WO2019166033A2 - Vitamin c-platinum complex, intermediate thereof, preparation method, pharmaceutical composition and use - Google Patents

Vitamin c-platinum complex, intermediate thereof, preparation method, pharmaceutical composition and use Download PDF

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WO2019166033A2
WO2019166033A2 PCT/CN2019/084838 CN2019084838W WO2019166033A2 WO 2019166033 A2 WO2019166033 A2 WO 2019166033A2 CN 2019084838 W CN2019084838 W CN 2019084838W WO 2019166033 A2 WO2019166033 A2 WO 2019166033A2
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human
cancer
reaction
optionally
cyclobutane
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PCT/CN2019/084838
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French (fr)
Chinese (zh)
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WO2019166033A3 (en
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韩建斌
高香倩
杨金娜
杨柳
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天津谷堆生物医药科技有限公司
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Priority to JP2020568589A priority Critical patent/JP7048769B2/en
Priority to KR1020207025357A priority patent/KR102482090B1/en
Publication of WO2019166033A2 publication Critical patent/WO2019166033A2/en
Publication of WO2019166033A3 publication Critical patent/WO2019166033A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D307/62—Three oxygen atoms, e.g. ascorbic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage

Definitions

  • the invention relates to a water-soluble platinum complex, in particular to a vitamin C-coupled platinum complex for tumor treatment, an intermediate thereof, a preparation method thereof, a pharmaceutical composition and use thereof.
  • Platinum anticancer drugs are a representative class of drugs in the field of cancer therapy. It belongs to the cell cycle non-specific drug and has therapeutic effects on sarcoma, malignant epithelial tumor, lymphoma and germ cell tumor.
  • representative platinum-based anticancer drugs widely used in clinical treatment in the world are: cisplatin, carboplatin and oxaliplatin.
  • the fatal shortcoming of platinum-based anticancer drugs is the extremely toxic side effects and the inherent and subsequent resistance problems.
  • all platinum-listed drugs generally have extremely low water solubility characteristics. The water solubility of cisplatin, carboplatin and oxaliplatin was 1.0, 17.0, 6.0 mg/ml, respectively.
  • the object of the present invention is to overcome the deficiencies in the prior art and to provide a vitamin C-coupled platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which has good water solubility Sexuality and better anti-tumor activity.
  • the present invention provides a vitamin C-coupled platinum complex represented by the formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof:
  • X and Y are ligands, each of which is independently selected from NH 3 , C 1 -C 8 linear or branched alkyl primary amines (optionally C 1 -C 6 linear or A branched alkyl primary amine, optionally a C 1 -C 3 linear or branched alkyl primary amine), a C 3 -C 8 cyclic alkyl primary amine (optionally a C 3 -C 6 cyclic alkane) a primary amine, a primary aromatic amine, one or more C 1 -C 4 alkyl substituted aromatic primary amines, a secondary amine of the formula R 1 -NH-R 2 wherein R 1 and R 2 are each independently And a C 1 -C 8 linear or branched alkyl group (optionally a C 1 -C 6 linear or branched alkyl group, optionally a C 1 -C 3 linear or branched alkyl group); R 1 -NH-R 2 together constitute a C 4
  • D is C 0 or C 1 alkylene
  • B is C 2 -C 8 alkylene (optionally C 2 -C 6 alkylene, optionally C 3 -C 5 alkylene);
  • n 0 or 1
  • R is selected from:
  • the X and Y are respectively NH 3 , or X, Y together are trans-(1R, 2R)-cyclohexanediamine, trans-(1S, 2S)-cyclohexanediamine, cis -(1R,2S)-cyclohexanediamine, cis-(1S,2R)-cyclohexanediamine, racemic trans-1,2-cyclohexanediamine or racemic cis-1,2-ring Hexamethylenediamine.
  • the X and Y are each NH 3 ; or X, Y together are trans-(1R, 2R)-cyclohexanediamine.
  • formula (I) is selected from the following complexes,
  • the present invention provides an intermediate of a vitamin C-coupled platinum complex represented by the formula (I), which is characterized by having the structure represented by the formula (III):
  • Each M independently represents a hydrogen atom, or a metal atom of Group IA of the periodic table, or two M atoms collectively represent a metal atom of Group IIA of the periodic table; optionally M independently represents H, Na, K , Li, Cs or two M together represent Ba;
  • n 0 or 1
  • R is:
  • the present invention provides a vitamin C-coupled platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a process for the preparation thereof, comprising: a compound of formula (II) a step of reacting with the compound of the formula (III) with water to adjust to an aqueous solution; optionally, the aqueous solution is adjusted to have a pH of 7 to 9 by adding a base.
  • the base is an inorganic base.
  • the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, lithium hydroxide, barium hydroxide or barium hydroxide.
  • X and Y are ligands, each of which is independently selected from NH 3 , C 1 -C 8 linear or branched alkyl primary amines (optionally C 1 -C 6 straight or branched) Alkyl primary amine, optionally a C 1 -C 3 linear or branched alkyl primary amine), a C 3 -C 8 cyclic alkyl primary amine (optionally a C 3 -C 6 cyclic alkyl group) An amine), a primary aromatic amine, one or more C 1 -C 4 alkyl-substituted aromatic primary amines, a secondary amine of the formula R 1 -NH-R 2 wherein R 1 and R 2 each independently represent C a 1 - C 8 linear or branched alkyl group (optionally a C 1 -C 6 straight or branched alkyl group, optionally a C 1 -C 3 linear or branched alkyl group); or R 1 -NH-R 2 together constitutes a
  • D is C 0 or C 1 alkylene
  • B is C 2 -C 8 alkylene (optionally C 2 -C 6 alkylene, optionally C 3 -C 5 alkylene);
  • a 1 and A 2 are the same or different and each independently represents a hydroxyl group, a nitrate or a perchlorate, or A 1 and A 2 together represent a sulfate or a carbonate;
  • Each M independently represents a hydrogen atom, or a metal atom of Group IA of the periodic table, or two M atoms collectively represent a metal atom of Group IIA of the periodic table; optionally M independently represents H, Na, K , Li, Cs or two M together represent Ba;
  • n 0 or 1
  • R is:
  • the inorganic base concentration is from 0.1 N to 5 N, preferably 1 N.
  • reaction can be carried out over a relatively wide temperature range.
  • the above reaction can be carried out over a relatively wide temperature range, for example, by selecting a temperature range of 0-100 ° C to carry out the above reaction. It is preferably from room temperature to, preferably from 25 to 90 ° C, more preferably from 60 to 90 ° C, with stirring being preferred.
  • the time required for the reaction according to different target products can vary widely. Depending on the nature of the different reactants, it usually takes from 1 hour to 30 days to complete. In more cases, it takes 3 hours to 2 days.
  • the water used for the above reaction to adjust the reaction compound to an aqueous solution is preferably deionized water.
  • the reaction when M in the formula (III) is a hydrogen atom, the reaction can be carried out by using a suitable inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, lithium hydroxide and hydrogen.
  • a suitable inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, lithium hydroxide and hydrogen.
  • the preparation of the complex represented by the formula (I) is carried out by ruthenium oxide or the like to adjust the pH of the aqueous solution to be between 7 and 9; when M is a metal atom, for example, sodium atom, potassium atom, lithium atom, ruthenium atom or ruthenium
  • the atom can be smoothly reacted in an aqueous solution. If necessary, a small amount of an aqueous solution of the above inorganic base is used to maintain the pH of the reaction solution between 7 and 9 to complete the synthesis of the complex represented by the formula (I).
  • the reaction when M is a hydrogen atom, the reaction can be carried out by using an equivalent amount of cesium hydroxide as an inorganic base, and a condensation reaction with a metal platinum sulfate compound represented by the formula (II) is carried out in an aqueous solution to prepare a formula ( I) the complex shown.
  • a condensation reaction with a metal platinum sulfate compound represented by the formula (II) is carried out in an aqueous solution to prepare a formula ( I) the complex shown.
  • the complex of the present invention is prepared by the method B, it is also possible to use a previously prepared phosphonium salt, that is, two M together represent a deuterium atom, and the metal platinum sulfate complex represented by the formula (II) is reacted in an aqueous solution. The preparation process of the complex is completed.
  • the compounds represented by the formula (II) in the methods A and B can be passed through the corresponding complexes of cis-platinum chloride with X and Y, for example, cis-dichloro-(1,2-diaminocyclohexane) platinum.
  • X and Y for example, cis-dichloro-(1,2-diaminocyclohexane) platinum.
  • X and Y for example, cis-dichloro-(1,2-diaminocyclohexane) platinum.
  • X and Y for example, cis-dichloro-(1,2-diaminocyclohexane) platinum.
  • X and Y for example, cis-dichloro-(1,2-diaminocyclohexane) platinum.
  • the method for purifying the product (I) prepared by the above method is not particularly limited, and may be purified by a conventional method in the prior art.
  • the mixture after the completion of the reaction may be first removed by filtration to remove precipitates which may be formed. Then, it is concentrated by distillation under reduced pressure, and then an organic solvent is added (optionally, the organic solvent is preferably an organic solvent miscible with water, such as an alcohol (for example, methanol, ethanol, propanol, butanol, isopropanol).
  • the product (I) obtained by purifying and purifying the above reaction can also be subjected to a method such as chromatography, for example, using an ion exchange resin, or by preparative liquid chromatography. Liquid chromatography separation and purification are generally carried out using methanol and water as mobile phases.
  • the compound (III) of the present invention can be produced by any one of the methods C, D or the methods E and F which are exemplified by the alkylation of vitamin C3-O by the following reaction formula:
  • the benzyloxyalkyl dibromide can be debenzylated and brominated to give the tribromide.
  • the resulting bromide is reacted with vitamin C in the presence of a base using 0.1 to 50 equivalents of bromide for the vitamin C compound or 0.1 to 50 equivalents of the vitamin C compound for the bromide.
  • the base to be used may be sodium hydrogencarbonate, potassium carbonate, calcium carbonate, sodium hydride, triethylamine, cesium carbonate or the like, and the amount of the base may correspond to vitamin C of 0.1 to 10 equivalents.
  • the obtained vitamin C derivative is double-substituted with a malonic acid diester under a base condition to obtain a vitamin C3-O alkylated coupling cyclobutane malonate compound.
  • the reaction conditions are from 0.1 to 50 equivalents of malonic acid diester for the vitamin C derivative or 0.1 to 50 equivalents of the vitamin C derivative for the malonic acid diester.
  • the malonic acid diester may be dimethyl malonate, diethyl malonate, diphenylmethyl malonate, cycloisolactone malonate, di-tert-butyl malonate or the like.
  • the base to be used may be sodium hydrogencarbonate, potassium carbonate, calcium carbonate, sodium hydride, triethylamine, cesium carbonate or the like.
  • the solvent used may be tetrahydrofuran, dichloromethane, toluene, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, dimethyl sulfoxide, etc.
  • Two reactants may also be used. Any one of them is used as a solvent to carry out the reaction.
  • the temperature of the reaction can be from 0 ° C to 100 ° C, and the reaction can generally be completed by heating at 60-80 ° C.
  • the time required for the reaction varies depending on the reactants, and can usually be completed in 1 hour to 7 days.
  • the obtained reaction product can be purified by a series of purification conditions, and generally, a silica gel chromatography method or a liquid chromatography column separation method can be used.
  • the obtained product can be finally subjected to the desired compound represented by the formula (III) by removing the protective group of malonic acid.
  • the method of deprotection varies depending on the protecting group used. If diphenylmethyl malonate is used, deprotection can be carried out by hydroreduction, if diethyl malonate or malonate is used.
  • the deprotection reaction can be carried out using an inorganic base in methanol-water or a THF-water solvent, and the ratio of the organic solvent to water is generally from 1:1 to 4:1.
  • the inorganic base to be used may be sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide or the like. If di-tert-butyl malonate is used, the deprotection reaction can be carried out under acidic conditions.
  • the reaction temperature is usually room temperature, and the reaction time is usually from 1 to 24 hours.
  • the purification of the compound formed by deprotection can be carried out by silica gel chromatography or ion exchange resin filtration, or by liquid chromatography. If the reaction solvent is directly removed by distillation, the resulting product will be the corresponding metal carboxylate. Acid salt.
  • vitamin C can also be converted into the corresponding 5,6-O isopropylidene-protected vitamin C, and then reacted with bromide.
  • the protection of vitamin C can be carried out according to the methods reported in the literature. For example, it can be completed by heating in acetone at room temperature or at 60 ° C for 1 to 24 hours.
  • the reaction conditions of the various steps other than vitamin C protection in Method D are the same as those described in Method C.
  • the preparation methods shown in the methods E and F are: the benzyloxyalkyl dibromide is first substituted with a malonate to obtain a four-membered ring derivative, followed by debenzylation, bromination and vitamin C reaction, and deprotection is finally obtained.
  • Compound (III) The above preparation route involves protection of vitamin C, substitution reaction under alkaline conditions, deprotection reaction, and reaction conditions and implementation methods are the same as those described in Process C and Method D.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described vitamin C-coupled platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof Or a plurality and optionally a pharmaceutically acceptable carrier.
  • the present invention provides the above vitamin C-coupled platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition as described above, in the preparation of an antitumor drug use.
  • the tumor is human lung cancer, human liver cancer, human colorectal cancer, human head and neck cancer, human prostate cancer, human breast cancer, human ovarian cancer, human cervical cancer, human leukemia, human lymphoma, human skin cancer, Human pancreatic cancer, human bladder cancer, human esophageal cancer, human gastric cancer, human male genital cancer, human thyroid cancer, human bone cancer, or human melanoma, human oral cancer.
  • the tumor cells are human colon cancer cell line HT29, human non-small cell lung cancer cell A549, human liver cancer cell SMMC7721, human breast cancer cell MCF-7, human ovarian cancer cell SKOV3, human esophageal cancer cell ECA109, human prostate cancer Cell DU145, human cervical cancer cell line Hela, human melanoma cell line A375, human oral epidermoid carcinoma cell line KB, human gastric cancer cell line HGC27, human thyroid cancer cell line SW579, human bladder cancer cell line 5637, human pancreatic cancer cell line Panc-1, human large cell Lung cancer cell H460, human plasma cell leukemia cell H929, human liver cancer cell HepG2, human monocytic leukemia THP-1.
  • the antitumor drug of the present invention is not particularly limited in its administration route, and the dose depends not only on the age, weight and condition of the patient but also on the type, nature and severity of the tumor. In general, however, it is preferred for adult patients to use between 10 mg and 1 gram of the compound per day. It is usually administered once or three times a week or several times.
  • the compounds provided by the present invention have good antitumor activity.
  • the complex provided by the invention has a water solubility of several tens of times to thousands of times compared with the existing platinum antitumor drugs, and the high water solubility characteristic can increase the excretion of the drug in the kidney and reduce the drug in the drug.
  • the accumulation in the body can alleviate the high renal toxicity and side effects generally found in platinum drugs, making these compounds easy to formulate, improving the stability of the preparation, and being more convenient for clinical application.
  • reaction mixture was cooled to room temperature, and 100 mL of ethyl acetate was added to the reaction mixture, and then washed with a saturated aqueous solution of ammonium chloride (1 ⁇ 50 mL), and the aqueous phase was extracted with ethyl acetate. (2 x 25 mL), combined organic phases.
  • the organic phase was washed successively with a saturated aqueous solution of ammonium chloride (1 ⁇ 100 mL), distilled water (1 ⁇ 100 mL), and saturated sodium chloride solution (1 ⁇ 100 mL), and then dried over anhydrous sodium sulfate.
  • the pale yellow oil was purified by silica gel column chromatography eluting elut elut elut
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.3 g of a final product, a white solid.
  • reaction solution was cooled to room temperature, diluted with 50 mL of water, and neutralized with 1 M diluted hydrochloric acid, and then extracted with 100 mL of ethyl acetate.
  • the organic phase was sequentially distilled water (1) After washing with a saturated sodium chloride solution (1 ⁇ 100 mL), dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (EtOAc (EtOAc)
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.4 g of a final product, a white solid.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.4 g of a final product, a white solid.
  • reaction mixture was cooled to room temperature, and 100 mL of ethyl acetate was added to the reaction mixture, and then washed with a saturated aqueous solution of ammonium chloride (1 ⁇ 50 mL), and the aqueous phase was extracted with ethyl acetate. (2 x 25 mL), combined organic phases. The organic phase was washed with saturated aqueous ammonium chloride (1 ⁇ 100 mL), EtOAc (EtOAc) Purification by silica gel column chromatography (EtOAc /EtOAcEtOAc
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.6 g of a final product, a white solid.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.8 g of a final product, a white solid.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.6 g of a final product, a white solid.
  • reaction mixture was cooled to room temperature, and 100 mL of ethyl acetate was added to the reaction mixture, and then washed with a saturated aqueous solution of ammonium chloride (1 ⁇ 50 mL), and the aqueous phase was extracted with ethyl acetate. (2 x 25 mL), combined organic phases. The organic phase was washed with saturated aqueous ammonium chloride (1 ⁇ 100 mL), distilled water (1 ⁇ 100 mL), and brine (1 ⁇ 100 mL). The oil was purified by silica gel chromatography eluting elut elut elut elut
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-precision liquid chromatography by semi-preparation, and lyophilized using a freeze dryer to obtain 0.9 g of a final product, a white solid.
  • reaction liquid was cooled to room temperature, diluted with 50 mL of water, and neutralized with 1 M diluted hydrochloric acid, and then extracted with ethyl acetate.
  • the organic phase was sequentially distilled water (1 ⁇ After washing with a saturated sodium chloride solution (1 ⁇ 100 ml), EtOAc m.
  • the product was obtained as a colorless transparent oil (yield: 1.7 g).
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-precision liquid chromatography by semi-preparation, and lyophilized using a freeze dryer to obtain 0.9 g of a final product, a white solid.
  • 6-O-(3-propionate-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid crude product (1.0g) was dissolved in 10mL of water, and the saturated solution of cesium hydroxide was added to adjust the pH of the reaction solution to 7 Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (0.8 g) was dissolved in 2 ml of water, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.7 g of a final product, a white solid.
  • the crude 2-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid (0.4g) was dissolved in 10mL of water, and the pH of the reaction solution was adjusted to 7 by adding a saturated solution of cesium hydroxide. Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (0.5 g) was dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with a saturated solution of cesium hydroxide, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.4 g of a final product, a white solid.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-pressure liquid chromatography by semi-preparation and lyophilized using a freeze dryer to obtain 0.5 g of a final product, a white solid.
  • the 6-O-(3-formate-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid crude product (0.5g) was dissolved in 10mL of water, and the saturated solution of cesium hydroxide was added to adjust the pH of the reaction solution to 7 Stir at room temperature for 30 minutes.
  • cyclohexylamine platinum sulfate (0.54 g) was dissolved in 2 ml of water, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark.
  • the reaction was detected by HPLC.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-pressure liquid chromatography by semi-preparation and lyophilized using a freeze dryer to obtain 0.5 g of a final product, a white solid.
  • the 2-O-(3-ethylene-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid crude product (0.8 g) was dissolved in 10 mL of water, and a saturated solution of cesium hydroxide was added to adjust the pH of the reaction solution to 7 Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (0.9 g) was dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with a saturated solution of cesium hydroxide, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.8 g of a final product, a white solid.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-precision liquid chromatography by semi-preparation, and lyophilized using a freeze dryer to obtain 0.9 g of a final product, a white solid.
  • the 6-O-(3-acetate-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid crude product (0.8 g) was dissolved in 10 mL of water, and a saturated cesium hydroxide solution was added to adjust the pH of the reaction solution to 7 Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (0.9 g) was dissolved in 2 ml of water, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.7 g of a final product, a white solid.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-pressure liquid chromatography by semi-preparation and lyophilized using a freeze dryer to obtain 1.0 g of a final product, a white solid.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-pressure liquid chromatography by semi-preparation and lyophilized using a freeze dryer to obtain 1.0 g of a final product, a white solid.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-precision liquid chromatography by semi-preparation, and lyophilized using a freeze dryer to obtain 0.9 g of a final product, a white solid.
  • the solubility of the platinum complex of the present invention in water is much greater than that of cisplatin, carboplatin and oxaliplatin which have been marketed, and the water solubility can be increased by several tens to several thousand times.
  • the following experiment was conducted to experimentally verify the proliferation inhibitory effect of the vitamin C-conjugated platinum complex for tumor treatment of the present invention on different kinds of human tumor cells.
  • a cell culture medium containing 10% fetal bovine serum was used.
  • HERAcell150i carbon dioxide incubator (Thermo), research-grade inverted fluorescence microscope (Nikon, Japan), multi-function microplate reader (Thermo), ultra-low temperature refrigerator (Thermo), biosafety cabinet (1300 Series A2, Thermo), micropipette (Eppendorf, Germany), ultrapure water system (Milli-Q, USA).
  • the cytotoxicity test was tested by the MTT method.
  • the log phase tumor cells were collected, the cell suspension concentration was adjusted, 100 ⁇ l was added to each well, and the density of the cells to be tested was adjusted to 1000-10000 cells/well (the edge cells were filled with sterile PBS).
  • the active ingredient to be tested was not added, and finally the tumor cells were obtained to detect the OD value at 490 nm.
  • the cell survival rate is 50% of the control group, and the drug concentration is the half inhibitory concentration of the drug on the tumor cells, that is, the IC 50 value of the drug.
  • the vitamin C-coupled platinum complex of the present invention has good antitumor activity.

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Abstract

A vitamin C-platinum complex as shown in formula (I), an intermediate thereof, a preparation method, a pharmaceutical composition and a use. The vitamin C-platinum complex has good anti-tumour activity. The complex of the present invention is dozens of times better than existing platinum-type anti-tumour drugs in terms of water solubility. The high water solubility can increase and improve drug excretion in the kidneys, and reduce the high renal toxic side effects which generally occur with platinum-type drugs. In addition, the compound is easy to formulate, and more convenient for clinical application.

Description

维生素C偶联铂配合物、其中间体、其制备方法、药物组合物及用途Vitamin C-coupled platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and use thereof 技术领域Technical field
本发明涉及一种水溶性铂配合物，特别涉及一种用于肿瘤治疗的维生素C偶联铂配合物、其中间体、其制备方法、药物组合物及用途。The invention relates to a water-soluble platinum complex, in particular to a vitamin C-coupled platinum complex for tumor treatment, an intermediate thereof, a preparation method thereof, a pharmaceutical composition and use thereof.
背景技术Background technique
铂类抗癌药是肿瘤治疗领域具有代表性的一类药物。其属于细胞周期非特异性药物，对肉瘤，恶性上皮肿瘤，淋巴瘤以及生殖细胞肿瘤都具有治疗功效。目前世界上广泛应用于临床治疗的具有代表性的铂类抗癌药主要有：顺铂，卡铂和奥沙利铂。铂类抗癌药物的致命缺点是具有极强的毒副作用以及固有的和后续形成的耐药性问题。另外由于此类药物是金属有机化合物，所有铂类上市药物普遍存在水溶性极低的特性。顺铂、卡铂和奥沙利铂的水溶性分别为1.0、17.0、6.0mg/ml。Platinum anticancer drugs are a representative class of drugs in the field of cancer therapy. It belongs to the cell cycle non-specific drug and has therapeutic effects on sarcoma, malignant epithelial tumor, lymphoma and germ cell tumor. At present, representative platinum-based anticancer drugs widely used in clinical treatment in the world are: cisplatin, carboplatin and oxaliplatin. The fatal shortcoming of platinum-based anticancer drugs is the extremely toxic side effects and the inherent and subsequent resistance problems. In addition, since these drugs are metal organic compounds, all platinum-listed drugs generally have extremely low water solubility characteristics. The water solubility of cisplatin, carboplatin and oxaliplatin was 1.0, 17.0, 6.0 mg/ml, respectively.
发明内容Summary of the invention
本发明的目的是克服现有技术中的不足，提供一种维生素C偶联铂配合物，或其光学异构体，或其药学上可接受的盐，或其溶剂化物，其具有良好的水溶性以及更好的抗肿瘤活性。The object of the present invention is to overcome the deficiencies in the prior art and to provide a vitamin C-coupled platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which has good water solubility Sexuality and better anti-tumor activity.
本发明提供一种式(I)所示的维生素C偶联铂配合物，或其光学异构体，或其药学上可接受的盐，或其溶剂化物：The present invention provides a vitamin C-coupled platinum complex represented by the formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof:
Figure PCTCN2019084838-appb-000001
Figure PCTCN2019084838-appb-000001
其中：X和Y是配位体，所述X和Y各自独立地选自NH 3、C 1-C 8直链或支链烷基伯胺(可选为C 1-C 6的直链或支链烷基伯胺，可选为C 1-C 3的直链或支链烷基伯胺)、C 3-C 8环状烷基伯胺(可选为C 3-C 6环状烷基伯胺)、芳香族伯胺、一个或多个C 1-C 4烷基取代的芳香族伯胺、分子式为R 1-NH-R 2的仲胺，其中R 1和R 2各自独立地表示C 1-C 8直链或支链烷基(可选为C 1-C 6的直链或支链烷基，可选为C 1-C 3的直链或支链烷基)；或R 1-NH-R 2共同组成C 4-C 8的脂环仲胺(可选为C 5-C 6的脂环仲胺)、含氮芳香族杂环化合物、一个或多个C 1-C 4直链或支链烷基取代的含氮芳香族杂环化合物、含硫芳香族杂环化合物或含硫非芳香族杂环化合物；其中，所述“芳香族伯胺”中的芳基为5～10元单环或稠合双环芳香基团，所述“芳香族杂环”为5～10元单环或稠合双环杂芳香环，所述“非芳香族杂环”为4～10元单环或多环脂杂环； Wherein: X and Y are ligands, each of which is independently selected from NH 3 , C 1 -C 8 linear or branched alkyl primary amines (optionally C 1 -C 6 linear or A branched alkyl primary amine, optionally a C 1 -C 3 linear or branched alkyl primary amine), a C 3 -C 8 cyclic alkyl primary amine (optionally a C 3 -C 6 cyclic alkane) a primary amine, a primary aromatic amine, one or more C 1 -C 4 alkyl substituted aromatic primary amines, a secondary amine of the formula R 1 -NH-R 2 wherein R 1 and R 2 are each independently And a C 1 -C 8 linear or branched alkyl group (optionally a C 1 -C 6 linear or branched alkyl group, optionally a C 1 -C 3 linear or branched alkyl group); R 1 -NH-R 2 together constitute a C 4 -C 8 alicyclic secondary amine (optionally a C 5 -C 6 alicyclic secondary amine), a nitrogen-containing aromatic heterocyclic compound, one or more C 1 - a C 4 linear or branched alkyl-substituted nitrogen-containing aromatic heterocyclic compound, a sulfur-containing aromatic heterocyclic compound or a sulfur-containing non-aromatic heterocyclic compound; wherein the aryl group in the "aromatic primary amine" a 5- to 10-membered monocyclic or fused bicyclic aromatic group, the "aromatic heterocyclic ring" being a 5- to 10-membered monocyclic or fused bicyclic heteroaromatic ring, said "non-aromatic Heterocycle "is 4 to 10-membered aliphatic monocyclic or polycyclic heterocyclic ring;
或X和Y一起构成式(Ⅳ)结构：Or X and Y together form the structure of formula (IV):
Figure PCTCN2019084838-appb-000002
Figure PCTCN2019084838-appb-000002
式(Ⅳ)中，D为C 0或C 1的亚烷基；B为C 2-C 8的亚烷基(可选为C 2-C 6的亚烷基、可 选为C 3-C 5的亚烷基)； In formula (IV), D is C 0 or C 1 alkylene; B is C 2 -C 8 alkylene (optionally C 2 -C 6 alkylene, optionally C 3 -C 5 alkylene);
n＝0、1、2、3、4、5或6(可选地，n＝0、1、2或3)；n = 0, 1, 2, 3, 4, 5 or 6 (optionally, n = 0, 1, 2 or 3);
m是0或1；m is 0 or 1;
R选自：
Figure PCTCN2019084838-appb-000003
R is selected from:
Figure PCTCN2019084838-appb-000003
可选地，所述X和Y分别为NH 3，或X,Y一起为反式-(1R，2R)-环己二胺，反式-(1S，2S)-环己二胺，顺式-(1R，2S)-环己二胺，顺式-(1S，2R)-环己二胺，消旋反式-1，2-环己二胺或消旋顺式-1，2-环己二胺。 Alternatively, the X and Y are respectively NH 3 , or X, Y together are trans-(1R, 2R)-cyclohexanediamine, trans-(1S, 2S)-cyclohexanediamine, cis -(1R,2S)-cyclohexanediamine, cis-(1S,2R)-cyclohexanediamine, racemic trans-1,2-cyclohexanediamine or racemic cis-1,2-ring Hexamethylenediamine.
可选地，所述X和Y分别为NH 3；或X,Y一起为反式-(1R，2R)-环己二胺。 Alternatively, the X and Y are each NH 3 ; or X, Y together are trans-(1R, 2R)-cyclohexanediamine.
可选地，所述式(I)选自下述配合物，Optionally, the formula (I) is selected from the following complexes,
Figure PCTCN2019084838-appb-000004
Figure PCTCN2019084838-appb-000004
Figure PCTCN2019084838-appb-000005
Figure PCTCN2019084838-appb-000005
Figure PCTCN2019084838-appb-000006
Figure PCTCN2019084838-appb-000006
另一方面，本发明提供一种式(I)所示的维生素C偶联铂配合物的中间体，其特征是具有式(III)所示的结构：In another aspect, the present invention provides an intermediate of a vitamin C-coupled platinum complex represented by the formula (I), which is characterized by having the structure represented by the formula (III):
Figure PCTCN2019084838-appb-000007
Figure PCTCN2019084838-appb-000007
其中：among them:
各个M各自独立地代表氢原子，或者元素周期表第IA族的金属原子，或者两个M共同代表元素周期表中第IIA族的金属原子；可选的M各自独立地代表H、Na、K、Li、Cs或两个M共同代表Ba；Each M independently represents a hydrogen atom, or a metal atom of Group IA of the periodic table, or two M atoms collectively represent a metal atom of Group IIA of the periodic table; optionally M independently represents H, Na, K , Li, Cs or two M together represent Ba;
n＝0、1、2、3、4、5或6(可选地，n＝0、1、2或3)；n = 0, 1, 2, 3, 4, 5 or 6 (optionally, n = 0, 1, 2 or 3);
m是0或1；m is 0 or 1;
R是：
Figure PCTCN2019084838-appb-000008
R is:
Figure PCTCN2019084838-appb-000008
另一方面，本发明提供一种维生素C偶联铂配合物，或其光学异构体，或其药学上可接受的盐，或其溶剂化物的制备方法，其包括：将式(II)化合物与式(III)化合物加水调节为水溶液进行反应的步骤；可选地，反应水溶液加碱调节pH为7-9，In another aspect, the present invention provides a vitamin C-coupled platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a process for the preparation thereof, comprising: a compound of formula (II) a step of reacting with the compound of the formula (III) with water to adjust to an aqueous solution; optionally, the aqueous solution is adjusted to have a pH of 7 to 9 by adding a base.
可选地，所述碱为无机碱，可选地，所述无机碱选自氢氧化钠，氢氧化钾，碳酸钠，碳酸氢钠，碳酸钾，氢氧化锂，氢氧化铯或氢氧化钡中的一种或多种；Optionally, the base is an inorganic base. Optionally, the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, lithium hydroxide, barium hydroxide or barium hydroxide. One or more of
所述(II)的结构式为：The structural formula of (II) is:
Figure PCTCN2019084838-appb-000009
Figure PCTCN2019084838-appb-000009
式(II)中：In formula (II):
X和Y是配位体，所述X和Y各自独立地选自NH 3、C 1-C 8直链或支链烷基伯胺(可选为C 1-C 6的直链或支链烷基伯胺，可选为C 1-C 3的直链或支链烷基伯胺)、C 3-C 8环状烷基伯胺(可选为C 3-C 6环状烷基伯胺)、芳香族伯胺、一个或多个C 1-C 4烷基取代的芳香族伯胺、分子式为R 1-NH-R 2的仲胺，其中R 1和R 2各自独立地表示C 1-C 8直链或支链烷基(可选为C 1-C 6的直链或支链烷基，可选为C 1-C 3的直链或支链烷基)；或R 1-NH-R 2共同组成C 4-C 8的脂环仲胺(可选为C 5-C 6的脂环仲胺)、含氮芳香族杂环化合物、一个或多个C 1-C 4直链或支链烷基取代的含氮芳香族杂环化合物、含硫芳香族杂环化合物或含硫非芳香族杂环化合物；其中，所述“芳香族伯胺”中的芳基为5～10元单环或稠合双环芳香基团，所述“芳香族杂环”为5～10元单环或稠合双环杂芳香环，所述“非芳香族杂环”为4～10元单环或多环脂杂环； X and Y are ligands, each of which is independently selected from NH 3 , C 1 -C 8 linear or branched alkyl primary amines (optionally C 1 -C 6 straight or branched) Alkyl primary amine, optionally a C 1 -C 3 linear or branched alkyl primary amine), a C 3 -C 8 cyclic alkyl primary amine (optionally a C 3 -C 6 cyclic alkyl group) An amine), a primary aromatic amine, one or more C 1 -C 4 alkyl-substituted aromatic primary amines, a secondary amine of the formula R 1 -NH-R 2 wherein R 1 and R 2 each independently represent C a 1 - C 8 linear or branched alkyl group (optionally a C 1 -C 6 straight or branched alkyl group, optionally a C 1 -C 3 linear or branched alkyl group); or R 1 -NH-R 2 together constitutes a C 4 -C 8 alicyclic secondary amine (optionally a C 5 -C 6 alicyclic secondary amine), a nitrogen-containing aromatic heterocyclic compound, one or more C 1 -C 4 a linear or branched alkyl-substituted nitrogen-containing aromatic heterocyclic compound, a sulfur-containing aromatic heterocyclic compound or a sulfur-containing non-aromatic heterocyclic compound; wherein the aryl group in the "aromatic primary amine" is 5 a ?10-membered monocyclic or fused bicyclic aromatic group, the "aromatic heterocyclic ring" being a 5- to 10-membered monocyclic or fused bicyclic heteroaromatic ring, said "non-aromatic heterocyclic ring" 4 to 10-membered aliphatic monocyclic or polycyclic heterocyclic ring;
或X和Y一起构成式(Ⅳ)结构Or X and Y together form the structure of formula (IV)
Figure PCTCN2019084838-appb-000010
Figure PCTCN2019084838-appb-000010
式(Ⅳ)中，D为C 0或C 1的亚烷基；B为C 2-C 8的亚烷基(可选为C 2-C 6的亚烷基、可选为C 3-C 5的亚烷基)； In formula (IV), D is C 0 or C 1 alkylene; B is C 2 -C 8 alkylene (optionally C 2 -C 6 alkylene, optionally C 3 -C 5 alkylene);
A 1和A 2相同或者不同，各自独立地代表羟基，硝酸根或高氯酸根，或者A 1和A 2共同代表硫酸根或碳酸根； A 1 and A 2 are the same or different and each independently represents a hydroxyl group, a nitrate or a perchlorate, or A 1 and A 2 together represent a sulfate or a carbonate;
所述(III)的结构式为：The structural formula of (III) is:
Figure PCTCN2019084838-appb-000011
Figure PCTCN2019084838-appb-000011
式(III)中：In formula (III):
各个M各自独立地代表氢原子，或者元素周期表第IA族的金属原子，或者两个M共同代表元素周期表中第IIA族的金属原子；可选的M各自独立地代表H、Na、K、Li、Cs或两个M共同代表Ba；Each M independently represents a hydrogen atom, or a metal atom of Group IA of the periodic table, or two M atoms collectively represent a metal atom of Group IIA of the periodic table; optionally M independently represents H, Na, K , Li, Cs or two M together represent Ba;
n＝0、1、2、3、4、5或6(可选地，n＝0、1、2或3)；n = 0, 1, 2, 3, 4, 5 or 6 (optionally, n = 0, 1, 2 or 3);
m是0或1；m is 0 or 1;
R是：
Figure PCTCN2019084838-appb-000012
R is:
Figure PCTCN2019084838-appb-000012
可选地，上述反应中每当量的化合物(III)选用0.5-4当量的化合物(II)，优选是1至2当量。Alternatively, 0.5 to 4 equivalents of the compound (II) is used per equivalent of the compound (III) in the above reaction, and preferably 1 to 2 equivalents.
可选地，所述无机碱浓度为0.1N-5N，优选1N。Optionally, the inorganic base concentration is from 0.1 N to 5 N, preferably 1 N.
可选地，上述反应可以在一个比较宽的温度范围内来进行，Alternatively, the above reaction can be carried out over a relatively wide temperature range.
可选地，上述反应可以在一个比较宽的温度范围内来进行，例如选择在0-100℃的温度范围来进行上述反应。最好是从室温到，优选为25-90℃，更优选为60-90℃，并同时伴随搅拌为好。根据不同的目标产物反应需要的时间可以不同变化范围也很宽。根据不同反应物的性质，一般需要1小时到30天来完成。更多的情况下需要3小时至2天的时间。Alternatively, the above reaction can be carried out over a relatively wide temperature range, for example, by selecting a temperature range of 0-100 ° C to carry out the above reaction. It is preferably from room temperature to, preferably from 25 to 90 ° C, more preferably from 60 to 90 ° C, with stirring being preferred. The time required for the reaction according to different target products can vary widely. Depending on the nature of the different reactants, it usually takes from 1 hour to 30 days to complete. In more cases, it takes 3 hours to 2 days.
可选地，上述反应将反应化合物调节为水溶液所用的水优选使用去离子水。Alternatively, the water used for the above reaction to adjust the reaction compound to an aqueous solution is preferably deionized water.
具体的制备可以利用下述的方法和反应式来完成：The specific preparation can be accomplished by the following methods and reaction formulas:
方法A：Method A:
Figure PCTCN2019084838-appb-000013
Figure PCTCN2019084838-appb-000013
方法B：Method B:
Figure PCTCN2019084838-appb-000014
Figure PCTCN2019084838-appb-000014
在方法A中，当式(III)中M是氢原子时，反应可以通过使用适当的无机碱，例如氢氧化钠，氢氧化钾，碳酸钠，碳酸氢钠，碳酸钾，氢氧化锂以及氢氧化铯等来调节反应水溶液的pH在7-9之间来完成式(I)所示配合物的制备；当M为金属原子时，例如：钠原子、钾原子、锂原子、钡原子或铯原子，反应可在水溶液中顺利进行，必要时使用少量的上述无机碱的水溶液维持反应溶液的pH在7-9之间即可完成式(I)所示配合物的合成。In the method A, when M in the formula (III) is a hydrogen atom, the reaction can be carried out by using a suitable inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, lithium hydroxide and hydrogen. The preparation of the complex represented by the formula (I) is carried out by ruthenium oxide or the like to adjust the pH of the aqueous solution to be between 7 and 9; when M is a metal atom, for example, sodium atom, potassium atom, lithium atom, ruthenium atom or ruthenium The atom can be smoothly reacted in an aqueous solution. If necessary, a small amount of an aqueous solution of the above inorganic base is used to maintain the pH of the reaction solution between 7 and 9 to complete the synthesis of the complex represented by the formula (I).
在方法B中，当M是氢原子时，反应可以通过使用等当量的氢氧化钡作为无机碱，在水溶液中完成与式(II)所示的金属铂硫酸盐化合物的缩合反应来制备式(I)所示配合物。由方法B制备本发明配合物时，亦可以使用事先制得的钡盐，即两个M共同代表一个钡原子，与式(II)所示的金属铂硫酸盐配合物在水溶液中进行反应来完成配合物的制备过程。In the method B, when M is a hydrogen atom, the reaction can be carried out by using an equivalent amount of cesium hydroxide as an inorganic base, and a condensation reaction with a metal platinum sulfate compound represented by the formula (II) is carried out in an aqueous solution to prepare a formula ( I) the complex shown. When the complex of the present invention is prepared by the method B, it is also possible to use a previously prepared phosphonium salt, that is, two M together represent a deuterium atom, and the metal platinum sulfate complex represented by the formula (II) is reacted in an aqueous solution. The preparation process of the complex is completed.
方法A和B中式(II)所表示的化合物可以通过相应的顺-二氯化铂与X和Y的配合物，例如：顺-二氯-(1，2-二氨基环己烷)合铂与2当量的硝酸银或1当量的硫酸银反应而制备。该反应最好在水溶液中进行，使用的水最好是去离子水。反应温度在室温比较合适。The compounds represented by the formula (II) in the methods A and B can be passed through the corresponding complexes of cis-platinum chloride with X and Y, for example, cis-dichloro-(1,2-diaminocyclohexane) platinum. Prepared by reacting with 2 equivalents of silver nitrate or 1 equivalent of silver sulfate. The reaction is preferably carried out in an aqueous solution, and the water used is preferably deionized water. The reaction temperature is suitably at room temperature.
本发明对采用上述方法制备所得的生成物(I)进行提纯的方法并没有特别的限制，可以采用现有技术常规的方法进行提纯，例如反应完成后的混合物可以先通过过滤除去可能生成的沉淀物，然后通过减压蒸馏浓缩，然后加入有机溶剂(可选地，所述有机溶剂优选采用能够与水互溶的有机溶剂，例如醇类(例如甲醇，乙醇，丙醇，丁醇，异丙醇等)，或者与水有一定互溶 性的醚类(例如二乙醚，甲基叔丁基醚，四氢呋喃，乙二醇二乙醚，乙二醇二甲醚等))，使目标化合物(I)沉淀析出，最后将得到的沉淀收集起来，例如通过过滤，就可以得到所需要的式(I)所表示的化合物。提纯和精制上述反应中得到的生成物(I)也可以用色谱等的方法，例如用离子交换树脂，或者用制备液相色谱。液相色谱分离精制一般使用甲醇和水作为流动相来进行。The method for purifying the product (I) prepared by the above method is not particularly limited, and may be purified by a conventional method in the prior art. For example, the mixture after the completion of the reaction may be first removed by filtration to remove precipitates which may be formed. Then, it is concentrated by distillation under reduced pressure, and then an organic solvent is added (optionally, the organic solvent is preferably an organic solvent miscible with water, such as an alcohol (for example, methanol, ethanol, propanol, butanol, isopropanol). Etc.), or an ether which is mutually soluble with water (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, etc.) to precipitate the target compound (I) Precipitation, and finally, the obtained precipitate is collected, for example, by filtration, to obtain the desired compound represented by the formula (I). The product (I) obtained by purifying and purifying the above reaction can also be subjected to a method such as chromatography, for example, using an ion exchange resin, or by preparative liquid chromatography. Liquid chromatography separation and purification are generally carried out using methanol and water as mobile phases.
本发明化合物(III)，可以由下述的反应式所给出以维生素C3-O烷基化为例的方法C，D或者方法E,F中的任意一种来进行制备：The compound (III) of the present invention can be produced by any one of the methods C, D or the methods E and F which are exemplified by the alkylation of vitamin C3-O by the following reaction formula:
方法CMethod C
Figure PCTCN2019084838-appb-000015
Figure PCTCN2019084838-appb-000015
方法DMethod D
Figure PCTCN2019084838-appb-000016
Figure PCTCN2019084838-appb-000016
方法EMethod E
Figure PCTCN2019084838-appb-000017
Figure PCTCN2019084838-appb-000017
方法FMethod F
Figure PCTCN2019084838-appb-000018
Figure PCTCN2019084838-appb-000018
以维生素C3-O烷基化为例，在方法C中，苄氧烷基二溴物可以通过脱苄，溴化得到三溴化物。得到的溴化物在碱的存在下与维生素C反应，反应的条件是针对维生素C化合物使用0.1-50当量的溴化物，或者相反针对溴化物使用0.1-50当量的维生素C化合物。使用的碱可以是碳酸氢钠，碳酸钾，碳酸钙，氢化钠，三乙胺，碳酸铯等，碱的量相当于维生素C可以是0.1-10当量。得到的维生素C衍生物在与丙二酸二酯在碱的条件下发生双取代，从而得到维生素C3-O烷基化偶联的环丁烷丙二酸酯化合物。反应的条件是针对维生素C衍生物使用0.1-50当量的丙二酸二酯，或者相反针对丙二酸二酯使用0.1-50当量的维生素C衍生物。丙二酸二酯可以是丙二酸二甲酯，丙二酸二乙酯，丙二酸二苯甲酯，丙二酸环异内酯，丙二酸二叔丁酯等。使用的碱可以是碳酸氢钠，碳酸钾，碳酸钙，氢化钠，三乙胺，碳酸铯等。所使用的溶剂可以是四氢呋喃，二氯甲烷，甲苯，乙二醇二甲醚，乙二醇二乙醚，N,N-二甲基甲酰胺，二甲基亚砜等也可以使用两种反应物中的任意一种当作溶剂来进行该反应。反应的温度可以从0℃到100℃，一般可以在60-80℃加热完成该反应。反应所需要的时间根据反应物的不同而不同，一般1小时至7天可以完成。得到的反应产物可以通过一系列的提纯条件来进行精制，一般可以使用硅胶层析分离法，或者液 相色谱柱分离法。得到的该产物，经过除去丙二酸的保护基就可以最后得到所需要的式(III)所表示的化合物。脱保护的方法根据使用的保护基的不同而不同，如果使用丙二酸二苯甲基酯，可以使用加氢还原的方法进行脱保护，如果使用丙二酸二乙酯或者丙二酸环异内酯进行反应时，脱保护反应可以使用无机碱在甲醇-水，或者THF-水溶剂中来进行，有机溶剂与水的比例一般为1:1-4:1。所使用的无机碱可以是氢氧化钠，氢氧化钾，氢氧化钡，氢氧化锂等。如果使用丙二酸二叔丁酯，脱保护反应可以在酸性条件下进行。反应温度一般为室温，反应时间一般为1-24小时。脱保护生成的化合物的提纯可以使用硅胶层析法或者离子交换树脂过滤法，或者使用液相色谱法来完成，如果用蒸馏法直接除去反应溶剂，所得到的生成物将会是相应的金属羧酸盐。Taking the alkylation of vitamin C3-O as an example, in method C, the benzyloxyalkyl dibromide can be debenzylated and brominated to give the tribromide. The resulting bromide is reacted with vitamin C in the presence of a base using 0.1 to 50 equivalents of bromide for the vitamin C compound or 0.1 to 50 equivalents of the vitamin C compound for the bromide. The base to be used may be sodium hydrogencarbonate, potassium carbonate, calcium carbonate, sodium hydride, triethylamine, cesium carbonate or the like, and the amount of the base may correspond to vitamin C of 0.1 to 10 equivalents. The obtained vitamin C derivative is double-substituted with a malonic acid diester under a base condition to obtain a vitamin C3-O alkylated coupling cyclobutane malonate compound. The reaction conditions are from 0.1 to 50 equivalents of malonic acid diester for the vitamin C derivative or 0.1 to 50 equivalents of the vitamin C derivative for the malonic acid diester. The malonic acid diester may be dimethyl malonate, diethyl malonate, diphenylmethyl malonate, cycloisolactone malonate, di-tert-butyl malonate or the like. The base to be used may be sodium hydrogencarbonate, potassium carbonate, calcium carbonate, sodium hydride, triethylamine, cesium carbonate or the like. The solvent used may be tetrahydrofuran, dichloromethane, toluene, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, dimethyl sulfoxide, etc. Two reactants may also be used. Any one of them is used as a solvent to carry out the reaction. The temperature of the reaction can be from 0 ° C to 100 ° C, and the reaction can generally be completed by heating at 60-80 ° C. The time required for the reaction varies depending on the reactants, and can usually be completed in 1 hour to 7 days. The obtained reaction product can be purified by a series of purification conditions, and generally, a silica gel chromatography method or a liquid chromatography column separation method can be used. The obtained product can be finally subjected to the desired compound represented by the formula (III) by removing the protective group of malonic acid. The method of deprotection varies depending on the protecting group used. If diphenylmethyl malonate is used, deprotection can be carried out by hydroreduction, if diethyl malonate or malonate is used. When the lactone is reacted, the deprotection reaction can be carried out using an inorganic base in methanol-water or a THF-water solvent, and the ratio of the organic solvent to water is generally from 1:1 to 4:1. The inorganic base to be used may be sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide or the like. If di-tert-butyl malonate is used, the deprotection reaction can be carried out under acidic conditions. The reaction temperature is usually room temperature, and the reaction time is usually from 1 to 24 hours. The purification of the compound formed by deprotection can be carried out by silica gel chromatography or ion exchange resin filtration, or by liquid chromatography. If the reaction solvent is directly removed by distillation, the resulting product will be the corresponding metal carboxylate. Acid salt.
如方法D所示，维生素C亦可以先转化成相应的5,6-O异亚丙基保护的维生素C，然后再实施与溴化物的反应，维生素C的保护可以按照文献报道的方法实施，例如在丙酮中室温或者在60℃加热1-24小时即可完成。方法D中除维生素C保护以外的各个步骤的反应条件与方法C中所描述的相同。As shown in Method D, vitamin C can also be converted into the corresponding 5,6-O isopropylidene-protected vitamin C, and then reacted with bromide. The protection of vitamin C can be carried out according to the methods reported in the literature. For example, it can be completed by heating in acetone at room temperature or at 60 ° C for 1 to 24 hours. The reaction conditions of the various steps other than vitamin C protection in Method D are the same as those described in Method C.
方法E和F所示的制备方法是将苄氧烷基二溴物先与丙二酸酯进行取代反应得到四元环衍生物，然后进行脱苄，溴化与维生素C反应，脱保护得到最后化合物(III)。上述制备路线中涉及维生素C的保护，碱性条件下的取代反应，脱保护反应，其反应条件和实施方法与方法C和方法D中所叙述的相同。The preparation methods shown in the methods E and F are: the benzyloxyalkyl dibromide is first substituted with a malonate to obtain a four-membered ring derivative, followed by debenzylation, bromination and vitamin C reaction, and deprotection is finally obtained. Compound (III). The above preparation route involves protection of vitamin C, substitution reaction under alkaline conditions, deprotection reaction, and reaction conditions and implementation methods are the same as those described in Process C and Method D.
另一方面，本发明提供一种药用组合物，其包括上述的维生素C偶联铂配合物，或其光学异构体，或其药学上可接受的盐，或其溶剂化物中的一种或多种以及任选存在的药学上可接受的载体。In another aspect, the present invention provides a pharmaceutical composition comprising the above-described vitamin C-coupled platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof Or a plurality and optionally a pharmaceutically acceptable carrier.
另一方面，本发明提供上述维生素C偶联铂配合物、或其光学异构体，或其药学上可接受的盐，或其溶剂化物，或者上述的药物组合物在制备抗肿瘤药物中的用途。In another aspect, the present invention provides the above vitamin C-coupled platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition as described above, in the preparation of an antitumor drug use.
可选地，所述的肿瘤为人肺癌，人肝癌，人大肠癌，人头颈癌，人前列腺癌，人乳腺癌，人卵巢癌，人子宫颈癌，人白血病，人淋巴癌，人皮肤癌，人胰腺癌，人膀胱癌，人食道癌，人胃癌，人男性生殖器癌，人甲状腺癌，人骨癌，或人黑色素癌，人口腔癌。Optionally, the tumor is human lung cancer, human liver cancer, human colorectal cancer, human head and neck cancer, human prostate cancer, human breast cancer, human ovarian cancer, human cervical cancer, human leukemia, human lymphoma, human skin cancer, Human pancreatic cancer, human bladder cancer, human esophageal cancer, human gastric cancer, human male genital cancer, human thyroid cancer, human bone cancer, or human melanoma, human oral cancer.
可选地，所述肿瘤细胞为人结肠癌细胞HT29，人非小细胞肺癌细胞A549，人肝癌细胞SMMC7721，人乳腺癌细胞MCF-7，人卵巢癌细胞SKOV3，人食管癌细胞ECA109，人前列腺癌细胞DU145，人宫颈癌细胞Hela，人黑色素瘤细胞A375，人口腔表皮样癌细胞KB，人胃癌细胞HGC27，人甲状腺癌细胞SW579，人膀胱癌细胞5637，人胰腺癌细胞Panc-1，人大细胞肺癌细胞H460，人浆细胞白血病细胞H929，人肝癌细胞HepG2，人单核细胞白血病THP-1。Optionally, the tumor cells are human colon cancer cell line HT29, human non-small cell lung cancer cell A549, human liver cancer cell SMMC7721, human breast cancer cell MCF-7, human ovarian cancer cell SKOV3, human esophageal cancer cell ECA109, human prostate cancer Cell DU145, human cervical cancer cell line Hela, human melanoma cell line A375, human oral epidermoid carcinoma cell line KB, human gastric cancer cell line HGC27, human thyroid cancer cell line SW579, human bladder cancer cell line 5637, human pancreatic cancer cell line Panc-1, human large cell Lung cancer cell H460, human plasma cell leukemia cell H929, human liver cancer cell HepG2, human monocytic leukemia THP-1.
本发明的抗肿瘤药物，其给药途径没有特别的限制，其剂量不仅取决于病人的年龄，体重以及病情，还取决于肿瘤的种类，性质和严重程度。但一般来说，对于成年病人，最好每天使用的该化合物的量为10毫克至1克之间。一般为每一至三周一次或几次用药。The antitumor drug of the present invention is not particularly limited in its administration route, and the dose depends not only on the age, weight and condition of the patient but also on the type, nature and severity of the tumor. In general, however, it is preferred for adult patients to use between 10 mg and 1 gram of the compound per day. It is usually administered once or three times a week or several times.
本发明提供的化合物具有良好的抗肿瘤活性。本发明所提供的配合物在水溶性方面与现有铂类抗肿瘤药品相比，都具有几十倍至上千倍的提高，这种高水溶性特点能够增加药物在肾脏的排泄，减少药物在身体内的积蓄，减轻铂类药物一般存在的高肾毒副作用，使这些化合物容 易制剂化，提高制剂的稳定性，在临床上的应用更方便。The compounds provided by the present invention have good antitumor activity. The complex provided by the invention has a water solubility of several tens of times to thousands of times compared with the existing platinum antitumor drugs, and the high water solubility characteristic can increase the excretion of the drug in the kidney and reduce the drug in the drug. The accumulation in the body can alleviate the high renal toxicity and side effects generally found in platinum drugs, making these compounds easy to formulate, improving the stability of the preparation, and being more convenient for clinical application.
具体实施方式Detailed ways
以下用具体的实施例来进一步说明本发明。作为本发明所提供的由式(I)所表示的用于肿瘤治疗的铂配合物，其优选化合物的代表性举例亦可以由下述表1列出，但本发明所涵盖的铂配合物不限于以下的举例。The invention is further illustrated by the following specific examples. As a platinum complex for tumor treatment represented by the formula (I) provided by the present invention, a representative example of a preferred compound may also be listed in the following Table 1, but the platinum complex encompassed by the present invention is not Limited to the following examples.
表1实施例化合物列表Table 1 List of Examples Compounds
Figure PCTCN2019084838-appb-000019
Figure PCTCN2019084838-appb-000019
Figure PCTCN2019084838-appb-000020
Figure PCTCN2019084838-appb-000020
Figure PCTCN2019084838-appb-000021
Figure PCTCN2019084838-appb-000021
Figure PCTCN2019084838-appb-000022
Figure PCTCN2019084838-appb-000022
实施例1Example 1
二氨基铂(II)【3-亚甲基-(2-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of diaminoplatinum(II) [3-methylene-(2-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000023
Figure PCTCN2019084838-appb-000023
(1)3-苄氧甲基-环丁烷-1,1-二甲酸二叔丁酯的制备(1) Preparation of 3-benzyloxymethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester
Figure PCTCN2019084838-appb-000024
Figure PCTCN2019084838-appb-000024
将氢化钠(286mg)混悬于5mL N,N-二甲基甲酰胺中，用氮气置换烧瓶内空气，并将烧瓶置于冰浴中。在氮气保护下缓慢滴加丙二酸二叔丁酯(1.6mL)，待反应0.5小时后，缓慢滴加2-苄氧甲基-1,3-二溴丙烷(1.15g)的N,N-二甲基甲酰胺(5mL)溶液，反应液升温至70℃，搅拌7小时。用TLC监测反应终点，待反应完成后，将反应液冷却至室温，向反应液中加入100mL乙酸乙酯，然后用饱和氯化铵水溶液(1×50mL)洗涤，将水相用乙酸乙酯萃取(2×25mL)，合并有机相。将有机相依次用饱和氯化铵水溶液(1×100mL)，蒸馏水(1×100mL)，饱和氯化钠溶液(1×100mL)洗涤，然后用无水硫酸钠干燥，减压浓缩溶剂，得到的淡黄色油状物用硅胶柱层析纯化(石油醚/乙酸乙酯＝50/1)，得到无色透明油状目的产物1.1g。Sodium hydride (286 mg) was suspended in 5 mL of N,N-dimethylformamide, the air in the flask was replaced with nitrogen, and the flask was placed in an ice bath. Di-tert-butyl malonate (1.6 mL) was slowly added dropwise under a nitrogen atmosphere. After 0.5 hour of reaction, 2-benzyloxymethyl-1,3-dibromopropane (1.15 g) of N, N was slowly added dropwise. - a solution of dimethylformamide (5 mL), the reaction mixture was warmed to 70 ° C and stirred for 7 hours. The end of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, and 100 mL of ethyl acetate was added to the reaction mixture, and then washed with a saturated aqueous solution of ammonium chloride (1×50 mL), and the aqueous phase was extracted with ethyl acetate. (2 x 25 mL), combined organic phases. The organic phase was washed successively with a saturated aqueous solution of ammonium chloride (1×100 mL), distilled water (1×100 mL), and saturated sodium chloride solution (1×100 mL), and then dried over anhydrous sodium sulfate. The pale yellow oil was purified by silica gel column chromatography eluting elut elut elut
1H NMR(600MHz,CDCl 3)δ7.35-7.27(m,5H),4.50(s,2H),3.43(d,J＝6.5Hz,2H),2.63- 2.58(m,1H),2.53(t,J＝10.2Hz,2H),2.24(t,J＝9.9Hz,2H),1.46(s,9H),1.43(s,9H).MS(m/z)：399.1[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ7.35-7.27 (m, 5H), 4.50 (s, 2H), 3.43 (d, J = 6.5Hz, 2H), 2.63- 2.58 (m, 1H), 2.53 ( t, J = 10.2 Hz, 2H), 2.24 (t, J = 9.9 Hz, 2H), 1.46 (s, 9H), 1.43 (s, 9H). MS (m/z): 399.1 [M+Na] +
(2)3-羟甲基-环丁烷-1,1-二甲酸二叔丁基酯的制备(2) Preparation of 3-hydroxymethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester
Figure PCTCN2019084838-appb-000025
Figure PCTCN2019084838-appb-000025
将3-苄氧甲基-环丁烷-1,1-二甲酸二叔丁酯(1.1g)溶解在10mL甲醇中，加入10％钯碳(0.1g)，用氮气置换烧瓶内空气3次，再用氢气置换烧瓶内氮气3次，反应液在氢气加压下室温搅拌过夜。反应完成后，用氮气置换烧瓶内氢气，抽滤，滤饼用甲醇淋洗3次，滤液减压浓缩至干，得到无色透明油状的产物0.8g。Dissolve 3-benzyloxymethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (1.1 g) in 10 mL of methanol, add 10% palladium on carbon (0.1 g), and replace the air in the flask three times with nitrogen. The nitrogen in the flask was replaced with hydrogen three times, and the reaction solution was stirred at room temperature under hydrogen pressure overnight. After the completion of the reaction, the hydrogen in the flask was replaced with nitrogen, and the mixture was filtered with suction. The filter cake was washed with methanol three times.
1H NMR(600MHz,CDCl 3)δ3.60(brs,2H),2.52(brs,3H),2.26-2.25(m,2H),1.47(s,9H),1.45(s,9H).MS(m/z)：309.1[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ 3.60 (brs, 2H), 2.52 (brs, 3H), 2.26-2.25 (m, 2H), 1.47 (s, 9H), 1.45 (s, 9H). m/z): 309.1 [M+Na] +
(3)3-溴甲基-环丁烷-1,1-二甲酸二叔丁酯的制备(3) Preparation of 3-bromomethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester
Figure PCTCN2019084838-appb-000026
Figure PCTCN2019084838-appb-000026
将3-羟甲基-环丁烷-1,1-二甲酸二叔丁基酯(0.8g)溶解于5mL干燥的二氯甲烷中，在冰浴下缓慢加入三苯基膦(1.1g)的二氯甲烷溶液(5mL)，待反应10分钟后，缓慢滴加四溴化碳(1.4g)的二氯甲烷溶液(5mL)，反应液缓慢升温至室温，搅拌1小时。用TLC监测反应终点，待反应完成后，减压浓缩溶剂，硅胶柱层析纯化(石油醚/乙酸乙酯＝50/1)，得到无色透明油状目的产物0.9g。Dissolve 3-hydroxymethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (0.8 g) in 5 mL of dry dichloromethane and slowly add triphenylphosphine (1.1 g) in an ice bath. The dichloromethane solution (5 mL) was reacted for 10 minutes, and a solution of carbon tetrabromide (1.4 g) in dichloromethane (5 mL) was slowly added dropwise, and the mixture was slowly warmed to room temperature and stirred for 1 hour. The end of the reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated.
1H NMR(600MHz,CDCl 3)δ3.41(d,J＝7.4Hz,2H),2.73-2.68(m,1H),2.58(t,J＝10.2Hz,2H),2.21(t,J＝9.9Hz,2H),1.46(s,9H),1.45(s,9H).MS(m/z)：371.1[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ 3.41 (d, J = 7.4 Hz, 2H), 2.73 - 2.68 (m, 1H), 2.58 (t, J = 10.2 Hz, 2H), 2.21. (t, J = 9.9 Hz, 2H), 1.46 (s, 9H), 1.45 (s, 9H). MS (m/z): 371.1 [M+Na] +
(4)5,6-O-亚异丙基-2-O-(3-亚甲基-环丁烷-1,1-二甲酸二叔丁酯)-3-O-苄基-L-抗坏血酸的制备(4) 5,6-O-isopropylidene-2-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester)-3-O-benzyl-L- Preparation of ascorbic acid
Figure PCTCN2019084838-appb-000027
Figure PCTCN2019084838-appb-000027
室温条件下将5,6-O-亚异丙基-3-苄基L-抗坏血酸(1.4g)和3-溴甲基-环丁烷-1,1-二甲酸二叔丁酯(0.8g)溶解于10mL二甲基亚砜中，向反应液中加入碳酸钾(0.6g)，反应液升温至50℃，搅拌3小时。用TLC监测反应终点，待反应完成后，将反应液冷却至室温，向反应液中加入50mL水稀释，用1M稀盐酸中和，然后用100mL乙酸乙酯萃取，将有机相依次用蒸馏水(1×100mL)，饱和氯化钠溶液(1×100mL)洗涤，然后用无水硫酸钠干燥，用旋转蒸发仪将溶剂蒸干，得到的油状物用硅胶柱色谱纯化(石油醚/乙酸乙酯＝5/1)，得到无色透明油状的产物0.9g。5,6-O-isopropylidene-3-benzyl L-ascorbic acid (1.4 g) and 3-bromomethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (0.8 g) The solution was dissolved in 10 mL of dimethyl sulfoxide, and potassium carbonate (0.6 g) was added to the reaction mixture, and the mixture was heated to 50 ° C and stirred for 3 hours. The reaction end point was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with 50 mL of water, and neutralized with 1 M diluted hydrochloric acid, and then extracted with 100 mL of ethyl acetate. The organic phase was sequentially distilled water (1) ×100 mL), washed with a saturated sodium chloride solution (1×100 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. 5/1) gave 0.9 g of the product as a colorless transparent oil.
1H NMR(600MHz,CDCl 3)δ7.43–7.34(m,5H),5.47(s,2H),4.54(d,J＝2.3Hz,1H),4.30-4.28(m,1H),4.12-4.07(m,2H),4.04-4.01(m,2H),2.71-2.69(m,1H),2.56-2.51(m,2H),2.36–2.29(m,2H),1.46(s,9H),1.43(s,9H),1.39(s,3H),1.36(s,3H).MS(m/z)：597.2[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ 7.43 - 7.34 (m, 5H), 5.47 (s, 2H), 4.54 (d, J = 2.3 Hz, 1H), 4.30-4.28 (m, 1H), 4.12 4.07 (m, 2H), 4.04-4.01 (m, 2H), 2.71-2.69 (m, 1H), 2.56-2.51 (m, 2H), 2.36 - 2.29 (m, 2H), 1.46 (s, 9H), 1.43(s,9H), 1.39(s,3H), 1.36(s,3H).MS(m/z):597.2[M+Na] +
(5)5,6-O-亚异丙基-2-O-(3-亚甲基-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸的制备(5) Preparation of 5,6-O-isopropylidene-2-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid
Figure PCTCN2019084838-appb-000028
Figure PCTCN2019084838-appb-000028
将5,6-O-亚异丙基-2-O-(3-亚甲基-环丁烷-1,1-二甲酸二叔丁酯)-3-O-苄基-L-抗坏血酸(0.9g)溶解在10mL乙醇中，加入5％钯碳(0.1g)，用氮气置换烧瓶内空气3次，再用氢气置换烧瓶内氮气3次，反应液在氢气加压下室温搅拌过夜。反应完成后，用氮气置换烧瓶内氢气，抽滤，滤饼用乙醇淋洗3次，滤液减压浓缩，得到无色透明油状的产物0.7g。5,6-O-isopropylidene-2-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester)-3-O-benzyl-L-ascorbic acid ( 0.9 g) was dissolved in 10 mL of ethanol, 5% palladium carbon (0.1 g) was added, the air in the flask was replaced with nitrogen three times, and the nitrogen in the flask was replaced with hydrogen three times, and the reaction solution was stirred at room temperature under hydrogen pressure overnight. After completion of the reaction, the hydrogen in the flask was replaced with nitrogen, and the mixture was filtered with suction. The filter cake was washed with ethanol three times.
1H NMR(600MHz,CDCl 3)δ4.65(d,J＝2.9Hz,1H),4.35-4.33(m,1H),4.19-3.99(m,4H),2.72–2.61(m,2H),2.54-2.52(m,3H),1.46(s,9H),1.46(s,9H),1.41(s,3H),1.37(s,3H).MS(m/z)：507.2[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ4.65 (d, J = 2.9Hz, 1H), 4.35-4.33 (m, 1H), 4.19-3.99 (m, 4H), 2.72-2.61 (m, 2H), 2.54-2.52(m,3H), 1.46(s,9H), 1.46(s,9H),1.41(s,3H), 1.37(s,3H).MS(m/z):507.2[M+Na] +
(6)2-O-(3-亚甲基-环丁烷-1,1-二甲酸)L-抗坏血酸的制备(6) Preparation of 2-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid
Figure PCTCN2019084838-appb-000029
Figure PCTCN2019084838-appb-000029
将5,6-O-亚异丙基-2-O-(3-亚甲基-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸(0.7g)溶解于10mL二氯甲烷中，冷却至0℃，在氮气保护下缓慢滴加三氟乙酸(5mL)。反应液缓慢升温至室温，搅拌过夜。待反应完成后，减压浓缩除去溶剂，用冷冻干燥机干燥后得到无色粘稠状液体 0.4g，粗产品直接用于下步反应。Dissolve 5,6-O-isopropylidene-2-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid (0.7 g) in 10 mL of dichloro In methane, it was cooled to 0 ° C, and trifluoroacetic acid (5 mL) was slowly added dropwise under nitrogen. The reaction solution was slowly warmed to room temperature and stirred overnight. After completion of the reaction, the solvent was concentrated under reduced pressure and dried using a freeze dryer to yield 0.4 g of colorless viscous liquid, and the crude product was directly used for the next step.
MS(m/z)：355.1[M+Na] + MS (m/z): 355.1 [M+Na] +
(7)二氨基铂(II)【3-亚甲基-(2-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备(7) Preparation of diaminoplatinum(II) [3-methylene-(2-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000030
Figure PCTCN2019084838-appb-000030
将2-O-(3-亚甲基-环丁烷-1,1-二甲酸)L-抗坏血酸粗产品(0.4g)溶解于10mL水中，加入氢氧化钡饱和溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将二胺硫酸铂(0.4g)溶解于2ml水中，将该溶液加入到上述反应液，用氢氧化钡饱和溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.3g最终产品，白色固体。2-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid crude product (0.4 g) was dissolved in 10 mL of water, and a saturated solution of cesium hydroxide was added to adjust the pH of the reaction solution to 7, Stir at room temperature for 30 minutes. Platinum diamine sulfate (0.4 g) was dissolved in 2 ml of water under a nitrogen atmosphere, and the solution was added to the above reaction solution, and the pH was adjusted to 7 with a saturated solution of cesium hydroxide, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.3 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ4.98(d,J＝1.3Hz,1H),4.20(brs,4H),4.09(td,J＝6.9,1.7Hz,1H),3.99(d,J＝4.6Hz,2H),3.75(d,J＝6.8Hz,2H),3.13-3.06(m,2H),2.68-2.62(m,3H). 1 H NMR (400MHz, D 2 O) δ4.98 (d, J = 1.3Hz, 1H), 4.20 (brs, 4H), 4.09 (td, J = 6.9,1.7Hz, 1H), 3.99 (d, J = 4.6 Hz, 2H), 3.75 (d, J = 6.8 Hz, 2H), 3.13 - 3.06 (m, 2H), 2.68 - 2.62 (m, 3H).
MS(m/z)：582.0[M+Na] + MS (m/z): 582.0 [M+Na] +
实施例2Example 2
二氨基铂(II)【3-亚甲基-(3-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of diaminoplatinum(II) [3-methylene-(3-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000031
Figure PCTCN2019084838-appb-000031
(1)5,6-O-亚异丙基-3-O-(3-亚甲基-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸的制备(1) Preparation of 5,6-O-isopropylidene-3-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid
Figure PCTCN2019084838-appb-000032
Figure PCTCN2019084838-appb-000032
在室温条件下将5,6-O-亚异丙基L-抗坏血酸(0.8g)溶解于5mL二甲基亚砜中，加入碳酸氢钠(0.3g)，待反应液搅拌20分钟后，加入3-溴甲基-环丁烷-1,1-二甲酸二叔丁酯(0.9g)的二甲基亚砜溶液(5mL)，反应液升温至60℃，搅拌过夜。用TLC监测反应终点，待反应完成后，将反应液冷却至室温，向反应液中加入50mL水稀释，用1M稀盐酸中和，然后用乙酸乙酯 100mL萃取，将有机相依次用蒸馏水(1×100mL)，饱和氯化钠溶液(1×100mL)洗涤，无水硫酸钠干燥，减压浓缩，得到的黄色油状物。硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)，得到无色透明油状目的产物0.87g。5,6-O-isopropylidene L-ascorbic acid (0.8 g) was dissolved in 5 mL of dimethyl sulfoxide at room temperature, sodium hydrogencarbonate (0.3 g) was added, and the reaction solution was stirred for 20 minutes, and then added. A solution of 3-bromomethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (0.9 g) in dimethyl sulfoxide (5 mL) was warmed to 60 ° C and stirred overnight. The reaction end point was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with 50 mL of water, and neutralized with 1 M diluted hydrochloric acid, and then extracted with 100 mL of ethyl acetate. The organic phase was sequentially distilled water (1) After washing with a saturated sodium chloride solution (1×100 mL), dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (EtOAc (EtOAc)
1H NMR(600MHz,CDCl 3)δ4.56(d,J＝2.8Hz,1H),4.45(d,J＝5.9Hz,2H),4.27-4.24(m,1H),4.14(t,J＝7.5Hz,1H),4.03(t,J＝7.8Hz,1H),2.76-2.71(m,1H),2.59-2.49(m,2H),2.33-2.30(m,2H),1.47(s,9H),1.45(s,9H),1.39(s,3H),1.37(s,3H).MS(m/z)：507.2[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ4.56 (d, J = 2.8Hz, 1H), 4.45 (d, J = 5.9Hz, 2H), 4.27-4.24 (m, 1H), 4.14 (t, J = 7.5 Hz, 1H), 4.03 (t, J = 7.8 Hz, 1H), 2.76-2.71 (m, 1H), 2.59-2.49 (m, 2H), 2.33-2.30 (m, 2H), 1.47 (s, 9H) ), 1.45 (s, 9H), 1.39 (s, 3H), 1.37 (s, 3H). MS (m / z): 507.2 [M + Na] +
(2)3-O-(3-亚甲基-环丁烷-1,1-二甲酸)L-抗坏血酸的制备(2) Preparation of 3-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid
Figure PCTCN2019084838-appb-000033
Figure PCTCN2019084838-appb-000033
将5,6-O-亚异丙基-3-O-(3-亚甲基-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸(0.87g)溶解于10mL二氯甲烷中，冷却至0℃，在氮气保护下缓慢滴加三氟乙酸(5mL)。反应液缓慢升温至室温，搅拌过夜。待反应完成后，减压除去溶剂，用冷冻干燥机干燥后得到无色粘稠状液体0.5g，粗产品直接用于下步反应。Dissolving 5,6-O-isopropylidene-3-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid (0.87 g) in 10 mL of dichloro In methane, it was cooled to 0 ° C, and trifluoroacetic acid (5 mL) was slowly added dropwise under nitrogen. The reaction solution was slowly warmed to room temperature and stirred overnight. After the completion of the reaction, the solvent was removed under reduced pressure and dried with a freeze-drying apparatus to obtain 0.5 g of a colorless viscous liquid, and the crude product was directly used for the next reaction.
MS(m/z)：355.1[M+Na] + MS (m/z): 355.1 [M+Na] +
(3)二氨基铂(II)【3-亚甲基-(3-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备(3) Preparation of diaminoplatinum(II) [3-methylene-(3-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000034
Figure PCTCN2019084838-appb-000034
将3-O-(3-亚甲基-环丁烷-1,1-二甲酸)L-抗坏血酸粗产品(0.5g)溶解于10mL水中，加入氢氧化钡饱和溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将二胺硫酸铂(0.5g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡饱和溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.4g最终产品，白色固体。3-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid crude product (0.5 g) was dissolved in 10 mL of water, and a saturated solution of cesium hydroxide was added to adjust the pH of the reaction solution to 7, Stir at room temperature for 30 minutes. Platinum diamine sulfate (0.5 g) was dissolved in 2 ml of water under a nitrogen atmosphere, and added to the above reaction liquid, and the pH was adjusted to 7 with a saturated solution of cesium hydroxide, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.4 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ4.95(d,J＝1.7Hz,1H),4.56-4.48(m,2H),4.19(brs,6H),4.07–4.01(m,1H),3.75-3.73(m,2H),3.14–3.03(m,2H),2.81-2.66(m,3H).MS(m/z)：582.0[M+Na] + 1 H NMR (400MHz, D 2 O) δ4.95 (d, J = 1.7Hz, 1H), 4.56-4.48 (m, 2H), 4.19 (brs, 6H), 4.07-4.01 (m, 1H), 3.75 -3.73 (m, 2H), 3.14 - 3.03 (m, 2H), 2.81-2.66 (m, 3H). MS (m/z): 582.0 [M+Na] +
实施例3Example 3
二氨基铂(II)【3-甲酸-(6-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of diaminoplatinum(II) [3-carboxylic acid-(6-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000035
Figure PCTCN2019084838-appb-000035
(1)3-甲酸-环丁烷-1,1-二甲酸二叔丁酯的制备(1) Preparation of 3-carboxylic acid-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester
Figure PCTCN2019084838-appb-000036
Figure PCTCN2019084838-appb-000036
将3-羟甲基-环丁烷-1,1-二甲酸二叔丁基酯(0.8g)溶解于10mL丙酮中，冰浴条件下缓慢滴加琼斯试剂(三氧化铬420mg，浓硫酸371μL，加水稀释至1.6mL)，反应液缓慢升温至室温，搅拌2小时，用TLC监测反应，待反应结束后，滴加几滴异丙醇除去过量的氧化剂。反应液抽滤，用旋转蒸发仪蒸干溶剂，得到的绿色油状物用水稀释，乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥，减压浓缩溶剂，得到类白色固体0.76g，粗产品直接用于下步反应。Dissolve 3-hydroxymethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (0.8 g) in 10 mL of acetone, and slowly add Jones reagent (chromium trioxide 420 mg, concentrated sulfuric acid 371 μL) under ice bath. Diluted to 1.6 mL with water, the reaction solution was slowly warmed to room temperature, stirred for 2 hours, and the reaction was monitored by TLC. After the reaction was completed, a few drops of isopropyl alcohol were added dropwise to remove excess oxidizing agent. The reaction mixture was filtered, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The white solid was 0.76 g and the crude product was used directly in the next step.
MS(m/z)：323.0[M+Na] + MS (m/z): 323.0 [M+Na] +
(2)2-O-苄基-3-O-苄基-6-O-(3-甲酸酯-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸的制备(2) Preparation of 2-O-benzyl-3-O-benzyl-6-O-(3-formate-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid
Figure PCTCN2019084838-appb-000037
Figure PCTCN2019084838-appb-000037
将3-甲酸-环丁烷-1,1-二甲酸二叔丁酯(0.76g)溶解于10mL二氯甲烷中，加入二环己基碳二亚胺(0.622g)，催化量4-二甲氨基吡啶，待反应液搅拌0.5小时后，缓慢滴加2-O-苄基-3-O-苄基-L-抗坏血酸(1.1g)的二氯甲烷溶液(5mL)，反应液室温下搅拌过夜。TLC监测反应，待反应结束后，抽滤，滤液用旋转蒸发仪浓缩，得到的黄色油状物直接用硅胶柱色谱纯化(石油醚/乙酸乙酯＝7/1)，得到类白色固体产物1.0g。3-carboxylic acid-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (0.76 g) was dissolved in 10 mL of dichloromethane, dicyclohexylcarbodiimide (0.622 g) was added, and the catalytic amount was 4-dimethyl After the reaction mixture was stirred for 0.5 hours, a solution of 2-O-benzyl-3-O-benzyl-L-ascorbic acid (1.1 g) in dichloromethane (5 mL) was slowly added dropwise, and the mixture was stirred at room temperature overnight. . The reaction was monitored by TLC. After the reaction was completed, the filtrate was filtered, and the filtrate was concentrated with EtOAc (EtOAc). .
1H NMR(400MHz,CDCl 3)δ7.40-7.20(m,10H),5.22–5.08(m,4H),4.67(d,J＝2.0Hz,1H),4.28(ddd,J＝16.3,11.5,5.9Hz,2H),4.09-4.05(m,1H),3.20–3.08(m,1H),2.77–2.61(m,4H),1.46(s,9H),1.43(s,9H).MS(m/z)：661.2[M+Na] + 1 H NMR (400MHz, CDCl 3 ) δ7.40-7.20 (m, 10H), 5.22-5.08 (m, 4H), 4.67 (d, J = 2.0Hz, 1H), 4.28 (ddd, J = 16.3,11.5 , 5.9 Hz, 2H), 4.09-4.05 (m, 1H), 3.20–3.08 (m, 1H), 2.77–2.61 (m, 4H), 1.46 (s, 9H), 1.43 (s, 9H). m/z): 661.2 [M+Na] +
(3)6-O-(3-甲酸酯-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸的制备(3) Preparation of 6-O-(3-formate-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid
Figure PCTCN2019084838-appb-000038
Figure PCTCN2019084838-appb-000038
将2-O-苄基-3-O-苄基-6-O-(3-甲酸酯-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸(1.0g)溶解在10mL乙醇中，加入(0.1g)5％钯碳，用氮气置换烧瓶内空气3次，再用氢气置换烧瓶内氮气3次，反应液在氢气加压下室温搅拌过夜。反应完成后，用氮气置换烧瓶内氢气，抽滤，滤饼用乙醇淋洗3次，减压浓缩溶剂，得到无色透明油状的产物0.68g，粗产品直接用于下步反应。Dissolving 2-O-benzyl-3-O-benzyl-6-O-(3-formate-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid (1.0 g) In 10 mL of ethanol, (0.1 g) of 5% palladium carbon was added, the air in the flask was replaced with nitrogen three times, and the nitrogen in the flask was replaced with hydrogen three times, and the reaction solution was stirred at room temperature under hydrogen pressure overnight. After the completion of the reaction, the hydrogen in the flask was replaced with nitrogen, and the mixture was filtered with suction. The filter cake was rinsed three times with ethanol, and the solvent was concentrated under reduced pressure to give the product (yield: 0.68 g).
MS(m/z)：481.2[M+Na] + MS (m/z): 481.2 [M+Na] +
(4)6-O-(3-甲酸酯-环丁烷-1,1-二甲酸)L-抗坏血酸的制备(4) Preparation of 6-O-(3-formate-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid
Figure PCTCN2019084838-appb-000039
Figure PCTCN2019084838-appb-000039
将6-O-(3-甲酸酯-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸(0.68g)溶解于10mL二氯甲烷中，冷却至0℃，在氮气保护下缓慢滴加三氟乙酸(5mL)。反应液缓慢升温至室温，搅拌过夜。待反应完成后，用旋转蒸发仪除去溶剂，用冷冻干燥机干燥后得到无色粘稠状液体0.5g，粗产品直接用于下步反应。6-O-(3-formate-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid (0.68g) was dissolved in 10mL of dichloromethane, cooled to 0 ° C, protected with nitrogen Trifluoroacetic acid (5 mL) was slowly added dropwise. The reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the solvent was removed by a rotary evaporator, and dried using a freeze dryer to obtain 0.5 g of a colorless viscous liquid, and the crude product was directly used for the next step.
MS(m/z)：369.2[M+Na] + MS (m/z): 369.2 [M+Na] +
(5)二氨基铂(II)【3-甲酸酯-(6-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备(5) Preparation of diaminoplatinum(II) [3-formate-(6-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000040
Figure PCTCN2019084838-appb-000040
将6-O-(3-甲酸酯-环丁烷-1,1-二甲酸)L-抗坏血酸粗产品(0.5g)溶解于10mL水中，加入饱和氢氧化钡溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将环己二胺硫酸铂(0.45g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.4g最终产品，白色固体。6-O-(3-formate-cyclobutane-1,1-dicarboxylic acid) crude L-ascorbic acid (0.5g) was dissolved in 10mL of water, and the pH of the reaction solution was adjusted to 7 by adding a saturated cesium hydroxide solution. Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (0.45 g) was dissolved in 2 ml of water, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.4 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ4.95(brs,1H),4.35-4.24(m,3H),4.20(brs,5H),3.28–3.16(m,3H),3.10-3.08(m,2H).MS(m/z)：596.0[M+Na] + 1 H NMR (400 MHz, D 2 O) δ 4.95 (brs, 1H), 4.35 - 4.24 (m, 3H), 4.20 (brs, 5H), 3.28 - 3.16 (m, 3H), 3.10 - 3.08 (m, 2H).MS(m/z):596.0[M+Na] +
实施例4Example 4
二氨基铂(II)【3-亚乙基-(2-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of diaminoplatinum(II) [3-ethylidene-(2-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000041
Figure PCTCN2019084838-appb-000041
(1)3-苄氧乙基-环丁烷-1,1-二甲酸二叔丁酯的制备(1) Preparation of 3-benzyloxyethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester
Figure PCTCN2019084838-appb-000042
Figure PCTCN2019084838-appb-000042
将氢化钠(452mg)混悬于10mL N,N-二甲基甲酰胺中，用氮气置换烧瓶内空气，并将烧瓶置于冰浴中。在氮气保护下缓慢滴加丙二酸二叔丁酯(2.5mL)，待反应0.5小时后，缓慢滴加2-苄氧乙基-1,3-二溴丙烷(1.9g)的N,N-二甲基甲酰胺溶液(5mL)，反应液升温至70℃，搅拌7小时。用TLC监测反应终点，待反应完成后，将反应液冷却至室温，向反应液中加入100mL乙酸乙酯，然后用饱和氯化铵水溶液(1×50mL)洗涤，将水相用乙酸乙酯萃取(2×25mL)，合并有机相。将有机相依次用饱和氯化铵水溶液(1×100mL)，蒸馏水(1×100mL)，饱和氯化钠溶液(1×100mL)洗涤，无水硫酸钠干燥，减压浓缩，得到的淡黄色油状物，硅胶柱层析纯化(石油醚/乙酸乙酯＝50/1)，得到无色透明油状的产物1.7g。Sodium hydride (452 mg) was suspended in 10 mL of N,N-dimethylformamide, the air in the flask was replaced with nitrogen, and the flask was placed in an ice bath. Di-tert-butyl malonate (2.5 mL) was slowly added dropwise under a nitrogen atmosphere. After 0.5 hour of reaction, 2-benzyloxyethyl-1,3-dibromopropane (1.9 g) of N, N was slowly added dropwise. - a solution of dimethylformamide (5 mL), the reaction mixture was warmed to 70 ° C and stirred for 7 hours. The end of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, and 100 mL of ethyl acetate was added to the reaction mixture, and then washed with a saturated aqueous solution of ammonium chloride (1×50 mL), and the aqueous phase was extracted with ethyl acetate. (2 x 25 mL), combined organic phases. The organic phase was washed with saturated aqueous ammonium chloride (1×100 mL), EtOAc (EtOAc) Purification by silica gel column chromatography (EtOAc /EtOAcEtOAc
1H NMR(600MHz,CDCl 3)δ7.35-7.27(m,5H),4.47(s,2H),3.40(t,J＝6.3Hz,2H),2.53(t,J＝10.2Hz,2H),2.46-2.40(m,1H),2.11(t,J＝9.9Hz,2H),1.72(q,J＝6.6Hz,2H),1.46(s,9H),1.44(s,9H).MS(m/z)：413.2[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ7.35-7.27 (m, 5H), 4.47 (s, 2H), 3.40 (t, J = 6.3Hz, 2H), 2.53 (t, J = 10.2Hz, 2H) , 2.46-2.40 (m, 1H), 2.11 (t, J = 9.9 Hz, 2H), 1.72 (q, J = 6.6 Hz, 2H), 1.46 (s, 9H), 1.44 (s, 9H). MS ( m/z): 413.2 [M+Na] +
(2)3-羟乙基-环丁烷-1,1-二甲酸二叔丁酯的制备(2) Preparation of 3-tert-butyl 3-hydroxyethyl-cyclobutane-1,1-dicarboxylate
Figure PCTCN2019084838-appb-000043
Figure PCTCN2019084838-appb-000043
将3-苄氧乙基-环丁烷-1,1-二甲酸二叔丁酯(1.7g)溶解在10mL甲醇中，加入10％钯碳(0.1g)，用氮气置换烧瓶内空气3次，再用氢气置换烧瓶内氮气3次，反应液在氢气加压下室温搅拌过夜。反应完成后，用氮气置换烧瓶内氢气，抽滤，滤饼用甲醇淋洗3次，滤液经减压浓缩，得到无色透明油状的产物1.3g。3-Benzyloxyethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (1.7 g) was dissolved in 10 mL of methanol, 10% palladium on carbon (0.1 g) was added, and the air in the flask was replaced with nitrogen three times. The nitrogen in the flask was replaced with hydrogen three times, and the reaction solution was stirred at room temperature under hydrogen pressure overnight. After completion of the reaction, the hydrogen in the flask was replaced with nitrogen, and the mixture was filtered with suction. The filtrate was washed with methanol three times.
1H NMR(600MHz,CDCl 3)δ3.59(t,J＝6.4Hz,2H),2.56(t,J＝9.9Hz,2H),2.45-2.39(m,1H),2.13(t,J＝10.8Hz,2H),1.68(q,J＝6.6Hz,2H),1.46(s,9H),1.44(s,9H).MS(m/z)：323.2[M+Na] + 1 H NMR (600 MHz, CDCl 3 ) δ 3.59 (t, J = 6.4 Hz, 2H), 2.56 (t, J = 9.9 Hz, 2H), 2.45-2.39 (m, 1H), 2.13 (t, J = 10.8 Hz, 2H), 1.68 (q, J = 6.6 Hz, 2H), 1.46 (s, 9H), 1.44 (s, 9H). MS (m/z): 323.2 [M+Na] +
(3)3-溴乙基-环丁烷-1,1-二甲酸二叔丁酯的制备(3) Preparation of 3-bromoethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester
Figure PCTCN2019084838-appb-000044
Figure PCTCN2019084838-appb-000044
将3-羟乙基-环丁烷-1,1-二甲酸二叔丁基酯(1.3g)溶解于10mL干燥的二氯甲烷中，在冰浴下缓慢加入三苯基膦(1.7g)的二氯甲烷溶液(5mL)，待反应10分钟后，缓慢滴加四溴化碳(2.1g)的二氯甲烷溶液(5mL)，反应液缓慢升温至室温，搅拌1小时。用TLC监测反应终点，待反应完成后，反应液经减压浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝50/1)，得到无色透明油状的产物1.4g。3-Hydroxyethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (1.3 g) was dissolved in 10 mL of dry dichloromethane, and triphenylphosphine (1.7 g) was slowly added in an ice bath. The dichloromethane solution (5 mL) was reacted for 10 minutes, and a solution of carbon tetrabromide (2.1 g) in dichloromethane (5 mL) was slowly added dropwise, and the mixture was slowly warmed to room temperature and stirred for 1 hour. The end of the reaction was monitored by TLC. After the reaction mixture was evaporated, m.
1H NMR(600MHz,CDCl 3)δ3.30(t,J＝6.8Hz,2H),2.58(t,J＝9.9Hz,2H),2.50-2.44(m,1H),2.11(t,J＝10.2Hz,2H),1.98(q,J＝6.9Hz,2H),1.47(s,9H),1.45(s,9H).MS(m/z)：385.1[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ3.30 (t, J = 6.8Hz, 2H), 2.58 (t, J = 9.9Hz, 2H), 2.50-2.44 (m, 1H), 2.11 (t, J = 10.2 Hz, 2H), 1.98 (q, J = 6.9 Hz, 2H), 1.47 (s, 9H), 1.45 (s, 9H). MS (m/z): 385.1 [M+Na] +
(4)5,6-O-亚异丙基-2-O-(3-亚乙基-环丁烷-1,1-二甲酸二叔丁酯)-3-O-苄基-L-抗坏血酸的制备(4) 5,6-O-isopropylidene-2-O-(3-ethylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester)-3-O-benzyl-L- Preparation of ascorbic acid
Figure PCTCN2019084838-appb-000045
Figure PCTCN2019084838-appb-000045
室温条件下将5,6-O-亚异丙基-3-O-苄基-L-抗坏血酸(2.4g)和3-溴乙基-环丁烷-1,1-二甲酸二叔丁酯(1.4g)溶解于10mL二甲基亚砜中，向反应液中加入碳酸钾(1.1g)，反应液升温至50℃，搅拌3小时。用TLC监测反应终点，待反应完成后，将反应液冷却至室温，向反应液中加入50mL水稀释，用1M稀盐酸中和，然后用乙酸乙酯萃取，将有机相依次用蒸馏水(1×100mL)，饱和氯化钠溶液(1×100mL)洗涤，无水硫酸钠干燥，减压浓缩，得到的淡黄色油状物，硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)，得到无色透明油状的产物1.7g。5,6-O-isopropylidene-3-O-benzyl-L-ascorbic acid (2.4 g) and 3-bromoethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester at room temperature (1.4 g) was dissolved in 10 mL of dimethyl sulfoxide, and potassium carbonate (1.1 g) was added to the reaction mixture, and the reaction mixture was heated to 50 ° C and stirred for 3 hours. The reaction end point was monitored by TLC. After the reaction was completed, the reaction liquid was cooled to room temperature, diluted with 50 mL of water, and neutralized with 1 M diluted hydrochloric acid, and then extracted with ethyl acetate. The organic phase was sequentially distilled water (1× The mixture was washed with aq. EtOAc (EtOAc (EtOAc) The product was obtained as a colorless transparent oil, 1.7 g.
1H NMR(600MHz,CDCl 3)δ7.46–7.34(m,5H),5.46(s,2H),4.54(brs,1H),4.30(brs,1H),4.11(t,J＝7.5Hz,1H),4.04(t,J＝7.5Hz,1H)4.01–3.90(m,2H),2.55(t,J＝9.9Hz,2H),2.45-2.39(m,1H),2.12(t,J＝9.0Hz,2H),1.81–1.74(m,2H),1.44(s,18H),1.39(s,3H),1.36(s,3H).MS(m/z)：611.3[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ 7.46 - 7.34 (m, 5H), 5.46 (s, 2H), 4.54 (brs, 1H), 4.30 (brs, 1H), 4.11 (t, J = 7.5 Hz, 1H), 4.04 (t, J = 7.5 Hz, 1H) 4.01 - 3.90 (m, 2H), 2.55 (t, J = 9.9 Hz, 2H), 2.45 - 2.39 (m, 1H), 2.12 (t, J = 9.0 Hz, 2H), 1.81 - 1.74 (m, 2H), 1.44 (s, 18H), 1.39 (s, 3H), 1.36 (s, 3H). MS (m/z): 611.3 [M+Na] +
(5)5,6-O-亚异丙基-2-O-(3-亚乙基-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸的制备(5) Preparation of 5,6-O-isopropylidene-2-O-(3-ethylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid
Figure PCTCN2019084838-appb-000046
Figure PCTCN2019084838-appb-000046
将5,6-O-亚异丙基-2-O-(3-亚乙基-环丁烷-1,1-二甲酸二叔丁酯)-3-O-苄基-L-抗坏血酸(1.7g)溶解在15mL乙醇中，加入5％钯碳(0.1g)，用氮气置换烧瓶内空气3次，再用氢气置换烧瓶内氮气3次，反应液在氢气加压下室温搅拌过夜。反应完成后，用氮气置换烧瓶内氢气，抽滤，滤饼用乙醇淋洗3次，滤液经减压浓缩，得到无色透明油状的产物1.3g。5,6-O-isopropylidene-2-O-(3-ethylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester)-3-O-benzyl-L-ascorbic acid ( 1.7 g) was dissolved in 15 mL of ethanol, 5% palladium carbon (0.1 g) was added, the air in the flask was replaced with nitrogen three times, and the nitrogen in the flask was replaced with hydrogen three times, and the reaction solution was stirred at room temperature under hydrogen pressure overnight. After the completion of the reaction, the hydrogen in the flask was replaced with nitrogen, and the mixture was filtered with suction.
1H NMR(400MHz,CDCl 3)δ4.68(d,J＝3.7Hz,1H),4.42-4.39(m,1H),4.19–4.02(m,4H),2.58–2.46(m,3H),2.34–2.23(m,2H),1.77(q,J＝5.6Hz,2H),1.47(s,9H),1.45(s,9H),1.42(s,3H),1.37(s,3H).MS(m/z)：521.2[M+Na] + 1 H NMR (400MHz, CDCl 3 ) δ4.68 (d, J = 3.7Hz, 1H), 4.42-4.39 (m, 1H), 4.19-4.02 (m, 4H), 2.58-2.46 (m, 3H), 2.34–2.23 (m, 2H), 1.77 (q, J = 5.6 Hz, 2H), 1.47 (s, 9H), 1.45 (s, 9H), 1.42 (s, 3H), 1.37 (s, 3H). (m/z): 521.2 [M+Na] +
(6)2-O-(3-亚乙基-环丁烷-1,1-二甲酸)L-抗坏血酸的制备(6) Preparation of 2-O-(3-ethylidene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid
Figure PCTCN2019084838-appb-000047
Figure PCTCN2019084838-appb-000047
将5,6-O-亚异丙基-2-O-(3-亚乙基-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸(1.3g)溶解于10mL二氯甲烷中，冷却至0℃，在氮气保护下缓慢滴加三氟乙酸(5mL)。反应液缓慢升温至室温，搅拌过夜。待反应完成后，反应液经减压浓缩，冷冻干燥机干燥后得到无色粘稠状液体0.8g，粗产品直接用于下步反应。Dissolving 5,6-O-isopropylidene-2-O-(3-ethylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid (1.3 g) in 10 mL of dichloro In methane, it was cooled to 0 ° C, and trifluoroacetic acid (5 mL) was slowly added dropwise under nitrogen. The reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, and dried in a freeze-drying apparatus to obtain a colorless viscous liquid (0.8 g), and the crude product was directly used for the next reaction.
MS(m/z)：369.1[M+Na] + MS (m/z): 369.1 [M+Na] +
(7)二氨基铂(II)【3-亚乙基-(2-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备(7) Preparation of diaminoplatinum(II) [3-ethylidene-(2-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000048
Figure PCTCN2019084838-appb-000048
将2-O-(3-亚乙基-环丁烷-1,1-二甲酸)L-抗坏血酸粗产品(0.8g)溶解于10mL水中，加入氢 氧化钡饱和溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将二胺硫酸铂(0.7g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡饱和溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.6g最终产品，白色固体。2-O-(3-ethylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid crude product (0.8 g) was dissolved in 10 mL of water, and a saturated solution of cesium hydroxide was added to adjust the pH of the reaction solution to 7, Stir at room temperature for 30 minutes. Platinum diamine sulfate (0.7 g) was dissolved in 2 ml of water under a nitrogen atmosphere, added to the above reaction solution, adjusted to pH 7 with a saturated solution of cesium hydroxide, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.6 g of a final product, a white solid.
1H NMR(600MHz,D 2O)δ4.82(d,J＝1.3Hz,1H),4.15(brs,5H),4.01(td,J＝6.9,1.7Hz,1H),3.89(d,J＝4.6Hz,2H),3.70(d,J＝6.8Hz,2H),3.08(brs,2H),2.42(t,J＝8.7Hz,2H),2.32-2.27(m,1H),1.75-1.73(m,2H).MS(m/z)：572.0[M-H] - 1 H NMR (600MHz, D 2 O) δ4.82 (d, J = 1.3Hz, 1H), 4.15 (brs, 5H), 4.01 (td, J = 6.9,1.7Hz, 1H), 3.89 (d, J = 4.6 Hz, 2H), 3.70 (d, J = 6.8 Hz, 2H), 3.08 (brs, 2H), 2.42 (t, J = 8.7 Hz, 2H), 2.32 - 2.27 (m, 1H), 1.75-1.73 (m, 2H). MS (m / z): 572.0 [MH] -
实施例5Example 5
二氨基铂(II)【3-亚乙基-(3-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of diaminoplatinum(II) [3-ethylidene-(3-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000049
Figure PCTCN2019084838-appb-000049
(1)5,6-O-亚异丙基-3-O-(3-亚乙基-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸的制备(1) Preparation of 5,6-O-isopropylidene-3-O-(3-ethylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid
Figure PCTCN2019084838-appb-000050
Figure PCTCN2019084838-appb-000050
在室温条件下将5,6-O-亚异丙基L-抗坏血酸(1.2g)溶解于10mL二甲基亚砜中，加入碳酸氢钠(0.5g)，待反应液搅拌20分钟后，加入3-溴乙基-环丁烷-1,1-二甲酸二叔丁酯(1.4g)的二甲基亚砜溶液(5mL)，反应液升温至60℃，搅拌过夜。用TLC监测反应终点，待反应完成后，将反应液冷却至室温，向反应液中加入50mL水稀释，用1M稀盐酸中和，然后用乙酸乙酯(100mL)萃取，将有机相依次用蒸馏水(1×100mL)，饱和氯化钠溶液(1×100mL)洗涤，然后用无水硫酸钠干燥，减压浓缩，得到的黄色油状物用硅胶柱色谱纯化(石油醚/乙酸乙酯＝5/1)，得到无色透明油状的产物1.6g。5,6-O-isopropylidene L-ascorbic acid (1.2 g) was dissolved in 10 mL of dimethyl sulfoxide at room temperature, sodium hydrogencarbonate (0.5 g) was added, and the reaction solution was stirred for 20 minutes, and then added. A solution of 3-bromoethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (1.4 g) in dimethyl sulfoxide (5 mL) was warmed to 60 ° C and stirred overnight. The reaction end point was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 50 mL of water, and neutralized with 1 M diluted hydrochloric acid, and then extracted with ethyl acetate (100 mL). (1×100 mL), EtOAc (EtOAc) (EtOAc) 1) The product was obtained as a colorless transparent oil, 1.6 g.
1H NMR(600MHz,CDCl 3)δ4.52(brs,1H),4.41(t,J＝6.2Hz,2H),4.26(brs,1H),4.14(t,J＝7.6Hz,1H),4.02(t,J＝7.5Hz,1H),2.56(t,J＝10.2Hz,2H),2.45-2.40(dt,1H),2.15(t,J＝10.2Hz,2H),1.85(q,J＝8.6Hz,2H),1.46(s,9H),1.45(s,9H),1.39(s,3H),1.36(s,3H).MS(m/z)：521.2[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ 4.52 (brs, 1H), 4.41 (t, J = 6.2 Hz, 2H), 4.26 (brs, 1H), 4.14 (t, J = 7.6 Hz, 1H), 4.02 (t, J = 7.5 Hz, 1H), 2.56 (t, J = 10.2 Hz, 2H), 2.45 - 2.40 (dt, 1H), 2.15 (t, J = 10.2 Hz, 2H), 1.85 (q, J = 8.6 Hz, 2H), 1.46 (s, 9H), 1.45 (s, 9H), 1.39 (s, 3H), 1.36 (s, 3H). MS (m/z): 521.2 [M+Na] +
(2)3-O-(3-亚乙基-环丁烷-1,1-二甲酸)L-抗坏血酸的制备(2) Preparation of 3-O-(3-ethylidene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid
Figure PCTCN2019084838-appb-000051
Figure PCTCN2019084838-appb-000051
将5,6-O-亚异丙基-3-O-(3-亚乙基-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸(1.6g)溶解于10mL二氯甲烷中，冷却至0℃，在氮气保护下缓慢滴加三氟乙酸(5mL)。反应液缓慢升温至室温，搅拌过夜。待反应完成后，减压除去溶剂，冷冻干燥机干燥后得到无色粘稠状液体1.0g，粗产品直接用于下步反应。MS(m/z)：369.1[M+Na] + Dissolving 5,6-O-isopropylidene-3-O-(3-ethylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid (1.6 g) in 10 mL of dichloro In methane, it was cooled to 0 ° C, and trifluoroacetic acid (5 mL) was slowly added dropwise under nitrogen. The reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the solvent was removed under reduced pressure, and dried in a freeze-drying apparatus to obtain 1.0 g of a colorless viscous liquid, and the crude product was directly used for the next reaction. MS (m/z): 369.1 [M+Na] +
(3)二氨基铂(II)【3-亚乙基-(3-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备(3) Preparation of diaminoplatinum(II) [3-ethylidene-(3-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000052
Figure PCTCN2019084838-appb-000052
将3-O-(3-亚乙基-环丁烷-1,1-二甲酸)L-抗坏血酸粗产品(1.0g)溶解于10mL水中，加入氢氧化钡饱和溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将二胺硫酸铂(0.9g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡饱和溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.8g最终产品，白色固体。3-O-(3-ethylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid crude product (1.0 g) was dissolved in 10 mL of water, and a saturated solution of cesium hydroxide was added to adjust the pH of the reaction solution to 7, Stir at room temperature for 30 minutes. Platinum diamine sulfate (0.9 g) was dissolved in 2 ml of water under a nitrogen atmosphere, and added to the above reaction liquid, and the pH was adjusted to 7 with a saturated solution of cesium hydroxide, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.8 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ4.82(brs,1H),4.49–4.34(m,2H),4.08(brs,6H),3.94(t,J＝6.3Hz,1H),3.64-3.62(m,2H),3.07-3.00(m,2H),2.46–2.35(m,2H),2.32-2.22(m,1H),1.77(q,J＝6.4Hz,2H).MS(m/z)：596.1[M+Na] + 1 H NMR (400 MHz, D 2 O) δ 4.82 (brs, 1H), 4.49 - 4.34 (m, 2H), 4.08 (brs, 6H), 3.94 (t, J = 6.3 Hz, 1H), 3.64 - 3.62 (m, 2H), 3.07-3.00 (m, 2H), 2.46 - 2.35 (m, 2H), 2.32 - 2.22 (m, 1H), 1.77 (q, J = 6.4 Hz, 2H). MS (m/z ):596.1[M+Na] +
实施例6Example 6
二氨基铂(II)【3-乙酸酯-(6-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of diaminoplatinum(II) [3-acetate-(6-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000053
Figure PCTCN2019084838-appb-000053
(1)3-乙酸-环丁烷-1,1-二甲酸二叔丁酯的制备(1) Preparation of 3-acetic acid-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester
Figure PCTCN2019084838-appb-000054
Figure PCTCN2019084838-appb-000054
将3-羟乙基-环丁烷-1,1-二甲酸二叔丁基酯(1.3g)溶解于10mL丙酮中，冰浴条件下缓慢滴加琼斯试剂(三氧化铬650mg，浓硫酸559μL，加水稀释至2.4mL)，反应液缓慢升温至室温，搅拌2小时，用TLC监测反应，待反应结束后，滴加异丙醇除去过量的氧化剂。反应液抽滤，滤液减压浓缩，得到的绿色油状物。油状物用水稀释，乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥，减压浓缩，得到类白色固体1.2g，粗产品直接用于下步反应。MS(m/z)：337.2[M+Na] + 3-Hydroxyethyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (1.3g) was dissolved in 10mL of acetone, and the Jones reagent (650mg of chromium trioxide, 559μL of concentrated sulfuric acid) was slowly added dropwise under ice bath. Diluted to 2.4 mL with water, the reaction solution was slowly warmed to room temperature, stirred for 2 hours, and the reaction was monitored by TLC. After the reaction was completed, isopropyl alcohol was added dropwise to remove excess oxidizing agent. The reaction mixture was filtered under suction, and the filtrate was evaporated. The oil was diluted with water, EtOAc (EtOAc)EtOAc. MS (m/z): 337.2 [M+Na] +
(2)2-O-苄基-3-O-苄基-6-O-(3-乙酸酯-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸的制备(2) Preparation of 2-O-benzyl-3-O-benzyl-6-O-(3-acetate-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid
Figure PCTCN2019084838-appb-000055
Figure PCTCN2019084838-appb-000055
将3-乙酸-环丁烷-1,1-二甲酸二叔丁酯(1.2g)溶解于二氯甲烷中，加入二环己基碳二亚胺(1.2g)，催化量4-二甲氨基吡啶，待反应液搅拌0.5小时后，缓慢滴加2-O-苄基-3-O-苄基-L-抗坏血酸(2.1g)的二氯甲烷溶液(5mL)，反应液室温下搅拌过夜。TLC监测反应，待反应结束后，抽滤，滤液经减压浓缩，得到的黄色油状物。硅胶柱层析纯化(石油醚/乙酸乙酯＝7/1)，得到类白色固体产物1.7g。Dissolving 3-acetic acid-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (1.2 g) in dichloromethane, adding dicyclohexylcarbodiimide (1.2 g), catalytic amount of 4-dimethylamino After the reaction mixture was stirred for 0.5 hour, a solution of 2-O-benzyl-3-O-benzyl-L-ascorbic acid (2.1 g) in methylene chloride (5 mL) was slowly dropwisely evaporated. The reaction was monitored by TLC. After the reaction was completed, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. Purification by silica gel column chromatography (EtOAc /EtOAcEtOAc
1H NMR(400MHz,CDCl 3)δ7.40–7.21(m,10H),5.23–5.08(m,4H),4.64(d,J＝2.1Hz,1H),4.24(ddd,J＝16.5,11.6,6.0Hz,2H),4.08–4.00(m,1H),2.73–2.57(m,3H),2.47(d,J＝7.1Hz,2H),2.23–2.11(m,2H),1.46(s,9H),1.44(s,9H).MS(m/z)：675.3[M+Na] + 1 H NMR (400 MHz, CDCl 3 ) δ 7.40 - 7.21 (m, 10H), 5.23 - 5.08 (m, 4H), 4.64 (d, J = 2.1 Hz, 1H), 4.24 (ddd, J = 16.5, 11.6 , 6.0 Hz, 2H), 4.08–4.00 (m, 1H), 2.73–2.57 (m, 3H), 2.47 (d, J=7.1 Hz, 2H), 2.23–2.11 (m, 2H), 1.46 (s, 9H), 1.44 (s, 9H). MS (m / z): 675.3 [M + Na] +
(3)6-O-(3-乙酸酯-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸的制备(3) Preparation of 6-O-(3-acetate-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid
Figure PCTCN2019084838-appb-000056
Figure PCTCN2019084838-appb-000056
将2-O-苄基-3-O-苄基-6-O-(3-乙酸酯-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸(1.7g)溶解在10mL乙醇中，加入5％钯碳(0.1g)，用氮气置换烧瓶内空气3次，再用氢气置换烧瓶内氮气3次，反应液在氢气加压下室温搅拌过夜。反应完成后，用氮气置换烧瓶内氢气，抽滤，滤饼用乙醇淋洗3次，滤液经减压浓缩，得到无色透明油状的产物1.1g，粗产品直接用于下步反应。MS(m/z)：495.2[M+Na] + Dissolving 2-O-benzyl-3-O-benzyl-6-O-(3-acetate-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid (1.7 g) To 10 mL of ethanol, 5% palladium carbon (0.1 g) was added, and the air in the flask was replaced with nitrogen three times, and the nitrogen in the flask was replaced with hydrogen three times, and the reaction solution was stirred at room temperature under hydrogen pressure overnight. After the completion of the reaction, the hydrogen in the flask was replaced with nitrogen, and the mixture was filtered with suction. The filtrate was washed three times with ethanol, and the filtrate was concentrated under reduced pressure to give a product (yield: 1.1 g). MS (m/z): 495.2 [M+Na] +
(4)6-O-(3-乙酸酯-环丁烷-1,1-二甲酸)L-抗坏血酸的制备(4) Preparation of 6-O-(3-acetate-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid
Figure PCTCN2019084838-appb-000057
Figure PCTCN2019084838-appb-000057
将6-O-(3-乙酸酯-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸(1.1g)溶解于10mL二氯甲烷中，冷却至0℃，在氮气保护下缓慢滴加三氟乙酸(5mL)。反应液缓慢升温至室温，搅拌过夜。待反应完成后，减压除去溶剂，冷冻干燥后得到无色粘稠状液体0.8g，粗产品直接用于下步反应。MS(m/z)：383.1[M+Na] + 6-O-(3-acetate-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid (1.1 g) was dissolved in 10 mL of dichloromethane, cooled to 0 ° C, protected with nitrogen Trifluoroacetic acid (5 mL) was slowly added dropwise. The reaction solution was slowly warmed to room temperature and stirred overnight. After the completion of the reaction, the solvent was removed under reduced pressure and lyophilized to give a colorless viscous liquid (0.8 g). The crude product was used directly in the next step. MS (m/z): 383.1 [M+Na] +
(5)二氨基铂(II)【3-乙酸酯-(6-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备(5) Preparation of diaminoplatinum(II) [3-acetate-(6-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000058
Figure PCTCN2019084838-appb-000058
将6-O-(3-乙酸酯-环丁烷-1,1-二甲酸)L-抗坏血酸粗产品(0.8g)溶解于10mL水中，加入饱和氢氧化钡溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将环己二胺硫酸铂(0.7g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.6g最终产品，白色固体。6-O-(3-acetate-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid crude product (0.8 g) was dissolved in 10 mL of water, and a saturated cesium hydroxide solution was added to adjust the pH of the reaction solution to 7, Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (0.7 g) was dissolved in 2 ml of water, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.6 g of a final product, a white solid.
1H NMR(600MHz,D 2O)δ4.91(d,J＝1.9Hz,1H),4.16(brs,5H),4.33–4.23(m,3H),3.15–3.13(m,2H),2.62–2.45(m,5H).MS(m/z)：610.1[M+Na] + 1 H NMR (600 MHz, D 2 O) δ 4.91 (d, J = 1.9 Hz, 1H), 4.16 (brs, 5H), 4.33 - 4.23 (m, 3H), 3.15 - 3.13 (m, 2H), 2.62 –2.45(m,5H).MS(m/z):610.1[M+Na] +
实施例7Example 7
二氨基铂(II)【3-亚丙基-(2-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of diaminoplatinum(II) [3-propylene-(2-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000059
Figure PCTCN2019084838-appb-000059
(1)3-苄氧丙基-环丁烷-1,1-二甲酸二叔丁酯的制备(1) Preparation of 3-benzyloxypropyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester
Figure PCTCN2019084838-appb-000060
Figure PCTCN2019084838-appb-000060
将氢化钠(549mg)混悬于10mL N,N-二甲基甲酰胺中，用氮气置换烧瓶内空气，并将烧瓶置于冰浴中。在氮气保护下缓慢滴加丙二酸二叔丁酯(3.1mL)，待反应0.5小时后，缓慢滴加2-苄氧丙基-1,3-二溴丙烷(2.4g)的N,N-二甲基甲酰胺(5mL)溶液，反应液升温至70℃，搅拌7小时。用TLC监测反应终点，待反应完成后，将反应液冷却至室温，向反应液中加入100mL乙酸乙酯，然后用饱和氯化铵水溶液(1×50mL)洗涤，将水相用乙酸乙酯萃取(2×25mL)，合并有机相。将有机相依次用饱和氯化铵水溶液(1×100mL)，蒸馏水(1×100mL)，饱和氯化钠溶液(1×100mL)洗涤，然后用无水硫酸钠干燥，减压浓缩，得到的淡黄色油状物，硅胶柱层析纯化(石油醚/乙酸乙酯＝50/1)，得到无色透明油状目的产物1.9g。Sodium hydride (549 mg) was suspended in 10 mL of N,N-dimethylformamide, and the air in the flask was replaced with nitrogen, and the flask was placed in an ice bath. Di-tert-butyl malonate (3.1 mL) was slowly added dropwise under a nitrogen atmosphere. After 0.5 hour of reaction, 2-benzyloxypropyl-1,3-dibromopropane (2.4 g) of N, N was slowly added dropwise. - a solution of dimethylformamide (5 mL), the reaction mixture was warmed to 70 ° C and stirred for 7 hours. The end of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, and 100 mL of ethyl acetate was added to the reaction mixture, and then washed with a saturated aqueous solution of ammonium chloride (1×50 mL), and the aqueous phase was extracted with ethyl acetate. (2 x 25 mL), combined organic phases. The organic phase was washed with saturated aqueous ammonium chloride (1×100 mL), distilled water (1×100 mL), and brine (1×100 mL). The oil was purified by silica gel chromatography eluting elut elut elut elut
1H NMR(600MHz,CDCl 3)δ7.38–7.27(m,5H),4.48(s,2H),3.43(t,J＝6.2Hz,2H),2.51(t,J＝10.2Hz,2H),2.30-2.25(m,1H),2.06(t,J＝10.2Hz,2H),1.56-1.51(m,4H),1.46(s,9H),1.44(s,9H).MS(m/z)：427.2[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ 7.38 - 7.27 (m, 5H), 4.48 (s, 2H), 3.43 (t, J = 6.2 Hz, 2H), 2.51 (t, J = 10.2 Hz, 2H) , 2.30-2.25 (m, 1H), 2.06 (t, J = 10.2 Hz, 2H), 1.56-1.51 (m, 4H), 1.46 (s, 9H), 1.44 (s, 9H). MS (m/z ): 427.2 [M+Na] +
(2)3-羟丙基-环丁烷-1,1-二甲酸二叔丁酯的制备(2) Preparation of 3-hydroxypropyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester
Figure PCTCN2019084838-appb-000061
Figure PCTCN2019084838-appb-000061
将3-苄氧丙基-环丁烷-1,1-二甲酸二叔丁酯(1.9g)溶解在10mL甲醇中，加入10％钯碳(0.1g)，用氮气置换烧瓶内空气3次，再用氢气置换烧瓶内氮气3次，反应液在氢气加压下室温搅拌过夜。反应完成后，用氮气置换烧瓶内氢气，抽滤，滤饼用甲醇淋洗3次，滤液经减压浓缩，得到无色透明油状的产物1.4g。Dissolve 3-benzyloxypropyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (1.9 g) in 10 mL of methanol, add 10% palladium on carbon (0.1 g), and replace the air in the flask three times with nitrogen. The nitrogen in the flask was replaced with hydrogen three times, and the reaction solution was stirred at room temperature under hydrogen pressure overnight. After the completion of the reaction, the hydrogen in the flask was replaced with nitrogen, and the mixture was filtered with suction. The filtrate was washed with methanol three times.
1H NMR(600MHz,CDCl 3)δ3.61(t,J＝6.0Hz,2H),2.52(t,J＝10.0Hz,2H),2.31-2.26(m,1H),2.06(t,J＝9.6Hz,2H),1.57-1.46(m,13H),1.44(s,9H).MS(m/z)：337.2[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ 3.61 (t, J = 6.0 Hz, 2H), 2.52 (t, J = 10.0 Hz, 2H), 2.31-2.26 (m, 1H), 2.06 (t, J = 9.6 Hz, 2H), 1.57-1.46 (m, 13H), 1.44 (s, 9H). MS (m/z): 337.2 [M+Na] +
(3)3-溴丙基-环丁烷-1,1-二甲酸二叔丁酯的制备(3) Preparation of 3-bromopropyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester
Figure PCTCN2019084838-appb-000062
Figure PCTCN2019084838-appb-000062
将3-羟丙基-环丁烷-1,1-二甲酸二叔丁基酯1.4g溶解于10mL干燥的二氯甲烷中，在冰浴下缓慢加入三苯基膦(1.7g)的二氯甲烷溶液(5mL)，待反应10分钟后，缓慢滴加四溴化碳(2.2g)的二氯甲烷溶液(5mL)，反应液缓慢升温至室温，搅拌1小时。用TLC监测反应终点，待反应完成后，反应液经减压浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝50/1)，得到无色透明油状目的产物1.6g。1.4 g of 3-hydroxypropyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester was dissolved in 10 mL of dry dichloromethane, and triphenylphosphine (1.7 g) was slowly added in an ice bath. The methyl chloride solution (5 mL) was reacted for 10 minutes, and a solution of carbon tetrabromide (2.2 g) in dichloromethane (5 mL) was slowly added dropwise, and the mixture was slowly warmed to room temperature and stirred for 1 hour. The end of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was evaporated.
1H NMR(600MHz,CDCl 3)δ3.37(t,J＝6.7Hz,2H),2.53(t,J＝9.9Hz,2H),2.32-2.26(m,1H),2.08(t,J＝9.6Hz,2H),1.80–1.74(m,2H),1.54(q,J＝7.6Hz,2H),1.46(s,9H),1.45(s,9H). MS(m/z)：399.1[M+Na] + 1 H NMR (600 MHz, CDCl 3 ) δ 3.37 (t, J = 6.7 Hz, 2H), 2.53 (t, J = 9.9 Hz, 2H), 2.32 - 2.26 (m, 1H), 2.08 (t, J = 9.6 Hz, 2H), 1.80 - 1.74 (m, 2H), 1.54 (q, J = 7.6 Hz, 2H), 1.46 (s, 9H), 1.45 (s, 9H). MS (m/z): 399.1 [ M+Na] +
(4)5,6-O-亚异丙基-2-O-(3-亚丙基-环丁烷-1,1-二甲酸二叔丁酯)-3-O-苄基-L-抗坏血酸的制备(4) 5,6-O-isopropylidene-2-O-(3-propylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester)-3-O-benzyl-L- Preparation of ascorbic acid
Figure PCTCN2019084838-appb-000063
Figure PCTCN2019084838-appb-000063
室温条件下将5,6-O-亚异丙基-3-O-苄基-L-抗坏血酸(2.6g)和3-溴丙基-环丁烷-1,1-二甲酸二叔丁酯(1.6g)溶解于15mL二甲基亚砜中，向反应液中加入碳酸钾(1.2g)，反应液升温至50℃，搅拌3小时。用TLC监测反应终点，待反应完成后，将反应液冷却至室温，向反应液中加入50mL水稀释，用1M稀盐酸中和，然后用乙酸乙酯萃取，将有机相依次用蒸馏水(1×100ml)，饱和氯化钠溶液(1×100ml)洗涤，然后用无水硫酸钠干燥，减压浓缩，得到的淡黄色油状物，硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)，得到无色透明油状的产物2.0g。5,6-O-isopropylidene-3-O-benzyl-L-ascorbic acid (2.6 g) and 3-bromopropyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester at room temperature (1.6 g) was dissolved in 15 mL of dimethyl sulfoxide, and potassium carbonate (1.2 g) was added to the reaction mixture, and the reaction mixture was heated to 50 ° C and stirred for 3 hours. The reaction end point was monitored by TLC. After the reaction was completed, the reaction liquid was cooled to room temperature, diluted with 50 mL of water, and neutralized with 1 M diluted hydrochloric acid, and then extracted with ethyl acetate. The organic phase was sequentially distilled water (1× The mixture was washed with a saturated aqueous solution of sodium chloride (1×100 ml). ), 2.0 g of a product as a colorless transparent oil was obtained.
1H NMR(600MHz,CDCl 3)δ7.44–7.33(m,5H),5.47(s,2H),4.54(d,J＝2.1Hz,1H),4.31-4.29(m,1H),4.14–3.93(m,4H),2.51(t,J＝10.2Hz,2H),2.30-2.25(m,1H),2.05(t,J＝10.2Hz,2H),1.59–1.52(m,2H),1.48-1.46(m,11H),1.44(s,9H),1.39(s,3H),1.36(s,3H).MS(m/z)：625.3[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ7.44-7.33 (m, 5H), 5.47 (s, 2H), 4.54 (d, J = 2.1Hz, 1H), 4.31-4.29 (m, 1H), 4.14- 3.93 (m, 4H), 2.51 (t, J = 10.2 Hz, 2H), 2.30-2.25 (m, 1H), 2.05 (t, J = 10.2 Hz, 2H), 1.59 - 1.52 (m, 2H), 1.48 -1.46(m,11H), 1.44(s,9H), 1.39(s,3H), 1.36(s,3H).MS(m/z):625.3[M+Na] +
(5)5,6-O-亚异丙基-2-O-(3-亚丙基-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸的制备(5) Preparation of 5,6-O-isopropylidene-2-O-(3-propylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid
Figure PCTCN2019084838-appb-000064
Figure PCTCN2019084838-appb-000064
将5,6-O-亚异丙基-2-O-(3-亚丙基-环丁烷-1,1-二甲酸二叔丁酯)-3-O-苄基-L-抗坏血酸(2.0g)溶解在10mL乙醇中，加入5％钯碳(0.2g)，用氮气置换烧瓶内空气3次，再用氢气置换烧瓶内氮气3次，反应液在氢气加压下室温搅拌过夜。反应完成后，用氮气置换烧瓶内氢气，抽滤，滤饼用乙醇淋洗3次，减压浓缩，得到无色透明油状的产物1.6g。5,6-O-isopropylidene-2-O-(3-propylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester)-3-O-benzyl-L-ascorbic acid ( 2.0 g) was dissolved in 10 mL of ethanol, 5% palladium carbon (0.2 g) was added, the air in the flask was replaced with nitrogen three times, and the nitrogen in the flask was replaced with hydrogen three times, and the reaction solution was stirred at room temperature under hydrogen pressure overnight. After completion of the reaction, the hydrogen in the flask was replaced with nitrogen, and the mixture was filtered with suction.
1H NMR(400MHz,CDCl 3)δ4.69(d,J＝3.7Hz,1H),4.44–4.37(m,1H),4.19–4.01(m,4H),2.58-2.49(m,2H),2.31-2.23(m,1H),2.12–1.99(m,2H),1.61–1.50(m,4H),1.46(s,9H),1.45 (s,9H),1.42(s,3H),1.37(s,3H).MS(m/z)：535.3[M+Na] + 1 H NMR (400MHz, CDCl 3 ) δ4.69 (d, J = 3.7Hz, 1H), 4.44-4.37 (m, 1H), 4.19-4.01 (m, 4H), 2.58-2.49 (m, 2H), 2.31-2.23 (m, 1H), 2.12–1.99 (m, 2H), 1.61–1.50 (m, 4H), 1.46 (s, 9H), 1.45 (s, 9H), 1.42 (s, 3H), 1.37 ( s,3H).MS(m/z):535.3[M+Na] +
(6)2-O-(3-亚丙基-环丁烷-1,1-二甲酸)L-抗坏血酸的制备(6) Preparation of 2-O-(3-propylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid
Figure PCTCN2019084838-appb-000065
Figure PCTCN2019084838-appb-000065
将5,6-O-亚异丙基-2-O-(3-亚丙基-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸(1.6g)溶解于10mL二氯甲烷中，冷却至0℃，在氮气保护下缓慢滴加三氟乙酸(5mL)。反应液缓慢升温至室温，搅拌过夜。待反应完成后，反应液经减压浓缩，冷冻干燥后得到无色粘稠状液体1.0g，粗产品直接用于下步反应。Dissolve 5,6-O-isopropylidene-2-O-(3-propylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid (1.6 g) in 10 mL of dichloro In methane, it was cooled to 0 ° C, and trifluoroacetic acid (5 mL) was slowly added dropwise under nitrogen. The reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and then evaporated to dryness to yield 1.0 g of colorless viscous liquid.
MS(m/z)：383.2[M+Na] + MS (m/z): 383.2 [M+Na] +
(7)二氨基铂(II)【3-亚丙基-(2-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备(7) Preparation of diaminoplatinum(II) [3-propylene-(2-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000066
Figure PCTCN2019084838-appb-000066
将2-O-(3-亚丙基-环丁烷-1,1-二甲酸)L-抗坏血酸粗产品(1.0g)溶解于10mL水中，加入饱和氢氧化钡溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将二胺硫酸铂(1.0g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.9g最终产品，白色固体。2-O-(3-propylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid crude product (1.0 g) was dissolved in 10 mL of water, and a saturated cesium hydroxide solution was added to adjust the pH of the reaction solution to 7, Stir at room temperature for 30 minutes. Platinum diamine sulfate (1.0 g) was dissolved in 2 ml of water under a nitrogen atmosphere, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-precision liquid chromatography by semi-preparation, and lyophilized using a freeze dryer to obtain 0.9 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ4.94(d,J＝1.6Hz,1H),4.18(brs,5H),4.08(td,J＝6.8,1.6Hz,1H),3.98(t,J＝6.7Hz,2H),3.75(d,J＝6.8Hz,2H),3.10(dd,J＝12.2,8.6Hz,2H),2.41(dd,J＝12.4,8.7Hz,2H),2.27-2.19(m,1H),1.68-1.57(m,2H),1.52-1.46(m,2H).MS(m/z)：610.0[M+Na] + 1 H NMR (400 MHz, D 2 O) δ 4.94 (d, J = 1.6 Hz, 1H), 4.18 (brs, 5H), 4.08 (td, J = 6.8, 1.6 Hz, 1H), 3.98 (t, J) = 6.7 Hz, 2H), 3.75 (d, J = 6.8 Hz, 2H), 3.10 (dd, J = 12.2, 8.6 Hz, 2H), 2.41 (dd, J = 12.4, 8.7 Hz, 2H), 2.27-2.19 (m, 1H), 1.68-1.57 (m, 2H), 1.52-1.46 (m, 2H). MS (m/z): 610.0 [M+Na] +
实施例8Example 8
二氨基铂(II)【3-亚丙基-(3-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of diaminoplatinum(II) [3-propylene-(3-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000067
Figure PCTCN2019084838-appb-000067
(1)5,6-O-亚异丙基-3-O-(3-亚丙基-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸的制备(1) Preparation of 5,6-O-isopropylidene-3-O-(3-propylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid
Figure PCTCN2019084838-appb-000068
Figure PCTCN2019084838-appb-000068
在室温条件下将5,6-O-亚异丙基L-抗坏血酸(1.4g)溶解于10mL二甲基亚砜中，加入碳酸氢钠(0.5g)，待反应液搅拌20分钟后，加入3-溴丙基-环丁烷-1,1-二甲酸二叔丁酯(1.6g)的二甲基亚砜溶液(5mL)，反应液升温至60℃，搅拌过夜。用TLC监测反应终点，待反应完成后，将反应液冷却至室温，向反应液中加入50mL水稀释，用1M稀盐酸中和，然后用乙酸乙酯萃取，将有机相依次用蒸馏水(1×100ml)，饱和氯化钠溶液(1×100ml)洗涤，然后用无水硫酸钠干燥，减压浓缩，得到的淡黄色油状物用硅胶柱色谱纯化(石油醚/乙酸乙酯＝5/1)，得到无色透明油状的产物1.7g。5,6-O-isopropylidene L-ascorbic acid (1.4 g) was dissolved in 10 mL of dimethyl sulfoxide at room temperature, sodium hydrogencarbonate (0.5 g) was added, and the reaction solution was stirred for 20 minutes, and then added. A solution of 3-bromopropyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (1.6 g) in dimethyl sulfoxide (5 mL) was warmed to 60 ° C and stirred overnight. The reaction end point was monitored by TLC. After the reaction was completed, the reaction liquid was cooled to room temperature, diluted with 50 mL of water, and neutralized with 1 M diluted hydrochloric acid, and then extracted with ethyl acetate. The organic phase was sequentially distilled water (1× After washing with a saturated sodium chloride solution (1×100 ml), EtOAc m. The product was obtained as a colorless transparent oil (yield: 1.7 g).
1H NMR(600MHz,CDCl 3)δ4.55(brs,1H),4.43(d,J＝5.6Hz,2H),4.27(brs,1H),4.15(t,J＝7.6Hz,1H),4.03(t,J＝7.5Hz,1H),2.53(t,J＝9.9Hz,2H),2.33-2.27(m,1H),2.06(t,J＝9.9Hz,2H),1.68–1.61(m,2H),1.53–1.47(m,2H),1.46(s,9H),1.44(s,9H),1.39(s,3H),1.37(s,3H).MS(m/z)：535.2[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ 4.55 (brs, 1H), 4.43 (d, J = 5.6 Hz, 2H), 4.27 (brs, 1H), 4.15 (t, J = 7.6 Hz, 1H), 4.03 (t, J = 7.5 Hz, 1H), 2.53 (t, J = 9.9 Hz, 2H), 2.33 - 2.27 (m, 1H), 2.06 (t, J = 9.9 Hz, 2H), 1.68 - 1.61 (m, 2H), 1.53–1.47 (m, 2H), 1.46 (s, 9H), 1.44 (s, 9H), 1.39 (s, 3H), 1.37 (s, 3H). MS (m/z): 535.2 [M +Na] +
(2)3-O-(3-亚丙基-环丁烷-1,1-二甲酸)L-抗坏血酸的制备(2) Preparation of 3-O-(3-propylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid
Figure PCTCN2019084838-appb-000069
Figure PCTCN2019084838-appb-000069
将5,6-O-亚异丙基-3-O-(3-亚丙基-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸(1.7g)溶解于15mL二氯甲烷中，冷却至0℃，在氮气保护下缓慢滴加三氟乙酸(5mL)。反应液缓慢升温至室温，搅拌过夜。待反应完成后，反应液经减压浓缩，冷冻干燥后得到无色粘稠状液体1.1g，粗产品直接用于下步反应。Dissolve 5,6-O-isopropylidene-3-O-(3-propylene-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid (1.7 g) in 15 mL of dichloro In methane, it was cooled to 0 ° C, and trifluoroacetic acid (5 mL) was slowly added dropwise under nitrogen. The reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and then evaporated to dryness to yield 1.1 g of colorless viscous liquid.
MS(m/z)：383.2[M+Na] + MS (m/z): 383.2 [M+Na] +
(3)二氨基铂(II)【3-亚丙基-(3-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备(3) Preparation of diaminoplatinum(II) [3-propylene-(3-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000070
Figure PCTCN2019084838-appb-000070
将3-O-(3-亚丙基-环丁烷-1,1-二甲酸)L-抗坏血酸粗产品(1.1g)溶解于10mL水中，加入饱和氢氧化钡溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将二胺硫酸铂(1.0g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.9g最终产品，白色固体。3-O-(3-propylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid crude product (1.1 g) was dissolved in 10 mL of water, and a saturated cesium hydroxide solution was added to adjust the pH of the reaction solution to 7, Stir at room temperature for 30 minutes. Platinum diamine sulfate (1.0 g) was dissolved in 2 ml of water under a nitrogen atmosphere, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-precision liquid chromatography by semi-preparation, and lyophilized using a freeze dryer to obtain 0.9 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ4.93(d,J＝1.8Hz,1H),4.60–4.45(m,2H),4.18(brs,5H),4.03(td,J＝7.0,1.7Hz,1H),3.81–3.69(m,2H),3.14-3.09(m,2H),2.48–2.38(m,2H),2.30-2.22(m,1H),1.79–1.66(m,2H),1.53(q,J＝7.3Hz,2H).MS(m/z)：610.0[M+Na] + 1 H NMR (400 MHz, D 2 O) δ 4.93 (d, J = 1.8 Hz, 1H), 4.60 - 4.45 (m, 2H), 4.18 (brs, 5H), 4.03 (td, J = 7.0, 1.7 Hz , 1H), 3.81–3.69 (m, 2H), 3.14–3.09 (m, 2H), 2.48–2.38 (m, 2H), 2.30-2.22 (m, 1H), 1.79–1.66 (m, 2H), 1.53 (q, J = 7.3 Hz, 2H). MS (m / z): 610.0 [M + Na] +
实施例9Example 9
二氨基铂(II)【3-丙酸酯-(6-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of diaminoplatinum(II) [3-propionate-(6-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000071
Figure PCTCN2019084838-appb-000071
(1)3-丙酸-环丁烷-1,1-二甲酸二叔丁酯的制备(1) Preparation of 3-propionic acid-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester
Figure PCTCN2019084838-appb-000072
Figure PCTCN2019084838-appb-000072
将3-羟丙基-环丁烷-1,1-二甲酸二叔丁基酯(1.4g)溶解于10mL丙酮中，冰浴条件下缓慢滴加琼斯试剂(三氧化铬669mg，浓硫酸576μL，加水稀释至2.5mL)，反应液缓慢升温至室温，搅拌2小时，用TLC监测反应，待反应结束后，滴加异丙醇除去过量的氧化剂。反应液抽滤，减压浓缩滤液，得到的绿色油状物。油状物用水稀释，乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥，减压浓缩，得到类白色固体1.3g，粗产品直接用于下步反应。MS(m/z)：351.2[M+Na] + Dissolve 3-hydroxypropyl-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (1.4g) in 10mL of acetone, and slowly add Jones reagent (chromium trioxide 669mg, concentrated sulfuric acid 576μL) under ice bath conditions. Dilute to 2.5 mL with water, the reaction solution was slowly warmed to room temperature, stirred for 2 hours, and the reaction was monitored by TLC. After the reaction was completed, isopropyl alcohol was added dropwise to remove excess oxidizing agent. The reaction mixture was suction filtered, and the filtrate was evaporated. The oil was diluted with water, EtOAc (EtOAc)EtOAc. MS (m/z): 351.2 [M+Na] +
(2)2-O-苄基-3-O-苄基-6-O-(3-丙酸酯-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸的制备(2) Preparation of 2-O-benzyl-3-O-benzyl-6-O-(3-propionate-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid
Figure PCTCN2019084838-appb-000073
Figure PCTCN2019084838-appb-000073
将3-丙酸-环丁烷-1,1-二甲酸二叔丁酯(1.3g)溶解于10mL二氯甲烷中，加入二环己基碳二亚胺(1.2g)，催化量4-二甲氨基吡啶，待反应液搅拌0.5小时后，缓慢滴加2-O-苄基-3-O-苄基-L-抗坏血酸(2.1g)的二氯甲烷溶液(5mL)，反应液室温下搅拌过夜。TLC监测反应，待反应结束后，抽滤，滤液减压浓缩，得到的黄色油状物，硅胶柱层析纯化(石油醚/乙酸乙酯＝7/1)，得到类白色固体产物2.0g。Dissolving 3-propionic acid-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester (1.3 g) in 10 mL of dichloromethane, adding dicyclohexylcarbodiimide (1.2 g), catalytic amount 4-di Methylaminopyridine. After the reaction solution was stirred for 0.5 hours, a solution of 2-O-benzyl-3-O-benzyl-L-ascorbic acid (2.1 g) in dichloromethane (5 mL) was slowly added dropwise, and the mixture was stirred at room temperature. overnight. The reaction was monitored by TLC. After the reaction was completed, filtered, and the filtrate was evaporated. mjjjjjjjjj
1H NMR(600MHz,CDCl 3)δ7.45–7.33(m,8H),7.25–7.19(m,2H),5.24–5.07(m,4H),4.66(brs,1H),4.25(ddd,J＝16.4,11.6,5.9Hz,2H),4.05(brs,1H),2.51(t,J＝9.0Hz,2H),2.31–2.22(m,3H),2.06(t,J＝9.9Hz,2H),1.72(q,J＝7.5Hz,2H),1.45(s,9H),1.44(s,9H).MS(m/z)：689.3[M+Na] + 1 H NMR (600MHz, CDCl 3 ) δ 7.45 - 7.33 (m, 8H), 7.25 - 7.19 (m, 2H), 5.24 - 5.07 (m, 4H), 4.66 (brs, 1H), 4.25 (ddd, J =16.4, 11.6, 5.9 Hz, 2H), 4.05 (brs, 1H), 2.51 (t, J = 9.0 Hz, 2H), 2.31 - 2.22 (m, 3H), 2.06 (t, J = 9.9 Hz, 2H) , 1.72 (q, J = 7.5 Hz, 2H), 1.45 (s, 9H), 1.44 (s, 9H). MS (m/z): 689.3 [M+Na] +
(3)6-O-(3-丙酸酯-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸的制备(3) Preparation of 6-O-(3-propionate-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid
Figure PCTCN2019084838-appb-000074
Figure PCTCN2019084838-appb-000074
将2-O-苄基-3-O-苄基-6-O-(3-丙酸酯-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸(2.0g)溶解在10mL乙醇中，加入5％钯碳(0.2g)，用氮气置换烧瓶内空气3次，再用氢气置换烧瓶内氮气3次，反应液在氢气加压下室温搅拌过夜。反应完成后，用氮气置换烧瓶内氢气，抽滤，滤饼用乙醇淋洗3次，滤液减压浓缩，得到无色透明油状的产物1.4g，粗产品直接用于下步反应。Dissolving 2-O-benzyl-3-O-benzyl-6-O-(3-propionate-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid (2.0 g) To 10 mL of ethanol, 5% palladium carbon (0.2 g) was added, and the air in the flask was replaced with nitrogen three times, and the nitrogen in the flask was replaced with hydrogen three times, and the reaction solution was stirred at room temperature under hydrogen pressure overnight. After completion of the reaction, the hydrogen in the flask was replaced with nitrogen, and the mixture was filtered with suction. The filter cake was rinsed with ethanol three times, and the filtrate was concentrated under reduced pressure to give a crude product (yield: 1.4 g).
MS(m/z)：509.1[M+Na] + MS (m/z): 509.1 [M+Na] +
(4)6-O-(3-丙酸酯-环丁烷-1,1-二甲酸)L-抗坏血酸的制备(4) Preparation of 6-O-(3-propionate-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid
Figure PCTCN2019084838-appb-000075
Figure PCTCN2019084838-appb-000075
将6-O-(3-丙酸酯-环丁烷-1,1-二甲酸二叔丁酯)L-抗坏血酸(1.4g)溶解于10mL二氯甲烷中，冷却至0℃，在氮气保护下缓慢滴加三氟乙酸(5mL)。反应液缓慢升温至室温，搅拌过夜。待反应完成后，用旋转蒸发仪除去溶剂，用冷冻干燥机干燥后得到无色粘稠状液体1.0g，粗产品直接用于下步反应。6-O-(3-propionate-cyclobutane-1,1-dicarboxylic acid di-tert-butyl ester) L-ascorbic acid (1.4g) was dissolved in 10mL of dichloromethane, cooled to 0 ° C, protected with nitrogen Trifluoroacetic acid (5 mL) was slowly added dropwise. The reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the solvent was removed by a rotary evaporator, and dried using a freeze dryer to obtain 1.0 g of a colorless viscous liquid, and the crude product was directly used for the next reaction.
MS(m/z)：397.1[M+Na] + MS (m/z): 397.1 [M+Na] +
(5)二氨基铂(II)【3-丙酸酯-(6-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备(5) Preparation of diaminoplatinum(II) [3-propionate-(6-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000076
Figure PCTCN2019084838-appb-000076
将6-O-(3-丙酸酯-环丁烷-1,1-二甲酸)-L-抗坏血酸粗产品(1.0g)溶解于10mL水中，加入饱和氢氧化钡溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将环己二胺硫酸铂(0.8g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.7g最终产品，白色固体。6-O-(3-propionate-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid crude product (1.0g) was dissolved in 10mL of water, and the saturated solution of cesium hydroxide was added to adjust the pH of the reaction solution to 7 Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (0.8 g) was dissolved in 2 ml of water, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.7 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ4.83(d,J＝1.6Hz,1H),4.35–4.24(m,3H),4.18(brs,5H),3.10(dd,J＝12.2,8.6Hz,2H),2.49–2.36(m,4H),2.27-2.19(m,1H),1.75(q,J＝7.4Hz,2H).MS(m/z)：624.1[M+Na] + 1 H NMR (400 MHz, D 2 O) δ 4.83 (d, J = 1.6 Hz, 1H), 4.35 - 4.24 (m, 3H), 4.18 (brs, 5H), 3.10 (dd, J = 12.2, 8.6 Hz , 2H), 2.49 - 2.36 (m, 4H), 2.27-2.19 (m, 1H), 1.75 (q, J = 7.4 Hz, 2H). MS (m/z): 624.1 [M+Na] +
实施例10Example 10
顺-【反式-(1R，2R)-二氨基环己烷】铂(II)【3-亚甲基-(2-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-methylene-(2-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000077
Figure PCTCN2019084838-appb-000077
将2-O-(3-亚甲基-环丁烷-1,1-二甲酸)-L-抗坏血酸粗产品(0.4g)溶解于10mL水中，加入氢氧化钡饱和溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将环己二胺硫酸铂(0.5g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡饱和溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.4g最终产品，白色固体。The crude 2-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid (0.4g) was dissolved in 10mL of water, and the pH of the reaction solution was adjusted to 7 by adding a saturated solution of cesium hydroxide. Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (0.5 g) was dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with a saturated solution of cesium hydroxide, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.4 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ5.75(brs,2H),5.03(brs,2H),4.94(d,J＝1.7Hz,1H),4.07(td,J＝6.7,1.6Hz,1H),3.97(d,J＝6.1Hz,2H),3.74(d,J＝6.7Hz,2H),3.11-3.07(m,2H),2.70–2.58(m,3H),2.43-2.33(m,2H),1.99(d,J＝12.0Hz,2H),1.53(d,J＝8.4Hz,2H),1.30–1.17(m,2H),1.16–1.03(m,2H).MS(m/z)：638.0[M-H] - 1 H NMR (400 MHz, D 2 O) δ 5.75 (brs, 2H), 5.03 (brs, 2H), 4.94 (d, J = 1.7 Hz, 1H), 4.07 (td, J = 6.7, 1.6 Hz, 1H) ), 3.97 (d, J = 6.1 Hz, 2H), 3.74 (d, J = 6.7 Hz, 2H), 3.11-3.07 (m, 2H), 2.70 - 2.58 (m, 3H), 2.43 - 2.33 (m, 2H), 1.99 (d, J = 12.0 Hz, 2H), 1.53 (d, J = 8.4 Hz, 2H), 1.30 - 1.17 (m, 2H), 1.16 - 1.03 (m, 2H). MS (m/z ): 638.0 [MH] -
实施例11Example 11
顺-【反式-(1R，2R)-二氨基环己烷】铂(II)【3-亚甲基-(3-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-methylene-(3-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000078
Figure PCTCN2019084838-appb-000078
将3-O-(3-亚甲基-环丁烷-1,1-二甲酸)L-抗坏血酸粗产品(0.5g)溶解于10mL水中，加入氢 氧化钡饱和溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将环己二胺硫酸铂(0.6g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡饱和溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.5g最终产品，白色固体。3-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid crude product (0.5 g) was dissolved in 10 mL of water, and a saturated solution of cesium hydroxide was added to adjust the pH of the reaction solution to 7, Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (0.6 g) was dissolved in 2 ml of water, added to the above reaction solution, and the pH was adjusted to 7 with a saturated solution of cesium hydroxide, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-pressure liquid chromatography by semi-preparation and lyophilized using a freeze dryer to obtain 0.5 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ5.75(brs,1H),5.07(brs,1H),4.95(brs,1H),4.57-4.49(m,2H),4.04(t,J＝5.7Hz,1H),3.80–3.68(m,2H),3.21–3.01(m,2H),2.79-2.71(m,3H),2.38(d,J＝8.7Hz,2H),2.03(d,J＝11.1Hz,2H),1.57(d,J＝6.6Hz,2H),1.36–1.21(m,2H),1.13(brs,2H).MS(m/z)：662.0[M+Na] + 1 H NMR (400 MHz, D 2 O) δ 5.75 (brs, 1H), 5.07 (brs, 1H), 4.95 (brs, 1H), 4.57-4.49 (m, 2H), 4.04 (t, J = 5.7 Hz , 1H), 3.80–3.68 (m, 2H), 3.21–3.01 (m, 2H), 2.79-2.71 (m, 3H), 2.38 (d, J=8.7 Hz, 2H), 2.03 (d, J=11.1) Hz, 2H), 1.57 (d, J = 6.6 Hz, 2H), 1.36 - 1.21 (m, 2H), 1.13 (brs, 2H). MS (m/z): 662.0 [M+Na] +
实施例12Example 12
顺-【反式-(1R，2R)-二氨基环己烷】铂(II)【3-甲酸酯-(6-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-formate-(6-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000079
Figure PCTCN2019084838-appb-000079
将6-O-(3-甲酸酯-环丁烷-1,1-二甲酸)-L-抗坏血酸粗产品(0.5g)溶解于10mL水中，加入饱和氢氧化钡溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将环己二胺硫酸铂(0.54g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.5g最终产品，白色固体。The 6-O-(3-formate-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid crude product (0.5g) was dissolved in 10mL of water, and the saturated solution of cesium hydroxide was added to adjust the pH of the reaction solution to 7 Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (0.54 g) was dissolved in 2 ml of water, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-pressure liquid chromatography by semi-preparation and lyophilized using a freeze dryer to obtain 0.5 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ5.74(brs,2H),5.08(brs,2H),4.86(d,J＝1.9Hz,1H),4.38–4.21(m,3H),3.28–3.14(m,3H),3.11–3.03(m,2H),2.38(brs,2H),2.01(d,J＝12.0Hz,2H),1.54(d,J＝8.4Hz,2H),1.31–1.21(m,2H),1.16-1.08(m,2H).MS(m/z)：676.0[M+Na] + 1 H NMR (400 MHz, D 2 O) δ 5.74 (brs, 2H), 5.08 (brs, 2H), 4.86 (d, J = 1.9 Hz, 1H), 4.38 - 4.21 (m, 3H), 3.28 - 3.14 (m, 3H), 3.11–3.03 (m, 2H), 2.38 (brs, 2H), 2.01 (d, J = 12.0 Hz, 2H), 1.54 (d, J = 8.4 Hz, 2H), 1.31–1.21 ( m, 2H), 1.16-1.08 (m, 2H). MS (m / z): 676.0 [M + Na] +
实施例13Example 13
顺-【反式-(1R，2R)-二氨基环己烷】铂(II)【3-亚乙基-(2-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-ethylidene-(2-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000080
Figure PCTCN2019084838-appb-000080
将2-O-(3-亚乙基-环丁烷-1,1-二甲酸)-L-抗坏血酸粗产品(0.8g)溶解于10mL水中，加入氢氧化钡饱和溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将环己二胺硫酸铂(0.9g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡饱和溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.8g最终产品，白色固体。The 2-O-(3-ethylene-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid crude product (0.8 g) was dissolved in 10 mL of water, and a saturated solution of cesium hydroxide was added to adjust the pH of the reaction solution to 7 Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (0.9 g) was dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with a saturated solution of cesium hydroxide, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.8 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ5.76(brs,2H),5.04(brs,2H),4.93(d,J＝1.2Hz,1H),4.08(td,J＝6.7,1.5Hz,1H),3.98(t,J＝6.6Hz,2H),3.75(d,J＝6.7Hz,2H),3.19-3.10(m,2H),2.53–2.33(m,5H),2.01(d,J＝11.7Hz,2H),1.81(d,J＝6.7Hz,2H),1.55(d,J＝7.9Hz,2H),1.31–1.06(m,4H). 1 H NMR (400 MHz, D 2 O) δ 5.76 (brs, 2H), 5.04 (brs, 2H), 4.93 (d, J = 1.2 Hz, 1H), 4.08 (td, J = 6.7, 1.5 Hz, 1H) ), 3.98 (t, J = 6.6 Hz, 2H), 3.75 (d, J = 6.7 Hz, 2H), 3.19 - 3.10 (m, 2H), 2.53 - 2.33 (m, 5H), 2.01 (d, J = 11.7 Hz, 2H), 1.81 (d, J = 6.7 Hz, 2H), 1.55 (d, J = 7.9 Hz, 2H), 1.31 - 1.06 (m, 4H).
MS(m/z)：676.1[M+Na] + MS (m/z): 676.1 [M+Na] +
实施例14Example 14
顺-【反式-(1R，2R)-二氨基环己烷】铂(II)【3-亚乙基-(3-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-ethylidene-(3-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000081
Figure PCTCN2019084838-appb-000081
将3-O-(3-亚乙基-环丁烷-1,1-二甲酸)-L-抗坏血酸粗产品(1.0g)溶解于10mL水中，加入氢氧化钡饱和调节反应液pH到7，室温搅拌30分钟。在氮气保护下将环己二胺硫酸铂(1.2g)溶解溶液于2ml水中，加入到上述反应液中，用氢氧化钡饱和溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.9g最终产品，白色固体。The crude 3-O-(3-ethylene-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid (1.0 g) was dissolved in 10 mL of water, and the pH of the reaction solution was adjusted to 7 by adding cesium hydroxide. Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (1.2 g) was dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with a saturated solution of cesium hydroxide, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-precision liquid chromatography by semi-preparation, and lyophilized using a freeze dryer to obtain 0.9 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ5.75(brs,1H),5.04(brs,1H),4.94(d,J＝1.6Hz,1H),4.59-4.47(m,2H),4.07–4.02(m,1H),3.77–3.71(m,2H),3.21–3.09(m,2H),2.57–2.47(m,2H),2.44-2.38(m,3H),2.02(d,J＝11.7Hz,2H),1.90(q,J＝6.3Hz,2H)1.56(d,J＝6.0Hz,2H),1.28-1.23(m,2H),1.12(brs,2H). 1 H NMR (400 MHz, D 2 O) δ 5.75 (brs, 1H), 5.04 (brs, 1H), 4.94 (d, J = 1.6 Hz, 1H), 4.59 - 4.47 (m, 2H), 4.07 - 4.02 (m,1H), 3.77–3.71 (m, 2H), 3.21–3.09 (m, 2H), 2.57–2.47 (m, 2H), 2.44–2.38 (m, 3H), 2.02 (d, J=11.7 Hz) , 2H), 1.90 (q, J = 6.3 Hz, 2H) 1.56 (d, J = 6.0 Hz, 2H), 1.28-1.23 (m, 2H), 1.12 (brs, 2H).
MS(m/z)：676.1[M+Na] + MS (m/z): 676.1 [M+Na] +
实施例15Example 15
顺-【反式-(1R，2R)-二氨基环己烷】铂(II)【3-乙酸酯-(6-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-acetate-(6-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000082
Figure PCTCN2019084838-appb-000082
将6-O-(3-乙酸酯-环丁烷-1,1-二甲酸)-L-抗坏血酸粗产品(0.8g)溶解于10mL水中，加入饱和氢氧化钡溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将环己二胺硫酸铂(0.9g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.7g最终产品，白色固体。The 6-O-(3-acetate-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid crude product (0.8 g) was dissolved in 10 mL of water, and a saturated cesium hydroxide solution was added to adjust the pH of the reaction solution to 7 Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (0.9 g) was dissolved in 2 ml of water, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by a semi-preparative high-pressure liquid chromatography, and lyophilized using a freeze dryer to obtain 0.7 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ5.74(brs,2H),5.03(brs,2H),4.91(d,J＝1.9Hz,1H),4.41–4.21(m,3H),3.23-3.12(m,2H),2.59-2.52(m,5H),2.36(brs,2H),2.00(d,J＝9.7Hz,2H),1.54(brs, 2H),1.27-1.19(m,2H),1.14-1.10(m,2H).MS(m/z)：690.1[M+Na] + 1 H NMR (400MHz, D 2 O) δ5.74 (brs, 2H), 5.03 (brs, 2H), 4.91 (d, J = 1.9Hz, 1H), 4.41-4.21 (m, 3H), 3.23-3.12 (m, 2H), 2.59-2.52 (m, 5H), 2.36 (brs, 2H), 2.00 (d, J = 9.7 Hz, 2H), 1.54 (brs, 2H), 1.27-1.19 (m, 2H), 1.14-1.10(m,2H).MS(m/z):690.1[M+Na] +
实施例16Example 16
顺-【反式-(1R，2R)-二氨基环己烷】铂(II)【3-亚丙基-(2-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-propylene-(2-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000083
Figure PCTCN2019084838-appb-000083
将2-O-(3-亚丙基-环丁烷-1,1-二甲酸)-L-抗坏血酸粗产品(1.0g)溶解于10mL水中，加入饱和氢氧化钡溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将环己二胺硫酸铂(1.2g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到1.0g最终产品，白色固体。Dissolve 2-O-(3-propylene-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid crude product (1.0g) in 10mL water, and add saturated cesium hydroxide solution to adjust the pH of the reaction solution to 7 Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (1.2 g) was dissolved in 2 ml of water, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After completion of the reaction, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-pressure liquid chromatography by semi-preparation and lyophilized using a freeze dryer to obtain 1.0 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ5.73(brs,1H),5.05(brs,1H),4.93(brs,1H),4.08(td,J＝6.7,1.5Hz,1H),3.98(t,J＝6.7Hz,2H),3.75(d,J＝6.8Hz,2H),),3.12-3.07(m,2H),2.44-2.39(m,4H),2.27-2.19(m,1H),2.03(d,J＝11.3Hz,2H),1.69–1.42(m,6H),1.26(brs,2H),1.20–1.06(m,2H).MS(m/z)：690.0[M+Na] + 1 H NMR (400MHz, D 2 O) δ5.73 (brs, 1H), 5.05 (brs, 1H), 4.93 (brs, 1H), 4.08 (td, J = 6.7,1.5Hz, 1H), 3.98 (t , J = 6.7 Hz, 2H), 3.75 (d, J = 6.8 Hz, 2H), ), 3.12-3.07 (m, 2H), 2.44 - 2.39 (m, 4H), 2.27-2.19 (m, 1H), 2.03 (d, J = 11.3 Hz, 2H), 1.69 - 1.42 (m, 6H), 1.26 (brs, 2H), 1.20 - 1.06 (m, 2H). MS (m/z): 690.0 [M+Na] +
实施例17Example 17
顺-【反式-(1R，2R)-二氨基环己烷】铂(II)【3-亚丙基-(3-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-propylene-(3-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000084
Figure PCTCN2019084838-appb-000084
将3-O-(3-亚甲基-环丁烷-1,1-二甲酸)-L-抗坏血酸粗产品(1.1g)溶解于10mL水中，加入饱和氢氧化钡溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将环己二胺硫酸铂(1.2g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到1.0g最终产品，白色固体。Dissolve 3-O-(3-methylene-cyclobutane-1,1-dicarboxylic acid)-L-ascorbic acid crude product (1.1g) in 10mL water, and add saturated cesium hydroxide solution to adjust the pH of the reaction solution to 7 Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (1.2 g) was dissolved in 2 ml of water, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After completion of the reaction, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-pressure liquid chromatography by semi-preparation and lyophilized using a freeze dryer to obtain 1.0 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ5.79(brs,2H),5.03(brs,2H),4.95(d,J＝1.7Hz,1H),4.60–4.47(m,2H),4.09–4.00(m,1H),3.75(d,J＝6.8Hz,2H),3.17-3.08(m,2H),2.51–2.35(m,4H),2.31-2.22(m,1H),2.02(d,J＝11.5Hz,2H),1.79–1.66(m,2H),1.55(d,J＝6.1Hz,4H),1.24(brs,2H),1.14-1.09(m,2H).MS(m/z)：690.0[M+Na] + 1 H NMR (400 MHz, D 2 O) δ 5.79 (brs, 2H), 5.03 (brs, 2H), 4.95 (d, J = 1.7 Hz, 1H), 4.60 - 4.47 (m, 2H), 4.09 - 4.00 (m, 1H), 3.75 (d, J = 6.8 Hz, 2H), 3.17 - 3.08 (m, 2H), 2.51 - 2.35 (m, 4H), 2.31-2.22 (m, 1H), 2.02 (d, J =11.5 Hz, 2H), 1.79–1.66 (m, 2H), 1.55 (d, J=6.1 Hz, 4H), 1.24 (brs, 2H), 1.14-1.09 (m, 2H). MS (m/z) :690.0[M+Na] +
实施例18Example 18
顺-【反式-(1R，2R)-二氨基环己烷】铂(II)【3-丙酸酯-(6-O-L-抗坏血酸)环丁烷-1,1-二甲酸】的制备Preparation of cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-propionate-(6-O-L-ascorbic acid)cyclobutane-1,1-dicarboxylic acid]
Figure PCTCN2019084838-appb-000085
Figure PCTCN2019084838-appb-000085
将6-O-(3-丙酸酯-环丁烷-1,1-二甲酸)L-抗坏血酸粗产品(1.0g)溶解于10mL水中，加入饱和氢氧化钡溶液调节反应液pH到7，室温搅拌30分钟。在氮气保护下将环己二胺硫酸铂(1.1g)溶解于2ml水中，加入到上述反应液中，用氢氧化钡溶液调节pH到7，室温避光搅拌3小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相色谱分离并使用冷冻干燥机冻干得到0.9g最终产品，白色固体。6-O-(3-propionate-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid crude product (1.0 g) was dissolved in 10 mL of water, and a saturated cesium hydroxide solution was added to adjust the pH of the reaction solution to 7, Stir at room temperature for 30 minutes. Under a nitrogen atmosphere, cyclohexylamine platinum sulfate (1.1 g) was dissolved in 2 ml of water, added to the above reaction solution, and the pH was adjusted to 7 with a cesium hydroxide solution, and stirred at room temperature for 3 hours in the dark. The reaction was detected by HPLC. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, separated by high-precision liquid chromatography by semi-preparation, and lyophilized using a freeze dryer to obtain 0.9 g of a final product, a white solid.
1H NMR(400MHz,D 2O)δ5.74(brs,2H),5.03(brs,2H),4.91(d,J＝1.9Hz,1H),4.41–4.21(m,3H),3.23-3.12(m,2H),2.59-2.52(m,5H),2.36(brs,2H),2.00(d,J＝9.7Hz,2H),1.75(q,J＝7.4Hz,2H),1.54(brs,2H),1.27-1.19(m,2H),1.14-1.10(m,2H).MS(m/z)：704.1[M+Na] + 1 H NMR (400MHz, D 2 O) δ5.74 (brs, 2H), 5.03 (brs, 2H), 4.91 (d, J = 1.9Hz, 1H), 4.41-4.21 (m, 3H), 3.23-3.12 (m, 2H), 2.59-2.52 (m, 5H), 2.36 (brs, 2H), 2.00 (d, J = 9.7 Hz, 2H), 1.75 (q, J = 7.4 Hz, 2H), 1.54 (brs, 2H), 1.27-1.19 (m, 2H), 1.14-1.10 (m, 2H). MS (m/z): 704.1 [M+Na] +
试验例1溶解度试验Test Example 1 Solubility Test
实验方法：用5mL的EP管取大约0.5mL蒸馏水，慢慢加入干燥的化合物至不能溶解(25℃超声震荡，仍出现浑浊)。将溶液过滤至另一个5mL干净且已称重的EP管中，再称重，计算出溶液的重量。将滤液冻干，称重并计算出所剩固体的溶质质量，这样就可以知道溶剂的重量和溶质的质量，从而计算出化合物在水中的溶解度。Experimental method: About 0.5 mL of distilled water was taken with a 5 mL EP tube, and the dried compound was slowly added until it could not be dissolved (ultrasonic oscillation at 25 ° C, and turbidity still occurred). The solution was filtered into another 5 mL clean and weighed EP tube and weighed to calculate the weight of the solution. The filtrate was lyophilized, weighed and the mass of the solute of the remaining solid was calculated, so that the weight of the solvent and the mass of the solute were known, thereby calculating the solubility of the compound in water.
表2实施例样品在水中的溶解度数据Table 2 Example Sample Solubility Data in Water
化合物Compound 溶解度(mg/mL)Solubility (mg/mL) 化合物Compound 溶解度(mg/mL)Solubility (mg/mL)
11 1332.91332.9 1010 395.4395.4
22 1292.51292.5 1111 298.1298.1
33 1500.01500.0 1212 580.6580.6
44 978.0978.0 1313 544.8544.8
55 1005.21005.2 1414 240.9240.9
66 1395.11395.1 1515 517.4517.4
77 1100.01100.0 1616 228.3228.3
88 1155.81155.8 1717 205.6205.6
99 1320.51320.5 1818 540.3540.3
顺铂Cisplatin 1.01.0 卡铂Carboplatin 17.017.0
奥沙利铂Oxaliplatin 6.06.0    
本发明铂类配合物在水中的溶解度远远大于已经上市的顺铂、卡铂和奥沙利铂，水溶性能够提高几十至上千倍。The solubility of the platinum complex of the present invention in water is much greater than that of cisplatin, carboplatin and oxaliplatin which have been marketed, and the water solubility can be increased by several tens to several thousand times.
试验例2Test example 2
以下实验针对本发明的用于肿瘤治疗的维生素C偶联铂配合物对不同种类的人肿瘤细胞的增殖抑制效果进行了实验验证。The following experiment was conducted to experimentally verify the proliferation inhibitory effect of the vitamin C-conjugated platinum complex for tumor treatment of the present invention on different kinds of human tumor cells.
(1)试验方法：(1) Test method:
细胞培养液：Cell culture fluid:
使用含有10％胎牛血清(fetal bovine serum)的细胞培养液。A cell culture medium containing 10% fetal bovine serum was used.
主要实验仪器：Main experimental instruments:
HERAcell150i型二氧化碳培养箱(Thermo)、研究级倒置荧光显微镜(Nikon,日本)、多功能酶标仪(Thermo)、超低温冰箱(Thermo)、生物安全柜(1300 Series A2,Thermo)、微量移液器(德国eppendorf)、超纯水系统(美国Milli-Q)。HERAcell150i carbon dioxide incubator (Thermo), research-grade inverted fluorescence microscope (Nikon, Japan), multi-function microplate reader (Thermo), ultra-low temperature refrigerator (Thermo), biosafety cabinet (1300 Series A2, Thermo), micropipette (Eppendorf, Germany), ultrapure water system (Milli-Q, USA).
实验试剂：Experimental reagents:
MTT:Sigma-Aldrich公司MTT: Sigma-Aldrich
DMSO:天津市江天化工技术有限公司DMSO: Tianjin Jiangtian Chemical Technology Co., Ltd.
肿瘤细胞：Tumor cells:
表3 MTT试验细胞列表Table 3 MTT test cell list
细胞编号Cell number 细胞类型Cell type
HT29HT29 人结肠癌细胞Human colon cancer cells
A549A549 人非小细胞肺癌细胞Human non-small cell lung cancer cells
SMMC7721SMMC7721 人肝癌细胞Human hepatoma cell
MCF-7MCF-7 人乳腺癌细胞Human breast cancer cell
SKOV3SKOV3 人卵巢癌细胞Human ovarian cancer cell
ECA109ECA109 人食管癌细胞Human esophageal cancer cells
DU145DU145 人前列腺癌细胞Human prostate cancer cell
HelaHela 人宫颈癌细胞Human cervical cancer cells
A375A375 人黑色素瘤细胞Human melanoma cell
KBKB 人口腔表皮样癌细胞Human oral epidermoid carcinoma cells
HGC27HGC27 人胃癌细胞Human gastric cancer cell
SW579SW579 人甲状腺癌细胞Human thyroid cancer cell
56375637 人膀胱癌细胞Human bladder cancer cell
Panc-1Panc-1 人胰腺癌细胞Human pancreatic cancer cell
H460H460 人大细胞肺癌细胞Human large cell lung cancer cells
H929H929 人浆细胞白血病细胞Human plasma cell leukemia cell
HepG2HepG2 人肝癌细胞Human hepatoma cell
THP-1THP-1 人单核细胞白血病Human monocytic leukemia
细胞毒性测试：Cytotoxicity test:
细胞毒性实验采用MTT法测试。收集对数期肿瘤细胞，调整细胞悬液浓度，每孔加入100μl，铺板调整待测细胞密度至1000-10000个/孔，(边缘孔用无菌PBS填充)。在5％CO 2，37℃孵育，至细胞贴壁(96孔平底板)，加入不同浓度梯度的药物，每孔100μl，设4个复孔。在5％CO 2，37℃条件下孵育72小时，倒置显微镜下观察。向96孔板中加入配制好的MTT溶液(5mg/ml), 每孔20μl，混匀，在37℃，5％CO 2条件下孵育4h后，弃掉板内液体，每孔加入150μl DMSO，酶标仪振荡3分钟，在490nm处检测OD值(光密度值)。 The cytotoxicity test was tested by the MTT method. The log phase tumor cells were collected, the cell suspension concentration was adjusted, 100 μl was added to each well, and the density of the cells to be tested was adjusted to 1000-10000 cells/well (the edge cells were filled with sterile PBS). Incubate at 5% CO 2 at 37 ° C until cell attachment (96-well flat bottom plate), add drugs of different concentration gradients, 100 μl per well, and set 4 replicate wells. Incubate for 72 hours at 5% CO 2 at 37 ° C and observe under an inverted microscope. Add 96 ml of the prepared MTT solution (5 mg/ml) to a 96-well plate, mix well, and incubate for 4 h at 37 ° C, 5% CO 2 , discard the liquid in the plate, and add 150 μl of DMSO to each well. The plate reader was shaken for 3 minutes, and the OD value (optical density value) was detected at 490 nm.
对照组：Control group:
在上述同样条件下不添加被测活性成分，最后取得肿瘤细胞在490nm处检测OD值。Under the same conditions as above, the active ingredient to be tested was not added, and finally the tumor cells were obtained to detect the OD value at 490 nm.
药物对肿瘤细胞的抑制活性IC 50： Inhibitory activity of drugs on tumor cells IC 50 :
细胞抑制率计算：按下列公式计算药物对肿瘤细胞生长的抑制率：Calculation of cell inhibition rate: Calculate the inhibition rate of drug growth on tumor cells according to the following formula:
1)细胞存活率(％)＝(治疗组OD值/对照组OD值)×1001) Cell viability (%) = (treatment group OD value / control group OD value) × 100
2)求出各药物浓度下的细胞存活率，用此对药物浓度作图。以此判断不同药物浓度对肿瘤细胞增殖抑制的药效。2) Determine the cell viability at each drug concentration and use this to plot the drug concentration. In this way, the efficacy of different drug concentrations on tumor cell proliferation inhibition was judged.
3)细胞存活率为对照组的50％时所对应的药物浓度，为药物对肿瘤细胞的半数抑制浓度，即药物的IC 50值。 3) The cell survival rate is 50% of the control group, and the drug concentration is the half inhibitory concentration of the drug on the tumor cells, that is, the IC 50 value of the drug.
上述每个药物浓度的实验重复4组，取平均OD值计算细胞存活率。The above experiments for each drug concentration were repeated in groups of 4, and the average OD value was taken to calculate the cell survival rate.
(2)实验结果：(2) Experimental results:
表4 MTT试验结果(一)Table 4 MTT test results (1)
IC 50(μM) IC 50 (μM) 11 22 33 44 55 66 77 88 99 卡铂Carboplatin
HT29HT29 20.8020.80 10.0510.05 35.6235.62 40.6140.61 24.2324.23 9.279.27 9.219.21 20.1420.14 18.4818.48 53.2053.20
SMMC7721SMMC7721 6.326.32 2.192.19 9.029.02 10.7410.74 6.446.44 2.182.18 2.092.09 5.165.16 6.156.15 12.0312.03
MCF-7MCF-7 101.12101.12 55.8155.81 162.38162.38 172.64172.64 65.1265.12 51.2151.21 47.1547.15 82.7982.79 101.23101.23 282.81282.81
A549A549 48.2548.25 13.5013.50 80.9780.97 81.4481.44 41.0141.01 15.1915.19 13.6613.66 38.5938.59 42.6842.68 95.2695.26
SKOV3SKOV3 153.42153.42 53.7253.72 243.73243.73 231.20231.20 148.37148.37 61.2961.29 53.4253.42 107.72107.72 123.65123.65 318.37318.37
ECA109ECA109 13.1313.13 4.954.95 18.3918.39 20.8820.88 10.8910.89 4.574.57 5.155.15 12.6712.67 9.989.98 26.8826.88
DU145DU145 49.7949.79 24.9624.96 68.2568.25 74.6774.67 39.1539.15 26.5726.57 21.2221.22 49.4249.42 48.5648.56 135.10135.10
HelaHela 14.9514.95 6.036.03 24.9924.99 24.2224.22 15.1615.16 6.066.06 6.676.67 12.7612.76 11.7911.79 34.1334.13
A375A375 11.4211.42 5.735.73 20.6720.67 22.2222.22 12.2512.25 5.715.71 5.325.32 12.6312.63 11.7411.74 31.2431.24
KBKB 14.3814.38 6.346.34 21.9021.90 23.0023.00 12.7812.78 6.096.09 6.556.55 14.5414.54 14.6814.68 33.5133.51
HGC27HGC27 23.3023.30 12.9412.94 42.0042.00 43.2243.22 20.8720.87 12.7612.76 12.8112.81 24.4624.46 23.9823.98 68.3168.31
SW579SW579 70.5670.56 33.4533.45 100.25100.25 112.65112.65 73.2873.28 32.2732.27 31.5631.56 80.0180.01 76.2376.23 170.46170.46
56375637 11.4511.45 5.055.05 17.7717.77 19.9819.98 10.4110.41 4.854.85 5.545.54 13.0113.01 12.1612.16 27.9027.90
Panc-1Panc-1 87.9687.96 40.2540.25 143.23143.23 150.22150.22 91.0291.02 41.8441.84 40.8440.84 87.2587.25 81.8781.87 213.94213.94
H929H929 6.366.36 4.454.45 13.1313.13 18.9318.93 9.129.12 4.134.13 3.933.93 10.0010.00 11.2311.23 23.1423.14
HepG2HepG2 17.2717.27 5.115.11 20.9920.99 21.6721.67 12.9912.99 5.875.87 5.195.19 14.3314.33 11.4711.47 29.7029.70
THP-1THP-1 3.933.93 2.942.94 11.4311.43 10.5510.55 7.777.77 2.892.89 2.542.54 7.157.15 8.128.12 15.0115.01
H460H460 10.7810.78 4.394.39 16.3316.33 17.0017.00 9.299.29 4.014.01 4.474.47 11.7611.76 11.1111.11 24.0924.09
表5 MTT试验结果(二)Table 5 MTT test results (2)
IC 50(μM) IC 50 (μM) 1010 1111 1212 1313 1414 1515 1616 1717 1818 卡铂Carboplatin
HT29HT29 30.6130.61 37.0937.09 9.159.15 12.7212.72 36.1636.16 19.919.9 8.268.26 12.4412.44 8.658.65 53.2053.20
SMMC7721SMMC7721 5.415.41 1.731.73 4.334.33 5.255.25 2.62.6 7.457.45 4.4384.438 4.324.32 4.094.09 12.0312.03
MCF-7MCF-7 48.2848.28 28.4728.47 28.7328.73 65.6365.63 32.6232.62 22.4522.45 21.3621.36 32.3232.32 17.4617.46 282.81282.81
A549A549 24.4524.45 19.5719.57 20.6820.68 18.9518.95 30.1730.17 18.8818.88 16.9216.92 34.7734.77 15.2515.25 95.2695.26
SKOV3SKOV3 104.75104.75 92.6292.62 102.71102.71 103.56103.56 102.36102.36 108.64108.64 109.32109.32 97.2997.29 92.7192.71 318.37318.37
ECA109ECA109 11.0511.05 12.0112.01 15.2715.27 15.3215.32 16.9816.98 16.8516.85 13.2513.25 15.0715.07 17.4517.45 26.8826.88
DU145DU145 59.7059.70 54.1654.16 10.2210.22 23.4423.44 33.1533.15 36.1736.17 51.0251.02 69.4269.42 28.5928.59 135.10135.10
HelaHela 24.1524.15 16.0316.03 11.1111.11 13.4513.45 20.1120.11 22.0622.06 11.6311.63 12.7112.71 11.7911.79 34.1334.13
A375A375 22.2222.22 20.7720.77 15.9015.90 20.2220.22 20.2520.25 17.7317.73 17.3217.32 17.2317.23 17.2417.24 31.2431.24
KBKB 12.5812.58 11.3411.34 12.9312.93 20.9920.99 16.7816.78 14.0914.09 10.5810.58 21.0421.04 24.6224.62 33.5133.51
HGC27HGC27 40.3940.39 32.1432.14 30.0030.00 44.3344.33 40.8440.84 35.2635.26 39.2139.21 34.4834.48 33.9833.98 68.3168.31
SW579SW579 103.22103.22 100.40100.40 103.21103.21 94.0094.00 101.11101.11 94.2494.24 105.23105.23 110.53110.53 100.88100.88 170.46170.46
56375637 11.4511.45 13.0213.02 12.1112.11 15.2215.22 11.4111.41 16.8716.87 16.5416.54 12.0112.01 15.1615.16 27.9027.90
Panc-1Panc-1 77.1677.16 58.3558.35 54.9954.99 67.3467.34 111.22111.22 134.84134.84 96.1496.14 41.2541.25 101.87101.87 213.94213.94
H929H929 3.333.33 5.635.63 3.563.56 7.887.88 12.1112.11 13.1313.13 14.2214.22 6.896.89 14.2314.23 23.1423.14
HepG2HepG2 12.2112.21 10.2110.21 18.4318.43 17.5217.52 12.5612.56 11.8711.87 20.1920.19 15.3315.33 14.4714.47 29.7029.70
THP-1THP-1 3.993.99 7.567.56 4.334.33 5.875.87 8.118.11 4.644.64 9.109.10 9.529.52 6.526.52 15.0115.01
H460H460 8.708.70 6.336.33 9.219.21 8.438.43 7.227.22 8.018.01 7.477.47 8.468.46 7.567.56 24.0924.09
本发明的维生素C偶联铂配合物具有良好的抗肿瘤活性。The vitamin C-coupled platinum complex of the present invention has good antitumor activity.

Claims (10)

  1. 一种式(I)所示的维生素C偶联铂配合物，或其光学异构体，或其药学上可接受的盐，或其溶剂化物：A vitamin C-coupled platinum complex represented by the formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof:
    Figure PCTCN2019084838-appb-100001
    Figure PCTCN2019084838-appb-100001
    其中：X和Y是配位体，所述X和Y各自独立地选自NH 3、C 1-C 8直链或支链烷基伯胺(可选为C 1-C 6的直链或支链烷基伯胺，可选为C 1-C 3的直链或支链烷基伯胺)、C 3-C 8环状烷基伯胺(可选为C 3-C 6环状烷基伯胺)、芳香族伯胺、一个或多个C 1-C 4烷基取代的芳香族伯胺、分子式为R 1-NH-R 2的仲胺，其中R 1和R 2各自独立地表示C 1-C 8直链或支链烷基(可选为C 1-C 6的直链或支链烷基，可选为C 1-C 3的直链或支链烷基)；或R 1-NH-R 2共同组成C 4-C 8的脂环仲胺(可选为C 5-C 6的脂环仲胺)、含氮芳香族杂环化合物、一个或多个C 1-C 4直链或支链烷基取代的含氮芳香族杂环化合物、含硫芳香族杂环化合物或含硫非芳香族杂环化合物；其中，所述“芳香族伯胺”中的芳基为5～10元单环或稠合双环芳香基团，所述“芳香族杂环”为5～10元单环或稠合双环杂芳香环，所述“非芳香族杂环”为4～10元单环或多环脂杂环； Wherein: X and Y are ligands, each of which is independently selected from NH 3 , C 1 -C 8 linear or branched alkyl primary amines (optionally C 1 -C 6 linear or A branched alkyl primary amine, optionally a C 1 -C 3 linear or branched alkyl primary amine), a C 3 -C 8 cyclic alkyl primary amine (optionally a C 3 -C 6 cyclic alkane) a primary amine, a primary aromatic amine, one or more C 1 -C 4 alkyl substituted aromatic primary amines, a secondary amine of the formula R 1 -NH-R 2 wherein R 1 and R 2 are each independently And a C 1 -C 8 linear or branched alkyl group (optionally a C 1 -C 6 linear or branched alkyl group, optionally a C 1 -C 3 linear or branched alkyl group); R 1 -NH-R 2 together constitute a C 4 -C 8 alicyclic secondary amine (optionally a C 5 -C 6 alicyclic secondary amine), a nitrogen-containing aromatic heterocyclic compound, one or more C 1 - a C 4 linear or branched alkyl-substituted nitrogen-containing aromatic heterocyclic compound, a sulfur-containing aromatic heterocyclic compound or a sulfur-containing non-aromatic heterocyclic compound; wherein the aryl group in the "aromatic primary amine" a 5- to 10-membered monocyclic or fused bicyclic aromatic group, the "aromatic heterocyclic ring" being a 5- to 10-membered monocyclic or fused bicyclic heteroaromatic ring, said "non-aromatic Heterocycle "is 4 to 10-membered aliphatic monocyclic or polycyclic heterocyclic ring;
    或X和Y一起构成式(Ⅳ)结构：Or X and Y together form the structure of formula (IV):
    Figure PCTCN2019084838-appb-100002
    Figure PCTCN2019084838-appb-100002
    式(Ⅳ)中，D为C 0或C 1的亚烷基；B为C 2-C 8的亚烷基(可选为C 2-C 6的亚烷基、可选为C 3-C 5的亚烷基)； In formula (IV), D is C 0 or C 1 alkylene; B is C 2 -C 8 alkylene (optionally C 2 -C 6 alkylene, optionally C 3 -C 5 alkylene);
    n＝0、1、2、3、4、5或6(可选地，n＝0、1、2或3)；n = 0, 1, 2, 3, 4, 5 or 6 (optionally, n = 0, 1, 2 or 3);
    m是0或1；m is 0 or 1;
    R选自：
    Figure PCTCN2019084838-appb-100003
    R is selected from:
    Figure PCTCN2019084838-appb-100003
  2. 根据权利要求1所述的维生素C偶联铂配合物，或其光学异构体，或其药学上可接受的盐，或其溶剂化物：其特征是所述X和Y分别为NH 3，或X,Y一起为反式-(1R，2R)-环己二胺，反式-(1S，2S)-环己二胺，顺式-(1R，2S)-环己二胺，顺式-(1S，2R)-环己二胺，消旋反式-1，2-环己二胺或消旋顺式-1，2-环己二胺。 The vitamin C-coupled platinum complex according to claim 1, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized in that said X and Y are each NH 3 , or X, Y together is trans-(1R,2R)-cyclohexanediamine, trans-(1S,2S)-cyclohexanediamine, cis-(1R,2S)-cyclohexanediamine, cis- (1S, 2R)-cyclohexanediamine, racemic trans-1,2-cyclohexanediamine or racemic cis-1,2-cyclohexanediamine.
  3. 根据权利要求2所述的维生素C偶联铂配合物，或其光学异构体，或其药学上可接受的盐，或其溶剂化物：其特征是所述X和Y分别为NH 3；或X,Y一起为反式-(1R，2R)-环己二胺。 The vitamin C-coupled platinum complex according to claim 2, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized in that said X and Y are each NH 3 ; X and Y together are trans-(1R, 2R)-cyclohexanediamine.
  4. 根据权利要求1任一项所述的环丁烷二羧酸铂配合物、或其光学异构体、或其药学上可 接受的盐、或其溶剂化物，所述式(I)选自下述配合物，The cyclobutanedicarboxylic acid platinum complex according to any one of claims 1 to 2, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the formula (I) is selected from the group consisting of Said complex,
    Figure PCTCN2019084838-appb-100004
    Figure PCTCN2019084838-appb-100004
    Figure PCTCN2019084838-appb-100005
    Figure PCTCN2019084838-appb-100005
  5. 一种式(I)所示的化合物：A compound of formula (I):
    Figure PCTCN2019084838-appb-100006
    Figure PCTCN2019084838-appb-100006
    其中：among them:
    各个M各自独立地代表氢原子，或者元素周期表第IA族的金属原子，或者两个M共同代表元素周期表中第IIA族的金属原子；可选的M各自独立地代表H、Na、K、Li、Cs或两个M 共同代表Ba；Each M independently represents a hydrogen atom, or a metal atom of Group IA of the periodic table, or two M atoms collectively represent a metal atom of Group IIA of the periodic table; optionally M independently represents H, Na, K , Li, Cs or two M together represent Ba;
    n是0、1、2、3、4、5或6；n is 0, 1, 2, 3, 4, 5 or 6;
    m是0或1；m is 0 or 1;
    R是：
    Figure PCTCN2019084838-appb-100007
    R is:
    Figure PCTCN2019084838-appb-100007
  6. 权利要求1-4任一项所述的维生素C偶联铂配合物，或其光学异构体，或其药学上可接受的盐，或其溶剂化物的制备方法，其特征是包括：将式(II)化合物与式(III)化合物加水调节为水溶液进行反应的步骤；可选地，反应水溶液加碱调节pH为7-9，A method for producing a vitamin C-coupled platinum complex according to any one of claims 1 to 4, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which comprises: (II) a step of reacting a compound with a compound of the formula (III) with water to adjust to an aqueous solution; optionally, the reaction solution is added with a base to adjust the pH to 7-9,
    可选地，所述碱为无机碱，可选地，所述无机碱选自氢氧化钠，氢氧化钾，碳酸钠，碳酸氢钠，碳酸钾，氢氧化锂，氢氧化铯或氢氧化钡中的一种或多种；Optionally, the base is an inorganic base. Optionally, the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, lithium hydroxide, barium hydroxide or barium hydroxide. One or more of
    所述(II)的结构式为：The structural formula of (II) is:
    Figure PCTCN2019084838-appb-100008
    Figure PCTCN2019084838-appb-100008
    式(II)中：In formula (II):
    X和Y的定义与式(I)中的相同；The definitions of X and Y are the same as in the formula (I);
    A 1和A 2相同或者不同，各自独立地代表羟基，硝酸根或高氯酸根，或者A 1和A 2共同代表硫酸根或碳酸根； A 1 and A 2 are the same or different and each independently represents a hydroxyl group, a nitrate or a perchlorate, or A 1 and A 2 together represent a sulfate or a carbonate;
    所述(III)的结构式为：The structural formula of (III) is:
    Figure PCTCN2019084838-appb-100009
    Figure PCTCN2019084838-appb-100009
    式(III)中：In formula (III):
    各个M各自独立地代表氢原子，或者元素周期表第IA族的金属原子，或者两个M共同代表元素周期表中第IIA族的金属原子；可选的M各自独立地代表H、Na、K、Li、Cs或两个M共同代表Ba；Each M independently represents a hydrogen atom, or a metal atom of Group IA of the periodic table, or two M atoms collectively represent a metal atom of Group IIA of the periodic table; optionally M independently represents H, Na, K , Li, Cs or two M together represent Ba;
    n＝0、1、2、3、4、5或6(可选地，n＝0、1、2或3)；n = 0, 1, 2, 3, 4, 5 or 6 (optionally, n = 0, 1, 2 or 3);
    m是0或1；m is 0 or 1;
    R是：
    Figure PCTCN2019084838-appb-100010
    R is:
    Figure PCTCN2019084838-appb-100010
  7. 一种药用组合物，其包括权利要求1-4任一项所述的维生素C偶联铂配合物，或其光学异构体，或其药学上可接受的盐，或其溶剂化物中的一种或多种以及任选存在的药学上可接受的载体。A pharmaceutical composition comprising the vitamin C-conjugated platinum complex according to any one of claims 1 to 4, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof One or more and optionally a pharmaceutically acceptable carrier.
  8. 权利要求1-4任一项所述的维生素C偶联铂配合物、或其光学异构体，或其药学上可接受的盐，或其溶剂化物，或者权利要求7所述的药物组合物在制备抗肿瘤药物中的用途。The vitamin C-coupled platinum complex according to any one of claims 1 to 4, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or the pharmaceutical composition according to claim 7. Use in the preparation of anti-tumor drugs.
  9. 根据权利要求8所述的用途，其中所述的肿瘤为人肺癌，人肝癌，人大肠癌，人头颈癌，人前列腺癌，人乳腺癌，人卵巢癌，人子宫颈癌，人白血病，人淋巴癌，人皮肤癌，人胰腺癌，人膀胱癌，人食道癌，人胃癌，人男性生殖器癌，人甲状腺癌，人骨癌，或人黑色素癌，人口腔癌。The use according to claim 8, wherein the tumor is human lung cancer, human liver cancer, human colorectal cancer, human head and neck cancer, human prostate cancer, human breast cancer, human ovarian cancer, human cervical cancer, human leukemia, human lymph Cancer, human skin cancer, human pancreatic cancer, human bladder cancer, human esophageal cancer, human gastric cancer, human male genital cancer, human thyroid cancer, human bone cancer, or human melanoma, human oral cancer.
  10. 根据权利要求9所述的用途，其特征在于所述肿瘤细胞为人结肠癌细胞HT29，人非小细胞肺癌细胞A549，人肝癌细胞SMMC7721，人乳腺癌细胞MCF-7，人卵巢癌细胞SKOV3，人食管癌细胞ECA109，人前列腺癌细胞DU145，人宫颈癌细胞Hela，人黑色素瘤细胞A375，人口腔表皮样癌细胞KB，人胃癌细胞HGC27，人甲状腺癌细胞SW579，人膀胱癌细胞5637，人胰腺癌细胞Panc-1，人大细胞肺癌细胞H460，人浆细胞白血病细胞H929，人肝癌细胞HepG2，人单核细胞白血病THP-1。The use according to claim 9, characterized in that the tumor cells are human colon cancer cells HT29, human non-small cell lung cancer cells A549, human liver cancer cells SMMC7721, human breast cancer cells MCF-7, human ovarian cancer cells SKOV3, human Esophageal cancer cell line ECA109, human prostate cancer cell line DU145, human cervical cancer cell line Hela, human melanoma cell line A375, human oral epidermoid carcinoma cell line KB, human gastric cancer cell line HGC27, human thyroid cancer cell line SW579, human bladder cancer cell line 5637, human pancreas Cancer cell Panc-1, human large cell lung cancer cell H460, human plasma cell leukemia cell H929, human liver cancer cell HepG2, human monocytic leukemia THP-1.
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CN105753922B (en) * 2016-02-05 2019-07-02 南开大学 For oncotherapy tetravalence platinum glycosyl complex and preparation method thereof

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CN114940692A (en) * 2022-06-17 2022-08-26 重庆文理学院 Compound with anti-lung cancer effect and preparation method and application thereof
CN114940692B (en) * 2022-06-17 2023-12-01 重庆文理学院 Compound with anti-lung cancer effect and preparation method and application thereof

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