TWI770093B - 製備苯并氧氮呯(benzoxazepin)噁唑啶酮化合物之方法 - Google Patents
製備苯并氧氮呯(benzoxazepin)噁唑啶酮化合物之方法 Download PDFInfo
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- TWI770093B TWI770093B TW106144193A TW106144193A TWI770093B TW I770093 B TWI770093 B TW I770093B TW 106144193 A TW106144193 A TW 106144193A TW 106144193 A TW106144193 A TW 106144193A TW I770093 B TWI770093 B TW I770093B
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- 238000000034 method Methods 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims description 7
- KVQCNKSKFIZOKW-UHFFFAOYSA-N O1C(NCC1)=O.O1N=CC=CC2=C1C=CC=C2 Chemical class O1C(NCC1)=O.O1N=CC=CC2=C1C=CC=C2 KVQCNKSKFIZOKW-UHFFFAOYSA-N 0.000 title abstract description 4
- 230000008569 process Effects 0.000 title description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 48
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000010949 copper Substances 0.000 claims description 13
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 11
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 11
- 229910052802 copper Inorganic materials 0.000 claims description 11
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 10
- 229940126657 Compound 17 Drugs 0.000 claims description 10
- 229910021529 ammonia Inorganic materials 0.000 claims description 10
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(i) oxide Chemical group [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 10
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical group [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 10
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 9
- 229940125773 compound 10 Drugs 0.000 claims description 9
- 229940126142 compound 16 Drugs 0.000 claims description 9
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 8
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 7
- 229940125758 compound 15 Drugs 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 7
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 5
- FRDZGSBXKJXGNR-HTQZYQBOSA-N (1r,2r)-2-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CN(C)[C@@H]1CCCC[C@H]1N FRDZGSBXKJXGNR-HTQZYQBOSA-N 0.000 claims description 4
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 claims description 4
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 claims description 4
- NPAXPTHCUCUHPT-UHFFFAOYSA-N 3,4,7,8-tetramethyl-1,10-phenanthroline Chemical compound CC1=CN=C2C3=NC=C(C)C(C)=C3C=CC2=C1C NPAXPTHCUCUHPT-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- XJMWHXZUIGHOBA-UHFFFAOYSA-N azane;propanoic acid Chemical compound N.CCC(O)=O XJMWHXZUIGHOBA-UHFFFAOYSA-N 0.000 claims description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims 4
- 229940126543 compound 14 Drugs 0.000 claims 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims 2
- 229940125797 compound 12 Drugs 0.000 claims 2
- XQISPVJWRLHHLT-UHFFFAOYSA-N 1-hydroxycyclohexa-2,4-diene-1-carboxylic acid Chemical compound OC(=O)C1(O)CC=CC=C1 XQISPVJWRLHHLT-UHFFFAOYSA-N 0.000 claims 1
- 230000000996 additive effect Effects 0.000 claims 1
- 150000003852 triazoles Chemical class 0.000 claims 1
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
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- 150000003839 salts Chemical class 0.000 description 20
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- KPGYPWXVADQHRR-REOHCLBHSA-N (4S)-4-(difluoromethyl)-1,3-oxazolidin-2-one Chemical compound FC([C@H]1NC(OC1)=O)F KPGYPWXVADQHRR-REOHCLBHSA-N 0.000 description 8
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- AEXFENNWPYZXMF-UHFFFAOYSA-N 8-bromo-2,3-dihydro-1,4-benzoxazepin-5-amine hydrochloride Chemical compound Cl.NC1=NCCOc2cc(Br)ccc12 AEXFENNWPYZXMF-UHFFFAOYSA-N 0.000 description 6
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- 229910019142 PO4 Inorganic materials 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
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- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
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- -1 benzoxazine oxazolidinone compound Chemical class 0.000 description 3
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- ODYBCPSCYHAGHA-ZYUZMQFOSA-N (1s,2s)-1,2-bis[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]ethane-1,2-diol Chemical compound O1C(C)(C)OC[C@@H]1[C@@H](O)[C@H](O)[C@@H]1OC(C)(C)OC1 ODYBCPSCYHAGHA-ZYUZMQFOSA-N 0.000 description 2
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- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
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- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical Kinetics & Catalysis (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本發明描述了製造苯并氧氮呯(BENZOXAZEPIN)噁唑啶酮化合物之方法，該等苯并氧氮呯噁唑啶酮化合物包括具有以下結構之化合物18
：
Description
本發明係關於製造苯并氧氮呯(BENZOXAZEPIN)噁唑啶酮化合物及有用的中間體之方法。
PI3激酶/Akt/PTEN途徑為癌症藥物開發之有吸引力的標靶，因為預計此類藥劑將抑制細胞增殖、阻遏來自支持癌細胞之存活及化學抗性的基質細胞之訊息、逆轉細胞凋亡之阻遏及克服癌細胞對細胞毒性劑之固有抗性。PI3K透過受體酪胺酸激酶傳訊以及活化PI3K之p110催化次單元之突變、腫瘤抑制基因PTEN之喪失或透過不常見的活化AKT之突變來活化。 苯并氧氮呯化合物具有作為PI3K α同功異型物之抑制劑的有效且選擇性的活性。命名為2-(4-(2-(1-異丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氫苯并[f]咪唑并[1,2-d][1,4]氧氮呯-9-基)-1H-吡唑-1-基)-2-甲基丙醯胺之他塞昔布(Taselisib) (GDC-0032，Roche RG7604，CAS登記號1282512-48-4, Genentech Inc.)具有有效的PI3K活性(Ndubaku, C. O.等人(2013) J. Med. Chem. 56:4597−4610；WO 2011/036280；US 8242104；US 8343955)，且正在患有局部晚期或轉移性實體瘤之患者中加以研究。他塞昔布(GDC-0032)為PI3K催化次單元之保留β-同功異型物之抑制劑(beta-isoform sparing inhibitor)，其對α次單元之選擇性相較於β為31倍大。與野生型PI3Kα相比，他塞昔布對突變型PI3Kα同功異型物展示更大的選擇性(Olivero AG等人, AACR 2013. 摘要 DDT02-01)。他塞昔布當前正在開發作為用於患有雌激素受體(ER)陽性、HER2陰性轉移性乳癌(mBC)及非小細胞肺癌(NSCLC)之患者的治療。存在對突變型PI3Kα同功異型物之新的選擇性抑制劑之需要。
本發明係關於製造苯并氧氮呯噁唑啶酮化合物之方法。 本發明之一態樣為一種用於製備具有以下結構之化合物18
之方法：
該方法包含使具有結構：
之化合物17
與N-羥基琥珀醯亞胺、氨及N
-(3-二甲基胺丙基)-N'
-乙基碳化二亞胺鹽酸鹽反應以形成化合物18
。 在一些實施例中，化合物17
藉由以下方法來製備，該方法包含使具有結構：
之化合物16
與(S
)-2-胺基丙酸及氧化銅(I)反應以形成化合物17
。 在一些實施例中，化合物16
藉由以下方法來製備，該方法包含使具有結構：
之化合物15
與具有結構：
之化合物10
、乙酸銅(II)及反式-N
,N
-二甲基環己烷-1,2-二胺反應以形成化合物16
。 在一些實施例中，化合物10
藉由包含以下之方法來製備： (a) 使具有結構：
之化合物6
與鄰苯二甲醯亞胺鉀反應以形成具有以下結構之化合物7：
； (b) 使化合物7
與肼在水中反應以形成具有以下結構之化合物8
：
； (c) 使化合物8
與鹽酸反應以形成具有以下結構之化合物9
：
；及 (d) 使化合物9
與三光氣反應以形成化合物10
。
相關申請案之交叉引用 本申請案主張2016年12月15日申請之美國臨時申請案第62/434,836號之優先權益，該申請案之內容據此以全文引用之方式併入。定義
術語「對掌性」係指分子具有與鏡像搭配物不可重疊之性質，而術語「非對掌性」係指分子可重疊於其鏡像搭配物上。 術語「立體異構物」係指具有相同化學組成，但在原子或基團於空間中之排列方面不同之化合物。 「非鏡像異構物」係指具有二或更多個對掌性中心且分子不互為鏡像之立體異構物。非鏡像異構物具有不同物理性質，例如熔點、沸點、光譜性質及反應性。非鏡像異構物之混合物可在諸如電泳及層析之高解析度分析程序下分離。 「鏡像異構物」係指化合物之兩個互為不可重疊鏡像之立體異構物。 本文中使用之立體化學定義及規則一般遵循S. P. Parker編輯,McGraw-Hill Dictionary of Chemical Terms
(1984) McGraw-Hill Book Company, New York；以及Eliel, E.及Wilen, S., 「Stereochemistry of Organic Compounds」, John Wiley & Sons, Inc., New York, 1994。本發明化合物可含有不對稱或對掌性中心(立體中心)，且因此以不同立體異構形式存在。預期本發明化合物之所有立體異構形式，包括但不限於非鏡像異構物、鏡像異構物及構型異構物，以及其混合物(諸如外消旋混合物)，皆形成本發明之一部分。許多有機化合物以光學活性形式存在，亦即其能夠使平面偏振光之平面旋轉。在描述光學活性化合物時，字首D及L或R
及S
用於表示分子圍繞其對掌性中心之絕對組態。字首d及l或(+)及(-)用於表明化合物使平面偏振光旋轉之記號，其中(-)或l意謂化合物為左旋的。字首為(+)或d之化合物為右旋的。對於既定化學結構，此等立體異構物為相同的，例外之處為其互為鏡像。特定立體異構物亦可稱為鏡像異構物，且此等異構物之混合物常稱為鏡像異構混合物。鏡像異構體之50:50混合物稱為外消旋混合物或外消旋物，其可在化學反應或過程中不存在立體選擇性或立體特異性時出現。術語「外消旋混合物」及「外消旋物」係指兩種鏡像異構物質之缺乏光學活性之等莫耳混合物。 術語「互變異構體」或「互變異構形式」係指具有不同能量之結構異構體，其可經由低能障壁相互轉化。舉例而言，質子互變異構體(亦稱為質子異變的互變異構體)包括經由質子遷移發生之相互轉化，諸如酮基-烯醇及亞胺-烯胺異構化。價態互變異構體包括藉由一些鍵接電子之重排發生之相互轉化。 如本文中所用之習語「醫藥學上可接受之鹽」係指本發明化合物之醫藥學上可接受之有機或無機鹽。示範性鹽包括但不限於硫酸鹽、檸檬酸鹽、乙酸鹽、草酸鹽、氯化物、溴化物、碘化物、硝酸鹽、硫酸氫鹽、磷酸鹽、酸式磷酸鹽、異菸酸鹽、乳酸鹽、水楊酸鹽、酸式檸檬酸鹽、酒石酸鹽、油酸鹽、丹寧酸鹽、泛酸鹽、酒石酸氫鹽、抗壞血酸鹽、琥珀酸鹽、馬來酸鹽、龍膽酸鹽(gentisinate)、富馬酸鹽、葡糖酸鹽、葡糖醛酸鹽、糖二酸鹽(saccharate)、甲酸鹽、苯甲酸鹽、麩胺酸鹽、甲烷磺酸鹽「甲磺酸鹽」、乙烷磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽及帕莫酸鹽(pamoate) (亦即1,1'-亞甲基-雙-(2-羥基-3-萘甲酸鹽))鹽。醫藥學上可接受之鹽可涉及包括另一分子，諸如乙酸根離子、琥珀酸根離子或其他相對離子。該相對離子可為使母體化合物上之電荷穩定的任何有機或無機部分。此外，醫藥學上可接受之鹽之結構中可具有一個以上帶電原子。多個帶電原子為醫藥學上可接受之鹽之一部分的情形可具有多個相對離子。因此，醫藥學上可接受之鹽可具有一或多個帶電原子及/或一或多個相對離子。 若本發明化合物為鹼，則所要醫藥學上可接受之鹽可藉由此項技術中可用之任何適合方法製備，例如用諸如鹽酸、氫溴酸、硫酸、硝酸、甲烷磺酸、磷酸及其類似酸之無機酸或用諸如乙酸、馬來酸、琥珀酸、扁桃酸、富馬酸、丙二酸、丙酮酸、草酸、乙醇酸、水楊酸、哌喃糖苷酸(pyranosidyl acid)(諸如葡糖醛酸或半乳糖醛酸)、α羥基酸(諸如檸檬酸或酒石酸)、胺基酸(諸如天冬胺酸或麩胺酸)、芳族酸(諸如苯甲酸或肉桂酸)、磺酸(諸如對甲苯磺酸或乙烷磺酸)或其類似酸之有機酸處理遊離鹼。 若本發明之化合物為酸，則所要醫藥學上可接受之鹽可藉由任何適合之方法製備，例如用諸如胺(一級、二級或三級胺)、鹼金屬氫氧化物或鹼土金屬氫氧化物或其類似鹼之無機或有機鹼處理遊離酸。適合的鹽之說明性實例包括但不限於衍生自胺基酸(諸如甘胺酸及精胺酸)、氨、一級胺、二級胺及三級胺、及環狀胺(諸如哌啶、嗎啉及哌嗪)之有機鹽，以及衍生自鈉、鈣、鉀、鎂、錳、鐵、銅、鋅、鋁及鋰之無機鹽。 「溶劑合物」係指一或多種溶劑分子與本發明化合物之締合物或錯合物。形成溶劑合物的溶劑之實例包括但不限於水、異丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸及乙醇胺。術語「水合物」係指溶劑分子為水之錯合物。 如本文中所用之習語「醫藥學上可接受之鹽」係指本發明化合物之醫藥學上可接受之有機或無機鹽。示範性鹽包括但不限於硫酸鹽、檸檬酸鹽、乙酸鹽、草酸鹽、氯化物、溴化物、碘化物、硝酸鹽、硫酸氫鹽、磷酸鹽、酸式磷酸鹽、異菸酸鹽、乳酸鹽、水楊酸鹽、酸式檸檬酸鹽、酒石酸鹽、油酸鹽、丹寧酸鹽、泛酸鹽、酒石酸氫鹽、抗壞血酸鹽、琥珀酸鹽、馬來酸鹽、龍膽酸鹽(gentisinate)、富馬酸鹽、葡糖酸鹽、葡糖醛酸鹽、糖二酸鹽(saccharate)、甲酸鹽、苯甲酸鹽、麩胺酸鹽、甲烷磺酸鹽「甲磺酸鹽」、乙烷磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽及帕莫酸鹽(pamoate) (亦即1,1'-亞甲基-雙-(2-羥基-3-萘甲酸鹽))鹽。醫藥學上可接受之鹽可涉及包括另一分子，諸如乙酸根離子、琥珀酸根離子或其他相對離子。該相對離子可為使母體化合物上之電荷穩定的任何有機或無機部分。此外，醫藥學上可接受之鹽之結構中可具有一個以上的帶電原子。多個帶電原子為醫藥學上可接受之鹽之一部分的情形可具有多個相對離子。因此，醫藥學上可接受之鹽可具有一或多個帶電原子及/或一或多個相對離子。苯并氧氮呯噁唑啶酮化合物之製備
本發明包括用於合成苯并氧氮呯噁唑啶酮化合物之製程、方法、試劑及中間體，該等苯并氧氮呯噁唑啶酮化合物包括具有以下結構之(S)-2-((2-((S)-4-(二氟甲基)-2-側氧基噁唑啶-3-基)-5,6-二氫苯并[f]咪唑并[1,2-d][1,4]氧氮呯-9-基)胺基)丙醯胺18
：
。 預期本發明化合物之所有立體異構形式，包括但不限於非鏡像異構物、鏡像異構物及構型異構物，以及其混合物(諸如外消旋混合物)，皆形成本發明之一部分。另外，本發明囊括所有幾何異構體及位置異構體。在本文中所示之結構中，在未指定任何特定對掌性原子之立體化學之情況下，所有立體異構體皆作為本發明化合物涵蓋且包括在內。在藉由表示特定組態之實心楔形或虛線來指定立體化學之情況下，則該立體異構體係如此指定及定義。 本發明化合物可以未溶劑化形式以及與醫藥學上可接受之溶劑(諸如水、乙醇及其類似物)之溶劑化形式存在，且預期本發明囊括溶劑化形式及未溶劑化形式兩者。 本發明化合物亦可以不同的互變異構形式存在，且所有此類形式皆囊括在本發明之範疇內。術語「互變異構體」或「互變異構形式」係指具有不同能量之結構異構體，其可經由低能障壁相互轉化。舉例而言，質子互變異構體(亦稱為質子異變的互變異構體)包括經由質子遷移發生之相互轉化，諸如酮基-烯醇及亞胺-烯胺異構化。價態互變異構體包括藉由一些鍵接電子之重排發生之相互轉化。 本發明化合物亦包括經同位素標記之化合物，其與本文中所述之彼等化合物相同，但以下事實除外：一或多個原子經原子質量或質量數不同於通常在自然界中所見之原子質量或質量數的原子置換。如所指定之任何特定原子或元素之所有同位素皆係涵蓋在本發明化合物及其用途之範疇內。可摻入本發明化合物中之示範性同位素包括氫、碳、氮、氧、磷、硫、氟、氯及碘之同位素，諸如2
H、3
H、11
C、13
C、14
C、13
N、15
N、15
O、17
O、18
O、32
P、33
P、35
S、18
F、36
Cl、123
I及125
I。某些經同位素標記之本發明化合物(例如，由3
H及14
C標記之彼等化合物)可用於化合物及/或受質組織分佈檢定。氚化(3
H)及碳-14(14
C)同位素因其製備簡便易行及可偵測性而加以使用。進一步地，用諸如氘(亦即，2
H)之較重同位素進行的取代可提供由於較大代謝穩定性(例如，活體內半衰期增加或劑量需求減少)所致之某些治療性優勢，且因此在某些情況下可能為較佳的。正電子發射同位素(諸如15
O、13
N、11
C及18
F)可用於正電子發射斷層攝影術(PET)研究以檢查受質受體佔有率。經同位素標記之本發明化合物通常可藉由按照與以下本文中實例中所揭示之彼等程序類似的程序，藉由用經同位素標記之試劑取代非經同位素標記之試劑來製備。 方案1及方案2中用於製備化合物之起始原料及試劑通常可自商業來源獲得或使用熟習此項技術者所熟知之方法來容易地製備(例如，藉由Louis F. Fieser及Mary Fieser,Reagents for Organic Synthesis
, 第1至19卷, Wiley, N.Y. (1967-1999編)或Beilsteins Handbuch der organischen Chemie
, 4, Aufl.編 Springer-Verlag, Berlin (包括增刊) (亦可經由拜斯坦線上資料庫(Beristein online database)獲得)中通常描述之方法來製備。 以下方案及實例說明用於合成苯并氧氮呯噁唑啶酮化合物之化學反應、製程及方法以及某些中間體及試劑。 方案1：
方案1顯示(S)-4-(二氟甲基)噁唑啶-2-酮10
之製備。將甘露醇(D-甘露醇，CAS登記號69-65-8)之雙丙酮化合物、(1S
,2S
)-1,2-雙((R
)-2,2-二甲基-1,3-二氧戊環-4-基)乙烷-1,2-二醇1
用過碘酸鈉氧化以形成(R
)-2,2-二甲基-1,3-二氧戊環-4-甲醛2
。使用二乙胺基三氟化硫(DAST)或其他氟化試劑諸如XtalFluor-E® (CAS登記號63517-29-3)或XtalFluro-M® (CAS登記號63517-33-9)對醛2
進行去氧氟化，產生(R
)-4-(二氟甲基)-2,2-二甲基-1,3-二氧戊環3
。在酸性條件下對3
進行丙酮化合物裂解，產生(R
)-3,3-二氟丙烷-1,2-二醇4
。用第三丁基二甲基矽基氯對4
之一級羥基進行化學選擇性保護，產生(R)-3-((第三丁基二甲基矽基)氧基)-1,1-二氟丙-2-醇5
。用三氟甲磺酸酐(triflic anhydride)即三氟甲烷磺酸酐(trifluoromethanesulfonic anhydride)將5
之二級羥基轉化為三氟甲磺酸酯，以形成(R)-3-((第三丁基二甲基矽基)氧基)-1,1-二氟丙-2-基三氟甲磺酸酯6
。用立體化學轉化藉由鄰苯二甲醯亞胺鉀置換替代三氟甲磺酸酯，產生(S
)-2-(3-((第三丁基二甲基矽基)氧基)-1,1-二氟丙-2-基)異吲哚啉-1,3-二酮7
。用含水肼對7
之鄰苯二甲醯亞胺基進行裂解，產生一級胺，(S
)-3-((第三丁基二甲基矽基)氧基)-1,1-二氟丙-2-胺8
。用鹽酸對8
進行矽基去除，產生呈鹽酸鹽形式之氯化(S
)-1,1-二氟-3-羥基丙-2-銨9
。隨後用三光氣：CCl3
OCO2
CCl3
、(雙(三氯甲基)碳酸酯(BTC)(CAS登記號32315-10-9)對9
進行環化，產生(S
)-4-(二氟甲基)噁唑啶-2-酮10
。 方案2：
a：i) Mg(OEt)2
、MeOH、MeTHF，ii) HCl、n-PrOH；b：ClCHCHO、KHCO3
、MeTHF、H2
O，c：NIS、DMF，d：EtMgBr、THF，e：10
、Cu(OAc)2
、反式-N,N'-二甲基環己烷-1,2-二胺、Cs2
CO3
、MeTHF，f：i) L-丙胺酸、Cu2
O、K3
PO4
、DMSO，ii) NH3
、MeOH、THF，g：i) NH3
、HOSu、EDC、THF、i-PrOH，ii) EtOH、H2
O 方案2顯示(S)-2-((2-((S)-4-(二氟甲基)-2-側氧基噁唑啶-3-基)-5,6-二氫苯并[f]咪唑并[1,2-d][1,4]氧氮呯-9-基)胺基)丙醯胺18
之製備。將氯化2-(5-溴-2-氰基苯氧基)乙-1-銨11
用乙醇鎂即Mg(OEt)2
於甲醇中環化，且用氯化氫於正丙醇中之溶液酸化，產生8-溴-2,3-二氫苯并[f
][1,4]氧氮呯-5-胺鹽酸鹽12
。在作為鹼的碳酸氫鉀存在下用含水氯乙醛對12
進行環化以形成咪唑環，產生9-溴-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯13
。用N
-碘琥珀醯亞胺NIS或其他碘化試劑諸如碘或一氯化碘對咪唑13
進行雙碘化，產生9-溴-2,3-二碘-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯14
。使用格任亞試劑諸如乙基溴化鎂或異丙基氯化鎂經由碘-金屬交換對14
進行選擇性還原，產生9-溴-2-碘-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯15
。在銅催化劑(諸如乙酸銅(II))、配位基(諸如反式-N
,N
'-二甲基環己烷-1,2-二胺、1,10-啡啉或3,4,7,8-四甲基-1,10-啡啉)、無機鹼(諸如碳酸銫或磷酸三鉀)及作為溶劑之2-甲基四氫呋喃或乙腈存在下用(S
)-4-(二氟甲基)噁唑啶-2-酮10
自15
中化學選擇性地置換碘化物，產生(S
)-3-(9-溴-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯-2-基)-4-(二氟甲基)噁唑啶-2-酮16
。在銅催化劑(諸如氧化銅(I))、無機鹼(諸如磷酸三鉀)及作為溶劑之DMSO存在下用(S
)-2-胺基丙酸自16
中置換溴化物，隨後使用氨於甲醇中之溶液作為氨來源在THF中形成銨鹽，產生(S
)-2-((2-((S
)-4-(二氟甲基)-2-側氧基噁唑啶-3-基)-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯-9-基)胺基)丙酸銨17
。用氨於2-丙醇中之溶液、添加劑(諸如N
-羥基琥珀醯亞胺(HOSu)或1-羥基苯并三唑(HOBt))及去水試劑(諸如N
-(3-二甲基胺丙基)-N'
-乙基碳化二亞胺鹽酸鹽EDC於THF中)實現羧酸鹽17
轉化為甲醯胺，產生18
。 實例 方案2a：向氯化2-(5-溴-2-氰基苯氧基)乙-1-銨11
(20.4 kg，97.8 wt %，71.9 mol，100 mol %)於MeOH (64.0 kg)中之懸浮液中加入固體乙醇鎂Mg(OEt)2
(17.9 kg，219 mol %)。將混合物在25℃下攪拌30 min，隨後添加2-甲基四氫呋喃2-MeTHF (140 kg)，將反應混合物加熱回流且攪拌40 h。反應完成後，將批料(batch)在減壓下在低於40℃下濃縮至約50 L。隨後添加2-MeTHF (172 kg)，在低於15℃下添加氯化氫於正丙醇(83.0 kg，5.00 M)中之溶液。將懸浮液在15℃下攪拌4 h，且過濾。將所得固體用2-MeTHF (10 kg)洗滌且在減壓下在50℃下乾燥，得到呈吸濕性固體狀之8-溴-2,3-二氫苯并[f
][1,4]氧氮呯-5-胺鹽酸鹽12
(17.6 kg，88%產率)，將其用於下一步驟。1
H NMR (500 MHz, DMSO-d 6
) δ 8.32 (s, 3H), 7.74 (d,J
= 8.3 Hz, 1H), 7.61 (d,J
= 1.5 Hz, 1H), 7.38 (dd,J
= 8.3, 1.5 Hz, 1H), 4.44 (t,J
= 5.2 Hz, 2H), 3.24 (t,J
= 5.2 Hz, 2H)。 方案2b：向8-溴-2,3-二氫苯并[f
][1,4]氧氮呯-5-胺鹽酸鹽12
(17.6 kg，63.4 mol，100 mol %)及2-MeTHF (122 kg)之混合物中加入40%氯乙醛水溶液(16.4 kg，132 mol %)及水(10 kg)。將混合物加熱至40℃且加入碳酸氫鉀水溶液。將反應混合物在45℃下攪拌21 h。反應完成後，將反應混合物冷卻至20℃，攪拌30 min，且過濾。將所得濾餅用2-MeTHF (33.0 kg)潤洗，且使合併之濾液沉降。將所得有機層用亞硫酸氫鈉水溶液(30 kg)洗滌，在減壓下在低於45℃下濃縮至約26 L。添加DMF (25 kg)後，將混合物在減壓下在低於45℃下濃縮至約26 L。在40℃下加入水(154 kg)，隨後加入9-溴-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯13
(1.20 kg)之晶種。將混合物在40℃下攪拌另外1.5 h且冷卻至20℃。在20℃下攪拌10 h後，過濾懸浮液。將所得固體用水洗滌兩次(25 kg ´2)，且在減壓下在45℃下乾燥，得到9-溴-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯13
(16.3 kg，97.5 wt %，95%產率)。1
H NMR (500 MHz, DMSO-d 6
) δ 8.33 (d,J
= 8.6 Hz, 1H), 7.35 (s, 1H), 7.31–7.22 (m, 2H), 7.06 (s, 1H), 4.45 (q,J
= 5.3 Hz, 4 H)；HRMS計算值。C11
H10
BrN2
O [M+H]+
：264.9971，實驗值為264.9976。 方案2c： 在40℃下向9-溴-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯13
(16.3 kg，97.5 wt %，59.9 mol，100 mol %)於DMF (78.0 kg)中之溶液中添加N
-碘琥珀醯亞胺NIS (29.0 kg，215 mol %)。將反應混合物緩慢加熱至70℃且攪拌6 h。反應完成後，在45℃下加入10%亞硫酸鈉水溶液(78.0 kg)，隨後加入水(154 kg)。將所得懸浮液在45℃下攪拌1 h，且冷卻至20℃。在20℃下攪拌8 h後，過濾懸浮液。將所得固體用水(160 kg)洗滌，且在減壓下在45℃下乾燥，得到呈灰白色固體狀之9-溴-2,3-二碘-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯14
(29.7 kg，100 wt %，96%產率)。1
H NMR (500 MHz, DMSO-d 6
) δ 8.21 (d,J
= 8.6 Hz, 1H), 7.32–7.24 (m, 2H), 4.51–4.45 (m, 2H), 4.39–4.34 (m, 2H)；HRMS計算值。C11
H8
BrI2
N2
O [M+H]+
：516.7904，實驗值為516.7911。 方案2d：在10℃下向9-溴-2,3-二碘-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯14
(39.4 kg，76.2 mol，100 mol %)於四氫呋喃THF (180 kg)中之溶液中添加2.0 M乙基溴化鎂於2-甲基四氫呋喃(44.0 kg，120 mol %)中之溶液。將反應混合物在10℃下攪拌2 h。反應完成後，加入5%乙酸(133 kg)，同時將批料溫度維持在30℃以下。加入乙酸乙酯(168 kg)，且將所得混合物在20℃下攪拌1 h。分離各層，且將水層用乙酸乙酯(77.8 kg)萃取。將合併之有機層用水(76.0 kg)洗滌，且透過矽膠墊(19.8 kg)過濾。將矽膠墊用乙酸乙酯(69.6 kg)潤洗。將合併之濾液在減壓下在低於50℃下濃縮至約100 L，且添加THF (146 kg)。將所得混合物加熱至60℃直至獲得清透溶液，之後將其在減壓下在低於50℃下濃縮至約100 L，且接著冷卻至30℃。加入正庚烷(86.8 kg)，且將所得混合物在30℃下攪拌2 h。藉由在減壓下在低於35℃下進行三個循環的批料濃縮，至約180 L且添加正庚烷(47.6 kg ´3)來將批料之溶劑轉換為正庚烷。將所得懸浮液冷卻至20℃，攪拌12 h，且過濾。將所得固體用正庚烷(64.0 kg)洗滌，且在減壓下在45℃下乾燥，得到呈淺棕褐色固體狀之9-溴-2-碘-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯15
(25.3 kg，98.7 wt %，84%產率)。1
H NMR (500 MHz, DMSO-d 6
) δ 8.23 (d,J
= 8.6 Hz, 1H), 7.55 (s, 1H), 7.32–7.24 (m, 2H), 4.44 (q,J
= 5.4 Hz, 4H)；HRMS計算值。C11
H9
BrIN2
O [M+H]+
：390.8937，實驗值為390.8949。 方案2e：將9-溴-2-碘-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯15
(6.90 kg，98.7 wt %，17.4 mol，100 mol %)加入反應器中，隨後加入(S
)-4-(二氟甲基)噁唑啶-2-酮10
(2.68 kg，112 mol %)、乙酸銅(II) (0.653 kg，20.6 mol %)及Cs2
CO3
(11.7 kg，206 mol %)。將反應器抽真空，且用氮氣回填三次。接著向反應器中加入2-甲基四氫呋喃(36.0 kg)及反式-N
,N
-二甲基環己烷-1,2-二胺(0.764 kg，30 mol %)。將反應器抽真空，且用氮氣回填三次。將反應混合物加熱至78℃且攪拌22 h。反應完成後，緩慢添加20 wt % NaHSO4
水溶液(42.0 kg)，同時將內部溫度維持在60至70℃之間。在65℃下分離各層，且去除水層。經由恆定體積蒸餾在減壓下在60至70℃下藉由添加乙腈(62.3 kg)將批料之溶劑轉換為乙腈。將水(14.1 kg)添加至反應器中，同時將批料溫度維持在60至70℃之間。將懸浮液以0.5℃/min之速率冷卻至20℃，攪拌18 h，且過濾。將所得固體用乙腈及水之混合物(50 kg，44:56，w/w)洗滌，且在減壓下在90℃下乾燥，得到呈棕褐色固體狀之(S
)-3-(9-溴-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯-2-基)-4-(二氟甲基)噁唑啶-2-酮16
(5.85 kg，91.9 wt %，77%產率)。1
H NMR (500 MHz, CDCl3
) δ 8.22 (d,J
= 8.8 Hz, 1H), 7.31 (s, 1H), 7.28–7.19 (m, 2H), 6.71–6.62 (m, 1H), 4.90 (ddd,J
= 24.0, 9.3, 3.8 Hz, 1H), 4.75 (dd,J
= 9.4, 3.9 Hz, 1H), 4.56 (t,J
= 9.3 Hz, 1H), 4.51–4.44 (m, 2H), 4.41–4.35 (m, 2H)；HRMS計算值。C15
H13
BrF2
N3
O3
[M+H]+
：400.0103，實驗值為400.0134。 方案2f：向反應器中加入(S
)-3-(9-溴-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯-2-基)-4-(二氟甲基)噁唑啶-2-酮16
(3.96 kg，91.9 wt %，9.19 mol，100 mol %)，隨後加入(S
)-2-胺基丙酸(2.49 kg，307 mol %)、K3
PO4
(5.84 kg，303 mol %)及DMSO (19.9 kg)。將混合物用氮氣噴洗1 h且加熱至95℃。接著將用氮氣預先噴洗30 min之氧化銅(I)(67.1 g，5.16 mol %)於DMSO (2.21 kg)中之漿液轉移至反應器中。將反應混合物在95℃下攪拌4 h。反應完成後，將反應混合物冷卻至20℃。將DCM (37.3 kg)添加至反應器中，隨後添加水(24.2 kg)。分離各層，且去除有機層。將水層再次用二氯甲烷DCM (26.6 kg)洗滌。依序向反應器中加入THF (35.2 kg)及硫酸氫鈉水溶液(19 wt %，20.7 kg)。分離各層，且去除水層。將有機層用15 wt %鹽水(2´12 kg)洗滌。加入SiliaMetS® DMT (Silicycle Inc.，1.60 kg)，且將批料在25℃下攪拌15 h且過濾以清除殘餘金屬。SiliaMetS® DMT為2,4,6-三巰基三嗪(三聚硫氰酸，TMT)之矽結合等效物，及多種金屬(包括釕催化劑及受阻Pd錯合物)之通用金屬清除劑。使用四氫呋喃THF (24.8 kg)來潤洗過濾器。將合併之濾液加熱至50℃。添加7 N的氨於甲醇(1.02 kg，100 mol %)中之溶液，隨後添加晶種((S
)-2-((2-((S
)-4-(二氟甲基)-2-側氧基噁唑啶-3-基)-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯-9-基)胺基)丙酸銨17
，19.5 g)於THF (0.395 kg)中之漿液。將所得懸浮液在50℃下攪拌2 h，且在40至60℃下在減壓下進行恆定體積蒸餾，以藉由添加無水THF (60.1 kg)來去除殘餘的水。添加7 N的氨於甲醇中之溶液(1.02 kg，100 mol %)。將懸浮液在50℃下攪拌15 h且過濾。將所得固體用THF (21.8 kg)洗滌，且在減壓下在25℃下乾燥，得到呈米色固體狀之(S
)-2-((2-((S
)-4-(二氟甲基)-2-側氧基噁唑啶-3-基)-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯-9-基)胺基)丙酸銨17
(3.19 kg，98.0 wt %，81%產率)。HRMS計算值。C18
H19
F2
N4
O5
[M+H]+
：409.1318，實驗值為409.1318。 方案2g：向反應器中加入(S
)-2-((2-((S
)-4-(二氟甲基)-2-側氧基噁唑啶-3-基)-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯-9-基)胺基)丙酸銨17
(5.60 kg，13.2 mol，100 mol %)，隨後加入N
-羥基琥珀醯亞胺、HOSu (1.52 kg，102 mol %)及THF (49.6 kg)。將批料用氮氣噴洗40 min且冷卻至10℃。依序向反應器中加入2 N的氨於2-丙醇(5.05 kg，101 mol %)中之溶液及N
-(3-二甲基胺丙基)-N'
-乙基碳化二亞胺鹽酸鹽EDC (5.20 kg，210 mol %)。將反應混合物在10℃下攪拌20 h。反應完成後，將混合物溫熱至20℃，且添加15 wt %鹽水(33.7 kg)。在35℃下分離各層，且去除水層。依序用15 wt %鹽水(2´16.9 kg)以及15 wt %鹽水(8.97 kg)及28.0至30.0 wt %氫氧化銨(7.55 kg)之混合物洗滌有機層，且接著透過拋光過濾器裝置來過濾。將過濾器裝置用THF (5.05 kg)潤洗。將合併之濾液在減壓下在50℃下蒸餾至其原始體積之約一半。在50℃下加入乙醇(8.90 kg)，隨後加入晶種((S
)-2-((2-((S
)-4-(二氟甲基)-2-側氧基噁唑啶-3-基)-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯-9-基)胺基)丙醯胺18
，27.1 g)於乙醇(0.340 kg)中之漿液。將所得懸浮液在50℃下攪拌30 min，且經由恆定體積蒸餾在減壓下在40至60℃下藉由添加乙醇(39.9 kg)將其溶劑轉換為乙醇。在50℃下添加水(0.379 kg)。將懸浮液冷卻至20℃，攪拌23 h，且過濾。將所得固體用乙醇及水之90:10 (w/w)混合物(27.9 kg)洗滌，且在減壓下在80℃下乾燥，得到呈淺粉色固體狀之((S
)-2-((2-((S
)-4-(二氟甲基)-2-側氧基噁唑啶-3-基)-5,6-二氫苯并[f
]咪唑并[1,2-d
][1,4]氧氮呯-9-基)胺基)丙醯胺18
(4.37 kg，99.7 wt %，83%產率)。1
H NMR (600 MHz, CD3
CN) δ 8.08 (d,J
= 8.8 Hz, 1H), 7.11 (s, 1H), 6.86–6.50 (m, 1H), 6.41 (dd,J
= 8.8, 2.3 Hz, 1H), 6.12 (d,J
= 2.4 Hz, 1H), 4.87 (dd,J
= 23.8, 8.8 Hz, 1H), 4.67–4.50 (m, 2H), 4.43–4.33 (m, 2H), 4.33–4.26 (m, 2H), 3.82 (q,J
= 7.0 Hz, 1H), 1.41 (d,J
= 7.0 Hz, 3H) (註：為了清楚起見，省略N-H質子);13
C NMR (151 MHz, CD3
CN) δ 178.2, 157.0, 155.1, 149.1, 141.6, 135.4, 130.8, 113.3, 108.9, 108.1, 107.7, 102.1, 68.5, 61.7, 56.1, 53.1, 49.6, 18.2；HRMS計算值。C18
H20
F2
N5
O4
[M+H]+
：408.1478，實驗值為408.1473。 儘管上述本發明已出於清楚理解之目的藉由說明及實例方式相當詳細地加以描述，但描述及實例不應解釋為限制本發明之範疇。因此，可認為所有合適之修改及等效物處於如隨附申請專利範圍所界定之本發明的範疇內。本文引用之所有專利及科學文獻之揭露內容皆以全文引用之方式明確併入。
Claims (20)
- 一種用於製備化合物18之方法，該化合物18具有以下結構：
- 如請求項1之方法，其中該添加劑為N-羥基琥珀醯亞胺(HOSu)。
- 如請求項1之方法，其中化合物17係藉由以下方法來製備，該方法包含使具有結構：
- 如請求項3之方法，其中該銅催化劑為氧化銅(I)。
- 如請求項3之方法，其中化合物16係藉由以下方法來製備，該方法包含使具有結構：
- 如請求項5之方法，其中該銅催化劑為乙酸銅(II)。
- 如請求項5之方法，其中該配位基為反式-N,N-二甲基環己烷-1,2-二胺。
- 如請求項5之方法，其中該配位基為3,4,7,8-四甲基-1,10-啡啉。
- 如請求項5之方法，其中化合物10係藉由包含以下步驟之方法來製備：(a)使具有結構：
- 如請求項5之方法，其中化合物15係藉由包含以下步驟之方法來製備：(a)使具有結構：
- 一種(S)-2-((2-((S)-4-(二氟甲基)-2-側氧基噁唑啶-3-基)-5,6-二氫苯并[f]咪唑并[1,2-d][1,4]氧氮呯-9-基)胺基)丙酸銨(化合物17)，其具有以下結構：
- 一種用於製備化合物18之方法，該化合物18具有以下結構：
- 如請求項12之方法，其中化合物17係藉由以下方法來製備，該方法包含使具有結構：
- 如請求項13之方法，其中該銅催化劑為氧化銅(I)。
- 如請求項13之方法，其中化合物16係藉由以下方法來製備，該方法包含使具有結構：
- 如請求項15之方法，其中該銅催化劑為乙酸銅(II)。
- 如請求項15之方法，其中該配位基為反式-N,N-二甲基環己烷-1,2-二胺。
- 如請求項15之方法，其中該配位基為3,4,7,8-四甲基-1,10-啡啉。
- 如請求項15之方法，其中化合物10係藉由包含以下步驟之方法來製備：(a)使具有結構：
- 如請求項15之方法，其中化合物15係藉由包含以下步驟之方法來製備：(a)使具有結構：
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| KR20220054347A (ko) | 2019-08-26 | 2022-05-02 | 아비나스 오퍼레이션스, 인코포레이티드 | 에스트로겐 수용체 분해제로서의 테트라히드로나프탈렌 유도체로 유방암을 치료하는 방법 |
| WO2021104146A1 (zh) * | 2019-11-25 | 2021-06-03 | 上海翰森生物医药科技有限公司 | 含三并环类衍生物的盐或晶型及其药物组合物 |
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| KR20240013791A (ko) | 2021-05-28 | 2024-01-30 | 제넨테크, 인크. | 벤족사제핀 옥사졸리디논 화합물을 제조하기 위한 공정 |
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| TW201127844A (en) * | 2009-09-28 | 2011-08-16 | Hoffmann La Roche | Benzoxazepin PI3K inhibitor compounds and methods of use |
| TW201712020A (zh) * | 2015-07-02 | 2017-04-01 | 赫孚孟拉羅股份公司 | 苯并氧氮呯噁唑啶酮化合物及其用途 |
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