JP7048769B2 - Vitamin C coupling platinum complex, its intermediate, its manufacturing method, pharmaceutical composition and use - Google Patents

Description

The present invention relates to a water-soluble platinum complex, and more particularly to a vitamin C coupling platinum complex for tumor treatment, an intermediate thereof, a method for producing the same, a pharmaceutical composition and use thereof.

Platinum-based anticancer agents are one of the representative drugs in the field of tumor treatment. It is a cell cycle non-specific drug and has a therapeutic effect on all of sarcoma, malignant epithelial tumor, lymphoma, and germ cell tumor. Currently, the representative platinum-based anticancer agents widely adopted in clinical treatment internationally are mainly cisplatin, carboplatin, and oxaliplatin. The fatal drawbacks of platinum-based anticancer drugs are their extremely strong toxic side effects and their inherent and later drug resistance problems. In addition, since this type of drug is a metal-organic compound, all platinum-based over-the-counter drugs are generally characterized by extremely low water solubility, and cisplatin, carboplatin, and oxaliplatin are water-soluble, respectively. , 1.0, 17.0, 6.0 mg / ml.

An object of the present invention is to eliminate the drawbacks present in the prior art, to have good water solubility and even better antitumor activity, a vitamin C coupling platinum complex, or an optical isomer thereof, or pharmaceutically acceptable thereof. The present invention is to provide a salt thereof, or a solvate thereof.

式中：Ｘ及びＹは配位子であり、前記Ｘ及びＹはそれぞれ独立して、ＮＨ_３、Ｃ_１－Ｃ_８直鎖又は分岐アルキル１級アミン（選択的に、Ｃ_１－Ｃ_６の直鎖又は分岐アルキル１級アミンであり、選択的に、Ｃ_１－Ｃ_３の直鎖又は分岐アルキル１級アミンである）、Ｃ_３－Ｃ_８環状アルキル１級アミン（選択的に、Ｃ_３－Ｃ_６環状アルキル１級アミンである）、芳香族１級アミン、１個又は複数個のＣ_１－Ｃ_４アルキル置換の芳香族１級アミン、分子式がＲ_１－ＮＨ－Ｒ_２である２級アミンから選択される。そのうち、Ｒ_１及びＲ_２はそれぞれ独立して、Ｃ_１－Ｃ_８の直鎖又は分岐アルキル基（選択的に、Ｃ_１－Ｃ_６の直鎖又は分岐アルキル基であり、選択的に、Ｃ_１－Ｃ_３の直鎖又は分岐アルキル基である）を表し、或いは、Ｒ_１－ＮＨ－Ｒ_２は一体となって、Ｃ_４－Ｃ_８の脂環式２級アミン（選択的に、Ｃ_５－Ｃ_６の脂環式２級アミンである）、含窒素芳香族複素環化合物、１個又は複数個のＣ_１－Ｃ_４直鎖又は分岐アルキル置換の含窒素芳香族複素環化合物、含硫黄芳香族複素環化合物、又は含硫黄非芳香族複素環化合物を形成している。ただし、前記「芳香族１級アミン」におけるアリール基は、５～１０員の単環又は縮合二環式芳香族基であり、前記「芳香族複素環」は、５～１０員の単環又は縮合二環式複素芳香環であり、前記「非芳香族複素環」は、４～１０員の単環又は多環脂肪族複素環である。 The present invention provides a vitamin C coupling platinum complex represented by the formula (I), an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

In the formula: X and Y are ligands, and the X and Y are independently NH ₃ , C1 _- C8 linear or branched alkyl _primary amines ₍ selectively, C1 _- C6). Linear or branched alkyl primary amines, optionally C1 _- C ₃ linear or branched primary amines), C3 _- C8 cyclic alkyl primary amines _{(selectively C 3 )} . _-C6 cyclic alkyl primary amine), aromatic primary amine, _one or more C1- _C4 alkyl substituted aromatic primary amines, molecular formula R1 _- NH-R2 ₂ Selected from primary amines. Of these, R ₁ and R ₂ are independently C1 _- C8 linear or branched alkyl groups ₍ selectively C1 _{- C6} linear or branched alkyl groups, and selectively C. ₁ -C ₃ is a linear or branched alkyl group), or R ₁ -NH-R ₂ are combined to form a C ₄ -C ₈ alicyclic secondary amine (optionally C). ₅ -C ₆ alicyclic secondary amine), nitrogen-containing aromatic heterocyclic compound, _one or more C1- _C4 linear or branched alkyl-substituted nitrogen-containing aromatic heterocyclic compounds, including It forms a sulfur aromatic heterocyclic compound or a sulfur-containing non-aromatic heterocyclic compound. However, the aryl group in the "aromatic primary amine" is a 5- to 10-membered monocyclic or fused bicyclic aromatic group, and the "aromatic heterocycle" is a 5- to 10-membered monocyclic or It is a fused bicyclic heteroaromatic ring, and the "non-aromatic heterocycle" is a 4- to 10-membered monocyclic or polycyclic aliphatic heterocycle.

［式（ＩＶ）中、Ｄは、Ｃ_０又はＣ_１アルキレン基である。Ｂは、Ｃ_２－Ｃ_８アルキレン基（選択的に、Ｃ_２－Ｃ_６アルキレン基であり、選択的に、Ｃ_３－Ｃ_５アルキレン基である）である。］
ｎ＝０、１、２、３、４、５又は６である（選択的に、ｎ＝０、１、２又は３である）。 Alternatively, X and Y together form the structure of formula (IV).

[In formula (IV), D is _{a C0} or C1 alkylene group. B is a C2 _- C8 alkylene group ₍ selectively a C2 _{- C6} alkylene group and selectively a C3 _{- C5} alkylene group). ]
n = 0, 1, 2, 3, 4, 5 or 6 (selectively, n = 0, 1, 2 or 3).

m is 0 or 1.

から選択される。 R is

Is selected from.

Optionally, X and Y are NH ₃ , respectively, or X and Y are integrated to trans- (1R, 2R) -cyclohexanediamine, trans- (1S, 2S) -cyclohexanediamine, cis. -(1R, 2S) -cyclohexanediamine, cis- (1S, 2R) -cyclohexanediamine, lasemitrans-1,2-cyclohexanediamine or lasemisis-1,2-cyclohexanediamine is formed.

Optionally, X and Y are NH ₃ respectively, or X and Y are integrated to form a trans- (1R, 2R) -cyclohexanediamine.

Optionally, the formula (I) is selected from the following complexes.

式中：
各Ｍはそれぞれ独立して、水素原子、又は周期表第ＩＡ族の金属原子を表し、或いは、２つのＭは一体となって、周期表の第ＩＩＡ族の金属原子を表し、選択的に、Ｍはそれぞれ独立して、Ｈ、Ｎａ、Ｋ、Ｌｉ、Ｃｓを表し、或いは、２つのＭは一体となってＢａを表し、
ｎ＝０、１、２、３、４、５又は６であり（選択的に、ｎ＝０、１、２又は３である）、
ｍは、０又は１であり、
Ｒは、

である。 In another aspect, the invention provides an intermediate of a vitamin C coupling platinum complex represented by formula (I), characterized by having a structure represented by formula (III).

During the ceremony:
Each M independently represents a hydrogen atom, or a metal atom of Group IA of the Periodic Table, or two Ms together represent a metal atom of Group IIA of the Periodic Table, selectively. M independently represents H, Na, K, Li, Cs, or two Ms together represent Ba.
n = 0, 1, 2, 3, 4, 5 or 6 (selectively, n = 0, 1, 2 or 3).
m is 0 or 1 and
R is

Is.

In another aspect, the present invention is a method for producing a vitamin C coupling platinum complex, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound of formula (II) and a solvate thereof are produced. Provided is a production method comprising a step of adding water to a compound of formula (III) to prepare an aqueous solution and reacting the compound. The pH may be adjusted to 7 to 9 by adding a base to the reaction aqueous solution.

Optionally, the base is an inorganic base, and selectively, the inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, lithium hydroxide, cesium hydroxide, or water. One or more selected from barium oxide.

である。
式（ＩＩ）中：
Ｘ及びＹは配位子であり、前記Ｘ及びＹはそれぞれ独立して、ＮＨ_３、Ｃ_１－Ｃ_８直鎖又は分岐アルキル１級アミン（選択的に、Ｃ_１－Ｃ_６の直鎖又は分岐アルキル１級アミンであり、選択的に、Ｃ_１－Ｃ_３の直鎖又は分岐アルキル１級アミンである）、Ｃ_３－Ｃ_８環状アルキル１級アミン（選択的に、Ｃ_３－Ｃ_６環状アルキル１級アミンである）、芳香族１級アミン、１個又は複数個のＣ_１－Ｃ_４アルキル置換の芳香族１級アミン、分子式がＲ_１－ＮＨ－Ｒ_２の２級アミンから選択される。そのうち、Ｒ_１及びＲ_２はそれぞれ独立して、Ｃ_１－Ｃ_８の直鎖又は分岐アルキル基（選択的に、Ｃ_１－Ｃ_６の直鎖又は分岐アルキル基であり、選択的に、Ｃ_１－Ｃ_３の直鎖又は分岐アルキル基である）を表し、或いは、Ｒ_１－ＮＨ－Ｒ_２は一体となって、Ｃ_４－Ｃ_８の脂環式２級アミン（Ｃ_５－Ｃ_６の脂環式２級アミンであっても良い）、含窒素芳香族複素環化合物、１個又は複数個のＣ_１－Ｃ_４直鎖又は分岐アルキル置換の含窒素芳香族複素環化合物、含硫黄芳香族複素環化合物、又は含硫黄非芳香族複素環化合物を形成している。ただし、前記「芳香族１級アミン」におけるアリール基は、５～１０員の単環又は縮合二環式芳香族基であり、前記「芳香族複素環」は、５～１０員の単環又は縮合二環式複素芳香環であり、前記「非芳香族複素環」は、４～１０員の単環又は多環脂肪族複素環である。 The structural formula of (II) is

Is.
In formula (II):
X and Y are ligands, and the X and Y are independently _NH3 , C1 _- C8 linear or branched alkyl primary amines ₍ selectively, C1 _{- C6} linear or Branched alkyl primary amines, selectively C1 _- C3 linear or branched _primary amines), C3 _- C8 cyclic alkyl primary amines (selectively C3 _- C _{6 )} . (Cyclic alkyl primary amine), aromatic primary amine, _one or more C1- _C4 alkyl substituted aromatic primary amines, secondary amines with molecular formula R1 _- NH- _R2 Will be done. Of these, R ₁ and R ₂ are independently C1 _- C8 linear or branched alkyl groups ₍ selectively C1 _{- C6} linear or branched alkyl groups, and selectively C. ₁ -C ₃ is a linear or branched alkyl group), or R ₁ -NH-R ₂ are combined to form a C ₄ -C ₈ alicyclic secondary amine (C ₅ -C ₆ ). (It may be an alicyclic secondary amine), a nitrogen-containing aromatic heterocyclic compound, _one or more C1- _C4 linear or branched alkyl-substituted nitrogen-containing aromatic heterocyclic compounds, sulfur-containing. It forms an aromatic heterocyclic compound or a sulfur-containing non-aromatic heterocyclic compound. However, the aryl group in the "aromatic primary amine" is a 5- to 10-membered monocyclic or fused bicyclic aromatic group, and the "aromatic heterocycle" is a 5- to 10-membered monocyclic or It is a fused bicyclic heteroaromatic ring, and the "non-aromatic heterocycle" is a 4- to 10-membered monocyclic or polycyclic aliphatic heterocycle.

［式（ＩＶ）中、Ｄは、Ｃ_０、又はＣ_１アルキレン基である。Ｂは、Ｃ_２－Ｃ_８アルキレン基である（選択的に、Ｃ_２－Ｃ_６アルキレン基であり、選択的に、Ｃ_３－Ｃ_５アルキレン基である）。］
Ａ_１及びＡ_２は同一でも異なっていてもよく、それぞれ独立して、ヒドロキシル基、ニトレート基、又はパークロレート基を表し、或いは、Ａ_１及びＡ_２は共に、サルフェート基、又はカーボネート基を表す。 Alternatively, X and Y together form the structure of formula (IV).

[In formula (IV), D is a C ₀ or C ₁ alkylene group. B is a C2 _- C8 alkylene group ₍ selectively a C2 _{- C6} alkylene group and selectively a C3 _{- C5} alkylene group). ]
A ₁ and A ₂ may be the same or different and independently represent a hydroxyl group, a nitrate group, or a perchlorate group, or both A ₁ and A ₂ represent a sulfate group or a carbonate group. ..

である。
式（ＩＩＩ）中：
各Ｍはそれぞれ独立して、水素原子、又は周期表第ＩＡ族の金属原子を表し、或いは、２つのＭは一体となって、周期表の第ＩＩＡ族の金属原子を表し、選択的に、Ｍはそれぞれ独立して、Ｈ、Ｎａ、Ｋ、Ｌｉ、Ｃｓを表し、或いは、２つのＭは一体となってＢａを表し、
ｎ＝０、１、２、３、４、５又は６であり（選択的に、ｎ＝０、１、２又は３である）、
ｍは、０又は１であり、
Ｒは、

である。 The structural formula of (III) is

Is.
In formula (III):
Each M independently represents a hydrogen atom, or a metal atom of Group IA of the Periodic Table, or two Ms together represent a metal atom of Group IIA of the Periodic Table, selectively. M independently represents H, Na, K, Li, Cs, or two Ms together represent Ba.
n = 0, 1, 2, 3, 4, 5 or 6 (selectively, n = 0, 1, 2 or 3).
m is 0 or 1 and
R is

Is.

Optionally, in the above reaction, 0.5 to 4 equivalents of compound (II) is used for compound (III) per equivalent, preferably 1 to 2 equivalents.

Optionally, the concentration of the inorganic base is 0.1N to 5N, preferably 1N.

Optionally, the reaction may be carried out over a relatively wide temperature range.

Optionally, the reaction may be carried out in a relatively wide temperature range, for example, the reaction is carried out by selecting a temperature range of 0 to 100 ° C. It is most preferably from room temperature, preferably 25 to 90 ° C, still more preferably 60 to 90 ° C, and is preferably accompanied by stirring at the same time. The reaction time may vary depending on the different target product, and the range of variation is wide. Depending on the nature of the different reactants, it generally takes 1 hour to 30 days to complete. In most cases, it takes 3 hours to 2 days.

Optionally, deionized water is preferably used as the water used for preparing the reaction compound in the above reaction into an aqueous solution.

Specifically, the following methods and reaction formulas can be used for the production thereof.

In method A, when M in formula (III) is a hydrogen atom, the reaction is carried out with appropriate inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, lithium hydroxide, and. By adjusting the pH of the reaction aqueous solution between 7 and 9 using cesium hydroxide or the like, the complex represented by the formula (I) can be produced. When M is a metal atom, for example a sodium atom, a potassium atom, a lithium atom, a barium atom, or a cesium atom, the reaction can be carried out smoothly in an aqueous solution, and if necessary, a small amount of the above aqueous solution of the inorganic base. If the pH of the reaction solution is maintained between 7 and 9, the complex represented by the formula (I) can be synthesized.

In method B, when M is a hydrogen atom, the reaction completes the condensation reaction with the metal platinum sulfate compound represented by the formula (II) in an aqueous solution using an equal amount of barium hydroxide as an inorganic base. Allows the complex represented by the formula (I) to be produced. When the complex of the present invention is produced by the method B, a pre-produced barium salt, that is, two Ms each representing one barium atom and a metal platinum sulfate complex represented by the formula (II) are used. , Can also be reacted in aqueous solution to complete the complex preparation process.

The compound represented by the formula (II) in the methods A and B is a complex of the corresponding cis-platinum dichloride and X and Y (for example, cis-dichloro- (1,2-diaminecyclohexane) / platinum). It can be produced by reacting with an equivalent amount of silver nitrate or an equivalent amount of silver sulfate. This reaction is most preferably carried out in an aqueous solution, and the water used is most preferably deionized water. It is relatively appropriate that the reaction temperature is room temperature.

The present invention is not particularly limited as to the method for purifying the product (I) produced by using the above method, and can be purified by using a conventional method of the prior art. For example, the mixture after completion of the reaction first removes the precipitate which may be formed by filtration, and then concentrates by vacuum distillation, and then an organic solvent (optionally, the organic solvent is an organic solvent which can be mixed with water. , For example, alcohols (eg, methanol, ethanol, propanol, butanol, isopropanol, etc.), or ethers having a certain compatibility with water (eg, diethyl ether, methyl-t-butyl ether, tetrahydrofuran, ethylene glycol diethyl ether, etc. It is preferable to use (preferably ethylene glycol dimethyl ether, etc.)) to precipitate the target compound (I) precipitate, and finally the obtained precipitate is collected by, for example, filtration. The compound represented by I) is obtained. For the purification / purification of the product (I) obtained by the above reaction, for example, a chromatographic method using an ion exchange resin, a liquid chromatograph, or the like can also be used. In the separation and purification of the liquid chromatograph, it is common to use methanol and water as the mobile phase.

The compound (III) of the present invention is produced by any one of the methods C, D, or methods E and F, which are represented by the following reaction formula, using the alkylation of 3-O of vitamin C as an example. be able to.

Taking the alkylation of 3-O of vitamin C as an example, in method C, a tribromide can be obtained by debenzylating and brominating benzyloxyalkyldibromid. The resulting bromide is reacted with Vitamin C in the presence of a base. As for the reaction conditions, 0.1 to 50 equivalents of the bromide is used for the vitamin C compound, or conversely, 0.1 to 50 equivalents of the vitamin C compound is used for the bromide. The base used is sodium hydrogen carbonate, potassium carbonate, calcium carbonate, sodium hydride, triethylamine, cesium carbonate and the like, and the amount of the base may be 0.1 to 10 equivalents with respect to vitamin C. .. The obtained vitamin C derivative is double-substituted with a malonic acid diester under the condition of a base to obtain a cyclobutane malonic acid ester compound in which 3-O of vitamin C is alkylated and coupled. As for the reaction conditions, 0.1 to 50 equivalents of malonic acid diesters are used for vitamin C derivatives, or conversely, 0.1 to 50 equivalents of vitamin C derivatives are used for malonic acid diesters. do. The malonic acid diester may be dimethyl malonate, diethyl malonate, diphenylmethyl malonic acid, isopropyridene malonic acid ester, di-t-butyl malonic acid or the like. The base used may be sodium hydrogen carbonate, potassium carbonate, calcium carbonate, sodium hydride, triethylamine, cesium carbonate and the like. The solvent used may be tetrahydrofuran, dichloromethane, toluene, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, dimethyl sulfoxide and the like, and one of the two types of reactants is used as the solvent. The reaction may be carried out using. The temperature of the reaction may be 0 ° C to 100 ° C, and generally, the reaction may be carried out by heating at 60 to 80 ° C. The time required for the reaction varies depending on the reactants, but can generally be completed in 1 hour to 7 days. The obtained reaction product may be purified under a series of purification conditions, and in general, separation by silica gel chromatography or separation by a liquid chromatography column can be adopted. By removing the protecting group of malonic acid from the obtained product, the compound represented by the required formula (III) is finally obtained. The deprotection method depends on the protecting group used, but when diphenylmethyl malonate is used, it can be deprotected by using the hydrogenation reduction method, and diethyl malonate or isopropyridene ester malonate is used. The deprotecting reaction can be carried out in methanol-water or THF-water solvent using an inorganic base, and the ratio of organic solvent to water is generally 1: 1 to 4: 1. It is 1. The inorganic base used may be sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide or the like. When di-t-butyl malonic acid is used, the deprotection reaction can be carried out under acidic conditions. The reaction temperature is generally room temperature and the reaction time is generally 1 to 24 hours. Purification of the deprotected and produced compound can be performed using silica gel chromatography, ion exchange resin filtration, or liquid chromatography, but the reaction solvent was directly removed using a distillation method. If so, the resulting product will be the corresponding metal carboxylate.

As shown in Method D, Vitamin C may first be converted to the corresponding 5,6-O isopropylene-protected Vitamin C and then reacted with the bromide, Vitamin C. The protection can be carried out according to the method reported in the literature, for example, heating in acetone at room temperature or 60 ° C. for 1 to 24 hours. In the method D, the reaction conditions of each step other than the protection of vitamin C are the same as those described in the method C.

In the production methods shown in Methods E and F, benzyloxyalkyldibromid is first substituted with a malonic acid ester to give a four-membered ring derivative, then debenzylated, bromoized and combined with Vitamin C. The reaction is carried out and deprotected to give the final compound (III). The above-mentioned production route is involved in the protection of vitamin C, the substitution reaction under basic conditions, and the deprotection reaction, and the reaction conditions and the implementation method are the same as those described in Method C and Method D.

In another aspect, the invention is one or more of the vitamin C coupling platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and any pharmaceutical. To provide a drug composition comprising an acceptable carrier.

In another aspect, the invention comprises an antitumor agent of the vitamin C coupling platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition thereof. Provides use for manufacturing.

Optionally, the tumors are human lung cancer, human liver cancer, human colon 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 reproductive organ cancer, human thyroid cancer, human bone cancer, or human melanoma, human oral cancer be.

Optionally, the tumor cells are human colon cancer cell HT29, human non-small cell lung cancer cell A549, human liver cancer cell SMMC7721, human breast cancer cell MCF-7, human ovary cancer cell SKOV3, human esophageal cancer cell. ECA109, human prostate cancer cell DU145, human cervical cancer cell Hela, human melanoma cell A375, human oral epidermal cancer cell KB, human gastric cancer cell HGC27, human thyroid cancer cell SW579, human bladder cancer cell 5637 , Human pancreatic 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.

The route of administration of the antitumor agent of the present invention is not particularly limited, and the dose thereof depends not only on the age, weight and medical condition of the patient, but also on the type, nature and severity of the tumor. However, generally speaking, in the case of an adult patient, the optimal amount of the compound administered per day is 10 mg to 1 g. Generally, it is administered once or multiple times every 1 to 3 weeks.

The compounds according to the invention have good antitumor activity. The complex according to the present invention is improved in water solubility by several tens to 1,000 times or more as compared with the conventional platinum-based antitumor agents, and due to such a highly water-soluble characteristic, the drug can be used in the kidney. It can increase excretion, reduce the accumulation of the drug in the body, reduce the highly nephrotoxic side effects normally present in platinum-based drugs, facilitate the formulation of these compounds, and increase the stability of the formulation. It will be improved and clinical application will be more convenient.

Hereinafter, the present invention will be further described with reference to specific examples. Representative examples of preferable compound compounds as platinum complexes for tumor treatment represented by the formula (I) according to the present invention are listed in Table 1 below, and the platinum complexes included in the present invention are listed below. Not limited to what you have.

Example 1
Preparation of diaminoplatinum (II) [3-methylene- (2-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

(1) Preparation of di-t-butyl 3-benzyloxymethyl-cyclobutane-1,1-dicarboxylic acid

Sodium hydride (286 mg) was mixed and suspended in 5 mL of N, N-dimethylformamide, the air in the flask was replaced with nitrogen gas, and the flask was placed in an ice bath. Under nitrogen protection, di-t-butyl malonic acid (1.6 mL) was slowly added dropwise and reacted for 0.5 hours before 2-benzyloxymethyl-1,3-dibromopropane (1.15 g). A solution of N, N-dimethylformamide (5 mL) was slowly added dropwise, the temperature of the reaction solution was raised to 70 ° C., and the mixture was stirred for 7 hours. The end point of the reaction is monitored by TLC, and after the reaction is completed, the reaction solution is cooled to room temperature, 100 mL of ethyl acetate is added to the reaction solution, the mixture is washed with saturated aqueous ammonium chloride solution (1 × 50 mL), and the aqueous phase is acetate. Extraction was made with ethyl (2 x 25 mL) and combined with the organic phase. The organic phase was washed in the order of saturated aqueous ammonium chloride solution (1 x 100 mL), distilled water (1 x 100 mL), and saturated sodium chloride solution (1 x 100 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained pale yellow oil was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50/1) to obtain 1.1 g of the target product of a colorless transparent oil.

^{1 1} H NMR (600 MHz, CDCl ₃ ) δ 7.35-7.27 (m, 5H), 4.50 (s, 2H), 3.43 (d, J = 6.5 Hz, 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) Preparation of di-t-butyl 3-hydroxymethyl-cyclobutane-1,1-dicarboxylic acid

Di-t-butyl 3-benzyloxymethyl-cyclobutane-1,1-dicarboxylate (1.1 g) is dissolved in 10 mL of methanol, 10% palladium carbon (0.1 g) is added, and nitrogen gas is used. The air in the flask was replaced 3 times, the nitrogen gas in the reaction flask was further replaced with hydrogen gas 3 times, and the reaction solution was stirred overnight at room temperature under hydrogen pressurization. After completion of the reaction, replace the hydrogen gas in the flask with nitrogen gas, suction filter, rinse the filtered cake with methanol three times, concentrate the filtrate under reduced pressure until dry, and add 0.8 g of the product of colorless transparent oil. Obtained.

^{1 1} H NMR (600 MHz, 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). MS (m / z): 309.1 [M + Na] ⁺

(3) Preparation of di-t-butyl 3-bromomethyl-cyclobutane-1,1-dicarboxylic acid

Di-t-butyl 3-hydroxymethyl-cyclobutane-1,1-dicarboxylate (0.8 g) is dissolved in 5 mL of dry dichloromethane and a solution of triphenylphosphine (1.1 g) in dichloromethane (5 mL) in an ice bath. ) Was slowly added and reacted for 10 minutes, then a dichloromethane solution (5 mL) of carbon tetrabromide (1.4 g) was slowly added dropwise, the reaction solution was slowly heated to room temperature, and the mixture was stirred for 1 hour. The end point of the reaction is monitored by TLC, and after the reaction is completed, the solvent is concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50/1) to obtain 0.9 g of the target product of a colorless transparent oil. Obtained.

^{1 1} H NMR (600 MHz, 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) Preparation of 5,6-O-isopropylidene-2-O- (3-methylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) -3-O-benzyl-L-ascorbic acid

5,6-O-isopropyridene-3-benzylL-ascorbic acid (1.4 g) and di-t-butyl 3-bromomethyl-cyclobutane-1,1-dicarboxylate (0.8 g) at room temperature. It was dissolved in 10 mL of dimethyl sulfoxide, potassium carbonate (0.6 g) was added to the reaction solution, the temperature of the reaction solution was raised to 50 ° C., and the mixture was stirred for 3 hours. The end point of the reaction is monitored by TLC, and after the reaction is completed, the reaction solution is cooled to room temperature, 50 mL of water is added to the reaction solution to dilute the reaction solution, the mixture is neutralized with 1 M dilute hydrochloric acid, and then extracted with 100 mL of ethyl acetate. The organic phase was washed with distilled water (1 x 100 mL) and saturated sodium chloride solution (1 x 100 mL) in this order, dried with anhydrous sodium sulfate, and the solvent was distilled off with a rotary evaporator to obtain the obtained oil. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 5/1) gave 0.9 g of a colorless transparent oil product.

^{1 1} H NMR (600 MHz, 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), 2.71-1.69 (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) Preparation of 5,6-O-isopropylidene-2-O- (3-methylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid

5,6-O-isopropylidene-2-O- (3-methylene-cyclobutane-1,1-dicarboxylate di-t-butyl) -3-O-benzyl-L-ascorbic acid (0.9 g), Dissolve in 10 mL of ethanol, add 5% palladium carbon (0.1 g), replace the air in the flask with nitrogen gas three times, and then replace the nitrogen gas in the reaction flask with hydrogen gas three times. , The reaction solution was stirred overnight at room temperature under hydrogen pressurization. After completion of the reaction, the hydrogen gas in the flask was replaced with nitrogen gas, suction filtration was performed, the filtered cake was rinsed with ethanol three times, and the filtrate was concentrated under reduced pressure to obtain 0.7 g of a colorless transparent oil product. ..

^{1 1} H NMR (600 MHz, CDCl ₃ ) δ 4.65 (d, J = 2.9 Hz, 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) Preparation of 2-O- (3-methylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid

5,6-O-isopropyridene-2-O- (3-methylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid (0.7 g) was dissolved in 10 mL of dichloromethane. , Cooled to 0 ° C., and trifluoroacetic acid (5 mL) was slowly added dropwise under the protection of nitrogen. The reaction solution was slowly heated to room temperature and stirred overnight. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent, dried in a freeze-dryer, and then 0.4 g of a colorless viscous liquid was obtained, and the crude product was used as it was in the next reaction.

MS (m / z): 355.1 [M + Na] ⁺

(7) Preparation of diaminoplatinum (II) [3-methylene- (2-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product (0.4 g) of 2-O- (3-methylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid is dissolved in 10 mL of water, and a saturated solution of barium hydroxide is added to the reaction solution. The pH of the mixture was adjusted to 7 and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, platinum diamine sulfate (0.4 g) is dissolved in 2 ml of water, this solution is added to the above reaction solution, the pH is adjusted to 7 with a saturated solution of barium hydroxide, and light is shielded at room temperature. And stirred for 3 hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 3 g was obtained and was a white solid.

^{1 1} H NMR (400 MHz, D ₂ O) δ 4.98 (d, J = 1.3 Hz, 1H), 4.20 (brs, 4H), 4.09 (td, J = 6.9, 1) .7 Hz, 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] ⁺

Example 2
Preparation of diaminoplatinum (II) [3-methylene- (3-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

(1) Preparation of 5,6-O-isopropylidene-3-O- (3-methylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid

Under room temperature conditions, 5,6-O-isopropyridene L-ascorbic acid (0.8 g) is dissolved in 5 mL of dimethyl sulfoxide, sodium hydrogen carbonate (0.3 g) is added, and the reaction solution is stirred for 20 minutes. After that, a dimethyl sulfoxide solution (5 mL) of 3-bromomethyl-cyclobutane-1,1-dicarboxylic acid di-t-butyl (0.9 g) was added, the temperature was raised to 60 ° C. of the reaction solution, and the mixture was stirred overnight. .. The end point of the reaction is monitored by TLC, and after the reaction is completed, the reaction solution is cooled to room temperature, 50 mL of water is added to the reaction solution to dilute it, neutralize it with 1 M dilute hydrochloric acid, and then it is extracted with 100 mL of ethyl acetate and organic. The phase was washed with distilled water (1 × 100 mL) and saturated sodium chloride solution (1 × 100 mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily substance. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 5/1) gave 0.87 g of the desired product as a colorless transparent oil.

^{1 1} H NMR (600 MHz, CDCl ₃ ) δ 4.56 (d, J = 2.8 Hz, 1H), 4.45 (d, J = 5.9 Hz, 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) Preparation of 3-O- (3-methylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid

5,6-O-isopropylidene-3-O- (3-methylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid (0.87 g) was dissolved in 10 mL of dichloromethane. , Cooled to 0 ° C., and trifluoroacetic acid (5 mL) was slowly added dropwise under the protection of nitrogen. The reaction solution was slowly heated to room temperature and stirred overnight. After completion of the reaction, the solvent was removed under reduced pressure, and after drying in a freeze-dryer, 0.5 g of a colorless viscous liquid was obtained, and the crude product was used as it was in the next reaction.

MS (m / z): 355.1 [M + Na] ⁺

(3) Preparation of diaminoplatinum (II) [3-methylene- (3-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product of 3-O- (3-methylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid (0.5 g) is dissolved in 10 mL of water, and a saturated solution of barium hydroxide is added to the reaction solution. The pH of the mixture was adjusted to 7 and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, platinum diamine sulfate (0.5 g) is dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with a saturated solution of barium hydroxide, and shielded from light at room temperature 3 Stir for hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 4 g was obtained and was a white solid.

^{1 1} H NMR (400 MHz, D ₂ O) δ 4.95 (d, J = 1.7 Hz, 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] ⁺

Example 3
Preparation of diaminoplatinum (II) [3-carboxylic acid- (6-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

(1) Preparation of 3-carboxylic acid-cyclobutane-1,1-dicarboxylic acid di-t-butyl

Di-t-butyl 3-hydroxymethyl-cyclobutane-1,1-dicarboxylate (0.8 g) was dissolved in 10 mL of acetone and Jones' reagent (chromium trioxide 420 mg, concentrated sulfuric acid 371 μL, water) under ice bath conditions. Add and dilute to 1.6 mL) slowly, slowly raise the temperature of the reaction solution to room temperature, stir for 2 hours, monitor the reaction with TLC, and after the reaction is completed, add a few drops of isopropanol to add excess. The oxidant was removed. The reaction mixture was suction filtered, the solvent was distilled off with a rotary evaporator, the green oily substance was diluted with water, extracted with ethyl acetate, the organic phase was washed with a saturated sodium chloride solution, and dried with anhydrous sodium sulfate. Then, the solvent was concentrated under reduced pressure to obtain 0.76 g of a white solid, and the crude product was used as it was in the next reaction.

MS (m / z): 323.0 [M + Na] ⁺
(2) Preparation of 2-O-benzyl-3-O-benzyl-6-O- (3-carboxylate-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid

Di-t-butyl 3-carboxylic acid-cyclobutane-1,1-dicarboxylic acid (0.76 g) was dissolved in 10 mL of dichloromethane to add dicyclohexylcarbodiimide (0.622 g) and a catalytic amount of 4-dimethylaminopyridine. In addition, after stirring the reaction solution for 0.5 hour, a dichloromethane solution (5 mL) of 2-O-benzyl-3-O-benzyl-L-ascorbic acid (1.1 g) was slowly added dropwise, and the reaction solution was brought to room temperature. Stirred overnight. The reaction is monitored by TLC, and after the reaction is completed, suction filtration is performed, the filtrate is concentrated by a rotary evaporator, and the obtained yellow oil is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7/1) as it is. To obtain 1.0 g of a white solid product.

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.20 (m, 10H), 5.22-5.08 (m, 4H), 4.67 (d, J = 2.0 Hz, 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). MS (m / z): 661.2 [M + Na] ⁺

(3) Preparation of 6-O- (3-carboxylate-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid

2-O-benzyl-3-O-benzyl-6-O- (3-carboxylate-cyclobutane-1,1-di-t-butyl dicarboxylate) L-ascorbic acid (1.0 g) in 10 mL of ethanol (0.1 g) 5% palladium carbon was added, the air in the flask was replaced with nitrogen gas three times, and the nitrogen gas in the reaction flask was replaced with hydrogen gas three times, and the reaction solution was prepared. Was stirred overnight at room temperature under hydrogen pressurization. After completion of the reaction, the hydrogen gas in the flask was replaced with nitrogen gas, suction filtered, the filtered cake was rinsed with ethanol three times, and the solvent was concentrated under reduced pressure to obtain 0.68 g of a colorless transparent oily product. The crude product was used as it was in the next reaction.

MS (m / z): 481.2 [M + Na] ⁺

(4) Preparation of 6-O- (3-carboxylate-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid

6-O- (3-carboxylate-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid (0.68 g) was dissolved in 10 mL of dichloromethane and cooled to 0 ° C. Trifluoroacetic acid (5 mL) was slowly added dropwise under the protection of nitrogen. The reaction solution was slowly heated to room temperature and stirred overnight. After completion of the reaction, the solvent was removed by a rotary evaporator, and after drying by a freeze-dryer, 0.5 g of a colorless viscous liquid was obtained, and the crude product was used as it was in the next reaction.

MS (m / z): 369.2 [M + Na] ⁺

(5) Preparation of diaminoplatinum (II) [3-carboxylate- (6-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product of 6-O- (3-carboxylate-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid (0.5 g) is dissolved in 10 mL of water, and a saturated barium hydroxide solution is added for the reaction. The pH of the solution was adjusted to 7, and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, cyclohexanediamine platinum sulfate (0.45 g) is dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with barium hydroxide solution, and shielded from light at room temperature 3 Stir for hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 4 g was obtained and was a white solid.

^{1 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] ⁺

Example 4
Preparation of diaminoplatinum (II) [3-ethylene- (2-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

(1) Preparation of 3-benzyloxyethyl-cyclobutane-1,1-dicarboxylic acid di-t-butyl

Sodium hydride (452 mg) was mixed and suspended in 10 mL of N, N-dimethylformamide, the air in the flask was replaced with nitrogen gas, and the flask was placed in an ice bath. Under nitrogen protection, di-t-butyl malonic acid (2.5 mL) was slowly added dropwise and reacted for 0.5 hours, followed by 2-benzyloxyethyl-1,3-dibromopropane (1.9 g). The N, N-dimethylformamide solution (5 mL) was slowly added dropwise, the temperature of the reaction solution was raised to 70 ° C., and the mixture was stirred for 7 hours. The end point of the reaction is monitored by TLC, and after the reaction is completed, the reaction solution is cooled to room temperature, 100 mL of ethyl acetate is added to the reaction solution, the mixture is washed with saturated aqueous ammonium chloride solution (1 × 50 mL), and the aqueous phase is acetate. Extraction was made with ethyl (2 x 25 mL) and combined with the organic phase. The organic phase was washed with saturated aqueous ammonium chloride solution (1 x 100 mL), distilled water (1 x 100 mL), and saturated sodium chloride solution (1 x 100 mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product. The pale yellow oil was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50/1) to obtain 1.7 g of a colorless transparent oil product.

^{1 1} H NMR (600 MHz, CDCl ₃ ) δ 7.35-7.27 (m, 5H), 4.47 (s, 2H), 3.40 (t, J = 6.3 Hz, 2H), 2 .53 (t, J = 10.2 Hz, 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) Preparation of di-t-butyl 3-hydroxyethyl-cyclobutane-1,1-dicarboxylic acid

Dissolve di-t-butyl 3-benzyloxyethyl-cyclobutane-1,1-dicarboxylate (1.7 g) in 10 mL of methanol, add 10% palladium carbon (0.1 g), and use nitrogen gas. The air in the flask was replaced 3 times, the nitrogen gas in the reaction flask was further replaced with hydrogen gas 3 times, and the reaction solution was stirred overnight at room temperature under hydrogen pressurization. After completion of the reaction, the hydrogen gas in the flask was replaced with nitrogen gas, suction filtration was performed, the filtered cake was rinsed with methanol three times, and the filtrate was concentrated under reduced pressure to obtain 1.3 g of a colorless transparent oil product. ..

^{1 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) Preparation of di-t-butyl 3-bromoethyl-cyclobutane-1,1-dicarboxylic acid

Di-t-butyl 3-hydroxyethyl-cyclobutane-1,1-dicarboxylate (1.3 g) is dissolved in 10 mL of dry dichloromethane and a solution of triphenylphosphine (1.7 g) in dichloromethane (5 mL) in an ice bath. ) Was slowly added and reacted for 10 minutes, then a dichloromethane solution (5 mL) of carbon tetrabromide (2.1 g) was slowly added dropwise, the reaction solution was slowly heated to room temperature, and the mixture was stirred for 1 hour. The end point of the reaction is monitored by TLC, and after the reaction is completed, the reaction solution is concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50/1) to obtain 1.4 g of a colorless transparent oily product. rice field.

^{1 1} H NMR (600 MHz, CDCl ₃ ) δ 3.30 (t, J = 6.8 Hz, 2H), 2.58 (t, J = 9.9 Hz, 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) Preparation of 5,6-O-isopropylidene-2-O- (3-ethylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) -3-O-benzyl-L-ascorbic acid

At room temperature conditions, 5,6-O-isopropyridene-3-O-benzyl-L-ascorbic acid (2.4 g), and 3-bromoethyl-cyclobutane-1,1-dicarboxylate di-t-butyl (1. 4 g) was dissolved in 10 mL of dimethyl sulfoxide, potassium carbonate (1.1 g) was added to the reaction solution, the temperature of the reaction solution was raised to 50 ° C., and the mixture was stirred for 3 hours. The end point of the reaction is monitored by TLC, and after the reaction is completed, the reaction solution is cooled to room temperature, 50 mL of water is added to the reaction solution to dilute the reaction solution, the mixture is neutralized with 1 M dilute hydrochloric acid, and then extracted with ethyl acetate to extract the organic phase. Was washed with distilled water (1 x 100 mL) and saturated sodium chloride solution (1 x 100 mL) in this order, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained pale yellow oily substance was subjected to silica gel column chromatography (petroleum oil). Purification with ether / ethyl acetate = 5/1) gave 1.7 g of a colorless transparent oily product.

¹ H NMR (600 MHz, 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) Preparation of 5,6-O-isopropylidene-2-O- (3-ethylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid

5,6-O-isopropylidene-2-O- (3-ethylene-cyclobutane-1,1-dicarboxylate di-t-butyl) -3-O-benzyl-L-ascorbic acid (1.7 g), Dissolve in 15 mL of ethanol, add 5% palladium carbon (0.1 g), replace the air in the flask with nitrogen gas three times, and then replace the nitrogen gas in the reaction flask with hydrogen gas three times. , The reaction solution was stirred overnight at room temperature under hydrogen pressurization. After completion of the reaction, the hydrogen gas in the flask was replaced with nitrogen gas, suction filtration was performed, the filtered cake was rinsed with ethanol three times, and the filtrate was concentrated under reduced pressure to obtain 1.3 g of a colorless transparent oil product. ..

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 4.68 (d, J = 3.7 Hz, 1H), 4.42-4.39 (m, 1H), 4.19-4.02 (m, 4H), 2.58-2.46 (m, 3H), 2.34-223 (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). MS (m / z): 521.2 [M + Na] ⁺

(6) Preparation of 2-O- (3-ethylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid

5,6-O-isopropylidene-2-O- (3-ethylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid (1.3 g) was dissolved in 10 mL of dichloromethane. , Cooled to 0 ° C., and trifluoroacetic acid (5 mL) was slowly added dropwise under the protection of nitrogen. The reaction solution was slowly heated to room temperature and stirred overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure and dried in a freeze-dryer to obtain 0.8 g of a colorless viscous liquid, and the crude product was used as it was in the next reaction.

MS (m / z): 369.1 [M + Na] ⁺

(7) Preparation of diaminoplatinum (II) [3-ethylene- (2-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product (0.8 g) of 2-O- (3-ethylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid is dissolved in 10 mL of water, and a saturated solution of barium hydroxide is added to the reaction solution. The pH of the mixture was adjusted to 7, and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, platinum diamine sulfate (0.7 g) is dissolved in 2 ml of water, added to the above reaction solution, the pH is adjusted to 7 with a saturated solution of barium hydroxide, and the mixture is shielded from light at room temperature 3 Stir for hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 6 g was obtained and was a white solid.

^{1 1} H NMR (600 MHz, D ₂ O) δ 4.82 (d, J = 1.3 Hz, 1H), 4.15 (brs, 5H), 4.01 (td, J = 6.9, 1) .7 Hz, 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] ^-

Example 5
Preparation of diaminoplatinum (II) [3-ethylene- (3-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

(1) Preparation of 5,6-O-isopropylidene-3-O- (3-ethylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid

Under room temperature conditions, 5,6-O-isopropyridene L-ascorbic acid (1.2 g) is dissolved in 10 mL of dimethyl sulfoxide, sodium hydrogen carbonate (0.5 g) is added, and the reaction solution is stirred for 20 minutes. After that, a dimethyl sulfoxide solution (5 mL) of 3-bromoethyl-cyclobutane-1,1-dicarboxylic acid di-t-butyl (1.4 g) was added, the temperature was raised to 60 ° C. of the reaction solution, and the mixture was stirred overnight. .. The end point of the reaction is monitored by TLC, and after the reaction is completed, the reaction solution is cooled to room temperature, 50 mL of water is added to the reaction solution to dilute the reaction solution, the mixture is neutralized with 1 M dilute hydrochloric acid, and then extracted with ethyl acetate (100 mL). , The organic phase was washed with distilled water (1 × 100 mL) and saturated sodium chloride solution (1 × 100 mL) in this order, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained yellow oil was chromatographed by silica gel column chromatography. Purification by chromatography (petroleum ether / ethyl acetate = 5/1) gave 1.6 g of a clear, colorless oil product.

^{1 1} H NMR (600 MHz, 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) Preparation of 3-O- (3-ethylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid

5,6-O-isopropylidene-3-O- (3-ethylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid (1.6 g) was dissolved in 10 mL of dichloromethane. , Cooled to 0 ° C., and trifluoroacetic acid (5 mL) was slowly added dropwise under the protection of nitrogen. The reaction solution was slowly heated to room temperature and stirred overnight. After completion of the reaction, the solvent was removed under reduced pressure, and after drying in a freeze-dryer, 1.0 g of a colorless viscous liquid was obtained, and the crude product was used as it was in the next reaction. MS (m / z): 369.1 [M + Na] ⁺

(3) Preparation of diaminoplatinum (II) [3-ethylene- (3-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product (1.0 g) of 3-O- (3-ethylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid is dissolved in 10 mL of water, and a saturated solution of barium hydroxide is added to the reaction solution. The pH of the mixture was adjusted to 7, and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, platinum diamine sulfate (0.9 g) is dissolved in 2 ml of water, added to the above reaction solution, the pH is adjusted to 7 with a saturated solution of barium hydroxide, and the mixture is shielded from light at room temperature 3 Stir for hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. An 8 g final product was obtained and was a white solid.

^{1 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] ⁺

Example 6
Preparation of diaminoplatinum (II) [3-acetate- (6-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

(1) Preparation of di-t-butyl 3-acetic acid-cyclobutane-1,1-dicarboxylic acid

Di-t-butyl 3-hydroxyethyl-cyclobutane-1,1-dicarboxylate (1.3 g) was dissolved in 10 mL of acetone and Jones' reagent (chrome trioxide 650 mg, concentrated sulfuric acid 559 μL, water) under ice bath conditions. (Diluted to 2.4 mL by adding Was removed. The reaction solution was suction-filtered, and the filtrate was concentrated under reduced pressure to obtain a green oil. The oil is diluted with water, extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.2 g of a white solid to give the crude product. It was used as it was for the next reaction. MS (m / z): 337.2 [M + Na] ⁺

(2) Preparation of 2-O-benzyl-3-O-benzyl-6-O- (3-acetate-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid

Di-t-butyl 3-acetic acid-cyclobutane-1,1-dicarboxylate (1.2 g) was dissolved in dichloromethane, and dicyclohexylcarbodiimide (1.2 g) and a catalytic amount of 4-dimethylaminopyridine were added. After stirring the reaction solution for 0.5 hours, a dichloromethane solution (5 mL) of 2-O-benzyl-3-O-benzyl-L-ascorbic acid (2.1 g) was slowly added dropwise, and the reaction solution was allowed to cool overnight at room temperature. Stirred. The reaction was monitored by TLC, and after the reaction was completed, suction filtration was performed and the filtrate was concentrated under reduced pressure to obtain a yellow oil. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 7/1) gave 1.7 g of a white solid product.

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) Preparation of 6-O- (3-acetate-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid

2-O-benzyl-3-O-benzyl-6-O- (3-acetate-cyclobutane-1,1-di-t-butyl dicarboxylate) L-ascorbic acid (1.7 g) in 10 mL of ethanol Dissolve, add 5% palladium carbon (0.1 g), replace the air in the flask with nitrogen gas three times, and further replace the nitrogen gas in the reaction flask with hydrogen gas three times to prepare the reaction solution. The mixture was stirred overnight at room temperature under hydrogen pressurization. After completion of the reaction, the hydrogen gas in the flask was replaced with nitrogen gas, suction filtration was performed, the filtered cake was rinsed 3 times with ethanol, and the filtrate was concentrated under reduced pressure to obtain 1.1 g of a colorless transparent oil product. , The crude product was used as it was for the next reaction. MS (m / z): 495.2 [M + Na] ⁺

(4) Preparation of 6-O- (3-acetate-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid

6-O- (3-acetate-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid (1.1 g) is dissolved in 10 mL of dichloromethane, cooled to 0 ° C., and nitrogen. Trifluoroacetic acid (5 mL) was slowly added dropwise under the protection of. The reaction solution was slowly heated to room temperature and stirred overnight. After completion of the reaction, the solvent was removed under reduced pressure, freeze-dried, and then 0.8 g of a colorless viscous liquid was obtained, and the crude product was used as it was in the next reaction. MS (m / z): 383.1 [M + Na] ⁺

(5) Preparation of diaminoplatinum (II) [3-acetate- (6-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product of 6-O- (3-acetate-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid (0.8 g) is dissolved in 10 mL of water, and a saturated barium hydroxide solution is added to the reaction solution. The pH of the mixture was adjusted to 7 and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, cyclohexanediamine platinum platinum (0.7 g) is dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with barium hydroxide solution, and shielded from light at room temperature 3 Stir for hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 6 g was obtained and was a white solid.

^{1 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] ⁺

Example 7
Preparation of diaminoplatinum (II) [3-propylene- (2-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

(1) Preparation of di-t-butyl 3-benzyloxypropyl-cyclobutane-1,1-dicarboxylic acid

Sodium hydride (549 mg) was mixed and suspended in 10 mL of N, N-dimethylformamide, the air in the flask was replaced with nitrogen gas, and the flask was placed in an ice bath. Under nitrogen protection, di-t-butyl malonic acid (3.1 mL) was slowly added dropwise and reacted for 0.5 hours before 2-benzyloxypropyl-1,3-dibromopropane (2.4 g). A solution of N, N-dimethylformamide (5 mL) was slowly added dropwise, the temperature of the reaction solution was raised to 70 ° C., and the mixture was stirred for 7 hours. The end point of the reaction is monitored by TLC, and after the reaction is completed, the reaction solution is cooled to room temperature, 100 mL of ethyl acetate is added to the reaction solution, the mixture is washed with saturated aqueous ammonium chloride solution (1 × 50 mL), and the aqueous phase is acetate. Extraction was made with ethyl (2 x 25 mL) and combined with the organic phase. The organic phase was washed in the order of saturated aqueous ammonium chloride solution (1 × 100 mL), distilled water (1 × 100 mL), and saturated sodium chloride solution (1 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product. The obtained pale yellow oil was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50/1) to obtain 1.9 g of the desired product as a colorless transparent oil.

^{1 1} H NMR (600 MHz, 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) Preparation of di-t-butyl 3-hydroxypropyl-cyclobutane-1,1-dicarboxylic acid

Dissolve di-t-butyl 3-benzyloxypropyl-cyclobutane-1,1-dicarboxylate (1.9 g) in 10 mL of methanol, add 10% palladium carbon (0.1 g), and use nitrogen gas. The air in the flask was replaced 3 times, the nitrogen gas in the reaction flask was further replaced with hydrogen gas 3 times, and the reaction solution was stirred overnight at room temperature under hydrogen pressurization. After completion of the reaction, the hydrogen gas in the flask was replaced with nitrogen gas, suction filtration was performed, the filtered cake was rinsed with methanol three times, and the filtrate was concentrated under reduced pressure to obtain 1.4 g of a colorless transparent oil product. ..

^{1 1} H NMR (600 MHz, 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) Preparation of di-t-butyl 3-bromopropyl-cyclobutane-1,1-dicarboxylic acid

Dissolve 1.4 g of di-t-butyl 3-hydroxypropyl-cyclobutane-1,1-dicarboxylate in 10 mL of dry dichloromethane and in an ice bath a solution of triphenylphosphine (1.7 g) in dichloromethane (5 mL). After slowly adding and reacting for 10 minutes, a dichloromethane solution (5 mL) of carbon tetrabromide (2.2 g) was slowly added dropwise, the reaction solution was slowly heated to room temperature, and the mixture was stirred for 1 hour. The end point of the reaction is monitored by TLC, and after the reaction is completed, the reaction solution is concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50/1) to obtain 1.6 g of the target product of a colorless transparent oil. Obtained.

^{1 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) Preparation of 5,6-O-isopropylene-2-O- (3-propylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) -3-O-benzyl-L-ascorbic acid

5,6-O-isopropyridene-3-O-benzyl-L-ascorbic acid (2.6 g) and di-t-butyl 3-bromopropyl-cyclobutane-1,1-dicarboxylate (1) at room temperature. .6 g) was dissolved in 15 mL of dimethyl sulfoxide, potassium carbonate (1.2 g) was added to the reaction solution, the temperature of the reaction solution was raised to 50 ° C., and the mixture was stirred for 3 hours. The end point of the reaction is monitored by TLC, and after the reaction is completed, the reaction solution is cooled to room temperature, 50 mL of water is added to the reaction solution to dilute the reaction solution, the mixture is neutralized with 1 M dilute hydrochloric acid, and then extracted with ethyl acetate to extract the organic phase. Was washed in the order of distilled water (1 × 100 ml) and saturated sodium chloride solution (1 × 100 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained pale yellow oil was subjected to silica gel column chromatography (1 × 100 ml). Purification with petroleum ether / ethyl acetate = 5/1) gave 2.0 g of a colorless transparent oily product.

^{1 1} H NMR (600 MHz, CDCl ₃ ) δ 7.44-7.33 (m, 5H), 5.47 (s, 2H), 4.54 (d, J = 2.1 Hz, 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) Preparation of 5,6-O-isopropylene-2-O- (3-propylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid

5,6-O-isopropylidene-2-O- (3-propylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) -3-O-benzyl-L-ascorbic acid (2.0 g), Dissolve in 10 mL of ethanol, add 5% palladium carbon (0.2 g), replace the air in the flask with nitrogen gas three times, and then replace the nitrogen gas in the reaction flask with hydrogen gas three times. , The reaction solution was stirred overnight at room temperature under hydrogen pressurization. After completion of the reaction, the hydrogen gas in the flask was replaced with nitrogen gas, suction filtration was performed, the filtered cake was rinsed with ethanol three times, and concentrated under reduced pressure to obtain 1.6 g of a colorless transparent oily product.

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 4.69 (d, J = 3.7 Hz, 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) Preparation of 2-O- (3-propylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid

5,6-O-isopropylidene-2-O- (3-propylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid (1.6 g) was dissolved in 10 mL of dichloromethane. , Cooled to 0 ° C., and trifluoroacetic acid (5 mL) was slowly added dropwise under the protection of nitrogen. The reaction solution was slowly heated to room temperature and stirred overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, freeze-dried, and then 1.0 g of a colorless viscous liquid was obtained, and the crude product was used as it was in the next reaction.

MS (m / z): 383.2 [M + Na] ⁺

(7) Preparation of diaminoplatinum (II) [3-propylene- (2-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product (1.0 g) of 2-O- (3-propylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid is dissolved in 10 mL of water, and a saturated barium hydroxide solution is added to the reaction solution. The pH of the mixture was adjusted to 7 and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, platinum diamine sulfate (1.0 g) is dissolved in 2 ml of water, added to the above reaction solution, the pH is adjusted to 7 with a barium hydroxide solution, and the mixture is shielded from light at room temperature for 3 hours. Stirred. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 9 g was obtained and was a white solid.

^{1 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] ⁺

Example 8
Preparation of diaminoplatinum (II) [3-propylene- (3-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

(1) Preparation of 5,6-O-isopropylene-3-O- (3-propylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid

Under room temperature conditions, 5,6-O-isopropyridene L-ascorbic acid (1.4 g) is dissolved in 10 mL of dimethyl sulfoxide, sodium hydrogen carbonate (0.5 g) is added, and the reaction solution is stirred for 20 minutes. After that, a dimethyl sulfoxide solution (5 mL) of 3-bromopropyl-cyclobutane-1,1-dicarboxylate di-t-butyl (1.6 g) was added, the temperature was raised to 60 ° C. of the reaction solution, and the mixture was stirred overnight. bottom. The end point of the reaction is monitored by TLC, and after the reaction is completed, the reaction solution is cooled to room temperature, 50 mL of water is added to the reaction solution to dilute the reaction solution, the mixture is neutralized with 1 M dilute hydrochloric acid, and then extracted with ethyl acetate to extract the organic phase. Was washed in the order of distilled water (1 × 100 ml) and saturated sodium chloride solution (1 × 100 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained pale yellow oil was subjected to silica gel column chromatography (1 × 100 ml). Petroleum ether / ethyl acetate = 5/1) Purification to obtain 1.7 g of a colorless transparent oily product.

^{1 1} H NMR (600 MHz, 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) Preparation of 3-O- (3-propylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid

5,6-O-isopropylidene-3-O- (3-propylene-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid (1.7 g) was dissolved in 15 mL of dichloromethane. , Cooled to 0 ° C., and trifluoroacetic acid (5 mL) was slowly added dropwise under the protection of nitrogen. The reaction solution was slowly heated to room temperature and stirred overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, freeze-dried, and then 1.1 g of a colorless viscous liquid was obtained, and the crude product was used as it was in the next reaction.

MS (m / z): 383.2 [M + Na] ⁺

(3) Preparation of diaminoplatinum (II) [3-propylene- (3-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product (1.1 g) of 3-O- (3-propylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid is dissolved in 10 mL of water, and a saturated barium hydroxide solution is added to the reaction solution. The pH of the mixture was adjusted to 7 and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, platinum diamine sulfate (1.0 g) is dissolved in 2 ml of water, added to the above reaction solution, the pH is adjusted to 7 with a barium hydroxide solution, and the mixture is shielded from light at room temperature for 3 hours. Stirred. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 9 g was obtained and was a white solid.

^{1 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] ⁺

Example 9
Preparation of diaminoplatinum (II) [3-propionate- (6-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

(1) Preparation of 3-propionic acid-cyclobutane-1,1-dicarboxylic acid di-t-butyl

Di-t-butyl 3-hydroxypropyl-cyclobutane-1,1-dicarboxylate (1.4 g) was dissolved in 10 mL of acetone and Jones' reagent (chromium trioxide 669 mg, concentrated sulfuric acid 576 μL, water) under ice bath conditions. Add and dilute to 2.5 mL) slowly, slowly raise the temperature of the reaction solution to room temperature, stir for 2 hours, monitor the reaction with TLC, and after the reaction is completed, add isopropanol and add excess oxidant. Was removed. The reaction solution was suction-filtered, and the filtrate was concentrated under reduced pressure to obtain a green oil. The oil is diluted with water, extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.3 g of a white solid to give the crude product. It was used as it was for the next reaction. MS (m / z): 351.2 [M + Na] ⁺

(2) Preparation of 2-O-benzyl-3-O-benzyl-6-O- (3-propionate-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid

Di-t-butyl 3-propionic acid-cyclobutane-1,1-dicarboxylic acid (1.3 g) was dissolved in 10 mL of dichloromethane to add dicyclohexylcarbodiimide (1.2 g) and a catalytic amount of 4-dimethylaminopyridine. In addition, after stirring the reaction solution for 0.5 hour, a dichloromethane solution (5 mL) of 2-O-benzyl-3-O-benzyl-L-ascorbic acid (2.1 g) was slowly added dropwise, and the reaction solution was brought to room temperature. Stird overnight. The reaction is monitored by TLC, and after the reaction is completed, suction filtration is performed, the filtrate is concentrated under reduced pressure, and the obtained yellow oil is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7/1) to be white. 2.0 g of the system solid product was obtained.

^{1 1} H NMR (600 MHz, 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), 2.31-222 (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) Preparation of 6-O- (3-propionate-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid

2-O-benzyl-3-O-benzyl-6-O- (3-propionate-cyclobutane-1,1-di-t-butyl dicarboxylate) L-ascorbic acid (2.0 g) in 10 mL of ethanol Dissolve, add 5% palladium carbon (0.2 g), replace the air in the flask with nitrogen gas three times, and further replace the nitrogen gas in the reaction flask with hydrogen gas three times to prepare the reaction solution. The mixture was stirred overnight at room temperature under hydrogen pressurization. After completion of the reaction, the hydrogen gas in the flask was replaced with nitrogen gas, suction filtration was performed, the filtered cake was rinsed 3 times with ethanol, and the filtrate was concentrated under reduced pressure to obtain 1.4 g of a colorless transparent oil product. , The crude product was used as it was for the next reaction.

MS (m / z): 509.1 [M + Na] ⁺

(4) Preparation of 6-O- (3-propionate-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid

6-O- (3-propionate-cyclobutane-1,1-dicarboxylic acid di-t-butyl) L-ascorbic acid (1.4 g) is dissolved in 10 mL of dichloromethane, cooled to 0 ° C., and nitrogen. Trifluoroacetic acid (5 mL) was slowly added dropwise under the protection of. The reaction solution was slowly heated to room temperature and stirred overnight. After completion of the reaction, the solvent was removed by a rotary evaporator, and after drying by a freeze-dryer, 1.0 g of a colorless viscous liquid was obtained, and the crude product was used as it was in the next reaction.

MS (m / z): 397.1 [M + Na] ⁺

(5) Preparation of diaminoplatinum (II) [3-propionate- (6-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product (1.0 g) of 6-O- (3-propionate-cyclobutane-1,1-dicarboxylic acid) -L-ascorbic acid is dissolved in 10 mL of water, and a saturated barium hydroxide solution is added to react. The pH of the solution was adjusted to 7, and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, cyclohexanediamine platinum platinum (0.8 g) is dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with barium hydroxide solution, and shielded from light at room temperature 3 Stir for hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 7 g was obtained and was a white solid.

^{1 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] ⁺

Example 10
Preparation of cis- [trans- (1R, 2R) -diaminocyclohexane] platinum (II) [3-methylene- (2-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product of 2-O- (3-methylene-cyclobutane-1,1-dicarboxylic acid) -L-ascorbic acid (0.4 g) is dissolved in 10 mL of water, and a saturated solution of barium hydroxide is added for the reaction. The pH of the solution was adjusted to 7, and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, cyclohexanediamine sulfate platinum (0.5 g) is dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with a saturated solution of barium hydroxide, and shielded from light at room temperature. The mixture was stirred for 3 hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 4 g was obtained and was a white solid.

^{1 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] ^-

Example 11
Preparation of cis- [trans- (1R, 2R) -diaminocyclohexane] platinum (II) [3-methylene- (3-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product of 3-O- (3-methylene-cyclobutane-1,1-dicarboxylic acid) L-ascorbic acid (0.5 g) is dissolved in 10 mL of water, and a saturated solution of barium hydroxide is added to the reaction solution. The pH of the mixture was adjusted to 7 and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, cyclohexanediamine sulfate platinum (0.6 g) is dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with a saturated solution of barium hydroxide, and shielded from light at room temperature. The mixture was stirred for 3 hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 5 g was obtained and was a white solid.

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), 1.36-121 (m, 2H), 1.13 (brs, 2H). MS (m / z): 662.0 [M + Na] ⁺

Example 12
Preparation of cis- [trans- (1R, 2R) -diaminocyclohexane] platinum (II) [3-carboxylate- (6-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product of 6-O- (3-carboxylate-cyclobutane-1,1-dicarboxylic acid) -L-ascorbic acid (0.5 g) is dissolved in 10 mL of water and a saturated barium hydroxide solution is added. The pH of the reaction solution was adjusted to 7, and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, cyclohexanediamine platinum sulfate (0.54 g) is dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with barium hydroxide solution, and shielded from light at room temperature 3 Stir for hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 5 g was obtained and was a white solid.

^{1 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] ⁺

Example 13
Preparation of cis- [trans- (1R, 2R) -diaminocyclohexane] platinum (II) [3-ethylene- (2-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product of 2-O- (3-ethylene-cyclobutane-1,1-dicarboxylic acid) -L-ascorbic acid (0.8 g) is dissolved in 10 mL of water, and a saturated solution of barium hydroxide is added for the reaction. The pH of the solution was adjusted to 7, and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, cyclohexanediamine sulfate platinum (0.9 g) is dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with a saturated solution of barium hydroxide, and shielded from light at room temperature. The mixture was stirred for 3 hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. An 8 g final product was obtained and was a white solid.

^{1 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 to 1.06 (m, 4H).
MS (m / z): 676.1 [M + Na] ⁺

Example 14
Preparation of cis- [trans- (1R, 2R) -diaminocyclohexane] platinum (II) [3-ethylene- (3-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product of 3-O- (3-ethylene-cyclobutane-1,1-dicarboxylic acid) -L-ascorbic acid (1.0 g) is dissolved in 10 mL of water, and a saturated solution of barium hydroxide is added for the reaction. The pH of the solution was adjusted to 7, and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, cyclohexanediamine sulfate platinum (1.2 g) is dissolved in 2 ml of water, added to the above reaction solution, the pH is adjusted to 7 with a saturated solution of barium hydroxide, and the mixture is shielded from light at room temperature. The mixture was stirred for 3 hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 9 g was obtained and was a white solid.

^{1 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] ⁺

Example 15
Preparation of cis- [trans- (1R, 2R) -diaminocyclohexane] platinum (II) [3-acetate- (6-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product of 6-O- (3-acetate-cyclobutane-1,1-dicarboxylic acid) -L-ascorbic acid (0.8 g) is dissolved in 10 mL of water, and a saturated barium hydroxide solution is added for the reaction. The pH of the solution was adjusted to 7, and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, cyclohexanediamine platinum sulfate (0.9 g) is dissolved in 2 ml of water, added to the above reaction solution, adjusted to pH 7 with barium hydroxide solution, and shielded from light at room temperature 3 Stir for hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 7 g was obtained and was a white solid.

^{1 1} H NMR (400 MHz, D ₂ O) δ 5.74 (brs, 2H), 5.03 (brs, 2H), 4.91 (d, J = 1.9 Hz, 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] ⁺

Example 16
Preparation of cis- [trans- (1R, 2R) -diaminocyclohexane] platinum (II) [3-propylene- (2-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product (1.0 g) of 2-O- (3-propylene-cyclobutane-1,1-dicarboxylic acid) -L-ascorbic acid is dissolved in 10 mL of water, and a saturated barium hydroxide solution is added for the reaction. The pH of the solution was adjusted to 7, and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, cyclohexanediamine sulfate platinum (1.2 g) is dissolved in 2 ml of water, added to the above reaction solution, the pH is adjusted to 7 with a barium hydroxide solution, and the mixture is shielded from light at room temperature 3 Stir for hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high-performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 0 g was obtained and was a white solid.

^{1 1} H NMR (400 MHz, D ₂ O) δ 5.73 (brs, 1H), 5.05 (brs, 1H), 4.93 (brs, 1H), 4.08 (td, J = 6.7) , 1.5 Hz, 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] ⁺

Example 17
Preparation of cis- [trans- (1R, 2R) -diaminocyclohexane] platinum (II) [3-propylene- (3-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

A crude product of 3-O- (3-methylene-cyclobutane-1,1-dicarboxylic acid) -L-ascorbic acid (1.1 g) is dissolved in 10 mL of water, and a saturated barium hydroxide solution is added for the reaction. The pH of the solution was adjusted to 7, and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, cyclohexanediamine sulfate platinum (1.2 g) is dissolved in 2 ml of water, added to the above reaction solution, the pH is adjusted to 7 with a barium hydroxide solution, and the mixture is shielded from light at room temperature 3 Stir for hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high-performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 0 g was obtained and was a white solid.

^{1 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] ⁺

Example 18
Preparation of cis- [trans- (1R, 2R) -diaminocyclohexane] platinum (II) [3-propionate- (6-OL-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

6-O- (3-propionate-cyclobutane-1,1-dicarboxylic acid) A crude product of L-ascorbic acid (1.0 g) is dissolved in 10 mL of water, and a saturated barium hydroxide solution is added to the reaction solution. The pH of the mixture was adjusted to 7 and the mixture was stirred at room temperature for 30 minutes. Under the protection of nitrogen, cyclohexanediamine sulfate platinum (1.1 g) is dissolved in 2 ml of water, added to the above reaction solution, the pH is adjusted to 7 with a barium hydroxide solution, and the mixture is shielded from light at room temperature 3 Stir for hours. The reaction is monitored by HPLC, and after the reaction is completed, the precipitate is removed using a centrifuge, the supernatant is collected, separated by semi-prepared high performance liquid chromatography, and freeze-dried using a freeze-dryer. A final product of 9 g was obtained and was a white solid.

^{1 1} H NMR (400 MHz, D ₂ O) δ 5.74 (brs, 2H), 5.03 (brs, 2H), 4.91 (d, J = 1.9 Hz, 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] ⁺

Test Example 1 Solubility test Experimental method: Take about 0.5 ml of distilled water in a 5 ml EP tube, and slowly add the dry compound until it becomes insoluble (even if it is shaken with ultrasonic waves at 25 ° C, it becomes turbid). rice field. The solution is collected by filtration into another 5 mL clean, weighed EP tube and weighed again to calculate the weight of the solution. If the filtrate is freeze-dried, weighed, and the mass of the solute of the residual solid content is calculated, the weight of the solvent and the mass of the solute can be grasped, thereby calculating the solubility of the compound in water.

The solubility of the platinum-based complex of the present invention in water far exceeds that of commercially available cisplatin, carboplatin, and oxaliplatin, and the water solubility is improved by several tens to 1,000 times or more.

Test Example 2
The following experiments verified the growth-inhibiting effect of the vitamin C-coupling platinum complex for tumor treatment of the present invention on different types of human tumor cells.

(1) Test method:
Cell culture medium:
A cell culture medium containing 10% fetal bovine serum is used.

Main experimental equipment:
HERAcell 150i carbon dioxide incubator (Thermo), research grade inverted fluorescence microscope (Nikon, Japan), multifunction microplate reader (Thermo), ultrapure water refrigerator (Thermo), biological safety cabinet (1300 Series A2, Thermo) ), Micropipette (Eppendorf, Germany), Ultrapure water system (Milli-Q, USA).

Experimental reagents:
MTT: Sigma-Aldrich DMSO: Tianjin Jiang Tian Chemical Technology Co., Ltd. Tumor cells:

Cytotoxicity test:
In the cytotoxicity experiment, the test was performed using the MTT method. Tumor cells in logarithmic stage were collected, the concentration of the cell suspension was adjusted, 100 μl was added per hole, and the density of the cells to be measured was adjusted to 1000 to 10000 cells / hole and inoculated into the culture plate ( Edge holes were filled with sterile PBS). Incubate at 5% CO ₂ , 37 ° C. until cells adhere (96-well flat bottom plate), 100 μl of drug with different concentration gradients was added per hole to provide 4 parallel holes in each hole. Incubated at 5% CO ₂ , 37 ° C. for 72 hours and observed under an inverted microscope. To a 96-well plate plate, add 20 μl of the prepared MTT solution (5 mg / ml) for each hole, mix uniformly, incubate for 4 hours under the conditions of 37 ° C. and 5% CO ₂ , and then add the liquid in the plate. After discarding, 150 μl of DMSO was added to each hole, and the mixture was shaken with a microplate reader for 3 minutes, and the OD value (optical density value) was measured at 490 nm.

Control group:
Under the same conditions as described above, the OD value measured at 490 nm of the tumor cells was finally obtained without adding the active ingredient to be measured.

Inhibitory activity of drug against tumor cells IC ₅₀ :
Calculation of cell inhibition rate: The inhibition rate of the drug against tumor cell proliferation was calculated by the following formula.

1) Cell survival rate (%) = (treatment group OD value / control group OD value) × 100
2) The cell viability at each drug concentration was calculated and plotted against the drug concentration. Based on this, the effect of inhibition on tumor cell proliferation of different drug concentrations was determined.
3) When the cell viability is 50% of the control group, the corresponding drug concentration is the half-inhibition concentration of the drug against the tumor cells, that is, the _IC50 value of the drug.

The above experiment of each drug concentration was repeated 4 times, and the cell survival rate was calculated by the average OD value.

(2) Experimental results:

The vitamin C coupling platinum complex of the present invention has good antitumor activity.

Claims (20)

A vitamin C coupling platinum complex represented by the formula (I), an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

_In the formula: X and Y are ligands, and the X and Y are independently _NH3 , C1 _- C8 linear or branched alkyl primary amines, and _{C3 -} C8 cyclic alkyl primary amines , respectively. , Aromatic primary amines, _one or more C1- _C4 alkyl substituted aromatic primary amines, secondary amines having a molecular formula of R1 _- NH- _R2 . Of these, R ₁ and R ₂ each independently represent a linear or branched alkyl group of C ₁ -C ₈ , or R ₁ -NH-R ₂ are integrated to form a fat of C ₄ -C ₈ . Cyclic secondary amine, nitrogen-containing aromatic heterocyclic compound, _one or more C1- _C4 linear or branched alkyl-substituted nitrogen-containing aromatic heterocyclic compounds, sulfur-containing aromatic heterocyclic compounds, or containing It forms a sulfur non-aromatic heterocyclic compound. However, the aryl group in the aromatic primary amine is a 5- to 10-membered monocyclic or fused bicyclic aromatic group, and the aromatic heterocycle is a 5- to 10-membered monocyclic or fused bicyclic. It is a heteroaromatic ring, and the non-aromatic heterocycle is a 4- to 10-membered monocyclic or polycyclic aliphatic heterocycle.
Alternatively, X and Y together form the structure of formula (IV).

[In formula (IV), D is an alkylene group of C ₀ or C ₁ , and B is an alkylene group of C ₂ -C ₈ . ]
n = 0, 1, 2, 3, 4, 5 or 6 .
m is 0 or 1.
R is

Is selected from. The X and Y are independently C. ₁ -C ₆ The vitamin C coupling platinum complex according to claim 1, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a linear or branched primary amine of the above. The X and Y are independently C. ₁ -C ₃ The vitamin C coupling platinum complex according to claim 2, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a linear or branched primary amine of the above. The X and Y are independently C. ₃ -C ₆ The vitamin C coupling platinum complex according to claim 1, which is a cyclic alkyl primary amine, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The R ₁ And R ₂ Are independent of each other, C ₁ -C ₆ The vitamin C coupling platinum complex according to claim 1, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a linear or branched alkyl group of the above. The R ₁ And R ₂ Are independent of each other, C ₁ -C ₃ The vitamin C coupling platinum complex according to claim 5, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a linear or branched alkyl group of the above. The R ₁ -NH-R ₂ Together, C ₅ -C ₆ The vitamin C coupling platinum complex according to claim 1, which is an alicyclic secondary amine, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. In the formula (IV), B is C. ₂ -C ₆ The vitamin C coupling platinum complex according to claim 1, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an alkylene group of the above. In the formula (IV), B is C. ₃ -C ₅ The vitamin C coupling platinum complex according to claim 8, the optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is the alkylene group of the above. The X and Y are NH ₃ , respectively, or X and Y are integrated into a trans- (1R, 2R) -cyclohexanediamine, a trans- (1S, 2S) -cyclohexanediamine, and a cis- (1R, 1R,). 2S) -Cyclohexanediamine, cis- (1S, 2R) -cyclohexanediamine, racemic trans-1,2-cyclohexanediamine, or racemicsis-1,2-cyclohexanediamine is formed according to claim 1. The above-mentioned vitamin C coupling platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The vitamin according to claim 10 , wherein each of the X and Y is NH ₃ , or X and Y together form a trans- (1R, 2R) -cyclohexanediamine. A C-coupling platinum complex, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The formula (I) is the cyclobutanedicarboxylic acid platinum complex according to claim 1 selected from the following complexes, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

The compound represented by the formula (III) .

During the ceremony:
Each M independently represents a hydrogen atom or a metal atom of Group IA of the Periodic Table, or two Ms together represent a metal atom of Group IIA of the Periodic Table.
n is 0, 1, 2, 3, 4, 5 or 6
m is 0 or 1 and
R is

Is. 13. The compound according to claim 13, wherein each of the Ms independently represents H, Na, K, Li or Cs, or two Ms together represent Ba. The method for producing a vitamin C coupling platinum complex according to any one of claims 1 to 12 , an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the formula ( The step of adding water to the compound II) and the compound of formula (III) to prepare and react as an aqueous solution may be included, and the pH may be adjusted to 7 to 9 by adding a base to the reaction aqueous solution .
The structural formula of (II) is

[In formula (II),
The definitions of X and Y are the same as in equation (I).
A ₁ and A ₂ may be the same or different and each independently represent a hydroxyl group, a nitrate group or a perchlorate group, or both A ₁ and A ₂ represent a sulfate group or a carbonate group. ]
And
The structural formula of (III) is

[In equation (III):
Each M independently represents a hydrogen atom or a metal atom of Group IA of the Periodic Table, or two Ms together represent a metal atom of Group IIA of the Periodic Table.
n = 0, 1, 2, 3, 4 , 5 or 6
m is 0 or 1 and
R is

Is. ]
A method for producing a vitamin C-coupling platinum complex, an optical isomer thereof, or a pharmaceutically acceptable salt or solvate thereof. The production method according to claim 15, wherein each of the Ms independently represents H, Na, K, Li or Cs, or two Ms together represent Ba. One or more of the vitamin C coupling platinum complex according to any one of claims 1 to 12 , or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and any of them. A pharmaceutical composition comprising a pharmaceutically acceptable carrier of. The vitamin C coupling platinum complex according to any one of claims 1 to 12 , or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical product according to claim 17 . Use of the composition to make antitumor agents. The tumors include human lung cancer, human liver cancer, human colon cancer, human head and neck cancer, human prostate cancer, human breast cancer, human ovarian cancer, human cervical cancer, human leukemia, human lymphoma, and human skin. Claim 18 for cancer, human pancreatic cancer, human bladder cancer, human esophageal cancer, human gastric cancer, human male reproductive organ cancer, human thyroid cancer, human bone cancer, or human melanoma, human oral cancer. Use as described in. The tumor cells include human colon cancer cell 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, and human. Prostate cancer cell DU145, human cervical cancer cell Hela, human melanoma cell A375, human oral epidermal cancer cell KB, human gastric cancer cell HGC27, human thyroid cancer cell SW579, human bladder cancer cell 5637, human pancreas 19. The use according to claim 19 , which is a cancer cell Panc-1, a human large cell lung cancer cell H460, a human plasma cell leukemia cell H929, a human liver cancer cell HepG2, and a human monocytic leukemia THP-1. ..