TWI749644B - 一種氰基取代的環肼衍生物及其應用 - Google Patents
一種氰基取代的環肼衍生物及其應用 Download PDFInfo
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- TWI749644B TWI749644B TW109124297A TW109124297A TWI749644B TW I749644 B TWI749644 B TW I749644B TW 109124297 A TW109124297 A TW 109124297A TW 109124297 A TW109124297 A TW 109124297A TW I749644 B TWI749644 B TW I749644B
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- pyrrolo
- reaction
- pyridine
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- -1 cyclic hydrazine derivative Chemical class 0.000 title claims abstract description 65
- 125000004093 cyano group Chemical group *C#N 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 202
- 230000000694 effects Effects 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 7
- 102000001253 Protein Kinase Human genes 0.000 claims abstract description 5
- 108060006633 protein kinase Proteins 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 5
- 150000004677 hydrates Chemical class 0.000 claims abstract description 4
- 201000010099 disease Diseases 0.000 claims abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- 230000002062 proliferating effect Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 169
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- 239000013543 active substance Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 5
- 239000002955 immunomodulating agent Substances 0.000 claims description 4
- 229940121354 immunomodulator Drugs 0.000 claims description 4
- 239000003018 immunosuppressive agent Substances 0.000 claims description 4
- 229940125721 immunosuppressive agent Drugs 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
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- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 238000006722 reduction reaction Methods 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
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- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 2
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- 239000003937 drug carrier Substances 0.000 claims description 2
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- 125000003386 piperidinyl group Chemical group 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 230000002584 immunomodulator Effects 0.000 claims 1
- VKHZYWVEBNIRLX-UHFFFAOYSA-N methanesulfonohydrazide Chemical compound CS(=O)(=O)NN VKHZYWVEBNIRLX-UHFFFAOYSA-N 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 239000002207 metabolite Substances 0.000 abstract description 2
- 229940002612 prodrug Drugs 0.000 abstract description 2
- 239000000651 prodrug Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 138
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 114
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 103
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 97
- 239000000243 solution Substances 0.000 description 89
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 85
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 75
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- 239000012074 organic phase Substances 0.000 description 59
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 51
- 238000003756 stirring Methods 0.000 description 49
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 229910052757 nitrogen Inorganic materials 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
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- 239000000706 filtrate Substances 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 30
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 29
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
- 229960000583 acetic acid Drugs 0.000 description 25
- 239000012141 concentrate Substances 0.000 description 25
- 239000000284 extract Substances 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
- 125000003118 aryl group Chemical group 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
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- 239000000203 mixture Substances 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 125000000753 cycloalkyl group Chemical group 0.000 description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 15
- 235000010288 sodium nitrite Nutrition 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 108091000080 Phosphotransferase Proteins 0.000 description 13
- 102000020233 phosphotransferase Human genes 0.000 description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 11
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 229910052736 halogen Inorganic materials 0.000 description 9
- 150000002367 halogens Chemical class 0.000 description 9
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- IUEDKJPOBOGQPE-UHFFFAOYSA-N 4-chloro-1-(4-methylphenyl)sulfonyl-5-nitropyrrolo[2,3-b]pyridine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=C([N+]([O-])=O)C(Cl)=C2C=C1 IUEDKJPOBOGQPE-UHFFFAOYSA-N 0.000 description 7
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- 229910052717 sulfur Inorganic materials 0.000 description 7
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- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 5
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Abstract
本發明提供了一種氰基取代的環肼衍生物,其特徵在於:為如式A所示的化合物或其立體異構體、幾何異構體、互變異構體、消旋體、水合物、溶劑化物、代謝產物以及藥學上可接受的鹽或前藥;
Description
本發明屬於藥物合成領域,具體地說,本發明涉及一種JAK酶抑制劑及其製備方法和用途。
蛋白激酶(Protein kinases)是一類催化蛋白質磷酸化反應的酶,是調節細胞訊號包括細胞增殖和細胞分化中關鍵因素,包括細胞生長、存活、分化、器官形成、形態發生、新血管形成、組織修復和再生等。
許多細胞激素如干擾素(IFN)家族、糖蛋白130 (gpl30)家族、γ-C家族(常見伽馬鏈,CD132家族—)及單鏈家族的訊號傳遞涉及Janus激酶家族(JAK),及JAK激酶下游的訊號傳遞和轉錄啟動因子(STAT)。目前,有四種已知的哺乳動物JAK家族成員:JAK1(亦稱Janus激酶-1)、JAK2(亦稱Janus激酶-2)、JAK3(Janus激酶-3)和TYK2(亦稱蛋白質-酪胺酸激酶2)。
在JAK激酶水準下的阻斷訊號轉導為炎性疾病、自身免疫病、骨髓增殖性疾病和癌症的治療方法的開發提供了前景。JAK激酶的抑制也有助於皮膚免疫疾病如銀屑病和皮膚過敏的治療。已經上市的托伐替尼(Toficitinib)和巴瑞克替尼(Baricitinib),用於治療類風濕性關節炎;以及魯索替尼(ruxolitinib),用於治療骨髓纖維化以及急性移植物抗宿主病。
然而,目前已有的一些JAK酶抑制劑也存在一些明顯的毒副作用。JAK抑制劑會引起的免疫相關的副作用:感染,包括肺炎、病毒感染(如帶狀皰疹感染)、細菌感染、放線菌感染(分枝桿菌感染)、真菌感染、免疫力下降(如NK細胞減少)以及貧血。但也有一些非免疫的副作用,如肺栓塞(可能致死)。研究表明,目前已有的JAK抑制劑對JAK家族激酶成員沒有選擇性,其肺栓塞的副作用與JAK2的抑制有關。
綜上所述,目前本領域迫切需要研發出Janus激酶或相關激酶的抑制劑,尤其是對JAK1具有高選擇性的抑制劑。
本發明的目的在於提供一種新型的對JAK1激酶有高活性,對JAK2激酶有較好選擇性的抑制劑及其製備方法和用途。
其中,環A為雜環基、稠合雜環基或螺雜環基;
上述R1
為相同或不相同的取代基,且n選自於1-3的自然數;
上述R1
選自氫、羥基、鹵素、胺基、氰基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的雜烷基、取代或未取代的環烷基,以及取代或未取代的雜環烷基;
上述R10
選自氰基和末端為氰基的基團;該末端為氰基的基團可以為飽和或不飽和的任意形式;
R2
選自氫、羥基、鹵素、硝基、胺基、取代的胺基、取代或未取代的烷基、取代或未取代的雜烷基、取代或未取代的環烷基,以及取代或未取代的雜環烷基;
R20
選自氫和胺基保護基。
上述環A最優選為:由4-9個原子構成的雜環基、或由6-12個原子構成的稠合雜雙環基,或由6-12個原子構成的螺雜雙環;
其中,雜原子為1-3個,各自獨立選自氮、氧和硫。
在本發明中取代或未取代的烷基指:
上述未取代的烷基一般為碳原子數不大於6的支鏈烷基或支鏈烷基;
上述取代的烷基指烷基碳鏈上的氫原子中的一個或一個以上為其他基團所取代,此處所指的其他基團可以為環烷基(以類似於等的形式進行取
代,該環烷基環上的任何氫原子還可以為鹵素、氰基、烷基、羥基、羧基等基團所取代)、雜環烷基(即、在前述的環烷基的基礎上,其烷基環上的至少一個碳原子為氧、硫、氮所替代)、鹵素(F,Cl,Br,I)、羧基、氰基(-CN)、磺醯基(-SO2
Ra
,Ra
為烷基、芳基等)、炔基(-C≡CH,-C≡CRb
,Rb
為烷基、芳基等)、醯胺基(-C(O)NRx
Ry
,Rx
Ry
為烷基、芳基等)、酯基(-C(O)O-Rz,Rz為烷基、芳基等)、芳基、雜芳基等等基團;
在本發明中取代或未取代的環烷基指:
上述未取代的環烷基一般為碳原子數為3-8的環烷基;
上述取代的環烷基指環基環上的一個或多個氫原子為其他基團所取代,此處所指的其他基團可以為烷基、取代的烷基(同上)、鹵素(F,Cl,Br,I)、羧基、氰基(-CN)、磺醯基(-SO2
Ra
,Ra
為氫、烷基、芳基等)、炔基(-C≡CH,-C≡CRb
,Rb
為烷基、芳基等)、醯胺基(-C(O)NRx
Ry
,Rx
Ry
為烷基、芳基等)、酯基(-C(O)O-Rz
,Rz
為烷基、芳基等)、芳基、雜芳基等等基團。
在本發明中取代或未取代的雜烷基指:指在上述取代或未取代的烷基的基礎上,其碳鏈上的一個或多個碳原子為氧、硫、氮所替代。
在本發明中取代或未取代的雜環烷基指:指在上述取代或未取代的環烷基的基礎上,其環上的一個或多個碳原子為氧、硫、氮所替代。
在本發明中取代或未取代的烷氧基指:
上述未取代的烷氧基一般為碳原子數不大於6的支鏈烷氧基或支鏈烷氧基;
上述取代的烷氧基指烷基碳鏈上的氫原子中的一個或一個以上為其他基團所取代,此處所指的其他基團可以為環烷基(以類似於等的形式進行取
代,該環烷基環上的任何氫原子還可以為鹵素、氰基、烷基、羥基、羧基等基團所取代)、雜環烷基(即、在前述的環烷基的基礎上,其烷基環上的至少一個碳原子為氧、硫、氮所替代)、鹵素(F,Cl,Br,I)、羧基、氰基(-CN)、磺醯基(-SO2
Ra
,Ra
為氫、烷基、芳基等)、炔基(-C≡CH,-C≡CRb
,Rb
為烷基、芳基等)、醯胺基(-C(O)NRx
Ry
,Rx
Ry
為烷基、芳基等)、酯基(-C(O)O-Rz
,Rz
為烷基、芳基等)、芳基、雜芳基等等基團。
在本發明中取代的胺基指:胺基(-NH2)上的氫原子中的一個或一個以上為其他基團所取代,此處所指的其他基團可以為烷基、環烷基、醯胺基、酯基等等基團。
其中,上述X選自取代或未取代的亞烷基、取代或未取代的雜亞烷基、-(CH2
)m
N(R3
)-、-(CH2
)m
C(O)N(R3
)-,以及-(CH2
)m
C(O)-;
X跟環A的連接鍵為單鍵或雙鍵;
R3
選自氫,取代或未取代的烷基,以及取代或未取代的雜烷基;
m選自於1-3的自然數。
在本發明中取代或未取代的亞烷基指:
上述未取代的亞烷基指-(CH2
)m
-的形式;
上述取代的亞烷基指-(CH2
)m
-碳鏈上的一個或一個以上的氫原子為其他基團所取代,該其他基團可以為烷基、環烷基(以類似於等的形式進行取
代,該環烷基環上的任何氫原子還可以為鹵素、氰基、烷基、羥基、羧基等基團所取代)、雜環烷基(即、在前述的環烷基的基礎上,其烷基環上的至少一個碳原子為氧、硫、氮所替代)、鹵素(F,Cl,Br,I)、羧基、氰基(-CN)、磺醯基(-SO2
Ra
,Ra
為氫、烷基、芳基等)、炔基(-C≡CH,-C≡CRb
,Rb
為烷基、芳基等)、醯胺基(-C(O)NRx
Ry
,Rx
Ry
為烷基、芳基等)、酯基(-C(O)O-Rz
,Rz
為烷基、芳基等)、芳基、雜芳基等等基團。
在本發明中取代或未取代的雜亞烷基指:上述未取代的亞烷基上的一個或幾個碳原子為氧、硫、氮所替代。
其中,環A’為雜環基、稠合雜環基或螺雜環基;
Y選自CR4
和N;
R4
選自氫、羥基、取代或未取代的烷基,以及取代或未取代的烷氧基;
所述X選自取代或未取代的亞烷基、取代或未取代的雜亞烷基、-(CH2
)m
N(R3
)-、-(CH2
)m
C(O)N(R3
)-,以及-(CH2
)m
C(O)-。
其中,上述a為0,1,2或3;A”為雜環基;
上述R10
’選自末端為氰基的基團。
其中,Z選自取代或未取代的亞烷基;
R5
選自氫、取代或未取代的烷基,以及取代或未取代的雜烷基。
其中,R5
選自氫和甲基。
S1 (步驟1)、以化合物II-1為原料,其上的NH基團被亞硝基化形成亞硝基產物II-2;
S2 (步驟2)、亞硝基產物II-2經還原反應轉化成化合物II-3;
S3 (步驟3)、將化合物II-3與化合物II-4,在鹼性條件下反應,得到化合物II-5;
S4 (步驟4)、化合物II-5中的硝基用氫化還原成胺基得到化合物II-6;
S5 (步驟5)、化合物II-6經關環反應獲得化合物II-7;
S6 (步驟6)、化合物II-7脫保護得到該氰基取代的環肼衍生物。
上述反應的具體過程可以為:如式II-1顯示的化合物可以從直接購得,或通過已知的常見合成方法獲得。式II-1可以被亞硝基化,HNO2
(NaNO2
加酸獲得),或烷基亞硝酸酯(如亞硝酸丁酯,亞硝酸異戊酯)來產生“N”亞硝基產物II-2。鐵粉,或鋅粉,或催化氫化可以講中間產物II-2轉化成II-3。II-3和II-4 (Ar選擇自苯基或苄基,合成見 Kulagowski, J J; et al.; Journal of Medicinal Chemistry (2012) 55, 5901)在鹼性條件下反應(乾燥的Na2
CO3
,無水DMF,加熱)得到化合物II-5。化合物II-5中的硝基用氫化(Pt-C, 1大氣壓的氫氣)還原成胺基得到II-6。關環反應可以通過多種已知條件來實現,常見條件有II-6和原酸三酯(R2
(OMe)3
. 如原乙酸三乙酯)在酸性條件下反應;或II-6和醯胺用三乙基氧四氟硼酸或其它鎓鹽脫水得到。最後,氫氧化鈉水溶液脫保護生成式I所顯示的化合物。
另外,本發明還提供了一種藥物組合物,其特徵在於:包含上述氰基取代的環肼衍生物和藥學上可接受的載體、賦形劑、稀釋劑、輔劑或媒介物中的至少一種;
其中,上述氰基取代的環肼衍生物的用量為藥物組合物總品質的0.01%-99.9%。
進一步地,本發明還提供了一種藥物組合物,其特徵還在於:還包含附加治療劑;
上述附加治療劑選自抗炎藥、免疫調節劑或免疫抑制劑、神經營養因子、用於治療心血管疾病的活性劑和用於治療糖尿病的活性劑。
上述免疫調節劑或免疫抑制劑包含用於治療自體免疫疾病的活性劑。
另外,本發明提供一種氰基取代的環肼衍生物或藥物組合物在製備藥物的用途,其特徵在於:該藥物用於抑制或調節蛋白激酶活性。
另外,本發明提供一種氰基取代的環肼衍生物或藥物組合物在製備藥物的用途,其特徵在於:用於預防、處理、治療或減輕患者自體免疫疾病或增殖性疾病。
其中,自體免疫疾病可以是類風濕性關節炎,銀屑病,I型糖尿病,因器官移植導致的併發症,異體移植,糖尿病,癌症,哮喘,異位性皮膚炎,自身免疫性甲狀腺病,潰瘍性結腸炎,克羅恩病,白血病和淋巴瘤;狼瘡,多發性硬化,肌肉縮性側索硬化。
1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-甲腈
步驟A:
將4-氯-7-氮雜吲哚(50.0 g,327.8 mmol)溶解在1 L二氯甲烷中,然後在0o
C下,分別加入三乙胺(66.3 g,655.6 mmol),對甲苯磺醯氯(64.4 g,37.6 mmol)和4-二甲胺基吡啶(0.4 g,3.3 mmol),然後在室溫下攪拌16小時。反應結束後,加入500 mL水洗滌,分出有機相,乾燥,過濾,減壓蒸除溶劑,得到化合物4-氯-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(99.8 g,產率99%)。
步驟B:
將化合物4-氯-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(50.0 g,163.0 mmol)溶解在600 mL二氯甲烷中。在0o
C下,加入四丁基硝酸銨(74.4 g,244.5 mmol)和三氟乙酸酐(53.1 g,252.6 mmol),然後氮氣保護下室溫反應20小時。反應結束後,加500 mL飽和碳酸氫鈉水溶液淬滅,分離有機相,並用1.2 L二氯甲烷分兩次萃取水相。合併有機相,用適量的水和飽和氯化鈉水溶液洗滌。將有機相用無水硫酸鈉乾燥,過濾,旋蒸,得到的漿狀物用80 mL乙酸乙酯超聲打漿,過濾,乾燥濾餅得到化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(30.1 g,產率52%)。1
H NMR (400 MHz, DMSO-d6
)δ
9.08 (s, 1H), 8.26 (d,J
= 4.0 Hz, 1H), 8.05 (d,J
= 8.4 Hz, 2H), 7.47 (d,J
= 8.4 Hz, 2H), 7.09 (d,J
= 4.0 Hz, 1H), 2.37 (s, 3H).
步驟C:
將化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(1.58 g,4.5 mmol)、N,N
-二異丙基乙胺(1.75 g,13.5 mmol)和1-胺基-4-哌啶醇(0.58 g,5.0 mmol)加入到50 mL異丙醇中(懸濁液)。在95 ℃攪拌反應16小時。反應完成後,冷卻至室溫,加入50 mL水,用乙酸乙酯萃取(3×50 mL)。合併有機相,無水硫酸鈉乾燥。過濾,旋乾,柱層析純化得化合物1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-醇(0.91 g,產率47%)。LCMS ESI(+)m/z:432.2(M+1).
步驟D:
將化合物1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-醇(0.91 g,2.1 mmol)加至15 mL乙醇和5 mL水的混合溶中(懸濁液),然後依次加入氯化銨固體(0.45 g,8.4 mmol)和鐵粉(0.59 g,10.5 mmol)。升溫至80 ℃攪拌4.5小時。反應完成後,過濾反應液,並用適量乙酸乙酯洗滌濾渣。減壓濃縮濾液,矽膠柱柱層析得化合物1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-醇(0.75 g,產率88%)。LCMS ESI(+)m/z:402.2(M+1).
步驟E:
將化合物1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-醇(750 mg,1.87 mmol)溶解在10 mL乙酸中,加入原甲酸三乙酯(2.77 g,18.7 mmol),升溫至116 ℃攪拌反應0.5小時。反應完成後減壓濃縮,矽膠柱柱層析得化合物1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-醇(453 mg,產率59%)。LCMS ESI(+)m/z:412.2(M+1).
步驟F:
將化合物1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-醇(150 mg,0.36 mmol)溶解在10 mL二氯甲烷中,加入甲基磺醯氯(82 mg,0.72 mmol)和三乙胺(109 mg,1.08 mmol),室溫下攪拌反應1小時。反應完成後減壓濃縮,矽膠柱柱層析得化合物1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基甲基磺酸酯(144 mg,產率82%)。LCMS ESI(+)m/z:490.2(M+1)。
步驟G:
將化合物1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基甲基磺酸酯(95 mg,0.19 mmol)溶解在5 mLN,N
-二甲基甲醯胺中,加入氰化鈉(82 mg,1.67 mmol),升溫至80 ℃,氮氣保護下攪拌反應16小時。反應完成後加入適量氫氧化鈉水溶液,用乙酸乙酯萃取(3×20 mL)。合併有機相,無水硫酸鈉乾燥。過濾,旋乾,得化合物1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-甲腈(42 mg,產率50%)。LCMS ESI(+)m/z:421.2(M+1)。
步驟H:
將化合物1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-甲腈(42 mg,0.1 mmol)溶解在8 mL甲醇中,加入叔丁醇鉀(56 mg,0.5 mmol),室溫攪拌反應6小時。反應完成後用乙酸調pH至7 - 8,減壓濃縮,高效液相製備得化合物1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-甲腈(12 mg,產率45%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.86 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 7.46 (t, 1H), 6.84 (dd,J
= 3.0, 1.8 Hz, 1H), 3.45 - 3.36 (m, 2H), 3.32 - 3.28 (m, 2H), 3.24 - 3.12 (m, 1H), 2.24 - 2.14 (m, 2H), 2.14 - 2.03 (m, 2H). LCMS ESI(+)m/z:267.2(M+1).
2-(1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈
步驟A:
將1-Boc
-4-氰基甲基哌啶(5.0 g,22.3 mmol)溶解在20 mL二氯甲烷中,在0 ℃下,緩慢加入三氟乙酸20 mL。然後室溫攪拌2小時。反應完成後減壓濃縮得到化合物4-氰基甲基哌啶三氟乙酸鹽(5.53 g,產率100%)。
步驟B:
將化合物4-氰基甲基哌啶三氟乙酸鹽(5.53 g,20.0 mmol)、亞硝酸鈉(2.76 g,40.0 mmol)溶解在30 mL水中,0 ℃下緩慢滴加乙酸5.0 mL。在35 ℃攪拌反應16小時。反應結束後,反應液用碳酸鈉調pH至8,用250 mL乙酸乙酯分五次萃取。合併有機相,用無水硫酸鈉乾燥,過濾,旋乾得化合物1-亞硝基-4-氰基甲基哌啶(5.3 g,產率70%)。LCMS ESI(+)m/z:154.1(M+1).
步驟C:
將化合物1-亞硝基-4-氰基甲基哌啶(5.2 g,20.0 mmol)溶解在15 mL甲醇中,加入鋅粉(3.92 g,60.0 mmol),0 ℃下緩慢滴加乙酸15 mL。滴加完成後在30 ℃攪拌反應3小時。反應完成後將反應液過濾,旋蒸濾液得化合物1-胺基-4-氰基甲基哌啶(5.3 g,產率60%)。LCMS ESI(+)m/z:140.1(M+1).
步驟D:
將化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(3.51 g,10.0 mmol)、N,N
-二異丙基乙胺(7.75 g,60.0 mmol)和1-胺基-4-氰甲基哌啶(2.09 g,15.0 mmol)加入到200 mL異丙醇中(懸濁液)。在95 ℃下攪拌反應16小時。反應完成後,冷卻至室溫,加入200 mL水,用乙酸乙酯萃取(3×250 mL),合併有機相,用300 mL飽和食鹽水洗滌,用無水硫酸鈉乾燥,過濾,旋蒸,矽膠柱層析純化得到化合物2-(1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(2.02 g,產率44%)。LCMS ESI(+)m/z:455.1(M+1).
步驟E:
將化合物2-(1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(1.37 g,3.0 mmol)加至60 mL 乙醇和20 mL水的混合溶中(懸濁液),然後依次加入氯化銨固體(0.64 g,12.0 mmol)和鐵粉(0.67 g,12.0 mmol)。升溫至80 ℃攪拌2.5小時。反應完成後,過濾反應液,並用50 mL乙酸乙酯洗滌濾渣。濾液加入50 mL水,用乙酸乙酯萃取(3×70 mL)。合併有機相,用150 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液得到化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(1.02 g,產率80%)。LCMS ESI(+)m/z:425.1(M+1).
步驟F:
將化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(424 mg,1.0 mmol)溶解在10 mL乙酸中,加入原甲酸三乙酯(1.48 g,10 mmol),升溫至116 ℃攪拌反應0.5小時。反應完成後減壓濃縮,矽膠柱柱層析得化合物2-(1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(256 mg,產率59%)。LCMS ESI(+)m/z:435.2(M+1).
步驟G:
將化合物2-(1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(95 mg,0.2 mmol)溶解在10 mL四氫呋喃中,加入60%的鈉氫(40 mg,1.0 mmol),室溫下攪拌反應6小時。反應完成後用乙酸調pH至7 - 8,減壓濃縮,矽膠柱柱層析和高效液相製備得化合物2-(1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(24 mg,產率42%)。1
H NMR (400 MHz, CDCl3
)δ
10.07 (s, 1H), 8.81 (s, 1H), 8.13 (s, 1H), 7.40 (s, 1H), 6.80 (s, 1H), 3.56 - 3.19 (m, 4H), 2.48 (d, J = 6.4 Hz, 2H), 2.13 - 2.08 (m, 2H), 2.07 - 1.94 (m, 1H), 1.91 - 1.75 (m, 2H). LCMS ESI(+)m/z:281.2(M+1)。
2-(1-(甲基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈
步驟A:
將三乙基氧嗡四氟化硼(190 mg, 1.0 mmol)和乙醯胺(59 mg, 1.0 mmol)溶解在10 mL四氫呋喃中,室溫下攪拌反應2小時。減壓濃縮得到無色油狀物,將其溶解在5 mL無水乙醇,加至溶解化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(212 mg,0.5 mmol)的5 mL無水乙醇中。升溫至75 ℃攪拌反應1小時。反應完成後用飽和碳酸氫鈉水溶液淬滅,加入30mL水,用乙酸乙酯萃取(3×30 mL),合併有機相,用50 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液,矽膠柱柱層析得化合物2-(1-(2-甲基-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(180 mg,產率80%)。LCMS ESI(+)m/z:448.1 (M+1).
步驟B:
將化合物2-(1-(2-甲基-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(180 mg,0.4 mmol)溶解在9 mL甲醇中,加入1 N氫氧化鈉水溶液4 mL,室溫攪拌反應16小時。反應完成後用乙酸調pH至7 - 8,減壓濃縮,矽膠柱柱層析和高效液相製備得到化合物2-(1-(2-甲基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H)-基)哌啶-4-基)乙腈(70 mg,產率60%)。1
H NMR (400 MHz, DMSO-d6
) δ 11.86 (s, 1H), 8.46 (s, 1H), 7.48 (t, J = 3.0 Hz,1H), 6.70 (dd, J = 3.2 Hz, 1.6 Hz, 1H), 3.57 (t, J = 10.2 Hz, 2H), 3.13 (d, J = 10.2 Hz, 2H), 2.64 (d, J = 6.4 Hz, 2H), 2.52 (s, 3H), 2.15 - 2.04 (m, 1H), 2.00 - 1.89 (m, 2H), 1.68 - 1.56 (m, 2H). LCMS ESI(+)m/z:295.2(M+1)。
2-(1-(乙基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈
步驟A:
將三乙基氧嗡四氟化硼(190 mg, 1.0 mmol)和丙醯胺(73 mg, 1.0 mmol)溶解在10 mL四氫呋喃中,室溫下攪拌反應2小時。減壓濃縮得到無色油狀物,將其溶解在5 mL無水乙醇,加至溶解化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(212 mg,0.5 mmol)的5 mL無水乙醇中。升溫至75o
C攪拌反應1小時。反應完成後用飽和碳酸氫鈉水溶液淬滅,加入30 mL水,用乙酸乙酯萃取(3×30 mL),合併有機相,用50 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液,矽膠柱柱層析得化合物2-(1-(2-乙基-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(180 mg,產率78%)。LCMS ESI(+)m/z:462.1 (M+1).
步驟B:
將化合物2-(1-(2-乙基-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(180 mg,0.39 mmol)溶解在9 mL甲醇中,加入1 N氫氧化鈉水溶液4 mL,室溫攪拌反應16小時。反應完成後用乙酸調pH至7 - 8,減壓濃縮,矽膠柱柱層析和高效液相製備得到化合物2-(1-(2-乙基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(75 mg,產率62%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.86 (s, 1H), 8.49 (s, 1H), 7.48 (t,J
= 3.0 Hz,1H), 6.71 (dd,J
= 3.2 Hz, 1.6 Hz, 1H), 3.59 (t,J
= 10.2 Hz, 2H), 3.12 (d,J
= 10.2 Hz, 2H), 2.92 (q,J
= 7.5 Hz, 2H), 2.65 (d,J
= 6.4 Hz, 2H), 2.16 - 2.05 (m, 1H), 2.00 - 1.91 (m, 2H), 1.68 - 1.56 (m, 2H), 1.31 (t,J
= 7.5 Hz, 3H). LCMS ESI(+)m/z:309.2(M+1)。
2-(1-(2-(羥甲基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈
步驟A:
將三乙基氧嗡四氟化硼(135 mg, 0.71 mmol)和羥基乙醯胺(53 mg, 0.71 mmol)溶解在10 mL四氫呋喃中,室溫下攪拌反應2小時。減壓濃縮得到無色油狀物,將其溶解在5 mL無水乙醇,加至溶解化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(100 mg,0.24 mmol)的5 mL無水乙醇中。升溫至75 ℃攪拌反應1小時。反應完成後用飽和碳酸氫鈉水溶液淬滅,加入30 mL水,用乙酸乙酯萃取(3×30 mL),合併有機相,用50 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液,矽膠柱柱層析得化合物2-(1-(2-(羥甲基)-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(80 mg,產率72%)。LCMS ESI(+)m/z:465.1(M+1).
步驟B:
將化合物2-(1-(2-(羥甲基)-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(80 mg,0.17 mmol)溶解在9 mL甲醇中,加入1 N氫氧化鈉水溶液3 mL,室溫攪拌反應16小時。反應完成後用乙酸調pH至7 - 8,減壓濃縮,矽膠柱柱層析和高效液相製備得到化合物2-(1-(2-(羥甲基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(20 mg,產率38%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.92 (s, 1H), 8.54 (s, 1H), 7.50 (t,J
= 3.0 Hz, 1H), 6.73 (dd,J
= 3.2, 1.8 Hz, 1H), 5.31 (t,J
= 6.0 Hz,1H), 5.16 (q,J
= 6.6 Hz, 1H), 4.70 (d,J
= 6.0 Hz, 2H), 3.57 (t,J
= 10.2 Hz,2H), 3.15 (dd,J
= 10.2Hz, 2H), 2.64 (d,J
= 6.4 Hz, 2H), 2.15 - 2.04 (m, 1H), 1.98 - 1.89 (m, 2H), 1.72 - 1.60 (m, 2H). LCMS ESI(+)m/z:311.2(M+1)。
2-(1-(2-(2-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈
步驟A:
將三乙基氧嗡四氟化硼(135 mg, 0.71 mmol)和3-羥基丙醯胺(64 mg, 0.71 mmol)溶解在10 mL四氫呋喃中,室溫下攪拌反應2小時。減壓濃縮得到無色油狀物,將其溶解在5 mL無水乙醇,加至溶解化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(100 mg,0.24 mmol)的5 mL無水乙醇中。升溫至75 ℃攪拌反應1小時。反應完成後用飽和碳酸氫鈉水溶液淬滅,加入30 mL水,用乙酸乙酯萃取(3×30 mL),合併有機相,用50 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液,矽膠柱柱層析得化合物2-(1-(2-(羥乙基)-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(60 mg,產率52%)。LCMS ESI(+)m/z:479.1(M+1).
步驟B:
將化合物2-(1-(2-(羥乙基)-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H)-基)哌啶-4-基)乙腈(60 mg,0.13 mmol)溶解在9 mL甲醇中,加入1 N氫氧化鈉水溶液3 mL,室溫攪拌反應16小時。反應完成後用乙酸調pH至7 - 8,減壓濃縮,矽膠柱柱層析和高效液相製備得到化合物2-(1-(2-(羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(20 mg,產率48%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.87 (s, 1H), 8.49 (s, 1H), 7.48 (d,J
= 3.4 Hz, 1H), 6.71 (d,J
= 3.4, 1.8 Hz, 1H), 4.80 (brs, 1H), 3.84 (t,J
= 7.0 Hz,2H), 3.59 (t,J
= 10.4Hz, 2H), 3.16 - 3.06 (m, 4H), 2.65 (d,J
= 6.4 Hz, 2H), 2.15 - 2.04 (m, 1H), 1.98 - 1.89 (m, 2H), 1.72 - 1.60 (m, 2H). LCMS ESI(+)m/z:325.1(M+1)。
(R
)-2-(1-(2-(1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈
步驟A:
將三乙基氧嗡四氟化硼(251 mg,1.32 mmol)和R
-乳醯胺(118 mg,1.32 mmol)溶解在8 mL四氫呋喃中,室溫下攪拌反應2小時。減壓濃縮得到無色油狀物,將其溶解在5 mL無水乙醇,加至溶解化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(189 mg,0.44 mmol)的5 mL無水乙醇中。升溫至75 ℃攪拌反應1小時。反應完成後用碳酸氫鈉水溶液淬滅,加入30 mL水,用乙酸乙酯萃取(3×30 mL),合併有機相,用50 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液,矽膠柱柱層析得化合物(R
)-2-(1-(2-(1-羥乙基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(110 mg,產率52%)。LCMS ESI(+)m/z:479.1(M+1).
步驟B:
將化合物(R
)-2-(1-(2-(1-羥乙基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(110 mg,0.23 mmol)溶解在9 mL甲醇中,加入1 N氫氧化鈉水溶液3 mL,室溫攪拌反應16小時。反應完成後用乙酸調pH至7 - 8,減壓濃縮,矽膠柱柱層析和高效液相製備得化合物(R
)-2-(1-(2-(1-羥乙基)-咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(30 mg,產率40%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.92 (s, 1H), 8.55 (s, 1H), 7.50 (d,J
= 3.4 Hz, 1H), 6.73 (d,J
= 3.4 Hz, 1H), 5.31 (s, 1H), 5.16 (q,J
= 6.6 Hz, 1H), 3.65 - 3.53 (m, 2H), 3.15 (dd,J
= 30.2, 10.0 Hz, 2H), 2.64 (d,J
= 6.4 Hz, 2H), 2.17 - 2.04 (m, 1H), 1.98 - 1.89 (m, 2H), 1.72 - 1.60 (m, 2H), 1.56 (d,J
= 6.6 Hz, 3H). LCMS ESI(+)m/z:325.0(M+1)。
(S
)-2-(1-(2-(1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈
步驟A:
將三乙基氧嗡四氟化硼(298 mg,1.56 mmol)和S
-乳醯胺(140 mg,1.56 mmol)溶解在10 mL四氫呋喃中,室溫下攪拌反應2小時。減壓濃縮得到無色油狀物,將其溶解在5 mL無水乙醇,加至溶解化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(222 mg,0.52 mmol)的5 mL無水乙醇中。升溫至75 ℃攪拌反應1小時。反應完成後用飽和碳酸氫鈉水溶液淬滅,加入30 mL水,用乙酸乙酯萃取(3×30 mL),合併有機相,用50 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液,矽膠柱柱層析得化合物(S
)-2-(1-(2-(1-羥乙基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(160 mg,產率64%)。LCMS ESI(+)m/z:479.1(M+1).
步驟B:
將化合物(S
)-2-(1-(2-(1-羥乙基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(160 mg)溶解在9 mL甲醇中,加入1 N氫氧化鈉水溶液3 mL,室溫攪拌反應16小時。反應完成後用乙酸調pH至7 - 8,減壓濃縮,矽膠柱柱層析和高效液相製備得到化合物(S
)-2-(1-(2-(1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(44.6mg,產率41%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.92 (s, 1H), 8.55 (s, 1H), 7.50 (d,J
= 3.4 Hz, 1H), 6.73 (d,J
= 3.4 Hz, 1H), 5.31 (s, 1H), 5.16 (q,J
= 6.6 Hz, 1H), 3.65 - 3.53 (m, 2H), 3.15 (dd,J
= 30.2, 10.0 Hz, 2H), 2.64 (d,J
= 6.4 Hz, 2H), 2.17 - 2.04 (m, 1H), 1.98 - 1.89 (m, 2H), 1.72 - 1.60 (m, 2H), 1.56 (d,J
= 6.6 Hz, 3H). LCMS ESI(+)m/z:325.0(M+1)。
2-(1-(2-胺基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈
步驟A:
將4-羥甲基哌啶(3.01 g,26.1 mmol)、亞硝酸鈉(2.76 g,40.0 mmol)溶解在30 mL水中,0 ℃下緩慢滴加乙酸4.0 mL。在30 ℃攪拌反應16小時。反應液用飽和碳酸氫鈉水溶液調pH至8,用250 mL乙酸乙酯分五次萃取。合併有機相,用無水硫酸鈉乾燥,過濾,旋蒸得到化合物1-亞硝基-4-羥甲基哌啶(2.87 g,產率76%)。LCMS ESI(+)m/z:145.1(M+1).
步驟B:
將化合物1-亞硝基-4-羥甲基哌啶(2.87 g,20.0 mmol)溶解在15 mL甲醇中,加入鋅粉(5.23 g,80.0 mmol),0 ℃條件下緩慢滴加乙酸15mL。滴加完成後在室溫攪拌反應16小時。反應液過濾,旋蒸濾液得到粗品化合物1-胺基-4-羥甲基哌啶(3.02 g,產率65%)。LCMS ESI(+)m/z:131.1(M+1).
步驟C:
將化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(2.32 g,6.6 mmol)、N,N
-二異丙基乙胺(3.41 g,26.4 mmol)和1-胺基-4-羥甲基哌啶(1.03 g,7.9 mmol)加入到60 mL異丙醇中(懸濁液)。在95 ℃下,攪拌反應16小時。反應完成後,冷卻至室溫,加入100 mL水,用乙酸乙酯萃取(3×100 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物(1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲醇(2.11 g,產率71%)。LCMS ESI(+)m/z:446.2(M+1)。
步驟D:
將化合物(1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲醇(1.5 g,3.37 mmol)溶解在30 mL無水二氯甲烷中,在0 ℃下,加入三乙胺(1.02 g,10.1 mmol),然後滴加甲磺醯氯(465 mg,4.06 mmol),在氮氣保護下,室溫反應18小時。反應結束後,在0 ℃下加水淬滅,用二氯甲烷萃取(3×80 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物(1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲基甲磺酸酯(1.6 g,產率91%)。LCMS ESI(+)m/z:524.1(M+1).
步驟E:
將化合物(1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲基甲磺酸酯(300 mg,0.57 mmol),鐵粉(193 mg,3.44 mmol)和氯化銨(61 mg,1.15 mmol)懸浮在9 mL乙醇和3 mL水的混合溶液中,在氮氣保護下,75 ℃攪拌2小時。反應結束後,過濾,旋乾,純化得到產物(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲基甲磺酸酯(85 mg,產率30%)。LCMS ESI(+)m/z:494.1(M+1).
步驟F:
將化合物(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲基甲磺酸酯(80 mg,0.16 mmol)和溴化氰(0.08 mL)溶在10 mL甲醇中,加入到封管中,在30 ℃下攪拌20小時。反應結束後,旋乾,柱層析純化得到產物(1-(2-胺基-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基))甲基甲磺酸酯(90 mg,產率100%)。LCMS ESI(+)m/z:519.1(M+1).
步驟G:
將化合物(1-(2-胺基-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基))甲基甲磺酸酯(80 mg,0.15 mmol),三甲基氰矽烷(31 mg,0.31 mmol)和碳酸鉀溶在10 mLN,N
-二甲基甲醯胺中,在氮氣保護下,室溫攪拌20小時。反應結束後,加水20 mL,用乙酸乙酯萃取(3×20 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物2-(1-(2-胺基-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(60 mg,產率87%)。LCMS ESI(+)m/z:450.1(M+1).
步驟H:
將化合物2-(1-(2-胺基-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(60 mg,0.13 mmol)溶解在二氯甲烷(10 mL)和甲醇(10 mL)混合溶液中,加入碳酸鉀(301 mg,2.18 mmol),在氮氣保護下,室溫攪拌18小時。反應結束後,過濾,加水20 mL,用乙酸乙酯萃取(5×50 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,純化得化合物2-(1-(2-胺基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(20 mg,產率51%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.50(s, 1H), 8.11 (s, 1H), 7.37 (t,J
= 3.2 Hz, 1H), 6.54(dd,J
= 3.2, 2.0 Hz, 1H), 6.24 (s, 1H), 3.49 (t,J
= 10.2 Hz, 2H), 3.04 (d,J
= 10.2 Hz, 2H), 2.61 (d,J
= 6.8 Hz, 1H), 2.03 - 1.96 (m, 1H), 1.91 - 1.88 (m, 2H),1.72 - 1.68 (m, 2H). LCMS ESI(+)m/z:296.1(M+1).
N
-((1-(4-(氰甲基)哌啶-1-基)-1,6-二氫咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-2-基)甲基)甲磺醯胺
步驟A:
氮氣下將Boc
-甘胺醯胺(328 mg,1.88 mmol)和三乙基氧鎓四氟硼酸加入(358 mg,1.88 mmol)到15 mL無水四氫呋喃中,30℃攪拌2小時。減壓濃縮反應液。將殘渣溶於15 mL乙醇,氮氣下加入化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(160 mg,0.38 mmol),75 ℃攪拌反應1小時。減壓濃縮反應液。加入飽和碳酸氫鈉溶液(10 mL)和乙酸乙酯(15 mL),攪拌5分鐘。分離有機相,用45 mL乙酸乙酯萃取3次水相。合併有機相,10 mL水洗,10 mL飽和食鹽水洗,無水硫酸鈉乾燥,減壓濃縮,矽膠柱層析得化合物叔丁基-((1-(4-(氰甲基)哌啶-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-2-基)甲基)胺基甲酸酯(200 mg,產率94%)。LCMS ESI(+)m/z:564.2(M+1).
步驟B:
將化合物叔丁基-((1-(4-(氰甲基)哌啶-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-2-基)甲基)胺基甲酸酯(100 mg,0.18 mmol)溶解在3 mL二氯甲烷中,在冰浴下滴加三氟乙酸(1 mL)。在氮氣保護下升至室溫攪拌4小時。減壓濃縮反應液。加入5 mL飽和碳酸氫鈉溶液,攪拌5分鐘。用15 mL二氯甲烷萃取3次。合併有機相,用5 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液得到化合物2-(1-(2-(胺甲基)-6-對甲苯磺醯基咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(82 mg,產率100%)。LCMS ESI(+)m/z:464.1(M+1)。
步驟C:
將化合物2-(1-(2-(胺甲基)-6-對甲苯磺醯基咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙腈(82 mg, 0.06 mmol)溶解在3 mL二氯甲烷中,冰浴和氮氣保護下加入三乙胺(54 mg,0.53 mmol)和甲基磺醯氯(30 mg,0.27 mmol)。冰浴下攪拌2小時。加入飽和碳酸氫鈉溶液(10 mL),室溫攪拌30分鐘。用15 mL二氯甲烷萃取3次,合併有機相,用3 mL飽和食鹽水洗滌,無水硫酸鈉乾燥,減壓濃縮,矽膠柱柱層析得化合物N
-((1-(4-(氰甲基)哌啶-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-2-基)甲基)甲磺醯胺(30 mg,產率71%)。LCMS ESI(+)m/z:542.1(M+1).
步驟D:
將化合物N
-((1-(4-(氰甲基)哌啶-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-2-基)甲基)甲磺醯胺(16 mg,0.03 mmol)溶解在3 mL甲醇中,加入1 N氫氧化鈉溶液(1 mL,1.0 mmol)。35 ℃攪拌6小時。用9 mL水稀釋反應液,減壓蒸除甲醇。用15 mL乙酸乙酯萃取殘餘物3次。合併有機相,無水硫酸鈉乾燥,抽濾,減壓蒸除溶劑。殘餘物用高效液相製備得化合物N
-((1-(4-(氰甲基)哌啶-1-基)-1,6-二氫咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-2-基)甲基)甲磺醯胺(48 mg,產率51%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.96 (s, 1H), 8.57 (s, 1H), 7.60 (s, 1H), 7.52 (t,J
= 2.6 Hz, 1H), 6.75 (d,J
= 2.6 Hz, 1H), 4.52 (s, 2H), 3.57 (t,J
= 10.2 Hz, 2H), 3.23 - 3.19 (m, 2H), 2.99 (s, 3H), 2.63 (d,J
= 6.5 Hz, 2H), 2.15 - 2.06 (m, 1H), 1.98 - 1.91 (m, 2H), 1.74 - 1.62 (m, 2H). LCMS ESI(+)m/z:388.1(M+1).
2-(1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)丙腈
步驟A:
將4-哌啶乙醇(21.1 g,100 mmol)溶解在200 mL水和90 mL乙酸中,將亞硝酸鈉(41.4 g,600 mmol)溶解在200 mL水中。0 ℃下將亞硝酸鈉水溶液緩慢滴加至反應體系中,並室溫反應16小時。反應完成後用150 mL乙酸乙酯分三次萃取。合併有機相,用無水硫酸鈉乾燥,過濾,減壓濃縮,矽膠柱柱層析得到化合物1-亞硝基-4-哌啶乙醇(9.5 g,產率60%)。LCMS ESI(+)m/z:159.1(M+1)。
步驟B:
將化合物1-亞硝基-4-哌啶乙醇(8.0 g, 50.1 mmol)溶解在40 mL甲醇中,加入鋅粉(3.14 g,48.0 mmol),室溫下滴加乙酸8 mL。滴加完成後30 ℃攪拌反應15分鐘。反應完成後過濾反應液,旋蒸濾液得到粗品化合物1-胺基-4-哌啶乙醇(4.37 g,產率60%)。LCMS ESI(+)m/z:145.1(M+1).
步驟C:
將化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(2.46 g,7.0 mmol)、N,N
-二異丙基乙胺(4.5 g,35.0 mmol)和1-胺基-4-哌啶乙醇(2.20 g,10.0 mmol)加入到200 mL異丙醇中(懸濁液)。在95 ℃下,攪拌反應16小時。反應完成後,冷卻至室溫,加入300 mL水,用乙酸乙酯萃取(3×250 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物2-(1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙醇(1.97 g,產率61%)。LCMS ESI(+)m/z:460.2(M+1).
步驟D:
將化合物2-(1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙醇(1.17 g,2.55 mmol)溶解在50 mL二氯甲烷中,加入甲基磺醯氯(876 mg, 7.65 mmol)和三乙胺(1.28 g, 12.75 mmol),室溫攪拌反應2小時。反應完成後減壓濃縮得到粗品化合物2-(1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙基甲磺酸酯(1.37 g,產率100%)。LCMS ESI(+)m/z:518.2(M+1)。
步驟E:
將化合物2-(1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙基甲磺酸酯(1.37 g,3.0 mmol)加至45 mL 乙醇和15 mL水的混合溶中(懸濁液),然後依次加入氯化銨固體(0.64 g,12.0 mmol)和鐵粉(0.67 g,12.0 mmol)。升溫至80 ℃,攪拌3小時。反應完成後,過濾反應液,並用適量乙酸乙酯洗滌濾渣。濾液中加入50 mL水,用乙酸乙酯萃取(3×50 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙基甲磺酸酯(1.26 g,產率97%)。LCMS ESI(+)m/z:430.2(M+1).
步驟F:
將化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙基甲磺酸酯(582 mg,1.35 mmol)溶解在25 mL乙酸中,加入原甲酸三乙酯(1.00 g,6.75 mmol),升溫至116 ℃攪拌反應1小時。反應完成後減壓濃縮,矽膠柱柱層析得到化合物2-(1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙基甲磺酸酯(253 mg,產率42%)。LCMS ESI(+)m/z:440.2(M+1).
步驟G:
將化合物2-(1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)乙基甲磺酸酯(253 mg,0.45 mmol)溶解在16 mLN,N
-二甲基甲醯胺中,分別加入碳酸鉀(187 mg,1.35 mmol)和三甲基氰矽烷(134 mg,1.35 mmol),升溫至100 ℃,氮氣保護下攪拌反應20小時。反應完成後加入適量氫氧化鈉水溶液,用乙酸乙酯萃取(3×100 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物3-(1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)丙腈(97 mg,產率48%)。LCMS ESI(+)m/z:449.2(M+1)。
步驟H:
將化合物3-(1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)丙腈(97 mg,0.22 mmol)溶解在9 mL甲醇中,加入1 N氫氧化鈉水溶液3 mL,室溫攪拌反應16小時。反應完成後用乙酸調pH至7 - 8,減壓濃縮,矽膠柱柱層析和高效液相製備得化合物2-(1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)丙腈(30 mg,產率48%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.82 (s, 1H), 8.58 (s, 1H), 8.55 (s, 1H), 7.44 (t,J
= 2.8 Hz, 1H), 6.73 (dd,J
= 3.1, 1.9 Hz, 1H), 3.36 - 3.33 (m, 1H), 3.31 - 3.26 (m, 3H), 2.61 (t,J
= 7.0 Hz, 2H), 1.96 - 1.90 (m, 2H), 1.71 - 1.46 (m, 5H). LCMS ESI(+)m/z:295.2(M+1).
6-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-6-氮雜螺[2.5]辛烷-1-甲腈
步驟A:
將二乙基(氰基甲基)膦酸酯(3.72 g,21.0 mmol)溶解在30 mL無水四氫呋喃中,在0 ℃下,加入60%的氫化鈉(0.84 g,21 mmol),在此溫度下反應半小時,然後滴加含有4-氧代哌啶-1-羧酸叔丁酯(2.09 g,10.5 mmol)的四氫鋰鋁溶液(10 mL),然後在氮氣保護下,室溫反應3小時。反應結束後,在0 ℃下加水淬滅,用乙酸乙酯(240 mL)分三次萃取,乾燥,旋乾,純化得到產物4-(氰基亞甲基)哌啶-1-羧酸叔丁酯(2.2 g,產率94%)。1
H NMR (400 MHz, CDCl3
)δ
5.19 (s, 1H), 3.54 - 3.48 (m, 4H), 2.56 (t,J
= 6.0 Hz, 1H), 2.33 (t,J
= 6.0 Hz,1H).
步驟B:
將叔丁醇鉀(1.11 g,9.9 mmol)溶解在20 mL二甲亞碸中,緩慢加入三甲基碘化亞碸(2.18 g,9.9 mmol),室溫反應1.5小時,往這個反應液裡加入含有4-(氰基亞甲基)哌啶-1-羧酸叔丁酯(2.0 g,9.0 mmol)的二甲亞碸溶液,氮氣保護下升溫到45 ℃攪拌16小時。反應結束後,用氯化銨水溶液淬滅,用乙酸乙酯(240 mL)分三次萃取,乾燥,旋乾,純化得到產物1-氰基-6-氮雜螺[2,4]辛烷-6-羧酸叔丁酯(1.8 g,產率85%)。LCMS ESI(+)m/z:237.1(M+1).
步驟C:
將化合物1-氰基-6-氮雜螺[2,4]辛烷-6-羧酸叔丁酯(1.8 g,7.6 mmol)溶解在20 mL二氯甲烷中,冰浴下,滴加三氟乙酸(2 mL),升溫到75 ℃攪拌18小時。反應結束後,旋乾得到粗品產物6-氮雜-螺[2.5]辛烷-1-甲腈三氟乙酸鹽(1.0 g,產率97%)。LCMS ESI(+)m/z:137.1(M+1).
步驟D:
將化合物6-氮雜-螺[2.5]辛烷-1-甲腈三氟乙酸鹽(1.0 g,7.4 mmol)溶在10 mL水和1 mL冰醋酸中,冰浴下滴加含有亞硝酸鈉(1.0 g, 14.7 mmol)的水溶液,室溫攪拌20小時。反應結束後,用碳酸氫鈉水溶液淬滅,用乙酸乙酯(240 mL)分三次萃取,旋乾、純化得化合物6-亞硝基-6-氮雜-螺[2.5]辛烷-1-甲腈(0.6 g,產率50%)。LCMS ESI(+)m/z:166.1.
步驟E:
將6-亞硝基-6-氮雜-螺[2.5]辛烷-1-甲腈(0.3 g,1.8 mmol),鋅粉(1.17 g,18 mmol)懸浮在甲醇(5 mL)和醋酸(0.5 mL)中,在氮氣保護下,室溫攪拌2小時。反應結束後,過濾,旋乾得到產物6-胺基-6-氮雜螺[2.5]辛烷-1-甲腈(274 mg,產率100%)。LCMS ESI(+)m/z:152.1(M+1)
步驟F:
將化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(634 mg,1.8 mmol)、N,N
-二異丙基乙胺(2.32 g,18 mmol)和6-胺基-6-氮雜螺[2.5]辛烷-1-甲腈(274 mg,1.8 mmol)加入到10 mL異丙醇中(懸濁液)。在95 ℃下,攪拌反應18小時。反應完成後,冷卻至室溫,加入100 mL水,用乙酸乙酯萃取(3×100 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物6-((5-硝基-1-對甲苯磺醯-1H-吡咯并[2,3-b
]吡啶-4-基)胺基)-6-氮雜螺[2.5]辛烷-1-甲腈(430 mg,產率51%)。LCMS ESI(+)m/z:467.1(M+1).
步驟G:
將化合物6-((5-硝基-1-對甲苯磺醯-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)-6-氮雜螺[2.5]辛烷-1-甲腈(430 mg,0.92 mmol)加至20 mL乙醇和4 mL水的混合溶中(懸濁液),然後依次加入氯化銨固體(99 mg,1.84 mmol)和鐵粉(300 mg,5.54 mmol)。升溫至80 ℃,攪拌3小時。反應完成後,過濾反應液,並用適量乙酸乙酯洗滌濾渣。濾液中加入20 mL水,用乙酸乙酯萃取(3×20 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物6-((5-胺基-1-對甲苯磺醯-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)-6-氮雜螺[2.5]辛烷-1-甲腈(347 mg,產率62%)。LCMS ESI(+)m/z:437.1(M+1).
步驟H:
將化合物6-((5-胺基-1-對甲苯磺醯-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)-6-氮雜螺[2.5]辛烷-1-甲腈(230 mg,0.53 mmol)溶解在5 mL乙酸中,加入原甲酸三乙酯(392 mg,2.65 mmol),升溫至116 ℃攪拌反應2小時。反應完成後減壓濃縮,矽膠柱柱層析得到化合物6-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-6-氮雜螺[2.5]辛烷-1-甲腈(120 mg,產率51%)。LCMS ESI(+)m/z:446.1 (M+1).
步驟I:
將化合物6-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-6-氮雜螺[2.5]辛烷-1-甲腈(110 mg,0.25 mmol)溶解在10 mL甲醇和10 mL二氯甲烷混合溶劑中,加入碳酸鉀(681 mg,4.9 mmol),在氮氣保護下,室溫攪拌18小時。反應結束後,過濾,加水20 mL,用乙酸乙酯萃取(5×50 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,高效液相製備得化合物6-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-6-氮雜螺[2.5]辛烷-1-甲腈(20 mg,產率28%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.86(s, 1H), 8.59 (s, 1H), 8.57 (s, 1H), 7.47 (t,J
= 3.0 Hz, 1H), 6.77 (dd,J
= 3.2, 2.0 Hz, 1H), 3.41 - 3.32 (m, 4H), 2.09 - 1.78 (m, 5H), 1.27 - 1.19 (m, 2H). LCMS ESI(+)m/z:293.1(M+1).
6-(2-((R
)-1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-6-氮雜螺[2.5]辛烷-1-甲腈
步驟A:
將三乙基氧嗡四氟化硼(1.31 g, 6.9 mmol)和R
-乳醯胺(612 mg,6.9 mmol)溶解在20 mL 四氫呋喃中,室溫攪拌反應2小時。減壓濃縮得到無色油狀物,將其溶解在10 mL無水乙醇,加至溶解化合物6-((5-胺基-1-對甲苯磺醯-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)-6-氮雜螺[2.5]辛烷-1-甲腈(504 mg,1.11 mmol)的10 mL無水乙醇中。升溫至75 ℃攪拌反應1小時。反應完成後用碳酸氫鈉水溶液淬滅,加入100 mL水,用乙酸乙酯萃取(3×100 mL),合併有機相,用200 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液,矽膠柱柱層析得化合物6-(2-((R
)-1-羥乙基)6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-6-氮雜螺[2.5]辛烷-1-甲腈(590 mg,產率52%)。LCMS ESI(+)m/z:490.1(M+1).
步驟B:
將化合物6-(2-((R
)-1-羥乙基)6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-6-氮雜螺[2.5]辛烷-1-甲腈(290 mg,0.59 mmol)溶解在15 mL甲醇中,加入1 N氫氧化鈉水溶液5 mL,30 ℃攪拌反應6小時。反應完成後用乙酸調pH至7 - 8,減壓濃縮,矽膠柱柱層析和高效液相製備得化合物6-(2-((R
)-1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-6-氮雜螺[2.5]辛烷-1-甲腈(80 mg,產率28%)。1
H NMR (400 MHz, DMSO-d6
)δ
12.18 (s, 1H), 8.64 (s, 1H), 7.64 (t,J
= 2.8 Hz, 1H), 7.47 (d,J
= 8.0 Hz, 1H), 6.68 (dd,J
= 3.3, 1.8 Hz, 1H), 5.26 (q,J
= 6.4 Hz, 1H), 3.78 - 3.62 (m, 2H), 3.33 - 3.16 (m, 2H), 2.43 - 2.22 (m, 2H), 1.60 (d,J
= 6.6 Hz, 3H), 1.49 (d,J
= 13.8 Hz, 1H), 1.40 - 1.21 (m, 4H). LCMS ESI(+)m/z:337.1(M+1).
2-(1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)-2-甲基丙腈
步驟A:
將1-Boc
-4-氰基甲基哌啶(4.5 g,20.0 mmol)溶解在130 mL無水四氫呋喃中,氮氣保護,冰浴條件下滴加雙(三甲基矽基)胺基鈉四氫呋喃溶液(2 M,30 mL,60.0 mmol)。滴加完成後冰浴條件下攪拌10分鐘,然後將碘甲烷(6.53 g,46.0 mmol)用20 mL無水四氫呋喃稀釋並緩慢滴加至反應液中,滴加完成後室溫氮氣保護攪拌反應16小時。反應液用適量氯化銨飽和溶液淬滅並加入150 mL水,用600 mL乙酸乙酯分三次萃取。合併有機相,用無水硫酸鈉乾燥,過濾,減壓濃縮得到粗品化合物4-(2-氰基丙-2-基)哌啶-1-羧酸叔丁酯(4.02 g,產率79%)。
步驟B:
將化合物4-(2-氰基丙-2-基)哌啶-1-羧酸叔丁酯(4.02 g,15.0 mmol)溶解在30 mL二氯甲烷中,在0 ℃下,緩慢加入三氟乙酸15 mL。室溫下攪拌4小時。減壓濃縮得到化合物2-甲基-2-(哌啶-4-基)丙腈三氟乙酸鹽(3.79 g,產率100%)。
步驟C:
將化合物2-甲基-2-(哌啶-4-基)丙腈三氟乙酸鹽(3.79 g,粗品,15.0 mmol)、亞硝酸鈉(1.55 g,22.5 mmol)溶解在50 mL水中,0 ℃下緩慢滴加乙酸2.6 mL。在35 ℃攪拌反應16小時。反應液用碳酸鈉調pH至8,用250 mL乙酸乙酯分五次萃取。合併有機相,用無水硫酸鈉乾燥,過濾,旋蒸得到化合物2-(1-亞硝基哌啶-4-基)-2-甲基丙腈(2.01 g,產率74%)。LCMS ESI(+)m/z:182.1(M+1).
步驟D:
將化合物2-(1-亞硝基哌啶-4-基)-2-甲基丙腈(1.00 g,5.0 mmol)溶解在30 mL甲醇中,分別加入鋅粉(4.71 g,88.0 mmol)和乙酸6 mL,30 ℃攪拌25分鐘。反應完成後,過濾反應液,減壓濃縮濾液得到化合物2-(1-胺基哌啶-4-基)-2-甲基丙腈(4.73 g,產率80%)。LCMS ESI(+)m/z:168.2(M+1).
步驟E:
將化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(2.11 g,6.0 mmol)、N,N
-二異丙基乙胺(3.88 g,30.0 mmol)和2-(1-胺基哌啶-4-基)-2-甲基丙腈(1.01 g,6.0 mmol)加入到150 mL異丙醇中(懸濁液)。在95 ℃下攪拌反應16小時。反應完成後,冷卻至室溫,加入250 mL水,用乙酸乙酯萃取(3×250 mL),合併有機相,用300 mL飽和食鹽水洗滌,用無水硫酸鈉乾燥,過濾,旋蒸,矽膠柱層析純化得化合物2-甲基-2-(1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)丙腈(1.47 g,產率50%)。LCMS ESI(+)m/z:483.1(M+1).
步驟F:
將化合物2-甲基-2-(1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)丙腈(1.47 g,3.0 mmol)加至75 mL乙醇和25 mL水的混合溶中(懸濁液),然後依次加入氯化銨固體(0.64 g,12.0 mmol)和鐵粉(0.67 g,12.0 mmol)。升溫至80 ℃,攪拌2小時。反應完成後,過濾反應液,並用50 mL乙酸乙酯洗滌濾渣。濾液加入50 mL水,用乙酸乙酯萃取(3×150 mL),合併有機相,用150 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液得到粗品化合物2-甲基-2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)丙腈(1.74 g)。LCMS ESI(+)m/z:453.1(M+1).
步驟G:
將合物2-甲基-2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)丙腈(540 mg,1.2 mmol)溶解在30 mL乙酸中,加入原甲酸三乙酯(890 mg,6.00 mmol)升溫至116℃攪拌反應45分鐘。反應完成後減壓濃縮,矽膠柱柱層析得化合物2-甲基-2-(1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b]吡啶-1(6H
)-基)哌啶-4-基)丙腈(301 mg,產率54%)。LCMS ESI(+)m/z:463.1(M+1).
步驟H:
將化合物2-甲基-2-(1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)丙腈(301 mg,0.65 mmol)溶解在12 mL甲醇和6 mL四氫呋喃中,加入1 N氫氧化鈉水溶液4 mL,35 ℃攪拌反應6小時。反應完成後用乙酸調pH至7 - 8,減壓濃縮,矽膠柱柱層析和高效液相製備得到化合物2-(1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)-2-甲基丙腈(71 mg,產率35%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.85 (s, 1H), 8.56 (s, 1H), 8.53 (s, 1H), 7.46 (t,J
= 2.9 Hz, 1H), 6.74 (dd,J
= 3.3, 1.9 Hz, 1H), 3.40 - 3.33 (m, 4H), 2.09 - 1.99 (m, 2H), 1.76 - 1.60 (m, 3H), 1.38 (s, 6H). LCMS ESI(+)m/z:309.0(M+1)。
(R
)-2-(1-(2-(1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)-2-甲基丙腈
步驟A:
將三乙基氧嗡四氟化硼(633 mg,3.33 mmol)和R
-乳醯胺(297 mg,3.33 mmol)溶解在10 mL 四氫呋喃中,室溫攪拌反應2小時。減壓濃縮得到無色油狀物,將其溶解在5 mL無水乙醇,加至溶解化合物2-甲基-2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)丙腈(504 mg,1.11 mmol)的10 mL無水乙醇中。升溫至75 ℃攪拌反應1小時。反應完成後用碳酸氫鈉水溶液淬滅,加入50 mL水,用乙酸乙酯萃取(3×50 mL),合併有機相,用100 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液,矽膠柱柱層析得化合物(R
)-2-(1-(2-(1-羥乙基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)-2-甲基丙腈(289 mg,產率57%)。LCMS ESI(+)m/z:507.2(M+1).
步驟B:
將化合物(R
)-2-(1-(2-(1-羥乙基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)-2-甲基丙腈(289 mg,0.57 mmol)溶解在15 mL甲醇中,加入1 N氫氧化鈉水溶液5 mL,30 ℃攪拌反應6小時。反應完成後用乙酸調pH至7 - 8,減壓濃縮,矽膠柱柱層析和高效液相製備得化合物(R
)-2-(1-(2-(1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)-2-甲基丙腈(110 mg,產率54%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.92 (s, 1H), 8.55 (s, 1H), 7.50 (t,J
= 3.0 Hz, 1H), 6.74 (dd,J
= 3.3, 1.8 Hz, 1H), 5.30 (d,J
= 6.3 Hz, 1H), 5.21 - 5.13 (m, 1H), 3.66 - 3.51 (m, 2H), 3.20 (dd,J
= 30.4, 10.2Hz,2H), 2.02 (d,J
= 10.7 Hz, 2H), 1.88 (t,J
= 12.0 Hz, 1H), 1.74 - 1.61 (m, 2H), 1.57 (d,J
= 6.6 Hz, 3H), 1.40 (s, 6H). LCMS ESI(+)m/z:353.2(M+1)。
2-(1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-亞基)乙腈
步驟A:
將戴斯-馬丁(2.5 g,6 mmol)懸浮在50 mL二氯甲烷中,然後加入化合物1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-醇(1.2 g,3 mmol),在氮氣保護下,室溫攪拌3小時。反應結束後,旋乾,柱層析純化得化合物1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-酮(550 mg,產率45%)。LCMS ESI(+)m/z:410.1(M+1).
步驟B:
將化合物1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-酮(110 mg,0.27 mmol)溶解在12 mL甲醇中,在0 ℃下加入氫氧化鈉水溶液(2 N,3 mL),在氮氣保護下,室溫攪拌16小時。反應結束後,加水20 mL,用二氯甲烷萃取(5×50 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,純化得化合物1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-酮(50mg,產率73%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.86 (s, 1H), 8.62 (s, 1H), 8.56 (s, 1H),7.47 (t,J
= 3.0 Hz,1H), 6.92 (dd,J
= 3.6, 2.0 Hz, 1H),3.64 - 3.26 (m, 4H), 2.72 - 1.88 (m, 4H).LCMS ESI(+)m/z:256.1 (M+1).
步驟C:
將氰甲基磷酸二乙酯(53 mg,0.3 mmol)溶解在2 mL無水四氫呋喃中,氮氣保護,0 ℃加入60%的鈉氫(24 mg,0.6 mmol)並攪拌30分鐘。將化合物1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-酮(37 mg,0.15 mmol)溶解在1 mL無水四氫呋喃中並加至反應液中,室溫氮氣保護下攪拌反應3小時。反應完成後加入適量飽和氯化銨水溶液,用乙酸乙酯萃取(3×10 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,純化得化合物2-(1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-亞基)乙腈(15 mg,產率39%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.84(s, 1H), 8.60 (s, 1H), 8.56 (s, 1H), 7.45 (d,J
= 3.2 Hz, 1H), 6.79 (d,J
= 3.2 Hz, 1H), 5.74 (s, 1H), 3.42 - 3.33 (m, 4H), 2.86 - 2.83 (m,2H), 2.74 - 2.71(m, 2H). LCMS ESI (+) m/z:279.1 (M+1).
2-(1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-4-甲基哌啶-4-基)乙腈
步驟A:
將化合物4-甲基-4-哌啶甲酸乙酯鹽酸鹽(2.0 g,9.6 mmol)溶解在10 mL水中。在0 ℃下,加入亞硝酸鈉(1.66 g,24.1 mmol),再滴加醋酸(1.16 g,19.2 mmol)。然後在30 ℃攪拌過夜。反應結束後,將反應液冷卻到0 ℃後用碳酸氫鈉將溶液調節pH至7 - 8,用乙酸乙酯萃取(2×20 mL),合併有機相,然後鹽水洗(40 mL),用無水硫酸鈉乾燥。過濾,旋乾,得黃色油狀化合物1-亞硝基-4-甲基-4-哌啶甲酸乙酯(1.91 g,產率99%)。LCMS ESI (+) m/z:201.1 (M+1).
步驟B:
將化合物1-亞硝基-4-甲基-4-哌啶甲酸乙酯(1.91 g,9.5 mmol)溶解在50 mL四氫呋喃中。在0 ℃下,緩慢加入2.5 M四氫鋰鋁溶液(11.4 mL,28.6 mmol )。氮氣環境下室溫攪拌三個小時。反應結束後,將反應液冷卻到0 ℃,緩慢加入水(1.1 mL),然後加入15%氫氧化鈉(1.1 mL)和水(3.3 mL),室溫下攪拌15分鐘後過濾,旋乾,柱層析純化得化合物1-胺基-4-甲基-4-羥甲基哌啶(1.15 g,產率80%)。LCMS ESI (+) m/z:145.1 (M+1).
步驟C:
將化合物1-胺基-4-甲基-4-羥甲基哌啶(806 mg,5.6 mmol),化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(966 mg,2.8 mmol)以及N,N
-二異丙基乙胺(2.13 g,16.5 mmol)溶解在50 mL異丙醇中,將反應液在88 ℃下攪拌過夜。反應結束後,將反應液旋乾,柱層析純化得黃色固體化合物(4-甲基-1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲醇(787 mg,產率62%)。LCMS ESI (+) m/z:460.1 (M+1).
步驟D:
將化合物(4-甲基-1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲醇(2.69 g,5.9 mmol)溶於30 mL二氯甲烷中,然後加入三乙胺(1.19 g,11.7 mmol)以及甲磺醯氯(805 mg,7.0 mmol),室溫下攪拌4小時。反應結束後,將反應液旋乾,柱層析純化得黃色固體化合物(4-甲基-1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲基甲磺酸酯(3.06 g,產率97%)。LCMS ESI (+) m/z:538.0 (M+1).
步驟E:
將化合物(4-甲基-1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲基甲磺酸酯(2.96 g,5.5 mmol)溶於90 mL乙醇中,然後加入鐵粉(2.46 g,44.1 mmol)以及氯化銨(2.36 g,44.1 mmol)溶於水(30 mL),80 ℃下攪拌2小時。反應結束後,將反應液過濾,旋乾,柱層析純化得固體化合物(4-甲基-1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲基甲磺酸酯(2.14 g,產率77%)。LC-MS: m/z508.1 (M+1).
步驟F:
將化合物(4-甲基-1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲基甲磺酸酯(1.3 g,2.5 mmol)溶於40 mL醋酸中,加入原甲酸三乙酯(1.85 g,12.5 mmol)升溫至116 ℃下攪拌45分鐘。反應結束後,將反應液旋乾,柱層析純化得固體化合物(4-甲基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)甲基甲磺酸酯(1.24 g,產率94%)。LCMS ESI (+) m/z:518.0 (M+1).
步驟G:
將化合物(4-甲基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)哌啶-4-基)甲基甲磺酸酯(100 mg,0.19 mmol)溶於5 mLN,N-二甲基甲醯胺中,然後加入氰化鈉(47 mg,0.97 mmol),120 ℃下攪拌16小時。反應結束後,將反應液旋乾,柱層析純化製備得化合物2-(1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-4-甲基哌啶-4-基)乙腈(28mg,產率49%).1
H NMR (400 MHz, CDCl3
)δ
9.72 (s, 1H), 8.80 (s, 1H), 8.17 (s, 1H), 7.38 (t,J
= 2.8 Hz,1H), 6.82 (dd,J
= 3.1, 2.1 Hz,1H), 3.52 - 3.36 (m, 2H), 3.36 - 3.24 (m, 2H),2.49 (s, 2H), 2.04 - 1.98(m, 2H), 1.90 - 1.82 (m, 2H), 1.37 (s, 3H). LCMS ESI (+) m/z:295.1 (M+1).
(R
)-2-(1-(2-(1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-4-甲基哌啶-4-基)乙腈
步驟A:
將R
-乳醯胺(263 mg,2.96 mmol)以及三乙基氧鎓四氟硼酸(561 mg,2.96 mmol)溶於10 mL四氫呋喃中,28 ℃下攪拌2小時。旋乾後的油狀物以及化合物(4-甲基-1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)甲基甲磺酸酯(500 mg,0.99 mmol)溶於乙醇(30 mL)中在75 ℃下攪拌2小時。反應結束後,將反應液旋乾,柱層析純化得化合物(R
)-(1-(2-(1-羥乙基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-4-甲基哌啶-4-基)甲基甲磺酸酯(337 mg,產率60%)。LCMS ESI (+) m/z:548.0 (M+1).
步驟B:
將化合物(R
)-(1-(2-(1-羥乙基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-4-甲基哌啶-4-基)甲基甲磺酸酯(200 mg,0.36 mmol)、三甲基氰矽烷(106 mg,1.07 mmol)以及碳酸鉀(148 mg,1.07 mmol)溶解在10 mLN,N
-二甲基甲醯胺中,將反應液在120 ℃攪拌72小時。反應結束後,加入30 mL水,用二氯甲烷萃取(3×30 mL),合併有機相,用食鹽水(100 mL)洗有機相,無水硫酸鈉乾燥。過濾,旋乾,製備得化合物(R
)-2-(1-(2-(1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-4-甲基哌啶-4-基)乙腈(48 mg,產率40%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.95 (s, 1H), 8.55 (s, 1H), 7.55 (t,J
= 3.0 Hz,1H), 6.64 (dd,J
= 3.2, 2.0 Hz, 1H), 5.28 (d,J
= 6.0 Hz,1H), 5.20 - 5.14 (m, 1H), 3.65 - 3.60 (m, 2H), 3.60 - 3.55 (m, 2H), 2.68 (s, 2H), 1.96 - 1.94 (m, 2H), 1.88 - 1.80 (m, 2H), 1.35 (s, 3H). LCMS ESI (+) m/z:339.1 (M+1).
2-(4-羥基-1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-哌啶-4-基)乙腈
步驟A:
將二異丙基胺基鋰(2 M,50 mL,100.0 mmol)加入到150 mL四氫呋喃中,-78 ℃氮氣保護下加入乙腈(4.10 g,100.0 mmol)並保持-78 ℃條件攪拌1小時。隨後將N-Boc
-4-哌啶酮(10.0 g, 50.0 mmol)用50 mL四氫呋喃溶解,滴加至反應體系中。滴加完成後緩慢升至室溫並保持反應1小時。反應完成後用適量飽和氯化銨水溶液淬滅,加入150 mL水,用600 mL乙酸乙酯分三次萃取。合併有機相,用300 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液,矽膠柱柱層析得到化合物N-Boc
-4-氰甲基-4-羥基哌啶(6.2 g,產率52%)。LCMS ESI(+)m/z:241.2(M+1).
步驟B:
將化合物N-Boc
-4-氰甲基-4-羥基哌啶(6.2 g,25.8 mmol)溶解在60 mL二氯甲烷中,0 ℃條件下加入15 mL三氟乙酸。滴加完成後室溫攪拌反應5小時。反應完成後減壓濃縮反應液得到化合物4-(氰甲基)-4-羥基哌啶三氟乙酸鹽(5.12 g,產率97%)。LCMS ESI(+)m/z:141.1(M+1).
步驟C:
將化合物4-(氰甲基)-4-羥基哌啶三氟乙酸鹽(5.12 g,25.0 mmol)溶解在30 mL水和50 mL乙酸中,將亞硝酸鈉(2.59 g,37.5 mmol)溶解在15 mL水中。0 ℃下將亞硝酸鈉水溶液緩慢滴加至反應體系中,並室溫攪拌反應16小時。反應完成後減壓濃縮反應液,矽膠柱柱層析得到化合物1-亞硝基-4-(氰甲基)-4-羥基哌啶(2.60 g,產率61%)。LCMS ESI(+)m/z:170.1(M+1).
步驟D:
將化合物1-亞硝基-4-(氰甲基)-4-羥基哌啶(2.30 g,13.5 mmol)溶解在100 mL甲醇中,加入鋅粉(17.8 g,272.0 mmol),室溫下滴加乙酸20 mL。滴加完成後30 ℃攪拌反應15分鐘。反應完成後過濾反應液,旋蒸濾液得到粗品化合物1-胺基-4-(氰甲基)-4-羥基哌啶(1.78 g,產率85%)。LCMS ESI(+)m/z:156.1(M+1).
步驟E:
將化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(4.02 g,11.4 mmol)、N,N
-二異丙基乙胺(5.89 g,45.6 mmol)和1-胺基-4-(氰基甲基)-4-羥基哌啶(1.78 g,11.4 mmol)加入到150 mL異丙醇中(懸濁液)。在95 ℃(油浴溫度)下,攪拌反應16小時。反應完成後,冷卻至室溫,加入200 mL水,用600 mL乙酸乙酯分三次萃取。合併有機相,用無水硫酸鈉乾燥,過濾,旋蒸純化得到化合物2-(4-羥基-1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(3.25 g,產率61%)。LCMS ESI(+)m/z:471.2(M+1).
步驟F:
將化合物2-(4-羥基-1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)哌啶-4-基)乙腈(3.25 g,3.9 mmol)加至90 mL乙醇和30 mL水的混合溶中(懸濁液),然後依次加入氯化銨固體(0.88 g,16.55 mmol)和鐵粉(0.92 g,16.55 mmol)。升溫至80 ℃,攪拌2.5小時。反應完成後,過濾反應液,並用50 mL乙酸乙酯洗滌濾渣。濾液加入50 mL水,用240 mL乙酸乙酯分三次萃取。合併有機相,用100 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液,矽膠柱柱層析得到化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)4-羥基哌啶-4-基)乙腈(1.88 g,62%)。LCMS ESI(+)m/z:441.2(M+1).
步驟G:
將化合物2-(1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)4-羥基哌啶-4-基)乙腈(562 mg,1.28 mmol)溶解在25 mL乙酸中,加入原甲酸三乙酯(948 mg,6.40 mmol),升至116 ℃攪拌1小時。冷卻至室溫,減壓濃縮,矽膠柱柱層析得到化合物2-(4-羥基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-哌啶-4-基)乙腈(360 mg,產率62%)。LCMS ESI(+)m/z:426.2(M+1).
步驟H:
將2-(4-羥基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-哌啶-4-基)乙腈(360 mg,0.80 mmol)溶解在15 mL甲醇和5 mL四氫呋喃中,加入2 N氫氧化鈉水溶液5 mL,在室溫條件攪拌反應16小時。反應液用乙酸調pH值至8 - 9,減壓濃縮,矽膠柱柱層析純化得到化合物2-(4-羥基-1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-哌啶-4-基)乙腈(60 mg,產率26%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.86 (s, 1H), 8.76 - 8.16 (m, 2H), 7.48 (s, 1H), 6.90 (s, 1H), 5.45 (s, 1H), 3.85 - 3.54 (m, 2H), 3.08 (d,J
= 9.9 Hz, 2H), 2.81 (s, 2H), 2.03 - 1.91 (m, 2H), 1.86 (d,J
= 12.2 Hz, 2H). LCMS ESI(+)m/z:297.1(M+1)。
2-(8-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-亞基)乙腈
步驟A:
將去甲托品醇(3.01 g,26.13 mmol)溶解在80 mL水中,0 ℃加入濃鹽酸80 mL,30 ℃下分批加入亞硝酸鈉(43.5 g,630.2 mmol),並繼續在30 ℃條件攪拌反應16小時。反應完成後用600 mL乙酸乙酯分四次萃取。合併有機相,用無水硫酸鈉乾燥,過濾,旋蒸濾液,矽膠柱層析純化得到化合物8-亞硝基-8-氮雜雙環[3.2.1]辛烷-3-醇(8.62 g,產率70%)。LCMS ESI(+)m/z:157.1(M+1).
步驟B:
將化合物8-亞硝基-8-氮雜雙環[3.2.1]辛烷-3-醇(7.0 g,44.8 mmol)溶解在150 mL甲醇中,加入鋅粉(29.3 g,448.0 mmol),0 ℃條件下滴加乙酸30 mL。滴加完成後30 ℃攪拌反應20分鐘。反應完成後過濾反應液,旋蒸濾液得到粗品化合物8-胺基-8-氮雜雙環[3.2.1]辛烷-3-醇(3.43 g,產率54%)。LCMS ESI(+)m/z:143.1(M+1).
步驟C:
將化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(3.52 g,10.0 mmol)、N,N
-二異丙基乙胺(5.17 g,40.0 mmol)和8-胺基-8-氮雜雙環[3.2.1]辛烷-3-醇(1.72 g,12.0 mmol)加入到150 mL異丙醇中(懸濁液)。在95 ℃下攪拌反應16小時。反應完成後,冷卻至室溫,加入300 mL水,用乙酸乙酯萃取(3×250 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物8-((5-硝基-1-對甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)胺基)8-氮雜雙環[3.2.1]辛烷-3-醇(3.17 g,產率70%)。LCMS ESI(+)m/z:458.2(M+1).
步驟D:
將化合物8-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)8-氮雜雙環[3.2.1]辛烷-3-醇(3.17 g,7.0 mmol)加至120 mL乙醇和40 mL水的混合溶中(懸濁液),然後依次加入氯化銨固體(1.50 g,28.0 mmol)和鐵粉(1.56 g,28.0 mmol)。升溫至80 ℃攪拌2小時。反應完成後,過濾反應液,並用適量乙酸乙酯洗滌濾渣,濾液中加入200 mL水,用乙酸乙酯萃取(3×250 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物8-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)8-氮雜雙環[3.2.1]辛烷-3-醇(3.02 g,產率100%)。LCMS ESI(+)m/z:428.2(M+1).
步驟E:
將化合物8-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)8-氮雜雙環[3.2.1]辛烷-3-醇(2.95 g,6.9 mmol)溶解在80 mL乙酸中,加入原甲酸三乙酯(5.11 g,34.5 mmol),升溫至116 ℃攪拌反應1小時。反應完成後減壓濃縮,矽膠柱柱層析得化合物8-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-醇(2.31 g,產率77%)。LCMS ESI(+)m/z:438.2(M+1).
步驟F:
將戴斯-馬丁氧化劑(3.01 g,7.1 mmol)溶解在80 mL二氯甲烷中,將化合物8-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-醇(2.05 g,4.7 mmol)溶解在20 mL二氯甲烷中並滴加至反應液中,室溫下攪拌反應2小時。反應完成後反應液分別用60 mL飽和碳酸氫鈉水溶液和60 mL飽和氯化鈉水溶液洗滌,用無水硫酸鈉乾燥,過濾,減壓濃縮濾液,矽膠柱柱層析純化得到化合物8-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-酮(1.3 g,產率64%)。LCMS ESI(+)m/z:436.2(M+1)。
步驟G:
將氰甲基磷酸二乙酯(798 mg,4.5 mmol)溶解在30 mL無水四氫呋喃中,氮氣保護,0 ℃加入60%的鈉氫(180 mg,4.5 mmol)並攪拌30分鐘。將化合物8-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-酮(1.31 g,3.0 mmol)溶解在15 mL無水四氫呋喃中並加至反應液中,室溫氮氣保護下攪拌反應2小時。反應完成後加入適量飽和氯化銨水溶液,用乙酸乙酯萃取(3×50 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物2-(8-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-亞基)乙腈(879 mg,產率64%)。LCMS ESI(+)m/z:459.2(M+1)。
步驟H:
將化合物2-(8-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-亞基)乙腈(820 mg, 1.8 mmol)溶解在24 mL甲醇和8 mL四氫呋喃中,加入1 N氫氧化鈉水溶液8 mL,35 ℃攪拌反應16小時。反應完成後用乙酸調pH至8 - 9,減壓濃縮,矽膠柱柱層析純化得化合物2-(8-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-亞基)乙腈(302 mg,產率55%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.81 (s, 1H), 8.55 (s, 1H), 8.26 (s, 1H), 7.43 (t,J
= 2.9 Hz, 1H), 6.90 (dd,J
= 3.2, 1.9 Hz, 1H), 5.76 (s,J
= 2.0 Hz,1H), 3.98 (d,J
= 20.5 Hz, 2H), 3.00 (d,J
= 14.7 Hz, 2H), 2.79 (d,J
= 15.0 Hz, 1H), 2.57 (d,J
= 15.2 Hz, 1H), 2.36 - 2.22 (m, 2H), 1.83 - 1.64 (m, 2H). LCMS ESI(+)m/z:305.2(M+1)。
2-(8-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜二環[3.2.1]辛烷-3-基)乙腈
步驟A:
將化合物2-(8-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-亞基)乙腈(100 mg, 0.33 mmol)溶解在10 mL甲醇中,加入鈀碳(106 mg,0.10 mmol),氫氣球條件下常溫攪拌反應16小時。過濾反應液,用適量甲醇洗滌濾渣,減壓濃縮濾液,高效液相製備得到化合物2-(8-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-基)乙腈(非對映異構體混合物,35 mg,產率40%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.80 (s, 1H), 8.53 (s, 1H), 8.24 (s, 0.38H), 8.20 (s, 0.62H), 7.45 - 7.42 (m, 1H), 6.89 (dd,J
= 3.2, 2.0 Hz, 0.38H), 6.81 (dd,J
= 3.2, 2.0 Hz, 0.62H), 3.82 (s, 2H), 2.75 (d,J
= 8.1 Hz, 1.24 H), 2.63 (d,J
= 8.1 Hz, 0.76 H), 2.59 – 2.57 (m, 0.38 H), 2.41 - 2.34 (m, 0.62H), 2.34 - 2.10 (m, 3H), 1.98 - 1.84 (m, 3H), 1.84 - 1.70 (m, 0.76H), 1.64 - 1.58 (m, 1.24H). LCMS ESI(+)m/z:307.2(M+1)。
2-(8-(2-((R
)-1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜二環[3.2.1]辛烷-3-亞基)乙腈
步驟A:
將將戴斯-馬丁氧化劑(7.30 g,17.1 mmol)溶解在70 mL二氯甲烷中,將化合物8-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)8-氮雜雙環[3.2.1]辛-3-醇(5.20 g,11.4 mmol)溶解在50 mL二氯甲烷中並滴加至反應液中,室溫下攪拌反應3小時。反應完成後加入適量飽和碳酸氫鈉水溶液,用二氯甲烷萃取(3×250 mL),合併有機相,用500 mL飽和氯化鈉水溶液洗滌,用無水硫酸鈉乾燥,過濾,減壓濃縮濾液,矽膠柱柱層析純化得到化合物8-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)8-氮雜雙環[3.2.1]辛-3-酮(5.6 g,產率72%)。LCMS ESI(+)m/z:456.2(M+1).
步驟B:
將氰甲基磷酸二乙酯(3.27 g,18.5 mmol)溶解在100 mL無水四氫呋喃中,氮氣保護,0 ℃加入60%的鈉氫(738 mg,60%,18.5 mmol)並攪拌30分鐘。將化合物8-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)8-氮雜雙環[3.2.1]辛-3-酮(5.6 g,12.3 mmol)溶解在100 mL無水四氫呋喃中並加至反應液中,室溫下氮氣保護下攪拌反應3小時。反應完成後加入適量飽和氯化銨水溶液,用乙酸乙酯萃取(3×250 mL),合併有機相,用無水硫酸鈉乾燥,過濾,旋蒸濃縮,矽膠柱柱層析得化合物2-(8-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b]吡啶-4-基)胺基)8-氮雜雙環[3.2.1]辛烷-3-亞基)乙腈(4.37 g,產率74%)。LCMS ESI(+)m/z:479.2(M+1).
步驟C:
將化合物2-(8-((5-硝基-1-對甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)胺基)8-氮雜雙環[3.2.1]辛烷-3-亞基)乙腈(2.37 g,5.0 mmol)加至120 mL乙醇和40 mL水的混合溶中(懸濁液),然後依次加入氯化銨固體(1.32 g,24.8 mmol)和鐵粉(1.38 g,24.8 mmol)。升溫至80 ℃攪拌2小時。反應完成後,過濾反應液,並用適量乙酸乙酯洗滌濾渣,濾液中加入200 mL水,用乙酸乙酯萃取(3×250 mL),合併有機相,用無水硫酸鈉乾燥,過濾,減壓濃縮濾液,矽膠柱柱層析得到化合物2-(8-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)8-氮雜雙環[3.2.1]辛烷-3-亞基)乙腈(1.58 g,產率65%)。LCMS ESI(+)m/z:449.2(M+1)。
步驟D:
將三乙基氧嗡四氟化硼(661 mg,3.48 mmol)和R-乳醯胺(310 mg,3.48 mmol)溶解在20 mL四氫呋喃中,室溫攪拌反應2小時。減壓濃縮得到無色油狀物,將其溶解在15 mL無水乙醇,加至溶解化合物2-(8-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)8-氮雜雙環[3.2.1]辛烷-3-亞基)乙腈(520 mg,1.16 mmol)的15 mL無水乙醇中。升溫至75 ℃攪拌反應1小時。反應完成後用碳酸氫鈉水溶液淬滅,加入50 mL水,用乙酸乙酯萃取(3×50 mL),合併有機相,用100 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液,矽膠柱柱層析得到化合物2-(8-(2-((R
)-1-羥乙基-6-對甲苯磺醯基咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-亞基)乙腈(480 mg,產率82%)。LCMS ESI(+)m/z:503.2(M+1)。
步驟E:
將化合物2-(8-(2-((R
)-1-羥乙基-6-對甲苯磺醯基咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-亞基)乙腈(360 mg,0.71 mmol)溶解在9 mL甲醇中,加入1 N氫氧化鈉水溶液3 mL,35 ℃攪拌反應8小時。反應完成後用乙酸調pH至8 - 9,減壓濃縮,矽膠柱柱層析和高效液相製備得到化合物2-(8-(2-((R
)-1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜二環[3.2.1]辛烷-3-亞基)乙腈(32 mg,產率12%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.77 (d,J
= 26.3 Hz, 1H), 8.49 (d,J
= 5.7 Hz, 1H), 7.46 - 7.30 (m, 1H), 6.95 (dd,J
= 115.2, 2.4 Hz, 1H), 5.47 (s, 1H), 4.98 - 4.80 (m, 1H), 4.31 - 3.72 (m, 2H), 2.73 (d,J
= 7.0 Hz, 1H), 2.70 - 2.54 (m, 3H), 2.38 - 1.73 (m, 6H), 1.64 (d,J
= 6.2 Hz, 3H), 1.57 - 1.44 (m, 1H). LCMS ESI(+)m/z:326.2(M+1)。
2-(8-(2-((R
)-1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜二環[3.2.1]辛烷-3-基)乙腈
步驟A:
將化合物2-(8-(2-((R
)-1-羥乙基-6-對甲苯磺醯基咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-亞基)乙腈(480 mg, 0.96 mmol)溶解在35 mL 甲醇中,加入鈀碳(202 mg,0.19 mmol),氫氣球條件下室溫攪拌反應16小時。過濾反應液,用適量甲醇洗滌濾渣,減壓濃縮濾液得到粗品化合物2-(8-(2-((R
)-1-羥乙基-6-對甲苯磺醯基咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-基)乙腈(360 mg,產率74%)。LCMS ESI(+)m/z:505.2(M+1)。
步驟B:
將化合物2-(8-(2-((R
)-1-羥乙基-6-對甲苯磺醯基咪唑[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜雙環[3.2.1]辛烷-3-基)乙腈(360 mg,0.71 mmol)溶解在9 mL甲醇中,加入1 N氫氧化鈉水溶液3 mL,35 ℃攪拌反應8小時。反應完成後用乙酸調pH至8 - 9,減壓濃縮,矽膠柱柱層析和高效液相製備得到化合物2-(8-(2-((R
)-1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-8-氮雜二環[3.2.1]辛烷-3-基)乙腈(非對映異構體,32 mg,產率12%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.80 (s, 1H), 11.73 (s, 1H), 8.49 (s, 1H), 8.48 (s, 1H), 7.43(t,J
= 2.4 Hz, 1H), 7.35 (t,J
= 2.5 Hz, 1H), 7.09 (d,J
= 2.1 Hz,1H), 6.80 (d,J
= 2.7 Hz, 1H), 5.55 - 5.45 (m, 1H), 5.45 - 5.35 (m, 1H), 4.98 - 4.88 (m, 1H), 4.88 - 4.78 (m, 1H), 4.25 (t,J
= 6.4 Hz, 1H), 4.05 - 4.00 (m, 1H), 3.84 (t,J
= 6.4 Hz, 1H), 3.80 - 3.75 (m, 1H), 2.73 (d,J
= 7.0 Hz, 2H), 2.66 (d,J
= 5.8 Hz, 2H), 2.64 - 2.52 (m, 4H), 2.38 - 1.73 (m, 12H), 1.65 (s, 3H), 1.64 (s, 3H),1.56 - 1.50 (m, 1H), 1.50 - 1.44 (m, 1H). LCMS ESI(+)m/z:326.2(M+1)。
3-(4-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)呱嗪-1-基)乙腈
步驟A:
將1-Boc
-呱嗪(1.86 g,10.0 mmol)溶解在20 mL水和9 mL乙酸中,將亞硝酸鈉(4.14 g,60.0 mmol)溶解在20 mL水中。0 ℃下將亞硝酸鈉水溶液緩慢滴加至反應體系中,室溫攪拌反應16小時。反應完成後用150 mL乙酸乙酯分三次萃取。合併有機相,用無水硫酸鈉乾燥,過濾,減壓濃縮,矽膠柱柱層析得到化合物1-Boc-4-亞硝基呱嗪(1.46 g,產率68%)。LCMS ESI(+)m/z:159.1(M+1).
步驟B:1-Boc
-4-胺基呱嗪
在室溫下,將1-Boc
-4-亞硝基呱嗪(1.46 g,6.8 mmol)溶解在10 mL甲醇中,加入鋅粉(2.20 g,33.8 mmol),冷卻到0 ℃,緩慢滴加醋酸(20 mL),然後在氮氣保護下,升溫到室溫攪拌2小時。反應結束後,過濾,用飽和碳酸氫鈉水溶液調pH到9 - 10,加入40 mL水,用180 mL二氯甲烷分三次萃取,合併有機相,用無水硫酸鈉乾燥,過濾,旋乾、純化得到化合物1-Boc
-4-胺基呱嗪(1.18 g,產率86%)。
步驟C:
將化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(1.18 g,5.87 mmol),N,N
-二異丙基乙胺(7.10 g,55 mmol)和1-Boc
-4-胺基呱嗪(1.18 g,5.87 mmol)加入到60 mL異丙醇中(懸濁液),氮氣保護下升溫到100 ℃攪拌16小時。反應結束後,冷卻到室溫,加入乙醚,有大量的黃色固體析出,過濾,收集固體乾燥得到產物1-Boc
-4-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)呱嗪(2.16 g,產率76%)。LCMS ESI(+)m/z:517.1(M+1).
步驟D:
將化合物1-Boc
-4-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)呱嗪(1.8 g,3.49 mmol)溶解在45 mL乙醇中,依次加入鐵粉(1.17 g,20.9 mmol),氯化銨(0.37 g,6.98 mmol)和水15 mL,升溫到75 ℃攪拌2小時。反應結束後,過濾,旋乾,柱層析純化得到產物1-Boc
-4-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)呱嗪(930 mg,產率54%)。LCMS ESI(+)m/z:487.1(M+1).
步驟E:
將化合物1-Boc
-4-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)呱嗪(930 mg,1.91 mmol)溶在30 mL甲苯中,依次加入原甲酸三乙酯(2 mL),吡啶鹽酸鹽(23 mg,0.2 mmol),在氮氣保護下,升溫到115 ℃下攪拌3小時。反應結束後,旋乾,柱層析純化得到產物1-Boc
-4-(6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)呱嗪(760 mg,產率80%)。LCMS ESI(+)m/z:497.1.
步驟F:
將化合物1-Boc
-4-(6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)呱嗪(200 mg,0.4 mmol)溶解在5 mL 1,4-二氧六環中,在冰浴下,加入氯化氫的1,4-二氧六環溶液(4 N,2 mL),在氮氣保護下,升到室溫下攪拌16小時。反應結束後,將反應液旋乾得到化合物4-(6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)呱嗪鹽酸鹽(180 mg,產率100%)。LCMS ESI(+)m/z:397.1(M+1).
步驟G:
將化合物4-(6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)呱嗪鹽酸鹽(200 mg,0.51 mmol)溶解在10 mL甲醇中,在0 ℃下加入氫氧化鈉水溶液(2 N,3 mL),在氮氣保護下,室溫攪拌16小時。反應結束後,加水20 mL,用二氯甲烷萃取(3×80 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物1-(呱嗪-1-基)-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(120 mg,產率97%)。LCMS ESI(+)m/z:243.1(M+1).
步驟H:
將化合物1-(呱嗪-1-基)-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(48 mg,0.2 mmol),溴乙腈(31 mg,0.26 mmol)和三乙胺(61 mg,0.6 mmol)溶解在5 mLN,N
-二甲基甲醯胺中,在氮氣保護下,室溫攪拌16小時。反應結束後,加水40 mL,用乙酸乙酯萃取(3×40 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,高效液相製備得化合物3-(4-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)呱嗪-1-基)乙腈(8 mg,產率16%)。1
H NMR (400 MHz, DMSO-d6
)δ
12.18(s, 1H), 8.93 (s, 1H), 8.74 (s, 1H), 7.57 (t,J
= 3.2 Hz, 1H), 6.81 (dd,J
= 3.2 Hz, 2.0 Hz, 1H), 3.91 (s, 2H), 3.41 - 3.39 (m, 4H), 2.87 - 2.81 (m, 4H). LCMS ESI(+)m/z:282.1(M+1).
3-(4-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)呱嗪-1-基)丙腈
步驟A:
將化合物1-(呱嗪-1-基)-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(52 mg,0.22 mmol),三乙胺(108 mg,1.1 mmol),溶解在3 mL 3-烯丙腈中,在氮氣保護下,100 ℃下攪拌1小時。反應結束後,過濾,加水20 mL,用乙酸乙酯萃取(5×40 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,高效液相製備得化合物3-(4-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)呱嗪-1-基)丙腈(32 mg,產率48%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.84 (s, 1H), 8.61(s,1H), 8.56 (s,1H), 7.45 (s, 1H), 6.74 (d,J
= 2.4 Hz, 1H), 3.34 (s, 4H), 2.78 - 2.71(m, 8H). LCMS ESI(+)m/z:296.1(M+1).
3-(4-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)呱嗪-1-基)氧代丙腈
步驟A:
將化合物1-(呱嗪-1-基)-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(70 mg,0.29 mmol),HATU(165 mg,0.43 mmol),2-氰基乙酸(30 mg,0.35 mmol)和N,N
-二異丙基乙胺(112 mg,0.87 mmol)溶解在5 mLN,N
-二甲基甲醯胺中,在氮氣保護下,室溫攪拌16小時。反應結束後,加水20 mL,用乙酸乙酯萃取(3×60 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,純化得化合物3-(4-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)呱嗪-1-基)氧代丙腈(30 mg,產率33%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.85 (s, 1H), 8.57(s, 1H), 8.56(s, 1H), 7.45 (t,J
= 2.8 Hz,1H), 6.78 (dd,J
= 3.2, 2.0 Hz, 1H), 4.19 (s, 2H),3.85 - 3.70 (m, 4H), 3.33 - 3.30 (m, 4H). LCMS ESI(+)m/z:310.1(M+1).
2-(1-(2-((R
)-1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-6-氮雜庚烷-4-基)乙腈
步驟A:
將鹽酸羥胺(6.12 g,88.1mmol)溶解在25 mL水中,加入乙酸鈉(9.64 g,118 mmol),室溫攪拌10分鐘。向反應中滴加化合物對環己酮甲酸乙酯(10.0 g,58.8 mmol)。45 ℃攪拌16小時。用50 mL乙酸乙酯萃取3次,合併有機相,用20 mL水洗滌,用20 mL飽和食鹽水洗滌,無水硫酸鈉乾燥,減壓濃縮,矽膠柱柱層析得到化合物4-甲酸乙酯環己酮肟(10.9 g,產率100%)。1
H NMR (400 MHz, CDCl3
)δ
8.02 (brs, 1H), 4.19 - 4.09 (m, 2H), 3.20 - 3.10 (m, 1H), 2.60 - 2.51 (m, 1H), 2.49 - 2.40 (m, 1H), 2.21 - 2.00 (m, 4H), 1.82 - 1.66(m, 2H), 1.26 (t,J
= 7.1 Hz, 3H).
步驟B:
將化合物4-甲酸乙酯環己酮肟(3.32 g,12.9 mmol)溶於吡啶(15 mL),-15 ℃氮氣保護下加入對甲苯磺醯氯(4.10 g,21.5 mmol)。-15 ℃氮氣保護下攪拌2小時。倒入60 mL冰水中,攪拌20分鐘,抽濾,30 mL水洗滌。收集濾餅,減壓乾燥,得到化合物4-((對甲苯磺醯氧基)亞胺基)環己烷-1-甲酸乙酯(4.87 g,產率80%)。1
H NMR (400 MHz, CDCl3
)δ
7.85 (d,J
= 8.3 Hz, 2H), 7.34 (d,J
= 8.0 Hz, 2H), 4.13 (q,J
= 7.1 Hz, 2H), 3.07 - 2.97 (m, 1H), 2.58 - 2.46 (m, 2H), 2.45 (s, 4H), 2.28 - 2.12 (m, 2H), 2.11 - 1.96 (m, 2H), 1.85 - 1.64 (m, 2H), 1.25 (t,J
= 7.1 Hz, 3H).
步驟C:
將化合物4-((對甲苯磺醯氧基)亞胺基)環己烷-1-甲酸乙酯(16.6 g,45.9 mmol)溶於35 mL乙酸中,室溫攪拌16小時。減壓濃縮反應液。加入40 mL飽和碳酸氫鈉水溶液,攪拌15分鐘,用150 mL乙酸乙酯萃取水相3次。合併有機相,50 mL飽和食鹽水洗,無水硫酸鈉乾燥,減壓濃縮,矽膠柱層析得到化合物7-氧代氮雜環庚烷-4-甲酸乙酯(5.33 g,產率63%)。1
H NMR (400 MHz, CDCl3
)δ
6.30 (s, 1H), 4.15 (q,J
= 7.1 Hz, 2H), 3.41 - 3.29 (m, 1H), 3.29 - 3.17 (m, 1H), 2.68 - 2.52 (m, 2H), 2.52 - 2.39 (m, 1H), 2.15 - 2.00(m, 2H), 1.92 - 1.76 (m, 2H), 1.37 - 1.18 (m, 3H).
步驟D:
將化合物7-氧代氮雜環庚烷-4-甲酸乙酯(3.72 g,20.1 mmol)溶解在50 mL四氫呋喃中,冰浴氮氣保護下滴加到氫化鋰鋁(3.81 g,100 mmol)的四氫呋喃(300 mL)溶液中。室溫攪拌2小時,60 ℃攪拌4小時。冷卻至0 ℃,依次滴加水(4 mL),15%氫氧化鈉溶液(4 mL),水(8 mL)。室溫攪拌3小時。矽藻土抽濾,50 mL四氫呋喃洗滌。減壓濃縮濾液,得到化合物4-羥甲基氮雜環庚烷(2.31 g,產率89%)。1
H NMR (400 MHz, CDCl3
)δ
3.56 - 3.45 (m, 2H), 3.08 - 2.72 (m, 4H), 1.94 - 1.73 (m, 4H), 1.66 - 1.52 (m, 1H), 1.50 - 1.35 (m, 2H).
步驟E:
將化合物4-羥甲基氮雜環庚烷(2.31 g,17.9 g)溶於100 mL二氯甲烷,室溫下依次加入亞硝酸鈉(3.70 g,53.6 mmol),一水合對甲苯磺酸(10.2 g,53.6 mmol)。35 ℃攪拌2小時,減壓濃縮反應液,矽膠柱層析得到化合物1-亞硝基-4-羥甲基氮雜環庚烷(2.19 g,產率77%)。1
H NMR (400 MHz, CDCl3
)δ
4.83 - 4.63 (m, 1H), 4.12 - 3.96 (m, 1H), 3.92 - 3.70 (m, 1H), 3.68 - 3.43 (m, 3H), 2.30 - 2.14 (m, 1H), 2.09 - 1.79 (m, 3H), 1.78 -1.40 (m, 3H), 1.27 - 1.00 (m, 1H).
步驟F:
將化合物1-亞硝基-4-羥甲基氮雜環庚烷(1.10 g,6.95 mmol)溶解在20 mL二氯甲烷中,冰浴氮氣保護下滴加三乙胺(1.19 g,10.4 mmol)和甲磺醯氯(1.19 g,10.4 mmol)。冰浴下攪拌2小時。加入水(10 mL),室溫攪拌15分鐘。加入乙酸乙酯(100 mL),分離有機相,用水(30 mL)洗2次,飽和食鹽水(30 mL)洗,無水硫酸鈉乾燥,抽濾,減壓濃縮,得到粗產品化合物(1-亞硝基氮雜環庚烷-4-基)甲基甲磺酸酯(1.64 g,產率100%)。
步驟G:
將化合物(1-亞硝基氮雜環庚烷-4-基)甲基甲磺酸酯(1.64 g,6.94 mmol)溶解在10 mL無水N,N
-二甲基甲醯胺(10 mL)中,氮氣下加入氰化鈉溶液(1.02 g,20.8 mmol)。80 ℃下攪拌5小時。減壓濃縮。將反應液倒入20 mL水中,用40 mL乙酸乙酯萃取3次。合併有機相,用水(20 mL)洗,飽和食鹽水(20 mL)洗,無水硫酸鈉乾燥,抽濾,減壓濃縮。矽膠柱柱層析得到化合物1-亞硝基-4-氰甲基氮雜環庚烷(1.09 g,產率94%)。
步驟H:
將化合物1-亞硝基-4-氰甲基氮雜環庚烷(600 mg,3.59 mmol)溶解在20 mL甲醇中,室溫下依次加入鋅粉(4.69 g,71.8 mmol),逐滴加入乙酸(5 mL)。35 ℃攪拌15分鐘。抽濾反應液,20 mL甲醇洗滌,濃縮濾液,所得油狀物1-胺基-4-氰甲基氮雜環庚烷直接用於下一步反應。
步驟I:
將上一步的粗產物化合物1-胺基-4-氰甲基氮雜環庚烷溶於25 mL異丙醇中,依次加入N,N
-二異丙基乙胺(2.20 mL,17.1 mmol)和4-氯-5-硝基-1-甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(1.00 g,2.84 mmol),氮氣保護下加熱到85 ℃,攪拌反應16小時。濃縮反應液,矽膠柱層析得到化合物2-(1-((5-硝基-1-甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)氮雜環庚烷-4-基)乙腈(450 mg,產率34%)。
步驟J:
將化合物2-(1-((5-硝基-1-甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)氮雜環庚烷-4-基)乙腈(527 mg,1.12 mmol)加入到25 mL乙醇中,室溫下依次加入鐵粉(1.26 g,22.5 mmol)和飽和氯化銨(1.5 mL),75 ℃攪拌反應5分鐘。趁熱矽藻土抽濾,20 mL甲醇洗滌,濃縮濾液。矽膠柱柱層析(乙酸乙酯),得到化合物2-(1-((5-胺基-1-甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)氮雜環庚烷-4-基)乙腈(200 mg,產率41%)。
步驟K:
氮氣下將R
-乳醯胺(107 mg,1.23 mmol)和三乙基氧鎓四氟硼酸加入(234 mg,1.24 mmol)到8 mL乾燥四氫呋喃中,30 ℃攪拌2小時。減壓濃縮反應液。將殘渣溶於3 mL乾燥乙醇,氮氣下加入化合物2-(1-((5-胺基-1-甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)氮雜環庚烷-4-基)乙腈(180 mg,0.41 mmol),75 ℃攪拌反應1小時。減壓濃縮反應液。加入飽和碳酸氫鈉溶液(10 mL)和乙酸乙酯(15 mL),攪拌5分鐘。分離有機相,用15 mL乙酸乙酯萃取3次水相。合併有機相,10 mL水洗,10 mL飽和食鹽水洗,無水硫酸鈉乾燥,減壓濃縮,矽膠柱層析得到化合物2-(1-(2-((R
)-1-羥乙基)-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)氮雜環庚烷-4-基)乙腈(980 mg,產率49%)。
步驟L:
將化合物2-(1-(2-((R
)-1-羥乙基)-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)氮雜環庚烷-4-基)乙腈(98 mg,0.2 mmol)溶解在3 mL甲醇中,加入1 N氫氧化鈉溶液(1 mL,1.0 mmol)。35 ℃攪拌7小時。用40 mL二氯甲烷稀釋反應液,無水硫酸鈉乾燥,抽濾,減壓蒸除溶劑。將殘餘物用TLC製備,得到化合物2-(1-(2-((R
)-1-羥乙基)咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-6-氮雜庚烷-4-基)乙腈(40 mg,產率59%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.87 (s, 1H), 8.59 - 8.47 (m, 1H), 7.52 - 7.44 (m, 1H), 6.76 - 6.64 (m, 1H), 5.36 - 5.25 (m, 1H), 5.25 - 5.14 (m, 1H), 3.90 - 3.62 (m, 2H), 3.28 - 3.01 (m, 2H), 2.69 - 2.59 (m, 2H), 2.12 - 1.63 (m, 7H), 1.58 (d,J
= 6.5 Hz, 3H). LCMS ESI(+)m/z:339.1(M+1).
3-(4-乙基-3-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)咪唑啉-1-基)-3-氧代丙腈
步驟A:
將化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(4.80 g,13.7 mmol),叔丁氧羰基肼(1.98 g,15.0 mmol),N,N
-二異丙基乙胺(3.81 mL,27.3 mmol)加入100 mL異丙醇中。在85 ℃氮氣保護下攪拌16小時。反應結束後,減壓蒸除溶劑。將所得殘餘物矽膠柱柱層析得到化合物2-(5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]-4-基)肼基叔丁酯(4.56 g,產率75%)。1
H NMR (400 MHz, CDCl3
)δ
9.73 (s, 1H), 9.11 (s, 1H), 8.06 (d,J
= 8.4 Hz, 2H), 7.61 (d,J
= 4.1 Hz, 1H), 7.31 (d,J
= 8.1 Hz, 2H), 6.96 (d,J
= 4.1 Hz, 1H), 6.68(s, 1H), 2.40 (s, 3H), 1.46 (s, 9H). LCMS ESI(+)m/z:448.1(M+1).
步驟B:
將化合物2-(5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]-4-基)肼基叔丁酯(4.56 g,10.2 mmol)溶於250 mL甲醇,在氮氣下加入10% 鈀碳(2.78 g)。將混合物在氫氣氛圍下室溫攪拌16小時。過濾反應液,甲醇(20 mL)洗滌2次。將濾液減壓蒸除溶劑,得到化合物2-(5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]-4-基)肼基叔丁酯(4.25 g,產率100%)。1
H NMR (400 MHz, CDCl3
)δ
7.99 (d,J
= 8.3 Hz, 2H), 7.87 (s, 1H), 7.49 (d,J
= 4.1 Hz, 1H), 7.23 (d,J
= 8.2 Hz, 3H), 6.69 (d,J
= 4.1 Hz, 1H), 6.56 (s, 2H), 2.36 (s, 4H), 1.43(s, 9H). LCMS ESI(+)m/z:418.1(M+1).
步驟C:
將化合物2-(5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]-4-基)肼基叔丁酯(4.25 g,10.2 mmol),原甲酸三乙酯(1.81 g,12.2 mmol)和吡啶鹽酸鹽(116 mg,1.0 mmol)加入到150 mL甲苯中。氮氣下升至115 ℃攪拌2小時。反應結束後,將反應液減壓蒸除溶劑。將所得殘餘物矽膠柱柱層析得化合物叔丁基 (6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基甲酸酯(4.35 g,產率100%)。1
H NMR (400 MHz, CDCl3
)δ
8.77 (s, 1H), 8.05 (d,J
= 8.3 Hz, 2H), 7.91 (brs, 1H), 7.91 (s, 1H), 7.58 (d,J
= 2.8 Hz, 1H), 7.25 (d,J
= 8.4 Hz, 1H), 6.58 (d,J
= 2.8 Hz, 1H), 2.35 (s, 3H), 1.49 (s, 9H). LCMS ESI(+)m/z:428.1(M+1).
步驟D:
將化合物叔丁基 (6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基甲酸酯(3.69 g,8.63 mmol)溶解在400 mL丙酮中,加入氫氧化鈉(726 mg,13.0 mmol)粉末,室溫攪拌10分鐘。向反應液中加入2-溴丁酸乙酯(5.05 g,25.9 mmol),室溫攪拌1.5小時。抽濾反應液,用二氯甲烷(50 mL)洗滌濾餅。減壓濃縮濾液,將所得殘餘物矽膠柱柱層析得到化合物乙基 2-((叔丁氧羰基)(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丁酸甲酯(4.08 g,產率87%)。1
H NMR (400 MHz, CDCl3
)δ
8.89 (s, 1H), 8.38 (s, 1H), 8.14 (d,J
= 8.4 Hz, 2H), 7.78 (d,J
= 4.0 Hz, 1H), 7.29 (d,J
= 8.3 Hz, 2H), 6.69 (d,J
= 3.9 Hz, 1H), 4.98 - 4.79 (m, 1H), 4.33 (q,J
= 7.1 Hz, 2H), 2.38 (s, 3H), 1.59 - 1.48 (m, 2H), 1.36 (t,J
= 9.2, 5.1 Hz, 3H), 1.33 - 1.12 (m, 9H), 0.81 (t,J
= 7.4 Hz, 3H). LCMS ESI(+)m/z:542.2(M+1).
步驟E:
將化合物乙基 2-((叔丁氧羰基)(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丁酸甲酯(4.08 g,7.53 mmol)溶解在33 mL二氯甲烷和甲醇的混合溶劑中(體積比為10比1),在冰浴下滴加4 N的氯化氫的二氧六環溶液(15 mL)。在氮氣保護下升至室溫攪拌16小時。減壓濃縮反應液。加入80 mL飽和碳酸氫鈉溶液,攪拌5分鐘。用乙酸乙酯萃取(3×50 mL),合併有機相,用50 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液得到化合物乙基 2-((6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丁酸甲酯(3.10 g,產率93%)。1
H NMR (400 MHz, CDCl3
)δ
8.85 (s, 1H), 8.10 (d,J
= 8.4 Hz, 2H), 8.03 (s, 1H), 7.77 (d,J
= 3.9 Hz, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 6.91 (d,J
= 4.0 Hz, 1H), 5.74 (d,J
= 7.8 Hz, 1H), 4.33 - 4.16 (m, 2H), 3.85 - 3.76 (m, 1H), 2.35 (s, 3H), 1.92 - 1.82 (m, 2H), 1.26 (t,J
= 7.2 Hz, 3H), 1.14 (t,J
= 7.4 Hz, 3H). LCMS ESI(+)m/z:442.1(M+1).
步驟F:
將化合物乙基 2-((6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丁酸甲酯(3.10 g,7.02 mmol)溶解在200 mL乙醇中,在冰浴,氮氣保護下下加入硼氫化鈉(797 mg,21.1 mmol),室溫攪拌48小時。在0 ℃下向反應中滴加1 N稀鹽酸溶液,將反應液調節至中性。加入50 mL水,室溫攪拌。用1 N稀鹽酸調至中性,減壓蒸除溶劑。用乙酸乙酯萃取(3×50 mL),合併有機相,用30 mL飽和食鹽水洗滌,無水硫酸鈉乾燥,減壓蒸除溶劑,矽膠柱柱層析得化合物2-((6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丁基-1-醇(1.97 g,產率69%)。1
H NMR (400 MHz, DMSO-d6
)δ
8.69 (s, 1H), 8.30 (s, 1H), 8.02 (d,J
= 8.4 Hz, 2H), 7.92 (d,J
= 4.0 Hz, 1H), 7.40 (d,J
= 8.1 Hz, 2H), 7.16 (d,J
= 4.0 Hz, 1H), 6.95(d,J
= 2.7 Hz, 1H), 4.89 (t,J
= 5.0 Hz, 1H), 3.54 - 3.44 (m, 1H), 3.37 - 3-.34 (m, 1H), 3.23 - 3.15 (m, 1H), 2.33 (s, 3H), 1.42 - 1.32 (m, 2H), 0.83 (t,J
= 7.5 Hz,3H). LCMS ESI(+)m/z:400.1(M+1).
步驟G:
在冰浴冷卻和氮氣保護下向120 mL甲苯中加入化合物2-((6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丁基-1-醇(1.72 g,4.31 mmol),DBU(3.28 g,21.5 mmol)和DPPA(3.55 g,12.9 mmol)。升溫到75 ℃,攪拌16小時。減壓濃縮反應液,將所得殘餘物矽膠柱柱層析得到化合物N-(1-疊氮丁-2-基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-胺(1.10 g,產率60%)。1
H NMR (400 MHz, CDCl3
)δ
8.88 (s, 1H), 8.12 (d,J
= 8.4 Hz, 2H), 7.96 (s, 1H), 7.81 (d,J
= 4.0 Hz, 1H), 7.27 (d,J
= 8.4 Hz, 2H), 7.01 (d,J
= 4.0 Hz, 1H), 5.41(s, 1H), 3.68 (dd,J
= 12.0, 2.8 Hz, 1H), 3.47 - 3.34 (m, 2H), 1.52 - 1.41 (m, 2H), 0.91 (t,J
= 7.5 Hz, 3H). LCMS ESI(+)m/z:425.1(M+1).
步驟H:
將化合物N-(1-疊氮丁-2-基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-胺(1.10 g,2.59 mmol)溶解在200 mL甲醇中,氮氣保護下加入10% 鈀碳(220 mg)。置換氫氣,在氫氣氛圍下室溫攪拌6小時。抽濾,用20 mL 甲醇洗滌濾餅。減壓濃縮濾液得化合物N2
-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)丁烷-1,2-二胺(1.03 g,產率100%)。1
H NMR (400 MHz, CDCl3
)δ
8.88 (s, 1H), 8.12 (d,J
= 8.4 Hz, 2H), 7.97 (s, 1H), 7.76 (d,J
= 3.9 Hz, 1H), 7.27 (d,J
= 8.0 Hz, 2H), 7.12 (d,J
= 4.0 Hz, 1H),5.99 (d,J
= 2.0 Hz, 1H), 3.15 (s, 1H), 3.09 (dd,J
= 13.1, 3.3 Hz, 1H), 2.64 (dd,J
= 13.1, 8.8 Hz, 1H), 2.36 (s, 3H), 1.44 - 1.27 (m, 3H), 0.83 (t,J
= 7.5 Hz, 3H). LCMS ESI(+)m/z:399.1(M+1).
步驟I:
將化合物N2
-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)丁烷-1,2-二胺(1.03 g,2.58 mmol)溶解在50 mL甲醇中,加入多聚甲醛(101 mg,3.36 mmol)。加熱到70 ℃,攪拌16小時。冷卻至室溫,抽濾,用10 mL甲醇洗滌。將濾液減壓蒸除溶劑,得到化合物1-(5-乙基咪唑烷-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(1.06 g,產率100%)。1
H NMR (400 MHz, CDCl3
)δ
8.94 - 8.77 (m, 1H), 8.13 - 8.07 (m, 2H), 7.79 - 7.67 (m, 1H), 7.28 - 7.24 (m, 1H), 7.08 (m, 1H), 4.53 - 3.97 (m, 2H), 3.80 - 3.37 (m, 3H), 2.42 - 2.30 (m, 3H),1.83 - 1.59 (m, 2H), 0.96 - 0.74 (m, 3H). LCMS ESI(+)m/z:411.1(M+1).
步驟J:
將化合物1-(5-乙基咪唑烷-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(60 mg,0.15 mmol)溶解在3 mL甲醇中,加入2 N氫氧化鈉溶液(1.0 mL,2.0 mmol)。室溫攪拌16小時。用10 mL水稀釋反應液,減壓蒸除甲醇。用乙酸乙酯萃取(3×5 mL),合併有機相,用5 mL飽和食鹽水洗滌有機相,無水硫酸鈉乾燥,抽濾,減壓蒸除溶劑。得到粗產物化合物1-(5-乙基咪唑烷-1-基)-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(50 mg,粗產率100%)。LCMS ESI(+)m/z:257.1(M+1).
步驟K:
將化合物1-(5-乙基咪唑烷-1-基)-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(50 mg,0.2 mmol)溶解在4 mL二氯甲烷中,氮氣保護和冰浴下依次加入氰基乙酸(20 mg,0.24 mmol),HOBT(37 mg,0.27 mmol),4-二甲胺基吡啶(38 mg,0.31 mmol)和EDCI(60 mg,0.31 mmol)。室溫攪拌16小時。減壓濃縮,矽膠柱層析和高效液相製備得到化合物3-(4-乙基-3-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)咪唑啉-1-基)-3-氧代丙腈(20 mg,產率32%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.90 (s, 1H), 8.75 - 8.17 (m, 2H), 7.47 (s, 1H), 6.70 (s, 1H), 5.03 - 4.68 (m, 2H), 4.24 - 3.85 (m, 4H), 3.54 - 3.42 (m, 1H), 1.51 - 1.28 (m, 2H), 0.82 - 0.69 (m, 3H). LCMS ESI(+)m/z:324.1(M+1).
步驟A:
將化合物1-(5-乙基咪唑烷-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(70 mg,0.17 mmol)和三乙胺(86 mg,0.85 mmol)溶解在3 mL丙烯腈中。120 ℃微波下攪拌16小時。減壓蒸除溶劑,矽膠柱層析得到化合物3-(4-乙基-3-(6-甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)咪唑烷-1-基)丙腈(50 mg,產率63%)。LCMS ESI(+)m/z:464.1(M+).
步驟B:
將化合物3-(4-乙基-3-(6-甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)咪唑烷-1-基)丙腈(50 mg,0.11 mmol)溶解在5 mL無水四氫呋喃中,冰浴下加入60%氫化鈉(22 mg,0.54 mmol)。升至室溫攪拌4小時。將反應液倒入15 mL飽和氯化銨水溶液。將反應液中和,減壓蒸除溶劑,矽膠柱層析得到化合物3-(4-乙基-3-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)咪唑烷-1-基)丙腈(150 mg,產率48%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.03 (s, 1H), 8.06 - 7.99 (m, 2H), 7.85 - 7.81 (m, 2H), 7.75 - 7.64 (m, 2H), 7.49 (d,J
= 8.4 Hz, 2H), 7.29 (dd,J
= 6.1, 2.5 Hz,1H), 6.16 - 6.10 (m, 2H), 5.18 (s, 2H), 2.01 (s, 1H), 0.86 - 0.76 (m, 4H). LCMS ESI(+)m/z:310.1(M+1).
3-(4-甲基-3-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)咪唑啉-1-基)-3-氧代丙腈
步驟A:
將化合物叔丁基 (6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基甲酸酯(3.60 g,8.42 mmol)溶解在400 mL丙酮中,加入氫氧化鈉(709 mg,12.6 mmol)粉末,室溫攪拌10分鐘。向反應液中加入2-溴丙酸乙酯(4.57 g,25.3 mmol),室溫攪拌1.5小時。抽濾反應液,用二氯甲烷(50 mL)洗滌濾餅。減壓濃縮濾液,將所得殘餘物矽膠柱柱層析得化合物2-((叔丁氧羰基)(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丙酸甲酯(2.85 g,產率64%)。1
H NMR (400 MHz, CDCl3
)δ
8.92 (s, 1H), 8.39 (s, 1H), 8.15 (d,J
= 8.2 Hz, 2H), 7.80 (d,J
= 3.9 Hz, 1H), 7.30 (d,J
= 8.3 Hz, 2H), 6.71 (d,J
= 4.0 Hz,1H), 5.24 - 5.04 (m, 1H), 4.29 (q,J
= 7.0 Hz, 2H), 2.38 (s, 3H), 1.40 - 1.14 (m, 15H). LCMS ESI(+)m/z:528.2(M+1).
步驟B:
將化合物2-((叔丁氧羰基)(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丙酸甲酯(2.85 g,5.4mmol)溶解在30 mL二氯甲烷和甲醇的混合溶劑中(體積比10:1),在冰浴下滴加4 N的氯化氫的二氧六環溶液(10 mL)。在氮氣保護下升至室溫攪拌16小時。減壓濃縮反應液。加入30 mL飽和碳酸氫鈉溶液,攪拌5分鐘。用乙酸乙酯萃取(3×50 mL),合併有機相,用50 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液得到化合物乙基 2-((6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丙酸甲酯(2.12 g,產率92%)。1
H NMR (400 MHz, CDCl3
)δ
8.86 (s, 1H), 8.11 (d,J
= 8.4 Hz, 2H), 8.05 (s, 1H), 7.78 (d,J
= 3.9 Hz, 1H), 7.26 (d,J
= 8.0 Hz, 2H), 6.90 (d,J
= 3.9 Hz,1H), 5.80 (d,J
= 6.1 Hz, 1H), 4.32 - 4.18 (m, 2H), 4.00 - 3.91 (m, 1H), 2.35 (s, 3H), 1.43 (d,J
= 7.1 Hz, 3H), 1.27 (t,J
= 7.1 Hz, 3H). LCMS ESI(+)m/z:428.0(M+1).
步驟C:
將化合物乙基 2-((6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丙酸甲酯(2.12 g,4.96 mmol)溶解在50 mL乙醇中,在冰浴,氮氣保護下加入硼氫化鈉(563 mg,14.9 mmol),室溫攪拌16小時。在0 ℃下向反應中滴加1 N稀鹽酸溶液,將反應液調節至中性,減壓蒸除溶劑。用乙酸乙酯萃取(3×50 mL),合併有機相,用30 mL飽和食鹽水洗滌,無水硫酸鈉乾燥,減壓蒸除溶劑,矽膠柱柱層析得化合物2-((6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丙基-1-醇(1.48 g,產率77%)。1
H NMR (400 MHz, DMSO-d6
)δ
8.70 (s, 1H), 8.29 (s, 1H), 8.02 (d,J
= 8.4 Hz, 2H), 7.92 (d,J
= 4.0 Hz, 1H), 7.40 (d,J
= 8.2 Hz, 2H), 7.15 (d,J
= 4.0 Hz, 1H), 7.03(s, 1H), 4.94 (d,J
= 5.2 Hz, 1H), 3.46 - 3.33 (m, 4H), 2.32 (s, 3H), 0.90 (d,J
= 5.7 Hz, 3H). LCMS ESI(+)m/z:386.1(M+1).
步驟D:
在冰浴冷卻和氮氣保護下向100 mL甲苯中加入化合物2-((6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丙基-1-醇(1.68 g,4.36 mmol),DBU(3.32 g,21.8 mmol)和DPPA(3.60 g,13.1 mmol)。升溫到100 ℃,攪拌4小時。減壓濃縮反應液,將所得殘餘物矽膠柱柱層析得化合物N
-(1-疊氮丙-2-基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-胺(1.26 g,產率67%)。1
H NMR (400 MHz, CDCl3
)δ
8.88 (s, 1H), 8.12 (d,J
= 8.2 Hz, 2H), 7.95 (s, 1H), 7.80 (d,J
= 4.0 Hz, 1H), 7.28 (d, 2H), 6.98 (d,J
= 4.0 Hz, 1H), 5.49 (s, 1H), 3.68 - 3.52 (m, 2H), 3.49 - 3.37 (m, 1H), 2.36 (s, 3H), 1.84 - 1.53 (m, 2H), 1.04 (d,J
= 6.1 Hz, 3H). LCMS ESI(+)m/z:411.1(M+1).
步驟E:
將化合物N
-(1-疊氮丙-2-基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-胺(1.20 g,2.59 mmol)溶解在100 mL甲醇中,氮氣保護下加入10% 鈀碳(240 mg)。置換氫氣,在氫氣氛圍下室溫攪拌16小時。抽濾,用20 mL甲醇洗滌濾餅。減壓濃縮濾液,得化合物N2
-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)丙烷-1,2-二胺(1.16 g,產率98%)。1
H NMR (400 MHz, CDCl3
)δ
8.88 (s, 1H), 8.11 (d,J
= 8.4 Hz, 2H), 7.96 (s, 1H), 7.76 (d,J
= 3.9 Hz, 1H), 7.26 (d,J
= 8.4 Hz, 5H), 7.10 (d,J
= 4.0 Hz, 1H), 6.06 (s, 1H), 3.39 - 3.29 (m, 1H), 3.02 (dd,J
= 13.2, 3.6 Hz, 1H), 2.65 (dd,J
= 13.2, 9.2 Hz, 1H), 2.35 (s, 3H), 0.92 (d,J
= 6.2 Hz, 3H). LCMS ESI(+)m/z:385.1(M+1).
步驟F:
將化合物N2
-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)丙烷-1,2-二胺(1.16 g,3.02 mmol)溶解在50 mL甲醇中,加入多聚甲醛(109 mg,3.62 mmol)。加熱到70 ℃,攪拌16小時。冷卻至室溫,抽濾,用10 mL甲醇洗滌。將濾液減壓蒸除溶劑,得到化合物1-(5-甲基咪唑烷-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(1.28 g,產率100%)。1
H NMR (400 MHz, CDCl3
)δ
8.73 (s, 1H), 8.57 (s, 1H), 8.01 (d,J
= 7.7 Hz, 2H), 7.88 (dd,J
= 21.5, 3.9 Hz, 1H), 7.39 (d,J
= 7.7 Hz, 2H), 7.24 (d,J
= 8.7 Hz,1H), 4.40 - 4.24 (m, 1H), 4.15 - 4.01 (m, 1H), 3.87 - 3.72 (m, 1H), 3.71 - 3.49 (m, 1H), 3.22 (dd,J
= 15.9, 8.6 Hz, 1H), 2.32 (s, 3H), 1.55 - 1.44 (m, 1H). LCMS ESI(+)m/z:397.1(M+1).
步驟G:
將化合物1-(5-甲基咪唑烷-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(400 mg,1.01 mmol)溶解在9 mL甲醇中,加入2 N氫氧化鈉溶液(3.0 mL,6.0 mmol)。35 ℃攪拌40小時。用15 mL水稀釋反應液,減壓蒸除甲醇。用乙酸乙酯萃取(3×6 mL),合併有機相,用5 mL飽和食鹽水洗滌有機相,無水硫酸鈉乾燥,抽濾,減壓蒸除溶劑。得到粗產物化合物1-(5-甲基咪唑烷-1-基)-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(223 mg,產率91%)。LCMS ESI(+)m/z:243.1(M+1).
步驟H:
將化合物1-(5-甲基咪唑烷-1-基)-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(100 mg, 0.41 mmol)溶解在6 mL二氯甲烷中,氮氣保護和冰浴下依次加入氰基乙酸(42 mg,0.50 mmol),HOBT(78 mg,0.58 mmol),4-二甲胺基吡啶(81 mg,0.66 mmol)和EDCI(127 mg,0.66 mmol)。室溫攪拌16小時。減壓濃縮,矽膠柱層析和高效液相製備得化合物3-(4-甲基-3-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)咪唑啉-1-基)-3-氧代丙腈(40 mg,產率31%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.91 (s, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 7.47 (s, 1H), 6.72 (d,J
= 16.2 Hz, 1H), 5.03 - 4.80 (m, 2H), 4.21 - 3.92 (m, 4H),3.44 - 3.38 (m, 1H), 3.31 - 3.23 (m, 1H), 1.09 - 0.88 (m, 3H). LCMS ESI(+)m/z:310.1(M+1).
3-(3-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)咪唑啉-1-基)-3-氧代丙腈
步驟A:
將化合物叔丁基(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基甲酸酯(4.00 g,9.36 mmol)溶解在400 mL丙酮中,加入氫氧化鈉(787 mg,14.0 mmol)粉末,室溫攪拌10分鐘。向反應液中加入2-溴乙酸乙酯(4.69 g,28.1 mmol),室溫攪拌1.5小時。抽濾反應液,用二氯甲烷(400 mL)洗滌濾餅。減壓濃縮濾液,將所得殘餘物矽膠柱柱層析得化合物2-((叔丁氧羰基)(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)乙酸甲酯(4.34 g,產率90%)。1
H NMR (400 MHz, CDCl3
)δ
8.91 (s, 1H), 8.28 (s, 1H), 8.12 (d,J
= 8.2 Hz, 2H), 7.81 (d,J
= 3.9 Hz, 1H), 7.29 (d,J
= 8.4 Hz, 2H), 6.72 (d,J
= 4.0 Hz, 1H), 5.17 -4.78 (m, 1H), 4.33 - 4.17 (m, 2H), 4.15 - 3.96 (m, 1H), 2.36 (s, 3H), 1.62 - 1.36 (m, 3H), 1.35 - 1.15 (m, 9H). LCMS ESI(+)m/z:514.1(M+1).
步驟B:
將化合物2-((叔丁氧羰基)(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)乙酸甲酯(4.34 g,8.45 mmol)溶解在45 mL二氯甲烷和甲醇的混合溶劑中(體積比為10:1),在冰浴下滴加4 N的氯化氫的二氧六環溶液(15 mL)。在氮氣保護下升至室溫攪拌16小時。減壓濃縮反應液。加入30 mL飽和碳酸氫鈉溶液,攪拌5分鐘。用乙酸乙酯萃取(3×30 mL),合併有機相,用10 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液得到化合物乙基 2-((6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)乙酸甲酯(3.49 g,產率100%)。1
H NMR (400 MHz, CDCl3
)δ
8.85 (s, 1H), 8.10 (d,J
= 8.4 Hz, 2H), 7.78 (d,J
= 4.0 Hz, 1H), 7.24 (d,J
= 8.4 Hz, 2H), 6.92 (d,J
= 4.0 Hz, 1H), 5.73 (s, 1H),4.26 (q,J
= 7.2 Hz, 2H), 3.95 (d,J
= 4.9 Hz, 2H), 2.35 (s, 3H), 1.27 (t,J
= 7.2 Hz, 3H).LCMS ESI(+)m/z:414.0(M+1).
步驟C:
將化合物乙基 2-((6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)乙酸甲酯(3.49 g,4.96 mmol)溶解在100 mL乙醇中,在冰浴,氮氣保護下下加入硼氫化鈉(958 mg,25.3 mmol)。室溫攪拌16小時。在0 ℃向反應中滴加1 N稀鹽酸溶液,將反應液調節至中性,減壓蒸除溶劑。用乙酸乙酯萃取(3×50 mL),合併有機相,用30 mL飽和食鹽水洗滌,無水硫酸鈉乾燥,減壓蒸除溶劑,矽膠柱柱層析得化合物2-((6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)乙基-1-醇(2.98 g,產率95%)。LCMS ESI(+)m/z:372.0(M+1).
步驟D:
在冰浴冷卻和氮氣保護下向100 mL甲苯中加入化合物2-((6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)乙基-1-醇(2.98 g,8.02 mmol),DBU(6.11 g,40.1 mmol)和DPPA(6.62 g,24.1 mmol)。升溫到110 ℃,攪拌1小時。減壓濃縮反應液,將所得殘餘物矽膠柱柱層析得化合物N
-(1-疊氮乙-2-基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-胺(1.16 g,產率36%)。1
H NMR (400 MHz, CDCl3
)δ
8.86 (s, 1H), 8.11 (d,J
= 8.4 Hz, 2H), 8.00 (s, 1H), 7.80 (d,J
= 4.0 Hz, 1H), 7.26 (d,J
= 8.4 Hz, 2H), 6.94 (d,J
= 4.0 Hz, 1H), 5.40 (t,J
= 5.2 Hz, 1H), 3.61 - 3.54 (m, 2H), 3.45 - 3.38 (m, 2H), 2.35 (s, 3H). LCMS ESI(+)m/z:397.1(M+1).
步驟E:
將化合物N
-(1-疊氮乙-2-基)-6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)-胺(1.06 g,2.59 mmol)溶解在60 mL甲醇中,氮氣保護下加入10% 鈀碳(212 mg)。置換氫氣,在氫氣氛圍下室溫攪拌16小時。抽濾,用20 mL甲醇洗滌濾餅。減壓濃縮濾液,得到粗產物化合物N2
-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)乙烷-1,2-二胺(1.16 g,產率100%)。LCMS ESI(+)m/z:371.1(M+1).
步驟F:
將化合物N2
-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)乙烷-1,2-二胺(1.16 g,3.13 mmol)溶解在50 mL甲醇中,加入多聚甲醛(113 mg,3.76 mmol)。加熱到70 ℃,攪拌16小時。冷卻至室溫,抽濾,用10 mL甲醇洗滌。將濾液減壓蒸除溶劑,得到化合物1-(咪唑烷-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(1.16 g,產率97%)。LCMS ESI(+)m/z:383.1(M+1).
步驟G:
將化合物1-(咪唑烷-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(400 mg,1.05 mmol)溶解在9 mL甲醇中,加入2 N氫氧化鈉溶液(3.0 mL,6.0 mmol)。室溫攪拌7小時。用10 mL水稀釋反應液,減壓蒸除甲醇。用15 mL乙酸乙酯萃取殘餘物3次。合併有機相,用5 mL飽和食鹽水洗滌有機相,無水硫酸鈉乾燥,抽濾,減壓蒸除溶劑。得到粗產物化合物1-(5-咪唑烷-1-基)-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(277 mg,粗產率100%)。LCMS ESI(+)m/z:229.1(M+1).
步驟H:
將化合物1-(5-咪唑烷-1-基)-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(100 mg,0.44 mmol)溶解在6 mL二氯甲烷中,氮氣保護和冰浴下依次加入氰基乙酸(45 mg,0.53 mmol),HOBT(83 mg,0.61 mmol),4-二甲胺基吡啶(86 mg,0.70 mmol)和EDCI(134 mg,0.70 mmol)。室溫攪拌16小時。減壓濃縮,矽膠柱層析和高效液相製備得到化合物3-(3-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)咪唑啉-1-基)-3-氧代丙腈(40 mg,產率30%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.88 (s, 1H), 8.58 (s, 1H), 8.39 - 8.32 (m, 1H), 7.50 - 7.43 (m, 1H), 6.77 - 6.70 (m, 1H), 4.95 - 4.79 (m, 2H), 4.19 - 3.99 (m, 2H), 3.86 - 3.74 (m, 4H). LCMS ESI(+)m/z:296.1(M+1).
(R
)-3-(4-乙基-3-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)咪唑啉-1-基)-3-氧代丙腈
步驟A:
將化合物D-2-胺基丁酸(25.0 g,242 mmol)溶解在200 mL甲醇中,冰浴氮氣保護下滴加氯化亞碸(35.2 mL,485 mmol)。冰浴下攪拌1小時,然後升溫至70 ℃攪拌3小時。反應結束後,降至室溫,減壓濃縮,得到化合物D-2-胺基丁酸甲酯鹽酸鹽(37.2 g,產率100%)。1
H NMR (400 MHz, DMSO-d6
)δ
8.68 (s, 3H), 3.96 (s, 1H), 3.75 (s, 3H), 1.90 - 1.80 (m, 2H), 0.92 (t,J
= 7.5 Hz, 3H). LCMS ESI(+)m/z:117.1(M+1).
步驟B:
將化合物D-2-胺基丁酸甲酯鹽酸鹽(10.0 g,65.1 mmol)溶解在200mL四氫呋喃中,室溫下依次加入三乙胺(9.05 mL,65.1 mmol)和苯甲醛(7.60 g,71.6 mmol)。30 ℃攪拌48小時,過濾,用75 mL四氫呋喃洗滌濾餅,減壓濃縮濾液,溶於200 mL甲醇,冰浴下分批加入硼氫化鈉(2.71 g,71.6 mmol)。冰浴下攪拌3小時。用1 N稀鹽酸淬滅反應,並調節pH至中性。用乙酸乙酯萃取(3×50 mL),合併有機相,用50 mL飽和食鹽水洗滌,無水硫酸鈉乾燥,減壓濃縮,矽膠柱層析得到化合物D-2-卞胺基丁酸甲酯(11.4 g,產率84%)。1
H NMR (400 MHz, CDCl3
)δ
7.38 - 7.20 (m, 5H), 3.81 (d,J
= 13.0 Hz, 1H), 3.72 (s, 3H), 3.64 (d,J
= 13.0 Hz, 1H), 3.23 (t,J
= 6.5 Hz, 1H), 1.74 - 1.62 (m, 2H),0.94 (t,J
= 7.4 Hz, 3H). LCMS ESI(+)m/z:208.1(M+1).
步驟C:
將化合物D-2-卞胺基丁酸甲酯(11.4 g,55.0 mmol)溶解在150 mL二氯甲烷中,室溫下依次加入亞硝酸鈉(5.69 g,82.5 mmol),一水合對甲苯磺酸(15.7 g,82.5 mmol)。30 ℃攪拌2小時,過濾,用50 mL二氯甲烷洗滌濾餅,減壓濃縮濾液。將殘餘物分層於100 mL乙酸乙酯和50 mL水。分離有機相,用乙酸乙酯萃取(3×10 mL),合併有機相,用30 mL飽和食鹽水洗滌,無水硫酸鈉乾燥,減壓濃縮,得到化合物D-2-((N
-卞基-N
-亞硝基)胺基)丁酸甲酯(12.3 g,產率95%)。1
H NMR (400 MHz, CDCl3
)δ
7.41 - 7.25 (m, 3.8H), 7.11 (m, 1.2H), 5.42 - 5.25 (m, 0.9H), 5.00 (d,J
= 14.8 Hz, 0.6H), 4.95 (dd,J
= 9.4, 6.0 Hz, 0.6H), 4.73 (t,J
= 7.5 Hz, 0.4H), 4.59 (d,J
= 14.8 Hz, 0.6H), 3.61 (s, 1.8H)), 3.46 (s, 1.2H), 2.29 - 1.90 (m, 1.6H), 1.75 - 1.57 (m, 0.5H), 0.87 (t,J
= 7.4 Hz, 1.9H), 0.81 (dt,J
=28.3, 7.4 Hz, 3H), 0.74 (t,J
= 7.5 Hz, 1.2H). LCMS ESI(+)m/z:237.1(M+1).
步驟D:
將四氫鋰鋁(3.21 g,84.7 mmol)懸浮在100 mL乙醚中,室溫氮氣下滴加化合物D-2-((N
-卞基-N
-亞硝基)胺基)丁酸甲酯(5.00 g,21.2 mmol)的乙醚(10 mL)溶液,保持滴速至反應回流。40 ℃攪拌反應0.5小時。冰浴下依次用3.2 mL水,3.2 mL15%的氫氧化鈉溶液和9.6 mL水淬滅反應。室溫攪拌5分鐘。分離有機相,無水硫酸鈉乾燥,過濾,濃縮濾液,所得油狀物(R
)-2-(1-苄基肼基)丁-1-醇直接用於下一步反應。1
H NMR (400 MHz, CDCl3
)δ
7.39 - 7.26 (m, 5H), 3.88 - 3.66 (m, 4H), 2.72 - 2.62 (m, 1H), 1.74 - 1.62 (m, 1H), 1.59 - 1.47 (m, 1H), 0.98 (t,J
= 7.5 Hz, 3H). LCMS ESI(+)m/z:195.1(M+1).
步驟E:
將上一步的粗產物化合物(R
)-2-(1-苄基肼基)丁-1-醇溶於100 mL異丙醇中,依次加入N,N
-二異丙基乙胺(10.2 mL,56.9 mmol)和化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(5.00 g,14.2 mmol),氮氣保護下加熱到85 ℃,攪拌反應16小時。濃縮反應液,矽膠柱層析得化合物(R
)-2-(1-卞基-2-(5-硝基-1-對甲苯磺醯基-1H
-吡咯[2,3-b
]吡啶-4-基)肼基)丁-1-醇(5.91 g,兩步產率82%)。1
H NMR (400 MHz, CDCl3
)δ
10.01 (d,J
= 112.2 Hz, 1H), 9.00 (d,J
= 5.2 Hz, 1H), 8.02 (dd,J
= 8.4, 4.3 Hz, 2H), 7.55 - 7.41 (m, 2H), 7.33 - 7.06 (m, 7H), 4.29 - 3.68 (m, 4H), 3.10 - 2.90 (m, 1H), 2.40 (s, 3H), 1.87 - 1.42 (m, 2H), 0.96 (dt,J
= 36.8, 7.5 Hz, 3H). LCMS ESI(+)m/z: 510.0(M+1).
步驟F:
將化合物(R
)-2-(1-卞基-2-(5-硝基-1-對甲苯磺醯基-1H
-吡咯[2,3-b]吡啶-4-基)肼基)丁-1-醇(5.90 g,11.6 mmol)加入到120 mL乙醇中,室溫下依次加入鐵粉(12.9 g,232 mmol)和飽和氯化銨(40 mL),80 ℃攪拌反應15分鐘。趁熱矽藻土抽濾,30 mL甲醇洗滌,濃縮濾液。將殘渣分層於60 mL水和60 mL乙酸乙酯。分離有機相,用60 mL乙酸乙酯萃取4次水相。合併有機相,30 mL水洗,30 mL飽和食鹽水洗,無水硫酸鈉乾燥,減壓濃縮,矽膠柱層析得化合物(R
)-2-(1-卞基-2-(5-胺基-1-對甲苯磺醯基-1H
-吡咯[2,3-b
]吡啶-4-基)肼基)丁-1-醇(2.45 g,產率44%)。1
H NMR (400 MHz, CDCl3
)δ
7.99 (d,J
= 8.4 Hz, 3H), 7.71 (s, 1H), 7.45 (d,J
= 4.1 Hz, 1H), 7.26 - 7.16 (m, 7H), 6.75 (d,J
= 3.9 Hz, 1H), 5.77 (s, 1H), 4.03 - 3.90 (m, 2H), 3.89 - 3.64 (m, 2H), 2.36 (s, 3H), 1.86 - 1.69 (m, 2H), 1.50 - 1.39 (m, 1H), 1.26 (t,J
= 7.1 Hz, 1H), 0.95 (t,J
= 7.6 Hz, 3H). LCMS ESI(+)m/z:480.1(M+1).
步驟G:
將化合物(R
)-2-(1-卞基-2-(5-胺基-1-對甲苯磺醯基-1H
-吡咯[2,3-b
]吡啶-4-基)肼基)丁-1-醇(480 mg,1.0 mmol)溶於6 mL乙酸,氮氣下加入原甲酸三乙酯(222 mg,1.5 mmol)。氮氣下100 ℃攪拌15分鐘。將反應液減壓蒸除溶劑。將所得殘餘物矽膠柱柱層析(純乙酸乙酯),得到化合物(R
)-2-(苄基(6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丁-1-醇(316 mg,產率65%)。LCMS ESI(+)m/z:490.1(M+1).
步驟H:
在冰浴冷卻和氮氣保護下向8 mL甲苯中加入化合物(R
)-2-(苄基(6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺基)丁-1-醇(316 mg,0.65 mmol),DBU(491 mg,3.23 mmol)和DPPA(533 mg,1.94 mmol)。升溫到100 ℃,攪拌16小時。減壓濃縮反應液,將所得殘餘物矽膠柱柱層析得到化合物(R
)-N
-(1-疊氮丁-2-基)-N
-卞基-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺(216 mg,產率65%)。LCMS ESI(+)m/z:515.2(M+1).
步驟I:
將化合物(R
)-N
-(1-疊氮丁-2-基)-N
-卞基-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺(167 mg,0.33 mmol)溶解在8 mL二氯甲烷中,氮氣保護下加入無水氯化鋁(346 mg,2.6 mmol), 室溫攪拌1小時。向反應液加入10 mL飽和碳酸氫鈉,攪拌5分鐘。用15 mL二氯甲烷萃取3次,合併有機相,10 mL飽和食鹽水洗,無水硫酸鈉乾燥,減壓濃縮濾液,將所得殘餘物矽膠柱柱層析得化合物(R
)-N
-(1-疊氮丁-2-基)-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺(89 mg,產率62%)。1
H NMR (400 MHz, CDCl3
)δ
8.90 (s, 1H), 8.22 (s, 1H), 8.12 (d,J
= 8.4 Hz, 2H), 7.83 (d,J
= 4.0 Hz, 1H), 7.28 (d, 2H), 7.03 (d,J
= 4.0 Hz, 1H), 5.65 (s, 1H),3.68 (dd,J
= 12.0, 2.8 Hz, 1H), 3.50 - 3.33 (m, 2H), 2.36 (s, 3H), 1.54 - 1.44 (m, 2H), 0.93 (t,J
= 7.5 Hz, 3H). LCMS ESI(+)m/z:425.0(M+1).
步驟J:
將化合物(R
)-N
-(1-疊氮丁-2-基)-6-對甲苯磺醯基咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)胺(86 mg,2.59 mmol)溶解在6 mL甲醇中,氮氣保護下加入10% 鈀碳(43 mg)。置換氫氣,在氫氣氛圍35 ℃攪拌2小時。抽濾,用10 mL 甲醇洗滌。減壓濃縮濾液,得到化合物(R
)-N2
-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)丁烷-1,2-二胺(79 mg,產率100%)。LCMS ESI(+)m/z:399.1(M+1).
步驟K:
將化合物(R
)-N2
-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)丁烷-1,2-二胺(79 mg,0.20 mmol)溶解在6 mL甲醇中,加入多聚甲醛(7 mg, 0.2 mmol)。加熱到70 ℃,攪拌16小時。冷卻至室溫,抽濾,用5 mL甲醇洗滌。將濾液減壓蒸除溶劑,得到化合物(R
)-1-(5-乙基咪唑烷-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(81 mg,產率100%)。1
H NMR (400 MHz, CDCl3
)δ
8.94 - 8.77 (m, 1H), 8.13 - 8.07 (m, 2H), 7.79 - 7.67 (m, 1H), 7.28 - 7.24 (m, 1H), 7.08 (m, 1H), 4.53 - 3.97 (m, 2H), 3.80 - 3.37 (m, 3H), 2.42 - 2.30 (m, 3H),1.83 -1.59 (m, 2H), 0.96 - 0.74 (m, 3H). LCMS ESI(+)m/z:411.1(M+1).
步驟L:
將化合物(R
)-1-(5-乙基咪唑烷-1-基)-6-對甲苯磺醯基-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(50 mg,0.12 mmol)溶解在6 mL甲醇中,加入2 N氫氧化鈉溶液(1.5 mL,3.0 mmol)。30 ℃攪拌16小時。用10 mL水稀釋反應液,減壓蒸除甲醇。用15 mL乙酸乙酯萃取殘餘物3次。合併有機相,用5mL飽和食鹽水洗滌有機相,無水硫酸鈉乾燥,抽濾,減壓蒸除溶劑。得到粗產物化合物(R
)-1-(5-乙基咪唑烷-1-基)-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(31 mg,產率100%)。LCMS ESI(+)m/z:257.1(M+1).
步驟M:
將化合物(R
)-1-(5-乙基咪唑烷-1-基)-1,6-二氫咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶(31 mg,0.14 mmol)溶解在6 mL二氯甲烷中,氮氣保護和冰浴下依次加入氰基乙酸(15 mg,0.17 mmol),HOBT(27 mg,0.20 mmol),4-二甲胺基吡啶(28 mg,0.23 mmol)和EDCI(44 mg,0.23 mmol)。室溫攪拌16小時。減壓濃縮,矽膠柱層析和高效液相製備得到化合物(R
)-3-(4-乙基-3-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)咪唑啉-1-基)-3-氧代丙腈(12 mg,產率26%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.89 (s, 1H), 8.87 - 8.03 (m, 2H), 7.47 (s, 1H), 6.70 (s, 1H), 5.05 - 4.69 (m, 2H), 4.30 - 3.68 (m, 4H), 3.56 - 3.41 (m, 1H),1.54 - 1.27 (m, 2H), 0.85 - 0.68 (m, 3H). LCMS ESI(+)m/z:324.1(M+1).
2-氰基-N
-(1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-基)乙醯胺
步驟A:
將叔丁基吡咯烷-3-基胺基甲酸酯(4.33 g,23.3 mmol)溶解在30 mL醋酸和10 mL水中,在0 ℃下,緩慢滴加含有亞硝酸鈉(3.21 g,46.6mmol)的水溶液(20 mL),然後在氮氣保護下,升到室溫攪拌18小時。反應結束後,在0 ℃下加水淬滅,用乙酸乙酯(240 mL)分三次萃取,過濾,旋乾,純化得到產物(1-亞硝基吡咯烷-3-基)叔丁基胺基甲酸叔丁酯(4.58 g,產率93%)。LCMS ESI(+)m/z:216.1(M+1).
步驟B:
將化合物(1-亞硝基吡咯烷-3-基)叔丁基胺基甲酸叔丁酯(4.58 g,21.3 mmol),鋅粉(13.8 g,213 mmol)懸浮在醋酸(5 mL)和甲醇(50 mL)中,氮氣保護下室溫攪拌2小時。反應結束後,過濾,旋乾,得到粗品(1-胺基吡咯烷-3-基)叔丁基胺基甲酸叔丁酯(4.28 g,產率100%)。LCMS ESI(+)m/z:202.1(M+1).
步驟C:
將化合物(1-胺基吡咯烷-3-基)叔丁基胺基甲酸叔丁酯(7.75 g, 22 mmol)溶在100 mL異丙醇中,然後加入(1-胺基吡咯烷-3-基)胺基甲酸叔丁酯(4.28 g, 21.3 mmol)和N,N
-二異丙基乙胺(11 g,85.3 mmol),升溫到100 ℃攪拌20小時。反應結束後,旋乾,柱層析純化得化合物(1-((5-硝基-1-對甲苯磺醯基-1-1H
-吡咯[2,3-b
]吡啶-4-基)胺基)吡啶-3-基)叔丁基胺基甲酸酯(6.6 g,產率60%)。LCMS ESI(+)m/z:517.1(M+1).
步驟D:
將化合物1-((5-硝基-1-對甲苯磺醯基-1-1H
-吡咯[2,3-b
]吡啶-4-基)胺基)吡啶-3-基)叔丁基胺基甲酸酯(1.5g,2.9mmol),鐵粉(977 mg,17.4 mmol)和氯化銨(311 mg,5.8 mmol)懸浮在12 mL乙醇和4 mL水中,在氮氣保護下,升溫到75 ℃攪拌1小時。反應結束後,過濾,旋乾、柱層析純化得到產物1-((5-胺基-1-對甲苯磺醯基-1-1H
-吡咯[2,3-b
]吡啶-4-基)胺基)吡啶-3-基)叔丁基胺基甲酸酯(770 mg,產率55%)。LCMS ESI(+)m/z:487.1.
步驟E:
將化合物1-((5-胺基-1-對甲苯磺醯基-1-1H
-吡咯[2,3-b
]吡啶-4-基)胺基)吡啶-3-基)叔丁基胺基甲酸酯(770 mg, 1.58 mmol),原甲酸三乙酯(1 mL)和吡啶鹽酸鹽(18 mg,0.16 mmol)溶在20 mL甲苯中,在氮氣保護下,升溫到115 ℃攪拌2小時。反應結束後,旋乾,柱層析純化得化合物(1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡啶-3-基)叔丁基胺基甲酸酯(700 mg,產率89%)。LCMS ESI(+)m/z:497.1.
步驟F:
將化合物(1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡啶-3-基)叔丁基胺基甲酸酯(700 mg,1.41 mmol)溶解在10 mL二氯甲烷中,在0 ℃下加入三氟乙酸(2 mL),在氮氣保護下,室溫攪拌5小時。反應結束後,旋乾,得到粗品化合物1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡啶-3-胺三氟甲磺酸鹽(560 mg,粗產率100%)。LCMS ESI(+)m/z:397.1(M+1).
步驟G:
將化合物1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡啶-3-胺三氟甲磺酸鹽(360 mg,0.91 mmol)溶解在10 mL甲醇中,在0 ℃下加入氫氧化鈉水溶液(2 N, 3 mL),在氮氣保護下,30 ℃攪拌18小時。反應結束後,加水20 mL,調pH到8 - 9,用二氯甲烷萃取(6×50 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,柱層析純化得化合物1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡啶-3-胺(140 mg,產率64%)。LCMS ESI(+)m/z:243.1(M+1).
步驟H:
將化合物1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡啶-3-胺(70 mg, 0.29 mmol),2-氰基乙酸(29 mg, 0.35 mmol)和HATU(165 mg, 0.43 mmol)溶解在5 mLN,N
-二甲基甲醯胺中,在0 ℃下加入和N,N
-二異丙基乙胺(112 mg, 0.87 mmol),在氮氣保護下,室溫攪拌16小時。反應結束後,加水20 mL,用乙酸乙酯萃取(3×50 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,高效液相製備純化得化合物2-氰基-N
-(1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-基)乙醯胺(30 mg,產率34%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.88 (s, 1H),8.76 (d,J
= 6.8 Hz, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 7.47 (t,J
= 3.0 Hz, 1H), 6.75 (dd,J
= 3.6, 2.0Hz, 1H), 4.56 - 4.48 (m, 1H), 3.70 (d,J
= 1.4 Hz,2H), 3.68 - 3.63 (m, 1H), 3.56 - 3.50 (m, 1H), 3.45 - 3.39 (m, 1H), 3.27 - 3.24 (m, 1H), 2.50 - 2.44 (m, 1H), 1.99 - 1.90 (m, 1H). LCMS ESI(+)m/z:310.1(M+1).
步驟A:
將化合物1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡啶-3-胺(70 mg,0.29 mmol),溴乙腈(42 mg,0.35 mmol)溶解在5 mLN,N
-二甲基甲醯胺中,在0 ℃下加入和三乙胺(88 mg,0.87 mmol),在氮氣保護下,室溫攪拌16小時。反應結束後,加水20 mL,用二氯甲烷萃取(5×50 mL),合併有機相,無水硫酸鈉乾燥,過濾,旋乾,高效液相製備純化得化合物2-((1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-基)胺基)乙腈(12 mg,產率15%)。1
H NMR (400 MHz, CD3
OD-d4
)δ
9.03 (s, 1H), 9.85 (s, 1H), 7.66 (d,J
= 3.4 Hz,1H), 7.20 (d,J
= 3.4 Hz, 1H), 4.09 (s, 2H), 4.07 - 4.00 (m, 1H), 3.89 - 3.84 (m, 1H), 3.75 - 3.69 (m, 1H), 3.65 - 3.58 (m, 2H), 2.66 - 2.58 (m, 1H), 2.24 - 2.16 (m, 1H). LCMS ESI(+)m/z:282.1(M+1).
(3S
,5R
)-5-乙基-1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-甲腈
步驟A:
將化合物(2S
,4R
)-N
-Cbz-2-甲酸乙酯-4-羥基吡咯烷(20.0 g,71.6 mmol)溶解在70 mLN,N
-二甲基甲醯胺中,室溫下加入咪唑(10.7 g,158 mmol)和TBDPSCl(23.6 g,85.9 mmol),攪拌16小時。將反應液倒入水(700 mL)中,用乙酸乙酯萃取(3×60 mL),合併有機相,飽和食鹽水(30 mL)洗,無水硫酸鈉乾燥,抽濾,減壓濃縮。將所得殘餘物矽膠柱柱層析得化合物(2S
,4R
)-N
-Cbz-2-甲酸乙酯-4-O
-TBDPS吡咯烷(34.3 g,產率92%)。1
H NMR (400 MHz, CDCl3
)δ
7.65 - 7.56 (m, 4H), 7.46 - 7.30 (m, 11H), 5.23 - 5.04 (m, 2H), 4.60 - 4.47 (m, 1H), 4.41 (m, 1H), 3.70 - 3.47 (s, 3H), 3.65 - 3.49 (m, 2H), 2.29 - 2.21 (m, 1H), 1.93 - 1.83 (m, 1H), 1.03 (s, 9H). LCMS ESI(+)m/z:518.2(M+1).
步驟B:
將化合物(2S
,4R
)-N
-Cbz-2-甲酸乙酯-4-O
-TBDPS吡咯烷(10.0 g,19.3 mmol)溶解在80 mL乙醇中(體積比為10:1),在冰浴下分批加入硼氫化鈉(2.19 g,58.0 mmol)。升至室溫攪拌16小時。用1 N 鹽酸溶液淬滅反應,並調至中性。減壓濃縮反應液。用甲醇/乙酸乙酯混合溶劑(體積比10:1,200 mL)萃取3次。合併有機相,用100 mL飽和食鹽水洗滌,無水硫酸鈉乾燥。抽濾,減壓濃縮濾液得到化合物(2S
,4R
)-N
-Cbz-2-羥甲基-4-O
-TBDPS吡咯烷(8.92 g,產率94%)。1
H NMR (400 MHz, CDCl3
)δ
7.67 - 7.56 (m, 4H), 7.46 - 7.29 (m, 11H), 5.21 - 5.09 (m, 2H), 4.38 - 4.25 (m, 2H), 3.74 - 3.50 (m, 3H), 3.31 - 3.20 (m, 1H), 2.08 - 1.97 (m, 1H), 1.56 - 1.45 (m, 1H), 1.03 (s, 9H).
步驟C:
將化合物(2S
,4R
)-N
-Cbz-2-羥甲基-4-O
-TBDPS吡咯烷(23.0 g,4.96 mmol)溶解在700 mL二氯甲烷中,室溫下加入戴斯馬丁氧化劑(29.9 g,70.5 mmol)。室溫攪拌1小時。矽藻土抽濾,50 mL二氯甲烷洗滌。向濾液加入飽和碳酸氫鈉(200 mL),攪拌30分鐘。抽濾,分離有機相,用二氯甲烷(100 mL)萃取2次水相。合併有機相,30 mL食鹽水洗,無水硫酸鈉乾燥,減壓蒸除溶劑,矽膠柱柱層析得化合物(2S
,4R
)-N
-Cbz-2-甲醛-4-O
-TBDPS吡咯烷(14.0 g,產率61%)。1
H NMR (400 MHz, CDCl3
)δ
9.45 (dd,J
= 57.2, 2.9 Hz, 1H), 7.68 - 7.55 (m, 4H), 7.49 - 7.29 (m, 11H), 5.25 - 5.09 (m, 2H), 4.57 - 4.34 (m, 2H), 3.74 - 3.34 (m, 2H), 2.10 (t,J
= 10.3 Hz, 1H), 1.88 - 1.77 (m, 1H), 1.05 (s, 9H). LCMS ESI(+)m/z:488.2(M+1).
步驟D:
在冰浴氮氣保護下向甲基三苯基溴化膦(20.5 g,57.4 mmol)的四氫呋喃(150 mL)溶液中加入叔丁醇鉀(6.44 g,57.4 mmol)。加熱至30 ℃攪拌30分鐘。將反應冷卻至0 ℃,滴加化合物(2S
,4R
)-N
-Cbz-2-甲醛-4-O
-TBDPS吡咯烷(14.0 g,28.7 mmol)的四氫呋喃(30 mL)溶液。保持溫度攪拌1小時。向反應中加入水(150 mL)和EA(150 mL),分離有機相,用乙酸乙酯(150 mL)萃取2次水相。合併有機相,水(100 mL),飽和食鹽水(50 mL)洗滌,無水硫酸鈉乾燥,抽濾,減壓蒸除溶劑,矽膠柱柱層析得化合物(2S
,4R
)-N
-Cbz-2-乙烯基-4-O
-TBDPS吡咯烷(13.0 g,產率93%)。1
H NMR (400 MHz, CDCl3
)δ
7.73 - 7.57 (m, 4H), 7.49 - 7.27 (m, 11H), 5.77 - 5.58 (m, 1H), 5.22 - 4.90 (m, 4H), 4.61 - 4.42 (m, 1H), 4.39 - 4.31 (m, 1H), 3.64 - 3.45 (m, 1H), 3.46 - 3.28 (m, 1H), 2.18 - 2.05 (m, 1H), 1.78 - 1.62 (m, 1H), 1.04 (s, 9H). LCMS ESI(+)m/z:487.2(M+1).
步驟E:
將1.0 M的三水正丁基氟化銨的四氫呋喃(53.5 mL,53.5 mmol)溶液中滴加上步反應的粗產物化合物(2S
,4R
)-N
-Cbz-2-乙烯基-4-O
-TBDPS吡咯烷的四氫呋喃(20 mL)溶液中,室溫攪拌16小時。減壓濃縮,矽膠柱柱層析得化合物(2S
,4R
)-N
-Cbz-2-乙烯基-4-羥基吡咯烷(6.15 g,產率93%)。1
H NMR (400 MHz, CDCl3
)δ
7.42 - 7.27 (m, 5H), 5.86 - 5.67 (m, 1H), 5.25 - 5.00 (m, 4H), 4.57 - 4.40 (m, 2H), 3.70 - 3.47 (m, 2H), 2.21 - 2.06 (m, 1H), 1.97 - 1.86 (m, 1H). LCMS ESI(+)m/z:248.1(M+1).
步驟F:
將化合物(2S
,4R
)-N
-Cbz-2-乙烯基-4-羥基吡咯烷(2.00 g, 8.09 mmol)溶解在50 mL二氯甲烷中,冰浴氮氣保護下滴加三乙胺(2.25 mL, 16.2 mmol)和甲磺醯氯(1.39 g,12.1 mmol)。冰浴下攪拌3小時。加入水(50 mL),攪拌15分鐘。加入乙酸乙酯(150 mL),分離有機相,用水(30 mL)洗2次,飽和食鹽水(30 mL)洗,無水硫酸鈉乾燥,抽濾,減壓濃縮,得到粗產品化合物(2S
,4R
)-N
-Cbz-2-乙烯基-4-甲磺酸酯吡咯烷(2.63 g,產率100%)。1
H NMR (400 MHz, CDCl3
)δ
7.45 - 7.28 (m, 5H), 5.88 - 5.66 (m, 1H), 5.28 - 5.04 (m, 5H), 4.60 - 4.46 (m, 1H), 4.06 - 3.84 (m, 1H), 3.74 - 3.61 (m, 1H), 3.00 (s, 3H), 2.57 - 2.41 (m, 1H), 2.13 - 2.01 (m, 1H).
步驟G:
將化合物(2S
,4R
)-N
-Cbz-2-乙烯基-4-甲磺酸酯吡咯烷(2.63 g, 8.08 mmol)溶解在50 mL無水N,N
-二甲基甲醯胺(50 mL)中,氮氣下加入氰化鈉溶液(1.19 g,24.3 mmol)。80℃下攪拌7小時,然後100 ℃下攪拌2小時。將反應液倒入300 mL水中,用乙酸乙酯萃取(3×50 mL),合併有機相,用水(50 mL)洗,飽和食鹽水(50 mL)洗,無水硫酸鈉乾燥,抽濾,減壓濃縮。矽膠柱柱層析得化合物(2S
,4S
)-N
-Cbz-2-乙烯基-4-氰基吡咯烷(1.17 g,產率56%)。1
H NMR (400 MHz, CDCl3
)δ
7.43 - 7.29 (m, 6H), 5.95 - 5.81 (m, 1H), 5.34 - 5.06 (m, 4H), 4.50 - 4.39 (m, 1H), 4.08 - 3.89 (m, 1H), 3.71 - 3.62 (m, 1H), 3.14 - 3.03 (m, 1H), 2.58 - 2.47 (m, 1H), 2.17 - 2.03 (m, 1H). LCMS ESI(+)m/z:257.1(M+1).
步驟H:
將化合物(2S
,4S
)-N
-Cbz-2-乙烯基-4-氰基吡咯烷(1.17 g,4.56 mmol)溶解在30 mL甲醇中,氮氣保護下加入10%鈀碳(234 mg)。置換氫氣。室溫攪拌16小時。抽濾,10 mL甲醇洗滌2次。減壓濃縮濾液,得到化合物(3S
,5R
)-5-乙基-吡咯烷-3-甲氰(567 mg,產率100%)。LCMS ESI(+)m/z:125.1(M+1).
步驟I:
將化合物(3S
,5R
)-5-乙基-吡咯烷-3-甲氰(456 mg,4.57 mmol)溶解在25 mL二氯甲烷中,室溫下依次加入亞硝酸鈉(347 mg,5.03 mmol),一水合對甲苯磺酸(847 mg,5.03 mmol)。攪拌3小時,過濾,用20 mL二氯甲烷洗滌濾餅,減壓濃縮濾液,矽膠柱層析得化合物(3S
,5R
)-1-亞硝基-5-乙基-吡咯烷-3-甲氰(210 mg,產率24%)。1
H NMR (400 MHz, CDCl3
)δ
4.52 - 4.40 (m, 1H), 4.31 - 4.19 (m, 1H), 3.74 - 3.65 (m, 1H), 3.20 - 3.09 (m, 1H), 2.75 - 2.63 (m, 1H), 2.40 - 2.28 (m, 1H), 2.26 - 2.12 (m, 1H), 2.01 - 1.90 (m, 1H), 1.09 (t,J
= 7.4 Hz, 3H). LCMS ESI(+)m/z:128.1(M+1).
步驟J:
將化合物(3S
,5R
)-1-亞硝基-5-乙基-吡咯烷-3-甲氰(210 mg,1.37 mmol)溶解在6 mL甲醇中,室溫下依次加入鋅粉(896 mg,13.7 mmol),逐滴加入乙酸(2 mL)。30 ℃攪拌2小時。抽濾反應液,5 mL甲醇洗滌,濃縮濾液。將殘渣用15 mL二氯甲烷提取,抽濾,濃縮濾液,所得油狀物(3S
,5R
)-1-胺基-5-乙基-吡咯烷-3-甲氰直接用於下一步反應。LCMS ESI(+)m/z:140.1(M+1).
步驟K:
將上一步的粗產物化合物(3S
,5R
)-1-胺基-5-乙基-吡咯烷-3-甲氰溶於12 mL異丙醇中,依次加入N,N
-二異丙基乙胺(1.86 g,14.4 mmol)和化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(758 mg,2.16 mmol),氮氣保護下加熱到85 ℃,攪拌反應16小時。濃縮反應液,矽膠柱層析得化合物(3S
,5R
)-5-乙基-1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)吡咯烷-3-甲氰(282 mg,2步產率43%)。1
H NMR (400 MHz, CDCl3
)δ
9.17 (s, 1H), 8.08 (d,J
= 8.4 Hz, 2H), 7.60 (d,J
= 4.0 Hz, 1H), 7.47 (d,J
= 4.0 Hz, 1H), 7.31 (d,J
= 8.1 Hz, 2H), 3.61 (d,J
= 9.6 Hz, 1H), 3.21 - 3.13 (m, 1H), 2.98 - 2.90 (m, 1H), 2.80 - 2.73 (m, 1H), 2.62 - 2.53 (m, 1H), 2.40 (s, 3H), 1.52 - 1.43 (m, 1H), 1.31 - 1.22 (m, 2H), 0.87 (t,J
= 7.5 Hz, 3H). LCMS ESI(+)m/z:455.1(M+1).
步驟L:
將化合物(3S
,5R
)-5-乙基-1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)吡咯烷-3-甲氰(250 mg,0.55 mmol)加入到12 mL乙醇中,室溫下依次加入鐵粉(922 mg,16.5 mmol)和飽和氯化銨(2 mL),80 ℃攪拌反應0.5小時。趁熱矽藻土抽濾,10 mL甲醇洗滌,濃縮濾液。將殘渣分層于6 mL水和20 mL乙酸乙酯。分離有機相,用20 mL乙酸乙酯萃取2次水相。合併有機相,10 mL飽和食鹽水洗,無水硫酸鈉乾燥。減壓濃縮,所得化合物(3S
,5R
)-5-乙基-1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)吡咯烷-3-甲氰的粗產物,直接用於下一步。LCMS ESI(+)m/z:425.1(M+1).
步驟M:
將化合物(3S
,5R
)-5-乙基-1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)吡咯烷-3-甲氰粗產物,原甲酸三乙酯(122 mg,0.82 mmol)和吡啶鹽酸鹽(6 mg,0.05 mmol)加入到15 mL甲苯中。氮氣下升溫至115 ℃,並攪拌2小時。將反應液減壓蒸除溶劑。將所得殘餘物矽膠柱柱層析得化合物(3S
,5R
)-5-乙基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-甲氰(82 mg,產率34%)。1
H NMR (400 MHz, CDCl3
)δ
8.90 (s, 1H), 8.23 - 8.08 (m, 3H), 7.81 (s, 1H), 7.29 (d,J
= 8.0 Hz, 2H), 7.00 (s, 1H), 3.86 - 3.72 (m, 1H), 3.60 - 3.27 (m, 3H), 2.74 - 2.63 (m, 1H), 2.36 (s, 3H), 2.19 - 2.09 (m, 1H), 1.52 – 1.40 (m, 2H), 0.80 (t,J
= 7.5 Hz, 3H). LCMS ESI(+)m/z:435.1(M+1).
步驟N:
將化合物(3S
,5R
)-5-乙基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-甲氰(79 mg,0.18 mmol)溶解在6 mL甲醇中,加入1 N氫氧化鈉溶液(2.0 mL,2.0 mmol)。30 ℃攪拌7小時。用10 mL水稀釋反應液,減壓蒸除甲醇。用10 mL乙酸乙酯萃取殘餘物4次。合併有機相,用10 mL飽和食鹽水洗滌有機相,無水硫酸鈉乾燥,抽濾,減壓蒸除溶劑。將殘餘物用高效液相製備,得到化合物(3S
,5R
)-5-乙基-1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-甲腈(20 mg,產率40%)。1
H NMR (400 MHz, DMSO-d6
)δ
11.85 (s, 1H), 9.10 - 8.01 (m, 2H), 7.46 (s, 1H), 6.76 (s, 1H), 3.92 - 3.52 (m, 4H), 2.67 (s, 1H), 1.98 - 1.87 (m, 1H), 1.40 - 1.26 (m, 2H), 0.72 (t,J
= 7.4 Hz, 3H). LCMS ESI(+)m/z:281.2(M+1).
2-((5R
)-5-乙基-1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-基)乙腈
步驟A:
將化合物(2S
,4R
)-N
-Cbz-2-乙烯基-4-羥基吡咯烷(3.50 g,14.2 mmol)溶解在200 mL甲醇中,氮氣保護下加入10%鈀碳(700 mg)。置換氫氣。室溫攪拌16小時。抽濾,20 mL甲醇洗滌2次。減壓濃縮濾液,得到化合物(2S
,4R
)-2-乙基-4-羥基吡咯烷(1.63 g,產率100%)。1
H NMR (400 MHz, CDCl3
)δ
4.42 (t,J
= 5.0 Hz, 1H), 3.37 - 3.27 (m, 1H), 3.19 (dd,J
= 11.9, 4.7 Hz, 1H), 2.92 (d,J
= 11.9 Hz, 1H), 1.95 (dd,J
= 13.5, 6.4 Hz, 1H), 1.62 - 1.37 (m, 3H), 0.95 (t,J
= 7.4 Hz, 3H). LCMS ESI(+)m/z:116.1(M+1).
步驟B:
將化合物(2S
,4R
)-2-乙基-4-羥基吡咯烷(1.63 g,14.2 mmol)溶解在70 mL二氯甲烷中,室溫下依次加入亞硝酸鈉(1.46 g,21.2 mmol),一水合對甲苯磺酸(4.04 g,21.2 mmol)。攪拌3小時,過濾,用20 mL二氯甲烷洗滌濾餅,減壓濃縮濾液,矽膠柱層析得化合物(2S
,4R
)-1-亞硝基-2-乙基-4-羥基吡咯烷(1.78 g,產率87%)。1
H NMR (400 MHz, CDCl3
)δ
4.63 - 4.52 (m, 2H), 3.86 (d,J
= 15.8 Hz, 1H), 3.61 (ddd,J
= 15.5, 4.8, 1.7 Hz, 1H), 2.37 - 2.26 (m, 2H), 1.96 - 1.74 (m, 3H), 1.04 (t,J
= 7.5 Hz, 3H). LCMS ESI(+)m/z:145.1(M+1).
步驟C:
將化合物(2S
,4R
)-1-亞硝基-2-乙基-4-羥基吡咯烷(950 mg,6.59 mmol)溶解在45 mL甲醇中,室溫下依次加入鋅粉(8.62 g,132 mmol),逐滴加入乙酸(9 mL)。30 ℃攪拌20分鐘。抽濾反應液,5 mL甲醇洗滌,濃縮濾液,所得油狀物(2S
,4R
)-1-胺基-2-乙基-4-羥基吡咯烷直接用於下一步反應。LCMS ESI(+)m/z:131.1(M+1).
步驟D:
將上一步的粗產物化合物(2S
,4R
)-1-胺基-2-乙基-4-羥基吡咯烷溶於50 mL異丙醇中,依次加入N,N
-二異丙基乙胺(4.70 mL,26.3 mmol)和化合物4-氯-5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶(3.01 g,8.56 mmol),氮氣保護下加熱到85 ℃,攪拌反應16小時。濃縮反應液,矽膠柱層析得化合物(3R
,5R
)-5-乙基-1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)吡咯烷-3-甲氰(1.61 g,產率55%)。1
H NMR (400 MHz, CDCl3
)δ
9.46 (s, 1H), 9.07 (s, 1H), 8.07 (d,J
= 8.4 Hz, 2H), 7.51 (t,J
= 4.9 Hz, 1H), 7.35 - 7.28 (m, 3H), 4.53 (d,J
= 5.5 Hz, 1H), 3.67 (dd,J
= 11.0, 5.5 Hz, 1H), 3.19 - 3.09 (m, 1H), 2.76 (dd,J
= 11.1, 3.4 Hz, 1H), 2.40 (s, 3H), 2.13 - 2.05 (m, 1H), 1.84 - 1.74 (m, 1H), 1.68 - 1.62 (m, 2H), 1.40 - 1.27 (m, 1H), 0.84 (t,J
= 7.5 Hz, 3H). LCMS ESI(+)m/z:446.1(M+1).
步驟E:
將化合物(3R
,5R
)-5-乙基-1-((5-硝基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)吡咯烷-3-甲氰(1.61 g,3.61 mmol)加入到80 mL乙醇中,室溫下依次加入鐵粉(6.05 g,108 mmol)和飽和氯化銨(20 mL),80 ℃攪拌反應20分鐘。趁熱矽藻土抽濾,10 mL甲醇洗滌,濃縮濾液。將殘渣分層於50 mL水和50 mL乙酸乙酯。分離有機相,用50 mL乙酸乙酯萃取2次水相。合併有機相,10 mL飽和食鹽水洗,無水硫酸鈉乾燥。減壓濃縮,矽膠柱柱層析得化合物(3R
,5R
)-5-乙基-1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)吡咯烷-3-甲氰(714 mg,產率48%)。1
H NMR (400 MHz, CDCl3
)δ
8.00 (d,J
= 8.4 Hz, 2H), 7.79 (s, 1H), 7.40 (d,J
= 4.0 Hz, 1H), 7.23 (d,J
= 8.0 Hz, 2H), 6.89 (d,J
= 4.0 Hz, 1H), 5.61 (s, 1H), 4.45(d,J
= 5.9 Hz, 1H), 3.60 (dd,J
= 11.0, 5.6 Hz, 1H), 3.05 - 2.97 (m, 1H), 2.58 (dd,J
= 10.9, 3.7 Hz, 1H), 2.42 - 2.36 (m, 1H), 2.35 (s, 3H), 2.01 (dd,J
= 14.1, 6.6Hz, 1H), 1.81 - 1.66 (m, 3H), 1.37 - 1.26 (m, 2H), 0.85 (t,J
= 7.5 Hz, 3H). LCMS ESI(+)m/z:416.1(M+1).
步驟F:
將化合物(3R
,5R
)-5-乙基-1-((5-胺基-1-對甲苯磺醯基-1H
-吡咯并[2,3-b
]吡啶-4-基)胺基)吡咯烷-3-甲氰(75 mg,0.18 mmol)溶於1 mL乙酸,氮氣下加入原甲酸三乙酯(40 mg,0.27 mmol)。氮氣下100 ℃攪拌5分鐘。將反應液減壓蒸除溶劑。將所得殘餘物矽膠柱柱層析(純乙酸乙酯),得到化合物(3R
,5R
)-5-乙基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-醇(55 mg,產率72%)。LCMS ESI(+)m/z:426.1(M+1).
步驟G:
將化合物(3R
,5R
)-5-乙基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-醇(55 mg, 0.13 mmol)溶解在10 mL二氯甲烷中,室溫下加入戴斯馬丁氧化劑(112 mg,0.26 mmol)。室溫攪拌1小時。矽藻土抽濾,10 mL二氯甲烷洗滌。向濾液加入飽和碳酸氫鈉(10 mL),攪拌30分鐘。抽濾,分離有機相,用二氯甲烷(10 mL)萃取2次水相。合併有機相,5 mL食鹽水洗,無水硫酸鈉乾燥,減壓蒸除溶劑,矽膠柱柱層析得化合物(3R
,5R
)-5-乙基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-酮(25 mg,產率45%)。LCMS ESI(+)m/z:424.1(M+1).
步驟H:
將二乙基(氰基甲基)膦酸酯(67 mg,0.38 mmol)溶解在8 mL四氫呋喃中,冰浴氮氣保護下加入60%鈉氫(15 mg,0.38 mmol)。室溫攪拌0.5小時。冰浴氮氣保護下加入化合物(3R
,5R
)-5-乙基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-酮(80 mg,0.19 mmol)的四氫呋喃溶液(1 mL)。冰浴下攪拌2小時。加入5 mL飽和氯化銨溶液,升至室溫,攪拌5分鐘。用乙酸乙酯萃取(3×5 mL),合併有機相,3 mL飽和食鹽水洗,無水硫酸鈉乾燥,減壓濃縮得粗產品化合物(R
)-2-(5-乙基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-亞基)乙腈直接用於下一步反應。LCMS ESI(+)m/z:447.1(M+1).
步驟I:
將粗產物化合物(R
)-2-(5-乙基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-亞基)乙腈溶解在10 mL甲醇中,氮氣保護下加入10%鈀碳(84 mg)。置換氫氣。室溫攪拌16小時。抽濾,5 mL甲醇洗滌2次。減壓濃縮濾液,矽膠柱柱層析得化合物2-((5R
)-5-乙基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-基)乙腈(67 mg,產率79%)。LCMS ESI(+)m/z:449.2(M+1).
步驟J:
將化合物2-((5R
)-5-乙基-1-(6-對甲苯磺醯咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-基)乙腈(30 mg,0.06 mmol)溶解在3mL甲醇中,加入1N氫氧化鈉溶液(1.0 mL,1.0 mmol)。30℃攪拌6小時。用5 mL乙酸乙酯萃取殘餘物4次。合併有機相,用1 mL飽和食鹽水洗滌有機相,無水硫酸鈉乾燥,抽濾,減壓蒸除溶劑。將殘餘物矽膠柱柱層析和高效液相製備,得到化合物2-((3S
,5R
)-5-乙基-1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-基)乙腈(36-1,10 mg,產率58%)和2-((3R
,5R
)-5-乙基-1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-基)乙腈(36-2,8 mg,產率20%)。
化合物36-1:2-((3S
,5R
)-5-乙基-1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-基)乙腈:1
H NMR (400 MHz, DMSO-d6
)δ
11.79 (s, 1H), 9.10 - 7.84 (m, 2H), 7.42 (s, 1H), 6.84 (s, 1H), 3.94 - 3.44 (m, 2H), 3.37 - 3.25 (m, 2H), 3.05 - 2.71 (m, 3H), 1.52 -1.40 (m, 1H), 1.35 - 1.19 (m, 2H), 0.69 (t,J
= 7.5 Hz, 3H).LCMS ESI(+)m/z:295.1(M+1).
化合物36-2:2-((3R
,5R
)-5-乙基-1-(咪唑并[4,5-d
]吡咯并[2,3-b
]吡啶-1(6H
)-基)吡咯烷-3-基)乙腈:1
H NMR (400 MHz, DMSO-d6
)δ
11.86 (s, 1H), 8.56 (s, 2H), 7.44 (s, 1H), 6.74 (s, 1H), 3.73 - 3.53 (m, 2H), 3.30 - 3.22 (m, 1H), 2.83 (d,J
= 6.6 Hz, 2H), 2.74 -2.66 (m, 1H), 2.11 - 1.90 (m, 2H), 1.38 - 1.22 (m, 2H), 0.71 (t,J
= 7.4 Hz, 3H).LCMS ESI(+)m/z:295.1(M+1).
實施例37
JAK激酶小分子抑制劑的活性檢測
實驗方案
1.試劑準備
(1)激酶反應緩衝液
配置激酶反應緩衝液,組分如下:50 mM HEPES, pH 7.5,1 mM EGTA,10 mM MgCl2,2 mM DTT,0.01% Tween20
(2)1X檢測緩衝液
配置檢測緩衝液,去離子水 9:1 稀釋10X檢測緩衝液至1X
(3)4X激酶溶液
激酶反應緩衝液稀釋JAK激酶至4X終濃度(JAK1:40 nM,JAK2:0.5 nM)
(4)4X底物溶液
激酶反應緩衝液稀釋 ULight™-JAK-1 (Tyr1023)底物至200nM(終濃度:50 nM)
(5)4X ATP溶液
激酶反應緩衝液稀釋ATP至4X終濃度(JAK1:160μM,JAK2:40μM)
(6)4X測試化合物溶液
DMSO溶解測試用化合物至10 mM儲存液,3倍梯度稀釋配置成所需濃度,每個化合物設置10個濃度點,測試化合物終濃度範圍為:10μM - 0.5 nM
(7)4X酶反應終止液:
1X檢測緩衝液溶解EDTA至40 mM(EDTA終濃度:10 mM)
(8)4X 檢測抗體溶液
1X檢測緩衝液稀釋Eu標記檢測抗體(anti-phosphotyrosine (PT66))至8 nM(抗體終濃度:2 nM)
2.實驗過程
(1)向384微孔盤中依次加入2.5μL,4X激酶溶液,和2.5μL,已經稀釋好的不同濃度的4X測試化合物溶液,每個濃度設置2個重複孔,同時設置酶溶液空白對照組和陰性對照組(DMSO組)
(2)震盪384多孔盤,混勻酶和化合物,1000轉,離心1分鐘,在室溫下孵育60分鐘
(3)向384多孔盤中加入2.5μL,4X底物溶液,1000轉離心1分鐘
(4)向384多孔盤中加入2.5μL,4XATP溶液,1000轉離心1分鐘,起始酶反應
(5)JAK1室溫反應2小時,JAK2室溫反應1小時
(6)JAK1反應的各組分終濃度分別為:JAK1:10 nM,底物:50 nM,ATP:40uM,測試化合物終濃度範圍為:10μM-0.5 nM
JAK2反應的各組分終濃度分別為:JAK2:0.125 nM,底物:50 nM,ATP:10μM,測試化合物終濃度範圍為:10μM - 0.5 nM
(7)酶反應結束後,向384多孔盤每孔中加入5μL,4X酶反應終止液,1000轉,離心1分鐘,在室溫下反應5分鐘
(8)向384多孔盤每孔中加入5μL,4X檢測抗體溶液,(檢測抗體終濃度為2 nM),1000轉,離心1分鐘,室溫條件下孵育1小時
(9)抗體反應結束後,在Envision盤式分析儀上測定各孔的訊號值
3.數據分析
(1)以酶溶液空白對照組為100%抑制率和陰性對照組(DMSO組)為0%抑制率,計算檢測化合物各個濃度對應的百分比抑制率
(2)在GraphPad Prism 軟體中對檢測化合物的濃度對數值和相對應的百分比抑制率進行非線性回歸分析,得到檢測化合物的半數抑制濃度(IC50
),所得實驗結果列在表1中
表1
實施例 | JAK1 (IC50 ,nM) | JAK2 (IC50 ,nM) | 實施例 | JAK1 (IC50 ,nM) | JAK2 (IC50 ,nM) | |
1 | 23.8 | 70.9 | 20 | 4.30 | 1.90 | |
2 | 0.28 | 1.70 | 21 | 0.92 | 4.77 | |
3 | 0.17 | 0.28 | 22 | 1.60 | 4.04 | |
4 | 0.47 | 0.95 | 23 | 2.71 | 6.07 | |
5 | 0.28 | 1.45 | 24 | 7.72 | 46.6 | |
6 | 0.66 | 3.89 | 25 | 5.20 | 5.30 | |
7 | 0.08 | 4.00 | 26 | 41.7 | 151 | |
8 | 1.50 | 5.00 | 27 | 1.70 | 2.30 | |
9 | 0.14 | 0.70 | 28 | 3.50 | 13.1 | |
10 | 0.80 | 6.10 | 29 | 13.9 | 27.5 | |
11 | 0.57 | 2.98 | 30 | 2.80 | 28.1 | |
12 | 1.77 | 3.28 | 31 | 6.90 | 71.8 | |
13 | 16.0 | 56.7 | 32 | 6.80 | 15.3 | |
14 | 13.5 | 7.50 | 33 | 11.2 | 29.1 | |
15 | 5.14 | 16.1 | 34 | 73.8 | 51.7 | |
16 | 1.31 | 16.1 | 35 | 9.50 | 61.3 | |
17 | 2.0 | 1.2 | 36-1 | 6.8 | 23.5 | |
18 | 6.31 | 13.8 | 36-2 | 43.6 | 126.9 | |
19 | 2.37 | 6.01 |
無
無
無
Claims (11)
- 一種藥物組合物,其特徵在於:包含請求項1至5中任一項所述之氰基取代的環肼衍生物和藥學上可接受的載體、賦形劑、稀釋劑、輔劑或媒介物中的至少一種;其中,所述氰基取代的環肼衍生物的用量為藥物組合物總重量的0.01%-99.9%。
- 如請求項7所述之藥物組合物,其特徵在於:還包含附加治療劑;所述附加治療劑選自抗炎藥、免疫調節劑或免疫抑制劑、神經營養因子、用於治療心血管疾病的活性劑和用於治療糖尿病的活性劑。
- 如請求項8所述之藥物組合物,其特徵在於:該免疫調節劑或免疫抑制劑包含用於治療自體免疫疾病的活性劑。
- 一種如請求項1至5中任一項所述之氰基取代的環肼衍生物在製備藥物的用途,其特徵在於,該藥物用於抑制或調節蛋白激酶活性。
- 一種如請求項1至5中任一項所述之氰基取代的環肼衍生物在製備藥物的用途,其特徵在於:用於預防、處理、治療或減輕患者自體免疫疾病或增殖性疾病。
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2020
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- 2020-06-11 EP EP20864315.5A patent/EP4032888A4/en active Pending
- 2020-06-11 CA CA3150955A patent/CA3150955A1/en active Pending
- 2020-06-11 WO PCT/CN2020/095605 patent/WO2021051899A1/zh unknown
- 2020-06-11 JP JP2022516640A patent/JP2022548123A/ja active Pending
- 2020-06-11 US US17/642,567 patent/US20220339146A1/en active Pending
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- 2020-06-11 MX MX2022003130A patent/MX2022003130A/es unknown
- 2020-07-17 TW TW109124297A patent/TWI749644B/zh active
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Patent Citations (1)
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CN102712640A (zh) * | 2010-01-12 | 2012-10-03 | 弗·哈夫曼-拉罗切有限公司 | 三环杂环化合物、其组合物和应用方法 |
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US20220339146A1 (en) | 2022-10-27 |
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CN110483514A (zh) | 2019-11-22 |
EP4032888A4 (en) | 2024-01-10 |
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