02-16

Similar Documents

Publication Publication Date Title
JP2008526758A (ja) ２−メチル−１−（２−メチルプロピル）−１ｈ−イミダゾ［４，５−ｃ］［１，５］ナフチリジン−４−アミンの製造方法
US9458115B2 (en) Synthesis of substituted pyrazines
US20090299067A1 (en) New synthesis of 2,6-diamino-3,5-dinitropyrazine-1-oxide from 2,6-diaminopyrazine-1-oxide
KR102396059B1 (ko) 신규 화합물 및 이의 제조방법
JPS61500614A (ja) 全硝酸ニトロ化プロセスにおけるｄｎｐｉの分解
TW201136867A (en) Mono-nitration of aromatic compounds
BR112014019961B1 (pt) processo telescópico (de recipiente único sequencial) para sintetizar sal de 5-amino-4-nitroso-1-alquil-1h-pirazol e para produção de um sal de 4,5-diamino-1-alquil-pirazol
CN114957125A (zh) 一种4-硝基5-硝胺吡唑的合成方法
KR101529507B1 (ko) 다이(아미노구아니듐) 4,4’,5,5’-테트라나이트로-2,2’-바이이미다졸 및 이의 제조 방법
EP1609792B1 (en) A process for the preparation of imiquimod and intermediates thereof
US11466014B2 (en) Process for preparing soluble guanylate cyclase stimulators
EP3604263A1 (en) Method for the synthesis of 9,10-bis(chloromethyl)anthracene
CN114262298B (zh) 2-溴-4-n,n-二甲氨基咪唑及其制备方法
CN114315773B (zh) 一种哌嗪化合物及其制备方法
Wang et al. Ceric ammonium nitrate (CAN) enabled concerted nitration/ureation of carbodiimides to synthesize o-nitroaryl ureas
KR100281825B1 (ko) 디니트로아미드염의 제조 방법
JPH03215488A (ja) ピリミドベンズイミダゾール誘導体
CN113912542A (zh) 一种直接氨化硝基氮杂环化合物的方法
CN104583204A (zh) 用于合成取代的γ内酰胺的方法
CN114057631A (zh) 一种3-氯-2-肼基吡啶的合成方法
CN102190660A (zh) 一种n-f朝格尔型季铵盐及其制备方法
PL176485B1 (pl) Sposób wytwarzania N-/2-chlorobenzylo/-2-/2-tienylo/-etyloaminy
JPS62114938A (ja) １−ブロモ−２−クロロ−４−フルオロ−５−ニトロベンゼンおよびその製造法
JP2001220382A (ja) 選択的ｏ−アルキル化方法

Legal Events

Date Code Title Description
MM4A Annulment or lapse of patent due to non-payment of fees