CN110218231A

CN110218231A - Cyclobutane dicarboxylic acid platinum complex, wherein mesosome, preparation method, pharmaceutical composition and purposes

Info

Publication number: CN110218231A
Application number: CN201910158841.8A
Authority: CN
Inventors: 高香倩; 韩建斌; 杨金娜; 杨柳
Original assignee: TIANJIN GUDUI BIOLOGICAL MEDICAL TECHNOLOGY CO LTD
Current assignee: TIANJIN GUDUI BIOLOGICAL MEDICAL TECHNOLOGY CO LTD
Priority date: 2018-03-02
Filing date: 2019-02-27
Publication date: 2019-09-10
Anticipated expiration: 2039-02-27
Also published as: KR20200118118A; JP2022517885A; KR102640022B1; CN110218231B; WO2019165964A1

Abstract

Cyclobutane dicarboxylic acid platinum complex, wherein mesosome, preparation method, pharmaceutical composition and purposes shown in a kind of formula (I).The cyclobutane dicarboxylic acid platinum complex has good anti-tumor activity.Complex provided by the present invention in terms of water solubility compared with existing platinum antineoplastic drug, all with tens times or more of raising, this highly-water-soluble feature can increase and improve drug in the excretion of kidney, mitigate platinum medicine generally there are high kidney toxic side effect, it is easy these compounds simultaneously formulation, application clinically is more convenient.

Description

Cyclobutane dicarboxylic acid platinum complex, wherein mesosome, preparation method, pharmaceutical composition And purposes

Technical field

The present invention relates to a kind of water-soluble platinum complex, wherein mesosome, preparation method, pharmaceutical composition and purposes.

Background technique

Platinum class anticarcinogen is the representative a kind of drug of therapeutic field of tumor.It belongs to non-specific cell cycle medicine Object all has therapeutic efficiency to sarcoma, carcinoma, lymthoma and germinoma.It answers extensively in the world at present Representative platinum class anticarcinogen for clinical treatment mainly has: cis-platinum, carboplatin and oxaliplatin.Platinum-containing anticancer drug Fatal defects are that have extremely strong toxic side effect and drug resistance problems that are intrinsic and being subsequently formed.Additionally, due to such drug It is metallo-organic compound, the extremely low characteristic of all generally existing water solubilitys of platinum class marketed drug, cis-platinum, carboplatin and oxaliplatin Water solubility be respectively 1.0,17.0,6.0mg/ml.

Summary of the invention

The purpose of the present invention is overcoming deficiency in the prior art, provide a kind of cyclobutane dicarboxylic acid platinum complex or its Optical isomer or its pharmaceutically acceptable salt or its solvate, with good water-soluble and good anti-swollen Tumor activity.

The present invention provides cyclobutane dicarboxylic acid platinum complex or its optical isomer or its pharmacy shown in a kind of formula (I) Upper acceptable salt or its solvate:

Wherein:

X and Y is ligand, and the X and Y are each independently selected from NH₃、C₁-C₈Linear or branched alkyl group primary amine (is chosen as C₁-C₆Linear or branched alkyl group primary amine, be chosen as C₁-C₃Linear or branched alkyl group primary amine), C₃-C₈Cyclic alkyl primary amine (can It is selected as C₃-C₆Cyclic alkyl primary amine), primary aromatic amine, one or more C₁-C₄The aromatic series primary that linear or branched alkyl group replaces Amine, molecular formula R₁-NH-R₂Secondary amine, wherein R₁And R₂It is same or different to be respectively expressed as C₁-C₈Linear or branched alkyl group (it is chosen as C₁-C₆Linear or branched alkyl group, be chosen as C₁-C₃Linear or branched alkyl group)；Or R₁-NH-R₂Collectively constitute C₄- C₈Alicyclic ring secondary amine (be chosen as C₅-C₆Alicyclic ring secondary amine), nitrogenous aromatic heterocyclic compounds, one or more C₁-C₄Straight chain or Nitrogenous aromatic heterocyclic compounds, sulfur-containing aromatic heterocyclic compound or the sulfur-bearing non-aromatic heterocyclic chemical combination that branched alkyl replaces Object；Wherein, the aryl in described " primary aromatic amine " is 5~10 unit monocycles or condensed-bicyclic aromatic group, and described " aromatic series is miscellaneous Ring " is 5~10 unit monocycles or condensed-bicyclic aromatic heterocycle；" non-aromatic heterocyclic " is that 4~10 unit monocycles or polycyclic rouge are miscellaneous Ring；

Or X and Y constitute formula (IV) structure together:

In formula (IV), D C₀Or C₁Alkylidene；B is C₂-C₈Alkylidene (be chosen as C₂-C₆Alkylidene, be chosen as C₃-C₅Alkylidene)；

N=0,1,2,3,4,5 or 6 (optionally, n=0,1,2,3 or 6, optionally, n=0,1,2 or 3)；

R is selected from following monosaccharide groups, and described monosaccharide 1- are substituted by α substitution or β substitution:

Optionally, R is selected from following monosaccharide groups, and monosaccharide 1- are substituted by α substitution or β substitution,

Optionally, the X and Y is respectively NH₃Or X, Y are trans--(1R, 2R)-cyclohexanediamine together, trans--(1S, 2S)-cyclohexanediamine, cis--(1R, 2S)-cyclohexanediamine, cis--(1S, 2R)-cyclohexanediamine, racemization anti-form-1,2- hexamethylene two Amine or racemic cis -1,2- cyclohexanediamine.

Optionally, the X and Y is respectively NH₃；Or X, Y are trans--(1R, 2R)-cyclohexanediamine together.

N=0,1,2,3 or 6；R is selected from following monosaccharide groups, and described monosaccharide 1- are substituted by α substitution or β substitution:

Optionally, the formula (I) is selected from following complexs,

Another aspect of the present invention provides formula (III) compound represented, may serve as ring shown in preparation formula (I) The intermediate of butane dicarboxylic acid's platinum complex,

In formula (III):

Each M is independently represented each other hydrogen atom, and perhaps the metallic atom of periodic table of elements group ia or two M are total With the metallic atom of group iia in representative element periodic table；Optional M is independently represented each other H, Na, K, Li, Cs or two M Ba is represented jointly；

N=0,1,2,3,4,5 or 6 (optionally, n=0,1,2,3 or 6, optionally, n=0,1,2 or 3)；

R is selected from hydrogen or following monosaccharide groups, and monosaccharide 1- are substituted by α substitution or β substitution:

Optionally, the formula (III) is selected from following compounds:

Formula (III-1), formula (III-2), in formula (III-3),

N=0,1,2,3 or 6 (optionally, n=0,1,2 or 3)；

M is independently represented each other H, Na, K, Li, Cs or two M represent Ba jointly.

Another aspect of the present invention provides above-mentioned cyclobutane dicarboxylic acid platinum complex or its optical isomer or its pharmacy The preparation method of upper acceptable salt, solvate comprising add water to be adjusted to formula (II) compound and formula (III) compound The step of aqueous solution is reacted；Optionally, it is 7-9 that reacting solution, which adds alkali to adjust pH,

Optionally, the alkali be inorganic base, optionally, the inorganic base be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, Sodium bicarbonate, potassium carbonate, lithium hydroxide, one of cesium hydroxide or barium hydroxide or a variety of；

The structural formula of (II) are as follows:

In formula (II):

Or X and Y mono- reinstate structural formula (IV) expression:

A₁And A₂It is same or different, it is independently represented each other hydroxyl, nitrate anion or perchlorate or A₁And A₂Jointly Represent sulfate radical or carbonate；

The structural formula of (III) are as follows:

In formula (III):

Each M is independently represented each other hydrogen atom, and perhaps the metallic atom of periodic table of elements TA race or two M are total With the metallic atom of group iia in representative element periodic table；Optional M is independently represented each other H, Na, K, Li, Cs or two M Ba is represented jointly；

N=0,1,2,3,4,5 or 6 (optionally, n=0,1,2,3 or 6)；

R is selected from hydrogen or R is selected from following monosaccharide groups, and monosaccharide 1- are substituted by α substitution or β substitution:

Optionally, in above-mentioned reaction, the compound (II) of compound (III) the selection 0.5-4 equivalent of every equivalent, preferably 1 To 2 equivalents.

Optionally, the inorganic alkali concentration is 0.1N-5N, preferably 1N.

Optionally, above-mentioned reaction can carry out within the scope of a wider temperature, such as selection is at 0-100 DEG C Temperature range carries out above-mentioned reaction, preferably 25-90 DEG C, more preferably 60-90 DEG C, and simultaneously with stirring preferably.According to The time that different target product reactions needs can be different.According to the property of differential responses object, generally require 1 hour to 30 days To complete.More often need 10 hours to 15 days time.

Optionally, compound of reaction is adjusted to water used in aqueous solution it is preferable to use deionized waters by above-mentioned reaction.

Its specific preparation can use following method and reaction equation to complete:

Method A:

Method B:

In method a, when M is hydrogen atom in formula (III), reaction can be by using inorganic base appropriate, such as hydrogen Sodium oxide molybdena, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, lithium hydroxide and cesium hydroxide etc. adjust reacting solution PH maintain between 7-9 the preparation for completing complex shown in formula (I)；When M is metallic atom, such as: sodium atom, potassium are former Son, lithium atom, barium atom or Cs atom, reaction can be gone on smoothly in aqueous solution, when necessary using a small amount of above-mentioned inorganic base Aqueous solution maintain the pH of reaction solution that the synthesis of complex shown in formula (I) can be completed between 7-9.

In method B, when M is hydrogen atom, reaction can by using the barium hydroxide of equivalent as inorganic base, It completes to prepare complex shown in formula (I) with the condensation reaction of metal platinum sulphate cpd shown in formula (II) in aqueous solution. When preparing complex of the present invention by method B, prior barium salt obtained can also be used, i.e. two M represent a barium atom jointly, It is reacted in aqueous solution with metal platinum sulphate complex shown in formula (II) to complete the preparation process of complex.

Compound represented by formula (II) can pass through the complex of corresponding cis- platinous chloride and X and Y in method A and B (such as: cis- two chloro- (1,2- diaminocyclohexanes) close platinum) and the silver nitrate of 2 equivalents or the sulfuric acid silver reaction of 1 equivalent and make It is standby.The reaction preferably carries out in aqueous solution, and the water used is preferably deionized water.Reaction temperature is proper in room temperature.

There is no special limits to the method that resulting product (I) is purified is prepared using the above method by the present invention System can be purified using the method for prior art routine, such as mixture after the reaction was completed can be first passed through and be filtered out The sediment that may be generated is removed, then by vacuum distillation concentration, organic solvent (optionally, the organic solvent is then added It is preferred that using organic solvent that can be miscible with water, such as alcohols (such as methanol, ethyl alcohol, propyl alcohol, butanol, isopropanol etc.), or Person and water have ethers (such as diethyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, ethylene glycol diethyl ether, the ethylene glycol of certain intersolubility Dimethyl ether etc.)), make target compound (I) Precipitation, finally collects obtained precipitating, such as pass through filtering, so that it may To obtain compound represented by required formula (I).In addition, purifying and refining product obtained in above-mentioned reaction (I) The method of chromatography etc., such as spent ion exchange resin can be used, or uses preparative liquid chromatography.Liquid chromatogram separation and purification is general First alcohol and water is used as mobile phase to carry out.

The compounds of this invention (III), can method C, D as given by following reaction equations by taking glucose as an example or It is prepared by any one in method E, F:

Method C:

Method D:

Method E:

Method F:

It,, can as the hydroxyl cyclobutane dicarboxylic acid ester derivant reacted with sugar in method C and D by taking glucose as an example By using hydroxyl 1,3- saturated dihalide hydrocarbon derivative and malonate compound such as dimethyl malenate, malonic acid two Ethyl ester, malonic acid benzhydryl ester, different lactone of malonic acid ring etc. according to conventional method known to document (such as: Molecules2016,21 (5), 612) it prepares.Obtained hydroxyl cyclobutane dicarboxylic acid ester derivant and glucose can be Condensation reaction is carried out in the presence of lewis acid in a solvent, to obtain the glucoside compounds of cyclobutane dicarboxylic acid ester.Contracting The condition for closing reaction is the hydroxyl cyclobutane dicarboxylic acid ester or phase purl that 0.1-50 equivalent is used for glucose compound The glucose of 0.1-50 equivalent is used hydroxyl cyclobutane dicarboxylic acid ester.The lewis acid used can be BF₃, SnCl₄, FeCl₃, AlCl₃, hydrochloric acid, p-methyl benzenesulfonic acid, camphorsulfonic acid etc., lewis acidic amount can be 0.1-10 relative to glucose and works as Amount.Used solvent can be tetrahydrofuran, and methylene chloride, toluene, glycol dimethyl ether, ethylene glycol diethyl ether etc. can also The reaction is carried out to use any one in two kinds of reactants as solvent.The temperature of reaction can from 0 DEG C to 100 DEG C, Generally the reaction can be completed in 60-80 DEG C of heating.Time required for reacting is different according to the difference of reactant, and general 1 Hour can complete to 7 days.Obtained reaction product can be refined by a series of purification condition, can generally be made With silica gel chromatography or liquid-phase chromatographic column partition method.The obtained product, the protecting group by removing malonic acid can To finally obtain compound represented by required formula (III).The method of deprotection according to the difference of the protecting group used and Difference, if the method that hydrogenating reduction can be used is deprotected using malonic acid benzhydryl ester, if using malonic acid When diethylester or the different lactone of malonic acid ring are reacted, inorganic base is can be used in methanol-water or THF- in deprotection reaction It is carried out in aqueous solvent, the ratio of organic solvent and water is generally 1: 1-4: 1.Used inorganic base can be sodium hydroxide, Potassium hydroxide, barium hydroxide, lithium hydroxide etc..Reaction temperature is generally room temperature, and the reaction time is generally 1-24 hours.Deprotection Silica gel chromatography perhaps ion exchange resin filtration method or using liquid chromatography can be used in the purification of the compound of generation It completes, if directly removing reaction dissolvent with the way of distillation, obtained product will be corresponding metal carboxylate.

Preparation method shown in method C and D is the sugar protected using acetyl group, or directly using non-protected sugar with contain Hydroxycyclobutane dicarboxylate derivatives are condensed the preparation that then deprotection obtains target product (III) in the presence of a lewis acid Route.

Preparation method shown in method E and F be first by hydroxyl 1,3- saturated dihalide hydrocarbon derivative and acetyl group protect or The non-protected sugar of person forms glycosides derivatives, then finally passes through de- with malonate condensation forms ring butane dicarboxylic acid's ester again Except protecting group obtains the preparation route of target product (III).

In method C and F, glucose can first be converted to corresponding acetyl glucose, then implement again with it is corresponding The acetylation of the condensation reaction of hydroxyl intermediate, glucose can be implemented according to method reported in the literature, such as in pyridine It can be completed within 1-24 hours using acetic anhydride as acetylation reagent in room temperature or in 60 DEG C of heating.

Another aspect of the present invention provides a kind of pharmaceutical composition comprising above-mentioned complex or its optical isomer, Or one of its pharmaceutically acceptable salt or its solvate or pharmaceutically acceptable load that is a variety of and being optionally present Body.

Another aspect of the present invention, provides one kind above-mentioned complex or its optical isomer or its is pharmaceutically acceptable Salt or its solvate or above-mentioned pharmaceutical composition are preparing the purposes in antitumor cell drug.

Optionally, the tumour cell is human lung cancer, human liver cancer, human large intestine cancer, number of people neck cancer, human prostata cancer, human milk Gland cancer, human ovarian cancer, human cervical carcinoma, human leukemia, people's lymph cancer, application on human skin cancer, human pancreas cancer, human bladder cancer, people's esophagus Cancer, human gastric cancer, people's male sex organ cancer, human thyroid carcinomas, people's bone cancer, human melanin cancer or human oral cancer.

Optionally, the tumour cell is human colon cancer cell HT29, Non-small cell lung carcinoma cell A549, and human liver cancer is thin Born of the same parents SMMC7721, human breast cancer cell line Bcap-37, Proliferation of Human Ovarian Cell SKOV3, esophageal cancer cell ECA109, human prostata cancer Cell DU145, human cervical carcinoma cell Hela, human melanoma cell A375, human mouth epidermoid carcinoma cell KB, gastric carcinoma cells HGC27, human thyroid cancer cell SW579, human bladder cancer cell 5637, human pancreatic cancer cell Panc-1, and human large cell lung cancer is thin Born of the same parents H460, people's plasma cell leukemia cell H929, human liver cancer cell HepG2, human monocytic leukaemia THP-1.

Anti-tumor drug of the invention, administration route are not particularly limited, and dosage depends not only on the year of patient Age, weight and the state of an illness additionally depend on the type of tumour, property and severity.But generally, for adult patient, most The amount of the good compound used daily is between 10 milligrams to 1 gram.It is generally each to once in three weeks or medication several times.

Compound provided by the invention has good anti-tumor activity.Complex provided by the present invention is in water solubility side Face all has tens times or more of raising compared with existing platinum antineoplastic drug, and this highly-water-soluble feature can increase medicine Object reduces drug in the intracorporal savings of body in the excretion of kidney, mitigate platinum medicine generally there are high kidney toxic side effect, simultaneously It is easy these compounds formulation, improves the stability of preparation, application clinically is more convenient.

Detailed description of the invention

Fig. 1 is compound 1,4,7,10 and open compound -1, the open compound -2 and carboplatin shown in the present invention IC in H460/Hela/5637 tumour cell₅₀The comparison diagram of value；

Fig. 2 is compound 1,4,7,10 and open compound -1, the open compound -2 and carboplatin shown in the present invention IC in HGC27/DU145/KB tumour cell₅₀The comparison diagram of value；

Fig. 3 is compound 1,4,7,10 and open compound -1, the open compound -2 and carboplatin shown in the present invention IC in ECA-109/SMMC7721/THP-1/A549 tumour cell₅₀The comparison diagram of value；

Fig. 4 is to show that compound 11,12 and open compound -1, open compound -2 and carboplatin in the present invention exist IC in H460/Hela/5637 tumour cell₅₀The comparison diagram of value；

Fig. 5 is to show that compound 11,12 and open compound -1, open compound -2 and carboplatin in the present invention exist IC in HGC27/DU145/KB tumour cell₅₀The comparison diagram of value；

Fig. 6 is to show compound 11,12 in the present invention and open compound -1, open compound -2 in ECA-109/ IC in SMMC7721/THP-1/A549 tumour cell₅₀The comparison diagram of value；

Fig. 7 is compound 13,16,19,22 and open compound -1, the open compound -2 and card shown in the present invention The comparison diagram of IC50 value of the platinum in H460/Hela/5637 tumour cell；

Fig. 8 is compound 13,16,19,22 and open compound -1, the open compound -2 and card shown in the present invention IC of the platinum in HGC27/DU145/KB tumour cell₅₀The comparison diagram of value；

Fig. 9 is compound 13,16,19,22 and open compound -1, the open compound -2 and card shown in the present invention IC of the platinum in ECA-109/SMMC7721/THP-1/A549 tumour cell₅₀The comparison diagram of value；

Figure 10 is to show that compound 23,24 and open compound -1, open compound -2 and carboplatin in the present invention exist IC in H460/Hela/5637 tumour cell₅₀The comparison diagram of value；

Figure 11 is to show that compound 23,24 and open compound -1, open compound -2 and carboplatin in the present invention exist IC in HGC27/DU145/KB tumour cell₅₀The comparison diagram of value；

Figure 12 is display the compounds of this invention 23,24 and open compound -1, open compound -2 and carboplatin in ECA- IC in 109/SMMC7721/THP-1/A549 tumour cell₅₀The comparison diagram of value；

Figure 13 is to show that compound 25 and open compound -1, open compound -2 and carboplatin in the present invention exist IC in H460/Hela/5637 tumour cell₅₀The comparison diagram of value；

Figure 14 is to show that compound 25 and open compound -1, open compound -2 and carboplatin in the present invention exist IC in HGC27/DU145/KB tumour cell₅₀It is worth comparison diagram；

Figure 15 is to show compound 25 in the present invention and open compound -1, open compound -2 and carboplatin in ECA- IC in 109/SMMC7721/THP-1/A549 tumour cell₅₀The comparison diagram of value；

Figure 16 is compound 15,18,20 and open compound -1, the open compound -2 and carboplatin shown in the present invention IC in H460/Hela/5637 tumour cell₅₀The comparison diagram of value；

Figure 17 is compound 15,18,20 and open compound -1, the open compound -2 and carboplatin shown in the present invention IC in HGC27/DU145/KB tumour cell₅₀It is worth comparison diagram；

Figure 18 is compound 15,18,20 and open compound -1, the open compound -2 and carboplatin shown in the present invention IC in ECA-109/SMMC7721/THP-1/A549 tumour cell₅₀The comparison diagram of value.

Specific embodiment

The present invention is further illustrated with specific embodiment below.Represented by (I) provided by the present invention by formula The platinum complex for oncotherapy, the representative citing of preferred compound can also be listed by following table 1, but the present invention The platinum complex covered citing not limited to the following.

1 embodiment compound list of table

Embodiment 1: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- (1-O-D- glucoside) ring fourth Alkane -1,1- dioctyl phthalate] preparation

The preparation of (1) 1,1- dicarboxylic acid ethyl ester -3- acetoxyl group-cyclobutane

60% sodium hydride (0.8g) is dissolved in diethyl malonate (1.6g) solution of n,N-Dimethylformamide (15ml) In.Mixture is stirred at room temperature 30 minutes.Then it will contain the N of the bromo- 2- ester group propane (1.3g) of 1,3- bis-, N- dimethyl methyl Amide solution (10ml) is added in reaction solution, and mixture stirs 6 hours at 80 DEG C.Revolving removes solvent, and residue is again It is dissolved in the mixed solution of ethyl acetate (150ml) and saturated ammonium chloride (150ml), liquid separation.Organic phase anhydrous sodium sulfate It is dry, it is concentrated under reduced pressure, silica gel column chromatography (petrol ether/ethyl acetate: 50/1) purifies, obtains colorless oil as product (0.66g).

¹H NMR (400MHz, CDCl₃) δ 5.02 (dt, J=10.0,7.4Hz, 1H), 4.29-4.07 (m, 4H), 2.93 (dt, J=17.6,6.3Hz, 2H), 2.64-2.52 (m, 2H), 2.05-1.95 (m, 3H), 1.24 (dt, J=14.3,4.3Hz, 6H) .MS (m/z): 281.0 [M+Na]⁺

The preparation of (2) 1,1- dicarboxylic acid ethyl ester -3- hydroxyl-cyclobutane

Upper step product (1.29g) is dissolved in the alcohol sodium solution (10ml) of 0.1M, is stirred at room temperature 2 hours, it will be remaining Object is dissolved in ethyl acetate solution (100ml) and ammonium chloride solution (100ml), liquid separation, and organic phase is dry with anhydrous sodium sulfate, It is concentrated under reduced pressure, silica gel column chromatography (petrol ether/ethyl acetate=4/1) purifying obtains colorless oil (0.75g).

¹H NMR (400MHz, CDCl₃) δ 5.02 (dt, J=10.0,7.4Hz, 1H), 4.29-4.07 (m, 4H), 2.92 (dt, J=17.6,6.3Hz, 2H), 2.62-2.49 (m, 2H), 1.24 (dt, J=14.3,4.3Hz, 6H) .MS (m/z): 239.0 [M+Na]⁺

(3) 1,1- dicarboxylic acid ethyl ester -3-[2,3,4,6-O- acetyl group -1-O-D- glucosides] cyclobutane preparation

At room temperature by 1,2,3,4,6-O- penta-acetyls-D-Glucose (1.84g) is added to containing 1,1- diformazan In methylene chloride (20ml) solution of acetoacetic ester -3- hydroxycyclobutane (1.02g), it is cooled to 0 DEG C, in nitrogen displacement flask The diethyl ether solution (98%, 1.19ml) of boron trifluoride is slowly added dropwise in air under nitrogen protection.Reaction solution is stirred 15 at 0 DEG C Minute, it is then slowly warming up to room temperature and stirs 12 hours.After the reaction was completed, revolving removes solvent, silica gel column chromatography (petroleum Ether/ethyl acetate=5/1) implement simple purification, obtain crude product 1.71g.

¹H NMR (400MHz, CDCl₃) δ 5.16 (t, J=9.5Hz, 1H), 5.05 (t, J=9.7Hz, 1H), 4.95 (dd, J =9.5,8.1Hz, 1H), 4.46 (d, J=8.0Hz, 1H), 4.41-4.28 (m, 1H), 4.20 (qd, J=12.6,5.8Hz, 5H), 4.09 (dd, J=12.3,2.2Hz, 1H), 3.65 (ddd, J=9.9,4.8,2.3Hz, 1H), 2.87-2.73 (m, 2H), 2.59 (dd, J=12.1,7.2Hz, 1H), 2.49 (dd, J=11.7,7.3Hz, 1H), 2.07 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.24 (td, J=7.1,2.3Hz, 6H)

MS (m/z): 569.1 [M+Na]⁺

(4) 1,1- dioctyl phthalate -3-[2,3,4,6- tetrahydroxy -1-O-D- glucosides] cyclobutane preparation

NaOH (0.72g) is dissolved in the water of 15ml at room temperature, is then slowly added into containing 1,1- dioctyl phthalate Ethyl ester -3-[2,3,4,6-O- acetyl group -1-O-D- glucosides] cyclobutane (1.09g) aqueous solution (7ml) in, increase temperature Degree stirs 8h at 90 DEG C.The aqueous solution of acid needed for being obtained after reaction solution is cooling by strong acidic ion resin (10ml), freeze-drying obtain white solid 0.93g.

(5) cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- (1-O-D- glucoside) cyclobutane -1,1- Dioctyl phthalate] preparation

By 1,1- dioctyl phthalate -3-[2,3,4,6- tetrahydroxy -1-O-D- glucosides] cyclobutane (0.9g) is dissolved in 20mL water In, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 minutes.In nitrogen The aqueous solution (7ml) containing sulfatodiamino cyctohexane platinum (0.82g) is added in above-mentioned gained reaction solution under gas shielded, room temperature is kept away Light stirs 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is lyophilized using freeze drier, is used The half preparation isolated 0.54g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 5.76 (s, 1H), 5.06 (s, 1H), 4.46 (d, J=8.0Hz, 1H), 4.42-4.35 (m, 1H), 3.89 (dd, J=12.3,1.7Hz, 1H), 3.70 (dd, J=12.4,5.7Hz, 1H), 3.52-3.28 (m, 5H), 3.24 (t, J=8.6Hz, 1H), 2.81 (dd, J=12.1,7.3Hz, 1H), 2.72 (dd, J=11.9,7.3Hz, 1H), 2.42- 2.30 (m, 2H), 1.99 (d, J=11.9Hz, 2H), 1.53 (d, J=8.3Hz, 2H), 1.29-1.18 (m, 2H), 1.08 (t, J =10.0Hz, 2H).

Embodiment 2: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- (1-O-D- mannoside) ring fourth Alkane -1,1- dioctyl phthalate] preparation

(1) 1,1- dicarboxylic acid ethyl ester -3-[2,3,4,6-O- acetyl group -1-O-D- mannosides] cyclobutane preparation

1,2,3,4,6-O- five acetyl-D-MANNOSE (1.84g) is added to containing 1,1- dioctyl phthalate at room temperature In methylene chloride (20ml) solution of ethyl ester -3- hydroxycyclobutane (1.02g), it is cooled to 0 DEG C, with sky in nitrogen displacement flask The diethyl ether solution (98%, 1.19ml) of boron trifluoride is slowly added dropwise in gas under nitrogen protection.Reaction solution is stirred 15 points at 0 DEG C Then clock is slowly warming up to room temperature and stirs 12 hours.After the reaction was completed, revolving removing solvent, silica gel column chromatography (petroleum ether/ Ethyl acetate=5/1) implement simple purification, obtain crude product 1.39g.

¹H NMR (400MHz, CDCl₃) 65.38-5.16 (m, 3H), 4.81 (d, J=1.1Hz, 1H), 4.36-4.14 (m, 6H), 4.09 (dd, J=12.2,2.1Hz, 1H), 4.04-3.97 (m, 1H), 2.82 (ddd, J=9.3,7.3,3.7Hz, 2H), 2.69-2.51 (m, 2H), 2.14 (s, 3H), 2.10 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H), 1.26 (q, J=7.2Hz, 6H) .MS (m/z): 569.1 [M+Na]⁺

(2) 1,1- dioctyl phthalate -3-[2,3,4,6- tetrahydroxy -1-O-D- mannosides] cyclobutane preparation

NaOH (0.72g) is dissolved in the water of 15ml at room temperature, is then slowly added into containing 1,1- dioctyl phthalate Ethyl ester -3-[2,3,4,6-O- acetyl group -1-O-D- mannosides] cyclobutane (1.09g) aqueous solution (7ml) in, increase temperature Degree, stirs 8h at 90 DEG C.The aqueous solution of acid needed for being obtained after reaction solution is cooling by strong acidic ion resin (10ml), freeze-drying obtain white solid 0.95g.

(3) cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- (1-O-D- mannoside) cyclobutane -1,1- Dioctyl phthalate] preparation

By 1,1- dioctyl phthalate -3-[2,3,4,6- tetrahydroxy -1-O-D- glucosides] cyclobutane (0.9g) is dissolved in 20mL water In, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 minutes.In nitrogen The aqueous solution (ml) containing sulfatodiamino cyctohexane platinum (0.82g) is added in above-mentioned gained reaction solution under gas shielded, room temperature is kept away Light stirs 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is lyophilized using freeze drier, is used The half preparation isolated 0.39g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 5.79 (s, 1H), 5.07 (d, J=9.3Hz, 1H), 4.94 (s, 1H), 4.29 (m, 1H), 4.00-3.88 (m, 2H), 3.87-3.57 (m, 4H), 3.51-3.40 (m, 1H), 3.37 (dd, J=11.2,6.3Hz, 1H), 2.87 (dd, J=11.9,7.4Hz, 1H), 2.77 (dd, J=11.8,7.4Hz, 1H), 2.41 (d, J=6.0Hz, 2H), 2.02 (d, J=11.3Hz, 2H), 1.56 (d, J=7.6Hz, 2H), 1.25 (d, J=8.6Hz, 2H), 1.11 (d, J=9.9Hz, 2H).

Embodiment 3: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- (1-O-D- galactoside) ring fourth Alkane -1,1- dioctyl phthalate] preparation

(1) 1,1- dicarboxylic acid ethyl ester -3-[2,3,4,6-O- acetyl group -1-O-D- galactosides] cyclobutane preparation

1,2,3,4,6-O- five acetyl-D- galactolipin (1.84g) is added to containing 1,1- dioctyl phthalate at room temperature In methylene chloride (20ml) solution of ethyl ester -3- hydroxycyclobutane (1.02g), it is cooled to 0 DEG C, with sky in nitrogen displacement flask The diethyl ether solution (98%, 1.19ml) of boron trifluoride is slowly added dropwise in gas under nitrogen protection.Reaction solution is stirred 15 points at 0 DEG C Then clock is slowly warming up to room temperature and stirs 12 hours.After the reaction was completed, revolving removes solvent, uses silica gel column chromatography (petroleum Ether/ethyl acetate=5/1) simple purification is implemented to reaction product, obtain crude product 1.55g.

¹H NMR (400MHz, CDCl₃) δ 5.35 (d, J=2.7Hz, 1H), 5.16 (dd, J=10.4,8.0Hz, 1H), 4.97 (dd, J=10.5,3.4Hz, 1H), 4.45-4.29 (m, 2H), 4.23-4.03 (m, 6H), 3.86 (dd, J=6.8, 6.1Hz, 1H), 2.88-2.71 (m, 2H), 2.59 (dd, J=12.2,7.2Hz, 1H), 2.49 (dd, J=11.8,7.3Hz, 1H), 2.12 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.96 (s, 3H), 1.23 (td, J=7.1,2.9Hz, 6H) .MS (m/z): 569.1 [M+Na]⁺

(3) cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- (1-O-D- galactoside) cyclobutane -1,1- Dioctyl phthalate] preparation

By 1,1- dioctyl phthalate -3-[2,3,4,6- tetrahydroxy -1-O-D- mannosides] cyclobutane (0.9g) is dissolved in 20mL water In, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 minutes.In nitrogen The aqueous solution (7ml) containing sulfatodiamino cyctohexane platinum (0.82g) is added in above-mentioned gained reaction solution under gas shielded, room temperature is kept away Light stirs 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is lyophilized using freeze drier, is used The half preparation isolated 0.54g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.46-4.35 (m, 2H), 3.90 (d, J=3.2Hz, 1H), 3.81-3.59 (m, 4H), 3.52-3.44 (m, 1H), 3.39 (dd, J=11.9,7.1Hz, 1H), 3.31 (dd, J=11.4,6.3Hz, 1H), 2.81 (dd, J=12.1,7.3Hz, 1H), 2.70 (dd, J=12.0,7.3Hz, 1H), 2.40-2.29 (m, 2H), 1.99 (d, J= 12.0Hz, 2H), 1.53 (d, J=8.2Hz, 2H), 1.24 (d, J=8.9Hz, 2H), 1.09 (t, J=10.1Hz, 2H)

Embodiment 4: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- methylene-(1-O-D- glucose Glycosides) cyclobutane -1,1- dioctyl phthalate] preparation

The preparation of (1) 1,1- dicarboxylic acid ethyl ester -3- benzyloxymethyl-cyclobutane

Under ice bath is cooling, sodium hydride (60%) (1.01g) solid is slowly added into containing diethyl malonate (2.02g) DMF (10ml) solution in, mixture solution is stirred at room temperature 30 minutes.Then it will contain the ((bromo- 3- (first of 4- at room temperature Base) butoxy) methyl) DMF (15ml) solution of benzene (2.03g) is further added in reaction solution, the reaction solution at 80 DEG C Stirring 12 hours.Revolving removes solvent.100ml ethyl acetate is added into reaction solution, then uses saturated aqueous ammonium chloride (1 × 50ml) washing, water phase is extracted with ethyl acetate (2 × 25ml), organic phase is merged.Organic phase is successively used into saturated ammonium chloride Aqueous solution (1 × 100ml), distilled water (1 × 100ml), saturated sodium-chloride water solution (1 × 100ml) washing, then with anhydrous sulphur Sour sodium is dry, is concentrated under reduced pressure, and silica gel column chromatography purifies (petrol ether/ethyl acetate=50/1), obtains colorless oil as product 1.64g。

¹H NMR (400MHz, CDCl₃) δ 7.37-7.27 (m, 5H), 4.49 (d, J=6.9Hz, 2H), 4.19 (dq, J= 17.9,7.1Hz, 4H), 3.44 (d, J=5.8Hz, 2H), 2.76-2.54 (m, 3H), 2.43-2.27 (m, 2H), 1.25 (ddd, J =14.5,8.5,4.5Hz, 6H) .MS (m/z): 343.1 [M+Na]⁺

The preparation of (2) 1,1- dicarboxylic acid ethyl ester -3- methylol-cyclobutane

Palladium carbon (0.11g) is added in the methanol solution containing upper step product (1.16g), at room temperature vacuum displacement hydrogen Gas, then reaction solution stirs 36 hours under hydrogen atmosphere.Diatomite filtering removes extra residue and obtains filtrate, and revolving removes molten Agent, silica gel column chromatography purify (petrol ether/ethyl acetate=4/1), obtain colorless oil as product 0.813g.

¹H NMR (400MHz, CDCl₃) δ 4.21 (dq, J=14.3,6.9Hz, 4H), 3.49 (t, J=6.5Hz, 2H), 2.58 (ddd, J=9.1,8.3,2.3Hz, 2H), 2.51-2.35 (m, 1H), 2.30-2.16 (m, 2H), 1.23 (td, J=7.5, 5.4Hz, 6H) .MS (m/z): 253.0 [M+Na]⁺

(3) 1,1- dicarboxylic acid ethyl ester -3- methylene-[2,3,4,6-O- acetyl group -1-O-D- glucoside] cyclobutane Preparation

1,2,3,4,6-O- five acetyl-D-Glucose (1.84g) is added to containing 1,1- dioctyl phthalate at room temperature In ethyl ester -3- methylol-cyclobutane (1.08g) methylene chloride (20ml) solution, ice bath is cooled to 0 DEG C, is replaced with nitrogen The diethyl ether solution (98%, 1.19ml) of boron trifluoride is slowly added dropwise in air in flask under nitrogen protection.By reaction solution at 0 DEG C Then stirring 15 minutes is slowly warming up to room temperature and stirs 12 hours.After the reaction was completed, revolving removes solvent, silica gel column chromatography (petrol ether/ethyl acetate=5/1) purifying, obtains crude product 1.71g.

¹HNMR (400MHz, CDCl₃) δ 5.14 (t, J=9.5Hz, 1H), 5.02 (t, J=9.7Hz, 1H), 4.92 (dd, J =9.6,8.0Hz, 1H), 4.45 (d, J=8.0Hz, 1H), 4.21-4.05 (m, 6H), 3.80 (dd, J=9.9,5.7Hz, 1H), 3.64 (ddd, J=9.9,4.7,2.3Hz, 1H), 3.41 (dd, J=9.9,6.2Hz, 1H), 2.64-2.48 (m, 3H), 2.28 (ddd, J=19.9,10.1,5.1Hz, 2H), 2.04 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.95 (s, 3H), 1.20 (td, J=7.1,3.7Hz, 6H) .MS (m/z): 583.1 [M+Na]⁺

The preparation of (4) 1,1- dioctyl phthalate -3- methylene-[2,3,4,6- tetrahydroxy -1-O-D- glucoside] cyclobutane

NaOH (0.72g) is dissolved in the water of 15ml at room temperature, is then slowly added into containing 1,1- dioctyl phthalate The aqueous solution (7ml) of ethyl ester -3- methylene-[2,3,4,6-O- acetyl group -1-O-D- glucoside] cyclobutane (1.12g) when In, it increases temperature and stirs 8h at 90 DEG C.Required acid is obtained by strong acidic ion resin after reaction solution is cooling Aqueous solution (10ml), freeze-drying obtain white solid 0.96g.

(5) cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- methylene-(1-O-D- glucoside) ring fourth Alkane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- methylene-[2,3,4,6- tetrahydroxy -1-O-D- glucoside] cyclobutane (0.93g) is molten In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing sulfatodiamino cyctohexane platinum (0.82g) is added to above-mentioned gained reaction solution under nitrogen protection In, room temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, freeze-drying is used Machine freeze-drying, with the half preparation isolated 0.49g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 5.71 (d, J=14.9Hz, 2H), 4.88 (s, 2H), 4.32 (d, J=7.9Hz, 1H), 3.86 (m, 2H), 3.77-3.52 (m, 5H), 3.44 (dd, J=9.7,8.1Hz, 1H), 3.05 (dd, J=20.1, 10.3Hz, 2H), 2.53 (ddd, J=22.8,17.2,9.2Hz, 3H), 2.32 (d, J=5.9Hz, 2H), 1.91 (d, J= 11.2Hz, 2H), 1.45 (d, J=7.3Hz, 2H), 1.14 (s, 2H), 1.05-0.93 (m, 2H)

Embodiment 5: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- methylene-(1-O-D- mannose Glycosides) cyclobutane -1,1- dioctyl phthalate] preparation

(1) 1,1- dicarboxylic acid ethyl ester -3- methylene-[2,3,4,6-O- acetyl group -1-O-D- mannoside] cyclobutane Preparation

1,2,3,4,6-O- five acetyl-D-MANNOSE (1.84g) is added to containing 1,1- dioctyl phthalate at room temperature In ethyl ester -3- methylol-cyclobutane (1.08g) methylene chloride (20ml) solution, ice bath is cooled to 0 DEG C, is replaced with nitrogen The diethyl ether solution (98%, 1.19ml) of boron trifluoride is slowly added dropwise in air in flask under nitrogen protection.By reaction solution at 0 DEG C Then stirring 15 minutes is slowly warming up to room temperature and stirs 12 hours.After the reaction was completed, revolving removes solvent, silica gel column chromatography (petrol ether/ethyl acetate=5/1) isolates and purifies, and obtains crude product 1.39g.

¹H NMR (400MHz, CDCl₃) δ 5.37-5.17 (m, 4H), 4.78 (s, 1H), 4.23 (ddt, J=14.2,10.2, 6.2Hz, 5H), 4.02-3.92 (m, 1H), 3.66 (dd, J=9.9,5.6 Hz, 1H), 3.46 (dd, J=9.8,5.4Hz, 1H), 2.71-2.59 (m, 3H), 2.33 (dd, J=8.4,5.4Hz, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H), 1.25 (s, 6H) .MS (m/z): 583.1 [M+Na]⁺

The preparation of (2) 1,1- dioctyl phthalate -3- methylene-[2,3,4,6- tetrahydroxy -1-O-D- mannoside] cyclobutane

NaOH (0.72g) is dissolved in the water of 15ml at room temperature, is then slowly added into containing 1,1- dioctyl phthalate The aqueous solution (7ml) of ethyl ester -3- methylene-[2,3,4,6-O- acetyl group -1-O-D- mannoside] cyclobutane (1.12g) when In, it increases temperature and stirs 8h at 90 DEG C.Required acid is obtained by strong acidic ion resin after reaction solution is cooling Aqueous solution (10ml), freeze-drying obtain white solid 0.95g.

(3) cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- methylene-(1-O-D- mannoside) ring fourth Alkane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- methylene-[2,3,4,6- tetrahydroxy -1-O-D- mannoside] cyclobutane (0.93g) is molten In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing sulfatodiamino cyctohexane platinum (0.82g) is added to above-mentioned gained reaction solution under nitrogen protection In, room temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, freeze-drying is used Machine freeze-drying, with the half preparation isolated 0.44g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 5.76 (d, J=25.8Hz, 2H), 4.94 (s, 2H), 4.79 (s, 1H), 3.91- 3.78 (m, 2H), 3.77-3.48 (m, 5H), 3.44 (dd, J=9.8,5.5Hz, 1H), 3.13-2.91 (m, 2H), 2.62 (dd, J =18.9,10.9Hz, 2H), 2.50 (dd, J=14.0,7.2Hz, 1H), 2.33 (s, 2H), 1.91 (d, J=10.8Hz, 2H), 1.45 (d, J=7.1Hz, 2H), 1.12 (dd, J=15.0,8.2Hz, 2H), 1.00 (d, J=9.8Hz, 2H)

Embodiment 6: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- methylene-(1-O-D- galactolipin Glycosides) cyclobutane -1,1- dioctyl phthalate] preparation

(1) 1,1- dicarboxylic acid ethyl ester -3- methylene-[2,3,4,6-O- acetyl group -1-O-D- galactoside] cyclobutane Preparation

1,2,3,4,6-O- five acetyl-D- galactolipin (1.84g) is added to containing 1,1- dioctyl phthalate at room temperature In ethyl ester -3- methylol-cyclobutane (1.08g) methylene chloride (20ml) solution, ice bath is cooled to 0 DEG C, is replaced with nitrogen The diethyl ether solution (98%, 1.19ml) of boron trifluoride is slowly added dropwise in air in flask under nitrogen protection.By reaction solution at 0 DEG C Then stirring 15 minutes is slowly warming up to room temperature and stirs 12 hours.After the reaction was completed, solvent, silica gel column chromatography is removed under reduced pressure (petrol ether/ethyl acetate=5/1) purifying, obtains crude product 1.57g.

¹H NMR (400MHz, CDCl₃) δ 5.36 (d, J=2.8Hz, 1H), 5.17 (dd, J=10.5,8.0Hz, 1H), 4.98 (dd, J=10.5,3.4Hz, 1H), 4.43 (d, J=7.9Hz, 1H), 4.23-4.09 (m, 6H), 3.91-3.78 (m, 2H), 3.44 (dd, J=9.9,6.4Hz, 1H), 2.73-2.50 (m, 3H), 2.31 (ddd, J=18.5,10.0,4.6Hz, 2H), 2.13 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.96 (s, 3H), 1.23 (td, J=7.1,2.8Hz, 6H) .MS (m/z): 583.1[M+Na]⁺

The preparation of (2) 1,1- dioctyl phthalate -3- methylene-[2,3,4,6- tetrahydroxy -1-O-D- galactoside] cyclobutane

NaOH (0.72g) is dissolved in the water of 15ml at room temperature, is then slowly added into containing 1,1- dioctyl phthalate The aqueous solution (7ml) of ethyl ester -3- methylene-[2,3,4,6-O- acetyl group -1-O-D- galactoside] cyclobutane (1.12g) when In, it increases temperature and stirs 8h at 90 DEG C.Required acid is obtained by strong acidic ion resin after reaction solution is cooling Aqueous solution (10ml), freeze-drying obtain white solid 0.98g.

(3) cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- methylene-(1-O-D- galactoside) ring fourth Alkane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- methylene-[2,3,4,6- tetrahydroxy -1-O-D- galactoside] cyclobutane (0.93g) is molten In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing sulfatodiamino cyctohexane platinum (0.82g) is added to above-mentioned gained reaction solution under nitrogen protection In, room temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, freeze-drying is used Machine freeze-drying, with the half preparation isolated 0.48g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.32 (d, J=8.1Hz, 1H), 3.92-3.79 (m, 2H), 3.77-3.52 (m, 5H), 3.44 (dd, J=9.7,8.1Hz, 1H), 3.03 (dd, J=20.1,10.7Hz, 2H), 2.55 (ddd, J=22.8, 17.2,9.3Hz, 3H), 2.32 (d, J=5.9Hz, 2H), 1.91 (d, J=11.2Hz, 2H), 1.45 (d, J=7.3Hz, 2H), 1.12 (s, 2H), 1.05-0.93 (m, 2H)

Embodiment 7: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- ethylidene-(1-O-D- glucose Glycosides) cyclobutane -1,1- dioctyl phthalate] preparation

The preparation of (1) 1,1- dicarboxylic acid ethyl ester -3- benzyloxyethyl-cyclobutane

Under ice bath is cooling, sodium hydride (60%) (1.01g) solid is slowly added into containing diethyl malonate (2.02g) DMF (10ml) solution in, mixture solution is stirred at room temperature 30 minutes.Then it will contain the ((bromo- 3- (first of 4- at room temperature Base) butoxy) methyl) DMF (15ml) solution of benzene (2.12g) is added in reaction solution, the reaction solution stirring 12 at 80 DEG C Hour.Revolving removes solvent.100ml ethyl acetate is added into reaction solution, then uses saturated aqueous ammonium chloride (1 × 50ml) Washing, water phase is extracted with ethyl acetate (2 × 25ml), merges organic phase.Organic phase is successively used into saturated aqueous ammonium chloride (1 × 100mL), distilled water (1 × 100ml), saturated sodium-chloride water solution (1 × 100ml) washing are then dry with anhydrous sodium sulfate It is dry, it is concentrated under reduced pressure, silica gel column chromatography purifies (petrol ether/ethyl acetate=50/1), obtains colorless oil as product 1.69g.

¹H NMR (400MHz, CDCl₃) δ 7.24 (dd, J=19.1,7.5Hz, 5H), 4.40 (s, 2H), 4.20-4.05 (m, 4H), 3.34 (dd, J=8.3,4.1Hz, 2H), 2.58 (dd, J=13.4,5.4Hz, 2H), 2.43 (dd, J=15.4,7.7Hz, 1H), 2.16 (dd, J=14.3,6.3Hz, 2H), 1.68 (dd, J=12.0,5.4Hz, 2H), 1.23-1.13 (m, 6H) .MS (m/ Z): 357.1 [M+Na]⁺

The preparation of (2) 1,1- dicarboxylic acid ethyl ester -3- ethoxy-cyclobutane

Palladium/carbon (0.11g) is added in the methanol solution containing upper step product (1.21g), at room temperature vacuum displacement Hydrogen, then reaction solution stirs 36 hours under hydrogen atmosphere.Diatomite filtering removes extra residue and obtains filtrate, and revolving removes molten Agent, silica gel column chromatography purify (petrol ether/ethyl acetate=4/1), obtain colorless oil as product 0.830g.

¹H NMR (400MHz, CDCl₃) δ 4.17 (dq, J=14.2,7.1Hz, 4H), 3.55 (t, J=6.5Hz, 2H), 2.63 (ddd, J=9.0,8.3,2.4Hz, 2H), 2.52-2.38 (m, 1H), 2.25-2.14 (m, 2H), 1.66 (dd, J= 13.8,6.7Hz, 2H), 1.22 (td, J=7.1,5.8Hz, 6H) .MS (m/z): 267.0 [M+Na]⁺

(3) 1,1- dicarboxylic acid ethyl ester -3- ethylidene-[2,3,4,6-O- acetyl group -1-O-D- glucoside] cyclobutane Preparation

1,2,3,4,6-O- five acetyl-D-Glucose (1.84g) is added to containing 1,1- dioctyl phthalate at room temperature In ethyl ester -3- ethoxy-cyclobutane (1.15g) methylene chloride (20ml) solution, it is cooled to 0 DEG C, with nitrogen displacement flask The diethyl ether solution (98%, 1.19ml) of boron trifluoride is slowly added dropwise in interior air under nitrogen protection.Reaction solution is stirred at 0 DEG C It 15 minutes, is then slowly warming up to room temperature and stirs 12 hours.After the reaction was completed, revolving removes solvent, uses silica gel column chromatography (petrol ether/ethyl acetate=5/1) implements simple purification to reaction product, obtains crude product 1.71g.

¹H NMR (400MHz, CDCl₃) δ 5.18 (t, J=9.5Hz, 1H), 5.07 (t, J=9.7Hz, 1H), 4.99-4.92 (m, 1H), 4.45 (d, J=8.0Hz, 1H), 4.30-4.08 (m, 6H), 3.82 (dt, J=9.8,6.0Hz, 1H), 3.67 (ddd, J=9.7,4.5,2.3Hz, 1H), 3.40 (dt, J=9.5,6.7Hz, 1H), 2.65-2.55 (m, 2H), 2.41 (dt, J= 16.2,8.1Hz, 1H), 2.20 (dd, J=11.2,6.3Hz, 2H), 2.08 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.68 (pd, J=13.6,6.6Hz, 2H), 1.24 (td, J=7.1,5.3Hz, 6H)

MS (m/z): 597.2 [M+Na]⁺

The preparation of (4) 1,1- dioctyl phthalate -3- ethylidene-[2,3,4,6- tetrahydroxy -1-O-D- glucoside] cyclobutane

NaOH (0.72g) is dissolved in the water of 15ml at room temperature, is then slowly added into containing 1,1- dioctyl phthalate The aqueous solution (7ml) of ethyl ester -3- ethylidene-[2,3,4,6-O- acetyl group -1-O-D- glucoside] cyclobutane (1.15g) when In, it increases temperature and stirs 8h at 90 DEG C.Required acid is obtained by strong acidic ion resin after reaction solution is cooling Aqueous solution (10ml), freeze-drying obtain white solid 1.0g.

(5) cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- ethylidene-(1-O-D- glucoside) ring fourth Alkane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- ethylidene-[2,3,4,6- tetrahydroxy -1-O-D- glucoside] cyclobutane (1.0g) is dissolved in In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing sulfatodiamino cyctohexane platinum (0.82g) is added to above-mentioned gained reaction solution under nitrogen protection In, room temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, freeze-drying is used Machine freeze-drying, with the half preparation isolated 0.52g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.76 (s, 1H), 3.89-3.77 (m, 3H), 3.68 (dd, J=11.7,5.1Hz, 2H), 3.57 (d, J=8.5Hz, 2H), 3.50-3.42 (m, 1H), 3.24 (d, J=12.1Hz, 1H), 3.02 (s, 1H), 2.50- 2.34 (m, 4H), 2.31-2.23 (m, 1H), 1.89 (d, J=7.8Hz, 2H), 1.70 (d, J=5.3Hz, 2H), 1.43 (s, 2H), 0.98 (d, J=8.0Hz, 4H)

Embodiment 8: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- ethylidene-(1-O-D- mannose Glycosides) cyclobutane -1,1- dioctyl phthalate] preparation

(1) 1,1- dicarboxylic acid ethyl ester -3- ethylidene-[2,3,4,6-O- acetyl group -1-O-D- mannoside] cyclobutane Preparation

1,2,3,4,6-O- five acetyl-D-MANNOSE (1.84g) is added to containing 1,1- dioctyl phthalate at room temperature In ethyl ester -3- ethoxy-cyclobutane (1.15g) methylene chloride (20ml) solution, it is cooled to 0 DEG C, with nitrogen displacement flask The diethyl ether solution (98%, 1.19ml) of boron trifluoride is slowly added dropwise in interior air under nitrogen protection.Reaction solution is stirred at 0 DEG C It 15 minutes, is then slowly warming up to room temperature and stirs 12 hours.After the reaction was completed, revolving removes solvent, uses silica gel column chromatography (petrol ether/ethyl acetate=5/1) implements simple purification to reaction product, obtains crude product 1.39g.

¹H NMR (400MHz, CDCl₃) δ 5.31-5.24 (m, 2H), 5.20 (dd, J=3.1,1.8Hz, 1H), 4.76 (d, J =1.4Hz, 1H), 4.31-4.14 (m, 5H), 4.08 (dd, J=12.2,2.3Hz, 1H), 3.97-3.89 (m, 1H), 3.62 (dt, J=9.7,6.6Hz, 1H), 3.38 (dt, J=9.7,6.4Hz, 1H), 2.73-2.59 (m, 2H), 2.45 (dt, J= 16.1,8.1Hz, 1H), 2.28-2.18 (m, 2H), 2.14 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H), 1.74 (ddd, J=13.8,8.5,5.2Hz, 2H), 1.25 (q, J=7.0Hz, 6H)

MS (m/z): 597.2 [M+Na]⁺

The preparation of (2) 1,1- dioctyl phthalate -3- ethylidene-[2,3,4,6- tetrahydroxy -1-O-D- mannoside] cyclobutane

NaOH (0.72g) is dissolved in the water of 15ml at room temperature, is then slowly added into containing 1,1- dioctyl phthalate The aqueous solution (7ml) of ethyl ester -3- ethylidene-[2,3,4,6-O- acetyl group -1-O-D- mannoside] cyclobutane (1.15g) when In, it increases temperature and stirs 8h at 90 DEG C.Required acid is obtained by strong acidic ion resin after reaction solution is cooling Aqueous solution (10ml), freeze-drying obtain white solid 0.98g.

(3) cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- ethylidene-(1-O-D- mannoside) ring fourth Alkane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- ethylidene-[2,3,4,6- tetrahydroxy -1-O-D- mannoside] cyclobutane (0.95g) is molten In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing sulfatodiamino cyctohexane platinum (0.82g) is added to above-mentioned gained reaction solution under nitrogen protection In, room temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, freeze-drying is used Machine freeze-drying, with the half preparation isolated 0.50g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.83 (s, 1H), 3.97-3.85 (m, 2H), 3.82 (d, J=6.5Hz, 1H), 3.73 (dd, J=19.4,8.5Hz, 2H), 3.63 (d, J=7.1Hz, 2H), 3.53 (dd, J=10.1,5.4Hz, 1H), 3.19 (d, J =8.0Hz, 1H), 3.07 (t, J=9.5Hz, 1H), 2.57-2.41 (m, 2H), 2.34 (dd, J=17.6,8.5Hz, 3H), 2.00 (d, J=11.5Hz, 2H), 1.79-1.64 (m, 2H), 1.54 (d, J=7.2Hz, 2H), 1.25 (s, 2H), 1.11 (d, J =10.1Hz, 2H)

Embodiment 9: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- ethylidene-(1-O-D- galactolipin Glycosides) cyclobutane -1,1- dioctyl phthalate] preparation

(1) 1,1- dicarboxylic acid ethyl ester -3- ethylidene-[2,3,4,6-O- acetyl group -1-O-D- galactoside] cyclobutane Preparation

1,2,3,4,6-O- five acetyl-D- galactolipin (1.84g) is added to containing 1,1- dioctyl phthalate at room temperature In ethyl ester -3- ethoxy-cyclobutane (1.15g) methylene chloride (20ml) solution, it is cooled to 0 DEG C, with nitrogen displacement flask The diethyl ether solution (98%, 1.19ml) of boron trifluoride is slowly added dropwise in interior air under nitrogen protection.Reaction solution is stirred at 0 DEG C It 15 minutes, is then slowly warming up to room temperature and stirs 12 hours.After the reaction was completed, revolving removes solvent, uses silica gel column chromatography (petroleum ether: ethyl acetate=5: simple purification 1) is implemented to reaction product, obtains crude product 1.54g.

¹H NMR (400MHz, CDCl₃) δ 5.34 (d, J=3.0Hz, 1H), 5.14 (dd, J=10.4,8.0Hz, 1H), 4.97 (dd, J=10.5,3.4Hz, 1H), 4.39 (d, J=7.9Hz, 1H), 4.21-4.07 (m, 6H), 3.93-3.73 (m, 2H), 3.47-3.31 (m, 1H), 2.64-2.52 (m, 2H), 2.40 (dt, J=16.1,8.1Hz, 1H), 2.17 (dd, J= 11.6,9.3Hz, 2H), 2.11 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 1.94 (s, 3H), 1.68 (ddd, J=19.7, 13.7,6.5Hz, 2H), 1.21 (dd, J=12.6,7.0Hz, 6H) .MS (m/z): 597.2 [M+Na]⁺

The preparation of (2) 1,1- dioctyl phthalate -3- ethylidene-[2,3,4,6- tetrahydroxy -1-O-D- galactoside] cyclobutane

NaOH (0.72g) is dissolved in the water of 15ml at room temperature, is then slowly added into containing obtained by step (1) 1,1- dicarboxylic acid ethyl ester -3- ethylidene-[2,3,4,6-O- acetyl group -1-O-D- galactoside] cyclobutane compound (1.15g) Aqueous solution (7ml) in, increase temperature stir 8h at 90 DEG C.Pass through strong acidic ion resin after reaction solution is cooling The aqueous solution (10ml) of acid needed for obtaining, freeze-drying obtain white solid 1.0g.

(3) cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- ethylidene-(1-O-D- galactoside) ring fourth Alkane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- ethylidene-[2,3,4,6- tetrahydroxy -1-O-D- galactoside] cyclobutane (0.95g) is molten In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing sulfatodiamino cyctohexane platinum (0.82g) is added to above-mentioned gained reaction solution under nitrogen protection In, room temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, freeze-drying is used Machine freeze-drying, with the half preparation isolated 0.54g final products of high pressure liquid chromatography.

¹H NMR (600MHz, D₂O) δ 5.93-5.63 (m, 2H), 5.02 (d, J=8.1Hz, 2H), 4.36 (d, J= 7.7Hz, 1H), 3.89 (s, 2H), 3.74 (dt, J=22.3,11.2Hz, 2H), 3.67-3.58 (m, 3H), 3.47 (t, J= 8.7Hz, 1H), 3.16-3.03 (m, 2H), 2.40 (dd, J=21.1,10.3Hz, 3H), 2.28-2.17 (m, 1H), 1.98 (d, J =10.8Hz, 2H), 1.50 (dd, J=45.9,22.0Hz, 5H), 1.19 (s, 2H), 1.06 (s, 2H)

Embodiment 10: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- propylidene-(1-O-D- glucose Glycosides) cyclobutane -1,1- dioctyl phthalate] preparation

The preparation of (1) 1,1- dicarboxylic acid ethyl ester -3- benzyloxy propyl-cyclobutane

Under ice bath is cooling, sodium hydride (60%) (1.01g) solid is slowly added into containing diethyl malonate (2.02g) DMF (10ml) solution in, mixture solution is stirred at room temperature 30 minutes.Then it will contain the ((bromo- 3- (first of 4- at room temperature Base) butoxy) methyl) DMF (15ml) solution of benzene (2.21g) is further added in reaction solution, the reaction solution at 80 DEG C Stirring 12 hours.Revolving removes solvent.100ml ethyl acetate is added into reaction solution, then uses saturated aqueous ammonium chloride (1 × 50ml) washing, water phase is extracted with ethyl acetate (2 × 25ml), organic phase is merged.Organic phase is successively used into saturated ammonium chloride Aqueous solution (1 × 100ml), distilled water (1 × 100ml), saturated sodium-chloride water solution (1 × 100ml) washing, then with anhydrous sulphur Sour sodium is dry, is evaporated solvent with Rotary Evaporators, obtained light yellow oil silica gel chromatography (petroleum ether/second Acetoacetic ester=50/1), obtain colorless oil as product 1.74g.

¹H NMR (400MHz, CDCl₃) δ 7.38-7.26 (m, 5H), 4.48 (s, 2H), 4.19 (dd, J=14.4,7.2Hz, 4H), 3.43 (t, J=6.1Hz, 2H), 2.67-2.54 (m, 2H), 2.34 (dt, J=16.0,7.9Hz, 1H), 2.22-2.12 (m, 2H), 1.62-1.40 (m, 4H), 1.24 (dd, J=13.4,7.0Hz, 6H)

The preparation of (2) 1,1- dicarboxylic acid ethyl ester -3- hydroxypropyl-cyclobutane

Palladium/carbon (0.11g) is added in the methanol solution containing upper step reaction product (1.26g), at room temperature vacuum Replacing hydrogen, then reaction solution stirs 36 hours under hydrogen atmosphere.Diatomite filtering removes extra residue and obtains filtrate, and revolving is removed Solvent is removed, obtained light yellow oil obtains colorless oil with silica gel chromatography (petrol ether/ethyl acetate=4/1) Product 0.868g.

¹H NMR (400MHz, CDCl₃) δ 4.17 (dq, J=14.2,7.1Hz, 4H), 3.61-3.53 (m, 2H), 2.67- 2.51 (m, 2H), 2.39-2.25 (m, 1H), 2.20-2.05 (m, 2H), 1.70 (s, 1H), 1.45 (dd, J=6.6,3.1Hz, 4H), 1.22 (dd, J=13.2,7.1Hz, 6H) .MS (m/z): 281.0 [M+Na]⁺

(3) 1,1- dicarboxylic acid ethyl ester -3- propylidene-[2,3,4,6-O- acetyl group -1-O-D- glucoside] cyclobutane Preparation

1,2,3,4,6-O- five acetyl-D-Glucose (1.84g) is added to containing 1,1- dioctyl phthalate at room temperature In ethyl ester -3- hydroxypropyl-cyclobutane (1.22g) methylene chloride (20ml) solution, it is cooled to 0 DEG C, with nitrogen displacement flask The diethyl ether solution (98%, 1.19ml) of boron trifluoride is slowly added dropwise in interior air under nitrogen protection.Reaction solution is stirred at 0 DEG C It 15 minutes, is then slowly warming up to room temperature and stirs 12 hours.After the reaction was completed, revolving removes solvent, uses silica gel column chromatography (petrol ether/ethyl acetate=5/1) implements simple purification to reaction product, obtains crude product 1.72g.

¹H NMR (400MHz, CDCl₃) δ 5.19 (t, J=9.5Hz, 1H), 5.08 (t, J=9.7Hz, 1H), 4.97 (dd, J =9.5,8.1Hz, 1H), 4.48 (t, J=8.0Hz, 1H), 4.30-4.09 (m, 6H), 3.83 (dd, J=9.8,6.1Hz, 1H), 3.68 (ddd, J=9.8,4.6,2.4Hz, 1H), 3.48-3.37 (m, 1H), 2.67-2.55 (m, 2H), 2.31 (dt, J= 15.1,7.5Hz, 1H), 2.16 (dd, J=10.0,8.0Hz, 2H), 2.08 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.45 (dt, J=17.6,9.7Hz, 4H), 1.27-1.21 (m, 6H)

MS (m/z): 611.2 [M+Na]⁺

The preparation of (4) 1,1- dioctyl phthalate -3- propylidene-[2,3,4,6- tetrahydroxy -1-O-D- glucoside] cyclobutane

NaOH (0.72g) is dissolved in the water of 15ml at room temperature, is then slowly added into containing 1,1- dioctyl phthalate The aqueous solution (7ml) of ethyl ester -3- propylidene-[2,3,4,6-O- acetyl group -1-O-D- glucoside] cyclobutane (1.18g) when In, it increases temperature and stirs 8h at 90 DEG C.Required acid is obtained by strong acidic ion resin after reaction solution is cooling Aqueous solution (10ml), freeze-drying obtain white solid 1.0g.

(5) cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- propylidene-(1-O-D- glucoside) ring fourth Alkane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- propylidene-[2,3,4,6- tetrahydroxy -1-O-D- glucoside] cyclobutane (1.0g) is dissolved in In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing sulfatodiamino cyctohexane platinum (0.82g) is added to above-mentioned gained reaction solution under nitrogen protection In, room temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, freeze-drying is used Machine freeze-drying, with the half preparation isolated 0.52g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 5.71 (s, 1H), 5.05 (s, 1H), 4.91 (d, J=3.5Hz, 1H), 4.37 (d, J =7.9Hz, 1H), 3.98-3.85 (m, 2H), 3.85-3.69 (m, 2H), 3.64 (ddd, J=13.2,8.7,3.8Hz, 2H), 3.52-3.42 (m, 1H), 3.15-3.01 (m, 2H), 2.38 (dd, J=23.2,10.4Hz, 4H), 2.22 (dt, J=15.8, 7.8Hz, 1H), 2.00 (d, J=12.0Hz, 2H), 1.56 (dd, J=15.6,7.9Hz, 4H), 1.46 (dd, J=14.7, 7.1Hz, 2H), 1.25 (d, J=8.9Hz, 2H), 1.12 (dd, J=19.5,8.9Hz, 2H)

Embodiment 11: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- propylidene-(1-O-D- mannose Glycosides) cyclobutane -1,1- dioctyl phthalate] preparation

(1) 1,1- dicarboxylic acid ethyl ester -3- propylidene-[2,3,4,6-O- acetyl group -1-O-D- mannoside] cyclobutane Preparation

1,2,3,4,6-O- five acetyl-D-MANNOSE (1.84g) is added to containing 1,1- dioctyl phthalate at room temperature In ethyl ester -3- hydroxypropyl-cyclobutane (1.22g) methylene chloride (20ml) solution, it is cooled to 0 DEG C, with nitrogen displacement flask The diethyl ether solution (98%, 1.19mL) of boron trifluoride is slowly added dropwise in interior air under nitrogen protection.Reaction solution is stirred at 0 DEG C It 15 minutes, is then slowly warming up to room temperature and stirs 12 hours.After the reaction was completed, revolving removes solvent, uses silica gel column chromatography (petrol ether/ethyl acetate=5/1) implements simple purification to reaction product, obtains crude product 1.41g.

¹H NMR (400MHz, CDCl₃) δ 5.36-5.21 (m, 3H), 4.79 (s, 1H), 4.33-4.07 (m, 6H), 4.02- 3.92 (m, 1H), 3.65 (d, J=9.3Hz, 1H), 3.49-3.36 (m, 1H), 2.72-2.58 (m, 2H), 2.41-2.30 (m, 1H), 2.16 (s, 5H), 2.11 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.57-1.44 (m, 4H), 1.28-1.24 (m, 6H) .MS (m/z): 611.2 [M+Na]⁺

The preparation of (2) 1,1- dioctyl phthalate -3- propylidene-[2,3,4,6- tetrahydroxy -1-O-D- mannoside] cyclobutane

NaOH (0.72g) is dissolved in the water of 15ml at room temperature, is then slowly added into containing 1,1- dioctyl phthalate The aqueous solution (7ml) of ethyl ester -3- propylidene-[2,3,4,6-O- acetyl group -1-O-D- mannoside] cyclobutane (1.18g) when In, it increases temperature and stirs 8h at 90 DEG C.Required acid is obtained by strong acidic ion resin after reaction solution is cooling Aqueous solution (10ml), freeze-drying obtain white solid 1.0g.

(3) cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- propylidene-(1-O-D- mannoside) ring fourth Alkane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- propylidene-[2,3,4,6- tetrahydroxy -1-O-D- mannoside] cyclobutane (1.0g) is dissolved in In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing sulfatodiamino cyctohexane platinum (0.82g) is added to above-mentioned gained reaction solution under nitrogen protection In, room temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, freeze-drying is used Machine freeze-drying, with the half preparation isolated 0.50g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.35 (d, J=7.9Hz, 1H), 3.83 (dd, J=8.1,4.2Hz, 2H), 3.65- 3.60 (m, 2H), 3.42-3.34 (m, 3H), 3.16 (t, J=8.6Hz, 1H), 3.06 (dd, J=18.6,9.3Hz, 2H), 2.49-2.22 (m, 5H), 1.91 (d, J=10.7Hz, 2H), 1.67 (d, J=6.6Hz, 2H), 1.45 (d, J=6.1Hz, 2H), 1.12 (s, 2H), 1.00 (d, J=9.1Hz, 2H)

Embodiment 12: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [1,1- dioctyl phthalate -3- propylidene-(1- O-D- galactoside) cyclobutane] preparation

(1) 1,1- dicarboxylic acid ethyl ester -3- propylidene-[2,3,4,6-O- acetyl group -1-O-D- galactoside] cyclobutane Preparation

1,2,3,4,6-O- five acetyl-D- galactolipin (1.84g) is added to containing 1,1- dioctyl phthalate at room temperature In ethyl ester -3- hydroxypropyl-cyclobutane (1.22g) methylene chloride (20ml) solution, it is cooled to 0 DEG C, with nitrogen displacement flask The diethyl ether solution (98%, 1.19ml) of boron trifluoride is slowly added dropwise in interior air under nitrogen protection.Reaction solution is stirred at 0 DEG C It 15 minutes, is then slowly warming up to room temperature and stirs 12 hours.After the reaction was completed, revolving removes solvent, uses silica gel column chromatography (petrol ether/ethyl acetate=5/1) implements simple purification to reaction product, obtains crude product 1.57g.

¹H NMR (400MHz, CDCl₃) 65.42-5.30 (m, 1H), 5.18 (d, J=7.9Hz, 1H), 5.01 (dd, J= 9.9,2.9Hz, 1H), 4.44 (d, J=7.2Hz, 1H), 4.27-4.04 (m, 6H), 3.87 (dt, J=10.7,6.0Hz, 2H), 3.43 (s, 1H), 2.70-2.53 (m, 2H), 2.36-2.26 (m, 1H), 2.15 (s, 6H), 2.05 (s, 5H), 1.99 (s, 3H), 1.56-1.38 (m, 4H), 1.27-1.20 (m, 6H) .MS (m/z): 611.2 [M+Na]⁺

The preparation of (2) 1,1- dioctyl phthalate -3- propylidene-[2,3,4,6- tetrahydroxy -1-O-D- galactoside] cyclobutane

NaOH (0.72g) is dissolved in the water of 15ml at room temperature, is then slowly added into containing 1,1- dioctyl phthalate The aqueous solution (7ml) of ethyl ester -3- propylidene-[2,3,4,6-O- acetyl group -1-O-D- galactoside] cyclobutane (1.18g) when In, it increases temperature and stirs 8h at 90 DEG C.Required acid is obtained by strong acidic ion resin after reaction solution is cooling Aqueous solution (10ml), freeze-drying obtain white solid 1.0g.

(3) cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- propylidene-(1-O-D- galactoside) ring fourth Alkane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- propylidene-[2,3,4,6- tetrahydroxy -1-O-D- galactoside] cyclobutane (1.0g) is dissolved in In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing sulfatodiamino cyctohexane platinum (0.82g) is added to above-mentioned gained reaction solution under nitrogen protection In, room temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, freeze-drying is used Machine freeze-drying, with the half preparation isolated 0.55g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 5.62 (s, 1H), 4.96 (s, 1H), 4.34 (d, J=8.0Hz, 1H), 3.87-3.49 (m, 4H), 3.46-3.25 (m, 3H), 3.14 (t, J=8.6Hz, 1H), 3.05-2.94 (m, 2H), 2.29 (dd, J=22.7, 10.1Hz, 4H), 2.13 (dt, J=15.6,7.9Hz, 1H), 1.91 (d, J=12.1Hz, 2H), 1.47 (t, J=11.3Hz, 4H), 1.40-1.29 (m, 2H), 1.22-1.10 (m, 2H), 1.02 (d, J=9.7Hz, 2H)

Embodiment 13: diamino platinum (II) [1,1- dioctyl phthalate -3- (1-O-D- glucoside) cyclobutane] preparation

By 1,1- dioctyl phthalate -3-[2,3,4,6- tetrahydroxy -1-O-D- glucosides] cyclobutane (0.9g) is dissolved in 20mL water In, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 minutes.In nitrogen The aqueous solution (7ml) containing diamines platinic sulfate (0.65g) is added in above-mentioned gained reaction solution under gas shielded, room temperature, which is protected from light, to be stirred It mixes 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is lyophilized using freeze drier, is made with half The standby isolated 0.41g final products of high pressure liquid chromatography.

¹H NMR (600MHz, D₂O) δ 4.40 (d, J=8.0Hz, 1H), 4.37-4.29 (m, 1H), 4.14 (brs, 6H), 3.84 (d, J=12.1Hz, 1H), 3.65 (dd, J=12.5,5.9Hz, 1H), 3.43-3.25 (m, 5H), 3.19 (t, J= 8.7Hz, 1H), 2.79-2.70 (m, 1H), 2.70-2.61 (m, 1H)

Embodiment 14: diamino platinum (II) [3- (1-O-D- mannoside) cyclobutane -1,1- dioctyl phthalate] preparation

By 1,1- dioctyl phthalate -3-[2,3,4,6- tetrahydroxy -1-O-D- mannosides] cyclobutane (0.9g) is dissolved in 20mL water In, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 minutes.In nitrogen The aqueous solution (7ml) containing diamines platinic sulfate (0.65g) is added in above-mentioned gained reaction solution under gas shielded, room temperature, which is protected from light, to be stirred It mixes 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is lyophilized using freeze drier, is made with half The standby isolated 0.42g final products of high pressure liquid chromatography.

¹H NMR (600MHz, D₂O) δ 4.37-4.31 (m, 2H), 4.16 (s, 6H), 3.85 (d, J=3.2Hz, 1H), 3.69 (m, 1H), 3.46-3.24 (m, 6H), 2.76 (dd, J=12.1,7.4Hz, 1H), 2.66 (dd, J=11.9,7.3Hz, 1H)

Embodiment 15: diamino platinum (II) [3- (1-O-D- galactoside) cyclobutane -1,1- dioctyl phthalate] preparation

By 1,1- dioctyl phthalate -3-[2,3,4,6- tetrahydroxy -1-O-D- galactosides] cyclobutane (0.9g) is dissolved in 20mL water In, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 minutes.In nitrogen The aqueous solution (7ml) containing diamines platinic sulfate (0.65g) is added in above-mentioned gained reaction solution under gas shielded, room temperature, which is protected from light, to be stirred It mixes 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is lyophilized using freeze drier, is made with half The standby isolated 0.44g final products of high pressure liquid chromatography.

1H NMR (400MHz, D₂O) δ 4.91 (d, J=13.8Hz, 1H), 3.96-3.60 (m, 6H), 3.45-3.25 (m, 2H), 2.91-2.57 (m, 2H)

Embodiment 16: the system of diamino platinum (II) [3- methylene-(1-O-D- glucoside) cyclobutane -1,1- dioctyl phthalate] It is standby

1,1- dioctyl phthalate -3- methylene-[2,3,4,6- tetrahydroxy -1-O-D- glucoside] cyclobutane (0.93g) is molten In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing diamines platinic sulfate (0.65g) is added in above-mentioned gained reaction solution under nitrogen protection, room Temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is frozen using freeze drier It is dry, with the half preparation isolated 0.41g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.83 (d, J=3.7Hz, 0.4H), 4.37 (d, J=8.0Hz, 0.6H), 4.11 (s, 5H), 3.87-3.74 (m, 2H), 3.71-3.55 (m, 3H), 3.49-3.29 (m, 3H), 3.23-3.16 (m, 2H), 2.68-2.41 (m, 3H)

Embodiment 17: diamino platinum (II) [3- methylene-(1-O-D- mannoside) cyclobutane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- methylene-[2,3,4,6- tetrahydroxy -1-O-D- mannoside] cyclobutane (0.93g) is molten In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing diamines platinic sulfate (0.65g) is added in above-mentioned gained reaction solution under nitrogen protection, room Temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is frozen using freeze drier It is dry, with the half preparation isolated 0.40g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.71 (d, J=1.4Hz, 1H), 4.04 (s, 5H), 3.83-3.46 (m, 7H), 3.35 (dd, J=9.9,5.7Hz, 1H), 2.99-2.83 (m, 2H), 2.61-2.32 (m, 3H)

Embodiment 18: diamino platinum (II) [3- methylene-(1-O-D- galactoside) cyclobutane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- methylene-[2,3,4,6- tetrahydroxy -1-O-D- galactoside] cyclobutane (0.93g) is molten In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing diamines platinic sulfate (0.65g) is added in above-mentioned gained reaction solution under nitrogen protection, room Temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is frozen using freeze drier It is dry, with the half preparation isolated 0.40g final products of high pressure liquid chromatography.

¹H NMR (600MHz, D₂O) δ 4.87 (d, J=3.2Hz, 0.4H), 4.32 (d, J=7.9Hz, 0.6H), 4.15 (s, 5H), 3.92-3.56 (m, 7H), 3.44 (t, J=8.9Hz, 1H), 3.01 (s, 2H), 2.59 (dd, J=24.8,12.1Hz, 2H), 2.50 (dd, J=14.8,7.3Hz, 1H)

Embodiment 19: the system of diamino platinum (II) [3- ethylidene-(1-O-D- glucoside) cyclobutane -1,1- dioctyl phthalate] It is standby

1,1- dioctyl phthalate -3- ethylidene-[2,3,4,6- tetrahydroxy -1-O-D- glucoside] cyclobutane (1.0g) is dissolved in In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing diamines platinic sulfate (0.65g) is added in above-mentioned gained reaction solution under nitrogen protection, room Temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is frozen using freeze drier It is dry, with the half preparation isolated 0.44g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.34 (d, J=8.0Hz, 1H), 4.09 (s, 5H), 3.87-3.71 (m, 2H), 3.66-3.52 (m, 2H), 3.46-3.31 (m, 2H), 3.31-3.22 (m, 1H), 3.15 (dd, J=9.1,8.2Hz, 1H), 3.11-2.96 (m, 2H), 2.49-2.33 (m, 2H), 2.26 (dd, J=16.2,7.8Hz, 1H), 1.65 (dd, J=13.7, 6.7Hz, 2H)

Embodiment 20: diamino platinum (II) [3- ethylidene-(1-O-D- mannoside) cyclobutane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- ethylidene-[2,3,4,6- tetrahydroxy -1-O-D- mannoside] cyclobutane (0.95g) is molten In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing diamines platinic sulfate (0.65g) is added in above-mentioned gained reaction solution under nitrogen protection, room Temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is frozen using freeze drier It is dry, with the half preparation isolated 0.41g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.86 (s, 1H), 3.99-3.86 (m, 2H), 3.86-3.70 (m, 3H), 3.69- 3.59 (m, 2H), 3.54 (d, J=4.1Hz, 1H), 3.23-3.05 (m, 2H), 2.50 (dd, J=21.3,12.1Hz, 2H), 2.41-2.29 (m, 1H), 1.85-1.64 (m, 2H)

Embodiment 21: diamino platinum (II) [3- ethylidene-(1-O-D- galactoside) cyclobutane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- ethylidene-[2,3,4,6- tetrahydroxy -1-O-D- galactoside] cyclobutane (0.95g) is molten In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing diamines platinic sulfate (0.65g) is added in above-mentioned gained reaction solution under nitrogen protection, room Temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is frozen using freeze drier It is dry, with the half preparation isolated 0.40g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.91 (d, J=3.6Hz, 1H), 3.97 (d, J=2.7Hz, 1H), 3.91 (t, J= 6.1Hz, 1H), 3.82 (ddd, J=21.5,10.3,3.4Hz, 2H), 3.71 (dd, J=19.2,6.6Hz, 3H), 3.54-3.44 (m, 1H), 3.17-3.05 (m, 2H), 2.48 (dt, J=12.2,7.8Hz, 2H), 2.34 (dt, J=16.1,8.0Hz, 1H), (1.84-1.65 m, 2H)

Embodiment 22: diamino platinum (II) [3- propylidene-(1-O-D- glucoside) cyclobutane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- propylidene-[2,3,4,6- tetrahydroxy -1-O-D- glucoside] cyclobutane (1.0g) is dissolved in In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing diamines platinic sulfate (0.65g) is added in above-mentioned gained reaction solution under nitrogen protection, room Temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is frozen using freeze drier It is dry, with the half preparation isolated 0.46g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.81 (d, J=3.5Hz, 0.6H), 4.36 (d, J=7.9Hz, 0.4H), 4.09 (s, 5H), 3.85-3.52 (m, 5H), 3.47-3.26 (m, 3H), 3.01 (dd, J=11.4,8.8Hz, 2H), 2.40-2.24 (m, 2H), 2.14 (dt, J=15.8,7.9Hz, 1H), 1.62-1.27 (m, 4H)

Embodiment 23: diamino platinum (II) [3- propylidene-(1-O-D- mannoside) cyclobutane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- propylidene-[2,3,4,6- tetrahydroxy -1-O-D- mannoside] cyclobutane (1.0g) is dissolved in In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing diamines platinic sulfate (0.65g) is added in above-mentioned gained reaction solution under nitrogen protection, room Temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is frozen using freeze drier It is dry, with the half preparation isolated 0.40g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.88 (s, 1H), 3.99-3.86 (m, 2H), 3.74 (dd, J=23.3,12.7Hz, 3H), 3.70-3.61 (m, 2H), 3.56 (d, J=4.7Hz, 1H), 3.12 (t, J=9.4Hz, 2H), 2.51-2.34 (m, 2H), 2.32-2.18 (m, 1H), 1.54 (dd, J=32.5,5.6Hz, 4H)

Embodiment 24: diamino platinum (II) [3- propylidene-(1-O-D- galactoside) cyclobutane -1,1- dioctyl phthalate] preparation

1,1- dioctyl phthalate -3- propylidene-[2,3,4,6- tetrahydroxy -1-O-D- galactoside] cyclobutane (1.0g) is dissolved in In 20mL water, solution acid alkalinity is adjusted to pH ≈ 8 with saturation barium hydroxide solution.The mixed solution is stirred at room temperature 30 points Clock.The aqueous solution (7ml) containing diamines platinic sulfate (0.65g) is added in above-mentioned gained reaction solution under nitrogen protection, room Temperature is protected from light stirring 12 hours.To after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is frozen using freeze drier It is dry, with the half preparation isolated 0.43g final products of high pressure liquid chromatography.

¹H NMR (400MHz, D₂O) δ 4.78 (d, J=3.4Hz, 0.8H), 4.23 (d, J=7.9Hz, 0.2H), 3.83- 3.46 (m, 7H), 3.44-3.29 (m, 1H), 3.03-2.87 (m, 2H), 2.32-2.20 (m, 2H), 2.15-2.00 (m, 1H), (1.51-1.18 m, 4H)

Embodiment 25: the system of diamino platinum (II) [3- hexylidene-(1-O-D- glucoside) cyclobutane -1,1- dioctyl phthalate] It is standby

(1) preparation of 6- benzyloxy -1- hexanol

1,6- hexylene glycol (2.36g) is dissolved in the dry n,N-Dimethylformamide of 60mL, it is slow to reaction solution at 0 DEG C Slowly it is added portionwise 60% sodium hydride (920mg), stirring was slowly added to cylite (2.38mL) after 30 minutes, and reaction solution is slowly increased to Room temperature is simultaneously stirred overnight.Reaction end is monitored with TLC, to after the reaction was completed, extra solvent be removed with vacuum rotary steam, to residual 100mL ethyl acetate is added in object, is then washed with saturated aqueous ammonium chloride (1 × 50mL), water phase ethyl acetate is extracted (100mL) is taken, organic phase twice is merged, and successively uses saturated aqueous ammonium chloride (1 × 100mL), distilled water (1 × 100mL), saturated sodium chloride solution (1 × 100mL) is washed, then dry with anhydrous sodium sulfate, is steamed solvent with Rotary Evaporators Dry, obtained light yellow oil obtains colorless and transparent oily with silica gel chromatography (petrol ether/ethyl acetate=4/1) Product 1.8g.

(2) preparation of benzyl -6- bromine hexyl ether

6. benzyloxy -1- hexanols (1.5g) are dissolved in the dry methylene chloride of 20mL, reaction solution is cooled to 0 DEG C, The dichloromethane solution (10mL) of carbon tetrabromide (3.5g) is slowly added dropwise, is then slowly added into the dichloromethane of triphenyl phosphorus (2.8g) Alkane solution (10mL), reaction solution stir 1 hour at 0 DEG C, reaction end are monitored with TLC, to which after the reaction was completed, vacuum rotary steam removes Extra solvent is removed, residue obtains colorless and transparent oily and produce through silica gel chromatography (petrol ether/ethyl acetate=20/1) Object 1.7g.

(3) preparation of 2- (6- benzyloxy hexyl) diethyl malonate

60% sodium hydride (222mg) is suspended in 5mL dry tetrahydrofuran solution in ice-water bath, is replaced and is burnt with nitrogen Air in bottle, is slowly added dropwise diethyl malonate (1.3mL) under nitrogen protection, after reaction is stirred 0.5 hour in ice-water bath, The dry tetrahydrofuran solution (2mL) of benzyl -6- bromine hexyl ether (1.5g) is slowly added dropwise into reaction solution, then reaction solution heats up To 70 DEG C and stir 5 hours.Reaction end is monitored with TLC, to which after the reaction was completed, reaction solution is cooled to room temperature, to reaction solution Middle addition 100mL ethyl acetate, is then washed with saturated aqueous ammonium chloride (1 × 50mL), water phase is extracted with ethyl acetate (2 × 50mL) merges organic phase twice, and organic phase is successively used to saturated aqueous ammonium chloride (1 × 100mL), distilled water (1 × 100mL), saturated sodium chloride solution (1 × 100mL) washing is then dry with anhydrous sodium sulfate, with Rotary Evaporators by solvent It is evaporated, obtained light yellow oil obtains colorless transparent oil with silica gel chromatography (petrol ether/ethyl acetate=20/1) Shape product 1.5g.

(4) preparation of 2- (6- benzyloxy hexyl) -1,3-PD

Tetrahydrochysene lithium aluminium (282mg) is suspended in 15mL anhydrous ether in ice-water bath, is slowly added dropwise under nitrogen protection The anhydrous ether solution (10mL) of 2- (6- benzyloxy hexyl) diethyl malonate (1.3g) monitors reaction end with TLC, to anti- After the completion of answering, it is slowly added to sal glauberi into reaction solution into reaction solution there is no gas generation, solid is filtered, collects Solvent is evaporated by filtrate with Rotary Evaporators, obtained light yellow oil silica gel chromatography (petroleum ether/acetic acid second Ester=2/1), obtain colorless and transparent oily product 0.8g.

(5) preparation of 6- benzyloxy hexyl -1,3- dibromopropane

2- (6- benzyloxy hexyl) -1,3-PD (0.6g) is dissolved in the dry methylene chloride of 8mL, by reaction solution It is cooled to 0 DEG C, the dichloromethane solution (4mL) of carbon tetrabromide (2.2g) is slowly added dropwise, is then slowly added into triphenylphosphine The dichloromethane solution (4mL) of (1.8g) reacts 1 hour at 0 DEG C, monitors reaction end with TLC, to after the reaction was completed, decompression Revolving removes extra solvent, and residue obtains colorless and transparent through silica gel chromatography (petrol ether/ethyl acetate=20/1) Oil product 0.8g.

The preparation of (6) 1,1- dicarboxylate -3- benzyloxy hexyl-cyclobutane

Under the conditions of ice-water bath, 60% sodium hydride (142mg) is suspended in the dry n,N-Dimethylformamide of 3mL, It is slowly added dropwise under nitrogen protection diethyl malonate (0.54mL), after stirring half an hour, 2- benzyl is slowly added dropwise into reaction solution N,N-Dimethylformamide (3mL) solution of oxygen hexyl -1,3- dibromopropane (0.7g), is then warming up to 70 DEG C simultaneously for reaction solution Stirring 7 hours.It is added to which after the reaction was completed, reaction solution is cooled to room temperature into reaction solution with TLC monitoring reaction end Then 100mL ethyl acetate is washed with saturated aqueous ammonium chloride (1 × 50mL), water phase is extracted with ethyl acetate (2 × 50mL), merge organic phase twice and successively use saturated aqueous ammonium chloride (1 × 100mL), distilled water (1 × 100mL) is satisfied It is washed with sodium chloride solution (1 × 100mL), it is then dry with anhydrous sodium sulfate, solvent is evaporated with Rotary Evaporators, is obtained Light yellow oil obtains colorless and transparent oily product 0.5g with silica gel chromatography (petrol ether/ethyl acetate=20/1).

The preparation of (7) 1,1- dicarboxylate -3- hydroxyl hexyl-cyclobutane

3- benzyloxy hexyl-cyclobutane -1,1- dicarboxylate (0.4g) dissolution is in 10mL methanol, is added 10% Palladium carbon (0.1g), with nitrogen by air displacement 3 times in reaction flask, then with hydrogen by nitrogen displacement 3 times in reaction flask, instead Liquid is answered to be stirred at room temperature overnight.Reaction end is monitored with TLC, to after the reaction was completed, with the hydrogen in nitrogen displacement reaction flask, Palladium carbon is filtered, filtrate is collected, then solvent is evaporated with Rotary Evaporators, obtains the product 0.3g of colorless and transparent oily.

(8) 1,1- dicarboxylate 3- hexylidene-[2,3,4,6-O- acetyl group -1-O-D- glucoside] cyclobutane Preparation

By 3- hydroxyl hexyl-cyclobutane -1,1- dicarboxylate (200mg) and 1,2,3,4,6- five acetyl-β-D- pyrans Glucose ester (286mg) is dissolved in 5mL dry methylene chloride, and reaction solution is cooled to 0 DEG C, and boron trifluoride is then slowly added dropwise Diethyl ether solution (1mL), reaction solution are slowly increased to room temperature by 0 DEG C and are stirred overnight.Reaction end is monitored with TLC, is completed wait react Afterwards, methylene chloride (100mL) is added into reaction solution, organic phase successively uses distilled water (1 × 100mL), and saturated sodium bicarbonate is molten Liquid (1 × 100mL) washing, it is then dry with anhydrous sodium sulfate, solvent is evaporated with Rotary Evaporators, obtained faint yellow oily Object obtains the product 60mg of colorless and transparent oily with silica gel chromatography (petrol ether/ethyl acetate=5/1).

The preparation of (9) 1,1- dioctyl phthalate -3- hexylidene-[1-O-D- glucoside] cyclobutane

1,1- dicarboxylate 3- hexylidene-[2,3,4,6-O- acetyl group -1-O-D- glucoside] cyclobutane (60mg) is dissolved in 1mL methanol, and the aqueous solution (2mL) of sodium hydroxide (34mg) is then added, reaction solution is warming up to 90 DEG C Reaction 5 hours is removed to which after the reaction was completed, reaction solution is cooled to room temperature with Rotary Evaporators with TLC monitoring reaction end Then storng-acid cation exchange resin is added into reaction solution and stirs half an hour, resin is filtered, filter is collected for methanol Liquid is dried using freeze drier, obtains colorless viscous shape liquid 35mg, and crude product is directly used in reacts in next step.

(10) prepared by diamino platinum (II) [3- hexylidene-(1-O-D- glucoside) cyclobutane -1,1- dioctyl phthalate]

1,1- dioctyl phthalate -3- hexylidene-[1-O-D- glucoside] cyclobutane crude product (35mg) is dissolved in 2mL water In, sodium hydrate aqueous solution is added and adjusts reaction solution pH to 7, room temperature stirs 30min under the conditions of being protected from light.Under nitrogen protection by two Amine platinum nitrate (30mg) is dissolved in 1mL water, is added dropwise to dropwise into above-mentioned reaction solution, and room temperature is protected from light stirring 1 hour.Use HPLC Detection reaction collects supernatant to after the reaction was completed, remove and precipitate using centrifuge, with half preparation high pressure liquid phantom preparing chromatogram It is isolated and purified, is then dried using low-temperature freeze-drying machine, obtain 20mg finished product, white solid.

¹H NMR (400MHz, D₂O) δ 4.91 (d, J=3.7Hz, 1H), 3.85 (dd, J=12.2,2.2Hz, 1H), 3.79- 3.66 (m, 4H), 3.56-3.51 (m, 2H), 3.39 (dd, J=21.2,11.2Hz, 1H), 3.08 (dd, J=11.4,9.5Hz, 2H), 2.40 (dd, J=11.6,9.6Hz, 2H), 2.25-2.17 (m, 1H), 1.68-1.59 (m, 2H), 1.44-1.29 (m, 8H).

Embodiment 26: cis- [trans--(1R, 2R)-diamines butylcyclohexane] platinum (II) [3- hexylidene-(1-O-D- glucose Glycosides) cyclobutane -1,1- dioctyl phthalate] preparation

By 1,1- dioctyl phthalate -3- hexylidene-[1-O-D- glucoside] cyclobutane prepared by 25 kinds of above-described embodiment In (35mg) 2mL water, sodium hydrate aqueous solution is added and adjusts reaction solution pH to 7, room temperature stirs 30min under the conditions of being protected from light.In nitrogen The aqueous solution 1mL that sulfatodiamino cyctohexane platinum (40m g) will be contained under gas shielded, is added dropwise to dropwise into above-mentioned reaction solution, room Temperature is protected from light stirring 1 hour.It is detected and is reacted with HPLC, to after the reaction was completed, be removed and precipitated using centrifuge, collected supernatant, use Half preparation high pressure liquid phantom preparing chromatogram is isolated and purified, and is then dried using low-temperature freeze-drying machine, and 30mg end is obtained Product, white solid.

¹H NMR (400MHz, D₂O) δ 5.75 (s, 1H), 5.03 (d, J=9.7Hz, 1H), 4.83 (s, 1H), 3.79-3.63 (m, 4H), 3.55-3.50 (m, 2H), 3.38 (dd, J=21.2,11.2Hz, 1H), 3.07 (dd, J=11.4,9.5Hz, 2H), 2.41 (dd, JJ=11.6,9.6Hz, 2H), 2.25-2.15 (m, 1H), 1.68-1.59 (m, 2H), 1.44-1.29 (m, 8H)

Test example 1: solubility test

Experimental method: about 0.5mL distilled water is taken with the EP pipe of 5mL, being slowly added into dry compound cannot extremely dissolve (25 DEG C of ultrasonic vibrations, muddiness still occur).Solution is filtered into the EP pipe that another 5mL is clean and has weighed, is re-weighed, is counted Calculate the weight of solution.It filtrate is lyophilized, weighs and calculates the Solute mass of remaining solid, in this way it is known that solvent The quality of weight and solute, to calculate the solubility of compound in water.

The dissolubility data of 2 embodiment sample of table in water

The solubility of platinum complexes of the present invention in water is far longer than the cis-platinum, carboplatin and oxaliplatin listed, Water solubility can be improved tens to thousands of times.

Test example 2: antitumor drug effect

Experiment is for the cyclobutane dicarboxylic acid platinum complex for oncotherapy of the invention to different types of people below The proliferation inhibiting effect of tumour cell has carried out experimental verification.

(1) test method:

Cell culture fluid:

Use the cell culture fluid for containing 10% fetal calf serum (fetal bovine serum).

Major experimental instrument:

HERAcell150i type carbon dioxide incubator (Thermo), research grade inverted fluorescence microscope (Nikon, day This), multi-function microplate reader (Thermo), ultra low temperature freezer (Thermo), Biohazard Safety Equipment (1300SeriesA2, Thermo), Micropipettor (German eppendorf), ultrapure water system (U.S. Milli-Q).

Experiment reagent:

MTT:Sigma-Aldrich company

DMSO: Tianjin sky over the river Chemical Engineering Technology Co., Ltd

Tumour cell:

3 MTT of table tests cell list

Cytotoxicity test:

Cytotoxicity experiment is tested using mtt assay.Logarithmic phase tumour cell is collected, adjusts concentration of cell suspension, every hole adds Enter 100 μ l, bed board adjusts cell density to be measured to 1000-10000/hole, (edge hole is filled with sterile PBS).In 5%CO₂, The drug of various concentration gradient, every 100 mountain of hole, if 4 multiple holes is added until cell is adherent (96 hole flat underside) in 37 DEG C of incubations.? 5%CO₂, it is incubated for 72 hours under the conditions of 37 DEG C, is observed under inverted microscope.Prepared MTT solution is added into 96 orifice plates (5mg/ml), every 20 μ l of hole are mixed, at 37 DEG C, 5%CO₂Under the conditions of be incubated for 4h after, discard liquid in plate, 150 μ l are added in every hole DMSO, microplate reader vibrate 3 minutes, detect OD value (OD value) at 490nm.

Control group:

It does not add tested active constituent under above-mentioned similarity condition, finally obtains tumour cell and detect OD value at 490nm.

Inhibitory activity IC of the drug to tumour cell₅₀:

Cell inhibitory rate calculates: drug is calculated according to the following formula to the inhibiting rate of growth of tumour cell:

1) cell survival rate (%)=(treatment group OD value/control group OD value) × 100

2) cell survival rate under each drug concentration is found out, is mapped with this to drug concentration.Judge that different pharmaceutical is dense with this Spend the drug effect to Cytostatic to tumor cell.

3) corresponding drug concentration when cell survival rate is the 50% of control group is that drug presses down the half of tumour cell Concentration processed, the i.e. IC of drug₅₀Value.

The experiment of above-mentioned each drug concentration repeats 4 groups, and average OD value is taken to calculate cell survival rate.

(2) experimental result: (IC₅₀(testing end value)

4 MTT test result (one) of table

5 MTT test result (two) of table

IC₅₀(μM) value	11	12	13	14	15	16	17	18	19	20	Carboplatin
												HT29	18.83	19.41	9.89	19.30	10.44	24.73	31.73	9.36	23.96	9.65	53.20
SMMC7721	4.95	4.70	1.76	5.23	2.23	4.96	8.04	2.17	4.13	2.23	12.03
												MCF-7	84.56	85.36	47.05	97.64	40.16	85.26	152.47	44.70	78.81	47.31	282.81
A549	37.83	35.80	14.00	35.49	15.34	41.97	67.49	17.98	36.9	16.62	95.26
												SKOV3	88.11	98.42	56.89	79.94	53.47	72.89	167.16	42.09	81.25	47.30	318.37
ECA109	12.54	10.05	4.56	12.58	5.15	10.99	20.21	4.66	10.34	5.36	26.88
												DU145	65.67	56.22	26.13	63.15	19.18	60.43	90.00	17.11	58.89	21.61	135.10
Hela	11.34	10.56	6.17	16.34	6.46	12.22	24.56	5.68	15.43	6.28	34.13
												A375	14.77	13.54	10.67	11.72	10.46	15.71	10.44	21.68	18.89	28.84	31.24
KB	10.11	15.00	5.73	15.27	5.65	14.16	27.33	5.59	17.23	5.54	33.51
												HGC27	32.23	25.21	12.53	31.94	13.04	31.95	44.89	12.94	30.11	11.36	68.31
SW579	73.34	75.11	30.04	77.41	24.05	75.38	91.45	29.89	72.22	27.18	170.46
												5637	13.44	11.78	5.53	12.99	5.42	13.21	19.09	5.07	9.67	5.18	27.90
Panc-1	78.55	70.22	40.42	92.12	42.48	75.98	122.23	41.45	76.78	40.55	213.94
												H929	9.33	8.11	4.09	9.71	3.65	9.43	15.55	8.88	9.67	3.81	23.14
HepG2	10.99	12.55	5.81	13.89	5.70	12.50	19.90	4.75	11.91	5.36	29.70
												THP-1	7.12	7.11	3.68	6.47	2.94	7.15	9.59	3.33	7.29	3.23	15.01

6 MTT test result (three) of table

Note: " -- " represents and does not test.

3 the compounds of this invention of test example is compared with the antitumor drug effect of known compound

The cyclobutane dicarboxylic acid platinum cooperation of following glycan molecule 3- couplings is disclosed in documents wO2008086783A2 Object: the antitumor drug effect that open compound -1 verifies complex of the present invention with open compound -2. is better than open compound, Implement following drug effect contrasts experiment:

(1) test method:

Test method is identical as the antitumor drug effect experimental method of experimental example 2, selects the compound compared for the present invention In contain the compound (compound -1,4,7,10,13,16,19,22,25) of identical glucose molecule structure with open compound, And the compounds of this invention (compound -11,20,23: mannose containing non-glucose molecular structure；Compound -12,15, 18, antitumor drug effect contrasts 24: galactolipin), are carried out with open compound, drug is obtained respectively and the half of tumour cell is inhibited Concentration, the i.e. IC of drug₅₀Value.

(2) test result:

7 MTT comparative efficacy test's result of table

The result shows that: compared with open compound, antineoplastic of the compounds of this invention in various different tumour cells Effect is significantly better than that open compound.

Claims

1. cyclobutane dicarboxylic acid platinum complex or its optical isomer shown in a kind of formula (I) or its is pharmaceutically acceptable Salt or its solvate:

Wherein:

X and Y is ligand, and the X and Y are each independently selected from NH₃、C₁-C₈Linear or branched alkyl group primary amine (is chosen as C₁-C₆ Linear or branched alkyl group primary amine, be chosen as C₁-C₃Linear or branched alkyl group primary amine), C₃-C₈Cyclic alkyl primary amine (is chosen as C₃-C₆Cyclic alkyl primary amine), primary aromatic amine, one or more C₁-C₄The primary aromatic amine of linear or branched alkyl group substitution divides Minor is R₁-NH-R₂Secondary amine, wherein R₁And R₂It is same or different to be respectively expressed as C₁-C₈Linear or branched alkyl group it is (optional For C₁-C₆Linear or branched alkyl group, be chosen as C₁-C₃Linear or branched alkyl group)；Or R₁-NH-R₂Collectively constitute C₄-C₈Rouge Ring secondary amine (is chosen as C₅-C₆Alicyclic ring secondary amine), nitrogenous aromatic heterocyclic compounds, one or more C₁-C₄Linear chain or branched chain alkane Nitrogenous aromatic heterocyclic compounds, sulfur-containing aromatic heterocyclic compound or the sulfur-bearing non-aromatic heterocyclic compound that base replaces；Its In, the aryl in " primary aromatic amine " is 5~10 unit monocycles or condensed-bicyclic aromatic group, and " heteroaromatic " is 5~10 unit monocycles or condensed-bicyclic aromatic heterocycle, " non-aromatic heterocyclic " are 4~10 unit monocycles or polycyclic alicyclic heterocyclic；

Or X and Y constitute formula (IV) structure together:

In formula (IV), D C₀Or C₁Alkylidene；B is C₂-C₈Alkylidene (be chosen as C₂-C₆Alkylidene, be chosen as C₃-C₅ Alkylidene)；

N=0,1,2,3,4,5 or 6 (optionally, n=0,1,2,3 or 6, optionally, n=0,1,2 or 3)；

2. cyclobutane dicarboxylic acid platinum complex according to claim 1 or its optical isomer or its is pharmaceutically acceptable Salt or its solvate, it is characterised in that the X and Y is respectively NH₃Or X, Y are trans--(1R, 2R)-hexamethylene two together Amine, trans--(1S, 2S)-cyclohexanediamine, cis--(1R, 2S)-cyclohexanediamine, cis--(1S, 2R)-cyclohexanediamine, racemization are anti- Formula -1,2- cyclohexanediamine or racemic cis -1,2- cyclohexanediamine.

3. cyclobutane dicarboxylic acid platinum complex according to claim 1 or 2 or its optical isomer or its pharmaceutically may be used The salt of receiving or its solvate, it is characterised in that the X and Y is respectively NH₃；Or X, Y are trans--(1R, 2R)-ring together Hexamethylene diamine.

4. cyclobutane dicarboxylic acid platinum complex according to claim 1-3 or its optical isomer or its pharmacy Upper acceptable salt or its solvate, wherein

The X and Y is respectively NH₃；Or X, Y are trans--(1R, 2R)-cyclohexanediamine together；

N=0,1,2,3 or 6；

。

5. cyclobutane dicarboxylic acid platinum complex according to claim 1-4 or its optical isomer or its pharmacy Upper acceptable salt or its solvate, the formula (I) are selected from following complexs,

6. a kind of formula (III) compound represented,

In formula (III):

Each M is independently represented each other the hydrogen atom perhaps metallic atom of periodic table of elements group ia or two M common generations The metallic atom of group iia in table element periodic table；Optional M is independently represented each other H, Na, K, Li, Cs or two M are common Represent Ba；

N=0,1,2,3,4,5 or 6 (optionally, n=0,1,2,3 or 6, optionally, n=0,1,2 or 3)；

Optionally, the formula (III) is selected from following compounds:

Formula (III-1), formula (III-2), in formula (III-3),

N=0,1,2,3 or 6 (optionally, n=0,1,2 or 3)；

7. the described in any item cyclobutane dicarboxylic acid platinum complexes of claim 1-5 or its optical isomer or its pharmaceutically may be used The preparation method of the salt of receiving, solvate, it is characterised in that including formula (II) compound and formula (III) compound are added water tune Section is the step of aqueous solution is reacted；Optionally, it is 7-9 that reacting solution, which adds alkali to adjust pH,

Optionally, the alkali is inorganic base, and optionally, the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, carbonic acid Hydrogen sodium, potassium carbonate, lithium hydroxide, one of cesium hydroxide or barium hydroxide or a variety of；

The structural formula of (II) are as follows:

In formula (II):

The definition of X and Y is identical as in formula (I),

A₁And A₂It is same or different, it is independently represented each other hydroxyl, nitrate anion or perchlorate or A₁And A₂Sulphur is represented jointly Acid group or carbonate；

The structural formula of (III) are as follows:

In formula (III):

N=0,1,2,3,4,5 or 6 (optionally, n=0,1,2,3 or 6)；

8. a kind of pharmaceutical composition comprising the described in any item cyclobutane dicarboxylic acid platinum complexes of claim 1-5 or its light Learn isomers or one of its pharmaceutically acceptable salt or its solvate or a variety of and be optionally present pharmaceutically Acceptable carrier.

9. the described in any item complexs of claim 1-5 or its optical isomer or its pharmaceutically acceptable salt or its The purposes of solvate or pharmaceutical composition as claimed in claim 7 in the preparation of antitumor drugs.

10. purposes according to claim 9, it is characterised in that the tumour is human lung cancer, human liver cancer, human large intestine cancer, people Head and neck cancer, human prostata cancer, human breast carcinoma, human ovarian cancer, human cervical carcinoma, human leukemia, people's lymph cancer, application on human skin cancer, people Cancer of pancreas, human bladder cancer, people's cancer of the esophagus, human gastric cancer, people's male sex organ cancer, human thyroid carcinomas, people's bone cancer, human melanin cancer, Or human oral cancer.

Optionally, the cell of the tumour is human colon cancer cell HT29, Non-small cell lung carcinoma cell A549, human liver cancer cell SMMC7721, human breast cancer cell line Bcap-37, Proliferation of Human Ovarian Cell SKOV3, esophageal cancer cell ECA109, human prostata cancer are thin Born of the same parents DU145, human cervical carcinoma cell Hela, human melanoma cell A375, human mouth epidermoid carcinoma cell KB, gastric carcinoma cells HGC27, human thyroid cancer cell SW579, human bladder cancer cell 5637, human pancreatic cancer cell Panc-1, and human large cell lung cancer is thin Born of the same parents H460, people's plasma cell leukemia cell H929, human liver cancer cell HepG2, human monocytic leukaemia THP-1.