CN114163435A - Intermediate compound for preparing tadalafil analogue containing sulfonyl fluoride group - Google Patents
Intermediate compound for preparing tadalafil analogue containing sulfonyl fluoride group Download PDFInfo
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- CN114163435A CN114163435A CN202111223677.8A CN202111223677A CN114163435A CN 114163435 A CN114163435 A CN 114163435A CN 202111223677 A CN202111223677 A CN 202111223677A CN 114163435 A CN114163435 A CN 114163435A
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- tda
- benzo
- indole
- pyrido
- tetrahydro
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 40
- OBTWBSRJZRCYQV-UHFFFAOYSA-N sulfuryl difluoride Chemical group FS(F)(=O)=O OBTWBSRJZRCYQV-UHFFFAOYSA-N 0.000 title claims abstract description 32
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical class C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 title claims abstract description 27
- 125000005605 benzo group Chemical group 0.000 claims abstract description 48
- 238000002360 preparation method Methods 0.000 claims abstract description 27
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000005917 acylation reaction Methods 0.000 claims abstract description 5
- -1 2-chloroacetyl Chemical group 0.000 claims description 50
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 16
- FFCZQVKVWGGQFB-UHFFFAOYSA-N 9h-pyrido[3,4-b]indole-1,4-dione Chemical compound N1C2=CC=CC=C2C2=C1C(=O)N=CC2=O FFCZQVKVWGGQFB-UHFFFAOYSA-N 0.000 claims description 7
- 230000010933 acylation Effects 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 238000003682 fluorination reaction Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 11
- 239000002246 antineoplastic agent Substances 0.000 abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 210000004881 tumor cell Anatomy 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 54
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 238000004896 high resolution mass spectrometry Methods 0.000 description 11
- 238000012844 infrared spectroscopy analysis Methods 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 230000008018 melting Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 9
- 238000002211 ultraviolet spectrum Methods 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 239000007789 gas Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- QXAUTQFAWKKNLM-UHFFFAOYSA-N methyl indole-3-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)=CNC2=C1 QXAUTQFAWKKNLM-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000005918 in vitro anti-tumor Effects 0.000 description 3
- GRRAMKXEZLMNOK-PPHPATTJSA-N methyl (2s)-2-amino-3-(5-hydroxy-1h-indol-3-yl)propanoate;hydrochloride Chemical compound Cl.C1=C(O)C=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 GRRAMKXEZLMNOK-PPHPATTJSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010183 spectrum analysis Methods 0.000 description 3
- UKHFPVCOXBJPIN-UHFFFAOYSA-N 9H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester Chemical compound N1C2=CC=CC=C2C2=C1C=NC(C(=O)OC)=C2 UKHFPVCOXBJPIN-UHFFFAOYSA-N 0.000 description 2
- 102000008096 B7-H1 Antigen Human genes 0.000 description 2
- 108010074708 B7-H1 Antigen Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 2
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 102000048362 human PDCD1 Human genes 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229960000835 tadalafil Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 1
- 229940000681 5-hydroxytryptophan Drugs 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- LFETXMWECUPHJA-UHFFFAOYSA-N methanamine;hydrate Chemical compound O.NC LFETXMWECUPHJA-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- LDCYZAJDBXYCGN-UHFFFAOYSA-N oxitriptan Natural products C1=C(O)C=C2C(CC(N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-UHFFFAOYSA-N 0.000 description 1
- 229940081310 piperonal Drugs 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to (+/-) -TDA-07 and (+/-) -TDA-08 intermediate compounds which are shown in a formula and can be used for preparing tadalafil analogues, a preparation method thereof, and a method for preparing the tadalafil analogues containing sulfonyl fluoride groups by using the intermediate compounds. The preparation method of the compound is that 1- (benzo [ D ] [1,3] dioxy-5-yl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid methyl ester isomer and chloroacetyl chloride are subjected to acylation reaction. The intermediate can be used for preparing tadalafil analogues containing sulfonyl fluoride groups, and products of the intermediate can be applied to preparation of antitumor drugs, and the intermediate has a novel structure, shows a strong inhibiting effect on tumor cells, and has an excellent application prospect. The preparation and synthesis process disclosed by the invention is simple to operate, does not use a metal reagent, is less in environmental pollution and is mild in condition.
Description
Technical Field
The present invention relates to an intermediate compound useful for the preparation of a tadalafil analog containing a sulfonyl fluoride group, a process for the preparation thereof, and a process for the preparation of a tadalafil analog containing a sulfonyl fluoride group using the intermediate compound.
Background
Tadalafil (Tadalafil), an inhibitor of phosphodiesterase type 5 (PDE5), was developed by lilly-Icos and approved by the FDA in 2003 to be marketed in the united states as a drug for the treatment of male erectile dysfunction. Moreover, another clinical application of the drug is found to be the treatment of pulmonary hypertension. Compared with similar medicines, the medicine has the advantages of high selectivity, long half-life period, greater autonomy of patients and the like.
Disclosure of Invention
It is a first object of the present invention to provide such compounds; a second object of the present invention is to provide a process for preparing the intermediate compound; it is a third object of the present invention to provide a process for preparing tadalafil analogs containing sulfonyl fluoride groups using the intermediate compounds of the present invention.
The structural formula of the tadalafil analogue containing sulfonyl fluoride groups is shown as a formula 1.
Wherein R is1Is (C)1-C6) Alkoxy group, (C)1-C6) An alkylamino group; r2Is free of hydrogen, (C)1-C6) Acyloxy, (C)1-C6) Alkyl, 2-haloacetoxy.
Preferably, the tadalafil analogue containing sulfonyl fluoride group has a structural formula shown in formula 2
Preferably, the tadalafil analogue containing sulfonyl fluoride group has a structural formula shown in formula 3
Preferably, the tadalafil analogue containing sulfonyl fluoride group has the structural formula shown in formula 4
Shown, wherein: r3Is (C)1-C6) Acyloxy, (C)1-C6) An alkyl group.
Preferably, the tadalafil analogue containing sulfonyl fluoride group has a structural formula shown in formula 5
Preferably, the tadalafil analogue containing sulfonyl fluoride group has a structural formula shown in formula 6
The intermediate compound of the present invention for preparing the above tadalafil analogs containing a sulfonyl fluoride group is 1- (benzo [ d ] [1,3] dioxol-5-yl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pir
A pair of enantiomers (+/-) -TDA-05 of pyrido [3,4-b ] indole-3-carboxylic acid methyl ester, the structural formula of which is shown in a formula 7.
The intermediate compound of the present invention for preparing the above tadalafil analogs containing a sulfonyl fluoride group is 1- (benzo [ d ] [1,3] dioxol-5-yl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-
A pair of enantiomers (+/-) -TDA-06 of pyrido [3,4-b ] indole-3-carboxylic acid methyl ester, the structural formula of which is shown in formula 3.
The intermediate compound for preparing the tadalafil analog containing the sulfonyl fluoride group of the present invention is
(+/-) -TDA-07 of a pair of enantiomers of 1- (benzo [ D ] [1,3] dioxo-5-yl) -2- (2-chloroacetyl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate, having the formula shown in formula 9:
the intermediate compound for preparing the tadalafil analog containing the sulfonyl fluoride group of the present invention is
(+/-) -TDA-08 of a pair of enantiomers of 1- (benzo [ D ] [1,3] dioxy-5-yl) -2- (2-chloroacetyl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate, having a structural formula as shown in formula X4.
And (3) forming a racemic structure by combining every two compounds, and detecting the racemic compounds when the activity is detected.
Two pairs of methyl 1- (benzo [ D ] [1,3] dioxol-5-yl) -2- (2-chloroacetyl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyridylmeth-o [3,4-b ] indole-3-carboxylate of the present invention
(+/-) -TDA-09 or (+/-) -TDA-10, which are enantiomers of epimers, can be prepared according to formula 11, i.e.: acylation of two pairs of epimeric (+/-) -TDA-05 or (+/-) -TDA-06 enantiomers of methyl 1- (benzo [ d ] [1,3] dioxol-5-yl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate, respectively, with chloroacetyl chloride in the presence of triethylamine gave the title product.
The preparation method of two pairs of enantiomers (+/-) -TDA-05 or (+/-) -TDA-06 of 1- (benzo [ d ] [1,3] dioxol-5-yl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid methyl ester as an intermediate compound, which is epimeric, is shown as the formula 12, namely: two pairs of enantiomers (+/-) -TDA-03 or (+/-) -TDA-04, which are epimers, of methyl 1- (benzo [ D ] [1,3] dioxy-5-yl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate are respectively subjected to sulfonyl fluorination with sulfonyl fluoride gas under the catalysis of triethylamine to obtain an intermediate compound
Two pairs of the methyl 1- (benzo [ d ] [1,3] dioxol-5-yl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate enantiomers (+/-) -TDA-05 or (+/-) -TDA-06 epimers.
The preparation method of the tadalafil analogue containing sulfonyl fluoride groups is shown as the formula 13, namely:
reacting 6- (benzo [1,3] dioxy-5-yl) -10-hydroxy-2-methyl-2-3, 6-, 7-, 12-, 12-hexahydropyrazine- [1',2': two pairs of enantiomers (+/-) -TDA-11 or (+/-) -TDA-12 of 1,6] pyrido [3,4-b ] indole-1, 4-dione which are epimeric with each other are subjected to sulfonyl fluorination reaction with sulfonyl fluoride gas under the catalysis of triethylamine to obtain (+/-) -TDA-13 and (+/-) -TDA-14 target products.
The preparation method of the tadalafil analogue containing sulfonyl fluoride groups is shown as a formula 14, namely: is divided into
Acylation of the two epimeric enantiomers (+/-) -TDA-03 or (+/-) -TDA-04 of methyl 1- (benzo [ D ] [1,3] dioxo-5-yl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate, respectively, with chloroacetyl chloride gave (+/-) -TDA-07 or (+/-) -TDA-4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate of the two epimeric enantiomers of 1- (benzo [ D ] [1,3] dioxo-5-yl) -2- (2-chloroacetyl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate, respectively +/-) -TDA-08, followed by ammonolysis of either (+/-) -TDA-07 or (+/-) -TDA-08 of two pairs of epimer enantiomers of 1- (benzo [ D ] [1,3] dioxo-5-yl) -2- (2-chloroacetyl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate with methylamine to give 6- (benzo [1,3] dioxo-5-yl) -10-hydroxy-2-methyl-2-3, 6-, 7-, 12-, 12-hexahydropyrazine- [1',2': (+/-) -TDA-11 or (+/-) -TDA-12 of two pairs of epimers of 1,6] pyrido [3,4-b ] indole-1, 4-dione, in turn followed by the aforementioned "6- (benzo [1,3] dioxy-5-yl) -10-hydroxy-2-methyl-2-3, 6-, 7-, 12-, 12-hexahydropyrazine- [1',2': the target products are prepared by a method that two pairs of enantiomers (+/-) -TDA-11 or (+/-) -TDA-12 of 1,6] pyrido [3,4-b ] indole-1, 4-dione which are epimers with each other and sulfonyl fluoride gas are subjected to sulfonyl fluorination under the catalysis of triethylamine to obtain the target products (+/-) -TDA-13 and (+/-) -TDA-14'.
The preparation method of (+/-) -TDA-07 or (+/-) -TDA-08 of two pairs of enantiomers which are epimers with each other of 1- (benzo [ D ] [1,3] dioxy-5-yl) -2- (2-chloroacetyl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate which is an intermediate compound of the present invention is shown as a formula 15, namely: the two pairs of epimers (+/-) -TDA-03 or (+/-) -TDA-04 of methyl 1- (benzo [ D ] [1,3] dioxo-5-yl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate, respectively, were reacted with chlorine
Acylation of acetyl chloride gave (+/-) -TDA-07 or (+/-) -TDA-08 of 1- (benzo [ D ] [1,3] dioxo-5-yl) -2- (2-chloroacetyl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate as two mutually epimeric enantiomers.
Any compound, including intermediate compounds, described in the invention is applied to antitumor drugs.
The combination of any compound, including intermediate compounds, is applied to antitumor drugs.
Corresponding experiments show that any compound or combination thereof can be applied to antitumor drugs.
The tadalafil analogue containing sulfonyl fluoride groups can be applied to preparation of antitumor drugs, and has certain in vitro antitumor activity through PD1/PD-L1 protein molecule biological binding inhibition tests, so that the compound can be used for preparing antitumor drugs. The tadalafil analogue containing sulfonyl fluoride groups has a novel structure, shows a strong inhibiting effect on tumor cells, and has an excellent application prospect. The preparation and synthesis process disclosed by the invention is simple to operate, does not use a metal reagent, is less in environmental pollution and is mild in condition.
Detailed Description
The invention will be illustrated by the following examples.
The compound of the invention can determine the structure by nuclear magnetism, high-resolution mass spectrum, infrared and ultraviolet.
Example 1: preparation method of 5-hydroxytryptophan methyl ester hydrochloride ((+/-) -TDA-02)
The structural formula of 5-hydroxytryptophan methyl ester hydrochloride ((+/-) -TDA-02) is shown as a formula 9, and the preparation method comprises the following steps:
2g (9.08mmol) of 5 hydroxytryptophan are dissolved in 20ml (493.7mmol) of methanol under the protection of argon, 1.22ml (18.16mmol) of thionyl chloride is added dropwise with stirring in an ice water bath, and after stirring for 10 minutes, the temperature is raised to 50 ℃ for reaction for 7 hours. And (4) performing rotary evaporation, and performing rotary drying on the methanol to obtain a dark green solid. Air-dry overnight, crush the solid the next day, add ethyl acetate and stir for 4 hours before pump filtration and washing to give 2.4293g of a grey solid (99.2% yield), see formula 10.
Example 2:
preparation of methyl 1- (benzo [ D ] [1,3] dioxy-5-yl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate ((+/-) -TDA-03 and (+/-) -TDA-04
Methyl 1- (benzo [ D ] [1,3] dioxy-5-yl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate ((+/-) -TDA-03 and (+/-) -TDA-04) is shown in formula 18 and is prepared as follows:
under the protection of argon, 2.7g (10mmol) of 5-hydroxytryptophan methyl ester hydrochloride and 1.65g (11mmol) of piperonal are dissolved in 25ml of isopropanol under stirring, the temperature is increased to 110 ℃, the reaction is carried out for 6 hours, and then the mixture is cooled to room temperature and stirred overnight. Adding saturated sodium carbonate solution, stirring for neutralization, extracting with ethyl acetate for three times, and washing with saturated saline solution once. Concentration and column chromatography (H60 silica gel, petroleum ether: ethyl acetate 1:1) gave (+/-) -TDA-03366.9mg (10% yield) and (+/-) -TDA-04353.5mg (9.7% yield), respectively, as epimers, as off-white solids.
(+/-) -TDA-03 characterization data as follows: 164-:1H NMR(400MHz,CDCl3)δ9.81(s,1H),7.33(d,J＝11.4Hz,1H),7.07(d,J＝8.6Hz,1H),7.07(d,J＝8.6Hz,1H),6.96–6.84(m,2H),6.83–6.76(m,2H),6.70(dd,J＝8.6,2.3Hz,1H),5.94(s,2H),5.14(s,1H),3.93(dd,J＝11.1,4.2Hz,1H),3.81(s,3H),3.12(dd,J＝15.0,2.6Hz,1H),3.00–2.81(m,1H)；13c NMR (101MHz, DMSO) δ 173.00,150.41,147.19,146.79,136.06,130.86,127.27,121.97,111.56,110.77,108.79,108.01,106.10,101.87,100.92,57.67,56.36,51.76,25.48,14.09. high resolution mass spectrometry: HRMS-ESI (M/z) 367.1436[ M-H]-Infrared spectroscopic analysis: IR (cm)-1) 3397.3,3214.4,3036.8,2995.8,2949.4,2904.2,2850.7,2596.4,2035.0,1847.3,1737.3,1626.4,1588.6,1543.4,1503.0,1487.5,1444.3,1359.4,1324.8,855.6,835.3,810.3,744.1,718.2,699.5,685.9,624.6 ultraviolet spectrum analysis: UVmax (CH)2Cl2) 202,206,210,214,218,228,246. (+/-) -TDA-04 melting Point: 169 ℃ 172 ℃, nuclear magnetic analysis:1H NMR(400MHz,CDCl3)δ9.79(s,1H),7.63(s,1H),7.00(dd,J＝8.6,3.8Hz,1H),6.85(d,J＝2.3Hz,1H),6.75–6.63(m,4H),5.92–5.85(m,2H),5.25(s,1H),3.91(dt,J＝11.0,5.5Hz,1H),3.69(d,J＝5.7Hz,3H),3.09(dd,J＝15.4,5.1Hz,1H),2.95(dd,J＝15.3,7.2Hz,1H)；13C NMR(101MHz,CDCl3) δ 174.08,149.87,148.01,147.47,135.70,131.40,127.59,121.89,111.89,111.57,108.79,108.22,107.93,103.36,101.22,60.59,54.84,52.28,29.62,14.28. high resolution mass spectrometry: HRMS-ESI (M/z) 367.1439[ M-H]-Infrared spectroscopic analysis: IR (cm)-1) 3395.2,3068.8,3028.1,2952.1,2897.9,2850.4,2780.6,2622.5,2037.3,1847.7,1732.4,1629.4,1599.4,1573.6,1501.8,1487.0,1448.7,1358.3,834.1,811.0,800.1,734.9,718.5,702.2,654.8,624.2 ultraviolet spectrum analysis: UVmax (CH)2Cl2)nm:202,206,210,216,220,228,246.。
Example 3:
preparation method of 1- (benzo [ D ] [1,3] dioxy-5-yl) -2- (2-chloroacetyl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-formate (+/-) -TDA-07
1- (benzo [ D ] [1,3] dioxy-5-yl) -2- (2-chloroacetyl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate ((+/-) -TDA-07 has a structural formula shown in formula 9, and is prepared by the following method:
338.7mg (0.9254mmol) of the substrate (1- (benzo [ D ]][1,3]Dioxy-5-yl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b]Enantiomer of methyl indole-3-carboxylate) was dissolved in 10ml of ethyl acetate solution containing 0.3ml (2.1583mmol) of triethylamine, and a solution of ethyl acetate containing 0.13ml (1.6332mmol) of chloroacetyl chloride was slowly added dropwise with stirring in an ice-water bath. After stirring for 10 minutes, the reaction mixture was allowed to react at 33 ℃ for 7 hours, then water was added thereto and the mixture was stirred, extracted three times with ethyl acetate and washed once with saturated brine. Concentration and column chromatography (H60 silica gel, petroleum ether: ethyl acetate 1:1) gave 281.6mg of a pale red solid (68.7% yield). (+/-) -TDA-07 melting Point: 253-:1H NMR(400MHz,DMSO)δ11.05(s,1H),7.78–7.62(m,1H),7.34(dd,J＝19.5,5.2Hz,2H),6.90(dd,J＝8.7,2.2Hz,1H),6.84–6.75(m,2H),6.68(s,1H),6.45(d,J＝8.1Hz,1H),5.98(d,J＝7.4Hz,2H),5.21(d,J＝6.5Hz,1H),4.84(d,J＝13.9Hz,1H),4.45(d,J＝13.9Hz,1H),3.43(t,J＝13.5Hz,1H),3.13–2.97(m,4H)；13c NMR (101MHz, DMSO) δ 170.34,167.70,146.83,143.34,134.30,133.33,131.69,131.50,128.64,122.40,115.36,111.80,110.31,109.11,107.59,106.69,101.07,65.02,51.81,29.80,18.64,13.53 high resolution mass spectrometry: HRMS-ESI (M/z) 443.1105[ M-H]-Infrared spectroscopic analysis: IR (cm)-1) 3347.2,3094.8,3060.4,3028.1,3011.7,2951.4,2933.1,2875.7,2851.6,2774.1,2608.8,2363.5,2118.5,1862.4,1765.7,1742.0,1667.1,1631.4,1611.7,1593.8,1505.0,1489.3,1457.0,1441.2,1411.4,1383.2,1355.4,1312.3,895.3,877.1,829.4,803.0,789.6,757.8,746.6,737.5,719.7,707.1,676.1,663.8,651.7,636.3,617.2 ultraviolet spectrum analysis: UVmax (CH)2Cl2)nm:206,210,218,228,246.。
Example 4:
a process for the preparation of enantiomer of 1- (benzo [ D ] [1,3] dioxo-5-yl) -2- (2-chloroacetyl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (+/-) -TDA-08:
the enantiomer of the epimer of 1- (benzo [ D ] [1,3] dioxy-5-yl) -2- (2-chloroacetyl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate ((+/-) -TDA-08 has the structural formula shown in formula 10, and is prepared by the following method:
580.1mg (1.5850mmol) of the substrate (1- (benzo [ D ]][1,3]Dioxy-5-yl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b]Enantiomer of the epimer of methyl indole-3-carboxylate) was dissolved in 10ml of ethyl acetate solution containing 0.51ml (3.6691mmol) of triethylamine, and a solution of 0.22ml (2.7639mmol) of chloroacetyl chloride in 5ml of ethyl acetate was slowly added dropwise with stirring in an ice-water bath. After stirring for 10 minutes, the reaction mixture was allowed to react at 33 ℃ for 8 hours, then water was added thereto and the mixture was stirred, extracted three times with ethyl acetate and washed once with saturated brine. Concentration and column chromatography (H60 silica gel, petroleum ether: ethyl acetate 1:1) gave 387.3mg (55.1% yield) of a pale yellow solid. (+/-) -TDA-08 melting Point: 206-:1H NMR(400MHz,DMSO)δ7.77–7.69(m,1H),7.69–7.63(m,1H),7.31(dd,J＝28.8,8.5Hz,2H),7.00–6.71(m,3H),6.06–5.84(m,2H),4.76–4.64(m,2H),4.26–4.18(m,2H),3.50(dd,J＝39.2,18.9Hz,4H)；13C NMR(101MHz,CDCl3) δ 167.90,167.02,144.25,134.88,132.43,131.06,128.97,126.67,119.99,115.84,111.94,110.62,106.74,65.73,41.14,32.06,30.70,29.82,22.82,19.31,14.32,13.85. high resolution mass spectrometry: HRMS-ESI (M/z) 443.1009[ M-H]-Infrared spectroscopic analysis: IR (cm)-1) 3305.6,3112.1,3079.1,2997.5,2951.6,2933.9,2918.3,2850.3,2781.6,2703.5,2055.9,1862.7,1746.4,1725.1,166.5,1584.6,1566.6,1503.7,1489.9,1453.9,1437.5,1368.9,1330.1,1311.3,884.6,865.4,837.5,808.8,787.4,765.1,751.4,741.0,725,6,692.1,682.2,652.1,628.5,607.2 ultraviolet spectrum analysis: UVmax (CH)2Cl2)nm:204,210,214,220,228,246.。
Example 5:
6- (benzo [1,3] dioxy-5-yl) -10-hydroxy-2-methyl-2-3, 6-, 7-, 12-, 12-hexahydropyrazine- [1',2': preparation of 1,6] pyrido [3,4-b ] indole-1, 4-dione (+/-) -TDA-11 and (+/-) -TDA-12
6- (benzo [1,3] dioxy-5-yl) -10-hydroxy-2-methyl-2-3, 6-, 7-, 12-, 12-hexahydropyrazine- [1',2': the structural formulas of 1,6] pyrido [3,4-b ] indole-1, 4-dione (+/-) -TDA-11 and (+/-) -TDA-12 are shown as formula 13 and formula 14, and the (+/-) -TDA-11 is prepared as follows (see formula 14):
281.6mg (0.636mmol) of the substrate are dissolved in 12ml of methanol under argon, and 290mg of 25% aqueous methylamine solution (9.337mmol) are added. Heating to 72 ℃, refluxing and reacting for 12 hours, adding water, stirring, extracting with ethyl acetate for three times, and washing with saturated salt solution once. Concentration and column chromatography (H60 silica gel, ethyl acetate) gave 57mg of a pale yellow solid (22.1% yield). (+/-) -TDA-11 melting Point: at 270 ℃ and 273 ℃, nuclear magnetic analysis:1H NMR(400MHz,DMSO)δ10.72(s,1H),8.70(s,1H),7.08(d,J＝8.6Hz,1H),6.86–6.70(m,4H),6.56(dd,J＝8.6,2.1Hz,1H),6.08(s,1H),5.92(s,2H),4.36(dd,J＝11.6,4.2Hz,1H),4.23–4.11(m,1H),3.94(d,J＝17.1Hz,1H),3.43–3.36(m,1H),2.96–2.82(m,4H)；13c NMR (101MHz, DMSO) δ 164.71,162.25,150.70,147.60,147.21,133.02,130.73,130.67,126.62,121.66,111.69,108.31,108.14,106.63,102.20,101.25,54.93,52.04,50.88,50.68,32.61,26.74. high resolution mass spectrometry: HRMS-ESI (M/z) 406.1663[ M-H]-Infrared spectroscopic analysis: IR (cm)-1) 3339.4,3278.4,2960.4,2899.7,2785.5,2615.2,1840.7,1736.6,1653.9,1606.2,1573.4,1502.7,1487.7,1454.5,1435.7,1401.9,1371.7,1344.7,1325.4,876.7,855.2,834.0,821.2,794.3,774.0,750.3,731.5,715.3,691.8,661.2,647.8,616.6 ultraviolet spectrum analysis: UVmax (CH)2Cl2)nm:206,210,214,228,246.。
Example 6:
6- (benzo [1,3] dioxy-5-yl) -10-hydroxy-2-methyl-2-3, 6-, 7-, 12-, 12-hexahydropyrazine- [1',2': preparation method of 1,6] pyrido [3,4-b ] indole-1, 4-dione (+/-) -TDA-12 (see formula X8)
283mg (0.636mmol) of substrate are dissolved in 11ml of methanol under argonFurther, 1.22g of 25% methylamine water solution (38.635mmol) was added. Heating to 70 deg.C, reflux reacting for 7 hr, adding water, stirring, extracting with ethyl acetate for three times, and washing with saturated saline solution once. Concentration and column chromatography (H60 silica gel, ethyl acetate) gave 134.6mg of a pale yellow solid (52.3% yield). (+/-) -TDA-12 melting Point: 208 ℃ 211 ℃, nuclear magnetic analysis:1H NMR(400MHz,DMSO)δ10.71(d,J＝10.7Hz,1H),8.68(d,J＝13.3Hz,1H),7.09(t,J＝9.1Hz,1H),6.86(dt,J＝12.0,6.0Hz,1H),6.76(d,J＝14.9Hz,3H),6.65–6.53(m,2H),6.11–5.87(m,2H),5.75(d,J＝1.8Hz,1H),4.24(d,J＝17.6Hz,1H),4.08–3.97(m,2H),3.14(dd,J＝15.2,4.1Hz,1H),2.95–2.77(m,4H)；13c NMR (101MHz, DMSO) δ 164.95,162.47,150.79,147.75,147.37,133.09,131.00,130.86,126.74,121.84,111.93,108.43,108.33,106.77,102.41,101.48,53.37,52.19,51.07,50.87,32.81,26.98. high resolution mass spectrometry: HRMS-ESI (M/z) 406.1482[ M-H]-Infrared spectroscopic analysis: IR (cm)-1) 3289.6,2916.4,2898.2,2849.0,2781.2,2597.1,1854.2,1730.2,1652.9,1598.1,1501.8,1486.7,1456.6,1441.5,1405.5,1371.9,1334.6,875.7,836.5,798.6,785.5,756.6,711.2,670.5,624.9,611.7 ultraviolet spectrum analysis: UVmax (CH)2Cl2)nm:202,206,210,214,218,228,246.。
Example 7 preparation of 6- (benzo [ d ] [1,3] dioxol-5-yl) -2-methyl-1, 4-dioxy-1, 2,3,4,4,6,7,12,12 a-octahydropyrazine [1',2':1,6] pyridine [3,4-b ] indol-10-yl-thiourea salt ((+/-) -TDA-13 and (+/-) -TDA-14)
The structural formulas of 6- (benzo [ d ] [1,3] dioxol-5-yl) -2-methyl-1, 4-dioxy-1, 2,3,4,4,6,7,12,12 a-octahydropyrazine [1',2':1,6] pyridine [3,4-b ] indol-10-yl thiourea salt ((+/-) -TDA-13 and (+/-) -TDA-14) are respectively shown as formula 5 and formula 6. The preparation method of (+/-) -TDA-13 comprises the following steps:
85.9mg (0.213mmol) of the substrate was dissolved with dichloromethane, 0.15ml (1.095mmol) of triethylamine was added, and then a reaction was carried out at room temperature for 5 hours by passing a sulfonyl fluoride gas through a balloon, followed by rotary evaporation and concentration, addition of water and stirring, extraction with ethyl acetate three times, and washing with saturated brine once. Concentration and column chromatography (H60 silica gel, petroleum ether: ethyl acetate 1:2) gave 48.3mg of a white solid (46.6% yield). (+/-) -TDA-Melting point (13): 275 ℃ and 278 ℃, specific optical rotation: [ alpha ] to]26.4 ═ -0.001(C ═ 0.14875, CHCl3), nuclear magnetic analysis:1H NMR(400MHz,DMSO)δ11.49(s,1H),7.85(d,J＝2.3Hz,1H),7.45(d,J＝8.9Hz,1H),7.20(dd,J＝8.8,2.4Hz,1H),6.88(s,1H),6.78(d,J＝7.9Hz,2H),6.14(s,1H),5.93(s,2H),4.41(dd,J＝11.7,3.9Hz,1H),4.25–4.12(m,1H),3.96(d,J＝17.2Hz,1H),3.64–3.56(m,1H),3.04–2.89(m,4H)；13C NMR(101MHz,DMSO)δ166.95,166.33,147.10,146.20,143.67,137.15,136.49,135.25,131.71,128.65,125.89,108.22,107.28,106.79,106.01,100.94,65.01,55.47,55.14,29.99,18.63,13.48；19f NMR (376MHz, DMSO) delta-100.01(s). high resolution mass spectrometry: HRMS-ESI (M/z) 488.1111[ M-H]-Infrared spectroscopic analysis: IR (cm)-1) 3299.1,3102.0,3087.5,2904.2,2869.6,2770.8,1865.7,1853.2,1678.1,1657.3,1630.8,1591.7,1502.4,1487.4,1445.7,1426.3,1402.8,1369.4,1326.5,890.6,848.9,827.5,801.9,789.6,750.5,720.7,695.8,639.0 ultraviolet spectral analysis UVmax (CH)2Cl2)nm:208,212,218,228,246.。
Example 8:
the enantiomer (+/-) -TDA-14 of 6- (benzo [ d ] [1,3] dioxol-5-yl) -2-methyl-1, 4-dioxy-1, 2,3,4,4,6,7,12,12 a-octahydropyrazine [1',2':1,6] pyridine [3,4-b ] indol-10-yl thiourea acid salt epimer was prepared as (see formula 13):
127.6mg (0.315mmol) of the substrate was dissolved in methylene chloride, 0.2ml (0.146mmol) of triethylamine was added thereto, and then a reaction was carried out at room temperature for 5 hours by introducing a sulfonyl fluoride gas through a balloon, followed by rotary evaporation and concentration, addition of water and stirring, extraction with ethyl acetate three times, and washing with saturated brine once. Concentration and column chromatography (H60 silica gel, petroleum ether: ethyl acetate 1:2) gave 37.3mg of a white solid (24.3% yield). (+/-) -TDA-14 melting Point: 271-274 ℃ specific optical rotation: [ alpha ] to]26.6 ═ -0.026(C ═ 0.18, CHCl3), nuclear magnetic resonance analysis:1H NMR(400MHz,DMSO)δ11.53(s,1H),7.83–7.75(m,1H),7.48(d,J＝8.9Hz,1H),7.25(dt,J＝15.2,7.6Hz,1H),6.90–6.83(m,2H),6.80(d,J＝1.7Hz,1H),6.62(dd,J＝8.1,1.4Hz,1H),6.11–5.88(m,2H),4.29–4.20(m,1H),4.11(dd,J＝11.8,4.1Hz,1H),4.07–3.99(m,1H),3.35(d,J＝4.3Hz,1H),3.03–2.92(m,1H),2.85(d,J＝6.0Hz,3H)；13C NMR(101MHz,DMSO)δ164.87,162.77,148.13,147.80,144.04,135.75,134.04,132.91,126.51,122.28,113.20,111.08,109.23,108.88,108.64,101.75,52.32,51.27,51.11,33.07,26.99；19F NMR(376MHz,CDCl3) Delta-100.01. high resolution mass spectrometry: HRMS-ESI (M/z) 488.1282[ M-H]-Infrared spectroscopic analysis: IR (cm)-1) 3185.4,3106.0,2923.4,2873.2,2773.1,2031.7,1853.4,1735.4,1663.4,1580.6,1503.1,1487.7,1450.1,1412.1,1400.9,1377.2,1358.0,1328.1,861.4,820.7,812.7,799.5,792.4,778.6,753.6,716.9,692.4,649.4,636.3,611.0 ultraviolet spectrum analysis: UVmax (CH)2Cl2)nm:206,210,214,220,228,246.。
Methyl 1- (benzo [ d ] [1,3] dioxol-5-yl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (+/-) -TDA-05 and (+/-) -TDA-06) are of formula 7 and formula 8, respectively.
Example 9:
preparation method of methyl 1- (benzo [ d ] [1,3] dioxol-5-yl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (+/-) -TDA-05
Referring to formula 12, 1.14g (3.115mmol) of substrate (1- (benzo [ D ] b) was reacted with dichloromethane][1,3]Dioxy-5-yl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b]Enantiomer of indole-3-carboxylic acid methyl ester), then 0.6ml (0.438mmol) of triethylamine is added, then the sulfonyl fluoride gas is added by balloon to react for 6 hours at room temperature, the mixture is evaporated and concentrated, water is added to be stirred, then ethyl acetate is used for extraction for three times, and the mixture is washed once by saturated saline solution. Concentration and column chromatography (H60 silica gel, petroleum ether: ethyl acetate: 2:1) gave 236.7mg of solid (15.6% yield). Melting Point (+/-) -TDA-05: 176-177 ℃ specific optical rotation: [ alpha ] to]26.2 ═ 0.008(C ═ 0.5, CHCl3), nuclear magnetic analysis:1H NMR(400MHz,CDCl3)δ7.72(d,J＝16.9Hz,1H),7.46(t,J＝6.2Hz,1H),7.23(d,J＝8.8Hz,1H),7.11–7.04(m,1H),6.87(dd,J＝7.9,1.5Hz,1H),6.80(d,J＝8.0Hz,2H),5.95(s,2H),5.15(s,1H),3.94(dd,J＝11.1,4.2Hz,1H),3.82(d,J＝5.1Hz,3H),3.17(ddd,J＝20.9,11.2,4.9Hz,1H),3.03–2.92(m,1H)；13C NMR(101MHz,DMSO)δ172.71,147.26,146.95,143.47,138.90,135.44,126.66,122.10,113.12,112.47,109.84,108.82,108.10,100.98,100.98,57.48,56.09,51.79,30.02,25.18；19f NMR (376MHz, DMSO) delta-166.77 high resolution Mass Spectrometry: HRMS-ESI (M/z) 449.1768[ M-H]-Infrared spectroscopic analysis: IR (cm)-1) 3452.3, 3435.8, 3331.4,3100.3, 3083.0,3011.1,2955.1,2894.5,2851.0,2827.8,2787.6,1849.3,1729.8,1627.8,1607.0,1580.5,1500.1,1485.3,1430.9,1373.2,1344.5,1324.3,1309.8,888.1,874.3,845.6,815.6,804.1,795.9,769.2,745.4,725.8,711.1,678.4,652.0,632.1,615.7 ultraviolet spectrum analysis: UVmax (CH)2Cl2)nm:206,210,216,228,238,246.。
Example 10:
preparation method of methyl 1- (benzo [ d ] [1,3] dioxol-5-yl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate (+/-) -TDA-06
1.14g (3.115mmol) of substrate (1- (benzo [ d ]) was washed with dichloromethane][1,3]Dioxol-5-yl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Enantiomer of epimer of indole-3-carboxylic acid methyl ester) was just dissolved, 0.6ml (0.438mmol) of triethylamine was added, sulfonyl fluoride gas was introduced into the mixture with a balloon at room temperature for reaction for 6 hours, the mixture was concentrated by rotary evaporation, water was added thereto, the mixture was stirred, extracted three times with ethyl acetate, and washed once with saturated saline. Concentration and column chromatography (H60 silica gel, petroleum ether: ethyl acetate ═ 2:1) afforded 251.7mg of a solid (16.6% yield). (+/-) -TDA-06 melting Point: 159-161 ℃ specific optical rotation: [ alpha ] to]26.3 ═ -0.022(C ═ 0.5, CHCl3), nuclear magnetic resonance analysis:1H NMR(400MHz,DMSO)δ11.06(s,1H),7.66(dd,J＝8.7,2.9Hz,1H),7.39(d,J＝8.8Hz,1H),7.17(dd,J＝8.8,2.4Hz,1H),6.85(dd,J＝4.7,3.1Hz,2H),6.70(dd,J＝8.0,1.4Hz,1H),5.99(d,J＝1.8Hz,2H),5.30(s,1H),3.85(t,J＝6.1Hz,1H),3.64(s,3H),3.10(dd,J＝15.2,5.2Hz,1H),2.93(dd,J＝15.2,7.0Hz,1H).；13C NMR(101MHz,DMSO)δ173.69,147.42,146.68,143.40,137.84,136.68,135.10,126.64,121.52,113.22,112.29,109.88,108.61,107.76,100.91,53.75,51.75,30.14,24.37,18.69；19f NMR (376MHz, DMSO). delta. -100.01. high resolution Mass Spectrometry: HRMS-ESI (M/z) 449.1600[ M-H]-Red, redExternal spectrum analysis: IR (cm)-1) 3303.7, 3271.8, 3070.3, 3032.7,2998.7,2955.5,2919.8,2851.0,2780.5,2039.3,1848.6,1740.7,1630.7,1610.0,1582.5,1504.2,1488.2,1460.4,1442.8,1400.2,1370.5,1356.7,1341.7,1323.5 ultraviolet spectrum analysis: UVmax (CH)2Cl2)nm:206,210,216,228,234,246.。
Example 11:
process for the preparation of enantiomer (+/-) -TDA-09 of methyl 1- (benzo [ d ] [1,3] dioxol-5-yl) -2- (2-chloroacetyl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyridylmethyl [3,4-b ] indole-3-carboxylate
Methyl 1- (benzo [ d ] [1,3] dioxol-5-yl) -2- (2-chloroacetyl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyridylmeth-o [3,4-b ] indole-3-carboxylate (+/-) -TDA-09, having the formula 4. methyl 1- (benzo [ d ] [1,3] dioxol-5-yl) -2- (2-chloroacetyl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyridylmeth-o [3,4-b ] indole-3-carboxylate enantiomer (+/-TDA-09, was prepared by:
236.7mg (0.5283mmol) of the substrate was dissolved in 15ml of ethyl acetate, 0.15ml (1.0566mmol) of triethylamine was added thereto, 0.63ml (0.7925mmol) of chloroacetyl chloride was added in an ice bath, the mixture was warmed to room temperature to react for 17 hours, water was added thereto and stirred, followed by extraction with ethyl acetate three times and washing with saturated brine once. Concentration and column chromatography (H60 silica gel, petroleum ether: ethyl acetate: 2:1) gave 175.2mg of a solid (63.2% yield). (+/-) -TDA-09 melting Point: 109-: [ alpha ] to]26.6＝0.048(C＝0.5,CHCl3) Nuclear magnetic analysis:1H NMR(400MHz,CDCl3)δ8.41(s,1H),7.54(d,J＝2.1Hz,1H),7.33(d,J＝8.8Hz,1H),7.16(dd,J＝8.8,2.2Hz,1H),6.84(s,2H),5.88(d,J＝8.3Hz,2H),4.94(s,1H),4.36(d,J＝12.3Hz,1H),4.21(d,J＝12.5Hz,1H),3.65(d,J＝15.7Hz,1H),3.27–3.10(m,4H).；13C NMR(101MHz,CDCl3)δ171.52,169.89,167.34,147.53,144.30,135.59,132.68,132.33,126.58,122.89,115.03,112.43,110.66,109.91,108.07,107.71,101.28,60.56,53.71,42.25,21.25,14.18；19f (376MHz, CDCl3) delta-75.87 Infrared spectroscopic analysis: IR (cm)-1):3296.9,3075.9,2952.3,2904.92850.2,2778.8,2663.2,2604.8,2253.9,2047.6,1852.7,1744.4,1655.7,1632.3,1597.2,1503.6,1443.1,1383.0,1369.2,1326.0,1309.5,872.0,848.8,818.7,787.3,758.9,729.8,678.9,648.0,631.7 ultraviolet spectroscopic analysis UVmax (CH)2Cl2)nm:206,212,222,228,234,246.。
Example 12: process for the preparation of the enantiomer (+/-) -TDA-10 of the epimer of methyl 1- (benzo [ d ] [1,3] dioxol-5-yl) -2- (2-chloroacetyl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyridylmethyl [3,4-b ] indole-3-carboxylate
The structural formula of the enantiomer (+/-) -TDA-10 of methyl 1- (benzo [ d ] [1,3] dioxol-5-yl) -2- (2-chloroacetyl) -6- ((fluorosulfonyl) oxy) -2,3,4, 9-tetrahydro-1H-pyridylmethyl [3,4-b ] indole-3-carboxylate of formula 5
251.7mg (0.5618mmol) of the substrate were dissolved in 15ml of ethyl acetate, 0.16ml (1.1236mmol) of triethylamine was added thereto, 0.64ml (0.8427mmol) of chloroacetyl chloride was added in an ice bath, the mixture was warmed to room temperature to react for 17 hours, water was added thereto and stirred, followed by extraction with ethyl acetate three times and washing with saturated brine once. Concentration and column chromatography (H60 silica gel, petroleum ether: ethyl acetate: 2:1) gave 133.4mg of a solid (45.3% yield). (+/-) -TDA-10 melting Point: 97-101 ℃, specific rotation: [ alpha ] to]26.7 ═ -0.015(C ═ 0.5, CHCl3), nuclear magnetic resonance analysis:1H NMR(400MHz,CDCl3)δ8.76(s,1H),7.44(s,1H),7.23(d,J＝8.8Hz,1H),7.07(dd,J＝8.8,2.2Hz,1H),6.91–6.67(m,3H),6.12(s,1H),5.92(s,3H),5.27(s,1H),4.20(d,J＝13.3Hz,1H),4.01(s,1H),3.69–3.53(m,4H)；13C NMR(101MHz,CDCl3)δ171.57,171.38,169.21,144.39,135.75,131.25,129.04,126.45,120.02,114.94,112.62,110.54,108.75,106.79,101.52,60.61,54.07,42.59,29.74,21.11,19.66,14.21；19f NMR (376MHz, CDCl3) delta-75.72. high resolution Mass Spectrometry: HRMS-ESI (M/z) 525.1124[ M-H]-Infrared spectroscopic analysis: IR (cm)-1) 3307.7,3073.1,2954.2,2916.0,2855.9,2779.8,2695.9,2605.8,2253.7,2037.7,1850.9,1740.2,1659.1,1589.9,1503.9,1489.0,1443.1,1368.3,1322.6,863.6,817.1,785.5,754.7,729.8,696.3,639.7 ultraviolet spectral analysis UVmax (CH)2Cl2)nm:206,210,214,226,228,234,246.。
The (+/-) -TDA-01, (+/-) -TDA-02, (+/-) -TDA-03, (+/-) -TDA-04, (+/-) -TDA-11 and (+/-) -TDA-12 described above are disclosed compounds wherein: (+/-) -TDA-01 and (+/-) -TDA-02 are commercially available compounds and (+/-) -TDA-03, (+/-) -TDA-04, (+/-) -TDA-11 and (+/-) -TDA-12 are disclosed in PCT patent WO0194345A 2.
The compounds have certain in vitro antitumor activity through PD1/PD-L1 protein molecule biological binding inhibition tests, wherein the compounds have certain in vitro antitumor activity. The activity of compounds (+/-) -TDA-13, (+/-) -TDA-14, (+/-) -TDA-09 and (+/-) -TDA-10 containing sulfonyl fluoride groups was higher than that of the corresponding compounds (+/-) -TDA-11, (+/-) -TDA-12, (+/-) -TDA-07 and (+/-) -TDA-08 containing sulfonyl fluoride groups. The test results are shown in table 1:
TABLE 1 Cisbio Human PD1/PD-L1Biochemical interaction experiments (Cisbio Human PD1/PD-L1biochemical interaction assay)
Remarking: test compound concentration: 50 μ M.
Claims (5)
1. An intermediate compound useful for preparing tadalafil analogues, said compound being named
(+/-) -TDA-07 has a structural formula shown in formula 9.
2. An intermediate compound useful for preparing tadalafil analogues, said compound being named
The compound (+/-) -TDA-08 has a structural formula shown in a formula 10.
3. A process for preparing an intermediate compound according to claim 1, characterized in that: acylation of the isomer (+/-) -TDA-03 of methyl 1- (benzo [ D ] [1,3] dioxo-5-yl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate with chloroacetyl chloride gave (+/-) -TDA-07 of the isomer of 1- (benzo [ D ] [1,3] dioxo-5-yl) -2- (2-chloroacetyl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate.
4. A process for preparing an intermediate compound according to claim 2, characterized in that: the isomer (+/-) -TDA-04 of methyl 1- (benzo [ D ] [1,3] dioxo-5-yl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate was acylated with chloroacetyl chloride to give the isomer (+/-) -TDA-08 of 1- (benzo [ D ] [1,3] dioxo-5-yl) -2- (2-chloroacetyl) -6-hydroxy-2, 3,4-, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylate.
5. A preparation method of tadalafil analogues containing sulfonyl fluoride groups is characterized by comprising the following steps: reacting 6- (benzo [1,3] dioxy-5-yl) -10-hydroxy-2-methyl-2-3, 6-, 7-, 12-, 12-hexahydropyrazine- [1',2': two pairs of enantiomers (+/-) -TDA-11 or (+/-) -TDA-12 of 1,6] pyrido [3,4-b ] indole-1, 4-dione which are epimeric with each other are subjected to sulfonyl fluorination reaction with sulfonyl fluoride gas under the catalysis of triethylamine to obtain (+/-) -TDA-13 and (+/-) -TDA-14 target products.
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| CN105198683A (en) * | 2015-09-24 | 2015-12-30 | 信阳师范学院 | Preparation method of sulfuryl fluoride compound |
| WO2017125952A1 (en) * | 2016-01-22 | 2017-07-27 | Council Of Scientific And Industrial Research | N-((1-phenyl-9h-pyrido[3,4-b]indol-3-yl)methyl)cinnamamides as anticancer agents and preparation thereof |
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| CN105198683A (en) * | 2015-09-24 | 2015-12-30 | 信阳师范学院 | Preparation method of sulfuryl fluoride compound |
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