201139337 六、發明說明： 本發明係關於一種用於製備有機硝酸酯（亦即硝酸與 有機羥基化合物之酯）的方法。一些有機硝酸酯除其眾^ 周知之應用（如炸藥及推進劑）之外，亦適用作醫藥活性 物質（例如三硝酸甘油酯）或合成醫藥·活性物質之中間物。 例如，4-硝基氧基丁 _1·醇（4·硝醯基氧基丁 _丨·醇，丨，^ 丁二 醇單硝酸酯）為合成萘普西諾（napr〇xcin〇d )(硝基萘普生 (nitronaproxen) ; WO 01/10814 A1 )之中間物。 製備有機硝酸醋之傳統方法包含使羥基化合物與硝酸 及硫酸之混合物反應。雖然此方法已在數十年炸藥（諸如 三硝酸甘油酯、乙二醇二硝酸酯或異戊四醇四硝酸酯）生 ^中最佳化，但其在製備由二元醇或多元醇衍生之單硝酸 酯時並不令人滿意，因為硝酸與硫酸之混合物具有高度反 應性，使得難以控制反應以獲得單硝酸酯作為主要產物之 方式進行。因此，一種自二醇製備單硝酸酯之已知方法為 首先製備二硝酸酯，隨後水解一個硝酸酯部分來獲得單硝 酸酯。另一可能性為先保護一個羥基（例如藉由醯化），隨 後其餘羥基與硝酸反應且保護基在後續步驟中分解（參見 例如 WO 2009/000723 A1 或 WO 2009/046992 A1 )。兩種方 式均冗長且需要至少一個額外反應步驟， 藉由使用大量過量之「穩定（stabilized)」硝酸以便獲 得合理反應速率及轉化率，並在反應中止之前監控石肖酸酉旨 4 201139337 形成進程（WO 2004/043897 A1 )，或仔細選擇毛細管反應 器中之滞留時間及流勤形態（WO 2009/080755 A1 )來嘗試 獲得及分離1，4- 丁二醇之單硝酸酯》然而，此等方法所需之 大量過量硝酸（WO 2004/043897 A1 :每莫耳1，4_丁二醇約 13 mol HN〇3 ; WO 2009/080755 A1 :每莫耳 l，4-丁 二醇約 8 至15 mol HN〇3)必須經中和且最終棄置，由此產生大量廢 料。此外，儘管小心監控硝酸酯形成，但仍形成相當大量 (W0.2004/043 897 Α1 :約 33 wt·% )之無用二石肖酸醋。 因此，本發明之一目標為提供一種安全製備一元醇、 二元醇或多元醇之硝酸酯的方法，其不需要將導致在處理 程序期間產生大量廢料的實質上過量之硝酸或另一硝酸酯 來源，该方法可連續操作，且允許產生二元醇之單硝酸酯， 而不形成實質上大量的相應二硝酸酯或其他無用副產物。 根據本發明，藉由一種包含以下步驟之方法自一元 醇、二元醇或多元醇製備有機硝酸酯 (1 )將以下物質同時饋入第一連續流動微型反應器單元 中《玄第連續流動微型反應器單元包含至少兩個反應性 流體入口、至少一伽，θ人r &區、至少一個反應區及一反應性 流體出口： (a )濃硝酸， (b)乙酸酐， ()視晴况選用之催化量的並非硝酸之強無機酸， 及 201139337 (d )視情況選用之溶劑， 從而獲得乙醯确酸酿溶液， 1 )將步驟（1 )中獲得之乙醯硝酸醋溶液及呈液體形 式或溶於溶劑中之該一元醇、 二連續流動微型反應器單元中 二元醇或多元醇同時饋入第 ’從而獲得該有機硝酸酯溶 包含至少兩個反應性 液，該第二連續流動微型反應器單元 一個反應區及一反應性 流體入口、至少一個混合區、至少 流體出口，及 (iii)視情況，將該有機硝酸_.自步驟（Η)獲得之溶 液中分離出來。 ，已知乙醢石肖酸醋為有效硝化劑，其可以化學計算量來 肖化例如方族化合物。&而，乙醯硝酸酯具有高度爆炸性 且不能以工業規模安全處置。根據本發明.，在微型反應器 單元中連續製備乙醯石肖酸雖，隨後在另一微型反應器單元 中連續反應’以便在任何指定時間點處理設備巾只存在少 量乙醯硝酸醋。 欲用於本發明方法中之連續流動微型反應器單元可為 此項技術中已知者，例如如w〇 2〇〇7/1 12945 A1中所述。 /、可由不會党該方法之起始材料及產物侵蝕或腐蝕的任何 材料製成。較佳材料為Hastelloy® c，其耐腐蝕且具有足夠 熱導率。 本文中，應瞭解表述「微型反應器單元（micr〇react〇r unit )」意謂包含所述要素之功能單元，與其實際機械組態 6 201139337 無關。實際上’本發明方法之步驟⑴及（ii)中微型反應 益單70可於單獨總成（assembly )中或於同一總成中（尤其 在使用如WO 2007/1 12945 A1中所述之模組化系統時）。當 微型反應器單元位於同一總成中時，其可位於單獨模組中 或位於同一模組中。若其位於同一總成中但位於單獨模組 中，則第一微型反應器單元之反應性流體出口在外部連接 至第二微型反應器單元之反應性流體入口之一。 在一較佳具體實例中，兩個微型反應器單元組合於一 個模組中，以使第一微型反應器單元之反應性流體出口在 内部連接至第二微型反應器之反應性流體入口之一且整個 模組在外觀上呈現為具有（至少）三個反應性流體入口且 具有兩個或兩個以上混合區且在每一對後續混合區之間有 一反應區，例如在第一與第二混合區之間。因為步驟（i) 〔亦即形成乙醯硝酸酯）所需時間（典型約丨分鐘）比步驟 (Π)多，步驟（ii)典型僅需少數幾秒或甚至更少時間，所 以第一微型反應器單之反應區實質上宜大於第二微型反 應器單元之反應區。 濃硝酸可為商業「濃硝酸」，其為濃度近似等於 hno3/h2o -元共$物之濃度的65_7G wt%;6肖酸水溶液，或 濃度為約90 wt%或90 wt%以上之所謂「強」或「白色發煙 硝酸。濃硝酸較佳為濃度為99 wt%或99 wt%以上之純無水 硝酸。 在步驟（1)及（11 )中，以使饋入微型反應器單元中的 反應物之莫耳比在整個製程操作時間中保持基本上恆定之 201139337 方式將反應物同時且連續饋入各別微型反應器單元中。 視有機硝酸酯之預期用途而定，可按原樣使用或在後 續步驟（iii)中分離及/或純化自第二微型反應器單元中排 出之產物。 在一較佳具體實例中，尤其當起始醇為二元醇或多元 醇且該二元醇或多元醇之一或多個羥基應保持完整時，用 水或諸如氫氧化鈉或氫氧化鉀之鹼水溶液中止自第二微型 反應益早兀中排出的步驟（ii)中獲得之產物溶液來停止反 應，及/或阻止步驟（i)中形成作為副產物之乙酸從而導致 不希望有的副反應，諸如二元醇或多元醇之該等剩餘羥基 之乙醯化。該中止較佳以亦適用於水解任何乙醢化副產物 之鹼水溶液來進行。宜以化學計算量使用鹼，亦即每莫耳 用作起始材料之乙酸酐使用2〇1〇1鹼，或使用稍過量之鹼。 可藉由在大量水或鹼水溶液中引入且收集產物溶液半連續 性進行此中止步驟。 在一更佳具體實例中，在饋入該產物溶液及水或如上 文所定義之驗水溶液之第三微型反應器單元中連續 止。 該第三微型反應器單元可位於單獨總成中，或位於與 第-微型反應器單元之同-總成中第三微型反應器單 :位於同-總成中’則其可位於單獨模組中或位於與第二 j型反應器單元之同一模組中。若位於同一總成中但位於 早獨模組中’貝’】第二微型反應器單元之反應性流體出口在 外。P連接至第三微型反應器單元之反應性流體人口之一。 201139337 本發明方法之產物的進一步分離及純化可藉由此項技 術中已知用於各別化合物之方法來進行。由於有機石肖酸酯 之固有不穩定性，因此可宜避免分離純形式之產物且將其 以於合適溶劑中之溶液形式儲存及船運。 可使用並非硝酸之強無機酸來催化自乙酸酐與硝酸形 成乙醯硝酸酯。在一較佳具體實例中，該並非硝酸之強無 機酸為硫酸。宜以（以硝酸計）〇1至5 〇 m〇1%、較佳〇.2 至2.〇 mol%、更佳〇_5至1.0 m〇l%之量來使用硫酸。 第一反應步驟（亦即形成乙醯硝酸酯）宜在〇_5(TC、 較佳0-4(TC、更佳20_40〇c、最佳、2〇_3(rc之溫度下進行。 所需反應時間視反應溫度及反應物濃度而定，且典型地為 至20分鐘’或一般為幾分鐘。 乙酸酐及硝酸宜以近似等莫耳之量使用，乙酸酐與硝 酸之莫耳比為1:1.5至丨.5:1，較佳1:1.2至1.2:1，更佳m 至 1.1:1 。 ,第二反應步驟（亦即形成一元醇、二元醇或多元醇之 硝酸酯）宜在0-40。。、較佳1〇_35。。、更佳1〇_2〇t之溫度 :進仃。反應典型地極快速且幾乎立即在第二微型反應器 單元之混合區中進行且較少程度在反應區t進行。總反應 時間視反應溫度及反應物濃度而定且典型地為—秒或幾秒 或甚至更少。 第三步驟（亦即乙醯化副產物之中止及水解）宜在_5 至+50C，較佳在〇-3(rc之溫度下進行。所需反應時間視反 應溫度及反應物濃度而定，且典型地為2,分鐘至約i小時。 201139337 宜以合適方式控制步驟（丨）及（Η)中之反應溫度，例 如藉由使用如WO 2007/1 12945 A1中所述之熱交換模組。 步驟（i )及（ii )中之溶劑（若存在）可相同或不同且 可為任何在反應條件下基本上呈惰性且能夠溶解及/或稀釋 起始材料及產物的溶劑。 在一較佳具體實例中，步驟（i)中之溶劑為二氣甲烷。 可將乙酸酐、硝酸、視情況選用之並非硝酸的強無機 酸及視情況選用之步驟（i)中之溶劑分別饋入第一連續流 動微型反應器單TL中，其限制條件為該微型反應器單元具 有適當數目之反應性流體入口。亦可將兩種或三種此等起 始材料預混合，其限制條件為乙酸酐與硝酸在其饋入微型 反應器單元中之前不得相互接觸。 在一較佳具體實例中，步驟（i)之進行方式為乙酸酐、 並非硝酸之強無機酸及/或視情況選用之溶劑在其饋入該第 連續流動微型反應器單元中之前經混合。隨後將此混人 物饋入一反應性流體入口中，同時將濃硝酸饋入另一反^ 性流體入口中並與該混合物在混合區中混合。 心 本發明方法較佳以化學計算量或稍微過量之硝酸來進 行，亦即每當量待醋化之一元醇、二元醇或多元醇1〇至 1-5更佳】_〇至12且最佳1.〇至1.1 mol ;e肖酸。1軎量一 7L醇、二元醇或多元醇意謂丨m〇1除以每個待酯化之分 羥基數。 刀 在一較佳具體實例中，有機硝酸酯具有下式· R】-Q-0-N〇2 ( I)， 10 201139337 其中 R1係選自由以下組成之群：氫、H〇_、02N_0_、R2〇·、 視情況經取代之芳基及視情況經取代之雜芳基， R2為C2·6烧醯基或芳酿基， 且Q為直鏈、分支鏈或環烷二基，該烷二基視情況經 一或多個如上文所定義之Ri部分取代，且該一元醇、二元 醇或多元醇具有下式 R丨-Q-oh (II)， 其中Q如上文所定義且汉1.與Ri相同，其限制條件為若 式Ϊ中R1部分之任一者為〇2Ν_〇•，則式π中之相應Ri•部 分亦可為HO-。 此處及下文中’「芳基（aryl )」意謂包含至少一個芳族 系統之任何碳環部分，諸如苯基、萘基、蒽基、菲基、第 基、聯苯基或芘基。因此，「雜芳基（heter〇aryl )」意謂包 含至少一個芳族系統之任何雜環部分，諸如吡咯基、呋喃 基塞％基、°比°坐基、°米。坐基、u比咬基、η密α定基、D比唤基、 ^ °朵基及其類似基團。 應瞭解表述「烧醯基（c2_6 alkanoyl )」意謂衍生自 具有2至6個碳原子之烷酸的任何醯基基團，諸如乙醯基、 土 丁酿基、異丁醯基、戊醯基（valeryl，pentanoyl )、 ' 基（3-甲基丁酿基）、己醯基（caproyl，hexanoyl ) 及其類似基團。 應瞭解表述「芳醯基（ar〇y )」意謂衍生自芳族單羧酸 4何醯基基團，諸如苯曱醯基或萘曱醯基。 11 201139337 應瞭解表述「直鏈、分支鏈或環烷二基（linear，branched or cyclic alkanediyl ) j意謂藉由自相同或不同（鄰接或非鄰 接）碳原子上移除兩個氫而衍生自直鍵、分支鏈或環烧烴 的任何二價部分，諸如亞甲基、亞乙基、1，2-乙二基、丨，；^ 丙二基 ' 1，3 -丙二基、1，2 -丁 二基、ι，3 -丁 二基、1，4 -丁二基、 1，5-戊二基、1，6-己二基、2-曱基-1，3-丙二基、2,2-二曱基_1，3· 丙二基、1，2-環戊二基、1，3-環戊二基、l，2-環己二基、丨，3_ 環己二基、1，4 -環己二基及·其類似基團。 更佳地’ Q為C2-8烧—基’ Ri為H0 -或O2N-O-，且r 1 _ 為H0-;或Q為（：2-8烷二基且Ri及Ri·為C2.6烷醯基氧基。 最佳地’ R1及Rr為H0-且Q為1，4-丁二基。 以下非限制性實施例意欲說明本發明之方法。 實施例1 4_硝基氧基丁 -1-醇（I ; r1 = HO-，Q = _(ch2)4-) 將二氣曱烧（325 g)、乙酸酐（49.58 g，486 mmol)及 硫酸（0.46 g，5 mmol)之混合物，以及硝酸（99 5%，3〇 85 g，490 mmol )在4分鐘期間連續且同時饋入具有如w〇 2010/130811 A2之圖8A及圖10之第e)項中所描繪之曲折 通道混合區及反應區配置的由Hastelloy® c製成之第一微 型反應器單元（基本上如WO 2007/112945 A1中所述）中。 微型反應器之尺寸如下：混合區之水力直徑：〇 95 mm，混 合區長度：0.29 m (截面〇_7xl.5 mm2，18曲），總通道長 度：2.6 m，總體積：10.9mL。使用熱交換模組及外部=溫 器使微型反應器單元之溫度保持在約2(rc且滯留時間為工〇 12 201139337 分鐘。發現第一微型反應器單元之流出物為基本上由二氯 甲烷中之乙醯硝酸酯組成之溶液（假定產率為100〇/〇，理論 濃度：12.6 wt%)，將其與無溶劑之丨，4-丁二醇（40 g，444 mmol )同時立即饋入由Hastelloy® C製成的於模組中之第 二微型反應器單元中（其形成另一模組化微型反應器總成 之一部分，如WO 2007/112945 A1中所述）。該第二微型反 應器單元之尺寸如下：曲折通道混合區，混合區之水力直 徑：0.71 mm，混合區長度：〇·2ΐ m (截面 〇.5xl.i mm2，14 曲），總通道長度：1 ·0 m，總體積：2.76 mL。如上所述使 第二微型反應器模組之溫度保持在20°C且滯留時間為7 秒。藉由在20°C下將第二微型反應器單元之流出物（發現 其含有7.4 wt%之4-硝基氧基丁-i_醇，相當於55%之產率 (以1，4-丁二醇計））收集於裝有水（281 g)之燒瓶中來中 止該流出物。分離所得兩相系統且用GC分析有機相。發現 4-硝基氧基丁 -1-醇為主要產物（ΐ2·ι面積％)，以及一些14_ 雙（硝基氧基）丁烧（約3.8面積％ )、乙酸4 -硝基氧基卞g旨（約 0.6面積％)及乙酸4_羥基丁酯（約〇·4面積％)。 在20°C下，用相同體積之水洗滌有機相1〇次以自有機 相中萃取4-硝基氧基丁 -1-醇，同時由於形成的副產物丨，‘ 雙（硝基氧基）丁烷在水中溶解度不良而殘留在有機相中。隨 後用二氯甲烷（5x40 mL )自合併之水相中萃取產物，從而 獲得基本上不含雙（硝基氧基）丁烷之4硝基氧基丁 + 醇之溶液，且隨後在減壓下濃縮，獲得15 wt% 4_硝基氧基 丁-1-醇於二氣曱烷中之溶液。 13 201139337 實施例2 4-確基氧基丁·i.醇（I; Rl = H〇_，q= (ch山） 將一氣曱烧（2.005 kg)、乙酸野（5〇4 〇 g，4 93 m〇1) 及瓜西夂（2.63 g ’ 26 mmol)之混合物，以及硝酸（99 5%， g 4·93 m〇l )在7分鐘期間連續且同時饋入如實施例 1中所述之由HaStelloy®c製成之第一微型反應器單元中。 使用熱交換模組及外部恆溫器使微型反應器單元之溫度保 寺在3 0 C且滞留時間為0 8分鐘。發現第—微型反應器之流 為土本上由—氣甲烧中之乙醯硝酸酯組成之溶液（假 產率為1 〇〇 /〇，理論濃度：1 8.1 wt% )，將其立即饋入由 elloy 成之第二微型反應器模組（其形成另一模組 化微型反應器總成之—部分，如實施们中所述）之第一 在合區中。同時將無溶劑之M 丁二醇（4G4 g，4 48则〇 第混5區中。使第二微型反應器單元之溫度保持在 30°c且滯留時間為4秒。 將第一微型反應器單元之流出物（發現其含有1 〇 _ 5 之4_硝基氧基丁-1-醇，相當於55%之產率（以M_丁二醇 •十））預冷部至5 C之溫度。隨後藉由將經預冷卻之溶液與 13 wt/。氫氧化納水溶液（3.921 kg，12 7㈣）同時饋入如 2007/112945 A1中所述，自HasteU〇y® c製成之於單獨 模”且化系統中之第三微型反應器單元中來中止該預冷卻之 洛液在滯留時間為〇丨分鐘時，中止溫度為5。〇在2〇_3〇它 下再攪拌所得產物乳液1〇分鐘來實現痕量乙醯化副產物之 水解。分離所得兩㈣統且用GC分析有機相。發現4_胡基 201139337 氧基丁-1-醇為主要產物（23 8面積％)，以及一些丨，4雙（硝 基氧基）丁烷（約5.6面積％)及乙酸4_硝基氧基丁酯（約 〇.7面積％ )。未偵測到乙酸4-羥基丁酯（<0· 1面積％ 。 在5-2〇C下，於萃取塔（例如Kueni塔）中用水（17 143 kg )洗條有機相以自有機相中萃取4_硝基氧基丁 _ 1 _醇，门 時由於形成的副產物Μ·雙（硝基氧基）丁烷在水中溶解度 不良而殘留在有機相中。隨後在第二萃取塔中用53〇〇 = 二氣甲烷自合併之水相中萃取產物，從而獲得基本上不含 Μ·雙（硝基氧基）丁烷之4_硝基氧基丁 醇之溶液，且隨1 在減壓下濃縮，獲得15 wt%(GC中24.0面積％) 4硝基氧 基丁-1-醇於二氯甲烷中之溶液eGC分析顯示一些丨，4•雙（硝 基氧基）丁烷（5.6面積％)及痕量乙酸4_硝基氧基丁酯（〇7 面積％ )為副產物。所獲產率為38-42%。 實施例3 4-硝基氧基丁-1-醇（I; Rl = H〇_, Q = (cH2)4〇 將二氯曱烷（1866.0 g)、乙酸酐（469 〇 g，4 59 m〇i) 及硫酸（2.45 g ’ 24 mmol)之混合物，以及硝酸（99 2糾％， 291.6 g，4.59 mol ’ 1.00 eq)在約5〇分鐘期間（產物分離 物之收集為42.8分鏵：^續且同時饋入如實施心中所述 之由HaStelloy® 〇製成之第—微型反應器單元中相當於第 -饋入之流動速率為54.60 g/min且第二饋入之流動速率為 6.80 g/min。使用熱交換模組及外部恆溫器使微型反應器單 元之溫度保持在3(TC且滯留時間為〇8分鐘。將第一微型反 應器單元之流出物饋入HaStell〇y® c毛細管（内徑3 15 15 201139337 mm，長度1.4 π〇中以增加滯留時間，且將該毛細管之流 出物（發現其為基本上由二氣曱㈣之乙酿硝㈣組成之 溶液（假定產率為1〇〇%，理論濃度：18 wt%))與無溶劑 之1，4·丁二醇（ 377.6 g，4.19 mol)按照乙醢硝酸酯：丁二 醇之莫耳比為1.1 (假定乙酸酐之轉化率為1〇〇%)立即同 時饋入另一模組化微型反應器總成内由Hastell〇y(g) c製成 之於模組中之第二微型反應器單元中（如實施例丨中所 述）；流動速率8.82以她=8.69〇11/_。使第二微型反應 器單元之溫度保持在30°C且滞留時間為4秒。 將第一微型反應器單元之流出物饋入第二Hastell〇y® c 毛細管（内徑1.6 mm，長度4.0 m)中以增加滞留時間，且 將該第二毛細管之流出物（發現其含有1〇 5 wt%之4·硝基 氧基丁-1-醇，相當於57%之產率（以M 丁二醇計））預冷 卻至5 C之溫度《隨後藉由將經預冷卻之溶液與丨3 氫氧 化鋼水溶液（3.69(^，11.99 111〇1)同時饋入由1^仙11〇7®。 製成之第三微型反應器單元中來中止該預冷卻之溶液。如 WO 2010/130811 A2之圖1〇之第c)項中所描繪的包含12 個切向混合室.之第三微型反應器之尺寸如下：混合區之水 力直徑：2.66 mm，混合區長度：〇.15m，總通道長度^ 5 m，總體積：ii.65 mL。在滞留時間為〇1分鐘時，中止溫 度為51。在另一滞留時間模組（3 15 mm内徑及2 〇出長 度之不鏽鋼毛細管）中將所得產物乳液加熱至25_3〇t：之溫 度持續1分鐘，隨後在25-30T：下再攪拌該乳液10分鐘以 實現痕量乙醯化副產物之水解（pH值為約13 )。分離所得 16 201139337 兩相系統且用GC分析有機相。發現4“肖基氧基丁小醇為 主要產物（23」面積％)，以及一些Μ.雙（硝基氧基）丁烧（約 5.4面積％)及乙酸4_硝基氧基丁醋（約〇6面積％)。未债 測到乙酸4-羥基丁酯（<〇. 1面積％ )。 13.87 kg)洗滌有機相 在5-20°C下，於萃取塔中用水 丁 -1-醇，同時由於形成的副 水中溶解度不良而殘留在有 以自有機相中萃取4-硝基氧基 產物M-雙（硝基氧基）丁烷在 機相中。隨後在第二萃取塔中用4.311 kgm自合併 之水相中萃取產物，從而獲得基本上不含M雙（硝基氧基） 丁烧之4-硝基氧基丁 _丨_醇之溶液，且隨後在減壓下濃縮’ 獲得15 wt% BDMN ( 4-硝基氧基丁 •醇）於二氯甲烷中之 溶液。所獲產率為38-42%。 實施例4 4-硝基氧基丁-1-醇（！ ； Ri = JJO-，Q = -(CIV) 將二氣曱烷（1656.0 g)、乙酸酐（252.0 g，2.47 mol) 及硫酸（2.34 g，23 mmol)之混合物，以及硝酸（99 5%， 157·0 g ’ 2.48 mol)在38分鐘期間（產物分離物之收集時 間為8分鐘）連續且同時饋入具有如w〇 2〇1〇/13〇811 A2 之圖8 A及圖1 〇之第e )項中所描繪之曲折通道混合區及反 應區配置的由Hastelloy® C製成之如實施例1中所述的第一 微型反應器單元（基本上如WO 2007/112945 A1中所述） 中。微型反應器單元之溫度保持在30°C (反應器溫度以恆 溫器控制）且滯留時間為1,2分鐘。發現第一微型反應器之 流出物為基本上由二氣甲烧中之乙醯硝酸酯組成之溶液 17 201139337 (假定產率為100%’理論濃度：12.6 wt%)，將其立即饋入 第二微型反應器模組之第一混合區之一入口中，該第二微 型反應器模組包含四個互連之微型反應器單元，其每一者 均由混合區及反應區組成’其中該混合區由一系列12個如 WO 201 〇/1 30811 A2之圖1 〇之第c )項中所描繪之切向混 合室構成。詳言之’該四·個微型反應器單元之尺寸如下： 混合區之水力直徑：2.01 mm，每一混合區之長度：〇 〇6 m , 每一單元之通道長度：0.6 m，總體積：11.2 mL。前三個單 元之每一者之出口直接連接至下一單元之混合區的兩個入 D 〇 第一混合區之第二入口關閉，以使該第二模組之第一 單元僅.用於增加滯留時間將無溶劑之1，4_丁二醇（203 7 g，2.25 m〇l )同時饋入該第二微型反應器模組之第二混合 區中。使第二微型反應器模組之溫度保持在3〇t且滞留時 間為3_3秒。發現第二微型反應器單元之流出物含有 wt%之4-硝基氧基丁-丨-醇，相當於55%之產率（以I〆·丁 二醇計）。藉由將水（ 362 g，20」mol)饋入同—微型反應 器模組之第三混合區中使其中止。在滯留時間& 6秒時: 中止溫度為30。〇分離所得兩相系統且用Gc分析有機相。 發現4·石肖基氧基丁小醇為主要產物（1〇98面積％)，以及 一些1，4-雙（确基氧基）丁烷（約4 〇面積％)、乙酸硝基氧 基丁酯（約0.4面積％)及乙酸4_羥基丁酯（約〇4面積 實施例5 4_硕基氧基丁-1-醇（I : R丨=H〇_，q = ·((：Η2)4〇 18 201139337 使用較高濃度之乙酸酐（以20.0 wt%代替13 wt%，相 當於乙醯硝酸酯之理論濃度為18.2 wt%)及較少硫酸（〇,6 mol%，以1，4- 丁二醇計）重複實施例4。第二微型反應器單 元如實施例1中所述（滯留時間：7秒）。在大量水中中止 第二微型反應器單元之流出物且分離所得兩相系統。用GC 分析有機相’且發現4-硝基氧基丁-1-醇為主要產物（21.i 面積％)，以及一些1,4-雙（硝基氧基）丁烷（約5.4面積％)、 乙酸4-硝基氧基丁酯（約0.7面積％ )及乙酸4-羥基丁酯（約 0.9面積％ )。 比較實施例1 (分批法） 1，4·雙（硝基氧基）丁烷（I ; r1 = 〇2N-〇-，Q = -(CH2)4-) 在-10°C下向二氯曱烷（18.7 mL)、乙酸酐（6.24 g，61 mmol)及96 wt%硫酸（〇_〇4 g，〇·3 3 mmol)之混合物中添 加硝酸（3.9 g，61 mmol)及事先製備之ι，4-丁二醇（5g， 5 5 mmol )於二氯甲烧（1.5 mL )中之溶液。在-1CTC下搜拌 反應混合物30分鐘之後’添加丨3 wt%氫氧化鈉水溶液（48」 g溶液’ 1 56 mmol )。使混合物升溫至室溫且分離所得兩相。 藉由GC分析有機相，且發現丨，4_雙（硝基氧基）丁烷為主要 產物（18.81面積％)’以及痕量之4_硝基氧基丁-丨_醇（約 0.2面積％)及二乙酸1，4-伸丁酯（約〇.1面積。/〇)。 比較實施例2 (分批法，反向添加） 4-硝基氧基丁 -1·醇（I ; Ri = H〇_，q = -(ch2)4-) 在-10C下向二氯曱燒（37.5 mL )、乙酸酐（I2.5g，122 mmol)及96 wt%硫酸（0.07 g，〇·7 mm〇1)之混合物中添 19 201139337 为西夂（7·7 g，122 mmol)。使所 ,^ ,斤传混合物升溫至20〇C並添 加事先製備之1，4_丁二醇（1〇 g 111 mmol)於二氯甲烷（3 〇 mL)中之溶液。將反應混合物冷卻至且添加13氫 氧化鈉水溶液（96.3 g溶液，3 1 3 mmol )。使混合物升溫至 室溫且分離所得兩相。藉由GC分析有機相，且發現4_确基 氧基丁-卜醇為主要產物（14.38面積％)，以及一些1，4_雙（石肖 基氧基）丁烷（約4.5面積％)、乙酸4-硝基氧基丁酯（約36 面積％)及痕量二乙酸1,4-伸丁酯（約0.8面積％)及乙酸 4-羥基丁酯（約0.1面積％)。 【圖式簡早說明】 無 【主要元件符號說明】 無 20201139337 VI. INSTRUCTIONS: The present invention relates to a process for the preparation of an organic nitrate ester (i.e., an ester of nitric acid and an organic hydroxy compound). Some organic nitrates are also suitable as intermediates for pharmaceutically active substances (such as glyceryl trinitrate) or synthetic medicines and active substances in addition to their well-known applications (such as explosives and propellants). For example, 4-nitrooxybutan-1-ol (4.Nenonyloxybutanol, hydrazine, ^butanediol mononitrate) is a synthetic naproxil (napr〇xcin〇d) (Intermediate of nitronaproxen; WO 01/10814 A1). A conventional method for preparing an organic nitrate vinegar comprises reacting a hydroxy compound with a mixture of nitric acid and sulfuric acid. Although this method has been optimized for decades of explosives (such as glyceryl trinitrate, ethylene glycol dinitrate or isobaric tetranitrate), it is derived from the preparation of glycols or polyols. The mononitrate is not satisfactory because the mixture of nitric acid and sulfuric acid is highly reactive, making it difficult to control the reaction to obtain a mononitrate as a main product. Therefore, a known method for preparing a mononitrate from a diol is to first prepare a dinitrate, followed by hydrolysis of a nitrate moiety to obtain a mononitrate. Another possibility is to first protect a hydroxyl group (for example by deuteration), after which the remaining hydroxyl groups are reacted with nitric acid and the protecting group is decomposed in a subsequent step (see for example WO 2009/000723 A1 or WO 2009/046992 A1). Both methods are tedious and require at least one additional reaction step, by using a large excess of "stabilized" nitric acid in order to obtain a reasonable reaction rate and conversion rate, and monitoring the formation of the rhodamine acid 4 201139337 before the reaction is stopped. (WO 2004/043897 A1), or careful selection of the residence time and flow pattern in the capillary reactor (WO 2009/080755 A1) to try to obtain and separate the mononitrate of 1,4-butanediol. However, such A large excess of nitric acid required for the process (WO 2004/043897 A1: about 13 mol HN〇3 per mole of 1,4-butanediol; WO 2009/080755 A1: about 8 to 4,4-butanediol per mole 15 mol HN〇3) must be neutralized and finally disposed of, thereby producing a large amount of waste. In addition, despite careful monitoring of nitrate formation, a considerable amount (W0.2004/043 897 Α1: about 33 wt.%) of useless dihydrated vinegar was formed. Accordingly, it is an object of the present invention to provide a process for the safe preparation of nitrates of monohydric, dihydric or polyhydric alcohols which does not require a substantial excess of nitric acid or another nitrate which will result in the production of large amounts of waste during the processing procedure. Source, the process can be operated continuously and allows the production of mononitrates of glycols without the formation of substantial amounts of corresponding dinitrates or other unwanted by-products. According to the present invention, an organic nitrate ester (1) is prepared from a monohydric alcohol, a glycol or a polyol by a method comprising the steps of simultaneously feeding a substance into a first continuous flow microreactor unit. The reactor unit comprises at least two reactive fluid inlets, at least one gamma, θ human r & region, at least one reaction zone, and a reactive fluid outlet: (a) concentrated nitric acid, (b) acetic anhydride, () The catalytic amount is not the strong mineral acid of nitric acid, and 201139337 (d) the solvent selected according to the situation, so as to obtain the acetaminophen acid solution, 1) the ethyl acetate solution obtained in step (1) and The diol or the polyol in a liquid form or dissolved in a solvent, the diol or the polyol in the continuous flow microreactor unit is simultaneously fed into the first portion to obtain the organic nitrate ester solution comprising at least two reactive liquids, the second continuous a flow microreactor unit having a reaction zone and a reactive fluid inlet, at least one mixing zone, at least a fluid outlet, and (iii) optionally, the organic nitric acid obtained from the step (Η) Separated out. Acetyl tartaric acid vinegar is known to be an effective nitrating agent, which can be stoichiometrically used to simulate, for example, a compound. & However, acetamidine nitrate is highly explosive and cannot be safely disposed of on an industrial scale. According to the present invention, the ettringyl acid is continuously produced in the microreactor unit, and then continuously reacted in another microreactor unit so that only a small amount of acetamidine nitrate is present at any given point in time. The continuous flow microreactor unit to be used in the process of the present invention can be as known in the art, for example as described in w〇 2〇〇7/1 12945 A1. /, may be made of any material that does not erode or corrode the starting materials and products of the method. The preferred material is Hastelloy® c, which is corrosion resistant and has sufficient thermal conductivity. In this context, it should be understood that the expression "microreactor unit (micr〇react〇r unit)" means that the functional unit containing the element is independent of its actual mechanical configuration 6 201139337. In fact, the microreaction benefit 70 in steps (1) and (ii) of the method of the invention may be in a separate assembly or in the same assembly (especially using a mold as described in WO 2007/1 12945 A1). When organizing the system). When the microreactor units are located in the same assembly, they can be located in separate modules or in the same module. If it is in the same assembly but in a separate module, the reactive fluid outlet of the first microreactor unit is externally connected to one of the reactive fluid inlets of the second microreactor unit. In a preferred embodiment, two microreactor units are combined in a module such that the reactive fluid outlet of the first microreactor unit is internally connected to one of the reactive fluid inlets of the second microreactor And the entire module appears to have (at least) three reactive fluid inlets and two or more mixing zones and a reaction zone between each pair of subsequent mixing zones, for example in the first and second Between the mixing zones. Since step (i) [i.e., formation of acetamidine nitrate) takes more time (typically about 丨 minutes) than step (Π), step (ii) typically takes only a few seconds or even less, so the first micro The reaction zone of the reactor unit is preferably substantially larger than the reaction zone of the second microreactor unit. Concentrated nitric acid can be a commercial "concentrated nitric acid", which is a concentration of 65_7G wt% which is approximately equal to the concentration of hno3/h2o-units; 6 aqueous solution of xiao acid, or a concentration of about 90 wt% or more than 90 wt%. Strong or "white fuming nitric acid. Concentrated nitric acid is preferably pure anhydrous nitric acid having a concentration of 99 wt% or more. In steps (1) and (11), it is fed into the microreactor unit. The molar ratio of the reactants remains substantially constant throughout the processing time of the process. The method is to feed the reactants simultaneously and continuously into the individual microreactor units. Depending on the intended use of the organic nitrate, it can be used as is or The product withdrawn from the second microreactor unit is separated and/or purified in a subsequent step (iii). In a preferred embodiment, especially when the starting alcohol is a glycol or polyol and the glycol or When one or more of the hydroxyl groups of the polyol should remain intact, the product solution obtained in the step (ii) discharged from the second microreaction is stopped by water or an aqueous solution of an alkali such as sodium hydroxide or potassium hydroxide to stop the reaction. And/or block in step (i) The formation of acetic acid as a by-product results in an undesirable side reaction, such as the acetylation of the remaining hydroxyl groups of the diol or polyol. The suspension is preferably applied to the aqueous base solution which hydrolyzes any by-product of the oximation. It is preferred to use a base in a stoichiometric amount, that is, to use acetic anhydride as a starting material per mole as a starting material, or to use a slightly excess of a base. It can be introduced in a large amount of water or an aqueous alkali solution. And collecting the product solution semi-continuously to carry out the step of stopping. In a more preferred embodiment, the third microreactor unit fed to the product solution and water or the aqueous solution as defined above is continuously stopped. The microreactor unit may be located in a separate assembly or in a third microreactor unit in the same-assembly as the first-microreactor unit: in the same-assembly, then it may be located in a separate module or located In the same module as the second j-reactor unit, if it is located in the same assembly but in the early single module, the reactive fluid outlet of the second microreactor unit is outside. P is connected to the third micro reactor One of the reactive fluid populations of the group. 201139337 Further isolation and purification of the products of the process of the invention can be carried out by methods known in the art for individual compounds. Due to the inherent instability of the organolithosilicate Therefore, it may be desirable to avoid the isolation of the product in pure form and to store and ship it as a solution in a suitable solvent. Strong inorganic acids other than nitric acid may be used to catalyze the formation of acetonitrile nitrate from acetic anhydride and nitric acid. In a preferred embodiment, the strong inorganic acid which is not nitric acid is sulfuric acid. It is preferably 1 to 5 〇m〇1%, preferably 〇2 to 2. 〇mol%, more preferably 〇5 to (in terms of nitric acid). Sulfuric acid is used in an amount of 1.0 m〇l%. The first reaction step (that is, the formation of acetonitrile nitrate) is preferably 〇5 (TC, preferably 0-4 (TC, more preferably 20_40〇c, optimal, 2) 〇_3 (performed at rc temperature). The reaction time required depends on the reaction temperature and the concentration of the reactants, and is typically up to 20 minutes' or generally several minutes. The acetic anhydride and the nitric acid are preferably used in an approximate molar amount, and the molar ratio of acetic anhydride to nitric acid is from 1:1.5 to 5.5:1, preferably from 1:1.2 to 1.2:1, more preferably from m to 1.1:1. . The second reaction step (i.e., the formation of a nitrate of a monohydric alcohol, a diol or a polyhydric alcohol) is preferably from 0 to 40. . Preferably, 1〇_35. . More preferably 1〇_2〇t temperature: enter the 仃. The reaction is typically carried out very rapidly and almost immediately in the mixing zone of the second microreactor unit and to a lesser extent in the reaction zone t. The total reaction time depends on the reaction temperature and the concentration of the reactants and is typically -second or a few seconds or even less. The third step (ie, the suspension and hydrolysis of the by-products of the oxime) is preferably carried out at _5 to +50 C, preferably at a temperature of 〇-3 (rc). The reaction time required depends on the reaction temperature and the concentration of the reactants. And typically from 2 minutes to about i hours. 201139337 The reaction temperatures in steps (丨) and (Η) are preferably controlled in a suitable manner, for example by using a heat exchange module as described in WO 2007/1 12945 A1. The solvents (if present) in steps (i) and (ii) may be the same or different and may be any solvent which is substantially inert under the reaction conditions and which is capable of dissolving and/or diluting the starting materials and products. In a preferred embodiment, the solvent in the step (i) is dihalomethane. The acetic acid, nitric acid, a strong inorganic acid which is not selected from nitric acid and optionally the solvent in the step (i) may be separately fed. In the first continuous flow microreactor single TL, the restriction is that the microreactor unit has an appropriate number of reactive fluid inlets. Two or three such starting materials may also be premixed, the limiting condition being acetic anhydride. With nitric acid in its feeding microreaction In a preferred embodiment, step (i) is carried out by acetic anhydride, a strong mineral acid other than nitric acid, and/or a solvent selected as appropriate to feed the continuous flow micro The reactor unit is previously mixed. The mixed character is then fed into a reactive fluid inlet while concentrated nitric acid is fed into the other reactive fluid inlet and mixed with the mixture in the mixing zone. Preferably, it is carried out in a stoichiometric amount or in a slight excess of nitric acid, that is, from 1 to 1-5 per equivalent of one of the alcohols, glycols or polyols to be acetified. _〇 to 12 and the best 1. 〇 To 1.1 mol; e xiao acid. 1 軎 a 7L alcohol, diol or polyol means 丨m〇1 divided by the number of hydroxyl groups to be esterified. Knife in a preferred embodiment, organic nitric acid The ester has the formula: R]-Q-0-N〇2 (I), 10 201139337 wherein R1 is selected from the group consisting of hydrogen, H〇_, 02N_0_, R2〇·, optionally substituted aryl And optionally substituted heteroaryl, R2 is C2·6 decyl or aryl, and Q is straight chain, branched or a cycloalkanediyl group which is optionally substituted with one or more Ri moie as defined above, and wherein the monohydric alcohol, diol or polyhydric alcohol has the formula R丨-Q-oh (II), wherein Q is as defined above and Han 1. Same as Ri, the constraint is that if any of the R1 parts of the formula 〇2Ν_〇•, the corresponding Ri• part of the formula π can also be HO-. And "aryl" as used herein and mean any carbocyclic moiety comprising at least one aromatic system, such as phenyl, naphthyl, anthryl, phenanthryl, decyl, biphenyl or fluorenyl. By "heter aryl" is meant any heterocyclic moiety comprising at least one aromatic system, such as pyrrolyl, furyl thiol, s, and s. Sitting group, u ratio bite base, η dense α base, D call base, ^ ° base and the like. It should be understood that the expression "c2_6 alkanoyl" means any sulfhydryl group derived from an alkanoic acid having 2 to 6 carbon atoms, such as an ethyl fluorenyl group, a butyl ketone group, an isobutyl fluorenyl group, a pentamidine group ( Valeryl, pentanoyl), 'yl (3-methylbutyryl), caproyl, hexanoyl and the like. It should be understood that the expression "ar〇y" means derived from an aromatic monocarboxylic acid group, such as a benzoinyl group or a naphthylquinone group. 11 201139337 It should be understood that the expression "linear, branched or cyclic alkanediyl" is derived from the removal of two hydrogens from the same or different (contiguous or non-contiguous) carbon atoms. Any divalent moiety of a straight bond, a branched chain or a cyclic hydrocarbon such as methylene, ethylene, 1,2-ethanediyl, anthracene, propylidene ' 1,3 -propyldiyl, 1, 2-butanediyl, iota, 3-butanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 2-mercapto-1,3-propanediyl , 2,2-dimercapto-1,3·propyldiyl, 1,2-cyclopentadienyl, 1,3-cyclopentadienyl, 1,2-cyclohexanediyl, anthracene, 3_cyclohexane a group, a 1,4-cyclohexanediyl group, and the like. More preferably, 'Q is a C2-8 alkyl group-R' is H0- or O2N-O-, and r 1 _ is H0-; or Q (: 2-8 alkanediyl and Ri and Ri· are C2.6 alkanoyloxy. Most preferably 'R1 and Rr are H0- and Q is 1,4-butanediyl. The following non-limiting examples The method is intended to illustrate the method of the present invention. Example 1 4_Nitrooxybutan-1-ol (I; r1 = HO-, Q = _(ch2)4-) Dioxane (325 g), B Anhydride (49.58 g, 4 a mixture of 86 mmol) and sulphuric acid (0.46 g, 5 mmol), and nitric acid (99 5%, 3 〇 85 g, 490 mmol) were continuously and simultaneously fed into Figure 8A with w〇2010/130811 A2 during 4 minutes. And the first microreactor unit made of Hastelloy® c (substantially as described in WO 2007/112945 A1) in the tortuous channel mixing zone and the reaction zone configuration depicted in item e) of Figure 10. The dimensions of the reactor are as follows: hydraulic diameter of the mixing zone: 〇95 mm, length of the mixing zone: 0.29 m (section 〇_7xl.5 mm2, 18 curved), total channel length: 2.6 m, total volume: 10.9 mL. The exchange module and the external = warmer maintain the temperature of the microreactor unit at about 2 (rc and the residence time is 〇12 201139337 minutes. It is found that the effluent of the first microreactor unit is essentially composed of dichloromethane. A solution of acetamidine nitrate (assuming a yield of 100 〇/〇, theoretical concentration: 12.6 wt%), which was fed immediately with solvent-free oxime, 4-butanediol (40 g, 444 mmol) Hastelloy® C is made in the second microreactor unit in the module (which forms another One part of the assembled microreactor assembly, as described in WO 2007/112945 A1. The dimensions of the second microreactor unit are as follows: a tortuous channel mixing zone, a hydraulic diameter of the mixing zone: 0.71 mm, the length of the mixing zone: 〇·2ΐ m (section 〇.5xl.i mm2, 14 songs), total channel length: 1 · 0 m, total volume: 2.76 mL. The temperature of the second microreactor module was maintained at 20 ° C and the residence time was 7 seconds as described above. The effluent of the second microreactor unit was found at 20 ° C (found to contain 7.4 wt% of 4-nitrooxybutan-i-alcohol, corresponding to a yield of 55% (by 1,4- The butanediol meter)) was collected in a flask containing water (281 g) to stop the effluent. The resulting two phase system was separated and the organic phase was analyzed by GC. 4-Nitrooxybutan-1-ol was found to be the main product (ΐ2·ι area%), and some 14_bis(nitrooxy)butylene (about 3.8 area%), 4-nitrooxyanthracene acetate g (about 0.6 area%) and 4-hydroxybutyl acetate (about 〇·4 area%). The organic phase was washed 1 times with the same volume of water at 20 ° C to extract 4-nitrooxybutan-1-ol from the organic phase, while due to the formation of by-product hydrazine, 'bis(nitrooxy) Butane is poorly soluble in water and remains in the organic phase. The product is then extracted from the combined aqueous phase with dichloromethane (5 x 40 mL) to give a solution of <RTI ID=0.0> Concentration was carried out to obtain a solution of 15 wt% of 4-nitrooxybutan-1-ol in dioxane. 13 201139337 Example 2 4-Acetoxybutane·I. Alcohol (I; Rl = H〇_, q= (ch Mountain) One gas is burned (2.005 kg), acetic acid field (5〇4 〇g, 4 a mixture of 93 m〇1) and guazuazone (2.63 g '26 mmol), and nitric acid (99 5%, g 4·93 m〇l) were continuously and simultaneously fed as described in Example 1 during 7 minutes. The first microreactor unit made of HaStelloy®c. The heat exchanger module and the external thermostat were used to keep the temperature of the microreactor unit at 30 ° C and the residence time was 0 8 minutes. The flow of the reactor is a solution consisting of acetonitrile nitrate in the gas-burning (false yield of 1 〇〇 / 〇, theoretical concentration: 1 8.1 wt%), which is immediately fed into the loyy a second microreactor module (which forms part of another modular microreactor assembly, as described in the embodiments) in the first in-compartment zone, while solvent-free M-butanediol ( 4G4 g, 4 48 is in the first mixing zone 5. The temperature of the second microreactor unit is maintained at 30 ° C and the residence time is 4 seconds. The effluent of the first microreactor unit It was found to contain 1 硝基 _ 5 of 4-nitrooxybutan-1-ol, which corresponds to a 55% yield (with M-butanediol • ten)) precooling to a temperature of 5 C. The pre-cooled solution was fed simultaneously with a 13 wt/aqueous sodium hydroxide solution (3.921 kg, 12 7 (iv)) as described in 2007/112945 A1, from Haste U〇y® c to a separate mold. The third microreactor unit is used to suspend the pre-cooling solution. When the residence time is 〇丨 minutes, the temperature is stopped at 5. The enthalpy is stirred at 2 〇 3 〇 for 3 minutes to achieve the product emulsion for 1 minute. Hydrolysis of trace amounts of acetamidine by-products. The obtained two (four) systems were separated and analyzed by GC. The organic phase was analyzed by GC. It was found that 4_huji 201139337 oxybutan-1-ol was the main product (23 8 area%), and some 丨, 4 Bis(nitrooxy)butane (about 5.6 area%) and 4-nitrooxybutyl acetate (about 0.7% by area). No 4-hydroxybutyl acetate was detected (<0·1) Area %. At 5-2 〇C, the organic phase is washed with water (17 143 kg) in an extraction column (such as Kueni Tower) to extract 4-nitrooxybutanol from the organic phase. by The by-product Μ·bis(nitrooxy)butane formed is poorly soluble in water and remains in the organic phase. The product is then extracted from the combined aqueous phase with 53〇〇=diqimethane in the second extraction column. , thereby obtaining a solution of 4-nitrooxybutanol substantially free of bismuth(bisoxy)butane, and concentrating under reduced pressure with 1 to obtain 15 wt% (24.0 area% in GC) eGC analysis of 4 nitrooxybutan-1-ol in dichloromethane showed some 丨,4•bis(nitrooxy)butane (5.6 area%) and traces of 4-nitrooxybutane acetate The ester (〇7 area%) is a by-product. The yield obtained was 38-42%. Example 3 4-Nitrooxybutan-1-ol (I; Rl = H〇_, Q = (cH2) 4〇 Dichlorodecane (1866.0 g), acetic anhydride (469 〇g, 4 59 m) 〇i) and a mixture of sulfuric acid (2.45 g '24 mmol), and nitric acid (99 2%, 291.6 g, 4.59 mol '1.00 eq) during a period of about 5 minutes (the collection of product isolates was 42.8 minutes: ^ Continued and simultaneously fed into the first-microreactor unit made of HaStelloy®® as described in the implementation, the flow rate corresponding to the first feed is 54.60 g/min and the flow rate of the second feed is 6.80 g. /min. The temperature of the microreactor unit was maintained at 3 (TC and the residence time was 〇8 minutes using a heat exchange module and an external thermostat. The effluent from the first microreactor unit was fed into the HaStell〇y® c capillary (Inner diameter 3 15 15 201139337 mm, length 1.4 π 〇 to increase the residence time, and the capillary effluent (found as a solution consisting essentially of Dinitrogen (4) B. (assuming a yield of 1〇〇%, theoretical concentration: 18 wt%)) with solvent-free 1,4-butanediol (377.6 g, 4.19 mol) according to acetonitrile nitrate: butyl The molar ratio of diol to 1.1 (assuming a conversion of acetic anhydride of 1%) is immediately fed into another modular microreactor assembly made of Hastelly(y)(g) c in the module. In the second microreactor unit (as described in Example )); flow rate 8.82 to her = 8.69 〇 11 / _. Keep the temperature of the second microreactor unit at 30 ° C and the residence time is 4 The effluent of the first microreactor unit is fed into a second Hastel〇®® c capillary (1.6 mm inner diameter, 4.0 m length) to increase the residence time and the effluent of the second capillary (discovered Containing 1〇5 wt% of 4·nitrooxybutan-1-ol, equivalent to 57% yield (based on M butanediol)) pre-cooled to a temperature of 5 C. Subsequent pre-cooling The solution is fed into a third microreactor unit made of 1 仙11〇7® simultaneously with a 丨3 aqueous solution of aluminum hydroxide (3.69 (^, 11.99 111 〇1) to stop the pre-cooled solution. The dimensions of the third microreactor comprising 12 tangential mixing chambers depicted in item c) of Figure 1 of WO 2010/130811 A2 are as follows: hydraulics in the mixing zone Diameter: 2.66 mm, mixing zone length: 〇.15m, total channel length ^ 5 m, total volume: ii.65 mL. When the residence time is 〇1 minute, the stop temperature is 51. In another residence time module ( The emulsion of the obtained product was heated to a temperature of 25_3〇t: for 1 minute in a stainless steel capillary having a diameter of 15 mm and a length of 2, and then the emulsion was further stirred at 25-30 T for 10 minutes to achieve a trace amount of acetamidine. Hydrolysis of by-products (pH about 13). Separation of the resulting 16 201139337 two-phase system and analysis of the organic phase by GC. 4 "Schottyloxybutanol was found to be the main product (23% area%), as well as some bis(nitrooxy) butane (about 5.4 area%) and 4-nitrooxybutyrate acetate ( About 6 area%). 4-hydroxybutyl acetate (<1.% area%) was detected without debt. 13.87 kg) Washing the organic phase at 5-20 ° C in the extraction column with butan-1-ol, while remaining in the formation of the sub-water solubility is poor in the extraction of 4-nitrooxy products from the organic phase M-bis(nitrooxy)butane is in the organic phase. The product is then extracted from the combined aqueous phase with 4.311 kgm in a second extraction column to obtain a solution substantially free of M bis(nitrooxy)butylate 4-nitrooxybutanol. And then concentrated under reduced pressure to give a solution of 15 wt% BDMN (4-nitrooxybutanol) in dichloromethane. The yield obtained was 38-42%. Example 4 4-Nitrooxybutan-1-ol (! ; Ri = JJO-, Q = -(CIV) Dioxane (1656.0 g), acetic anhydride (252.0 g, 2.47 mol) and sulfuric acid ( 2.34 g, 23 mmol) of the mixture, and nitric acid (99 5%, 157.0 g ' 2.48 mol) were continuously and simultaneously fed with a value such as w〇2 during 38 minutes (the collection time of the product isolate was 8 minutes). 1曲/13〇811 A2 Figure 8A and Figure 1 is the first to be described in Example 1 of the zigzag channel mixing zone and reaction zone configuration described in item e) The microreactor unit (substantially as described in WO 2007/112945 A1). The temperature of the microreactor unit was maintained at 30 ° C (reactor temperature was controlled with a thermostat) and the residence time was 1, 2 minutes. The effluent of the first microreactor was found to be a solution consisting essentially of acetamidine nitrate in a gas-fired sinter 17 201139337 (assuming a yield of 100% 'theoretical concentration: 12.6 wt%), which was immediately fed into the first In the inlet of one of the first mixing zones of the two microreactor modules, the second microreactor module comprises four interconnected microreactor units, each of which consists of a mixing zone and a reaction zone. The mixing zone consists of a series of 12 tangential mixing chambers as depicted in item c) of Figure 1 of WO 201 〇/1 30811 A2. In detail, the dimensions of the four microreactor units are as follows: Hydraulic diameter of the mixing zone: 2.01 mm, length of each mixing zone: 〇〇6 m, channel length per unit: 0.6 m, total volume: 11.2 mL. The outlet of each of the first three units is directly connected to the two inlets of the mixing unit of the next unit. The second inlet of the first mixing zone is closed so that the first unit of the second module is only used. Increasing the residence time The solvent-free 1,4-butanediol (203 7 g, 2.25 m〇l) was simultaneously fed into the second mixing zone of the second microreactor module. The temperature of the second microreactor module was maintained at 3 Torr and the residence time was 3 _ 3 seconds. The effluent of the second microreactor unit was found to contain wt% 4-nitrooxybutyl-indole-alcohol, corresponding to a yield of 55% (based on I?-butanediol). The water is stopped by feeding water (362 g, 20" mol) into the third mixing zone of the same-microreactor module. At the residence time & 6 seconds: The abort temperature is 30. The resulting two phase system was separated and the organic phase was analyzed by Gc. It was found that 4·Shishaooxybutanol is the main product (1〇98 area%), and some 1,4-bis(decyloxy)butane (about 4% area%), nitrooxybutyl acetate (about 0.4 area%) and 4-hydroxybutyrate acetate (about 面积4 area Example 5 4 _ 基 oxybutan-1-ol (I : R 丨 = H 〇 _, q = · ((: Η 2) 4〇18 201139337 Use a higher concentration of acetic anhydride (20.0 wt% instead of 13 wt%, equivalent to the theoretical concentration of acetamidine nitrate 18.2 wt%) and less sulfuric acid (〇, 6 mol% to 1,4 - Butanediol meter) Example 4 was repeated. The second microreactor unit was as described in Example 1 (residence time: 7 seconds). The effluent of the second microreactor unit was stopped in a large amount of water and the resulting two phases were separated. System. Analyze the organic phase with GC' and found 4-nitrooxybutan-1-ol as the main product (21.i area%), and some 1,4-bis(nitrooxy)butane (about 5.4) Area %), 4-nitrooxybutyl acetate (about 0.7 area%) and 4-hydroxybutyl acetate (about 0.9 area%). Comparative Example 1 (batch method) 1,4·bis (nitro group) Oxy)butane (I; r1 = 〇2N -〇-,Q = -(CH2)4-) to -Chlorane (18.7 mL), acetic anhydride (6.24 g, 61 mmol) and 96 wt% sulfuric acid (〇_〇4 g, at -10 °C, To a mixture of 〇·3 3 mmol), a solution of nitric acid (3.9 g, 61 mmol) and previously prepared ι,4-butanediol (5 g, 5 5 mmol) in dichloromethane (1.5 mL) was added. After mixing the reaction mixture for 30 minutes at -1 CTC, 'add 3 wt% aqueous sodium hydroxide solution (48 g g solution '1 56 mmol). The mixture was allowed to warm to room temperature and the resulting two phases were separated. The organic phase was analyzed by GC. And found that 丨, 4_bis(nitrooxy)butane is the main product (18.81 area%)' and a trace amount of 4-nitrooxybutan-ol (about 0.2 area%) and diacetic acid 1, 4-butyl butyl ester (about 面积1 area. / 〇). Comparative Example 2 (batch method, reverse addition) 4-nitrooxybutan-1-ol (I; Ri = H〇_, q = -(ch2)4-) a mixture of dichlorohydrazine (37.5 mL), acetic anhydride (I2.5g, 122 mmol) and 96 wt% sulfuric acid (0.07 g, 〇·7 mm〇1) at -10C中添19 201139337 is Xiqiao (7·7 g, 122 mmol). The mixture is heated to 20〇C and added. A solution of 1,4-butanediol (1 〇 g 111 mmol) prepared in dichloromethane (3 〇 mL) was added in advance. The reaction mixture was cooled to and a solution of 13 aqueous sodium hydroxide (96.3 g, EtOAc). The mixture was allowed to warm to room temperature and the resulting two phases were separated. The organic phase was analyzed by GC, and it was found that 4-decyloxybutanol was the main product (14.38 area%), and some 1,4_bis(shidocyloxy)butane (about 4.5 area%), acetic acid. 4-Nitrooxybutyl ester (about 36 area%) and trace amounts of di-butyl butyl butylate (about 0.8 area%) and 4-hydroxybutyl acetate (about 0.1 area%). [Simplified explanation of the drawing] None [Description of main component symbols] None 20