TWI690524B - 氧雜螺環類衍生物的製備方法及其中間產物 - Google Patents
氧雜螺環類衍生物的製備方法及其中間產物 Download PDFInfo
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- TWI690524B TWI690524B TW107134070A TW107134070A TWI690524B TW I690524 B TWI690524 B TW I690524B TW 107134070 A TW107134070 A TW 107134070A TW 107134070 A TW107134070 A TW 107134070A TW I690524 B TWI690524 B TW I690524B
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- 208000005298 acute pain Diseases 0.000 description 1
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- 230000001404 mediated effect Effects 0.000 description 1
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- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
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- 238000012856 packing Methods 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
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- 239000011593 sulfur Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Engineering & Computer Science (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本發明涉及一種氧雜螺環類衍生物的製備方法及其中間產物,該方法縮短了反應步驟、提高了反應產率、簡單易操控、利於工業擴大生產。
Description
本申請要求申請日為2017年9月28日的中國專利申請CN201710896555.2的優先權。本申請引用上述中國專利申請的全文。
本發明涉及一種氧雜螺環類衍生物的製備方法及其中間產物。
術後疼痛是最常見的急性疼痛,常用藥物是鴉片類藥,如芬太尼、嗎啡、配西汀、羥考酮等,其鎮痛的藥理活性是透過激活表達於中樞神經系統以及腸胃道的細胞膜上的Gαi蛋白受體(μ鴉片受體,MOR),抑制神經纖維超極化來實現。鴉片受體是一類重要的G蛋白偶聯受體(G protein coupled receptor, GPCR),是內源性鴉片肽及鴉片類藥物結合的靶點,鴉片受體激活後對神經系統免疫及內分泌系統具有調節作用,鴉片類藥物是目前最強且常用的中樞鎮痛藥。內源性鴉片肽是哺乳動物體內天然生成的鴉片樣活性物質,目前已知的內源性鴉片肽大致分為腦啡肽、內啡肽、強啡肽和新啡肽幾類(Pharmacol Rev 2007; 59: 88-123)。中樞神經系統中存在其相應的鴉片受體,即μ(MOR)、δ(DOR)、κ(KOR)受體等。MOR是內源性腦啡肽和嗎啡等鴉片類鎮痛藥物的作用標的。
鴉片類藥物長期使用會產生耐受以及呼吸抑制、便秘等副作用,而這些副作用被證明與β-arrestin的功能密切相關。為了減小鴉片類藥物的副作用,可基於MOR的負性β-arrestin偏愛性配體設計藥物,使β-arrestin介導的副作用降低,增強治療效果,對於本發明的氧雜螺環類衍生物在作為MOR選擇性藥物的研究中,TrevenaInc公司研究發現芳基苄位取代時活性較差(J.Med.Chem.2013,56,8019−8031);專利申請WO2017063509A1(公開日2017-04-20)公開了單一構型的MOR化合物(式(III)所示),化學名為(1S
,4S
)-4-乙氧基-N
-(2-((R
)-9-(吡啶-2-基)-6-氧雜螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氫萘-1-胺的化合物,其製備方法如下, 。
該方法存在批量小、後處理方法使用手性色譜柱分離提純、薄層色譜法純化、產率低等問題,其中製備化合物19的反應產率僅為35%;在製備5a化合物中所用的還原劑DIBAL是一種危險易燃試劑,並且,反應過程中產生較大的雜質,不利於工業擴大生產,有必要改進其製備方法。
本發明提供一種用於製備D1所示化合物或其鹽的方法,其包括:式D所示化合物或其鹽經手性拆分的步驟,所述手性拆分方法優選自色譜拆分法(如手性高效液相法HPLC)或化學拆分法(如使用手性拆分劑拆分),其中,R選自芳基或雜芳基,所述芳基或雜芳基任選被選自烷基、鹵代烷基、鹵素、胺基、硝基、氰基、側氧基、烯基、鹵代烷氧基、羥烷基、環烷基、雜環基、芳基、雜芳基、OR3
、C(O)R3
、C(O)OR3
、S(O)m
R3
或NR4
R5
中的一個或多個取代基所取代; R3
選自氫原子、烷基、氘代烷基、胺基、烷氧基、羥烷基、環烷基、雜環基、芳基或雜芳基,其中所述的烷基、環烷基、雜環基、芳基和雜芳基任選被選自烷基、鹵素、羥基、胺基、硝基、氰基、烷氧基、羥烷基、環烷基、雜環基、芳基或雜芳基中的一個或多個取代基所取代; R4
和R5
各自獨立地選自氫原子、烷基、烷氧基、羥烷基、羥基、胺基、羧酸酯基、環烷基、雜環基、芳基或雜芳基,其中所述的烷基、環烷基、雜環基、芳基和雜芳基任選被選自烷基、鹵素、羥基、胺基、羧酸酯基、硝基、氰基、烷氧基、羥烷基、環烷基、雜環基、芳基或雜芳基中的一個或多個取代基所取代; m為0、1或2。
在一些實施方案中,手性拆分法中所用拆分劑為鹼性手性拆分劑,可以為S-
苯乙胺、奎尼丁、辛可尼汀或精胺酸。
在一些實施方案中,手性拆分法中所用拆分劑為S-
苯乙胺。
在一些實施方案中,水解反應所用鹼選自氫氧化鈉、氫氧化鉀或氫氧化鋰等。
本發明還提供用於製備式D1-1所示化合物的方法,包括:包括式D所示化合物與手性拆分劑M反應得到式D1-1所示化合物的步驟,所述手性拆分劑優選鹼性手性拆分劑,更優選S-
苯乙胺、奎尼丁、辛可尼汀或精胺酸,, 其中,R如式D1中所定義。
本發明還提供了用於製備式B所示化合物或其立體異構體的方法,其包括:式D所示化合物或其立體異構體通過一步或一步以上反應製備得式B所示化合物或其立體異構體的步驟,, 其中,R如式D1所示化合物中所定義,優選自。
本領域中,由含有羧基的化合物經還原得到含有醛基的化合物有諸多熟知的方法,通常經由一步反應、兩步反應或兩步以上的反應製備含有醛基的化合物,本發明優選兩步反應製備得到含有醛基的化合物。
在一些實施方案中,製備式B所示化合物或其立體異構體的方法還包括前述製備式D1所示化合物或其鹽的方法步驟。
在一些實施方案中,製備式C2所示化合物的方法還包括前述製備式D-1所示化合物方法的步驟。
本發明還提供了用於製備式I所示化合物或其鹽的方法,其包括式D所示化合物或其立體異構體反應後得到式B所示化合物或其立體異構體,式B所示化合物或其立體異構體與式A所示化合物或其立體異構體反應得到式I所示化合物的步驟,, 其中,R1選自氫原子或烷基;R2選自任選取代的芳基或雜芳基,所述取代基選自氫原子、烷基、鹵代烷基、鹵素、胺基、硝基、氰基、側氧基、烯基、鹵代烷氧基、羥烷基、環烷基、雜環基、芳基、雜芳基、-OR3、-C(O)R3、-C(O)OR3、-S(O)mR3或-NR4R5,其中所述的烷基、烷氧基、烯基、鹵代烷基、環烷基、雜環基、芳基和雜芳基任選被選自氘原子、烷基、鹵代烷基、鹵素、胺基、硝基、氰基、羥基、烷氧基、鹵代烷氧基、羥烷基、環烷基、雜環基、芳基或雜芳基中的一個或多個取代基所取代;n選自0、1、2或3;R、R3、R4、R5、m如式D1所示化合物所定義。
在一些實施方案中,製備式I所示化合物或其鹽的方法還包括前述製備式D1所示化合物或其鹽的方法步驟。
在一些實施方案中,製備式I所示化合物或其鹽的方法還包括前述製備式B所示化合物或其立體異構體的方法步驟。
優選地,用於製備式III所示化合物的方法,包括: 第一步、中間產物D-1的合成 式(E)所示化合物在有機溶劑中與鹼反應、水解成式D-1所示化合物;所述鹼性條件優選氫氧化鈉、氫氧化鉀或氨水。
第二步、中間產物D2-1的合成 式D-1所示化合物在醇類溶劑中與手性拆分試劑反應生成式D2-1所示化合物;所述手性拆分試劑優選鹼性手性拆分劑,更優選S-苯乙胺、奎尼丁、辛可尼汀或精胺酸;所述醇類溶劑優選甲醇、乙醇或異丙醇。
第三步、中間產物D2的合成 在鹼性條件下將式D2-1所示化合物游離,得到式D2所示化合物;所述鹼性條件優選氫氧化鈉、氫氧化鉀或氨水。
第四步、中間產物C2的合成 式D2所示化合物與N,O-二甲羥胺鹽酸鹽、1-(3-二甲胺基丙基)-3-乙基碳二亞胺鹽酸鹽、4-二甲胺基吡啶在鹼性條件下反應得式C2所示化合物;所述鹼性條件優選N,N-二異丙基乙胺、三乙胺或二異丙胺。
第五步、中間產物B2的合成 式C2所示化合物與還原劑反應得式B2所示化合物;所述還原劑優選紅鋁。
第六步、式(III)所示化合物的合成 式B2所示化合物與式A1所示化合物反應得到式III所示化合物。
本發明還提供一種製備式I、式II、式III、式IV所示化合物的藥學上可接受的鹽的方法,包括前述方案中的步驟,以及通過式I、式II、式III、式IV所示化合物與酸反應製備得到其藥學上可接受的鹽的步驟,所述酸選自有機酸或無機酸,優選有機酸;所述有機酸選自乙酸、馬來酸、富馬酸、酒石酸、檸檬酸、甲磺酸、苯磺酸或對甲苯磺酸,優選富馬酸;所述無機酸選自鹽酸、氫溴酸、硫酸或磷酸。
術語:本發明所述“鹵素或鹵素原子”是指氟原子、氯原子、溴原子、碘原子等。
本發明所述“烷基”是指直鏈或支鏈的含有1-20個碳原子的烷基,包括例如“C1-6
烷基”、“C1-4
烷基”等,具體實例包括但不限於:甲基、乙基、正丙基、異丙基、正丁基、異丁基、二級丁基、三級丁基、正戊基、異戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、異己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本發明所述“烯基”是指含有至少一個雙鍵且碳原子數為2-20的直鏈或支鏈的基團,包括例如“C2-6
烯基、C2-4
烯基”等。其實例包括但不限於:乙烯基、丙烯基、2-丁烯基、2-戊烯基、3-戊烯基、2-己烯基、3-己烯基等。
本發明所述的“鹵代烷基”指一個或多個“鹵素原子”取代“烷基”上的一個或多個氫原子所衍生的基團,所述“鹵素原子”和“烷基”如前文所定義。
本發明所述的“羥基烷基或羥烷基”指一個或多個“羥基”取代“烷基”上的一個或多個氫原子所衍生的基團,所述“烷基”如前文所定義。
本發明所述的“烷氧基、鹵代烷氧基、烷基羰基、烷氧羰基、烷氧羰基、羰基烷氧基、烷基羰基胺基、烷基胺基羰基、烷基胺基、二烷基胺基、烷基磺醯胺基或烷基磺醯基”是指以烷基-O-、鹵代烷基-O-、烷基-C(O)-、烷基-O-C(O)-、C(O)-烷基-O-、烷基-C(O)-NH-、烷基-NH-C(O)-、烷基-NH-、(烷基)2
-N-、烷基-S(O)2
-NH-或烷基-S(O)2
-方式連接的基團,其中“烷基、鹵代烷基”如前文所定義。
本發明所述的“側氧基”指=O。
本發明所述“環烷基”是指飽和或部分不飽和單環或多環環狀烴取代基,其包括3至20個碳原子,優選包括3至12個碳原子,更優選環烷基環包含3至10個碳原子,最優選環烷基環包含3至6個碳原子。單環環烷基的非限制性實施例包含環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等,優選環丙基、環己烯基。多環環烷基包括螺環、稠環和橋環的環烷基。
本發明所述的“芳基”指具有共軛的π電子體系的6至14元全碳單環或稠合多環(也就是共享毗鄰碳原子對的環)基團,優選為6至10元的芳基,更優選苯基、萘基、二氫萘基、四氫萘基、茚基或茀基,最優選苯基。
本發明所述的“雜環基”指飽和或部分不飽和單環或多環環狀烴取代基,其包括3至20個環原子,其中至少一個環原子為雜原子,例如氮原子、氧原子或硫原子,其餘環原子為碳;任選地,環狀結構中的環原子(例如碳原子、氮原子或硫原子)可以被氧化。優選包括3至12個環原子或5至12個環原子,其中1-4個是雜原子,更優選雜環基環包含3至8個環原子,更優選雜環基環包含5至6個環原子。單環雜環基的非限制性實施例包含吡咯烷基、哌啶基、哌基、嗎福林基、硫代嗎福林基、高哌基、吡喃基、二氫呋喃基、四氫呋喃基等。多環雜環基包括螺環、稠環和橋環的雜環基。
本發明所述的“雜芳基”指具有1至4個雜原子作為環原子,其餘的環原子為碳的5至14元芳基,其中雜原子包括氧、硫或氮。優選為5至10元的雜芳基,更優選為5元至6元的雜芳基,具體實例包括但不僅限於呋喃基、噻吩基、吡咯基、噻唑基、異噻唑基、噻二唑基、噁唑基、異噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、、二氫吲哚基、2-吡啶酮基、4-吡啶酮基、嘧啶基、嗒基、吡基、1,2,3-三基、1,3,5-三基、1,2,4,5-四基、氮雜環庚三烯基、1,3-二氮雜環庚三烯基、氮雜環辛四烯基等;所述雜芳基還可以稠合於芳基、雜環基或環烷基環上。
本發明所述的“碳原子、氮原子或硫原子被氧代/氧化”是指形成C=O、N=O、S=O或SO2
的結構。
本發明所述的“醇類溶劑”是指一個或多個“羥基”取代“C1-6
烷基”上的一個或多個氫原子所衍生的基團,所述“羥基”和“C1-6
烷基”如前文所定義,具體實例包括但不限於:甲醇、乙醇、異丙醇、正丙醇、異戊醇或三氟乙醇。
本發明所述的“立體異構”分為構象異構(conformational isomers)和組態異構(configurational isomers),而組態異構還分為順反異構和旋光異構(或對映異構)。構象異構是指具有一定構型的有機物分子由於碳、碳單鍵的旋轉或扭曲而使得分子各原子或原子團在空間產生不同的排列方式的一種立體異構現象,常見的有烷烴和環烷烴類化合物的結構,如環己烷結構中出現的椅式構象和船式構象。“旋光異構體(或對映異構體)”,指當本發明化合物含有一個或多個不對稱中心,因而可作為外消旋體和外消旋混合物、單一對映異構體、非對映異構體混合物和單一非對映異構體。本發明化合物有不對稱中心,這類不對稱中心各自會獨立地產生兩個光學異構體,本發明的範圍包括所有可能的光學異構體和非對映異構體混合物和純的或部分純的化合物。本發明所述的化合物若含有烯烴雙鍵,除非特別說明,本發明包括順式異構體和反式異構體。本發明所述的化合物可以以互變異構體形式存在,其通過一個或多個雙鍵位移而具有不同的氫的連接點。例如,酮和它的烯醇形式是酮-烯醇互變異構體。各互變異構體及其混合物都包括在本發明中。對映異構體、非對映異構體、外消旋體、內消旋體、順反異構體、互變異構體、幾何異構體、差向異構體及其混合物,均包括在本發明範圍中。
化合物的結構是通過核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移以10-6 (ppm)的單位给出。NMR的測定是用Bruker AVANCE-400核磁儀,測定溶劑为氘代試劑,内標為四甲基矽烷(TMS)。
MS的測定用FINNIGAN LCQAd (ESI)質譜儀(生產商: Thermo, 型號:Finnigan LCQ advantage MAX)。
HPLC的測定使用安捷倫1200DAD高壓液相色譜儀和Waters 2695-2996高壓液相色譜儀,以十八烷基矽烷鍵合矽膠為色譜柱填料。
本「先前技術」段落只是用來幫助瞭解本發明內容,因此在「先前技術」中所揭露的內容可能包含一些沒有構成所屬技術領域中具有通常知識者所知道的習知技術。此外,在「先前技術」中所揭露的內容並不代表該內容或者本發明一個或多個實施例所要解決的問題,也不代表在本發明申請前已被所屬技術領域中具有通常知識者所知曉或認知。
以下結合實施例用於進一步描述本發明,但這些實施例並非限制本發明的範圍。
第一步、中間產物(D-1)的合成 將式(E1)所示化合物(25g)、氫氧化鉀(22.4g)和乙二醇(150mL)混合,在150℃下攪拌16小時,停止反應。反應液冷卻至室溫,加入水(150mL)稀釋,用二氯甲烷萃取(150mL×2),水相用3M
的鹽酸調節pH為6~7,用二氯甲烷萃取(200mL×4),合併有機相,用飽和氯化鈉溶液洗滌(200mL),無水硫酸鈉乾燥,過濾,濾液減壓濃縮,得到產物(26.1g,淡黃色油狀物),產率97.4%,HPLC純度92%。
第二步、中間產物(D2-1)的合成 將式(D-1)所示化合物(28g)溶於無水乙醇(100mL)中,升溫至50℃,將拆分試劑S-
苯乙胺(6.2g)溶於無水乙醇(100mL)中,50℃下將S-
苯乙胺溶液滴入上述溶液中,升溫至回流,攪拌2小時。自然降溫至10℃,固體析出,過濾,洗滌,得到產物(13g,固體),ee值:96.7%; 重結晶:將13g固體加入無水乙醇(80mL)中,升溫至回流,攪拌6小時,自然冷卻至10℃,固體析出,過濾,洗滌,乾燥,得到產物(10.6g),ee值:99.0%。
第三步、中間產物(D2)的合成 將KOH(2.18g)溶於水(120mL)中,將式(D2-1)所示化合物溶於該溶液中,二氯甲烷萃取(100mL×3),用1N HCl溶液調節水相pH值至6~7,二氯甲烷萃取(150mL×3),合併有機相,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,得到產物(7g),產率50%。ee值:99.4%; MS m/z (ESI): 276.71 [M+H]+
,298.68 [M+Na]+
; 1H NMR (400 MHz, CDCl3) δ 8.50-8.51(m, 1H), 7.73-7.77(m, 1H), 7.51-7.53(d, 1H), 7.21-7.24(m, 1H), 3.73-3.84(m, 2H), 2.78-2.81(d, 1H), 2.58-2.63(m, 1H), 2.53-2.56(d, 1H), 2.39-2.43(m, 1H), 1.98-2.02(d, 1H), 1.87-1.94(m, 1H), 1.76-1.80(m, 1H), 1.61-1.65(m, 1H), 1.39-1.58(m, 4H), 1.14-1.19(m, 1H), (m, 1H), (m, 1H)。
第四步、中間產物(C2)的合成 在反應瓶中加入二氯甲烷(8.5kg),攪拌下加入原料(R
)-2-(9-(吡啶-2-基)-6-氧雜螺[4.5]癸烷-9-基)乙酸(350g)、N,O-二甲羥胺鹽酸鹽(148.8g)、EDCI(292.3g)、DMAP(15.5g),攪拌15~25min後加入DIPEA(492.4g),氬氣保護,室溫攪拌反應16~18h,反應液加入飽和氯化銨水溶液(2.8kg),攪拌5~10min後分液;有機相用飽和氯化銨水溶液(2.8kg×2)洗滌,飽和食鹽水(2.7kg)洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮幹,再加入二氯甲烷(2.5kg)繼續減壓濃縮至乾得油狀物(372.03g),產率92.0%。 MS m/z (ESI): 319.1 [M+H]+
,341.3 [M+Na]+
; 1H NMR (400 MHz, CDCl3) δ 8.50-8.51(m, 1H), 7.66-7.71 (m, 1H), 7.43-7.45 (d, 1H), 7.15-7.18(m, 1H), 3.63-3.66(m, 2H), 3.47(s, 3H), 2.86-2.88 (d, 3H), 2.62-2.65 (d, 1H), 2.50-2.57(m, 1H), 2.36-2.39(d, 1H), 1.96-2.00 (d, 1H), 1.80-1.86 (m, 1H), 1.68-1.72 (m, 1H), 1.48-1.55 (m, 1H), 1.31-1.46 (m, 4H), 1.03-1.07 (m, 1H), 0.63-0.71 (m, 1H) 。
第五步、中間產物(B2)的合成 在反應瓶中將式(C2)所示化合物(334.4g)溶於甲苯(2.2kg)中,冷卻至-45℃~-35℃,氬氣保護,控制滴加溫度-45~-35℃,滴加紅鋁(348.76g),加畢於-45~-35℃攪拌反應3~4h,然後在-45~-35℃向反應液中滴加10%的檸檬酸水溶液(1kg),再加入濃鹽酸溶液調節pH至2~3,加入乙酸乙酯(1.8kg),攪拌,靜置分層,水相用5 N氫氧化鈉溶液調pH至11~13,用二氯甲烷萃取(3.3kg×2),合併二氯甲烷層,用飽和氯化鈉溶液(2.7kg)洗滌,用無水硫酸鈉乾燥,過濾,濾液減壓濃縮,再加入二氯甲烷(3.3kg)繼續減壓濃縮,得淡紅色油狀物,直接投入下一步反應。
第六步、式(III)所示化合物的合成 將上述油狀物加入到反應瓶中,再將二氯甲烷(8.5kg)、式(A1)所示化合物(134.56g)加入反應瓶中,攪拌反應2~3h,反應液中加入三乙醯氧基硼氫化鈉(373.86g),室溫攪拌反應16~18h,加入飽和碳酸鈉溶液(2.66kg),再用5N氫氧化鈉水溶液調pH至11~13,分層,有機相用飽和氯化銨水溶液(2.83kg)洗滌,飽和氯化鈉水溶液(2.74kg)洗滌,用無水硫酸鈉乾燥,過濾,濾液減壓濃縮乾,加入乙腈(120g),室溫攪拌16~18h析晶,過濾,乾燥得到產物(206.87g),產率68.0%。 MS m/z (ESI): 435.3 [M+H]+
;1
H NMR (400 MHz, CDCl3
) δ 9.74 (d, 1H), 9.58 (d, 1H), 8.94 (d, 1H), 8.37 (d, 1H), 7.94 (d, 1H), 7.67 (d, 1H), 7.52 (d, 1H), 7.47 (t, 1H), 4.46-4.49 (m, 1H), 4.30-4.33 (m, 1H), 3.84-3.87 (m, 1H), 3.66-3.70 (m, 2H), 3.53-3.56 (m, 2H), 2.82-2.85 (d, 2H), 2.67 (s, 2H), 2.39-2.41 (m, 4H), 2.30-2.33 (m, 4H), 1.85 (s, 2H), 1.48-1.52 (m, 6H), 1.27 (m, 3H)。
第一步、中間產物(D-1)的合成 將式(E1)所示化合物(13.5Kg;1.0eq)、氫氧化鉀(2.6 Kg;2.0eq)和乙二醇(135L;10vol)混合,升溫至在110℃下攪拌24小時,停止反應。減壓濃縮除掉乙醇;剩餘物中加入二氯甲烷(26L攪拌溶解);用飽和氯化鈉溶液洗滌(5L)洗滌兩次,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,得到產物(13kg,黃色油狀物),產率90%,HPLC純度95%。
第二步、中間產物(D2-1)的合成 將上步產物(13kg)溶於乙二醇(65L;5vol)中,升溫至50℃,將拆分試劑S-苯乙胺(5.7Kg;1.0eq)溶於乙二醇(1L)中,50℃下將S-苯乙胺溶液滴入上述溶液中,升溫至回流,攪拌3小時。自然降溫至室溫,固體析出,過濾,洗滌,得到產物(6600g,固體), 重結晶:將6600g固體加入乙二醇(3L)中,升溫至回流,攪拌6小時,自然冷卻至室溫,固體析出,過濾,洗滌,乾燥,得到產物(4700g),ee值:99.0%。
第三步、中間產物(D2)的合成 將4700g固體,加水溶解,再加氫氧化鉀1.2eq攪拌溶清,用30L*3二氯甲烷(DCM)萃取,除去有機相,用鹽酸將水相調節pH至6-7,用DCM 30L*5,合併有機相,乾燥,濃縮,得到產物3200g,ee值:99.42%,純度:99%。
惟以上所述者,僅為本發明之較佳實施例而已,當不能以此限定本發明實施之範圍,即大凡依本發明申請專利範圍及發明說明內容所作之簡單的等效變化與修飾,皆仍屬本發明專利涵蓋之範圍內。另外,本發明的任一實施例或申請專利範圍不須達成本發明所揭露之全部目的或優點或特點。此外,摘要部分和標題僅是用來輔助專利文件搜尋之用,並非用來限制本發明之權利範圍。
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Claims (28)
- 一種用於製備式D1所示化合物或其鹽的方法,
- 如申請專利範圍第1項所述的方法,其中所述手性拆分方法選自色譜拆分法或化學拆分法。
- 如申請專利範圍第1項所述的方法,其中所述化學拆分法所用拆分劑為鹼性手性拆分劑。
- 如申請專利範圍第3項所述的方法,其中所述鹼性手性拆分劑選自S-苯乙胺、奎尼丁、辛可尼汀或精胺酸。
- 如申請專利範圍第5項所述的方法,其中所述E所示化合物製備得式D所示化合物的反應條件選自鹼性水解。
- 如申請專利範圍第11項所述的化合物或其鹽,其中,所述M選自S-苯乙胺。
- 如申請專利範圍第13項所述的方法,其中還包括申請專利範圍第1-8項中任一項所述的方法步驟。
- 一種用於製備式I所示化合物或其鹽的方法,其包括式D所示化合物或其立體異構體反應後得到式B所示化合物或其立體異構體,式B所示化合物或其立體異構體與式A所示化合物或其立體異構體反應得到式I所示化合物的步驟,
- 如申請專利範圍第22項所述的方法,其還包括申請專利範圍第1-8項中任一項所述的方法步驟或申請專利範圍第13-18項中任一項所述的方法步驟。
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