TWI810675B - 用於合成鞘胺醇-1-磷酸酯受體促效劑的中間體的製造方法 - Google Patents
用於合成鞘胺醇-1-磷酸酯受體促效劑的中間體的製造方法 Download PDFInfo
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- TWI810675B TWI810675B TW110138010A TW110138010A TWI810675B TW I810675 B TWI810675 B TW I810675B TW 110138010 A TW110138010 A TW 110138010A TW 110138010 A TW110138010 A TW 110138010A TW I810675 B TWI810675 B TW I810675B
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- 238000000034 method Methods 0.000 title claims abstract description 18
- 229940121846 Sphingosine 1-phosphate receptor agonist Drugs 0.000 title description 2
- 230000002194 synthesizing effect Effects 0.000 title description 2
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- 238000006243 chemical reaction Methods 0.000 claims description 24
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
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- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
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- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 1
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- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
- C07C45/676—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton by elimination of carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/29—Saturated compounds containing keto groups bound to rings
- C07C49/303—Saturated compounds containing keto groups bound to rings to a six-membered ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/29—Saturated compounds containing keto groups bound to rings
- C07C49/337—Saturated compounds containing keto groups bound to rings containing hydroxy groups
- C07C49/345—Saturated compounds containing keto groups bound to rings containing hydroxy groups polycyclic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/62—Use of additives, e.g. for stabilisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/28—Hydrogenated naphthalenes
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本發明係關於一種用於合成鞘胺醇-1-磷酸酯受體促效劑的中間體的製造方法。更具體而言,本發明係關於一種新的製備方法,該製備方法能夠在溫和條件下以簡單的製程以高產率(yield)大量生產下式5之中間體化合物:
其中,
R1和R2各自獨立地為氫、烷基、鹵素、鹵烷基或烷氧烷基。
鞘胺醇-1-磷酸(S1P)係經由細胞內神經醯胺途徑所產生,其中,神經醯胺為起始材料。神經醯胺是經由兩種途徑所產生的,其中第一種是重新生合成(de novo biosynthetic)途徑。神經醯胺亦為藉由降解細胞中細胞膜成分的神經鞘磷脂產生。各組織中的S1P量級係藉由兩種生物合成鞘胺醇激酶(SphK)
和兩種可生物降解的S1P磷酸酶(S1P裂解酶和溶血磷脂磷酸酶)所控制。已知藉由鞘胺醇激酶磷酸化鞘胺醇所產生的S1P調控各種細胞反應,例如細胞增殖、細胞骨架組織和遷移、黏附和緊密連接組裝以及形態發生。S1P以與包括白蛋白的血漿蛋白質的結合形式存在於血漿中為高量級(100至1,000nM)而在組織中為低量級。
S1P與S1P受體(一種G蛋白偶聯受體)結合以顯示各種生物學功能。作為S1P受體亞型,迄今為止已知的S1P1至S1P5分別被命名為內皮分化基因(EDG)受體1、5、3、6和8。已知S1P受體參與各種生物學功能,例如白血球再循環、神經細胞增殖、形態變化、遷移、內皮功能、血管調節(vasoregulation)和心血管發育。
近年來,許多研究發現經由這些受體之S1P訊號過程在一系列包含發炎反應及修復過程之有關多發性硬化症之反應中扮演重要角色,且非選擇性S1P1促效劑實際上已被批准作為多發性硬化症之治療劑。S1P受體在與多發性硬化症誘導相關的許多細胞中廣泛表達。特別地,S1P1受體在免疫系統中有主要作用。S1P1受體主要表達於淋巴細胞表面,例如T細胞和B細胞,且對S1P作出反應從而參與淋巴細胞的再循環。正常情況下,體液中的S1P濃度較高於淋巴組織,且因此淋巴細胞藉由S1P濃度的差異離開淋巴組織,在輸出淋巴循環後循環。然而,如果淋巴細胞中的S1P1受體被S1P1促效劑下調,則不發生淋巴細胞從淋巴組織中流出,導致自體侵襲性(autoaggressive)淋巴細胞浸潤減少,從而導致中樞神經系統(CNS)發炎和組織損傷。結果,獲得對多發性硬化症的治療效果。芬戈莫德(Fingolimod)為一種非選擇性S1P1促效劑,已被批
准作為治療多發性硬化症的口服藥。當其與S1P1受體結合被激活時,該受體反效果地從淋巴細胞表面降解或內化,從而發揮功能性的S1P1拮抗作用。
關於這種S1P受體,韓國專利申請公開案第10-2014-0104376號揭露下式1之新型化合物,其為有效於作為S1P受體促效劑:
其中,
X代表C或N,
R1代表H或任選的經取代的烷基,
R2代表H、任選的經取代的烷基、鹵素、CN、CF3或COCF3,
W代表C、N、C-烷氧基、C-鹵素或C-CN,
S係選自以下殘基:
其中,
m和n獨立地代表0、1、2或3,
R3至R10獨立地代表H、烷基、鹵素、鹵烷基或烷氧烷基,
上述文件的一具體實例中揭露根據以下反應式1製備1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸(反應式1中之「SG35」係指「1-氯-6-羥基-3,4-二氫-萘-2-甲醛」)。
在上述反應式1中,製備1-氯-6-羥基-3,4-二氫-萘-2-甲醛之步驟可詳細描述於以下反應式2。
首先,在0℃將N,N-二甲基甲醯胺(DMF)和氯化磷醯(POCl3)滴加至其中有6-甲氧基-3,4-二氫萘-1(2H)-酮(6-methoxy-3,4-dihydronaphthalen-1(2H)-one)溶解於甲苯中的溶液,隨後在70℃攪拌6小時。將反應混合物倒入冰中並用乙酸乙酯萃取。將有機層用鹽水洗滌、乾燥及濃縮,由矽凝膠管柱層析法(己烷:乙酸乙酯=20:1至10:1)將結果之殘留物純化,以獲得1-氯-6-甲氧基-3,4-二氫-2-萘甲醛。
接著,在0℃將氯化鋁(AlCl3)加入至二氯甲烷中的1-氯-6-甲氧基-3,4-二氫-2-萘甲醛之溶液,然後在50℃攪拌6小時。將反應混合物倒入冰中
並用乙酸乙酯萃取。將有機層乾燥及濃縮,由矽凝膠管柱層析法(己烷:四氫呋喃=5:1至3:1將結果之殘留物純化,以獲得1-氯-6-羥基-3,4-二氫-2-萘甲醛。
然而,在維爾斯邁爾-哈克(Vilsmeier-Haack)反應獲得1-氯-6-甲氧基-3,4-二氫-2-萘甲醛時,由於其在70℃之高溫反應,可能導致放熱問題,並且由於總產率為80%,需要提高產率。此外,在獲得1-氯-6-羥基-3,4-二氫-2-萘甲醛之反應中,可能由於使用AlCl3導致反應器污染問題,或由於使用危險試劑導致安全問題。在使用AlCl3時,根據反應停止或副反應進度,可能會因發生批次失敗而導致穩定性問題,且由於總產率為70%,有需要提高產率。
因此,本發明的技術課題是提供一種適合用於藉由更簡單的製程以高產率大量生產式5之化合物的方法,該式5之化合物是合成優良的鞘胺醇-1-磷酸酯受體促效劑之關鍵中間體。
為了解決上述技術課題,本發明提供一種用於製備下式5之中間體化合物之方法,包括以下步驟:
i)藉由在有機溶劑中使式2之化合物與乙醯化劑和鹼反應製備式3之化合物的步驟;
ii)藉由該式3之化合物的維爾斯邁爾-哈克反應製備式4之化合物的步驟;以及
iii)藉由從該式4之化合物中移除乙醯基製備式5之化合物的步驟:
其中,
R1和R2各自獨立地為氫、烷基、鹵素、鹵烷基或烷氧烷基。
以下詳細地描述本發明。
根據本發明之一實施例,在上式中,R1和R2各自獨立地為氫、C1-C6烷基、鹵素、鹵-C1-C6烷基或C1-C6烷氧基-C1-C6烷基。
根據本發明之另一實施例,在上式中,R1和R2各自獨立地為氫或C1-C4烷基。
在本發明之製備方法中,在步驟(i)中,該式3之化合物係經由該式2之化合物與乙醯化劑和鹼在有機溶劑中反應所製備。
在根據本發明之之另一實施例中,步驟(i)可為選自例如二氯甲烷(DCM)、二氯乙烷(DCE)、甲苯、乙腈(ACN)及其混合物中之一者或多者。
在根據本發明之另一實施例中,步驟(i)之乙醯化劑可為氯化乙醯或乙酐。
在根據本發明之另一實施例中,步驟(i)之鹼可為選自三乙胺(TEA)、N,N-二異丙基乙胺(DIPEA)、1,8-二氮雜二環[5.4.0]十一碳-7-烯(DBU)、氫氧化鈉(NaOH)、碳酸鉀(K2CO3)、碳酸鈉(Na2CO3)及其混合物中之一者或多者。
在揭露之製備方法中,在步驟(ii)中,該式4之化合物係經由該式3之化合物的維爾斯邁爾-哈克反應所製備。
在根據本發明之另一實施例中,在步驟(ii)中的該維爾斯邁爾-哈克反應可在30℃或更低之溫度進行,更佳為在20至25℃之溫度進行。
在本發明之製備方法中,在步驟(iii)中,該式5之化合物係經由脫保護所製備,其中從該式4之化合物移除乙醯基。
在根據本發明之另一實施例中,該乙醯基之移除可使用例如K2CO3進行。
在根據本發明之另一實施例中,用於移除該乙醯基之脫保護反應可在室溫進行。
在根據本發明之另一實施例中,步驟(iii)中所製備之該式5之化合物可直接結晶-例如-藉由逐滴加入鹽酸(HCl)而無需諸如乾燥或過濾之製程。
本發明之製備方法不使用會污染反應器的危險試劑,例如AlCl3,而且沒有反應停止或副反應之製程所導致的批次失敗的問題。結果,本發明之該製備方法在保證安全性和穩定性的同時,在室溫由進行維爾斯邁爾-哈克反應和進行脫保護反應,可在溫和的條件下以高產率提供式5之中間體之大量生產。
在下文中,藉由以下實例更詳細地解釋本發明。然而,必須理解的是,本發明的保護範圍並不限於實例。
實例1-1:乙酸5-側氧-5,6,7,8-四氫-萘-2-基酯之合成
將6-羥基-3,4-二氫-2H-萘-1-酮(3.9kg,24.07mol)和二氯甲烷(DCM,25.88kg)加入反應器,並將內部溫度冷卻至0℃。將氯化乙醯(AcCl,2.08kg,26.47mol)在10℃或以下緩慢逐滴加入,當添加完成後,將三乙胺(TEA,2.92kg,28.88mol)在10℃或以下逐滴加入以繼續進行反應。將內部溫度提升至
室溫,並將反應進行1小時。由HPLC進行離子對層析法(IPC),且反應完成(6-羥基-3,4-二氫-2H-萘-1-酮<1%)。藉由將19.5kg的純化水加入反應產物中終止反應。進行層分離以從上層移除水,並用19.5kg的純化水額外洗滌有機層,在減少的壓力下蒸餾以獲得標題化合物(4.66kg,淨產率:95%)。
1H NMR(400MHz,CDCl3):2.10(m,2H),2.30(s,3H),2.60(t,2H),2.95(t,2H),7.00(s,1H),7.05(d,1H),8.05(d,1H)
實施例1-2:1-氯-6-羥基-3,4-二氫-萘-2-甲醛之合成
將氯化磷醯(POCl3,10.5Kg,68.45mol)加入反應器,並將內部溫度冷卻至0℃。將二甲基甲醯胺(DMF,8.34kg,114.09mol)在10℃或以下緩慢逐滴加入,隨後攪拌30分鐘。將4.66Kg的5-側氧-5,6,7,8-四氫-萘-2-基酯在30℃或以下緩慢滴加至反應器,當添加完成後,將反應進行3小時。由HPLC進行IPC,且反應完成(乙酸5-側氧-5,6,7,8-四氫-萘-2-基酯<2%)。將46.60Kg的純化水和29.42kg的乙酸乙酯(EtOAc)加入另一個反應器,並將內部溫度冷卻至0℃。將上述溶液中緩慢逐滴加入以藉由分解剩餘的POCl3進行淬火。層分離後,將有機層收集在另一個反應器中,並將水層進一步用12.61kg EtOAc萃取。將水層移除,並將另一個反應器中的有機層加入。將所收集的有機層用23.30kg的純水洗滌,然後將其在減少的壓力下蒸餾以移除溶劑。將甲醇(MeOH,22.95Kg)和K2CO3(2.68Kg,19.39mol)加入殘留物中,並將該反應在室溫進行約2小時。由HPLC進行IPC,並且當該反應完成(乙酸5-氯-6-甲醯基-7,8-二氫萘-2-基酯<1%),將19.39Kg的3N鹽酸逐滴加入以繼續進行結晶。當晶體成
形,將晶體保持30分鐘、過濾,用24.31Kg的純化水洗滌並用氮氣乾燥以獲得標題化合物(4.31Kg,淨產率:90.5%)。
1H NMR(500MHz,CDCl3):2.30(s,3H),2.65(t,2H),2.85(t,2H),7.00(s,1H),7.05(m,1H),7.90(d,1H),10.40(s,1H)
Claims (10)
- 如請求項1所述的方法,其中,R1和R2各自獨立地為氫或C1-C4烷基。
- 如請求項1所述的方法,其中,步驟(i)的該有機溶劑係選自二氯甲烷、二氯乙烷、甲苯、乙腈及其混合物。
- 如請求項1所述的方法,其中,步驟(i)的該乙醯化劑係氯化乙醯或乙酐。
- 如請求項1所述的方法,其中,步驟(i)的該鹼係選自三乙胺、N,N-二異丙基乙胺、1,8-二氮雜二環[5.4.0]十一碳-7-烯、氫氧化鈉、碳酸鉀、碳酸鈉及其混合物。
- 如請求項1所述的方法,其中,步驟(ii)的該維爾斯邁爾-哈克反應係在30℃或以下之溫度所進行。
- 如請求項6所述的方法,其中,該維爾斯邁爾-哈克反應係在20至25℃之溫度進行。
- 如請求項1所述的方法,其中,在步驟(iii)中,該乙醯基之移除係使用K2CO3所進行。
- 如請求項1所述的方法,其中,步驟(iii)的反應係在室溫進行。
- 如請求項1所述的方法,其中,步驟(iii)中所製備的該式5之化合物係直接結晶。
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