NL2035261B1 - Synthetic method for 3,4-dihydroisoquinolin-1-one compounds - Google Patents
Synthetic method for 3,4-dihydroisoquinolin-1-one compounds Download PDFInfo
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- NL2035261B1 NL2035261B1 NL2035261A NL2035261A NL2035261B1 NL 2035261 B1 NL2035261 B1 NL 2035261B1 NL 2035261 A NL2035261 A NL 2035261A NL 2035261 A NL2035261 A NL 2035261A NL 2035261 B1 NL2035261 B1 NL 2035261B1
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- dihydroisoquinoline
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- YWPMKTWUFVOFPL-UHFFFAOYSA-N 3,4-dihydro-2h-isoquinolin-1-one Chemical class C1=CC=C2C(=O)NCCC2=C1 YWPMKTWUFVOFPL-UHFFFAOYSA-N 0.000 title claims description 10
- 238000010189 synthetic method Methods 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 230000004224 protection Effects 0.000 claims abstract description 6
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 5
- 239000011261 inert gas Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229930192474 thiophene Natural products 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 34
- 238000012512 characterization method Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- -1 3,4-DIHYDROISOQUINOLIN-1-ONE COMPOUNDS Chemical class 0.000 description 4
- 238000011160 research Methods 0.000 description 3
- MQKFSXLBPPCAGR-UHFFFAOYSA-N 6,7-dimethoxy-3,4-dihydro-2h-isoquinolin-1-one Chemical compound C1CNC(=O)C2=C1C=C(OC)C(OC)=C2 MQKFSXLBPPCAGR-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- WPKMGEQXTYQXGI-UHFFFAOYSA-N thalifolin Chemical compound C1CN(C)C(=O)C2=C1C=C(OC)C(O)=C2 WPKMGEQXTYQXGI-UHFFFAOYSA-N 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- BMHZAHGTGIZZCT-LJQANCHMSA-N (4r)-2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4,3'-pyrrolidine]-1,2',3,5'-tetrone Chemical compound C1([C@]2(C(NC(=O)C2)=O)C2=O)=CC(F)=CC=C1C(=O)N2CC1=CC=C(Br)C=C1F BMHZAHGTGIZZCT-LJQANCHMSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- SBFSGQVISGZPJH-UHFFFAOYSA-N Doryphornine Natural products C1=CN(C)C(=O)C2=C1C=C(OC)C(O)=C2 SBFSGQVISGZPJH-UHFFFAOYSA-N 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- LZAZURSABQIKGB-AEKGRLRDSA-N Narciclasine Chemical compound C1=C2C3=C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 LZAZURSABQIKGB-AEKGRLRDSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 238000012966 insertion method Methods 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate Chemical compound [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000003951 lactams Chemical group 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229950002259 minalrestat Drugs 0.000 description 1
- VSEJCXBFXFEXPW-UHFFFAOYSA-N narciclasine Natural products OC1CC2=C(C(O)C1O)c3cc4OCOc4c(O)c3C(=O)N2 VSEJCXBFXFEXPW-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 235000014101 wine Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a synthetic method for 3,4— dihydroisoguinolin—l—one compounds, including the following steps: under the protection of inert gas, dissolving a compound as shown in formula (I) in an aprotic solvent, and sequentially adding 1—2 mol/L tetrahydrofuran solvent of alkali and a compound as shown in formula (II) while stirring; and allowing reaction under heating conditions, and, then collecting a compound, as shown. in formula (III) from the reaction product; wherein aromatic groups in formula (I) and formula (II) are selected from any one of phenyl, substituted phenyl, naphthyl, pyridine, furan and thiophene. The present invention has the beneficial effects that the synthetic method for 3,4—dihydroisoguinolin—l—one compounds provided by the present invention is green, efficient, easy to operate, more widely applicable and more economical, and has very important theoretical value and practical significance in the field.
Description
P1807 /NL
SYNTHETIC METHOD FOR 3,4-DIHYDROISOQUINOLIN-1-ONE COMPOUNDS
The present invention relates to the field of organic synthe- sis, and particularly relates to a synthetic method for 3,4- dihydroisoguinolin-1l-one compounds.
3,4-dihydroisogquinolin-1-0ne compounds are the parent core structures widely existing in the natural alkaloids and the phar- maceutical industry. The representative alkaloids containing the 3,4-dihydroisoguinolin-1-0ne parent core include Corydaldine,
Thalifoline, N-methylcoryaldine, Minalrestat, Narciclasine and the like. Compounds containing such frame have a wide range of biolog- ical activities, such as anti human immunodeficiency virus, anti- bacterial, antidepressant, anticancer, antioxidant and antithrom- botic effects. Therefore, it has always been a research hotspot in the fields of medicinal chemistry and synthetic chemistry to de- velop an effective synthetic method for such important lactam ring core. ete AT 2
As RY : NH Ho Ar AQ Re : nN ST CL XX 1 OH it ì il i ì it . i a
LC mg $06 2 gr 9 TT
HN in
Corydalding Thalitoling N-methyl coryaidine Minslrastat Narsiclasine
At the early stage, the synthesis of 3,4-dihydroisoquinolin- l-one compounds mainly depended on the intramolecular cyclization of active amides or amide precursors, including carbamate, isocya- nate, azide amide and urea. However, the strong acidity conditions of these methods limit the range of substrates. In recent years, a large number of researches have been conducted on the preparation of such compounds, and the representative methods include: (1) palladium catalyzed carbonyl insertion method; (2) transition met- al catalyzed C-H bond activation method; (3) cyclohexylamine oxi- dation method; and (4) domino reaction without metal participa- tion, etc.
Intrrasoireudar syslizstion iN 9 1 Ce EEL gt a pg RE
RK is ¢ 5 Rg d
ED Carbonyl insenien 5 x : 1 H : ss pet ns + Zea piest, Er” nF
Riz 1 ie Satta
Ag OR Rr?
A= Lar OTR {23 Transition weil satalyaed CAE sotivation a 7 in eN Ay + gts ROR NN ™
Ha i it 4
R EJ TEN RE
Re
Kd, DMe, OBoq, or CE £3) Guidation of cycle wines 2 nN Re . i
PO LL VON va Med De $41 hos o o 5 oa > 5 rng RE al AR en 1 Ee A VIT ~
St uv [Jer oN DR | ar Safa on
NY we FR RE a a ro —~{_} ~My x 2
The above researches have provided several effective synthet- ic methods for the preparation of 3,4-dihydroisoquinolin-1-0ne.
Although substantial progress has been made and the methods have been applied in the pharmaceutical field, these methods still have some shortcomings that cannot be ignored, including use of transi- tion metals, pre-preparation of complex substrates, harsh reaction conditions and cumbersome post-treatment. Therefore, it has very important theoretical value and practical significance in this field to seek for a more widely applicable, economical, green and convenient synthetic method.
The objective of the present invention is to overcome the de- fects existing in the prior art, and provide a synthetic method for 3,4-dihydroisoguinolin-1-0ne compounds, including the follow- ing steps:
S1. under the protection of inert gas, dissolving a compound as shown in formula (I) in an aprotic solvent, and sequentially adding 1-2 mol/L tetrahydrofuran solvent of alkali and a compound as shown in formula (II) while stirring; and 82. allowing reaction under heating conditions, and then col- lecting a compound as shown in formula (III) from the reaction product;
0 ©
RR ; Ry
OOS ED «CCX, ek A= ík,
FH
{1 {ny 8) wherein the aromatic groups in formula (I) and formula (IT) are selected from any one of phenyl, substituted phenyl, naphthyl, pyridine, furan and thiophene.
Preferably, in $82, a temperature of the reaction under the heating conditions is 60-100°%, and a reaction time is 12-16 h.
Preferably, in 31, the alkali is selected from sodium bis (trimethylsilyl)amide.
Preferably, a molar ratio of the compound in formula (I), the compound in formula (II) and the alkali is 1:1-2:2-3.
Preferably, in S1, the aprotic solvent is selected from any one of 1,4-dioxane, cyclopentyl methyl ether, toluene, tetrahydro- furan and dimethoxyethane.
The present invention has the advantages that the synthetic method for 3,4-dihydroisoquinolin-l-one compounds provided by the present invention is green, efficient, easy to operate, more wide- ly applicable and more economical, and has very important theoret- ical value and practical significance in the field.
FIG. 1 is a flow chart of a synthetic method for 3,4- dihydroisoquinolin-l-one compounds provided by the present inven- tion.
The present invention will be further described below in com- bination with the embodiments. The description of the following embodiments is only for better understanding the present inven- tion. It should be noted that for those of ordinary skill in the art, some modifications may be made to the present invention with- out deviating from the principle of the present invention. These improvements and modifications should also fall into the protec- tion scope of the claims of the present invention.
A synthetic method for 3,4-dihydroisoquinclin-l-one compounds provided by the embodiments of the present invention is as fol-
lows:
Under the protection of inert gas, 0.2 mmol of compound as shown in formula (I) is dissolved in 2 mL of 1,4-dioxane or tolu- ene, and 0.24 mmol of compound as shown in formula (II) and 0.3 mL of tetrahydrofuran solvent containing 0.6 mmol of sodium bis(trimethylsilyl)amide (lithium bis (trimethylsilyl)amide may al- so be used) were sequentially added while stirring, reaction is allowed at 60-100°C for 12-16 h, then 3 drops of water are added for quenching, a small amount of silica gel powder and anhydrous sodium sulfate are used for filtration, evaporation under reduced pressure 1s performed after washing with ethyl acetate, and the mixture is separated using column chromatography (PE: EA=10:1-3:2) to obtain a product (III). i / A i xy 1,
A = Ca ze
U {1 (B wherein the aromatic groups in formula (I) and formula (II) are selected from any one of phenyl, substituted phenyl, naphthyl, pyridine, furan and thiophene.
The structure of a series of 3,4-dihydroisoguinolin-1-one de- rivatives synthesized by the present invention is as follows:
PQ Pg Pg Lg : Si RR - Ea * ZEN . DS ee “ay ha Bu Fp oF,
EN gs) (1-3) (id) ocr MM ot po OH a NH
IF AA # Ny AAAs
GIS) (6) (i167) {4i-8) pa a 0 Br OQ “> © { i | ! i
G> A : ANA SF Sy “Fr SN
J do lo = Sa oF rd
IB) {H-10} TH) {4-12} 5 » > in 1 SF 0 > Le? Q
YY IN f 5 NH i A oo Cy Cr. Ot.
SF 4 TC Ty {H-13) {i-14} UH-15} {1-18}
The following examples are for further explanation.
Example 1:
Preparation and characterization of compound III-1: 9
O / ap “No I NH cop Ur AAS 5 (1-1) {1-1} {= a 10 mL reaction tube was taken, and a stirrer was added. Un- der the protection of nitrogen gas, the compound (48.2 mg, 0.2 mmol) as shown in formula (I-1) was added, add 1,4 dioxane {2.0 mL} was added and dissolved by stirring, and 0.24 mmol of compound as shown in formula (II-1) and sodium bis (trimethylsilyl)amide (2.0 mol/L, 0.3 mL, 0.6 mmol) were sequentially added; after re- acting at 100°C for 12 h, 3 drops of water were added for quench- ing, a small amount of silica gel powder and anhydrous sodium sul- fate were used for filtration, evaporation under reduced pressure was performed after washing with ethyl acetate, and the mixture was eluted using column chromatography (PE: EA=10:1) to obtain a compound III-1; the compound III-1 was white solid, and a yield was 88%; 'H NMR (500 MHz,CDCls): & 7.41 - 7.35 (m, 4H), 7.34 — 7.31 (m, 1H), 6.96 (s, 1H), 6.82 (s, 1H), 6.55 (s, 1H), 4.72(dd, J= 11.2, 4.0 Hz, 1H), 3.13 (dd, J=15.3, 11.2 Hz, 1H), 3.00 (dd, J= 15.3, 4.2 Hz, 1H}, 2.68 (s, 3H), 2.31 (s, 3H).
Example 2
Preparation and characterization of compound III-2:
Oo
Te) 7 i , NH
NTR + AJ me =~ DD ‘Buy (1-1) (11-2) (1-2)
The preparation conditions were the same as those in example 1. The compound III-2 was white solid, and a yield was 86%; ‘H NMR (500 MHz, CDCl): & 7.43 — 7.40 (m, 2H), 7.35 - 7.32 (m, 2H), 6.97 (s, 1H), 6.84 (s,1H), 6.10 (s, 1H), 4.71 (dd, J=11.8, 4.0 Hz, 1H), 3.16 (dd, J=15.3, 11.8 Hz, 1H), 2.97 (dd, J=15.3, 3.8 Hz, 1H), 2.69 (s, 3H), 2.32 (s, 3H), 1.33 (s, SH).
Example 3
Preparation and characterization of compound III-3:
Q
Oo | , we So "NH
SNS C
" ze ’ Ph (1) (1-3) (11-3)
The preparation conditions were the same as those in example 1. The compound III-3 was white solid, and a yield was 91%; ‘H NMR (500 MHz, CDCl): & 7.62-7.58 (m, 4H), 7.48-7.44 (m, 4H), 7.39 - 7.35 (Im, 1H), 6.98 (s, 1H), 6.85 (s, 1H), 6.24 (s, 1H), 4.78 (dd,
J = 11.4, 4.1 Hz, 1H), 3.19 (dd, J = 15.3, 11.3 Hz, 1H), 3.05 (dd, J = 15.3, 4.1 Hz, 1H), 2.71 (s, 3H), 2.33(s, 3H).
Example 4
Preparation and characterization of compound III-4:
OG
= ;
AA 4 NY Soi TM ® rt Fac TN “CF {1-1} {1-4} 4)
The preparation conditions were the same as those in example 1. The compound III-4 was white solid, and a yield was 81%; :H NMR (500 MHz, CDCl;3): & 7.62 (d, J = 8.0Hz, 2H), 7.51 (d, J = 8.0 Hz, 5 2H), 6.96 (s, 1H), 6.81 (s, 1H), 6.76 (s, 1H), 4.82 (t, J = 7.5
Hz, 1H), 3.13 - 3.09 (m, 2H), 2.64 {(s, 3H), 2.30 (s, 3H).
Example 5
Preparation and characterization of compound III-5:
Nx + Fo “Oo NH
X . p= 9 moe F | ]
I
F
{i-1) (1-5) {1ii-8)
The preparation conditions were the same as these in example 1. The compound III-5 was light yellow solid, and a yield was 75%; 'H NMR (500 MHz, CDCls): & 7.39 - 7.34 (m, 2H), 7.08 — 7.03 (m, 2H), 6.96 (s, 1H), 6.82 (s, 1H), 6.24 (s, 1H), 4.72 (dd, J = 11.2, 4.2Hz, 1H), 3.11 (dd, J = 15.3, 11.1 Hz, 1H), 3.00 (dd, J = 15.3, 4.2 Hz, 1H), 2.67 {s, 3H), 2.31 (s, 3H).
Example 6
Preparation and characterization of compound III-6:
Q AN
“Oo | NH Ci
ON + —
NF
(-1) (11-6) {11-6}
The preparation conditions were the same as those in example 1. The compound III-6 was white solid, and a yield was 84%; ‘H NMR (500 MHz, CDCl:): & 7.46 (dd, J = 7.3, 2.1 Hz,1H}, 7.38 (dd, J = 7.5, 1.7 Hz, 1H), 7.28 - 7.22 (m, 2H), 6.96 (s, 1H), 6.82 (s, 1H), 6.12 {(s, 1H}, 5.25 - 5.22 {m, 1H), 3.23 (dd, J = 15.4, 4.8 Hz,
1H), 3.06 (dd, J = 15.4, 9.2 Hz, 1H), 2.70 {(s, 3H), 2.30 (s, 3H).
Example 7
Preparation and characterization of compound III-7:
O o I
No i NH = ES , Sed N | N rE 1-1) (1-7) (1-7)
The preparation conditions were the same as those in example 1. The compound III-7 was white solid, and a yield was 70%; ‘H NMR (500 MHz, CDCl:): & 8.60 (d, J = 2.2 Hz, 1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 7.74 - 7.72 (m, 1H), 7.31 - 7.28 (m, 1H), 6.95 (s, 1H), 6.80 (s, 1H), 6.58 (s, 1H), 4.80 - 4.77 {(m, 1H), 3.15 - 3.08 {m, 2H), 2.64 (s, 3H), 2.29 (s, 3H).
Example 6
Preparation and characterization of compound III-8:
Oo 0 + 3 do | | Sor” “NH y — { 3 YW 2 s
Sn
Ww 1) {1-8} (11-8)
The preparation conditions were the same as those in example 1. The compound III-8 was white solid, and a yield was 86%; *‘H NMR {500 MHz, CDCl:): & 7.23 (dd, J = 5.1, 1.2 Hz, 1H), 7.04 - 7.03 {m, 1H), 6.98 - 6.95 (m, 2H), 6.85 (s, 1H), 6.31 (s, 1H), 5.01 - 4.98 (rm, 1H), 3.21 (dd, J = 15.3, 9.7 Hz, 1H), 3.16 (dd, JT = 15.3, 4.7 Hz, 1H), 2.67 (s, 3H), 2.31 (s, 3H).
Example 9
Preparation and characterization of compound III-9: 0
QO
“po i NH re 2, TC {1-2) {1-1} {11-8}
The preparation conditions were the same as those in example 1. The compound III-9 was white solid, and a yield was 87%; ‘H NMR (500 MHz, CDCl:): & 7.42 — 7.37 (m, 4H), 7.35 - 7.32 (m, 1H), 7.29 {t, 3 = 7.5 Hz, 1H}, 7.15 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 7.4
Hz, 1H), 6.38 (s, 1H), 4.75 (dd, J = 11.5, 4.1 Hz, 1H), 3.19 (dd,
J = 15.3, 11.4 Hz, 1H), 3.05 (dd, 0 = 15.4, 4.1 Hz, 1H), 2.72 (s, 3H).
Example 10
Preparation and characterization of compound III-10: cl 0
Cl OQO rT No i NH
Ny fl | ‚ í C (1-3) {H-1) (11-10) ;
The preparation conditions were the same as those in example 1 except for the selected aprotic solvent and the reaction temper- ature. DME was used as the solvent, and the reaction was performed at 80°C; the compound III-10 was white solid, and a yield was 87%; 'H NMR (500 MHz, CDCls): & 7.41 — 7.30 (m, 7H), 7.09 (d, J = 7.4
Hz, 1H), 6.31 (s, 1H), 4.78 — 4.74 (m, 1H), 3.21 (dd, J = 15.4, 11.1 Hz, 1H), 3.09 (dd, J = 15.4, 4.0 Hz, 1H).
Example 11
Preparation and characterization of compound III-11:
Br OQ
Br Oo oo «Rp NH
VON + | — mw
OL 5 © (4) {1-1} (1-11)
The preparation conditions were the same as those in example 1 except for the reaction temperature, and the reaction was per- formed at 60°C; the compound III-11 was white solid, and a yield was 83%; 'HNMR (500 MHz, CDCl:): & 7.62 (d, J = 7.9 Hz, 1H}, 7.42 — 7.33 (m, SH), 7.22 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 7.4 Hz,
1H), 6.21 (s, 1H), 4.78 - 4.74 (m, 1H), 3.24 (dd, J = 15.4, 11.3
Hz, 1H), 3.09 (dd, J = 15.3, 3.8 Hz,1lH).
Example 12
Preparation and characterization of compound III-12: ~. .
Q 0 >> i gy + | J Rl {IS +
CD mg MEF Ne
SF
Le (8) en (12)
The preparation conditions were the same as those in example 1. The compound III-12 was white solid, and a yield was 89%; *‘H NMR {500 MHz; CDCl3)}: & 7.40 - 7.35 (m, 5H), 7.34 - 7.31 (m, 1H}, 6.91 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 6.01 (s, 1H), 4.74 - 4.71 (m, 1H), 3.94 (s, 3H), 3.17 (dd, J = 15.3, 11.2 Hz, 1H), 3.04 (dd, J = 15.3, 3.8 Hz, 1H).
Example 13
Preparation and characterization of compound III-13:
Ph ©
Ph ©
Xv Np i x NH + [0 ee (1-6) (1-1) (11-13)
The preparation conditions were the same as those in example 1. The compound III-13 was white solid, and a yield was 98%; *‘H NMR (500 MHz, CDCl:): & 7.46 — 7.41 (m, 5H), 7.40 — 7.33 (m, GH), 7.24 (d, J = 7.5 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 6.06 (s, 1H), 4.90 - 4.87 {(m, 1H), 3.28 (dd, J = 15.5, 10.8Hz, 1H), 3.18 (dd, J = 15.6, 4.1 Hz, 1H).
Example 14
Preparation and characterization of compound III-14:
Sz / 0
O 0 i me + a. NH
NTN
= CC {-7) (H-1} {in-14)
The preparation conditions were the same as those in example 1. The compound III-14 was white solid, and a yield was 60%; ‘H NMR (500 MHz, CDCl:): & 7.44 - 7.34 {(m, 8H), 7.19 (d, J = 7.3 Hz, 1H), 7.08 - 7.05 (m, 2H), 6.11 (s, 1H), 4.87 - 4.84 (m, 1H), 3.26 (dd,
J = 15.6, 10.8 Hz, 1H), 3.16 (dd, J = 15.6, 4.2 Hz, 1H).
Example 15
Preparation and characterization of compound III-15:
N
N >)
SY HE
“oo ey Ng i © 4 de i { e= ih = NH
Sy NTA i 6 yi SEEN
NC A
{8} {1-1} (1-13)
The preparation conditions were the same as those in example 1. The compound III-15 was white solid, and a yield was 92%; ‘H NMR {500MHz, CDCl:): & 8.57 —- 8.56 {m, ZH), 7.46 (t, J = 7.6 Hz, 1H), 7.42 - 7.33 {(m, SH), 7.26 - 7.24 (m, 3H), 7.14 (d, J = 7.5 Hz, 1H), 6.16 (s, 1H), 4.88 - 4.85 {(m, 1H), 3.27 (dd, J = 15.7, 10.7
Hz, 1H), 3.18 (dd, J = 15.6, 4.4 Hz, 1H).
Example 16
Preparation and characterization of compound III-16:
NT
NT Ry id 7 0
NP re Ry i :
GQ + ij | — 5
Jl Ls NH
TOONT ° Le jj ee
Lo Jef a a i pr {9} {H-1} 1-18}
The preparation conditions were the same as those in example 1. The compound III-16 was white solid, and a yield was 85%; ‘H NMR
(500MHz, CDCl,): & 8.55 — 8.53 (m, 2H), 7.68 — 7.66 (m, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.42 — 7.33 (m, 5H), 7.28 (dd, J = 7.8, 4.9
Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.20 (s, IH), 4.88 — 4.85 (m, 1H), 3.27 (dd, J = 15.6, 10.7 Hz, 1H), 3.19 (dd, J = 15.6, 4.3 Hz, 1H).
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