TW201313726A - 製造合成之中間體之方法 - Google Patents

製造合成之中間體之方法 Download PDF

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TW201313726A
TW201313726A TW101133871A TW101133871A TW201313726A TW 201313726 A TW201313726 A TW 201313726A TW 101133871 A TW101133871 A TW 101133871A TW 101133871 A TW101133871 A TW 101133871A TW 201313726 A TW201313726 A TW 201313726A
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compound
formula
polar aprotic
mixture
aprotic solvent
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Stefan Abele
Eike J Bergner
Christian Bukovec
Jacques-Alexis Funel
Christian Hubschwerlen
Azely Mirre
Ivan Schindelholz
Jean-Philippe Surivet
Acklin Cornelia Zumbrunn
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Actelion Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems

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Abstract

本發明係關於一種製造式I-6化合物：□或製造該化合物之鹽之方法，該化合物係一種常用於製備抗生素化合物之合成中間體。本發明另外係關於該方法中所使用的中間體化合物，即6,7-二氫-[1,4]氧雜硫嗪并[2,3-c]噠嗪-3(2H)-酮、三氟甲磺酸6,7-二氫-[1,4]氧雜硫嗪并[2,3-c]噠嗪-3-基酯及6,7-二氫-[1,4]氧雜硫嗪并[2,3-c]噠嗪-3-羧酸甲酯及其鹽。

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製造合成之中間體之方法
本發明係關於一種製造用於製備抗生素化合物中已知的中間體之新穎方法，以及新穎性的合成中間體。
式I-6化合物： 係製備抗生素化合物中常用的合成中間體，此合成中間體用於製備抗生素化合物之用途係揭示於(例如)WO 2007/081597、WO 2007/071936、WO 2008/003690、WO 2008/009700、WO 2008/116815、WO 2008/125594、WO 2009/128953、WO 2009/000945、WO 2010/067332或WO 2010/116337中。
然而，用於製備式I-6化合物之已知方法並非最適於大規模製造，特別是因為在最終步驟為了獲得所要的醛而使用含有毒性重金屬的氧化劑(參見例如，WO 2007/071936，其中係使用OsO4)。因此，咸欲獲得一種更廉價、更有效且對環境更友好的製備該等化合物之方法(特定言之，是避免使用OsO4的方法)。
吾等申請者現已發現一種可獲得式I-6化合物之經改良 的製造途徑，其係使用下式I-1、I-2及I-3之新穎性中間體：
該製造途徑開始於已知的式I-0化合物： 式I-0化合物可根據熟習此項技術者所熟知的習知方法加以製備。
下文將呈現本發明各種實施例：
1)本發明首先係關於一種於製備前述式I-6化合物的新穎性合成中間體(即下式I-1化合物)： 或係關於該化合物之鹽。
2)本發明亦關於一種製造實施例1)中所定義的式I-1化合物之方法，該方法包括以下兩個步驟：a)於極性非質子性溶劑或極性非質子性溶劑混合物中，在鹼存在下，使式I-0化合物與2-巰基乙醇反應： b)於極性非質子性溶劑或極性非質子性溶劑混合物中，使經以上步驟a)後所得的中間體與三苯基膦及偶氮二羧酸二異丙酯或偶氮二羧酸二乙酯反應。
3)用於根據實施例2)之方法的步驟a)中，較佳的鹼係TEA、吡啶或DIPEA(且特別是DIPEA)。
4)以根據實施例2)或實施例3)之方法中的步驟a)及步驟b)而言，較佳的極性非質子性溶劑或極性非質子性溶劑混合物係DMF、MeCN、THF及DME其中一者或多者，且特別係MeCN及THF之混合物(尤其是每一體積THF中有5至12體積MeCN之混合物，例如每一體積THF中有7至10體積MeCN)。
5)以根據實施例2)或實施例3)之方法中的步驟a)及步驟b)而言，特佳的極性非質子性溶劑混合物係MeCN及THF的混合物，其每公斤式I-0化合物含有5至15 L MeCN及每公 斤式I-0化合物含有1至5 L THF(特別係每公斤式I-0化合物含有約7 L MeCN及每公斤式I-0化合物含有約2 L THF的MeCN及THF之混合物)。
6)進行根據實施例2)至實施例5)中任一項之方法中的步驟a)較佳是每當量式I-0化合物使用1至1.25當量的2-巰基乙醇及每當量式I-0化合物使用1.5至4當量的鹼，且特別是每當量式I-0化合物使用1至1.15當量的2-巰基乙醇及每當量式I-0化合物使用1.5至2.5當量的鹼。
7)進行根據實施例2)至實施例6)中任一項之方法中的步驟b)較佳是每當量步驟a)所得的中間體使用1至1.25當量的三苯基膦及每當量步驟a)所得的中間體使用1至1.25當量的DIAD或DEAD，且特別是每當量步驟a)所得的中間體使用1至1.15當量的三苯基膦及每當量步驟a)所得的中間體使用1至1.15當量的偶氮二羧酸二異丙酯。
8)較佳地，根據實施例2)至實施例7)中任一項之方法係使其步驟a)在介於50℃至該反應混合物之回流溫度之間進行(且特別是在介於65℃至該反應混合物之回流溫度之間)。
9)較佳地，根據實施例2)至實施例8)中任一項之方法係使其步驟b)在介於50℃至該反應混合物之回流溫度之間進行(且特別是在介於65℃至該反應混合物之回流溫度之間)。
10)根據實施例2)至實施例9)中任一項之方法的較佳變化方法，經步驟a)後所獲得的產物未經分離，且步驟a)及步驟b)係於同一反應器中進行(即，該2步驟方法係以所謂的「單鍋法」進行)。
以單鍋法實施例2)至實施例9)中任一項之方法具有可免於步驟a)後分離所得的惡臭中間硫衍生物且可以藉由簡單過濾法(無需其他純化作用)收集該式I-1化合物的優點。
11)本發明另外係關於另一種於製備前述式I-6化合物的新穎性合成中間體(即下式I-2化合物)： 或係關於該化合物的鹽。
12)本發明亦關於一種製備如實施例11)中所定義之式I-2化合物之方法，該方法包括於極性非質子性溶劑或極性非質子性溶劑混合物中，在吡啶存在下，使如實施例1)中所定義之式I-1化合物與三氟甲磺酸酐反應。
13)根據實施例12)之方法的較佳變化方法，於吡啶存在下，式I-1化合物與三氟甲磺酸酐的反應係每當量式I-1化合物使用1至1.5當量的三氟甲磺酸酐及每當量式I-1化合物使用1至1.5當量的吡啶，且特別是每當量式I-1化合物使用1至1.2當量的三氟甲磺酸酐及每當量式I-1化合物使用1至1.2當量的吡啶。
14)較佳地，根據實施例12)或實施例13)之方法係於室溫下進行。
15)實施例12)至實施例14)中任一項之方法中的極性非質子性溶劑或極性非質子性溶劑混合物特定言之係DCM。
16)本發明亦關於一種如實施例11)中所定義之式I-2化合物於製備式I-3化合物： 之方法中的用途，該方法包括使如實施例11)中所定義之式I-2化合物與一氧化碳及甲醇反應，該反應係於40至80℃的溫度(特別係40至60℃的溫度且較佳50至60℃的溫度)下，於極性非質子性溶劑或極性非質子性溶劑混合物中且於鈀羰化觸媒、雙齒膦配體及鹼存在下進行。
17)根據實施例16)之用途的較佳變化方法，式I-2化合物與一氧化碳及甲醇的反應係相對按照式I-2化合物使用1至10莫耳%鈀羰化觸媒及相對按照式I-2化合物使用1至15莫耳%雙齒膦配體，且特別係相對按照式I-2化合物使用1至5莫耳%鈀羰化觸媒及相對按照式I-2化合物使用4至8莫耳%雙齒膦配體加以進行。
18)較佳地，在實施例16)或實施例17)之用途中，該鈀羰化觸媒係二乙酸鈀(II)。
19)較佳地，在實施例16)至實施例18)中任一項之方法中，該雙齒膦配體係1,1'-雙-(二苯基膦基)二茂鐵或1,3-雙-(二苯基膦基)丙烷。
20)較佳地，在實施例16)至實施例19)中任一項之方法 中，式I-2化合物與一氧化碳及甲醇的反應係使用壓力至少為1或2巴的一氧化碳進行(例如1或2巴至100巴，且特別係至少4巴，特定言之約7巴)。
21)用於實施例16)至實施例20)中任一項之方法之較佳的鹼係DIPEA、TEA、K2CO3、Na2CO3、Cs2CO3及NaOH其中一者或多者(更佳地係DIPEA及TEA其中一者或多者，且特定言之係DIPEA)。
22)用於實施例16)至實施例20)中任一項之方法之另一較佳的鹼係吡啶，其可單獨使用或與DIPEA、TEA、K2CO3、Na2CO3、Cs2CO3及NaOH其中一者或多者成混合物(且更佳係DIPEA及吡啶其中一者或多者)。
23)因此，用於實施例16)至實施例20)中任一項之方法之特佳的鹼係DIPEA、吡啶及DIPEA與吡啶之混合物其中一者或多者。
24)用於實施例16)至實施例23)中任一項之方法之較佳溶劑係DMF。
25)本發明另外係關於又一種於製備如實施例1)中所定義之式I化合物中的新穎性合成中間體(即式I-3化合物)或其鹽：
26)本發明亦關於一種如實施例25)中所定義之式I-3化合物於製造式I-6化合物中之用途： 該式I-6化合物係用於製備如實施例1)中所定義之式I化合物。
27)本發明另一目標係關於一種製造式I-6化合物之方法： 該方法包括還原如實施例25)中所定義之式I-3化合物。
28)根據實施例27)之方法的變化方法，還原該式I-3化合物係藉由以下步驟進行：a)使該式I-3化合物與LiOH、NaOH或KOH反應，以獲得式I-4化合物： b)於極性非質子性溶劑或極性非質子性溶劑混合物中，在鹼、選自由N,N'-二環己基碳化二亞胺(DCC)、1-乙基-3-(3-二甲胺基丙基)碳化二亞胺(EDCI)、丙基膦酸酐(T3P)、O-(7-氮雜苯并***-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸鹽(HATU)及碳酸N,N'-二琥珀醯亞胺酯(DSC)所組成之群之活性劑，及視需要於1-羥基苯并***(HOBT)或1-羥基-7-氮雜苯并***(HOAT)之存在下，使該式I-4化合物與N,O-二甲基羥胺或其鹽反應，以獲得式I-5a化合物： 或於極性非質子性溶劑或極性非質子性溶劑混合物中，於鹼、選自由N,N'-二環己基碳化二亞胺、1-乙基-3-(3-二甲胺基丙基)碳化二亞胺(EDCI)、丙基膦酸酐(T3P)、O-(7-氮雜苯并***-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸鹽(HATU)及碳酸N,N'-二琥珀醯亞胺酯(DSC)組成之群之活性劑，及視需要於1-羥基苯并***(HOBT)或1-羥基-7-氮雜苯并***(HOAT)之存在下，使該式I-4化合物與嗎啉或其鹽反應，以獲得式I-5b化合物： 或於極性非質子性溶劑或極性非質子性溶劑混合物中，使該式I-4化合物與草醯氯或亞硫醯氯反應，且使因此獲得的中間體與N,O-二甲基羥胺反應，以獲得式I-5a化合物；或於極性非質子性溶劑或極性非質子性溶劑混合物中，使該式I-4化合物與草醯氯或亞硫醯氯反應，且使因此獲得的中間體與嗎啉反應，以獲得式I-5b化合物；及c)於極性非質子性溶劑或極性非質子性溶劑混合物中，使該式I-5a或I-5b化合物與選自氫化二異丁基鋁(DIBAH)、LiAlH4及雙(2-甲氧基乙氧基)氫化鋁鈉(Red-Al)之還原劑反應，以獲得式I-6化合物。
此實施例之方法中的步驟a)具有可藉由簡單過濾法或常用於固體分離之其他操作(如離心)即能夠收集式I-4化合物的優點(無需其他純化作用)。
29)較佳地，實施例28)之方法中的步驟a)係於水及(C1-C3)烷醇之混合物中進行，且特定言之是水及甲醇之混合物。
30)較佳地，進行實施例28)或實施例29)之方法中的步驟a)係每當量式I-3化合物使用1至1.25當量的LiOH、NaOH或 KOH，且特別係每當量式I-3化合物使用1至1.15當量的LiOH、NaOH或KOH。
31)較佳地，實施例28)至實施例30)中任一項之方法中的步驟a)係於室溫下進行。
32)較佳地，實施例28)至實施例31)中任一項之方法中的步驟b)中所使用的極性非質子性溶劑或極性非質子性溶劑混合物係DCM、THF或EA(且特別係DCM)。
33)較佳地，在不涉及式I-4化合物與草醯氯或亞硫醯氯之反應的變化方法中，用於實施例28)至實施例32)中任一項之方法中的步驟b)中的鹼係TEA。
34)較佳地，進行實施例28)至實施例33)中任一項之方法的步驟b)係：‧每當量式I-4化合物使用1.5至5當量的鹼、每當量式I-4化合物使用1至3當量的N,O-二甲基羥胺、嗎啉或N,O-二甲基羥胺或嗎啉之鹽、每當量式I-4化合物使用1至3當量的活性劑及視需要每當量式I-4化合物使用0.5至1當量的HOBT或HOAT(且特別是每當量式I-4化合物使用1.5至3當量的鹼、每當量式I-4化合物使用1至2當量的N,O-二甲基羥胺、嗎啉或N,O-二甲基羥胺或嗎啉之鹽、每當量式I-4化合物使用1至2當量的活性劑及視需要每當量式I-4化合物使用0.7至0.9當量的HOBT或HOAT)；或者‧每當量式I-4化合物使用1至1.25當量的草醯氯或亞硫醯氯，且其後每當量式I-4化合物使用1至3當量的N,O-二甲基羥胺或嗎啉(且特別是每當量式I-4化合物使用1至1.15 當量的草醯氯或亞硫醯氯，且其後每當量式I-4化合物使用1至2當量的N,O-二甲基羥胺或嗎啉)。
35)較佳地，實施例28)至實施例34)中任一項之方法的步驟b)係於低於10℃的溫度下進行，且特定言之係低於0℃的溫度(例如約-5℃的溫度)。
36)較佳地，實施例28)至實施例35)中任一項之方法的步驟c)中所使用的極性非質子性溶劑或極性非質子性溶劑混合物係DCM或DCM與己烷、庚烷、環己烷及甲苯其中一者或多者之混合物，且特別係DCM(特定言之是當步驟c)中使用DIBAH作為還原劑時)。
37)較佳地，用於實施例28)至實施例36)之方法之步驟c)中的還原劑係DIBAH。
38)較佳地，進行實施例28)至實施例37)中任一項之方法的步驟c)是每當量式I-5a或I-5b化合物使用1至1.4當量的還原劑，特定言之是每當量式I-5a或I-5b化合物使用1至1.25當量的還原劑，且特別是每當量式I-5a或I-5b化合物使用1至1.15當量的還原劑。
39)較佳地，實施例28)至實施例38)中任一項之方法的步驟c)係於低於10℃的溫度下進行，且特定言之是低於0℃的溫度(例如0至-10℃的溫度)。
40)根據實施例27)之方法之另一變化方法，式I-3化合物還原成式I-6化合物是使用DIBAH進行。
41)較佳地，實施例40)之方法中所使用的極性非質子性溶劑或極性非質子性溶劑混合物係DCM。
42)較佳地，進行實施例40)或實施例41)之方法係每當量式I-3化合物使用1.25至1.75當量的DIBAH，且特別是每當量式I-3化合物使用1.4至1.6當量的DIBAH。
43)較佳地，實施例40)至實施例42)中任一項之方法係於低於-50℃的溫度下進行，且特定言之是低於-70℃的溫度(例如-75至-80℃的溫度)。
44)根據實施例28)至實施例43)中任一項之方法之較佳變化方法，經步驟a)及b)後所獲得的產物未經分離，且步驟a)、b)及c)係於同一反應器中進行(即，該3步驟方法係以所謂的「單鍋法」進行)
以單鍋法進行實施例28)至實施例43)中任一項之方法具有免於分離兩種中間體之優點。
根據上文所揭示的不同實施例之相關性，以下實施例因此係可能且意欲並因此以個別形式具體揭示：‧1；‧2,3+2,4+3+2,4+2,5+3+2,5+2,6+5+3+2,6+5+2,6+4+3+2,6+4+2,6+3+2,6+2,7+6+5+3+2,7+6+5+2,7+6+4+3+2,7+6+4+2,7+6+3+2,7+6+2,7+5+3+2,7+5+2,7+4+3+2,7+4+2,7+3+2,7+2,8+7+6+5+3+2,8+7+6+5+2,8+7+6+4+3+2,8+7+6+4+2,8+7+6+3+2,8+7+6+2,8+7+5+3+2,8+7+5+2,8+7+4+3+2,8+7+4+2,8+7+3+2,8+7+2,8+6+5+3+2,8+6+5+2,8+6+4+3+2,8+6+4+2,8+5+3+2,8+5+2,8+4+3+2,8+4+2,8+3+2,8+2,9+8+7+6+5+3+2,9+8+7+6+5+2,9+8+7+6+4+3+2,9+8+7+6+4+2,9+8+7+6+3+2,9+8+7+6+2,9+8+7+5+3+2,9+8+7+5+2,9+8+7+4+3+2,9+8+7+4+2,9+8+7+3+2, 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在先前列表中，該等數字係指上文提供的對應編號的實施例，而「+」表示與另一實施例之相關性。不同的個別實施例係由逗號隔開。換言之，例如，「4+3+2」係指實施例4)與實施例3)相關且與實施例2)相關，即實施例「4+3+2」相當於實施例2)另外由實施例3)及4)之特徵所限制。
本文中所使用的縮寫及術語 縮寫：
整個專利說明書及實例中使用以下縮寫： wt% 重量%
本文中所使用的特定術語之定義
以下段落提供本發明化合物之各種化學基團及本文中所使用的其他特定術語之定義，且意欲一致地應用於整個說明書及申請專利範圍，除非另有明確闡述的定義提供更寬 廣或更狹隘的定義：
術語「極性非質子性溶劑」係指沒有顯示氫鍵結、不具有酸性氫，但可使離子安定之溶劑。極性非質子性溶劑之代表性實例包括DCM、EA、iPrOAc、THF、2-甲基-四氫呋喃、DMAC、DME、DMF、二噁烷、***、第三丁基甲醚或環戊基甲醚。
術語「極性非質子性溶劑混合物」係指包括至少一種如先前所定義之極性非質子性溶劑及至少另一種非質子性溶劑(其可為極性或非極性)之溶劑混合物。極性非質子性溶劑混合物之代表性實例包括(但不限於)兩種選自由DCM、EA、iPrOAc、THF、DMAC、DME、DMF、二噁烷及***組成之群之溶劑的混合物；甲苯與DCM、EA、iPrOAc、THF、2-甲基-四氫呋喃、DMAC、DME、DMF、二噁烷或***其中一者或多者之混合物；己烷與DCM、EA、iPrOAc、THF、DMAC、DME、DMF、二噁烷、***、第三丁基甲醚或環戊基甲醚其中一者或多者之混合物；庚烷與DCM、EA、iPrOAc、THF、2-甲基-四氫呋喃、DMAC、DME、DMF、二噁烷、***、第三丁基甲醚或環戊基甲醚其中一者或多者 之混合物；及甲苯與己烷或庚烷，及DCM、EA、iPrOAc、THF、2-甲基-四氫呋喃、DMAC、DME、DMF、二噁烷、***、第三丁基甲醚或環戊基甲醚其中一者或多者之混合物。
術語「烷醇」係指含有1至6個碳原子及1個羥基之脂族一級、二級或三級醇。術語「(C1-Cx)烷醇」係指含有1至x個碳原子及1個羥基之脂族一級、二級或三級醇。烷醇之實例包括甲醇、乙醇及異丙醇。
如文中所使用，術語「鈀羰化觸媒」係指任何包含可催化羰化反應之鈀型式觸媒。鈀羰化觸媒之代表性實例包括二乙酸鈀(II)、二乙醯基丙酮酸鈀(II)、肆(三苯基膦)鈀(0)、參(二亞苄基丙酮)二鈀(0)、氯化烯丙基鈀(II)二聚物及氯化鈀(II)。
如文中所使用，術語「雙齒膦配體」係指任何可在羰化反應中輔助鈀羰化觸媒的膦類配體。雙齒膦配體之代表性實例包括dppf、dppp、1,1-雙(二苯基膦基)甲烷(dppm)、1,2-雙(二甲基膦基)乙烷(dmpe)、1,2-雙(二異丙基膦基)乙烷(dippe)、1,2-雙(二苯基膦基)乙烷(dppe)、苯基茴香基甲基膦二聚物(DIPAMP)、1,4-雙(二苯基膦基)丁烷(dppb)、2,3-雙(二苯基膦基)丁烷(Chiraphos)、2,2'-雙(二苯基膦基)-1,1'-聯萘(BINAP)、4,5-雙(二苯基膦基)-9,9-二甲基二苯并哌喃(Xantphos)、4,4,4',4',6,6'-六甲基-2,2'-螺雙色滿-8,8'-二基雙(二苯基磷烷)(SPANphos)、4,4'-聯-1,3-苯并二氧雜戊烯-5,5'-二 基雙(二苯基磷烷)(SEGPHOS)及1,2-雙(2,5-二甲基磷雜環戊基)苯(Me-DuPhos)。
如文中所使用，術語「室溫」係指20至30℃及較佳25℃的溫度。
除非用於溫度，否則本申請案中置於數值「X」前的術語「約」係指X減去10% X至X加上10% X的區間，且較佳係指X減去5% X至X加上5% X的區間。在溫度之特定情況下，本申請案中置於溫度「Y」前的術語「約」係指比Y低10℃至比Y高10℃的區間，且較佳係比Y低5℃至比Y高5℃的區間。
本發明之特定實施例係揭示於以下實例中，其等係用於更詳細地闡釋本發明且不以任何方式限制其範圍。
實例
所有既定溫度係內部溫度且以℃表示。藉由1H-NMR(400 MHz)或13C-NMR(100 MHz)(Bruker；化學位移δ係以相對於所使用溶劑之ppm表示；多重性：s=單重峰；d=雙重峰；t=三重峰；p=五重峰；hex=六重峰；hept=七重峰；m=多重峰；br.=寬，偶合常數係以Hz表示)、LC-MS方法1及2(具有HP 1100二元泵及DAD之Finnigan Navigator)分析化合物之特徵。除非另有說明，否則產率係如文中所指。純度數據係使用98%純化1,4-二甲氧基苯作為內標準物根據NMR分析所測定的。
LC-MS及TLC方法之參數： LC-MS方法1：
LC-MS方法2：
TLC方法1：
洗脫劑：EA/MeOH 9/1+3滴AcOH(或5 mL EtOH)。使用 UV及KMnO4染色進行檢測。
TLC方法2：
洗脫劑：EA。使用UV及KMnO4染色進行檢測。
實例1：6,7-二氫-[1,4]氧雜硫嗪并[2,3-c]噠嗪-3(2H)-酮： 方法A
在與經填充10%漂白劑之洗滌器連接的30 L Büchi反應器中，將DIPEA(2460 mL，19.0 mol，2.0當量)添加至溶於MeCN(13.2 L)之4-溴-1,2-二氫噠嗪-3,6-二酮(1881 g，9.5 mol)溶液中。於70℃的IT下，攪拌所得混合物5分鐘以便完全溶解。隨後於N2超壓下，歷時15分鐘經由聚乙烯管添加2-巰基乙醇(742 mL，10.5 mol，1.1當量)(注意：有惡臭氣味！)。完成添加後，該混合物加熱回流4小時。在此狀態下，TLC(方法1)顯示完全轉化。歷時1分鐘一滴滴加入溶於THF(2700 mL)之Ph3P(2742 g，13.0 mol，1.1當量)溶液。使該混合物冷卻至略低於回流溫度(ET=70℃)且歷時30分鐘小心地添加DIAD(2182 mL，10.5 mol，1.1當量)。然後將該混合物加熱回流1小時。在此狀態下，藉由TLC觀察到完全轉化。添加MeCN(11.5 L)且使該混合物回流30分鐘。然後歷時3小時使其冷卻至RT。過濾掉所得固體，使用MeCN(4.6 L)沖洗並於真空(50℃，10 mbar)下於旋轉蒸發器中乾燥直至恆重，以獲得呈白色固體的標題化合物(857 g，53%產率；純度：96.4重量%)。
1H-NMR(d6-DMSO)：δ=12.0(br.s,1H),6.79(s,1H),4.45-4.43(m,2H),3.21-3.19(m,2H)。
TLC(方法1)：Rf=0.8(LC-MS：[M+1]+=171)。
方法B
於20℃下，將2-巰基乙醇(2.0 mL，27.4 mmol，1.1當量)添加至4-溴-1,2-二氫噠嗪-3,6-二酮(5 g，25.0 mol)及DIPEA(8.5 mL，50 mmol，2.0當量)之溶液中。所得混合物加熱回流4小時。一滴滴加入溶於THF(5 mL)之PPh3(7.2 g，27.4 mmol，1.1當量)溶液，接著小心地添加溶於甲苯(12.5 mL，27.4 mmol，1.1當量)之40% DEAD溶液。於回流下攪拌2小時。在此期間，沉澱會發生。使其冷卻至20℃，過濾，用EA沖洗且於減壓(50℃，10 mbar)下乾燥，以獲得呈白色固體的標題化合物(2.5 g，60%產率)。
該產物具有相當於獲自實例1方法A之彼等產物的NMR數據。
實例2：三氟甲磺酸6,7-二氫-[1,4]氧硫嗪并[2,3-c]噠嗪-3-基酯： 方法A
20℃下，將吡啶(618 mL，7.68 mol，1.1當量)添加至溶於DCM(13 L)之實例1化合物(1287 g，6.98 mol)溶液中。使所得混合物冷卻至0℃，且歷時15分鐘一滴滴加入Tf2O(1292 mL，7.68 mL，1.1當量)，以便IT不超過20℃。於RT下攪拌20分鐘。在此狀態下，TLC(方法2)顯示完全轉化。添加水(6.5 L)。分離各層，且用水(6.5 L)再沖洗該有機相。將該有機層濃縮至乾(50℃，10 mbar)，直至恆重，以獲得呈灰白色粉末的標題化合物(定量：2153 g。產 率：94%重量%純度)，其即可使用且無需另外純化。
方法B
使用變化方法A之方案以獲得粗製的標題化合物。然而，在此方案中，如下文所述，將末了的化合物純化。於20℃下，將10 g的粗製產物懸浮於EA(20 mL)及TBME(20 mL)中，該混合物加熱回流且添加TBME(80 mL)直至觀察到渾濁度。使其自身冷卻至20℃。過濾掉該所得固體，用庚烷(20 mL)沖洗並於減壓(50℃，10 mbar)下乾燥直至恆重，以獲得白色粉末(7.1 g，71%產率)。
1H-NMR(d6-DMSO)：δ=8.07(br.s,1H),4.70-4.67(m,2H),3.37-3.35(m,2H)。
TLC(方法2)：Rf=0.55。
方法C
將吡啶(42 mL，0.52 mol，1.05當量)添加至溶於DCM(425 mL)之實例1化合物(85.1 g，0.50 mol)溶液中，且使該混合物冷卻至0至4℃。緩慢添加Tf2O(155.1 g，0.55 mol，1.10當量)且使該反應混合物自身升溫至20℃。添加水(300 mL)且接著添加1.5 M HCl水溶液(150 mL)。然後添加水(150 mL)。於真空(40℃，800 mbar)下將該粗製產物溶液濃縮至其體積之三分之二。添加庚烷(600 mL)並於0至4℃下攪拌該混合物1小時。過濾掉該所得固體並於40℃下乾燥過夜(淺黃色固體，143 g，95%產率)。
該產物具有相當於獲自實例2方法B之彼等產物的NMR數據。
實例3：6,7-二氫-[1,4]氧雜硫嗪并[2,3-c]噠嗪-3-羧酸甲酯： 方法A
於50 L高壓釜中，於55℃下及於7巴的一氧化碳下，攪拌溶於MeOH(12 L)及DMF(24 L)之實例2化合物(1000 g，3.30 mol)、Pd(OAc)2(22.4 g,0.1 mol，0.03當量)、dppf(0.2 mol，0.06當量)及DIPEA(636 mL，6.6 mol，2當量)之溶液4.5小時。使該反應混合物冷卻至RT，釋放壓力且使用氮氣淨化該高壓釜。過濾掉該混合物且將其蒸發至恆重(55℃，10 mbar)。將該所得暗色固體溶解於DCM(6 L)中並用水(4 L)沖洗三次。將經合併有機萃取物濃縮至乾(40℃，800 mbar)。將該殘餘物於THF(4 L)中調成漿液。蒸餾掉THF(2 L)且使該混合物冷卻至5至8℃，在此溫度範圍內產物會結晶。將其過濾掉，用冷(4℃)THF(0.5 L)沖洗3次並於減壓(40℃，10 mbar)下乾燥，以獲得呈淺黃色粉末的標題化合物(477 g，68%產率)。
1H-NMR(d6-DMSO)：δ=8.07(br.s,1H),4.70-4.68(m,2H),3.90(s,3H),3.36-3.33(m,2H)。
LC-MS(方法1)：tR=0.53分鐘；[M+1]+=213。
方法B
於100 mL高壓釜中，於70℃下及於10巴的一氧化碳下，攪拌溶於MeOH(39 mL)及DMF(26 mL)之實例2化合物(2.5 g，8.3 mmol)、Pd(OAc)2(56 mg，0.25 mol，0.03當量)、dppp(206 mg，0.5 mmol，0.06當量)及TEA(2.5 mL，18.3 mol，2.2當量)之溶液4.5小時。使該反應混合物冷卻至RT，釋放壓力且使用氮氣淨化該高壓釜。過濾掉該混合物且蒸發至恆重(55℃，10 mbar)。將該所得暗色固體於EA中調成漿液，過濾並藉由矽膠急驟層析法純化，以DCM溶劑洗脫，以獲得呈淺黃色粉末的標題化合物(0.44 g，25%產率)。
該產物具有相當於獲自實例3方法A之彼等產物的NMR數據。
方法C
將實例2化合物(10 g，33 mmol)、Pd(OAc)2(0.225 g，1 mmol，0.03當量)及dppf(0.929 g，1.7 mmol，0.05當量)溶解於MeOH(50 mL)、DMF(100 mL)及吡啶(4.5 mL；55.7 mmol；1.7當量)中。於7至8巴的CO下加壓該高壓釜。於55℃下攪拌該反應混合物24小時。然後於真空(10 mbar，60℃)下將該反應混合物濃縮至乾。添加水(100 mL)且將該混合物加熱回流1小時。將該反應混合物傾析1小時。使其冷卻至20℃且用DCM(2x50 mL)萃取。使該等經合併有機相濾過使用EA(50 mL)為洗脫劑之矽膠柱(20 g)。將該有機相濃縮至乾。添加EA(15 mL)並於0至4℃下攪拌該混合物。過濾掉該固體且於40℃下乾燥過夜。獲得白色固體(3.9 g，65%產率)。
該產物具有相當於獲自實例3方法A之彼等產物的NMR數據。
實例4：6,7-二氫-[1,4]氧雜硫嗪并[2,3-c]噠嗪-3-甲醛： 4.A.1. 6,7-二氫-[1,4]氧雜硫嗪并[2,3-c]噠嗪-3-羧酸：
於RT下，歷時15分鐘將溶於水(1.8 L)之LiOH.H2O(250 g，5.95 mol，1.1當量)溶液添加至溶於MeOH(6 L)之實例3化合物(1215 g，5.41 mol)懸浮液中，以便IT<30℃。經攪拌2分鐘後，獲得澄清溶液。經攪拌另外10分鐘後，獲得懸浮液。樣品測試(LC-MS)顯示完全轉化。添加水性2 M HCl(3.25 L，6.50 mol，2當量)且攪拌該混合物10分鐘。將其過濾掉並用水(6 L)沖洗，且接著用丙酮(3 L)沖洗。於減壓(50℃，10 mbar)下將其乾燥直至恆重，以獲得呈白色固體的標題化合物(定量：1088 g。產率：93重量%純度)。
1H-NMR(d6-DMSO)：δ=13.6(br.s,1H),8.04(br.s,1H),4.69-4.67(m,2H),3.35-3.33(m,2H)。
LC-MS(方法1)：tR=0.38分鐘；[M+1]+=199。
4.A.2. N-甲氧基-N-甲基-6,7-二氫-[1,4]氧雜硫嗪并[2,3-c]噠嗪-3-甲醯胺： 方法A
將中間體4.A.1(1 kg，4.71 mol)懸浮於DCM(5 L)中。隨後一滴滴加入Et3N(1.31 L，9.41 mol，2當量)。於20℃下攪拌5至10分鐘後獲得澄清溶液。然後於20℃下添加N,O-二甲基羥胺鹽酸鹽(689 g，7.06 mol，1.5當量)且接著添加HOBT(509 g，3.77 mol，0.8當量)。隨後添加EDCI(1354 g，7.06 mol，1.5當量)。觀察到IT升溫至30℃。於20℃下攪拌該所得混合物15小時。歷時10分鐘添加飽和水 性NaHCO3(5 L)。添加水(5 L)並於20℃下強力攪拌該混合物20分鐘。分離各層。將飽和水性NaHCO3(10 L)添加至該有機相中且於20℃下攪拌該混合物1小時。在此狀態下，該有機層之樣品測試顯示不再存在殘留的HOBT。分離各層。使用DCM(2 L)再萃取該水相。隨後於旋轉蒸發器(40℃，800 mbar)下將該等經合併有機萃取物濃縮至乾，以獲得850 g粗製產物。將末了的化合物溶解於回流EA(6.8 L)中。添加庚烷(1.7 L)。使其冷卻至60℃，種晶並於IT=60℃下攪拌30分鐘。隨後歷時3小時使該混合物冷卻至20℃。將其過濾掉(10 L過濾器，3分鐘過濾時間)。使用庚烷(4.5 L)沖洗該濾餅且於氮氣正壓下乾燥過夜，隨後於旋轉蒸發器(50℃，10 mbar)下乾燥直至恆重，以獲得呈淺灰棕色粉末的標題中間體(775 g)。在經過額外的DCM萃取該水相及結晶過程後，獲得另外的產物(120 g)。因此，獲得895 g(75%產率，96%重量%純度)之標題中間體。
1H-NMR(d6-DMSO)：δ=7.79(br.s,1H),4.67-4.64(m,2H),3.66(br.s,3H),3.36-3.33(m,2H),3.29(br.s,3H)。
LC-MS(方法1)：tR=0.50分鐘；[M+1]+=242。
方法B
使溶解於DMF(12.5 mL)之中間體4.A.1(2.5 g，12.6 mmol)冷卻至0至4℃，且添加N,O-二甲基羥胺鹽酸鹽(1.25 g，12.6 mmol，1當量)。緩慢添加丙基膦酸酐(50重量%，溶解於DMF)，以便IT不超過5℃。緩慢添加TEA(3.75 g，37.0 mmol，3當量)並歷時2小時使該懸浮液自身升溫至 20℃。於真空(10 mbar，60℃)下，將該反應混合物濃縮至乾。將該殘餘物溶解於DCM(25 mL)中並添加水(12.5 mL)。藉由添加50% NaOH水溶液將pH調節至8.5。分離各相，且使用DCM(2x12.5 mL)萃取該水相。於Na2SO4上乾燥該等經合併有機相，過濾並於真空(10 mbar，50℃)下蒸發至乾。將該殘餘物溶解於EA(7.5 mL)中並添加25 mL庚烷。於RT下攪拌該所得懸浮液過夜，過濾並用庚烷沖洗。於40℃下將其乾燥過夜，以獲得呈淺棕色固體的標題中間體(2.7 g，90%產率)。
該產物具有相當於獲自方法A步驟4.A.2之彼等產物的NMR數據。
4.A.3. 6,7-二氫-[1,4]氧雜硫嗪并[2,3-c]噠嗪-3-甲醛： 變化方法A：
於20℃下，將中間體4.A.2(717 g，2.85 mol)懸浮於THF(3.6 L)中。使其冷卻至IT=-5℃。歷時45分鐘一滴滴加入溶於DCM之1 M DIBAH溶液(3.14 L，3.14 mol，1.1當量)，以便IT不超過-5℃。於IT=-5℃下攪拌該混合物1小時。在此狀態下，TLC(方法2)顯示微量殘留的初始物質(Rf=0.3)。再添加溶於DCM之1 M DIBAH(100 mL；0.1 mol，0.03當量)。10分鐘後，TLC顯示完全轉化。然後，一滴滴加入水(720 mL)及EtOH(3.6 L)之混合物，以便IT不超過10℃。於20℃下攪拌25分鐘後，獲得膠狀(可攪拌)混合物。一滴滴加入25重量%酒石酸鈉鉀鹽水溶液(7.2 L)，以便IT不超過25℃。於20℃下強力攪拌該所得混合物至少 4小時，以便觀察到清晰的相分離。分離各層，且用EA/DCM(4 L/1 L)萃取該水相。使用鹽水(3.5 L)沖洗該等經合併有機萃取物並將其蒸發至乾(40℃，800 mbar)，以獲得呈灰棕色固體的粗製物質(定量：536 g。產率：88%重量%純度)。將末了的化合物懸浮於EtOH(10 L)中並加熱回流。添加最少量的水(4 L)以觀察澄清溶液。使其冷卻至65℃，種晶並於IT=65℃下攪拌30分鐘。隨後歷時4小時使該混合物冷卻至0℃。將其過濾掉(10 L過濾器，1分鐘過濾時間)並於氮氣正壓下乾燥過夜，隨後於旋轉蒸發器(50℃，10 mbar)下乾燥直至恆重，以獲得呈淺灰色粉末的標題化合物(275 g，53%產率，98重量%純度)。
1H-NMR(d6-DMSO)：δ=10.0(s,1H),7.99(br.s,1H),4.73-4.71(m,2H),3.36-3.35(m,2H)。
TLC(方法2)：Rf=0.5。
LC-MS(方法2)：tR=0.51分鐘；[M+1]+=183。
變化方法B：
於20℃下，將中間體4.A.2(40 g，0.15 mol)懸浮於THF(200 mL)中。使其冷卻至IT=-5℃。歷時45分鐘一滴滴加入溶於DCM之1 M DIBAH溶液(160 mL，0.16 mol，1.1當量)，以便IT不超過-5℃。於IT=-5℃下攪拌該混合物30分鐘至1小時。在此狀態下，TLC(方法2)顯示微量殘留的初始物質(Rf=0.3)。再添加溶於DCM之1 M DIBAH(16 mL；16 mmol，0.1當量)。10分鐘後，TLC顯示完全轉化。然後，一滴滴加入水(40 mL)及EtOH(200 mL)之混合物，以 便IT不超過10℃。於20℃下攪拌25分鐘後，獲得膠狀(可攪拌)混合物。一滴滴加入25重量%酒石酸鈉鉀鹽水溶液(400 mL)，以便IT不超過25℃。於20℃下強力攪拌該所得混合物至少4小時，以便觀察到清晰的相分離。分離各層，且用EA(300 mL)萃取該水相。使用鹽水(200 mL)沖洗該等經合併有機萃取物並將其蒸發至乾(40℃，800 mbar)，以獲得呈灰棕色固體的粗製物質(30.5 g)。將此物質懸浮於EA(300 mL)中並加熱回流1小時。使其冷卻至5℃，過濾並於減壓(50℃，10 mbar)下乾燥，以獲得呈灰棕色固體的標題化合物(23 g，87%產率，88重量%純度)。
該產物具有相當於獲自變化方法A步驟4.A.3之彼等產物的NMR數據。
變化方法C：
將DMF(40 μL，0.46 mmol，0.1當量)添加至溶於DCM(10 mL)之中間體4.A.1(1g，4.6 mmol)溶液。使其冷卻至4℃。隨後將草醯氯(430 μL，4.6 mmol，1當量)添加至該懸浮液中並導致氣體逸出。於20℃下，將該所得混合物攪拌15小時。隨後於20℃下添加嗎啉(800 μL，9.2 mmol，2當量)。於20℃將其攪拌30分鐘。一滴滴加入溶於DCM之1 M DIBAH溶液(9.2 mL，9.2 mol，2.0當量)，以便該IT不超過-5℃。於IT=-5℃下攪拌該混合物30分鐘至1小時。再添加溶於DCM之1 M DIBAH(2.3 mL；2.3 mmol，0.5當量)。20分鐘後，TLC顯示完全轉化。然後，一滴滴加入水(1 mL)及EtOH(5 mL)之混合物，以便IT不超過10℃。於 20℃下攪拌25分鐘後，獲得膠狀(可攪拌)混合物。一滴滴加入25重量%酒石酸鈉鉀鹽水溶液(5 mL)，以便IT不超過25℃。於20℃下強力攪拌該所得混合物至少4小時，以便觀察到清晰的相分離。分離各層且用EA(5 mL)萃取該水相。使用鹽水(5 mL)沖洗該等經合併有機萃取物並將其蒸發至乾(40℃，800 mbar)，以獲得呈灰棕色固體的粗製物質(300 mg)。
該產物具有相當於獲自變化方法A步驟4.A.3之彼等產物的NMR數據。
變化方法D：
於-70℃下，歷時30分鐘將溶於DCM之1 M DIBAH溶液(67.1mL，67.1mmol，1.5當量)一滴滴加入至溶於DCM(200 mL)之實例3化合物(10 g，44.8 mmol)溶液中，以便IT不超過-70℃。於-70℃下攪拌5小時後，藉由添加EtOH(12.5 mL)/水(2.5 mL)使其淬滅，並導致IT上升至-35℃。隨後使該混合物於1小時內升溫至20℃且強力攪拌。添加25%酒石酸鈉鉀鹽水溶液(100 mL)並於20℃下強力攪拌該混合物過夜。分離各層且用EA(100 mL)萃取該水相。於減壓(50℃，250 mbar)下濃縮該等經合併有機層，以獲得預期的粗製產物。將該粗製殘餘物懸浮於EtOH(60 mL)中。添加H2O(21 mL)直至獲得澄清溶液。蒸餾掉26 mL溶劑並使該混合物自身冷卻至20℃過夜。將其過濾，用冷EtOH(4℃)沖洗並於減壓(50℃，10 mbar)下乾燥，以獲得灰棕色固體(4.5 g，55%產率)。
該產物具有相當於獲自變化方法A步驟4.A.3之彼等產物的NMR數據。
變化方法E：
將中間體4.A.2(100 g，0.41 mol)溶解於THF(1000 mL)及DCM(1000 mL)中，並使其冷卻至-5至0℃。緩慢添加溶於庚烷之20% DIBAH溶液(490 mL；0.51 mol；1.22當量)，以便IT不超過0℃。於此溫度下攪拌1小時。緩慢添加水(100 mL)及EtOH(400 mL)之混合物(IT最大=5℃)。攪拌30分鐘後，將所得混合物添加至溶於水(850 mL)中之酒石酸鈉鉀(250 g)溶液，以便IT不超過5℃。使該反應混合物升溫至20℃，並攪拌至少5小時。分離各層且用EA(1000 mL)萃取該水層。使用鹽水(1000 mL)沖洗該等經合併有機相，並於真空(>300 mbar，50℃)下將其濃縮(>300 mbar，50℃)。添加EA(300 mL)並於真空下濃縮該混合物。添加EA(300 mL)並將該混合物濃縮至總體積為500mL。使該混合物冷卻至5至10℃並攪拌1小時。將其過濾掉並用EA(4 x 30 mL)沖洗。於40℃下將其乾燥過夜，以獲得呈灰白色固體的標題產物(55.6 g，74%產率)。
該產物具有相當於獲自變化方法A步驟4.A.3之彼等產物的NMR數據。
變化方法F：
將溶於THF之2 M氫化鋰鋁溶液(7 mL；14 mmol，0.35當量)小心地(氣體逸出)添加至溶於THF(50 mL)及DCM(50 mL)之中間體4.A.2(10 g，39.8 mmol)之***液(4℃)中。 30分鐘後，小心地添加水(0.5 mL)且接著添加15% NaOH水溶液(0.5 mL)。隨後添加水(1.5 ml)並於20℃下強力攪拌該混合物。於矽藻土上將其過濾並濃縮至乾。將該粗製殘餘物懸浮於EtOH(70 mL)中並將其加熱回流。添加水(20 mL)。使該混合物冷卻至4℃。將其過濾掉，以獲得呈灰白色固體的標題產物(1.6 g，20%產率)。
該產物具有相當於獲自變化方法A步驟4.A.3之彼等產物的NMR數據。

Claims (16)

  1. 一種式I-1化合物或該化合物之鹽：
  2. 一種製造如請求項1中所定義的式I-1化合物之方法，該方法包括以下兩個步驟：a)於極性非質子性溶劑或極性非質子性溶劑混合物中，於鹼存在下，使式I-0化合物與2-巰基乙醇反應： b)於極性非質子性溶劑或極性非質子性溶劑混合物中，使經以上步驟a)後所獲得的中間體與三苯基膦及偶氮二羧酸二異丙酯或偶氮二羧酸二乙酯反應。
  3. 如請求項2之方法，其中步驟a)中所使用的鹼係三乙胺、吡啶或N,N-二異丙基乙胺。
  4. 如請求項2或3之方法，其中用於步驟a)及步驟b)之極性非質子性溶劑或極性非質子性溶劑混合物係乙腈及四氫呋喃之混合物。
  5. 一種式I-2化合物或該化合物之鹽：
  6. 一種製造如請求項5中所定義之式I-2化合物之方法，該方法包括於極性非質子性溶劑或極性非質子性溶劑混合物中，於吡啶存在下，使如請求項1中所定義之式I-1化合物與三氟甲磺酸酐反應。
  7. 如請求項6之方法，其中該極性非質子性溶劑或極性非質子性溶劑混合物係二氯甲烷。
  8. 一種式I-3化合物或該化合物之鹽：
  9. 一種製造如請求項8中所定義之式I-3化合物之方法，該方法包括使如請求項5中所定義之式I-2化合物與一氧化碳及甲醇反應，該反應係於40至80℃的溫度下，於極性非質子性溶劑或極性非質子性溶劑混合物中且於鈀羰化觸媒、雙齒膦配體及鹼存在下進行。
  10. 如請求項9之方法，其中該鈀羰化觸媒係二乙酸鈀(II)，且該雙齒膦配體係1,1'-雙-(二苯基膦基)二茂鐵或1,3-雙-(二苯基膦基)丙烷。
  11. 如請求項9或10之方法，其中該反應係於二甲基甲醯胺 中進行。
  12. 如請求項9至11中任一項之方法，其中該鹼係選自N,N-二異丙基乙胺、吡啶及N,N-二異丙基乙胺及吡啶之混合物。
  13. 一種製造式I-6化合物之方法： 該方法包括還原如請求項8中所定義之式I-3化合物。
  14. 如請求項13之方法，其中式I-3化合物之還原作用係藉由以下步驟進行：a)使該式I-3化合物與LiOH、NaOH或KOH反應，以獲得式I-4化合物： b)於極性非質子性溶劑或極性非質子性溶劑混合物中，於鹼、選自由N,N'-二環己基碳化二亞胺、1-乙基-3-(3-二甲胺基丙基)碳化二亞胺、丙基膦酸酐、O-(7-氮雜苯并***-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸鹽及碳酸N,N'-二琥珀醯亞胺酯組成之群之活性劑之存在 下，及視需要於1-羥基苯并***或1-羥基-7-氮雜苯并***之存在下，使該式I-4化合物與N,O-二甲基羥胺或其鹽反應，以獲得式I-5a： 或於極性非質子性溶劑或極性非質子性溶劑混合物中，於鹼、選自由N,N'-二環己基碳化二亞胺、1-乙基-3-(3-二甲胺基丙基)碳化二亞胺、丙基膦酸酐、O-(7-氮雜苯并***-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸鹽及碳酸N,N'-二琥珀醯亞胺酯組成之群之活性劑之存在下，及視需要於1-羥基苯并***或1-羥基-7-氮雜苯并***之存在下，使該式I-4化合物與嗎啉或其鹽反應，以獲得式I-5b： 或於極性非質子性溶劑或極性非質子性溶劑混合物中，使該式I-4化合物與草醯氯或亞硫醯氯反應，且使因此獲得的中間體與N,O-二甲基羥胺反應，以獲得 式I-5a化合物；或於極性非質子性溶劑或極性非質子性溶劑混合物中，使該式I-4化合物與草醯氯或亞硫醯氯反應，且使因此獲得的中間體與嗎啉反應，以獲得式I-5b化合物；及c)於極性非質子性溶劑或極性非質子性溶劑混合物中，使該式I-5a或I-5b化合物與選自氫化二異丁基鋁、LiAlH4及雙(2-甲氧基乙氧基)氫化鋁鈉之還原劑反應，以獲得式I-6化合物。
  15. 如請求項14之方法，其中式I-3化合物之還原作用係使用氫化二異丁基鋁進行。
  16. 如請求項15之方法，其中步驟c)中所使用的極性非質子性溶劑或極性非質子性溶劑混合物係選自二氯甲烷及二氯甲烷與己烷、庚烷、環己烷及甲苯其中一者或多者之混合物。
TW101133871A 2011-09-16 2012-09-14 製造合成之中間體之方法 TW201313726A (zh)

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