CN116925001A - Synthesis method of letrozole analogue of breast cancer resisting medicine - Google Patents
Synthesis method of letrozole analogue of breast cancer resisting medicine Download PDFInfo
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- letrozole
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- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical class C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 206010006187 Breast cancer Diseases 0.000 title claims abstract description 19
- 208000026310 Breast neoplasm Diseases 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title abstract description 14
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003560 cancer drug Substances 0.000 claims abstract description 13
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 claims abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 7
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 11
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 10
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 229940125904 compound 1 Drugs 0.000 claims description 9
- 229940125782 compound 2 Drugs 0.000 claims description 9
- 229940126214 compound 3 Drugs 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 6
- 239000012300 argon atmosphere Substances 0.000 claims description 5
- BHXFKXOIODIUJO-UHFFFAOYSA-N benzene-1,4-dicarbonitrile Chemical compound N#CC1=CC=C(C#N)C=C1 BHXFKXOIODIUJO-UHFFFAOYSA-N 0.000 claims description 5
- BFSQJYRFLQUZKX-UHFFFAOYSA-L nickel(ii) iodide Chemical compound I[Ni]I BFSQJYRFLQUZKX-UHFFFAOYSA-L 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- KLXUSFHSWONPAC-UHFFFAOYSA-N trisilylsilane Chemical compound [SiH3][SiH]([SiH3])[SiH3] KLXUSFHSWONPAC-UHFFFAOYSA-N 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 238000005055 short column chromatography Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- MKCBRYIXFFGIKN-UHFFFAOYSA-N bicyclo[1.1.1]pentane Chemical group C1C2CC1C2 MKCBRYIXFFGIKN-UHFFFAOYSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 150000001299 aldehydes Chemical class 0.000 abstract description 2
- 150000001500 aryl chlorides Chemical class 0.000 abstract description 2
- -1 benzyl triazole compound Chemical class 0.000 abstract description 2
- 230000008878 coupling Effects 0.000 abstract description 2
- 238000010168 coupling process Methods 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 229960003881 letrozole Drugs 0.000 description 24
- 229940079593 drug Drugs 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 102000014654 Aromatase Human genes 0.000 description 5
- 108010078554 Aromatase Proteins 0.000 description 5
- 230000003169 placental effect Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 2
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 description 2
- 229940122815 Aromatase inhibitor Drugs 0.000 description 2
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 2
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 239000003886 aromatase inhibitor Substances 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 230000001076 estrogenic effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 238000003032 molecular docking Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003354 benzotriazolyl group Chemical class N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 208000030776 invasive breast carcinoma Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 238000010401 macromolecular docking Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthesis method of letrozole analogues of an anti-breast cancer drug, which takes commercial 4-chlorobenzaldehyde as a starting material and is driven by one-step light under the irradiation of purple light (1.1.1)]Coupling the propeller alkane with the multi-component free radicals of 4-chlorobenzaldehyde and 1, 3-dioxypentacyclic, and hydrolyzing under the condition of dilute hydrochloric acid to obtain an intermediate bicyclo [1.1.1]]Pentane (BCP) aldehyde, which is subsequently converted into cyano group, is then hydroxychlorinated under thionyl chloride, and is subsequently reacted with 1,2, 4-triazole in the presence of potassium carbonate in a single step S N 2, obtaining a benzyl triazole compound containing a BCP structure, and finally obtaining a target product by one-step photo-promoted nickel-catalyzed aryl chloride cyanidation reaction. The invention has low price of raw materials, short synthesis steps and mild conditions, and the obtained target product is expected to become a product with better pharmacological activityNovel breast cancer resisting medicine.
Description
Technical Field
The invention belongs to the technical field of chemical pharmaceutical synthesis, and particularly relates to a synthesis method of an letrozole analogue of an anti-breast cancer drug.
Background
Letrozole (Letrozole), chemical name: 4,4' - (1H-1, 2, 4-triazole-1-ylmethylene) -bisbenzonitrile is a new generation of high-selectivity aromatase inhibitor, is a synthetic benzotriazole derivative, and can reduce the estrogen level by inhibiting the aromatase, thereby eliminating the stimulation of the estrogen on tumor growth. The British medicine and health care product supervision authorities in 12 months 2005 approved that letrozole (Freron) produced by Nohua corporation in Switzerland was used to treat breast cancer patients, allowing it to be used in surgically treated, post-menopausal hormone positive, early invasive breast cancer patients, clinical studies showed that letrozole is a highly selective non-adrenocortical steroid drug, has strong antitumor effect, high specificity, few toxic and side effects, and has 150-250 times stronger in vivo activity than the first generation aromatase inhibitor aminoglutethimide. The structural formula is shown as follows;
the success of drug discovery depends on the fact that the effective drugs have good activity/affinity for the target and satisfactory absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters. In order to improve the physicochemical properties of candidate drugs, pharmaceutical chemists are increasingly inclined to use bioisostere alternatives to increase sp in the drug structure 3 Proportion of hybridized carbon centers. In recent years, pharmacists found bicyclo [1.1.1]]Pentane (BCP) is a class of bridged ring frameworks with important physiological activities in new drug research and is of great interest in the current drug development field. As bioisosteres of benzene rings, BCP backbones are introduced into drug molecules, which can effectively improve their solubility, cell membrane penetrability and drug metabolic stability, and thus, it is expected that such structures will be widely used in the development of new drugs. The successful use of BCP as a substitute for para-disubstituted benzene has made it a very valuable pharmacophore in the last decade due to the action of the strained bicyclic structure as a bioisostere. At present, a method for substituting benzene rings in letrozole by using BCP skeleton has not been reported yet. In view of this, we have devised a synthetic method for BCP letrozole drug molecules. The structural formula is as follows:
disclosure of Invention
The invention aims to provide a synthetic method of an letrozole analogue of an anti-breast cancer drug, which has the advantages of low raw material cost, short reaction steps, simple operation and mild conditions.
The synthesis method of the letrozole analogue of the breast cancer resistant drug provided by the invention comprises the following steps:
step 1: under argon atmosphere, 4-chlorobenzaldehyde and [1.1.1] propeller alkane are dissolved in 1, 3-dioxypentacyclic to react for 3-6 hours under the irradiation of purple light, crude separation is carried out by short column chromatography, and the crude product is hydrolyzed by dilute hydrochloric acid and then purified by column chromatography to obtain the compound 1.
Step 2: dissolving the compound 1, hydroxylamine hydrochloride, stannous chloride dihydrate and sodium bicarbonate in acetonitrile, and heating the reaction system to 75-85 ℃ for reflux for 36-48 hours to obtain the compound 2.
Step 3: dissolving the compound 2 in chloroform, adding thionyl chloride, and reacting for 10-12 hours at room temperature to obtain the compound 3.
Step 4: n, N-dimethylformamide is used as a solvent, and the compound 3 is reacted with 1,2, 4-triazole in the presence of potassium carbonate to obtain a compound 4.
Step 5: under argon atmosphere, the compound 4 and terephthalonitrile are dissolved in anisole, and then nickel iodide, 4 '-di-tert-butyl-2, 2' -bipyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, tri (trisilyl) silane and trimethyl bromosilane are sequentially added for reaction for 30-36 hours under the irradiation of purple light, so that a compound 5 containing a bicyclo [1.1.1] pentane skeleton, namely letrozole analogue (BCP letrozole for short) is obtained.
In the step 1 and the step 5, the wavelength range of the purple light is 360-365 nm or 390-395 nm.
In the step 1, the molar ratio of the [1.1.1] propeller alkane to the 4-chlorobenzaldehyde is preferably 1:1.5 to 2.2.
In the step 1, the solvent used for the hydrolysis is preferably acetone, the temperature of the hydrolysis is 45-55 ℃, the time is 4-6 hours, and the concentration of the dilute hydrochloric acid is 1.0-3.0 mol/L.
In the step 2, the molar ratio of the compound 1, hydroxylamine hydrochloride, stannous chloride dihydrate and sodium bicarbonate is preferably 1:1.1 to 2.0:0.1 to 0.3:1.0 to 1.5.
In the above step 3, the molar ratio of the compound 2 to thionyl chloride is preferably 1:2.0 to 4.0.
In the step 4, the reaction temperature is preferably 75 to 85 ℃ and the reaction time is preferably 16 to 24 hours.
In the step 4, the molar ratio of the compound 3, 1,2, 4-triazole to potassium carbonate is preferably 1:1.2-1.6:2.0-2.5.
In the above step 5, the molar ratio of the compound 4, terephthalonitrile, nickel iodide, 4 '-di-tert-butyl-2, 2' -bipyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, tri (trisilyl) silane, and trimethylbromosilane is preferably 1:2.0 to 2.5:0.15 to 0.2:0.15 to 0.2:2.0 to 2.5:1.5 to 2.0:1.5 to 2.0.
The beneficial effects of the invention are as follows:
the invention uses the bicyclo [1.1.1]]Pentane (BCP) as 1, 4-diThe bioisostere of the substituted benzene replaces benzene ring in letrozole of the breast cancer resisting medicine to improve the solubility, the cell membrane penetrability and the medicine metabolic stability. The method uses commercial 4-chlorobenzaldehyde as a starting material, and adopts one-step light driving [1.1.1] under the irradiation of purple light]Coupling the propeller alkane with the multi-component free radicals of 4-chlorobenzaldehyde and 1, 3-dioxypentacyclic, and hydrolyzing under the condition of dilute hydrochloric acid to obtain an intermediate bicyclo [1.1.1]]Pentane (BCP) aldehyde, which is subsequently converted into cyano group, is then hydroxychlorinated under thionyl chloride, and is subsequently reacted with 1,2, 4-triazole in the presence of potassium carbonate in a single step S N 2, obtaining a benzyl triazole compound containing a BCP structure, and finally obtaining a target product BCP letrozole by one-step photo-promoted nickel-catalyzed aryl chloride cyanidation reaction. The invention has low price of raw materials, short synthesis steps, mild conditions and simple operation, and the obtained target product is expected to become a novel anti-breast cancer drug with better pharmacological activity.
Drawings
FIG. 1 is an IC of letrozole and BCP letrozole synthesized in example 1 against MCF-7 50 And (5) measuring.
FIG. 2 is a molecular docking of human placental estrogenic enzyme cytochrome P450 (PDB number: 3 EQM) with letrozole.
FIG. 3 is a molecular docking of human placental estrogenic enzyme cytochrome P450 (PDB number: 3 EQM) with BCP letrozole synthesized in example 1.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, but the scope of the present invention is not limited to these examples.
Example 1
The synthetic route and synthetic method of BCP letrozole of this example are as follows:
step 1: into a 250mL reaction flask was charged 2.8g (20.0 mmol) of 4-chlorobenzaldehyde, and then the reaction flask was evacuated three times and filled with argon. Then 11.0mL of a 0.9mol/L (10.0 mmol) solution of [1.1.1] propeller in diethyl ether (freshly prepared according to the method in literature "Science 2016,351,241-246") and 90mL of 1, 3-dioxane were added, followed by stirring and irradiation with two 30W 390-395 nm violet LEDs at 30℃for 3 hours. The reaction was cooled to room temperature and concentrated in vacuo to give the crude product. The crude product was isolated by short column chromatography (eluting with a volume ratio of PE/ea=4:1) and the isolated mixture was dissolved in 15mL of acetone and 15mL of 2mol/L of dilute hydrochloric acid was added and heated to 50 ℃ for reaction for 4 hours. After cooling to room temperature after the reaction, concentration in vacuo and purification of the concentrated product by column chromatography (using a mixture of volume ratio DCM: meoh=200:1→80:1 as eluent) gave 800mg of compound 1 as a white solid in 34% yield.
The structural characterization data for compound 1 are: 1 H NMR(400MHz,CDCl 3 )δ9.56(s,1H),7.33(d,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,2H),4.74(s,1H),1.88(qd,J＝9.6,1.6Hz,6H)； 13 C NMR(100MHz,CDCl 3 )δ199.0,139.5,133.5,128.7,127.3,72.9,48.2,44.4,43.9；HRMS(ESI)m/z C 13 H 13 ClNaO 2 [M+Na] + theoretical values: 259.0496, found: 259.0495.
step 2: 140mg (0.59 mmol) of Compound 1, 46mg (0.65 mmol) of hydroxylamine hydrochloride, 50mg (0.59 mmol) of sodium hydrogencarbonate, 14mg (0.1 mmol) of stannous chloride dihydrate and 3.0mL of acetonitrile were added to a 25mL reaction flask, and the reaction mixture was heated to 80℃and reacted under reflux for 48 hours. After the reaction is completed, cooling to room temperature, adding saturated sodium chloride aqueous solution and ethyl acetate for dilution extraction to obtain an organic phase, performing reduced pressure distillation to obtain a crude product, and performing column chromatography purification by taking a mixed solution with a volume ratio of PE/EA=4:1 as an eluent to obtain 70mg of white solid compound 2, wherein the yield is 50%.
The structural characterization data for compound 2 are: 1 H NMR(400MHz,CDCl 3 )δ7.33(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,2H),4.69(s,1H),2.08(qd,J＝9.5,1.7Hz,6H),1.91(brs,1H)； 13 C NMR(100MHz,CDCl 3 )δ139.0,133.7,128.7,127.1,117.7,71.9,52.0,47.0,24.2；HRMS(ESI)m/z C 13 H 13 ClNaO 2 [M+Na] + theoretical values: 259.0496, found 259.0501.
Step 3: 110mg (0.47 mmol) of Compound 2, 168mg (1.41 mmol) of thionyl chloride and 5mL of chloroform were added to a 25mL reaction flask, and the reaction was stirred at room temperature for 12 hours. After the reaction, the mixture was concentrated in vacuo to give a crude product. The crude product was purified by column chromatography using a mixture of PE/ea=30:1 as eluent to give 115mg of compound 3 as a yellow oil in 97% yield.
The structural data for compound 3 is characterized as: 1 H NMR(400MHz,CDCl 3 )δ7.34(d,J＝8.5Hz,2H),7.20(d,J＝8.4Hz,2H),4.87(s,1H),2.20-2.10(m,6H)； 13 C NMR(100MHz,CDCl 3 )δ136.2,134.7,129.0,128.5,117.4,60.5,52.6,47.2,24.2；HRMS(ESI)m/z C 13 H 11 Cl 2 NNaO[M+Na] + theoretical values: 274.0161, found: 274.0160.
step 4: 124mg (0.90 mmol) of potassium carbonate and 47mg (0.68 mmol) of 1,2, 4-triazole are dissolved in 1.5mL of N, N-dimethylformamide under argon atmosphere and stirred at room temperature for 20 minutes; 113mg (0.45 mmol) of Compound 3 was dissolved in 2.0mL of N, N-dimethylformamide and then added dropwise to the reaction system, and the mixture was heated to 80℃and reacted with stirring for 16 hours, after completion of the reaction, cooled to room temperature. The reaction solution was extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated crude product was purified by column chromatography using a mixed solution of PE/ea=1:2 as an eluent to give 107mg of compound 4 as a colorless foam in 84% yield.
The structural characterization data for compound 4 are: 1 H NMR(400MHz,CDCl 3 )δ8.05(s,1H),8.00(s,1H),7.34(d,J＝8.4Hz,2H),7.23(d,J＝8.4Hz,2H),5.36(s,1H),2.32-2.15(m,6H)； 13 C NMR(100MHz,CDCl 3 )δ152.4,143.3,135.1,134.0,129.4,128.8,117.1,63.0,53.7,45.3,24.9；HRMS(ESI)m/z C 15 H 13 ClN 4 Na[M+Na] + theoretical values: 307.0721, found: 307.0718.
step 5: 70mg (0.25 mmol) of Compound 4 and 64mg (0.50 mmol) of terephthalonitrile, 2.5mL of anisole were charged into a 10mL reaction tube, evacuated and filled 3 times with argon, then 11.8mg (0.0375 mol) of nickel iodide, 10.0mg (0.037) were sequentially added5 mol) 4,4 '-di-tert-butyl-2, 2' -bipyridine (dtbbpy), 75mg (0.50 mmol) 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU), 62mg (0.50 mmol) tris (trisilyl) silane ((TMS) 3 SiH), 38mg (0.50 mmol) of trimethylbromosilane (TMSBr) and under 390-395 nm violet irradiation for 36 hours. After the reaction, cooling to room temperature, vacuum concentrating, and purifying the crude product by column chromatography with a mixed solution of PE/EA=1:3 as an eluent to obtain 38mg of colorless oily compound 5, namely BCP letrozole, with a yield of 55%.
The structural data of BCP letrozole are characterized as: 1 H NMR(400MHz,CDCl 3 )δ8.10(s,1H),8.04(s,1H),7.68(d,J＝8.2Hz,2H),7.43(d,J＝8.2Hz,2H),5.46(s,1H),2.31-2.20(m,6H)； 13 C NMR(100MHz,CDCl 3 )δ152.7,143.6,140.6,133.0,128.1,118.1,116.9,113.2,63.0,53.8,45.1,25.0；HRMS(ESI)m/z C 16 H 13 N 5 Na[M+Na] + theoretical values: 298.1063, found: 298.1064.
example 2
In step 1 of this example, 2.8g (20.0 mmol) of 4-chlorobenzaldehyde was charged into a 250mL reaction flask, and the reaction flask was then evacuated three times and filled with argon. Then, 11.0mL of a 0.9mol/L (10.0 mmol) diethyl ether solution of [1.1.1] propeller and 90mL of 1, 3-dioxane were added, followed by stirring and irradiation with two 30W 360-365 nm violet LEDs at 30℃for 3 hours. The reaction was cooled to room temperature and concentrated in vacuo to give the crude product. The crude product was isolated by short column chromatography (eluting with a volume ratio of PE/ea=4:1) and the isolated mixture was dissolved in 15mL of acetone and 15mL of 2mol/L of dilute hydrochloric acid was added and heated to 50 ℃ for reaction for 4 hours. After cooling to room temperature after the reaction, concentration in vacuo and purification of the concentrated product by column chromatography (using a mixture of volume ratio DCM: meoh=200:1→80:1 as eluent) gave 592mg of compound 1 as a white solid in 25% yield. Other steps were carried out in the same manner as in example 1 to obtain BCP letrozole.
To determine BCP letrozole-induced cytotoxicity obtained in example 1, experiments were performed in 96-well plates using MTT-based cell viability assays, and letrozole was compared. MCF-7 cellsPlanted at a density of 10000 cells per well, and then incubated for 12 hours. The corresponding compound was dissolved in dimethyl sulfoxide to prepare a stock solution of 10 mmol/L. Appropriate amounts of the above stock solutions were added to the cell culture medium to obtain the desired concentrations and incubated for 24 hours. The medium was then replaced with fresh DMEM. Subsequently, the cells were co-incubated with MTT for 4 hours, and the formazan crystals formed were dissolved in 100 μl lysis buffer. The 570nm absorbance of each well was measured on Spectra Max M384 (Molecular Devices) and the data recorded using Softmax Pro 6.4 software as shown in fig. 1. Calculation of IC for Compounds using Graphpad Prism 5 50 Values. IC of the obtained trazozole 50 IC of BCP letrozole at 4.087. Mu.M 50 3.061. Mu.M.
To further determine the aromatase inhibitory activity of BCP letrozole obtained in example 1, we performed macromolecular docking of letrozole and BCP letrozole to human placental aromatase cytochrome P450 (PDB number: 3 EQM). After removal of crystal ligands and water molecules from the crystal structure, the box parameters were set to center x= 85.027, center y= 54.737, center z= 46.428; dimension x=50, dimension y=50, and dimension z=50. The results show that hydrophobic interactions and hydrogen bonding are the primary binding forces between human placental aromatase cytochrome P450 and the compound. The cyano group of letrozole forms two hydrogen bonds with amino acid residues ARG-145 and TRP-141 (see FIG. 2). The bicyclo [1.1.1] pentanecyano group of BCP letrozole forms three hydrogen bonds with amino acid residues ARG-435 and TRP-141 (see FIG. 3). This result indicates that BCP letrozole binds more stably to human placental aromatase cytochrome P450.
Claims (9)
1. A method for synthesizing an letrozole analog of an anti-breast cancer drug, which is characterized by comprising the following steps:
step 1: under argon atmosphere, dissolving 4-chlorobenzaldehyde and [1.1.1] propeller alkane in 1, 3-dioxypentacyclic, reacting for 3-6 hours under the irradiation of purple light, carrying out crude separation by short column chromatography, hydrolyzing the crude product by dilute hydrochloric acid, and purifying by column chromatography to obtain a compound 1;
step 2: dissolving the compound 1, hydroxylamine hydrochloride, stannous chloride dihydrate and sodium bicarbonate in acetonitrile, heating a reaction system to 75-85 ℃ and refluxing for 36-48 hours to obtain a compound 2;
step 3: dissolving the compound 2 in chloroform, adding thionyl chloride, and reacting for 10-12 hours at room temperature to obtain a compound 3;
step 4: reacting a compound 3 with 1,2, 4-triazole in the presence of potassium carbonate by taking N, N-dimethylformamide as a solvent to obtain a compound 4;
step 5: under argon atmosphere, dissolving a compound 4 and terephthalonitrile in anisole, sequentially adding nickel iodide, 4 '-di-tert-butyl-2, 2' -bipyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, tri (trisilyl) silane and trimethyl bromosilane, and reacting for 30-36 hours under ultraviolet irradiation to obtain a compound 5 containing a bicyclo [1.1.1] pentane skeleton, namely letrozole analogues;
2. the method for synthesizing the letrozole analog as an anti-breast cancer drug according to claim 1, wherein: in the step 1 and the step 5, the wavelength range of the purple light is 360-365 nm or 390-395 nm.
3. The method for synthesizing the letrozole analog as an anti-breast cancer drug according to claim 1, wherein: in the step 1, the molar ratio of the [1.1.1] propeller alkane to the 4-chlorobenzaldehyde is 1:1.5-2.2.
4. The method for synthesizing the letrozole analog as an anti-breast cancer drug according to claim 1, wherein: in the step 1, the solvent used for hydrolysis is acetone, the temperature of the hydrolysis is 45-55 ℃, the time is 4-6 hours, and the concentration range of the dilute hydrochloric acid is 1.0-3.0 mol/L.
5. The method for synthesizing the letrozole analog as an anti-breast cancer drug according to claim 1, wherein: in the step 2, the molar ratio of the compound 1 to hydroxylamine hydrochloride to stannous chloride dihydrate to sodium bicarbonate is 1:1.1-2.0:0.1-0.3:1.0-1.5.
6. The method for synthesizing the letrozole analog as an anti-breast cancer drug according to claim 1, wherein: in the step 3, the molar ratio of the compound 2 to the thionyl chloride is 1:2.0-4.0.
7. The method for synthesizing the letrozole analog as an anti-breast cancer drug according to claim 1, wherein: in the step 4, the reaction temperature is 75-85 ℃ and the reaction time is 16-24 hours.
8. The method for synthesizing the letrozole analog as an anti-breast cancer drug according to claim 1, wherein: in the step 4, the molar ratio of the compound 3, the 1,2, 4-triazole to the potassium carbonate is 1:1.2-1.6:2.0-2.5.
9. The method for synthesizing the letrozole analog as an anti-breast cancer drug according to claim 1, wherein: in the step 5, the molar ratio of the compound 4, terephthalonitrile, nickel iodide, 4 '-di-tert-butyl-2, 2' -bipyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, tri (trisilyl) silane and trimethyl bromosilane is 1:2.0-2.5:0.15-0.2:0.15-0.2:2.0-2.5:1.5-2.0:1.5-2.0.
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